Crumpled triangulations and critical points in 4D simplicial quantum gravity
[资料]thesearchfortheanti-·agingpill成分剖析
READING PASSAGE 30Y ou should spend about 20 minutes on Questions 28—40, which are based on Reading Passage 30The Search for the Anti-·aging Pill0In government laboratories and elsewhere, scientists are seeking a drug able to prolong life and youthful vigor.Studies of caloric restriction are showing the way.0As researchers主on aging noted谓recently,(no treatment主on the market today has been proved to谓slow human aging-补)宾从the build-up of molecular and cellular damage that increases vulnerability to infirmity 定从as we grow older.But (one intervention,consumption of a low-calorie*yet nutritionally balanced diet主).W orks谓incredibly well in a broad range of animals,状(increasing longevity and prolonging good health).伴随状语Those findings主suggest谓(that caloric restriction could delay aging and increase longevity in humans,too宾从).0Unfortunately, for maximum benefit,状people主would probably have to reduce谓their caloric intake宾(by roughly thirty per cent,equivalent to dropping from 2,500 calories a day to l,750.宾补)Few mortals主could stick to 谓that harsh a regimen,宾(especially for years on end.状)But what if someone主could create谓 a pill宾that 定从mimicked the physiological effects of eating less without actually forcing people to eat less?Could such a‘caloric-restriction mimetic’,主as we call it,enable谓people 宾to stay healthy longer, postponing age-related disorders宾补(such as diabetes,arteriosclerosis,heart disease and cancer)until very late in life? Scientists 主first posed 谓this question宾in the mid-1990s.状(after引导时间状语从句researchers came upon a chemical agent that in rodents seemed to reproduce many of caloric restriction's benefits.)No compound主that would safely achieve the same feat in people定从has been found谓yet,but the search主has been informative and has fanned 谓hope宾that caloric-restriction (CR) mimetics can indeed be developed eventually.定从00The benefits of caloric restriction0The hunt for CR mimetics主grew out 谓of a desire to better understand caloric restriction's many effects on the body.状Scientists主first recognized 谓the value of 宾the practice more than 60 years ago,状(when they found that rats fed a low-calorie diet lived longer on average than free-feeding rats and also had a reduced incidence of conditions that become increasingly common in old age.状语从句)What is more,some of the treated animals主survived谓longer than the oldest—living animals in the control group,补which定从means that the maximum lifespan(the oldest attainable age),not merely the normal lifespan,increased.V arious interventions,主(such as infection-fighting drugs,插入语_)can Increase 谓a population's average survival time,宾but only approaches 主(that slow the body's rate of aging定从)will increase谓the maximum lifespan.宾00The rat findings主have been replicated谓many times and extended并列谓语to creatures补ranging from yeast to fruit flies,worms,fish,spiders,mice and hamsters.分词作伴随状语Until fairly recently,状the studies主were limited谓to short-lived creatures 补genetically distant from humans.But caloric.restriction projects主(underway in two species more closely related to humans-rhesus and squirrel monkeys后置定语)-(have made 谓scientists宾optimistic that CR mimetics could help people.宾补)00The monkey projects主demonstrate谓that, compared with过去分词作状语control animals that eat normally, (caloric-restricted monkeys have lower body temperatures and levels of the pancreatic hormone insulin,and they retain more youthful levels of certain hormones that tend to fall with age宾从).00The caloric-restricted animals 主also look系better 表on indicators of risk for age-related diseases.For example,they主have谓lower blood pressure and triglyceride levels宾(signifying a decreased likelihood of heart disease),and they 主have谓more normal blood glucose levels宾(pointing to a reduced risk for diabetes,which is marked by unusually high blood glucose levels).Further, it has recently been shown that rhesus monkeys kept on caloric—restricted diets for an extended time(nearly 15 years)have less chronic disease.宾从)They and the other monkeys主must be followed 情态动词+过去分词still longer, however, to know whether low-calorie intake can increase both average and maximum lifespans in monkeys.目的状语Unlike the multitude of elixirs being touted as the latest anti-aging cure,状语CR mimetics主would alter谓fundamental processes宾(that underlie aging.定从) W e 主aim to谓develop 补compounds (that fool cells into activating maintenance and repair.定从) 0How a prototype caloric—restriction mimetic works00The best-studied candidate主for a caloric-restriction mimetic,2DG 同位语(2-deoxy-D-glucose),works谓by interfering with the way状cells process glucose.定从It 主has proved谓toxic at some doses in animals and so cannot be used 并列谓语in humans.But it 主has demonstrated 谓that chemicals can replicate the effects of caloric restriction宾从;the trick 主is finding 谓the right one.宾00Cells主use谓the glucose宾from food to generate A TP宾补(adenosine triphosphate),the molecule that powers many activities in the body定从.By limiting food intake状,caloric restriction主minimizes谓the amount of glucose entering cells and decreases A TP generation.宾When 2DG is administered to animals that eat normally,时间状语从句glucose主reaches谓cells宾in abundance but the drug 主prevents谓most of it 宾from being processed 宾补and thus reduces并列谓语A TP synthesis宾.Researchers主have proposed 谓several explanations 宾for why interruption of glucose processing and A TP production might retard aging.原因状语One possibility 主relates to谓the ATP-making machinery’s emission of free radicals,宾(which are thought to contribute to aging and to such age-related diseases as cancer by damaging cells.非限制定从)Reduced operation 主of the machinery should limit 谓their production宾and thereby constrain并列谓语the damage.宾Another hypothesis 主suggests谓that decreased processing of glucose主could indicate to谓cells宾that food is scarce(even if it isn’t)and i nduce并列谓语them宾to shift into an anti-aging mode宾补( that emphasizes preservation of the organism over such‘luxuries’as growth and reproduction.宾从)0Ant Intelligence00(When we think of intelligent members the animal kingdom, 时间状语从句)the creatures 主that spring immediately to mind定从are系apes and monkeys.表But in fact the social lives主of some members of the insect kingdom are系sufficiently complex to 表suggest more than a hint of intelligence.表补Among these,状the world of the ant 主has come in 谓for considerable scrutiny 补lately,and the idea主that ants demonstrate sparks of cognition 定从has certainly not been rejected谓by those involved in these investigations.00Ants主store谓food.宾repel attackers and use chemical signals to contact one another in case of attack.宾补Such chemical communication 主can be compared to谓the human use 宾of visual and auditory channels(as in religious chants,advertising images and jingles,political slogans and martial music)to arouse and propagate moods and attitudes.宾补The biologist Lewis Thomas 主wrote,谓((Ants are so much like human beings as to be an embarrassment.They farm fungi, raise aphids*as livestock,1aunch armies to war, use chemical sprays to alarm and confuse enemies,capture slaves,engage in child labour, exchange information ceaselessly.They do everything but watch television.’宾从))00However, in ants 状there is no cultural transmission主-everything must be encoded 谓in the genes-whereas in humans the opposite is true. Only basic instincts主are carried谓in the genes of a newborn baby,状other skills主being learned from谓others宾in the community as the child grows up. It may seem系that this cultural continuity gives us ahuge advantage over ants.表从They have never mastered fire nor progressed. Their fungus farming and aphid herding crafts主are系sophisticated表(when compared to the agricultural skills of humans five thousand years ago时间状从)but have been totally overtaken 谓by modern human agribusiness.00Or have they? The farming methods of ants主are 系at least sustainable表.They 主do not ruin谓environment s宾or use谓enormous amounts of energy宾.Moreover, recent evidence主suggests 谓(that the crop farming of ants may be more sophisticated and adaptable than was thought.宾从)00Ants 主were系farmers表fifty million years before humans were状.Ants主c an’t digest 谓the cellulose宾in leaves-but some fungi并列主语can.谓The ants 主therefore cultivate 谓these fungi宾in their nests,(bringing them leaves to feed on,现在分词作伴随状语)and then use 并列谓语them宾as a source of food.Farmer ants主secrete谓antibiotics宾( to control other fungi 状that might act as‘weeds’,and spread waste tofertilise the crop.定从)00It was once thought that宾从the fungus that ants cultivate定从was a single type( that they had propagated.Essentially unchanged from the distant past.定从)Not so. Ulrich Mueller of Maryland and his colleagues主genetically screened 谓862 different types of fungi宾taken from ants’nests.分词作后置定语These 主turned out 谓to be highly diverse:表it seems系that ants are continually domesticating new species.表从Even more impressively, DNA analysis主of the fungi suggests谓(that the ants improve or modifythe fungi by regularly swapping and sharing strains with neighbouring ant colonies.宾从)00Whereas prehistoric man主had 谓no exposure 宾to Urban lifestyles宾补-the forcing house of intelligence—the evidence主suggests谓(that ants have lived in urban settings for close on a hundred million years,developing and maintaining underground cities of speciaiised chambers and tunnels.宾从)00(When we survey Mexico City, Tokyo,Los Angeles.时间从句)we主are amazed at 谓what has been accomplished by humans宾.Y et HoeIldobler and Wilson’s magnificent work 主for ant lovers, The Ants,同位语describes谓 a supercolony of the ant宾Formica yessensis on the Ishikari Coast of Hokkaido.This‘megalopolis’主was reported 谓to be composed of 360 million workers and a million queens living in 4,500 Interconnected nests across 谓补a territory of 2.7 square kilometres.0Such enduring and intricately meshed levels主of technical achievement outstrip 谓by far anything宾achieved by our distant ancestors.过去分词作后置定语We 主hail谓as masterpieces the cave Paintings宾jn southern France and elsewhere,dating back some 20,000 years.现在分词作状语Ant societies主existed谓in something地点状语like their present form 同位语more than seventy million years ago.Beside this, prehistoric man主looks系technologically primitive.表Is this then some kind of intelligence,albeit of a different kind?补00Research conducted主at Oxford,Sussex and Zurich Universities状has shown 谓(thatwhen desert ants return from a foraging trip, they navigate by integrating bearings and distances,宾从)( which they continuously update in their heads.非限制定语从句)They 主combine谓the evidence宾of visual landmarks with a mental library宾of local directions, all (within a framework状Which is consulted and updated.定从)So ants主can learn谓too.00And in a twelve-year Programme of work,Ryabko and Reznikova主have found谓evidence宾that ants can transmit very complex messages.同位语从句Scouts主who had Iocated food in a maze定从returned 谓to mobilise their foraging teams,They主engaged in 谓contact sessions,宾(at the end of which the scout was removed in order to observe what her team might do.定从)Often the foragers 主proceeded谓to the exact spot宾in the maze where the food had been定从.Elaborate precautions主were taken 谓to prevent the foraging team using odour clues.谓补Discussion主now centres on 谓(whether the route through the maze is communicated as a‘left-right’sequence of turns or as a ‘compass bearing and distance’ message.宾从)00During the course of this exhaustive study, Reznikova 主has grown系so attached to 表her laboratory ants that she feels She knows them as individuals同位语从句-even without the paint spots used to mark them.伴随状语It’s no surprise that{{Edward Wilson,主in his essay,‘In the company of ants’, advises谓readers宾(who ask what to do with the ants in their kitchen宾从)to:‘W atc h宾补where you step.Be careful of little lives’.表从}}00volcanoes-earth-shattering news0When Mount Pinatubo suddenly erupted on 9 June 1991,the power of volcanoes past and present again hit the headlines00A V olcanoes主are系the ultimate earth-moving machinery.表A violent eruption主can blow谓the top few kilometres off a mountain宾,scatter并列谓语fine ash 宾practically all over the globe and hurl 并列谓语rock fragments 宾into the stratosphere to darken the skies 宾补a continent away.00But the classic eruption主-(cone-shaped mountain,big bang,mushroom cloud and surges of molten lava同位语)-is 系only a tiny part of a global story表.Vulcanism,主(the name given to volcanic processes,同位语)really has shaped谓the world. 宾Eruptions主have rifted 谓continents,宾raised 谓mountain宾chains,constructed 谓islands宾and shaped谓the topography宾of the earth. The entire ocean floor 主has 谓a basement of volcanic宾basalt.00V olcanoes 主have not only made谓the continents,宾t hey主are also thought to谓have made谓补the world’s first stable atmosphere and provided all the water for the oceans, rivers and ice-caps.There are now about 600 active volcanoes. Every year they 主add谓two or three cubic kilometres of rock宾to the continents.Imagine a similar number of volcanoes smoking 现在分词作伴随状语away for the last 3,500million years. That主is系enough rock表to explain表补the continental crust.0What comes out of volcanic craters主从is系mostly gas.表More than 90%of this gas 主is 系water vapour表from the deep earth:(enough to explain, over 3,500 million years, the water in the oceans.补)The rest of the gas主is 系(nitrogen,carbon dioxide,sulphur dioxide,methane,ammonia and hydrogen.表)The quntity of these gases,主(again multiplied over 3,500 million years,插入语)js系enough to explain the mass of the world’s atmosphere.表W e 主are系alive 表(because volcanoes provided the soil,air and water we need.原因状语从句)0B Geologists 主consider谓the earth宾(as having a molten core,surrounded by a semi-molten mantle and a brittle,outer skin,宾补)lt主helps谓to(think of a soft-boiled egg with a runny yolk,a firm but squishy white and a hard shell.谓补)(If the shell is even slightly cracked during boiling,条件状语从句)the white material 主bubbles out and sets谓(like a tiny mountain chain over the crack-like an archipelago of volcanic islands such as the Hawaiian Islands.谓补)But the earth主is系so much bigger表and the mantle并列状语below is 系so much hotter,表00(Even though the mantle rocks are kept solid by overlying pressure,让步状语从句)they主can still slowly‘flow谓’like thick”treacle. The flow主,thought to be in the form of convection currents,is 系powerful enough表(to fracture the‘eggshell’of the crust intoplates,and keep them bumping and grinding against each other, or even overlapping ,表补)at the rate of a few centimetres a year. These fracture zones, 主where the collisions occur,定从are系where earthquakes happen.表And,very often,volcanoes.00C T hese zones主are 系lines of weakness, or hot spots.表Every eruption 主is系different,表but put at its simplest, 过去分词作定语(where there are weaknesses, rocks deep in the mantle, heated to 1,350。
二甲双胍联合度拉糖肽治疗2型糖尿病
·药物与临床·糖尿病新世界2022年11月二甲双胍联合度拉糖肽治疗2型糖尿病的临床效果探讨邬旭日内蒙古鄂尔多斯市中心医院内分泌科,内蒙古鄂尔多斯017000[摘要]目的探究度拉糖肽应用于2型糖尿病患者治疗中的临床效果探讨。
方法选取2021年5月—2022年5月期间鄂尔多斯市中心医院收治并确诊为2型糖尿病患者112例为研究对象,将其依照随机数表法分为对照组与研究组,每组56例。
对照组使用二甲双胍联合格列美脲方法,研究组采用二甲双胍联合度拉糖肽治疗方法,比较治疗后两组患者的生活质量、不良反应发生率、空腹血糖(FPG)水平、餐后2h血糖(2hPG)水平、并发症发生率和治疗有效率。
结果研究组生活质量、治疗有效率情况均优于对照组,差异有统计学意义(P<0.05);研究组不良反应发生率低于对照组,差异有统计学意义(P<0.05);研究组FPG、2hPG水平低于对照组,差异有统计学意义(P<0.05);研究组并发症发生率低于对照组,差异有统计学意义(P<0.05)。
结论在临床上2型糖尿病患者治疗中应用度拉糖肽方法具有良好的治疗效果。
[关键词]度拉糖肽;2型糖尿病;血糖水平[中图分类号]R587.1[文献标识码]A[文章编号]1672-4062(2022)11(a)-0100-04Clinical Effect of Metformin Combined with Dura-glycopeptide in the Treatment of Diabetes Mellitus Type2WU XuriDepartment of Endocrinology,Inner Mongolia Erdos Central Hospital,Erdos,Inner Mongolia Autonomous Region, 017000China[Abstract]Objective To exploring the clinical effect of dulaglutide in the treatment of diabetes mellitus type2pa⁃tients.Methods112patients with diabetes mellitus type2who were admitted to Ordos Central Hospital from May 2021to May2022were selected as research subjects.They were divided into control group and study group according to random number table method,56cases in each group.The control group was treated with metformin combined with glimepiride and the study group was treated with metformin combined with Dura-glycopeptide.The quality of life,in⁃cidence of adverse effects,fasting blood glucose(FPG)level,2h postprandial blood glucose(2hPG)level,complica⁃tion rate and treatment efficiency were compared between the two groups after treatment.Results The quality of life and the effective rate of treatment in the study group were better than those in the control group,and the difference was statistically significant(P<0.05);the incidence of adverse reactions in the study was lower than that in the control group,and the difference was statistically significant(P<0.05);the levels of FPG and2hPG in the study group were lower than those in the control group,and the difference was statistically significant(P<0.05);the incidence of compli⁃cations in the study group was lower than that in the control group,and the difference was statistically significant(P<0.05).Conclusion The application of Dura-glycopeptide method in the clinical treatment of type2diabetic patientshas a good therapeutic effect.[Key words]Dura-glycopeptide;Type2diabetes mellitus;Blood glucose level随着社会的发展和人们生活水平的提高,生活习惯以及生活状态也发生了相应的变化,生活节奏加快、饮食不健康、缺乏运动,导致2型糖尿病的发病率逐年攀升[1],2型糖尿病属于慢性代谢性疾病,DOI:10.16658/ki.1672-4062.2022.21.100[作者简介]邬旭日(1983-),女,本科,副主任医师,研究方向为糖尿病、甲状腺、骨代谢内分泌相关疾病。
重庆理工大学材料科学基础双语翻译第3章modified翻译
Review
1. Atomic structure结构 2. The two atomic models cited引用, and note the differences between them.
3. The important quantum-mechanical 量子力学principle原理 that relates to electron energies.
Fundamentals of Materials Science and Engineering
Learing Objectives目的
Understand the concept概念 of unit cell (晶包) and know how to utilize使用 it to explain the crystal structures晶体 结构 of metals金属. Know what are the main three metallic crystal structures 金属晶体结构 and illustrate举例 how the atoms are arranged for为 做安排 FCC, BCC and HCP structures. Understand the concepts概念 of the crystallographic 结晶 的directions and planes (晶向和晶面); grasp 抓住the general 一般的steps in插入 determining 决定the index指 数 of a given crystal direction结晶定向 or plane面.
线粒体融合和裂变失衡 英文
线粒体融合和裂变失衡英文Mitochondrial Fusion and Fission Imbalance.Mitochondria are dynamic organelles that undergo continuous fusion and fission events. These processes are essential for maintaining mitochondrial morphology, function, and quality control. Fusion allows mitochondria to exchange genetic material and proteins, thereby promoting complementation and repair. Fission, on the other hand, enables the segregation of damaged mitochondria for subsequent removal by mitophagy.An imbalance between mitochondrial fusion and fission can lead to various cellular abnormalities and diseases. Excessive fusion can result in the formation of hyperfused mitochondrial networks, which may impede mitochondrial motility and hinder the efficient distribution of mitochondria to subcellular compartments. Conversely, excessive fission can lead to mitochondrial fragmentation, which may compromise mitochondrial function and increasethe susceptibility to mitophagy.Causes of Mitochondrial Fusion and Fission Imbalance.Several factors can disrupt the balance between mitochondrial fusion and fission, including:Mutations in mitochondrial fusion and fission genes: Mutations in genes encoding mitochondrial fusion proteins (e.g., Mfn1, Mfn2, OPA1) or fission proteins (e.g., Drp1, Fis1) can impair their function and lead to an imbalance in fusion and fission events.Oxidative stress: Excessive reactive oxygen species (ROS) production can induce mitochondrial fission by activating Drp1 and inhibiting Mfn2.Calcium overload: Elevated intracellular calciumlevels can trigger mitochondrial fission by activating calcineurin, which dephosphorylates Drp1 and promotes its translocation to the mitochondria.Metabolic stress: Nutrient deprivation or hypoxia can induce mitochondrial fission to promote mitophagy and conserve energy.Viral infections: Certain viruses can interfere with mitochondrial fusion and fission processes, leading to mitochondrial dysfunction and cell death.Neurodegenerative diseases: Mitochondrial fusion and fission imbalances have been implicated in the pathogenesis of several neurodegenerative diseases, includingAlzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS).Consequences of Mitochondrial Fusion and Fission Imbalance.Mitochondrial fusion and fission imbalance can have a range of consequences, including:Impaired mitochondrial function: Excessive fusion or fission can disrupt mitochondrial oxidative phosphorylation,ATP production, and calcium homeostasis.Increased susceptibility to apoptosis: Mitochondrial fragmentation can trigger the release of pro-apoptotic factors and promote cell death.Neurological dysfunction: Mitochondrial fusion and fission imbalances have been linked to cognitive decline, synaptic dysfunction, and neuroinflammation.Cardiovascular disease: Impaired mitochondrial fusion and fission can contribute to cardiac dysfunction and heart failure.Metabolic disorders: Mitochondrial fusion and fission imbalances have been implicated in obesity, insulin resistance, and type 2 diabetes.Therapeutic Strategies.Modulating mitochondrial fusion and fission processes holds therapeutic potential for treating a variety ofdiseases. Strategies aimed at restoring the balance between fusion and fission include:Pharmacological interventions: Small molecules that target mitochondrial fusion or fission proteins are being developed as potential therapeutic agents.Gene therapy: Gene therapy approaches aim to correct mutations in mitochondrial fusion and fission genes.Antioxidant therapies: Antioxidants can combat oxidative stress and protect mitochondria from excessive fission.Dietary interventions: Dietary modifications that promote mitochondrial biogenesis and reduce oxidative stress may improve mitochondrial fusion and fission dynamics.Conclusion.Mitochondrial fusion and fission are essentialprocesses for maintaining mitochondrial homeostasis and function. Imbalances between these processes can lead to cellular dysfunction and the development of various diseases. Understanding the mechanisms underlying mitochondrial fusion and fission imbalance and developing therapeutic strategies to restore balance hold promise for treating a range of pathological conditions.。
微生物屏障试验 DIN 58953-6_2010 Test report
Interlaboratory T est …Microbial barrier testing of packa ging materials for medical devices which are tobe ster ili ze d“according to DIN 58953-6:2010Test re portJanuary 2013Author: Daniel ZahnISEGA Forschungs- und Untersuchungsgesellschaft mbHTest report Page 2 / 15Table of contentsSeite1.General information on the Interlaboratory Test (3)1.1 Organization (3)1.2 Occasion and Objective (3)1.3 Time Schedule (3)1.4 Participants (4)2.Sample material (4)2.1 Sample Description and Execution of the Test (4)2.1.1 Materials for the Analysis of the Germ Proofness under Humidityaccording to DIN 58953-6, section 3 (5)2.1.2 Materials for the Analysis of the Germ Proofness with Air Permeanceaccording to DIN 58953-6, section 4 (5)2.2 Sample Preparation and Despatch (5)2.3 Additional Sample and Re-examination (6)3.Results (6)3.1 Preliminary Remark (6)3.2 Note on the Record of Test Results (6)3.3 Comment on the Statistical Evaluation (6)3.4 Outlier tests (7)3.5 Record of Test Results (7)3.5.1 Record of Test Results Sample F1 (8)3.5.2 Record of Test Results Sample F2 (9)3.5.3 Record of Test Results Sample F3 (10)3.5.4 Record of Test Results Sample L1 (11)3.5.5 Record of Test Results Sample L2 (12)3.5.6 Record of Test Results Sample L3 (13)3.5.7 Record of Test Results Sample L4 (14)4.Overview and Summary (15)Test report Page 3 / 15 1. General Information on the Interlaboratory Test1.1 OrganizationOrganizer of the Interlaboratory Test:Sterile Barrier Association (SBA)Mr. David Harding (director.general@)Pennygate House, St WeonardsHerfordshire HR2 8PT / Great BritainRealization of the Interlaboratory Test:Verein zur Förderung der Forschung und Ausbildung fürFaserstoff- und Verpackungschemie e. V. (VFV)vfv@isega.dePostfach 10 11 0963707 Aschaffenburg / GermanyTechnical support:ISEGA Forschungs- u. Untersuchungsgesellschaft mbHDr. Julia Riedlinger / Mr. Daniel Zahn (info@isega.de)Zeppelinstraße 3 – 563741 Aschaffenburg / Germany1.2 Occasion and ObjectiveIn order to demonstrate compliance with the requirements of the ISO 11607-1:2006 …Packaging for terminally sterilized medical devices -- Part 1: Requirements for materials, sterile barrier systems and packaging systems“ validated test methods are to be preferably utilized.For the confirmation of the microbial barrier properties of porous materials demanded in the ISO 11607-1, the DIN 58953-6:2010 …Sterilization – Sterile supply – Part 6: Microbial barrier testing of packaging materials for medical devices which are to be sterilized“ represents a conclusive method which can be performed without the need for extensive equipment.However, since momentarily no validation data on DIN 58953-6 is at hand concerns emerged that the method may lose importance against validated methods in a revision of the ISO 11607-1 or may even not be considered at all.Within the framework of this interlaboratory test, data on the reproducibility of the results obtained by means of the analysis according to DIN 58953-6 shall be gathered.1.3 Time ScheduleSeptember 2010:The Sterile Barrier Association queried ISEGA Forschungs- und Unter-suchungsgesellschaft about the technical support for the interlaboratory test.For the realization, the Verein zur Förderung der Forschung und Ausbildungfür Faserstoff- und Verpackungschemie e. V. (VFV) was won over.November 2010: Preliminary announcement of the interlaboratory test / Seach for interested laboratoriesTest report Page 4 / 15 January toDecember 2011: Search for suitable sample material / Carrying out of numerous pre-trials on various materialsJanuary 2012:Renewed contact or search for additional interested laboratories, respectively February 2012: Sending out of registration forms / preparation of sample materialMarch 2012: Registration deadline / sample despatchMay / June 2012: Results come in / statistical evaluationJuly 2012: Despatch of samples for the re-examinationSeptember 2012: Results of the re-examination come in / statistical evaluationNovember 2012: Results are sent to the participantsDecember 2012/January 2013: Compilation of the test report1.4 ParticipantsFive different German laboratories participated in the interlaboratory test. In one laboratory, the analyses were performed by two testers working independently so that six valid results overall were received which can be taken into consideration in the evaluation.To ensure an anonymous evaluation of the results, each participant was assigned a laboratory number (laboratory 1 to laboratory 6) in random order, which was disclosed only to the laboratory in question. The complete laboratory number breakdown was known solely by the ISEGA staff supporting the proficiency test.2. Sample Material2.1 Sample Description and Execution of the TestUtmost care in the selection of suitable sample material was taken to include different materials used in the manufacture of packaging for terminally sterilized medical devices.With the help of numerous pre-trials the materials were chosen covering a wide range of results from mostly germ-proof samples to germ permeable materials.Test report Page 5 / 15 2.1.1 Materials for the Analysis of Germ Proofness under Humidity according to DIN 58953-6, section 3:The participants were advised to perform the analysis on the samples according to DIN 58953-6, section 3, and to protocol their findings on the provided result sheets.The only deviation from the norm was that in case of the growth of 1 -5 colony-forming units (in the following abbreviated as CFU) per sample, no re-examination 20 test pieces was performed.2.1.2 Materials for the Analysis of Germ Proofness with Air Permeance according to DIN 58953-6, section 4:The participants were advised to perform the analysis on the samples according to DIN 58953-6, section 4, and to protocol their findings on the provided result sheets.2.2 Sample Preparation and DespatchFor the analysis of the germ proofness under humidity, 10 test pieces in the size of 50 x 50 mm were cut out of each sample and heat-sealed into a sterilization pouch with the side to be tested up.Out of the 10 test pieces, 5 were intended for the testing and one each for the two controls according to DIN 58953-6, sections 3.6.2 and 3.6.3. The rest should remain as replacements (e.g. in case of the dropping of a test piece on the floor etc.).For the analysis of the germ proofness with air permeance, 15 circular test pieces with a diameter of 40 mm were punched out of each sample and heat-sealed into a sterilization pouch with the side to be tested up.Test report Page 6 / 15 Out of the 15 test pieces, 10 were intended for the testing and one each for the two controls according to DIN 58953-6, section 4.9. The rest should remain as replacements (e.g. in case of the dropping of a test piece on the floor etc.).The sterilization pouches with the test pieces were steam-sterilized in an autoclave for 15 minutes at 121 °C and stored in an climatic room at 23 °C and 50 % relative humidity until despatch.2.3 Additional Sample and Re-examinationFor the analysis of the germ proofness under humidity another test round was performed in July / August 2012. For this, an additional sample (sample L4) was sent to the laboratories and analysed (see 2.1.2). The results were considered in the evaluation.For validation or confirmation of non-plausible results, occasional samples for re-examination were sent out to the laboratories. The results of these re-examinations (July / August 2012) were not taken into consideration in the evaluation.3. Results3.1 Preliminary RemarkSince the analysis of germ proofness is designed to be a pass / fail – test, the statistical values and precision data were meant only to serve informative purposes.The evaluation of the materials according to DIN58953-6,sections 3.7and 4.7.6by the laboratories should be the most decisive criterion for the evaluation of reproducibility of the interlaboratory test results. Based on this, the classification of a sample as “sufficiently germ-proof” or “not sufficiently germ-proof” is carried out.3.2 Note on the Record of Test Results:The exact counting of individual CFUs is not possible with the required precision if the values turn out to be very high. Thus, an upper limit of 100 CFU per agar plate or per test pieces, respectively, was defined. Individual values above this limit and values which were stated with “> 100” by the laboratories, are listed as 100 CFU per agar plate or per test piece, respectively, in the evaluation.Test report Page 7 / 153.3 Comment on the Statistical EvaluationThe statistical evaluation was done based on the series of standards DIN ISO 5725-1ff.The arithmetic laboratory mean X i and the laboratory standard deviation s i were calculated from the individual measurement values obtained by the laboratories.The overall mean X of the laboratory means as well as the precision data of the method (reproducibility and repeatability) were determined for each sample3.4 Outlier testsThe Mandel's h-statistics test was utilised as outlier test for differences between the laboratory means of the participants.A laboratory was identified as a “statistical outlier” as soon as an exceedance of Mandel's h test statistic at the 1 % significance level was detected.The respective results of the laboratories identified as outliers were not considered in the statistical evaluation.3.5 Record of Test ResultsOn the following pages, the records of the test results for each interlaboratory test sample with the statistical evaluation and the evaluation according to DIN 58953-6 are compiled.Test report Page 8 / 153.5.1 Record of Test Results Sample F1Individual Measurement values:Statistical Evaluation:Comment:Laboratory 4, as an outlier, has not been taken into consideration in the statistical Evaluation.Outlier criterion: Mandel's h-statistics (1 % level of significance)Overall mean X:91.0CFU / agar plateRepeatability standard deviation s r:17.9CFU / agar plateReproducibility standard deviation s R:19.8CFU / agar plateRepeatability r:50.0CFU / agar plateRepeatability coefficient of variation:19.6%Reproducibility R:55.5CFU / agar plateReproducibility coefficient of variation:21.8%Evaluation according to DIN 58953-6, Section 3.7:Lab. 1 - 6:Number of CFU > 5, i.e. the material is classified as not sufficiently germ-proof.Conclusion:All of the participants, even the Laboratory 4 which was identified as an outlier, came to the same results and would classify the sample material as “not sufficiently germ-proof”Test report Page 9 / 153.5.2 Record of Test Results Sample F2Individual Measurement values:Statistical Evaluation:Comment:Laboratory 4, as an outlier, has not been taken into consideration in the statistical Evaluation.Outlier criterion: Mandel's h-statistics (1 % level of significance)Overall mean X:0CFU / agar plateRepeatability standard deviation s r:0CFU / agar plateReproducibility standard deviation s R:0CFU / agar plateRepeatability r:0CFU / agar plateRepeatability coefficient of variation:0%Reproducibility R:0CFU / agar plateReproducibility coefficient of variation:0%Evaluation according to DIN 58953-6, Section 3.7:Lab. 1 – 3:Number of CFU = 0, i.e. the material is classified as sufficiently germ-proofLab. 4:Number of CFU ≤ 5, i.e. a re-examination on 20 test pieces would have to be done Lab. 5 – 6:Number of CFU = 0, i.e. the material is classified as sufficiently germ-proofConclusion:All of the participants, except for the Laboratory 4 which was identified as an outlier, came to the same results and would classify the sample material as “sufficiently germ-proof”.Test report Page 10 / 153.5.3 Record of Test Results Sample F3Individual Measurement values:Statistical Evaluation:Overall mean X:30.1CFU / agar plateRepeatability standard deviation s r:17.2CFU / agar plateReproducibility standard deviation s R:30.9CFU / agar plateRepeatability r:48.2CFU / agar plateRepeatability coefficient of variation:57.1%Reproducibility R:86.5CFU / agar plateReproducibility coefficient of variation:103%Evaluation according to DIN 58953-6, Section 3.7:Lab. 1 - 4:Number of CFU > 5, i.e. the material is classified as not sufficiently germ-proof. Lab. 5:Number of CFU = 0, i.e. the material is classified as sufficiently germ-proof. Lab. 6:Number of CFU > 5, i.e. the material is classified as not sufficiently germ-proof.Conclusion:Five of the six participants came to the same result and would classify the sample as “not sufficiently germ-proof”. Only laboratory 5 would classify the sample material as “sufficiently germ-proof”.Test report Page 11 / 153.5.4 Record of Test Results Sample L1Individual Measurement values:Statistical Evaluation:Overall mean X:0.09CFU / test pieceRepeatability standard deviation s r:0.32CFU / test pieceReproducibility standard deviation s R:0.33CFU / test pieceRepeatability r:0.91CFU / test pieceRepeatability coefficient of variation:357%Reproducibility R:0.93CFU / test pieceReproducibility coefficient of variation:366%Evaluation according to DIN 58953-6, Section 4.7:Lab. 1 - 6:Number of CFU < 15, i.e. the material is classified as sufficiently germ-proof.Conclusion:All participants came to the same result and would classify the sample as “sufficiently germ-proof”.Test report Page 12 / 153.5.5 Record of Test Results Sample L2Individual Measurement values:Statistical Evaluation:Overall mean X:0.73CFU / test pieceRepeatability standard deviation s r: 1.10CFU / test pieceReproducibility standard deviation s R: 1.18CFU / test pieceRepeatability r: 3.07CFU / test pieceRepeatability coefficient of variation:151%Reproducibility R: 3.32CFU / test pieceReproducibility coefficient of variation:163%Evaluation according to DIN 58953-6, Section 4.7:Lab. 1:Number of CFU > 15, i.e. the material is classified as not sufficiently germ-proof. Lab. 2 - 6:Number of CFU < 15, i.e. the material is classified as sufficiently germ-proof.Conclusion:Five of the six participants came to the same result and would classify the sample as “sufficiently germ-proof”. Only laboratory 1 exceeds the limit value slightly by 1 CFU, so that the sample would be classified as “not sufficiently germ-proof”.Test report Page 13 / 153.5.6 Record of Test Results Sample L3Individual Measurement values:Statistical Evaluation:Overall mean X:0.36CFU / test pieceRepeatability standard deviation s r: 1.00CFU / test pieceReproducibility standard deviation s R: 1.06CFU / test pieceRepeatability r: 2.79CFU / test pieceRepeatability coefficient of variation:274%Reproducibility R: 2.98CFU / test pieceReproducibility coefficient of variation:293%Evaluation according to DIN 58953-6, Section 4.7:Lab. 1 - 6:Number of CFU < 15, i.e. the material is classified as sufficiently germ-proof.Conclusion:All participants came to the same result and would classify the sample as “sufficiently germ-proof”.Test report Page 14 / 153.5.7 Record of Test Results Sample L4Individual Measurement values:Statistical Evaluation:Overall mean X:35.1CFU / test pieceRepeatability standard deviation s r:18.8CFU / test pieceReproducibility standard deviation s R:42.6CFU / test pieceRepeatability r:52.7CFU / test pieceRepeatability coefficient of variation:53.7%Reproducibility R:119CFU / test pieceReproducibility coefficient of variation:122%Evaluation according to DIN 58953-6, Section 4.7:Lab. 1 - 3:Number of CFU > 15, i.e. the material is classified as not sufficiently germ-proof. Lab. 4:Number of CFU < 15, i.e. the material is classified as sufficiently germ-proof. Lab. 5 - 6:Number of CFU > 15, i.e. the material is classified as not sufficiently germ-proof.Conclusion:Five of the six participants came to the same result and would classify the sample as“not sufficiently germ-proof”.Test report Page 15 / 15 4. Overview and SummarySummary:In case of four of the overall seven tested materials, a 100 % consensus was reached regarding the evaluation as“sufficiently germ-proof”and“not sufficiently germ-proof”according to DIN 58 953-6.As for the other three tested materials, there were always 5 concurrent participants out of 6 (83 %). In each case, only one laboratory would have evaluated the sample differently.It is noteworthy that the materials about the evaluation of which a 100 % consensus was reached were the smooth sterilization papers. The differences with one deviating laboratory each occurred with the slightly less homogeneous materials, such as with the creped paper and the nonwoven materials.。
Uncovering the Origin of Metallurgy
Uncovering the Origin of MetallurgyMetallurgy is the science and technology of extracting metals from their ores, refining them, and preparing them for use. It is a crucial aspect of human civilization and has played a significant role in shaping our world. The origin of metallurgy is a topic of great interest to historians, archaeologists, and scientists alike. In this essay, we will explore the different perspectives on the origin of metallurgy and try to uncover the truth behind this fascinating subject. One perspective on the origin of metallurgy is that it emerged independently in different parts of the world. This theory suggests that humans discovered the properties of metals through trial and error and developed the necessarytechniques to extract and refine them. This is supported by the fact that early metallurgy was found in several regions, including the Middle East, Asia, andSouth America. For example, the ancient Egyptians were known to have used copper and gold for decorative purposes, while the people of the Andes used copper to create intricate jewelry and ornaments. Another perspective on the origin of metallurgy is that it was developed through cultural diffusion. This theory suggests that metallurgy was first developed in one region and then spread toother parts of the world through trade and migration. For example, some historians believe that metallurgy was first developed in the Middle East and then spread to Europe and Asia. This is supported by the fact that the earliest known metal objects were found in the Middle East, such as the copper beads from the 6th millennium BCE found in the area now known as Iraq. A third perspective on the origin of metallurgy is that it was developed as a result of environmental factors. This theory suggests that the availability of certain metals in a particularregion led to the development of metallurgy in that area. For example, the abundance of copper in the Middle East and the Andes may have led to the development of early metallurgy in those regions. Similarly, the availability of iron in certain parts of Africa may have led to the development of ironworking in those areas. Regardless of the origin of metallurgy, it is clear that it played a crucial role in the development of human civilization. The ability to extract and refine metals allowed humans to create tools and weapons that were stronger and more durable than those made from stone or wood. This, in turn, led to thedevelopment of agriculture, trade, and the rise of civilizations. In conclusion, the origin of metallurgy is a fascinating subject that has captured the attention of historians, archaeologists, and scientists for centuries. While there are different perspectives on how metallurgy first emerged, it is clear that it played a crucial role in shaping our world. The ability to extract and refine metals allowed humans to create tools and weapons that were stronger and more durable, leading to the development of agriculture, trade, and the rise of civilizations. As we continue to uncover new evidence about the origin of metallurgy, we will gain a deeper understanding of our shared history and the remarkable achievements of our ancestors.。
怎样批判性地阅读文献3
2005 年复旦大学生物医学前沿文献讨论课参考资料2Dr. Plopper’s Guide To Critical Reading of Primary Literature Overall tips: 总技巧1. Just because a scientific study has been published, this does not mean it is perfect. And the imperfections are not so minute that a non-expert cannot find them. Any student of science can, and indeed should, read science critically. This means you can read a paper by a Nobel laureate andfind fault with it. It is in fact expected that, as a practicing scientist, you can criticize any science. The level of your critical analysis will differ with your experience level, but you should be able to criticize science even as a relatively inexperienced undergraduate.1、科学研究不能仅因为已发表,就认为它是完美的。
它们的不足也不是微小到只有专业人员才能发现。
任何从事科研的学生都能,而且确实应该能够,批判性地阅读科学文献。
这意味着你读一篇诺贝尔奖获得者的文章都能在其中发现不足。
它实际上期望作为科学工作者的你能对任何学科进行分析评论。
你分析评论的水平会因你的经验水平而有差异,但你应该至少能够象一名相对无经验的本科生来分析科学文献。
“生物药”--Wharton’s jelly源间充质干细胞
“生物药”--Wharton’s jelly源间充质干细胞高连如【摘要】干细胞治疗代表生物冶疗进入到了一个崭新的时代。
间充质干细胞是存在于胚胎或成体组织中来源于中胚层具有多向分化潜能的干细胞。
由于成体间充质干细胞的质量与数量自身缺陷,使之应用受到了很大限制。
Wharton’s jelly组织,是起始于胚胎发育第13天的胚外中胚层组织。
使用基因微阵列分析及功能分析,首次发现Wharton’s jelly源间充质干细胞( Wharton’s jelly derived mesenchymal stem cells,WJMSCs)高表达胚胎早期干性基因及心肌细胞分化早期特异转录因子,可分化心肌细胞等多种细胞。
进而,应用临床级WJMSCs经冠状动脉移植治疗ST抬高型急性心肌梗死患者的随机双盲临床试验,首次证明WJMSCs可明显改善心肌活力及心脏功能。
因此,WJMSCs具有极其重要益处;无伦理涉及,有强的分化潜能,无致瘤性;加之,WJMSCs可作为产品,在任何时候病情需要时立即应用。
为此,WJMSCs作为真正意义上的干细胞族,将最有希望成为具有应用前景的干细胞生物药。
%Cell-based treatment represents a new generation in the evolution of biological therapeutics. Mesenchymal stem cells ( MSCs) are mesoderm-derived multipotent stromal cells that reside in embryonic and adult tissues. The use of adult MSCs is limited by the quality and quantity of host stem cells. Wharton’s jelly of the umbilical cord originates from the extraembryonic and/or the embryonic mesoderm at day 13 of embryonic development. Using Affymetrix GeneChip microarray and functional network analyses, we found for the first time that Wharton’s jelly-derived MSCs ( WJMSCs) , except for their expression of stemness molecular markers in common with human ESCs ( hESCs) ,exhibited a high expression of early cardiac transcription factor genes and could be in-duced to differentiate into cardiomyocyte-like cells. Further, we demonstrated for the first time that intracoronary delivery of prepared clinical-grade WJMSCs was safe in treating patients with an ST-AMI attack by double-blind, randomized controlled trial and could significantly improve myocardial viability and heart function. It is therefore important to consider the benefits of WJMSCs, which are not ethically sensitive, have differentiation potential, and do not have the worrying issue of teratoma formation. Moreover, as the off the shelf product, WJMSCs can be applied immediately, and on de-mand. Thus, WJMSCs constitute a true stem cell population and are promising cells as a biological drug for stem cell-based therapies.【期刊名称】《转化医学杂志》【年(卷),期】2016(005)004【总页数】5页(P193-197)【关键词】间充质干细胞;Wharton’s jelly源间充质干细胞;生物药物【作者】高连如【作者单位】100048 北京,海军总医院心脏中心【正文语种】中文【中图分类】R329.2+4[Abstract]Cell-based treatment represents a new generation in the evolution of biological therapeutics.Mesenchymal stem cells(MSCs)are mesoderm-derived multipotent stromal cells that reside in embryonic and adult tissues.The use of adult MSCs is limited by the quality and quantity of host stem cells.Wharton’s jelly of the umbilical cord originates from the extraembryonic and/or the embryonic mesoderm at day 13 of embryonic ing Affymetrix GeneChip microarray and functional network analyses,we found for the first time that Wharton’s jelly-derived MSCs (WJMSCs),except for their expression of stemness molecular markers in common with human ESCs (hESCs),exhibited a high expression of early cardiac transcription factor genes and could be induced to differentiate into cardiomyocyte-like cells.Further,we demonstrated for the first time that intracoronary delivery of prepared clinical-grade WJMSCs was safe in treating patients with an STAMI attack by double-blind,randomized controlled trial and could significantly improve myocardial viability and heart function.It is therefore important to consider the benefits of WJMSCs,which are not ethically sensitive,have differentiation potential,and do not have the worrying issue of teratoma formation.Moreover,as the off the shelf product,WJMSCs can be applied immediately,and on demand.Thus,WJMSCs constitute a true stem cell population and are promising cells as a biological drug for stem cell-based therapies.[Key words]Mesenchymal stem cells(MSCs);Wharton’s jelly-derived mesenchymal stem cells(WJMSCs);Biological drug21世纪,人类疾病治疗模式在继现代医学——药物、手术、机械辅助等手段后,一个崭新的充满希望的新理念——细胞生物治疗理论诞生了,这将给人类带来什么样的变化与影响,如此快速之进展,正如Science、Nature中所表述的“即使站在世界最前沿的科学家也难以预料”[1-2]。
开启片剂完整性的窗户(中英文对照)
开启片剂完整性的窗户日本东芝公司,剑桥大学摘要:由日本东芝公司和剑桥大学合作成立的公司向《医药技术》解释了FDA支持的技术如何在不损坏片剂的情况下测定其完整性。
太赫脉冲成像的一个应用是检查肠溶制剂的完整性,以确保它们在到达肠溶之前不会溶解。
关键词:片剂完整性,太赫脉冲成像。
能够检测片剂的结构完整性和化学成分而无需将它们打碎的一种技术,已经通过了概念验证阶段,正在进行法规申请。
由英国私募Teraview公司研发并且以太赫光(介于无线电波和光波之间)为基础。
该成像技术为配方研发和质量控制中的湿溶出试验提供了一个更好的选择。
该技术还可以缩短新产品的研发时间,并且根据厂商的情况,随时间推移甚至可能发展成为一个用于制药生产线的实时片剂检测系统。
TPI技术通过发射太赫射线绘制出片剂和涂层厚度的三维差异图谱,在有结构或化学变化时太赫射线被反射回。
反射脉冲的时间延迟累加成该片剂的三维图像。
该系统使用太赫发射极,采用一个机器臂捡起片剂并且使其通过太赫光束,用一个扫描仪收集反射光并且建成三维图像(见图)。
技术研发太赫技术发源于二十世纪九十年代中期13本东芝公司位于英国的东芝欧洲研究中心,该中心与剑桥大学的物理学系有着密切的联系。
日本东芝公司当时正在研究新一代的半导体,研究的副产品是发现了这些半导体实际上是太赫光非常好的发射源和检测器。
二十世纪九十年代后期,日本东芝公司授权研究小组寻求该技术可能的应用,包括成像和化学传感光谱学,并与葛兰素史克和辉瑞以及其它公司建立了关系,以探讨其在制药业的应用。
虽然早期的结果表明该技术有前景,但日本东芝公司却不愿深入研究下去,原因是此应用与日本东芝公司在消费电子行业的任何业务兴趣都没有交叉。
这一决定的结果是研究中心的首席执行官DonArnone和剑桥桥大学物理学系的教授Michael Pepper先生于2001年成立了Teraview公司一作为研究中心的子公司。
TPI imaga 2000是第一个商品化太赫成像系统,该系统经优化用于成品片剂及其核心完整性和性能的无破坏检测。
孟德尔生平介绍
遗传学名人小传(Great Geneticists)之孟德尔罗静初1822年7月22日,约翰•孟德尔(Johann Mendel)出生在奥地利莫拉维亚(Moravia)一个名叫海钦多夫(Heinzendorf)的村子里(现已划归捷克)。
孟德尔生于一个农民家庭,排行第二,是家中唯一的男孩。
小时候,孟德尔一直在果园里劳作,生活十分艰辛。
6岁时进了村里的小学,学习语文、数学等基础课程,以及养蜂、果树嫁接等实际操作。
孟德尔自幼勤奋好学、成绩突出。
父亲听从了老师的建议,让他继续上初中和高中。
由于家境贫寒,付不起学费,高中阶段的学习生活已经十分拮据。
高中毕业后,孟德尔打算进厄尔姆兹学院(Olmults)进行两年的大学预科学习。
不幸的是,由于他父亲健康状况不佳而无力供养他继续深造。
就在人生中最困难的时刻,孟德尔的妹妹变卖自己的嫁妆,资助他完成了学业。
这使他永生难忘,并且把感激化为学习的动力,学业一直名列前茅。
然而,家境的窘迫,难以圆他大学之梦。
孟德尔意识到,必须先要找到一份可以聊生的职业,才有可能继续深造。
他接受了老师的建议,于1843年9月进入布隆(Brunn,现名Brno)市的修道院当了一名修道士,Gregor是他的教名。
布隆是莫拉维亚省的首府,也是奥匈帝国工农业生产和经济中心。
修道院相当富足,拥有一个藏书20000册的图书馆,可和当时的大学图书馆媲美,也是当时全市宗教和文化中心。
教士们文化素质很高,不少牧师都有正式的园艺、音乐、哲学等学位。
在修道院,孟德尔进行了系统的宗教学习,成绩突出,仅用3年时间就完成了4年的学业。
学习结束,孟德尔被任命为教区教士,但他并不喜欢这一工作。
修道院院长也觉察出了孟德尔的喜好,特意安排他到本地一所高中担任临时性的教学工作。
出色的教学效果,使孟德尔很很快在学生中建立了声誉。
按规定,担任高中教师,通常需要大学学历并通过资格考试。
考虑到孟德尔的实际情况,评审委员会决定保留他的教师资格,并建议他到维也纳大学完成大学学业。
生物专业英语试题及答案
生物专业英语试题及答案一、选择题(每题2分,共20分)1. Which of the following is not a type of cell organelle?A. MitochondriaB. NucleusC. RibosomeD. Cell wall2. The process of DNA replication is catalyzed by:A. PolymeraseB. TransposaseC. LigaseD. Helicase3. In eukaryotic cells, where is the transcription of DNA primarily carried out?A. CytoplasmB. MitochondriaC. NucleusD. Ribosomes4. What is the basic unit of heredity in all living organisms?A. GeneB. ChromosomeC. DNA moleculeD. Protein5. The term "genome" refers to:A. The complete set of genes of an organismB. The entire DNA of an organismC. The sum of all the proteins in an organismD. The collection of all the cells in an organism6. Which of the following is a method of genetic engineering?A. CrossbreedingB. CloningC. CRISPR-Cas9D. Natural selection7. What is the role of tRNA in protein synthesis?A. To provide the energy for the processB. To carry specific amino acids to the ribosomeC. To serve as the template for protein synthesisD. To catalyze the formation of peptide bonds8. The Hardy-Weinberg principle states that the allele frequencies in a population will remain constant in the absence of:A. MigrationB. Genetic driftC. Natural selectionD. All of the above9. Which of the following is not a type of mutation?A. DeletionB. InsertionC. TranslocationD. Translation10. The process of photosynthesis primarily occurs in the:A. Cell wallB. CytoplasmC. ChloroplastsD. Nucleus二、填空题(每空1分,共10分)1. The chemical structure of DNA is a double ________ helix.2. The process by which a fertilized egg develops into a mature organism is called ________.3. In genetics, the term "dominant" refers to an allele that expresses its effect when ________.4. The scientific name for a species is composed of two parts: the genus name and the ________ name.5. The primary function of the Golgi apparatus is to ________, modify, and package proteins for secretion or delivery toother organelles.三、简答题(每题10分,共20分)1. Explain the difference between prokaryotic and eukaryotic cells.2. Describe the process of mitosis and its significance incell division.四、翻译题(每题15分,共30分)1. Translate the following sentence into English:"基因编辑技术,如CRISPR-Cas9,为研究和治疗遗传性疾病提供了新的可能性。
Reproduction numbers and sub-threshold endemic equilibria for compartmental models of disease trans
Reproduction numbers and sub-threshold endemicequilibria for compartmental models of disease transmissionP.van den Driesschea,1,James Watmough b,*,2aDepartment of Mathematics and Statistics,University of Victoria,Victoria,BC,Canada V8W 3P4b Department of Mathematics and Statistics,University of New Brunswick,Fredericton,NB,Canada E3B 5A3Received 26April 2001;received in revised form 27June 2001;accepted 27June 2001Dedicated to the memory of John JacquezAbstractA precise definition of the basic reproduction number,R 0,is presented for a general compartmental disease transmission model based on a system of ordinary differential equations.It is shown that,if R 0<1,then the disease free equilibrium is locally asymptotically stable;whereas if R 0>1,then it is unstable.Thus,R 0is a threshold parameter for the model.An analysis of the local centre manifold yields a simple criterion for the existence and stability of super-and sub-threshold endemic equilibria for R 0near one.This criterion,together with the definition of R 0,is illustrated by treatment,multigroup,staged progression,multistrain and vector–host models and can be applied to more complex models.The results are significant for disease control.Ó2002Elsevier Science Inc.All rights reserved.Keywords:Basic reproduction number;Sub-threshold equilibrium;Disease transmission model;Disease control1.IntroductionOne of the most important concerns about any infectious disease is its ability to invade a population.Many epidemiological models have a disease free equilibrium (DFE)at whichtheMathematical Biosciences 180(2002)29–48/locate/mbs*Corresponding author.Tel.:+1-5064587323;fax:+1-5064534705.E-mail addresses:pvdd@math.uvic.ca (P.van den Driessche),watmough@unb.ca (J.Watmough).URL:http://www.math.unb.ca/$watmough.1Research supported in part by an NSERC Research Grant,the University of Victoria Committee on faculty research and travel and MITACS.2Research supported by an NSERC Postdoctoral Fellowship tenured at the University of Victoria.0025-5564/02/$-see front matter Ó2002Elsevier Science Inc.All rights reserved.PII:S0025-5564(02)00108-630P.van den Driessche,J.Watmough/Mathematical Biosciences180(2002)29–48population remains in the absence of disease.These models usually have a threshold parameter, known as the basic reproduction number,R0,such that if R0<1,then the DFE is locally as-ymptotically stable,and the disease cannot invade the population,but if R0>1,then the DFE is unstable and invasion is always possible(see the survey paper by Hethcote[1]).Diekmann et al.[2]define R0as the spectral radius of the next generation matrix.We write down in detail a general compartmental disease transmission model suited to heterogeneous populations that can be modelled by a system of ordinary differential equations.We derive an expression for the next generation matrix for this model and examine the threshold R0¼1in detail.The model is suited to a heterogeneous population in which the vital and epidemiological parameters for an individual may depend on such factors as the stage of the disease,spatial position,age or behaviour.However,we assume that the population can be broken into homo-geneous subpopulations,or compartments,such that individuals in a given compartment are indistinguishable from one another.That is,the parameters may vary from compartment to compartment,but are identical for all individuals within a given compartment.We also assume that the parameters do not depend on the length of time an individual has spent in a compart-ment.The model is based on a system of ordinary equations describing the evolution of the number of individuals in each compartment.In addition to showing that R0is a threshold parameter for the local stability of the DFE, we apply centre manifold theory to determine the existence and stability of endemic equilib-ria near the threshold.We show that some models may have unstable endemic equilibria near the DFE for R0<1.This suggests that even though the DFE is locally stable,the disease may persist.The model is developed in Section2.The basic reproduction number is defined and shown to bea threshold parameter in Section3,and the definition is illustrated by several examples in Section4.The analysis of the centre manifold is presented in Section5.The epidemiological ramifications of the results are presented in Section6.2.A general compartmental epidemic model for a heterogeneous populationConsider a heterogeneous population whose individuals are distinguishable by age,behaviour, spatial position and/or stage of disease,but can be grouped into n homogeneous compartments.A general epidemic model for such a population is developed in this section.Let x¼ðx1;...;x nÞt, with each x i P0,be the number of individuals in each compartment.For clarity we sort the compartments so that thefirst m compartments correspond to infected individuals.The distinc-tion between infected and uninfected compartments must be determined from the epidemiological interpretation of the model and cannot be deduced from the structure of the equations alone,as we shall discuss below.It is plausible that more than one interpretation is possible for some models.A simple epidemic model illustrating this is given in Section4.1.The basic reproduction number can not be determined from the structure of the mathematical model alone,but depends on the definition of infected and uninfected compartments.We define X s to be the set of all disease free states.That isX s¼f x P0j x i¼0;i¼1;...;m g:In order to compute R0,it is important to distinguish new infections from all other changes inpopulation.Let F iðxÞbe the rate of appearance of new infections in compartment i,Vþi ðxÞbe therate of transfer of individuals into compartment i by all other means,and VÀi ðxÞbe the rate oftransfer of individuals out of compartment i.It is assumed that each function is continuously differentiable at least twice in each variable.The disease transmission model consists of non-negative initial conditions together with the following system of equations:_x i¼f iðxÞ¼F iðxÞÀV iðxÞ;i¼1;...;n;ð1Þwhere V i¼VÀi ÀVþiand the functions satisfy assumptions(A1)–(A5)described below.Sinceeach function represents a directed transfer of individuals,they are all non-negative.Thus,(A1)if x P0,then F i;Vþi ;VÀiP0for i¼1;...;n.If a compartment is empty,then there can be no transfer of individuals out of the compartment by death,infection,nor any other means.Thus,(A2)if x i¼0then VÀi ¼0.In particular,if x2X s then VÀi¼0for i¼1;...;m.Consider the disease transmission model given by(1)with f iðxÞ,i¼1;...;n,satisfying con-ditions(A1)and(A2).If x i¼0,then f iðxÞP0and hence,the non-negative cone(x i P0, i¼1;...;n)is forward invariant.By Theorems1.1.8and1.1.9of Wiggins[3,p.37]for each non-negative initial condition there is a unique,non-negative solution.The next condition arises from the simple fact that the incidence of infection for uninfected compartments is zero.(A3)F i¼0if i>m.To ensure that the disease free subspace is invariant,we assume that if the population is free of disease then the population will remain free of disease.That is,there is no(density independent) immigration of infectives.This condition is stated as follows:(A4)if x2X s then F iðxÞ¼0and VþiðxÞ¼0for i¼1;...;m.The remaining condition is based on the derivatives of f near a DFE.For our purposes,we define a DFE of(1)to be a(locally asymptotically)stable equilibrium solution of the disease free model,i.e.,(1)restricted to X s.Note that we need not assume that the model has a unique DFE. Consider a population near the DFE x0.If the population remains near the DFE(i.e.,if the introduction of a few infective individuals does not result in an epidemic)then the population will return to the DFE according to the linearized system_x¼Dfðx0ÞðxÀx0Þ;ð2Þwhere Dfðx0Þis the derivative½o f i=o x j evaluated at the DFE,x0(i.e.,the Jacobian matrix).Here, and in what follows,some derivatives are one sided,since x0is on the domain boundary.We restrict our attention to systems in which the DFE is stable in the absence of new infection.That is, (A5)If FðxÞis set to zero,then all eigenvalues of Dfðx0Þhave negative real parts.P.van den Driessche,J.Watmough/Mathematical Biosciences180(2002)29–4831The conditions listed above allow us to partition the matrix Df ðx 0Þas shown by the following lemma.Lemma 1.If x 0is a DFE of (1)and f i ðx Þsatisfies (A1)–(A5),then the derivatives D F ðx 0Þand D V ðx 0Þare partitioned asD F ðx 0Þ¼F 000 ;D V ðx 0Þ¼V 0J 3J 4;where F and V are the m Âm matrices defined byF ¼o F i o x j ðx 0Þ !and V ¼o V i o x jðx 0Þ !with 16i ;j 6m :Further ,F is non-negative ,V is a non-singular M-matrix and all eigenvalues of J 4have positive real part .Proof.Let x 02X s be a DFE.By (A3)and (A4),ðo F i =o x j Þðx 0Þ¼0if either i >m or j >m .Similarly,by (A2)and (A4),if x 2X s then V i ðx Þ¼0for i 6m .Hence,ðo V i =o x j Þðx 0Þ¼0for i 6m and j >m .This shows the stated partition and zero blocks.The non-negativity of F follows from (A1)and (A4).Let f e j g be the Euclidean basis vectors.That is,e j is the j th column of the n Ân identity matrix.Then,for j ¼1;...;m ,o V i o x jðx 0Þ¼lim h !0þV i ðx 0þhe j ÞÀV i ðx 0Þh :To show that V is a non-singular M-matrix,note that if x 0is a DFE,then by (A2)and (A4),V i ðx 0Þ¼0for i ¼1;...;m ,and if i ¼j ,then the i th component of x 0þhe j ¼0and V i ðx 0þhe j Þ60,by (A1)and (A2).Hence,o V i =o x j 0for i m and j ¼i and V has the Z sign pattern (see Appendix A).Additionally,by (A5),all eigenvalues of V have positive real parts.These two conditions imply that V is a non-singular M-matrix [4,p.135(G 20)].Condition (A5)also implies that the eigenvalues of J 4have positive real part.Ã3.The basic reproduction numberThe basic reproduction number,denoted R 0,is ‘the expected number of secondary cases produced,in a completely susceptible population,by a typical infective individual’[2];see also [5,p.17].If R 0<1,then on average an infected individual produces less than one new infected individual over the course of its infectious period,and the infection cannot grow.Conversely,if R 0>1,then each infected individual produces,on average,more than one new infection,and the disease can invade the population.For the case of a single infected compartment,R 0is simply the product of the infection rate and the mean duration of the infection.However,for more complicated models with several infected compartments this simple heuristic definition of R 0is32P.van den Driessche,J.Watmough /Mathematical Biosciences 180(2002)29–48insufficient.A more general basic reproduction number can be defined as the number of new infections produced by a typical infective individual in a population at a DFE.To determine the fate of a‘typical’infective individual introduced into the population,we consider the dynamics of the linearized system(2)with reinfection turned off.That is,the system _x¼ÀD Vðx0ÞðxÀx0Þ:ð3ÞBy(A5),the DFE is locally asymptotically stable in this system.Thus,(3)can be used to de-termine the fate of a small number of infected individuals introduced to a disease free population.Let wi ð0Þbe the number of infected individuals initially in compartment i and letwðtÞ¼w1ðtÞ;...;w mðtÞðÞt be the number of these initially infected individuals remaining in the infected compartments after t time units.That is the vector w is thefirst m components of x.The partitioning of D Vðx0Þimplies that wðtÞsatisfies w0ðtÞ¼ÀV wðtÞ,which has the unique solution wðtÞ¼eÀVt wð0Þ.By Lemma1,V is a non-singular M-matrix and is,therefore,invertible and all of its eigenvalues have positive real parts.Thus,integrating F wðtÞfrom zero to infinity gives the expected number of new infections produced by the initially infected individuals as the vector FVÀ1wð0Þ.Since F is non-negative and V is a non-singular M-matrix,VÀ1is non-negative[4,p.137 (N38)],as is FVÀ1.To interpret the entries of FVÀ1and develop a meaningful definition of R0,consider the fate of an infected individual introduced into compartment k of a disease free population.The(j;k)entry of VÀ1is the average length of time this individual spends in compartment j during its lifetime, assuming that the population remains near the DFE and barring reinfection.The(i;j)entry of F is the rate at which infected individuals in compartment j produce new infections in compartment i. Hence,the(i;k)entry of the product FVÀ1is the expected number of new infections in com-partment i produced by the infected individual originally introduced into compartment k.Fol-lowing Diekmann et al.[2],we call FVÀ1the next generation matrix for the model and set R0¼qðFVÀ1Þ;ð4Þwhere qðAÞdenotes the spectral radius of a matrix A.The DFE,x0,is locally asymptotically stable if all the eigenvalues of the matrix Dfðx0Þhave negative real parts and unstable if any eigenvalue of Dfðx0Þhas a positive real part.By Lemma1, the eigenvalues of Dfðx0Þcan be partitioned into two sets corresponding to the infected and uninfected compartments.These two sets are the eigenvalues of FÀV and those ofÀJ4.Again by Lemma1,the eigenvalues ofÀJ4all have negative real part,thus the stability of the DFE is determined by the eigenvalues of FÀV.The following theorem states that R0is a threshold parameter for the stability of the DFE.Theorem2.Consider the disease transmission model given by(1)with fðxÞsatisfying conditions (A1)–(A5).If x0is a DFE of the model,then x0is locally asymptotically stable if R0<1,but un-stable if R0>1,where R0is defined by(4).Proof.Let J1¼FÀV.Since V is a non-singular M-matrix and F is non-negative,ÀJ1¼VÀF has the Z sign pattern(see Appendix A).Thus,sðJ1Þ<0()ÀJ1is a non-singular M-matrix;P.van den Driessche,J.Watmough/Mathematical Biosciences180(2002)29–483334P.van den Driessche,J.Watmough/Mathematical Biosciences180(2002)29–48where sðJ1Þdenotes the maximum real part of all the eigenvalues of the matrix J1(the spectral abscissa of J1).Since FVÀ1is non-negative,ÀJ1VÀ1¼IÀFVÀ1also has the Z sign pattern.Ap-plying Lemma5of Appendix A,with H¼V and B¼ÀJ1¼VÀF,we have ÀJ1is a non-singular M-matrix()IÀFVÀ1is a non-singular M-matrix:Finally,since FVÀ1is non-negative,all eigenvalues of FVÀ1have magnitude less than or equal to qðFVÀ1Þ.Thus,IÀFVÀ1is a non-singular M-matrix;()qðFVÀ1Þ<1:Hence,sðJ1Þ<0if and only if R0<1.Similarly,it follows thatsðJ1Þ¼0()ÀJ1is a singular M-matrix;()IÀFVÀ1is a singular M-matrix;()qðFVÀ1Þ¼1:The second equivalence follows from Lemma6of Appendix A,with H¼V and K¼F.The remainder of the equivalences follow as with the non-singular case.Hence,sðJ1Þ¼0if and only if R0¼1.It follows that sðJ1Þ>0if and only if R0>1.ÃA similar result can be found in the recent book by Diekmann and Heesterbeek[6,Theorem6.13].This result is known for the special case in which J1is irreducible and V is a positive di-agonal matrix[7–10].The special case in which V has positive diagonal and negative subdiagonal elements is proven in Hyman et al.[11,Appendix B];however,our approach is much simpler(see Section4.3).4.Examples4.1.Treatment modelThe decomposition of fðxÞinto the components F and V is illustrated using a simple treat-ment model.The model is based on the tuberculosis model of Castillo-Chavez and Feng[12,Eq.(1.1)],but also includes treatment failure used in their more elaborate two-strain model[12,Eq.(2.1)].A similar tuberculosis model with two treated compartments is proposed by Blower et al.[13].The population is divided into four compartments,namely,individuals susceptible to tu-berculosis(S),exposed individuals(E),infectious individuals(I)and treated individuals(T).The dynamics are illustrated in Fig.1.Susceptible and treated individuals enter the exposed com-partment at rates b1I=N and b2I=N,respectively,where N¼EþIþSþT.Exposed individuals progress to the infectious compartment at the rate m.All newborns are susceptible,and all indi-viduals die at the rate d>0.Thus,the core of the model is an SEI model using standard inci-dence.The treatment rates are r1for exposed individuals and r2for infectious individuals. However,only a fraction q of the treatments of infectious individuals are successful.Unsuc-cessfully treated infectious individuals re-enter the exposed compartment(p¼1Àq).The diseasetransmission model consists of the following differential equations together with non-negative initial conditions:_E¼b1SI=Nþb2TI=NÀðdþmþr1ÞEþpr2I;ð5aÞ_I¼m EÀðdþr2ÞI;ð5bÞ_S¼bðNÞÀdSÀb1SI=N;ð5cÞ_T¼ÀdTþr1Eþqr2IÀb2TI=N:ð5dÞProgression from E to I and failure of treatment are not considered to be new infections,but rather the progression of an infected individual through the various compartments.Hence,F¼b1SI=Nþb2TI=NB B@1C CA and V¼ðdþmþr1ÞEÀpr2IÀm Eþðdþr2ÞIÀbðNÞþdSþb1SI=NdTÀr1EÀqr2Iþb2TI=NB B@1C CA:ð6ÞThe infected compartments are E and I,giving m¼2.An equilibrium solution with E¼I¼0has the form x0¼ð0;0;S0;0Þt,where S0is any positive solution of bðS0Þ¼dS0.This will be a DFE if and only if b0ðS0Þ<d.Without loss of generality,assume S0¼1is a DFE.Then,F¼0b100;V¼dþmþr1Àpr2Àm dþr2;givingVÀ1¼1ðdþmþr1Þðdþr2ÞÀm pr2dþr2pr2m dþmþr1and R0¼b1m=ððdþmþr1Þðdþr2ÞÀm pr2Þ.A heuristic derivation of the(2;1)entry of VÀ1and R0are as follows:a fraction h1¼m=ðdþmþr1Þof exposed individuals progress to compartment I,a fraction h2¼pr2=ðdþr2Þof infectious individuals re-enter compartment E.Hence,a fractionh1of exposed individuals pass through compartment I at least once,a fraction h21h2passthroughat least twice,and a fraction h k 1h k À12pass through at least k times,spending an average of s ¼1=ðd þr 2Þtime units in compartment I on each pass.Thus,an individual introduced into com-partment E spends,on average,s ðh 1þh 21h 2þÁÁÁÞ¼s h 1=ð1Àh 1h 2Þ¼m =ððd þm þr 1Þðd þr 2ÞÀm pr 2Þtime units in compartment I over its expected lifetime.Multiplying this by b 1gives R 0.The model without treatment (r 1¼r 2¼0)is an SEI model with R 0¼b 1m =ðd ðd þm ÞÞ.The interpretation of R 0for this case is simpler.Only a fraction m =ðd þm Þof exposed individuals progress from compartment E to compartment I ,and individuals entering compartment I spend,on average,1=d time units there.Although conditions (A1)–(A5)do not restrict the decomposition of f i ðx Þto a single choice for F i ,only one such choice is epidemiologically correct.Different choices for the function F lead to different values for the spectral radius of FV À1,as shown in Table 1.In column (a),treatment failure is considered to be a new infection and in column (b),both treatment failure and pro-gression to infectiousness are considered new infections.In each case the condition q ðFV À1Þ<1yields the same portion of parameter space.Thus,q ðFV À1Þis a threshold parameter in both cases.The difference between the numbers lies in the epidemiological interpretation rather than the mathematical analysis.For example,in column (a),the infection rate is b 1þpr 2and an exposed individual is expected to spend m =ððd þm þr 1Þðd þr 2ÞÞtime units in compartment I .However,this reasoning is biologically flawed since treatment failure does not give rise to a newly infected individual.Table 1Decomposition of f leading to alternative thresholds(a)(b)Fb 1SI =N þb 2TI =N þpr 2I 0000B B @1C C A b 1SI =N þb 2TI =N þpr 2I m E 000B B @1C C A Vðd þm þr 1ÞE Àm E þðd þr 2ÞI Àb ðN ÞþdS þb 1SI =N dT Àr 1E Àqr 2I þb 2TI =N 0B B @1C C A ðd þm þr 1ÞE ðd þr 2ÞI Àb ðN ÞþdS þb 1SI =N dT Àr 1E Àqr 2I þb 2TI =N 0B B @1C C A F0b 1þpr 200 0b 1þpr 2m 0 V d þm þr 10Àm d þr 2d þm þr 100d þr 2 q (FV À1)b 1m þpr 2mðd þm þr 1Þðd þr 2Þffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffib 1m þpr 2mðd þm þr 1Þðd þr 2Þs 36P.van den Driessche,J.Watmough /Mathematical Biosciences 180(2002)29–484.2.Multigroup modelIn the epidemiological literature,the term‘multigroup’usually refers to the division of a het-erogeneous population into several homogeneous groups based on individual behaviour(e.g., [14]).Each group is then subdivided into epidemiological compartments.The majority of mul-tigroup models in the literature are used for sexually transmitted diseases,such as HIV/AIDS or gonorrhea,where behaviour is an important factor in the probability of contracting the disease [7,8,14,15].As an example,we use an m-group SIRS-vaccination model of Hethcote[7,14]with a generalized incidence term.The sample model includes several SI multigroup models of HIV/ AIDS as special cases[8,15].The model equations are as follows:_I i ¼X mj¼1b ijðxÞS i I jÀðd iþc iþ iÞI i;ð7aÞ_S i ¼ð1Àp iÞb iÀðd iþh iÞS iþr i R iÀX mj¼1b ijðxÞS i I j;ð7bÞ_Ri¼p i b iþc i I iþh i S iÀðd iþr iÞR i;ð7cÞfor i¼1;...;m,where x¼ðI1;...;I m;S1;...;S m;R1;...;R mÞt.Susceptible and removed individu-als die at the rate d i>0,whereas infected individuals die at the faster rate d iþ i.Infected in-dividuals recover with temporary immunity from re-infection at the rate c i,and immunity lasts an expected1=r i time units.All newborns are susceptible,and a constant fraction b i are born into each group.A fraction p i of newborns are vaccinated at birth.Thereafter,susceptible individuals are vaccinated at the rate h i.The incidence,b ijðxÞdepends on individual behaviour,which determines the amount of mixing between the different groups(see,e.g.,Jacquez et al.[16]). The DFE for this model isx0¼ð0;...;0;S01;...;S0m;R01;...;R0mÞt;whereS0 i ¼b i d ið1Àp iÞþr iðÞd iðd iþh iþr iÞ;R0 i ¼b iðh iþd i p iÞd iðd iþh iþr iÞ:Linearizing(7a)about x¼x0givesF¼S0i b ijðx0ÞÂÃandV¼½ðd iþc iþ iÞd ij ;where d ij is one if i¼j,but zero otherwise.Thus,FVÀ1¼S0i b ijðx0Þ=ðd iÂþc iþ iÞÃ:P.van den Driessche,J.Watmough/Mathematical Biosciences180(2002)29–4837For the special case with b ij separable,that is,b ijðxÞ¼a iðxÞk jðxÞ,F has rank one,and the basic reproduction number isR0¼X mi¼1S0ia iðx0Þk iðx0Þd iþc iþ i:ð8ÞThat is,the basic reproduction number of the disease is the sum of the‘reproduction numbers’for each group.4.3.Staged progression modelThe staged progression model[11,Section3and Appendix B]has a single uninfected com-partment,and infected individuals progress through several stages of the disease with changing infectivity.The model is applicable to many diseases,particularly HIV/AIDS,where transmission probabilities vary as the viral load in an infected individual changes.The model equations are as follows(see Fig.2):_I 1¼X mÀ1k¼1b k SI k=NÀðm1þd1ÞI1;ð9aÞ_Ii¼m iÀ1I iÀ1Àðm iþd iÞI i;i¼2;...;mÀ1;ð9bÞ_Im¼m mÀ1I mÀ1Àd m I m;ð9cÞ_S¼bÀbSÀX mÀ1k¼1b k SI k=N:ð9dÞThe model assumes standard incidence,death rates d i>0in each infectious stage,and thefinal stage has a zero infectivity due to morbidity.Infected individuals spend,on average,1=m i time units in stage i.The unique DFE has I i¼0,i¼1;...;m and S¼1.For simplicity,define m m¼0. Then F¼½F ij and V¼½V ij ,whereF ij¼b j i¼1;j6mÀ1;0otherwise;&ð10ÞV ij¼m iþd i j¼i;Àm j i¼1þj;0otherwise:8<:ð11ÞLet a ij be the(i;j)entry of VÀ1.Thena ij¼0i<j;1=ðm iþd iÞi¼j;Q iÀ1k¼jm kQ ik¼jðm kþd kÞj<i:8>>><>>>:ð12ÞThus,R0¼b1m1þd1þb2m1ðm1þd1Þðm2þd2Þþb3m1m2ðm1þd1Þðm2þd2Þðm3þd3ÞþÁÁÁþb mÀ1m1...m mÀ2ðm1þd1Þ...ðm mÀ1þd mÀ1Þ:ð13ÞThe i th term in R0represents the number of new infections produced by a typical individual during the time it spends in the i th infectious stage.More specifically,m iÀ1=ðm iÀ1þd iÀ1Þis the fraction of individuals reaching stage iÀ1that progress to stage i,and1=ðm iþd iÞis the average time an individual entering stage i spends in stage i.Hence,the i th term in R0is the product of the infectivity of individuals in stage i,the fraction of initially infected individuals surviving at least to stage i,and the average infectious period of an individual in stage i.4.4.Multistrain modelThe recent emergence of resistant viral and bacterial strains,and the effect of treatment on their proliferation is becoming increasingly important[12,13].One framework for studying such sys-tems is the multistrain model shown in Fig.3,which is a caricature of the more detailed treatment model of Castillo-Chavez and Feng[12,Section2]for tuberculosis and the coupled two-strain vector–host model of Feng and Velasco-Hern a ndez[17]for Dengue fever.The model has only a single susceptible compartment,but has two infectious compartments corresponding to the two infectious agents.Each strain is modelled as a simple SIS system.However,strain one may ‘super-infect’an individual infected with strain two,giving rise to a new infection incompartment。
药学英语第五版第三单元
Biochemistry Seeks to Explain Life in Chemical TermsThe molecules of which living organisms are composed conform to all the familiar laws of chemistry, but they alsointeract with each other in accordance with another set of principles, which we shall refer to collectively as the molecularlogic of life. These principles do not involve new or yet undiscovered physical laws or forces. Instead, they are a set ofrelationships characterizing the nature, function, and interactions of biomolecules.If living organisms are composed of molecules that are intrinsically inanimate, how do these molecules confer theremarkable combination of characteristics we call life? How is it that a living organism appears to be more than the sum ofits inanimate parts? Philosophers once answered that living organisms are endowed with a mysterious and divine life force,but this doctrine (vitalism) has been firmly rejected by modern science. The basic goal of the science of biochemistry is todetermine how the collections of inanimate molecules that constitute living organisms interact with each other to maintainand perpetuate life. Although biochemistry yields important insights and practical applications in medicine, agriculture,nutrition, and industry, it is ultimately concerned with the wonder of life itself.All Macromolecules Are Constructed from a Few Simple CompoundsMost of the molecular constituents of living systems are composed of carbon atoms covalently joined with other carbonatoms and with hydrogen, oxygen, or nitrogen. The special bonding properties of carbon permit the formation of a greatvariety of molecules. Organic compounds of molecular weight less than about 500, such as amino acids, nucleotidase, andmonosaccharide, serve as monomeric subunits of proteins, nucleic acids, and polysaccharides, respectively. A single proteinmolecule may have 1,000 or more amino acids, and deoxyribonucleic acid has millions of nucleotides.Each cell of the bacterium Escherichia coli (E. coli) contains more than 6,000 different kinds of organic compounds,including about 3,000 different proteins and a similar number of different nucleic acid molecules. In humans there may betens of thousands of different kinds of proteins, as well as many types of polysaccharides (chains of simple sugars), avariety of lipids, and many other compounds of lower molecular weight.To purify and to characterize thoroughly all of these molecules would be an insuperable task, it were not for the factthat each class of macromolecules (proteins, nucleic acids, polysaccharides) is composed of a small, common set of monomericsubunits. These monomeric subunits can be covalently linked in a virtually limitless variety ofsequences, just as the 26letters of the English alphabet can be arranged into a limitless number of words, sentiments, or books.Deoxyribonucleic acids (DNA) are constructed from only four different kinds of simple monomeric subunits, thedeoxyribonucleotides, and ribonucleic acids (RNA) are composed of just four types of ribonucleotides. Proteins are composedof 20 different kinds of amino acids. The eight kinds of nucleotides from which all nucleic acids are built and the 20different kinds of amino acids from which all proteins are built are identical in all living organisms.Most of the monomeric subunits from which all macromolecules are constructed serve more than one function in livingcells. The nucleotides serve not only as subunits of nucleic acids, but also as energy-carrying molecules. The amino acidsare subunits of protein molecules, and also precursors of hormones, neurotransmitters, pigments, and many other kinds ofbiomolecules.From these considerations we can now set out some of the principles in the molecular logic of life: All living organismshave the same kinds of monomeric subunits. There are underlying patterns in the structure of biological macromolecules. Theidentity of each organism is preserved by its possession of distinctive sets of nucleic acids and of proteins.ATP Is the Universal Carrier of Metabolic Energy, Linking Catabolism and AnabolismCells capture, store, and transport free energy in a chemical form. Adenosine triphosphate (ATP) functions as the majorcarrier of chemical energy in all cells. ATP carries energy among metabolic pathways by serving as the shared intermediatethat couples endergonic reactions to exergonic ones. The terminal phosphate group of ATP is transferred to a variety ofacceptor molecules, which are thereby activated for further chemical transformation. The adenosine diphosphate (ADP) thatremains after the phosphate transfer is recycled to become ATP, at the expense of either chemical energy (during oxidativephosphorylation) or solar energy in photosynthetic cells (by the process of photophosphorylation). ATP is the majorconnecting link (the shared intermediate) between the catabolic and anabolic networks of enzyme-catalyzed reactions in thecell. These linked networks of enzyme-catalyzed reactions are virtually identical in all living organisms.Genetic Continuity Is Vested in DNA MoleculesPerhaps the most remarkable of all the properties of living cells and organisms is their ability to reproduce themselveswith nearly perfect fidelity for countless generations. This continuity of inherited traits impliesconstancy, over thousandsor millions of years, in the structure of the molecules that contain the genetic information. Very few historical records ofcivilization, even those etched in copper or carved in stone, have survived for a thousand years. But there is good evidencethat the genetic instructions in living organisms have remained nearly unchanged over much longer periods; many bacteria havenearly the same size, shape, and internal structure and contain the same kinds of precursor molecules and enzymes as thosethat lived a billion years ago.Hereditary information is preserved in DNA, a long, thin organic polymer so fragile that it will fragment from the shearforces arising in a solution that is stirred or pipetted. A human sperm or egg, carrying the accumulated hereditaryinformation of millions of years of evolution, transmits these instructions in the form of DNA molecules, in which the linearsequence of covalently linked nucleotide subunits encodes the genetic message. Genetic information is encoded in the linearsequence of four kinds of subunits of DNA. The double-helical DNA molecule has an internal template for its own replicationand repair.The Structure of DNA Allows for Its Repair and Replication with Near-Perfect FidelityThe capacity of living cells to preserve their genetic material and to duplicate it for the next generation results fromthe structural complementarity between the two halves of the DNA molecule. The basic unit of DNA is a linear polymer of fourdifferent monomeric subunits, deoxyribonucleotides, arranged in a precise linear sequence. It is this linear sequence thatencodes the genetic information. Two of these polymeric strands are twisted about each other to form the DNA double helix,in which each monomeric subunit in one strand pairs specifically with the complementary subunit in the opposite strand. Inthe enzymatic replication or repair of DNA, one of the two strands serves as a template for the assembly of another,structurally complementary DNA strand. Before a cell divides, the two DNA strands separate and each serves as a template forthe synthesis of a complementary strand, generating two identical double-helical molecules, one for each daughter cell. Ifone strand is damaged, continuity of information is assured by the information present on the other strand.The Linear Sequence in DNA Encodes Proteins with Three-Dimensional StructuresThe information in DNA is encoded as a linear (one-dimensional) sequence of the nucleotide units of DNA, but theexpression of this information results in a three-dimensional cell. This change from one to threedimensions occurs in twophases. A linear sequence of deoxyribonucleotides in DNA codes (through the intermediary, RNA) for the production of aprotein with a corresponding linear sequence of amino acids. The protein folds itself into a particular three-dimensionalshape, dictated by its amino acid sequence. The precise three-dimensional structure (native conformation) is crucial to theprotein’s function as either catalyst or structural element. This principle emerges: The linear sequence of amino acids in a protein leads to the acquisition of a unique three-dimensional structure by aself-assembly procession.Once a protein has folded into its native conformation, it may associate noncovalently with other proteins, or withnucleic acids or lipids, to form supramolecular complexes such as chromosomes, ribosomes, and membranes. These complexes arein many cases self-assembling. The individual molecules of these complexes have specific, high-affinity binding sites foreach other, and within the cell they spontaneously form functional complexes.Individual macromolecules with specific affinity for other macromolecules self-assemble into supramolecular complexes.Noncovalent Interactions Stabilize Three-Dimensional StructuresThe forces that provide stability and specificity to the three-dimensional structures of macromolecules andsupramolecular complexes are mostly noncovalent interactions. These interactions, individually weak but collectively strong,include hydrogen bonds, ionic interactions among charged groups, van der Waals interactions, and hydrophobic interactionsamong nonpolar groups. These weak interactions are transient; individually they form and break in small fractions of a second.The transient nature of noncovalent interactions confers a flexibility on macromolecules that is critical to their function.Furthermore, the large numbers of noncovalent interactions in a single macromolecule makes it unlikely that at any givenmoment all the interactions will be broken; thus macromolecular structures are stable over time.Three-dimensional biological structures combine the properties of flexibility and stability.The flexibility and stability of the double-helical structure of DNA are due to the complementarity of its two strandsand many weak interactions between them. The flexibility of these interactions allows strand separation during DNAreplication; the complementarity of the double helix is essential to genetic continuity.Noncovalent interactions are also central to the specificity and catalytic efficiency of enzymes. Enzymes bindtransition-state intermediates through numerous weak but precisely oriented interactions. Because the weak interactions areflexible, the complex survives the structural distortions as the reactant is converted into product.The formation of noncovalent interactions provides the energy for self-assembly of macromolecules by stabilizing nativeconformations relative to unfolded, random forms. The native conformation of a protein is that in which the energeticadvantages of forming weak interactions counterbalance the tendency of the protein chain to assume random forms. Given aspecific linear sequence of amino acids and a specific set of conditions (temperature, ionic conditions, pH), a protein willassume its native conformation spontaneously, without a template or scaffold to direct the folding.The Physical Roots of the Biochemical WorldWe can now summarize the various principles of the molecular logic of life:A living cell is a self-contained, self-assembling, self-adjusting, self-perpetuating isothermal system of molecules thatextracts free energy and raw materials from its environment.The cell carries out many consecutive reactions promoted by specific catalysts, called enzymes, which it produces itself.The cell maintains itself in a dynamic steady state, far from equilibrium with its surroundings. There is great economyof parts and processes, achieved by regulation of the catalytic activity of key enzymes.Self-replication through many generations is ensured by the self-repairing, linear information-coding system. Geneticinformation encoded as sequences of nucleotide subunits in DNA and RNA specifies the sequence of amine acids in each distinctprotein, which ultimately determines the three-dimensional structure and function of each protein.Many weak (noncovalent) interactions, acting cooperatively, stabilize the three-dimensional structures of biomoleculesand supramolecular complexes.。
在地幔部分熔融时高度不相容
在地幔部分熔融时高度不相容英文回答:When the mantle partially melts, it undergoes a process called partial melting or partial fusion. This occurs due to the presence of certain minerals that have different melting points. The mantle is composed of various minerals, including silicates such as olivine and pyroxene. These minerals have different chemical compositions and melting points.During partial melting, some minerals may start to melt at lower temperatures while others remain solid. This creates a situation where the molten portion becomes chemically distinct from the solid portion. The molten portion is referred to as magma, while the solid portion is called residue or restite.The immiscibility of the molten and solid portions is due to the differences in their chemical compositions. Forexample, if we consider a simplified scenario where the mantle is composed of two minerals A and B, with A having a lower melting point than B. When the mantle undergoes partial melting, mineral A will start to melt first, forming a molten portion rich in A. This molten portionwill be chemically distinct from the remaining solid portion, which is enriched in mineral B.This immiscibility can be compared to oil and water. Just like oil and water do not mix, the molten portion and solid portion in the mantle do not mix due to their different chemical compositions. They remain separate entities, with the molten portion rising towards theEarth's surface through volcanic activity, while the solid portion remains in the mantle.中文回答:地幔部分熔融时发生的是部分熔融或部分熔化的过程。
Investigating the Properties of Plasmas
Investigating the Properties ofPlasmasPlasma is one of the four fundamental states of matter, alongside solid, liquid, and gas. Unlike the other three, plasma is not commonly found on Earth, but rather in the universe at large. Despite its rarity, however, plasma plays a key role in many natural phenomena, such as lightning, auroras, and even the sun. In human-made devices, such as plasma TVs and fluorescent bulbs, plasma is used to create light. Because of its unique properties, plasma is also used in a variety of scientific experiments and industrial processes. In this article, we will explore the properties of plasma and some of the ways in which it is used.What is Plasma?Plasma is a gaseous state of matter in which the atoms or molecules are ionized, or stripped of their electrons. This creates a cloud of positively charged ions and negatively charged electrons. Because of the presence of charged particles, plasma is electrically conductive and can be influenced by magnetic fields. Plasma can be generated in many ways, such as heating a gas to high temperatures or applying a high voltage or electric current to a gas.Properties of PlasmaPlasma has several unique properties that set it apart from the other states of matter. One of these is its ability to conduct electricity. Because plasma is made up of ions and free electrons, it can carry electric current. This property is utilized in devices like plasma TVs, which use a gas discharge to create light.Another property of plasma is its ability to be manipulated by magnetic fields. This property is used in fusion research, where magnetic fields are used to contain and control the plasma in order to create fusion reactions.Plasma also has properties that make it useful in industrial processes. For example, plasma can be used to clean surfaces by breaking down contaminants and producing free radicals that react with the surface. This process, called plasma cleaning, is used in the semiconductor industry to prepare surfaces for the deposition of thin films.Applications of PlasmaPlasma has numerous applications in science and technology. One of the most well-known applications is in plasma TVs, which use a gas discharge to create the colored pixels on the screen. Plasma is also used in welding, where it is used to heat and melt metals to create a bond.In the field of energy, plasma is being investigated as a potential source of fusion energy. Fusion reactions release energy by fusing atomic nuclei together, which can then be harnessed to generate electricity. However, creating and controlling the high-temperature plasma needed for fusion is a significant scientific and engineering challenge.Plasma is also used in the medical field, where it is used to sterilize medical equipment and treat a variety of medical conditions. Plasma can be used to break down cancer cells, kill bacteria and viruses, and promote wound healing.ConclusionPlasma is an important and fascinating state of matter that has numerous applications in science and technology. Understanding the properties of plasma is crucial to many scientific fields, from fusion research to plasma cleaning. As our understanding of plasma continues to grow, so too will our ability to harness its power for a range of applications.。
bcl3的成键过程 -回复
bcl3的成键过程-回复【BCl3的成键过程】Introduction:BCl3, also known as boron trichloride, is a chemical compound with the formula BCl3. It is a colorless gas that has an important role in various chemical reactions and industrial processes. The formation of chemical bonds in BCl3 follows a specific process, which involves the interaction of boron and chlorine atoms. In this article, we will explore the step-by-step process of bonding in BCl3.Step 1: Boron atom and chlorine atom interactionThe first step in the bonding process of BCl3 involves the interaction of a boron atom with three chlorine atoms. Boron in its ground state has an electron configuration of 1s²2s²2p¹, while chlorine has a configuration of 1s²2s²2p⁶3s²3p⁵. Boron has three valence electrons, and chlorine has seven valence electrons.Step 2: Formation of covalent bondsBoron, being in Group 13 of the periodic table, tends to lose its three valence electrons to achieve a stable electron configuration, which is similar to the noble gas helium. On the other hand,chlorine, in Group 17, tends to gain one electron to achieve a stable electron configuration, similar to the noble gas argon. The formation of covalent bonds in BCl3 involves the sharing of electrons between boron and chlorine atoms.Step 3: Boron's electron deficiencyAs boron shares its three valence electrons with three chlorine atoms, it achieves a stable configuration with a formal charge of +1. This electron deficiency leaves an empty p orbital on the boron atom, making it an electron acceptor. This electron-deficient boron atom is crucial for the reactivity of BCl3, as it can readily accept an electron pair.Step 4: Chlorine's electron-richnessChlorine, on the other hand, gains one electron from each of the three boron atoms it is bonded to. This sharing of electrons allows chlorine to achieve a stable electron configuration with a formal charge of -1. Chlorine's electron-richness enables it to readily donate an electron pair to electron-deficient atoms or molecules, which makes it an electron donor.Step 5: Formation of coordinate covalent bondsWith the electron-deficient boron atom and electron-rich chlorine atoms, the bonding in BCl3 is achieved through coordinate covalent bonds. In a coordinate covalent bond, one atom donates a pair of electrons (the donor), while the other atom accepts the electron pair (the acceptor). In BCl3, the chlorine atoms act as electron donors, while the boron atom acts as an electron acceptor.Step 6: Molecular shape and polarityThe bonding in BCl3 results in a trigonal planar molecular structure. The three chlorine atoms arrange themselves in a triangular arrangement around the central boron atom. The molecule is trigonal planar because the boron atom shares three electron pairs with the three chlorine atoms. As the chlorine atoms have the same electronegativity, the molecule is nonpolar.Conclusion:In conclusion, the bonding in BCl3 involves the interaction of boron and chlorine atoms through the formation of covalent bonds. The boron atom, being electron-deficient, accepts electron pairs from the chlorine atoms, which act as electron donors. This results in the formation of coordinate covalent bonds and a trigonal planarmolecular structure. Understanding the bonding process in BCl3 is important for various applications, such as its use in the production of boron trifluoride and other chemical compounds.。
Short-term and long-term effects of osteoporosis therapy
Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland 1142,New Zealand.i.reid@ Short-term and long-term effects of osteoporosis therapiesIan R. ReidAbstract | Progress continues to be made in the development of therapeutics for fracture prevention. Bisphosphonates are now available orally and intravenously, often as inexpensive generics, and remainthe most widely used interventions for osteoporosis. The major safety concern associated with the use of bisphosphonates is the development of femoral shaft stress fractures and, although rare, this adverse event affords the principal rationale for restricting bisphosphonate therapy to those individuals with femoral T‑scores <–2.5, and for providing drug holidays in those individuals requiring therapy for >5 years. Newer antiresorptive therapies, in the form of denosumab and cathepsin K inhibitors, might increase efficacy and possibly circumvent some of the safety concerns associated with bisphosphonate use (for example, gastrointestinal and renal complications). The combination of teriparatide with antiresorptives markedly increases effectson BMD; new anabolic agents are also very promising in this regard. However, whether or not these changes in BMD translate into improved efficacy of fracture prevention remains to be determined. Vitamin D is important for the prevention of osteomalacia, but does not influence BMD or fracture risk in patients not deficient in vitamin D. The balance of risks and benefits of calcium supplementation is contentious, but patients should be encouraged to adhere to a balanced diet aimed at maintaining a healthy body weight. Consideration of a patient’s risk of falling, and its mitigation, are also important. In this Review, I summarize the short‑term and long‑term effects of osteoporosis therapies.Reid, I. R. Nat. Rev. Endocrinol. advance online publication 12 May 2015; doi:10.1038/nrendo.2015.71IntroductionWorldwide, life expectancy has progressively increasedover the past 100 years1 and this trend shows no signof abating. In Asia and Africa, this increase is probablyattributable to improvements in nutrition, sanitationand healthcare. In the West, increasing life expectancyis driven by declining cardiovascular and cancer mortal-ity;1 lifestyle changes and advances in healthcare are alsocontributing factors. The number of elderly individualsis, thus, increasing. In New Zealand, for example, thepopulation >80 years more than trebled between 1980and 2013, and is expected to double again before 2030.2With advancing age, musculoskeletal disease contrib-utes to increasing morbidity, principally as a result ofosteo p orotic fractures and osteoarthritis.3 Osteoporoticfractures are associated with increased mortality4 and sub-stantial long-term loss of independence, in addition to thepain and disability immediately resulting from a fractureevent. Data from Europe demonstrate that osteo p orosiscauses the loss of more disability-adjusted life yearsthan any type of cancer other than lung cancer.3 In otherregions of the world, where the prevalence of smoking ismuch lower than that in Europe, osteoporosis is probablyresponsible for the loss of more disability-adjusted lifeyears than all types of cancer, individually.This Review will reflect on the nature of the osteo-porotic process and its implications for treatment indi-cations, and consider the pros and cons of availableinterventions to reduce fracture risk.The nature of osteoporosisIn the past 20–30 years, osteoporosis has been char-acterized as a disease to which a succession of defini-tions have been applied. Prior to the availability of bonedensito m etry, the definition of osteoporosis requiredlow-trauma fracture. Subsequently, a definition based onBMD was implemented,5 and more recently some clini-cians have interpreted the move to define interventionthresholds in terms of absolute fracture risk,6 as a furtherredefinition of osteoporosis. This situation is confusingfor both health practitioners and the public, and can leadto quite disparate estimates of the prevalence of osteo-porosis. Clinicians’ approach to osteoporosis is distortedby this confusion, as a disease-based view of the condi-tion mandates, first, that a diagnosis be made, and thenassumes that intervention will inevitably follow. In fact,osteoporosis is a process operative in almost all individu-als past middle age;7 osteoporosis results in fractures inabout half of postmenopausal white women, and aboutone-third of older white men.8 For those individuals whodo not experience a fracture, the presence or absence ofosteoporosis has not been demonstrated to have anyinfluence on their welfare; therefore, intervention is Competing interestsI.R.R. has received research grants or speaking and/orconsulting fees from Amgen, Lilly, Merck, Novartis and Sanofi.REVIEWSnot necessarily required. These realizations, together with the development of straightforward methods for assessing fracture risk, require a reconceptualization of osteo p orosis. Osteoporosis is a near-universal process, which can result in adverse medical events such as frac-tures. The task for healthcare providers is not to make the diagnosis of osteoporosis but, rather, to assess the short-term and long-term risk of fractures and to provide re c ommendations regarding interventions.Treatment decisionsWith the availability of fracture risk estimators,9,10 recom m endations for intervention can now be based on cost-effectiveness analyses. Even interventions of com-parable efficacy (for example, generic versus brand-name bisphosphonates) differ in cost-effectiveness. The cost-effectiveness of a generic bisphosphonate, for example, is very different from that of a brand name injectableanabolic preparation. Therefore, a simple yes or no answer to the question of whether or not a particular therapy is appropriate is not possible.In considering interventions for osteoporosis, a cost-effectiveness approach needs to be applied to both pharma c eutical and nonpharmaceutical interventions. Where generic bisphosphonates are available, their pur-chase can be less expensive than that of calcium supple-ments; some supervised exercise interventions can also be costly. By contrast, some nonpharmaceutical interven-tions (for example, smoking cessation, weight mainte-nance, regular physical activity and moderation of alcohol intake) can be widely advocated, as they effectively have a zero short-term cost.Given that the cost of generic osteoporosis medica-tions is progressively declining, a simple cost–benefit analysis suggests that the entire elderly population should receive treatment. In this situation, it is not the financial cost that needs to be balanced against benefit, but the risks associated with use of particular interven-tions. In patients at low short-term risk of fractures, even very rare adverse effects of drug interventions can elimi-nate the benefits of that intervention, particularly if the efficacy of the intervention is modest or unproven (such as with calcium supplements).FallsThe focus on absolute fracture risk as the basis of thera-peutic decisions has increased awareness among clini-cians of the importance of factors other than BMD in determining fracture risk. Some of these risk factors, such as age, are not amenable to intervention, and others require changes in lifestyle rather than medica-tion. The Garvan Fracture Risk calculator demonstrates the profound influence of a history of falls in the past year on fracture risk;10 practitioners using other calcu-lators need to elicit this information and incorporate it into their treatment recommendations. If fracture risk is high solely on the basis of frequent falls, whether this risk is attenuated by pharmaceuticals that increase BMD is unknown. The HIP study 11 of risedronate sug-gested that bisphosphonates were ineffective at reducing frailty-related fractures, even though the study was not adequately powered to definitively address this question. Thus, those providing care for patients at risk of osteo-porotic fractures need to be aware of the issues involved in falls prevention. These issues include balance and strengthening exercises, optimization of vision, reduc-tion or elimination of sedative drugs, prevention and/or treatment of postural hypotension and provision of a safe home environment, including the provision of handrails and removal of falls hazards.Calcium and vitamin DAlthough calcium and vitamin D are distinct entities, they have historically been considered together. Neither calcium nor vitamin D are adequate monotherapies for osteoporosis, as they do not have significant anti-fracture efficacy (Figures 1 and 2). The adverse effects of calcium supplements on renal calculi,12 gastrointestinalFavours treatmentFavours controlCalcium Vitamin DCalcium + vitamin DAlendronateRisedronate Ibandronate BisphosphonatesZoledronate Raloxifene Strontium Denosumab Odanacatib TeriparatidePTH 1–84Figure 1 | Efficacy of treatments for the prevention of hip fractures. Data forstrontium,77 odanacatib 107 and PTH 1–8493 are relative risks; other data are odds ratios sourced from elsewhere.113 Values are shown ±95% CI. As data is derived from a range of separate studies, which have differences in entry criteria and patient characteristics, comparison between agents should be interpreted with caution.symptoms 13 and myocardial infarction 14 probably negate any beneficial effect on bone (reviewed elsewhere 15). Trends in adverse effects of calcium monotherapy on myocardial infarction have been duplicated in other meta-analyses,16,17 but are not apparent across the broad disease category of coronary heart disease.16 Whether the same adverse effect is observed for supplementa-tion with both calcium and vitamin D depends on what studies are included in the meta-analysis; inclusion of 20,000 women in the Women’s Health Initiative study 12 who self-administered calcium, and a nonblinded, cluster-randomized study of calcium and vitamin D co- supplementation 18 resulted in this adverse cardiovascular effect no longer being apparent.16,19Vitamin D is mainly important for the prevention of osteomalacia; treatment of mild vitamin D defi-ciency does not seem to confer significant benefits in terms of BMD 20 or fracture risk.21 The main evidence for a benefit from the use of vitamin D and calcium comes from a study that was carried out in a mark-edly vitamin D-deficient population,22 and might well represent treatment of osteomalacia in a subset of par-ticipants. Supplementation with calcium and vitamin D in c o mmunity-dwelling individuals not receiving hormone therapy did not reduce the risk of hip fractures (relative risk [RR] 1.12).23 Previous meta-analyses, which were conducted without awareness of the significant interactions between randomization to hormones or to calcium plus vitamin D and the effect on hip fracture in the Women’s Health Initiative,24 produced more positive findings.25 Therefore, it is important that serum levels of 25-hydroxyvitamin D >40 nmol/l are maintained to prevent osteomalacia, but, at present, there is little evi-dence from clinical trials for a benefit of maintaining 25-hydroxyvitamin D at levels substantially >75 nmol/l.26BisphosphonatesBisphosphonates are analogues of pyrophosphate that strongly bind to the hydroxyapatite component of bone, and remain near the bone surface for months to years. Bisphosphonates are ingested by osteoclasts during bone resorption, and inhibit additional resorption through direct inhibition of a critical metabolic pathway in these cells.27 Bisphosphonates are the most widely used ca t egory of therapeutic agent in osteoporosis.EfficacyAlthough commonly used bisphosphonates reduce frac-ture risk in the short-term (Figures 1 and 2), the criti-cal question in osteoporosis therapeutics, now, is what should be done after 3 years, which is the termination point of most of the pivotal bisphosphonate trials. The FLEX study 28 attempted to address this question for alendronate. BMD at the hip was maintained in women taking alendronate for 5 years who continued at the orig-inal dose (10 mg per day) or at half that dose, whereas BMD at the hip tended to return to baseline levels over the second quinquennium in women randomized to receive placebo. Total numbers of non v ertebral fractures were similar in all groups, but post hoc analyses indi-cated that, in those with femoral neck T-scores <–2.5, continuation of alendronate reduced nonvertebral frac-tures by 50%.29 Clinical vertebral fractures were also reduced by ~50% in the group receiving alendronate.28Similar data have now been presented for zoledronate use up to 9 years 30 (Figure 3), although the number of participants in that study makes conclusions regarding fracture incidence unreliable. Similar to alendronate, hip BMD seems to peak with zoledronate use between 4 and 5 years, even though bone loss in those individu-als who discontinued treatment at 6 years was <1% in the following 3 years.30 Analysis of fracture data between year 3 and year 6 for zoledronate use suggests a partial loss of vertebral fracture efficacy associated with drug discontinuation, particularly in women whose femoral neck T-score remained <–2.5.31On the basis of these findings, the practice of initiating bisphosphonate therapy for a period of 3–5 years and re-assessing BMD at this time to determine whether contin-ued drug administration is necessary has evolved. A hip T-score <–2.5 is regarded as an indication for continued treatment. In the case of alendronate, continuation at half the standard dose (that is 70 mg every 2 weeks) is adequate.28 My own practice with zoledronate, which is based on the prolonged antiresorptive and antifrac-ture efficacy of a single infusion,32,33 is to initiate dosing at 18-month intervals, increasing the interdose interval to 2–3 years in those with satisfactory BMD responses. Markers of bone turnover remain suppressed with these inter-dose intervals.32In those individuals for whom a drug holiday is appro-priate, a duration of 1–2 years is usual for alendronate (although one study has suggested offset of this drug within 12 months 34), whereas 6–12 months is appropri-ate for risedronate, as offset of the effects of this drug on bone turnover are rapid.35,36 Scant other reliable evidenceFavours treatmentFavours controlCalcium Vitamin DCalcium + vitamin DAlendronateRisedronate Ibandronate BisphosphonatesZoledronate Raloxifene Strontium Denosumab Odanacatib TeriparatidePTH 1–84Figure 2 | Efficacy of treatments for the prevention of nonvertebral fractures. Data for strontium,77 odanacatib 107 and PTH 1–8493 are relative risks; other data are odds ratios sourced from elsewhere.113 Values are shown ±95% CI.REVIEWSproviding evidence of offset of the drug effect, and repeat-ing BMD measurements at ~2 years is common practice. However, neither measurements have been shown to predict fractures.37SafetyOral bisphosphonates are associated with adverse effects on the upper gastrointestinal tract in ~20% of patients,38 and intravenous aminobisphosphonates produce an acute-phase response in about one-third of patients.39 Adequate renal function (that is, glomerular filtration rate >35 ml/min/1.73 m2) is a prerequisite for the use of intravenous bisphosphonates. The long-term safety of these drugs has been reviewed elsewhere.15Two conditions remain a concern for bisphosphonate use: osteonecrosis of the jaw (ONJ) and atypical sub-trochanteric femoral fractures (AFFs). ONJ is clearly an issue for patients with disseminated cancer who are treated with monthly infusions of intravenous bisphos-phonates (or denosumab), and occurs in ~5% of these patients.40 Similar nonhealing oral lesions have been described in patients with osteoporosis, irrespective of whether or not they are treated with bisphosphonates.41–43 Postmarketing reports have suggested that the incidence of ONJ in patients with osteoporosis who are treated with bisphosphonates is ~2:100,000 patient-years.40 These individuals seem to present with less advanced ONJ,44 and a high percentage of their lesions heal.45 Given that ONJ is a rare event and the causal role of bisphos-phonates is unclear, ONJ is not a major consideration in the management of osteoporosis.By contrast, the occurrence of stress fractures in the lateral cortex of the femoral shaft (referred to as AFFs) is46 The47,48 A study conducted in5047 which suggests that the rate of51 for example, showed that betweenWhether any of the subtro c hanteric fractures reported in the FLEX study were atypical is unknown, as radiographs were not available; however, the atypical proportion of subtrochanteric fractures is usually <10%.50,52 Prospectively collected trial data in patients with a clearly documented bisphosphonate dosing history do not suggest that the incidence of AFFs is approaching that of conventional femoral fractures.51 However, the need for continued bisphosphonate therapy should be periodically reviewed and drug holidays provided for patients who are no longer defined as osteoporotic by BMD measurements. These actions will ensure that effec-tive interventions continue to be provided to patients with osteoporosis at high risk of fractures.Estrogen and SERMsGiven that the decline in ovarian estrogen production is the critical change that results in postmenopausal bone loss, provision of estrogen from the start of menopause maintains BMD and reduces fracture risk.53 However, as estrogen receptors are widely distributed in the body, the administration of estrogen can affect many tissues and outcomes. This caveat was made clear in the Women’s Health Initiative, in which beneficial effects on fractures and colon cancer incidence were counterbalanced by changes in cardiovascular, cerebrovascular and venous thromboembolic events.54,55 This balance seems to be different for estrogen alone in comparison with estrogen plus progestins, and is likely to vary further according to the specific estrogen and progestin used. Complexity in this area has caused many patients and physicians to lose enthusiasm for estrogen as a bone-protective therapy, even though its efficacy is beyond question. A reappraisalof the literature on this topic suggests that, in the small number of women who have increased fracture risk in the decade following menopause, the balance of benefit versus risk is probably positive.56During the 1990s, compounds that can bind to the estrogen receptor were recognized to have agonistic or antagonistic effects, and that the balance of these effects varied among different tissues.57 Many investigators sought to discover the optimal selective estrogen receptor modulator (SERM) that could mediate agonistic effects on bone and the vasculature, which also balanced the antagonistic effects on the breast, endometrium and liver. The perfect SERM remains elusive, but raloxifene has been widely used in the management of osteo p orosis.58 The effects of raloxifene on BMD are significantly less than those of estrogen59 and it reduces only vertebral fractures with no effect on hip and other nonvertebral fr a ctures.60 Similar to estrogen, raloxifene increases the risk of th r omboembolic disease.60A combination of the SERM bazedoxifene and conju-gated estrogens has been marketed in the USA. Clinical trial data indicate that this combination improves vaso-motor symptoms, vulvovaginal atrophy and BMD, and does not cause adverse events in the breast or endo-metrium;61,62 however, the antifracture efficacy of this combination has not been studied. Analyses of BMD data show that most doses of the combination of baze-doxifene and conjugated estrogens are more effec-tive at increasing BMD than raloxifene;63 however, the reported changes in BMD are somewhat less than those observed with potent antiresorptives such as alendro-nate and denosumab. Therefore, it would be surprising if b a zedoxifene–conjugated-estrogen combinations were as effective as the potent antiresoprtives in preventing fractures. Surprisingly, increased numbers of venous thrombo e mbolic events have not been reported with the combination of bazedoxifene and conjugated estrogens, which might be due to the modest size of the trial popula-tions studied. At the present time, SERMs are regarded as having an adjunctive role in osteoporosis prevention but are not widely used as a primary therapy in patients at high risk of fractures.DenosumabMany factors affect the development of osteoclasts; however, the critical regulator of this process seems to be receptor activator of nuclear factor κB ligand (RANKL, also known as tumour necrosis factor ligand superfamily member 11), which is produced predominantly by osteo-cytes.64 Denosumab is a monoclonal antibody directed against RANKL which, when used in the treatment of osteoporosis, is administered as a subcutaneous injection at 6-month intervals.EfficacyDenosumab profoundly reduces bone turnover (both bone formation and bone resorption), with a median bone formation rate of zero after 2–3 years of use.65 The anti r esorptive effects of denosumab decline rapidly >6 months after each injection, as circulating levels of the antibody decrease, which leads to a rapid increase in bone resorption and loss of BMD.66 In the phase III FREEDOM trial, reductions in vertebral fractures of 68%, hip fractures of 40% and nonvertebral fractures of 20% were observed,67 similar to the reductions reported for zoledronate use.68 Ongoing follow-up of the active group from the FREEDOM trial,69 however, suggests a differ-ent evolution of BMD and fracture effects from those seen with bisphosphonates (Figure 3). Thus, lumbar spine BMD is 18.5% above baseline at year 8 and, in the total hip, BMD is 8.2% above baseline in compliant indi-viduals.69 In the blinded phase of this trial,67 a sustained, though modest, reduction in nonvertebral fracture risk was observed. In the open-label phase of this study, a further 25% reduction in fracture risk after 3 years was reported.70 Again, this contrasts with the bisphospho-nate studies,71,72 in which the reduction in nonvertebral fracture rate was maintained with open-label therapy but did not decline further. In the absence of a control group past 3 years, and with know l edge that the number of participants withdrawing from the study progressively increased with longer follow-up, the significance of these observations is uncertain, even though the results suggest that denosumab is one of the most effective interventions available for osteoporosis management.SafetyIn the phase III trial of denosumab an increased risk of cellulitis was observed,67 but was neither confirmed in long-term follow-up69 nor in other studies using this agent.73 In oncology practice, the use of denosumab is associated with ONJ,73 but, similar to bisphosphonates, this association does not seem to be a major issue in treat-ing patients with osteoporosis. Data from the Amgen postmarketing database have recently been published.74 By September 2013, exposure to Prolia® (Amgen, USA), the brand of denosumab marketed for osteoporosis treat-ment, was 1,252,566 patient-years. The data included four adjudicated reports of AFFs, all in individuals who had used bisphosphonates previously; 32 adjudicated cases of ONJ (risk factors included glucocorticoid use, chemo-therapy, prior bisphosphonate use, older age and invasive dental procedures), with resolution in one-third of cases; eight cases of severe sympto m atic hypo c alcaemia, seven of whom had chronic kidney disease; and five cases of anaphylaxis.74 AFFs have also been reported in the exten-sion to the phase III trial.69 These findings are consistent with the impression of denosumab as a well-tolerated pharmaceutical and do not suggest detectable adverse consequences as a result of denosumab’s sustained pr o found inhibition of bone turnover.StrontiumStrontium is a divalent cation located immediately below calcium in the periodic table. The chemical properties of strontium are, therefore, similar to those of calcium and, biologically, strontium seems to act as a calcimimetic. Strontium ions can replace calcium ions in hydroxy-apatite, can bind to the extracellular calcium-sensing receptor (also known as CaSR), and its absorptionREVIEWSfrom the gut closely correlates with that of calcium.64,75 Strontium has been developed for the treatment of osteo-porosis in the form of strontium ranelate, which is taken as a powder daily.EfficacyUse of strontium is associated with substantial increases in BMD,76,77 but these increases are, at least in part, arte-factual, as they result from the heavier strontium ions replacing calcium ions in hydroxyapatite. Strontium has been reported to decrease the risk of vertebral fractures by 40%76 and of nonvertebral fractures by 16%;77 risk of hip fracture was not decreased in the primary analy-sis,77 even though a just-significant effect was found in a post hoc analysis of a subgroup judged to be at high risk of hip fracture.77 The mechanism of the antifracture effect exerted by strontium is uncertain. Although both anabolic effects and anticatabolic effects (possibly medi-ated through CaSR) have been suggested, these effects are not supported by independent investigations.78 Changes in the physical properties of the hydroxyapatite crystal might be involved. The modest benefits of strontium use in terms of fracture efficacy are expected to be further undermined by poor long-term compliance.79SafetyThe key issue determining the role of strontium ranelate in osteoporosis management is likely to be one of safety. Severe dermatological reactions to strontium ranelate have been reported, but these are rare events.80,81 How e ver, re-analysis of the original pivotal trial data demonstrated that use of strontium ranelate is associated with a 60% increased risk of myocardial infarction.82,83 Surpris i ngly, this finding was not noted by the manufacturer, the investigators or the regulators when these trials were first completed. A strik-ing parallel exists between this finding and the increase in myocardial infarction associated with administration of calcium,84 which suggests that the calcimimetic effects of strontium (for example, on arterial walls, platelet function or co a gulation) might underlie this finding. Strontium use is no longer widely endorsed owing to its limited efficacy, low patient compliance and substanti a l patient safety concerns.Parathyroid hormone preparationsFor much of the past century parathyroid hormone (PTH) was regarded as having a negative effect on bone, by acting primarily to increase bone resorption.64 Accordingly, sug-gestions in the 1980s that PTH might have a beneficial effect in the management of osteo p orosis85 were met with scepticism, even though the vertebral osteosclerosis (also known as rugger-jersey spine) associated with secondary hyperparathyroidism in patients with renal failure was well recognized as a manifestation of an anabolic effect on bone.64EfficacyExtensive investigations over the past two decades have shown that PTH stimulates both bone formation and bone resorption, and that the balance between these processes is determined by the dosing regimen. The sustained excess of PTH, characteristic of primary hyperparathyroidism, results in increased stimulation of bone resorption, par-ticularly in cortical bone, which leads to bone loss.86 By contrast, daily pulses of PTH seem to have an anabolic effect, particularly in axial trabecular bone. Teriparatide (PTH1–34) transiently increases the activation frequency of bone remodelling,87 but progressive increases in BMD have been demonstrated with 18–36 months of treatment.88,89 The anabolic effects of PTH are, to some extent, site-specific. In the first year of therapy, PTH has little bene-ficial effect on femoral neck BMD, even though beyond 12 months positive changes have been observed.88,90 In the radius, the conventional dose of teriparatide (20 μg/day) has no beneficial effect, and 40 μg per day accelerates bone loss.91 Despite these observations, both doses of teriparatide reduced the risk of vertebral fractures by two-thirds and nonvertebral fractures by one-third over a median treatment period of 21 months.91 It should be noted that, as only nine hip fractures occurred in this trial (four in the placebo group, two in the teriparatide 20 μg group and three in the teriparatide 40 μg group), the safety and efficacy of teriparatide with respect to hip fracture is unknown. Further assessment 18 months after the end of this study indicated sustained reductions in vertebral fracture rates following cessation of teriparatide therapy.92 A phase III trial using the full length polypeptide, PTH1–84, has also been undertaken.93 In this study, 2,679 women with osteoporosis were randomly assigned to the PTH1–84group or the placebo group; however, only 1,701 women completed the 18-month study, with the dropout rate in the PTH1–84group being greater than in the placebo group. Vertebral fractures were decreased by 40–60% in the PTH1–84group (depending on how the dropouts were dealt with in the analysis), but were of border l ine statistical significance; nonvertebral fracture rates were not affected by PTH1–84.93 Although BMD effects at the spine were com-parable to those seen with teriparatide, at other sites, the benefits seemed less than with teriparatide, which is con-sistent with the fracture data.91 Thus, there is no evidence that the full-length PTH peptide has greater efficacy than the 1–34 fragment; indeed, the opposite seems probable. PTH1–84is not current l y market e d in the USA or Europe. In 2012, a Japanese study assessed the efficacy of teripa-ratide given at a dose of 56.5 μg per week over 72 weeks.94 Vertebral fractures were reduced by 80%, but clinical nonvertebral fractures were not significantly reduced (RR 0.98, 95%CI 0.47–2.07).94 New agents in this class of therapeutic are in development, including an analogue of parathyroid hormone-related protein (also known as PTHrP),95 which is currently in phase III trials. Results from one of the phase III trials have been reported:96 ver-tebral fractures were reduced by 86% and nonvertebral fractures were reduced by 43%. This report indicates that PTHrP analogues are a potentially important addition to our therapeutic repetoire.Combination therapyGiven that PTH is an anabolic treatment with greatest efficacy in trabecular bone, it seems logical to combineREVIEWS。
如何测定肾组织中庆大霉素的药物浓度及方法步骤
A NTIMICROBIAL A GENTS AND C HEMOTHERAPY, 0066-4804/97/$04.00ϩ0June1997,p.1237–1245Vol.41,No.6Copyright©1997,American Society for MicrobiologyAttenuation of Gentamicin-Induced Nephrotoxicity inRats by FleroxacinDENIS BEAUCHAMP,1*GUY LAURENT,2LOUIS GRENIER,1PIERRETTE GOURDE,1JACQUELINE ZANEN,2JEANINE-ANNE HEUSON-STIENNON,2AND MICHEL G.BERGERON1Centre de Recherche en Infectiologie,Centre de Recherche du Centre Hospitalier de l’Universite´Laval,and De´partement de Microbiologie,Faculte´de Me´decine,Universite´Laval,Sainte-Foy,Que´bec,Canada,1and Service d’Histologie et de Cytologie Expe´rimentale,Faculte´de Me´decine,Universite´de Mons-Hainaut,Mons,Belgium2Received17September1996/Returned for modification20February1997/Accepted7April1997The effect offleroxacin on gentamicin-induced nephrotoxicity was evaluated with female Sprague-Dawleyrats.Animals were injected during4or10days with saline(NaCl;0.9%),gentamicin alone at doses of10and40mg/kg of body weight/12h(subcutaneously),fleroxacin alone at a dose of25mg/kg/12h(intraperitoneally),or the combination gentamicin-fleroxacin in the same regimen.Gentamicin induced a dose-and time-depen-dent renal toxicity as evaluated by gentamicin cortical levels,sphingomyelinase activity in the renal cortex,histopathologic and morphometric analysis,blood urea nitrogen and serum creatinine levels,and cellularregeneration([3H]thymidine incorporation into DNA of cortical cells).The extent of these changes wassignificantly reduced when gentamicin was given in combination withfleroxacin.Although the mechanisms bywhichfleroxacin reduces the nephrotoxic potential of gentamicin are unknown,we propose that thefleroxacin-gentamicin combination enhances exocytosis activity in proximal tubular cells,as suggested by the higherexcretion of urinary enzymes and lower cortical levels of gentamicin observed in animals treated with thecombinationfleroxacin-gentamicin compared with those treated with gentamicin alone.The protective effect offleroxacin on gentamicin nephrotoxicity should be investigated further.Fleroxacin is a synthetic broad-spectrum antibiotic belong-ing to the class offluoroquinolones(1).It shows a good anti-microbial activity against many gram-negative bacteria,espe-cially members of the family Enterobacteriaceae,and less activity against gram-positive bacteria(2,39).In humans,fleroxacin reaches peak serum levels within2h after its injec-tion and has a serum half-life of about10h(8,32,39).In contrast with several other quinolones,fleroxacin is not me-tabolized and is mainly excreted unchanged in the urine.How-ever,a fraction offleroxacin eliminated by the kidney is reab-sorbed at the proximal level of renal tubules(24,32,39).In fact,high concentrations offleroxacin have been measured in the kidneys of rabbits with healthy and Escherichia coli-in-fected thigh muscles(16)and in the human kidneys(15). Moreover,the accumulation offleroxacin was higher in the kidneys of patients with symptomatic complicated urinary tract infection(14).Like all other aminoglycosides,gentamicin is essentially eliminated by glomerularfiltration.Gentamicin also undergoes partial reabsorption by proximal tubular cells as a consequence of adsorptive endocytosis.Gentamicin-loaded endocytic vacu-oles fuse with lysosomes where the drug accumulates(7,19, 38).This accumulation leads to the development of a lysoso-mal phospholipidosis characterized by an impairment of phos-pholipase A1and sphingomyelinase activities and by phospho-lipid accumulation within the lysosomal compartment(25). This phospholipidosis eventually results in tubular necrosis, which in turn leads to tubular regeneration(18,26,27). Several drugs or polypeptides have been shown to alleviate or enhance the nephrotoxicity of aminoglycosides when given in combination.Recently,we have observed that the concom-itant injection of daptomycin(6,11,40),poly-L-aspartic acid (4),or ceftriaxone(5)reduces significantly the renal toxicity of aminoglycosides in experimental animals.In view of the par-ticular distribution offleroxacin within the kidney,we report here results concerning the effect of this quinolone on gentam-icin-induced nephrotoxicity.MATERIALS AND METHODSAnimals and treatment.Female Sprague-Dawley rats(nϭ6to10individuals per experimental group)weighing175to200g were used in the present study. The animals were purchased from Charles River Breeding Laboratories,Inc. (Montre´al,Que´bec,Canada).They were dosed during4or10days with saline (NaCl;0.9%),gentamicin alone at doses of10and40mg/kg of body weight/12 h(subcutaneously),fleroxacin alone at a dose of25mg/kg/12h(intraperitone-ally),or the combination gentamicin-fleroxacin in the same regimen.Urine collection.Urine analysis was performed separately for experimental animals individually housed in metabolic cages where they had free access to food and water.Urine was collected over a period of24h(under mineral oil to prevent evaporation)on day0of treatment and2,4,and8days after starting drug administration.The volume of collected urine was measured to evaluate diuresis.Urine was centrifuged(1,430ϫg)for15min,and enzymatic activities were assayed in supernatants on the day of urine collection.Sacrifice and tissue sampling.Animal groups other than those employed for urine analysis were killed15to18h after the last injection of gentamicin(days 5and11).One hour before sacrifice,all animals received an intraperitoneal injection of[3H]thymidine(200Ci).At the time of sacrifice,animals were killed by decapitation and blood was collected from the stump for the assay of serum creatinine and blood urea nitrogen(BUN).Both kidneys were rapidly removed and bisected.The renal cortex of one-half of the left kidney was separated by sharp dissection and snap frozen in dry ice for further determination of the [3H]thymidine/DNA ratio.The cortex of the other half was also dissected.One part was snap frozen for gentamicin assay.The other part was immediately immersed in drops of ice-cold electron microscopyfixative(2%glutaraldehyde, 4%sucrose,0.1M phosphate buffer,pH7.4),minced to obtain small(approxi-mately1mm3)tissue blocks,and kept overnight at4°C in the samefixative.The cortices of both halves of the right kidney were also dissected,snap frozen in dry ice,and stored atϪ20°C until biochemical analysis.Drug assay and biochemical analysis.Measurement of gentamicin accumula-tion in renal cortex was performed by afluorescence polarized immunoassay*Corresponding author.Mailing address:Laboratoire et Service d’Infectiologie,Centre de Recherche du CHUL,urier, Room RC-709,Ste-Foy,Que´bec,Canada G1V4G2.Phone:(418) 654-2705.Fax:(418)654-2715.E-mail:denis.beauchamp@crchul.ulaval.ca.1237(TDX System;Abbott Laboratories)as recently described(40).The lower limit of sensitivity of the assay was1.26g/g of tissue.The percent gentamicin recov-ery in renal cortex homogenates was78.0Ϯ2.9.The interday coefficients of variations were3.44%at1g/ml and2.72%at8g/ml of tissue homogenate. Fleroxacin levels in renal cortex were not measured since previous data from our laboratory showed that levels offleroxacin in tissue were below the detection limit of our microbiological assay12h after drug injection.Serum creatinine and BUN levels,used as markers of renal function,were measured by automated enzymatic assays on a Hitachi737analyzer.Enzymuria related to drug administration was documented by the assays of N-acetylglu-cosaminidase(NAG),-galactosidase(-Gal),and␥-glutamyl-transpeptidase (␥-GT)activities according to established procedures(28,35).The effect of gentamicin and/orfleroxacin on phospholipid metabolism in renal tissue was assessed by measuring sphingomyelinase activity according to a methodology published previously(25).The proliferative response associated with nephro-genic repair was estimated by pulse-labeling with[3H]thymidine and by measur-ing the specific radioactivity of DNA extracted from renal cortex as described previously(26).Tissue embedding and sectioning.Tissue specimensfixed in glutaraldehyde were postfixed in1%osmium tetroxide and dehydrated by passage through graded ethanol solutions.The specimens were then transferred to propylene oxide andfinally embedded in Araldite502epoxy resin(J.B.EM.Service Inc., Pointe-Claire,Que´bec,Canada).One-micrometer-thick plastic sections were cut with an Ultracut S Reichert-Jung ultramicrotome(Leica Instruments GmbH, Montre´al,Que´bec,Canada)equipped with a diamond knife,mounted on glass slides,and stained with1%toluidine blue in2%Na2B4O7.Single-blind evaluation of tissue injury.Histopathological abnormalities were scored on plastic sections atϫ400magnification.Each slide was coded so that the identification of the group was not possible for the observer(L.G.).Sections came from three different regions of renal cortex for each rat,and four rats per group were used.The following lesions in renal cortex were scored:single-cell necrosis,tubular necrosis(proximal tubule profile with more than50%necrotic cells),complete desquamation(proximal tubule profile with a denuded basement membrane),metachromatic materials in the tubular lumina,and the number of interstitial cells(no specific identification of cell type was made).The total number of proximal tubule profiles was also determined on each section.The number of tubule profiles with single-cell necrosis,extensive necrosis,complete cellular desquamation,or the presence of metachromatic material in lumen was expressed as the percentage of the total number of proximal tubule profiles on each respective section.Scores were assigned as follows:0to9%,1;10to19%, 2;20to29%,3;etc.The score for interstitial cell infiltration was obtained by dividing the total number of interstitial cells by the total number of proximal tubules on each respective slice.All these histopathological scores werefinally summed up to produce a single toxicity score for each tissue slice. Morphologic evaluation of lysosome alterations.Morphometric analysis of lysosomes relied on the fact that they exhibit a deep blue appearance after staining with toluidine blue.As described in earlier reports(33,41),the relative size of lysosomes in proximal tubular cells was estimated by computer-assisted morphometry.Briefly,the analysis was carried out in a single-blind fashion and performed in a system specifically designed for size and color assessment in light microscopy(Syste`me d’Analyses Microscopiques a`Balayage Automatique;Al-catel TINT Answare,Grenoble,France).The setting consisted of a high-reso-lution JVC video camerafitted on a Zeiss Axioplan microscope and connected to a Compaq IBM-compatible microcomputer.Cortical tissue sections(one perexperimental animal)were scanned at400-fold magnification,and at least10 profiles of proximal tubules were picked up at random for analysis.Each profile was delineated in the interactive mode,and lysosomes were detected by gray-level discrimination(green channel).Tubule section surface and the aggregated area of lysosome profiles were calculated with software developed by one of us (J.Z.).Approximately25,000m2of proximal tubule profiles was thus analyzed per experimental animal,and the data were expressed as the aggregated area of lysosomes relative to the surface of tubular epithelium.Statistics.Results are expressed as meansϮstandard deviations.Statistical analysis of the differences between groups wasfirst performed by analysis of variance.If P values wereϽ0.05,group comparisons were done by the Fisher protected least-significant-difference post hoc test.A P value less than0.05was considered significant.Calculations were made with Statview software. Materials.Gentamicin was kindly donated by Schering Canada Inc.(Pointe-Claire,Que´bec,Canada).Fleroxacin was kindly provided by Hoffmann-La Roche Inc.(Mississauga,Ontario,Canada).[methyl-3H]thymidine(47Ci/mmol)and[N-methyl-14C]sphingomyelin(58mCi/mmol)came from Amersham Canada Ltd. (Oakville,Ontario,Canada).Sphingomyelin(from bovine brain)came from Sig-ma Chemical Co.(St.Louis,Mo.).Other reagents were of analytical grade and were purchased from Fisher Scientific Ltd.(Que´bec,Que´bec,Canada)and Sigma.RESULTSAccumulation of gentamicin in renal cortex.Figure1shows the cortical accumulation of gentamicin after4and10days of treatment with the aminoglycoside given alone or in combina-tion withfleroxacin.At day4,significantly higher levels of gentamicin were measured in the renal cortex of animals treated with gentamicin alone at a dose of40mg/kg compared with animals treated with gentamicin at a dose of10mg/kg (PϽ0.01).Similar results were observed in animals treated with the gentamicin-fleroxacin combination.Fleroxacin had no effect on gentamicin cortical accumulation over4days of treat-ment.In animals exposed for10days to gentamicin alone,the extent of aminoglycoside accumulation within renal cortex was also dose related(PϽ0.01).Interestingly,fleroxacin reduced significantly the accumulation of gentamicin in the renal cortex of animals treated at40mg/kg compared with animals treated with gentamicin alone at the same dosage(PϽ0.01).At the lower dose of10mg/kg,fleroxacin also tended to reduce gen-tamicin accumulation,though the difference did not appear significant.Aminoglycoside-induced phospholipidosis.Development of a lysosomal phospholipidosis is known to be one of the early manifestations of aminoglycoside nephrotoxicity.Therefore, we examined the activity of sphingomyelinase,a key enzyme in phospholipid catabolism,in the renal cortex of rats exposed to gentamicin with or withoutfleroxacin.Data appear in Fig.2. After4days of treatment,gentamicin given with saline atdoses FIG.1.Effects offleroxacin on the accumulation of gentamicin(micrograms per gram of tissue)in the renal cortex.Animals were treated with gentamicin at doses of10and40mg/kg/12h during4and10days combined with either saline orfleroxacin at a dose of25mg/kg/12h.ء,significantly different from gentamicin at10mg/kg(PϽ0.01);ءء,significantly different from all other groups(PϽ0.01).1238BEAUCHAMP ET AL.A NTIMICROB.A GENTS C HEMOTHER.of 10and 40mg/kg induced a significant decrease of sphingo-myelinase activity compared with control animals (P Ͻ0.01).A similar reduction was observed in animals treated with the com-bination fleroxacin-gentamicin.Thus,fleroxacin had no effect on gentamicin-induced inhibition of sphingomyelinase activity after 4days of treatment.After 10days of treatment,the sphingo-myelinase activity measured in animals treated with gentamicin at a dose of 40mg/kg was significantly lower than that in animals treated with gentamicin at a dose of 10mg/kg (P Ͻ0.01).Fleroxa-cin administered alone increased by 15%the sphingomyelinase activity compared with control animals (P Ͻ0.05).The enzyme activity was significantly less inhibited in animals given the combination fleroxacin-gentamicin compared with rats treated with gentamicin alone at doses of 10and 40mg/kg (P Ͻ0.05).Phospholipid accumulation resulting from exposure to gen-tamicin was also assessed by the morphological analysis of proximal tubules and in particular by the morphometric anal-ysis of lysosomes.Figures 3and 4illustrate the aspect of renal cortex in treated animals and controls,as revealed by light micrographs of plastic sections.Following gentamicin treat-ment,lysosomes in proximal tubular cells enlarge,develop irregular shapes,and frequently exhibit a heterogeneous con-tent (Fig.3C),a well-known consequence of phospholipid overloading (33,41).Lysosomal abnormality evolves with theduration of treatment with gentamicin (Fig.4A)and persists until the emergence of tubular necrosis (Fig.4B).In contrast,exposure to fleroxacin alone does not influence the appearance of lysosomes (Fig.3A and B).Strikingly,lysosomal alteration also appears less severe in animals receiving the gentamicin-fleroxacin combination compared to those receiving gentami-cin alone (Fig.3C and D).The seemingly protective effect of fleroxacin on the lysoso-mal phospholipidosis induced by gentamicin was explored fur-ther by the morphometric analysis of these organelles accord-ing to an objective,computer-assisted procedure (Fig.5).Although the administration of fleroxacin in association with gentamicin did not diminish the enlargement of lysosomes in proximal tubules of rats receiving 10mg of gentamicin per kg,fleroxacin significantly alleviated the lysosomal alteration caused by gentamicin at 40mg/kg.Figure 6shows the mean histopathologic nephrotoxicity score for animals treated during 10days.Scores for single-cell necrosis,tubular necrosis,complete desquamation,metachro-matic material,and interstitial cells were summed up to pro-duce these mean histopathological scores.The total nephro-toxicity score was significantly higher in animals treated with gentamicin alone at a dose of 40mg/kg than in control animals (P Ͻ0.01)and animals treated with gentamicin at a dose of 10mg/kg.By contrast,the total nephrotoxicity score was significantly lower in animals given the combination fleroxacin-gentamicin than in those given gentamicin alone at 40mg/kg (P Ͻ0.05).Renal dysfunction and enzymuria.Serum creatinine and BUN levels appear in Fig.7.After 4days of treatment,no significant difference was observed between groups (data not shown).Gentamicin given for 10days at 40mg/kg induced a significant increase in serum creatinine levels and BUN com-pared with control animals and animals treated with gentami-cin at the dose of 10mg/kg.Concomitant administration of fleroxacin with gentamicin reduced significantly the elevation of serum creatinine and BUN caused by gentamicin at 40mg/kg (P Ͻ0.01)although both parameters were still signifi-cantly higher in the rats receiving both drugs in combination than in control animals (P Ͻ0.05)and animals treated with fleroxacin alone (P Ͻ0.05).Regenerative hyperplasia.Figure 8shows the effects of fleroxacin on gentamicin-induced increase of cell turnover in renal cortex.After 4days of treatment,a significantly higher incorporation of [3H]thymidine was observed only in the renal cortex of animals treated with gentamicin at a dose of 40mg/kg with or without fleroxacin compared with control animals (P Ͻ0.01).After 10days of treatment,gentamicin given alone in-duced a significant and dose-dependent increase in the incor-poration of [3H]thymidine into DNA (P Ͻ0.01).The nephro-genic repair was significantly lower in animals treated with the combination fleroxacin-gentamicin compared with animals treated with gentamicin alone at doses of 10and 40mg/kg (P Ͻ0.01).Figure 9illustrates the effect of drug administration on the urinary excretion of NAG on days 0,2,4,and 8of treatment.In animals treated with low doses of gentamicin,no significant difference was observed between groups (upper panel).By contrast,NAG activity in urine was significantly higher in an-imals treated with gentamicin at 40mg/kg on day 8compared with control animals or rats exposed to fleroxacin alone.In-creased excretion of NAG caused by gentamicin was even greater when fleroxacin was administered in combination with the aminoglycoside (P Ͻ0.01).The assay of two other en-zymes,-Gal (Fig.10)and ␥-GT (Fig.11),in urine of treated animals gave patterns similar to that observed for NAG.Thus,fleroxacin administration in combination with gentamicinatFIG.2.Effects of fleroxacin on gentamicin-induced inhibition of sphingomy-elinase activity.Animals were treated with saline (NaCl;0.9%)or gentamicin at doses of 10and 40mg/kg/12h combined with either saline or fleroxacin at a dose of 25mg/kg/12h during 4and 10days.ء,significantly different from saline-treated animals (P Ͻ0.01);ءء,significantly different from animals treated with saline and with gentamicin alone (10mg/kg/12h);§,significantly different from animals treated with saline,fleroxacin (25mg/kg/12h),and gentamicin alone (10mg/kg/12h)(P Ͻ0.05);¥,significantly different from animals treated with saline,fleroxacin (25mg/kg/12h),and gentamicin alone (40mg/kg/12h)(P Ͻ0.05).V OL .41,1997FLEROXACIN AND GENTAMICIN NEPHROTOXICITY 12391240BEAUCHAMP ET AL.A NTIMICROB.A GENTS C HEMOTHER.low or high doses tended to exacerbate the enzymuria induced by the aminoglycoside.DISCUSSIONThis study strongly suggests thatfleroxacin protects proximal tubular cells of renal cortex against gentamicin-induced neph-rotoxicity.This assumption is based on various criteria such as the alleviation of gentamicin-induced lysosomal phospholipi-dosis,the modification of renal dysfunction caused by genta-micin at a high dose,and a lesser extent of postnecrotic tubular regeneration.A possible protective effect offleroxacin is also substantiated by a lower accumulation of gentamicin and less severe histopathological lesions in the renal cortex of animals receiving the combinationfleroxacin-gentamicin compared with animals treated with gentamicin alone.However,discrep-ant results were obtained with urinary excretion of enzymes (-Gal,NAG,and␥-GT),for which a significantly higher ex-cretion was observed in animals treated with the combination fleroxacin-gentamicin compared with animals treated with fleroxacin or gentamicin alone.Quinolones have a nephrotoxic potential.Among possible untoward effects,crystalluria is probably the most important one since no nephropathologic changes occur in its absence (10).However,since it is a phenomenon related to the lower solubility of quinolones at alkaline pH,crystalluria occurs mainly in animals which have urine more alkaline than that of humans(10).Crystalluria and other nephrotoxic effects includ-ing elevation of serum creatinine,cylindruria,hematuria,and increased renal weight occur in less than2%of treated patients (10,34,37).Furthermore,quinolones have no direct effect on glomerular and tubular functions.Our results show indeed that fleroxacin alone at the dosage regimen that we used affects neither renal function nor urinary enzyme excretion.However, the presence of many small vesicles within the lysosomes of proximal tubular cells and a small increase in the activity of the renal cortex sphingomyelinase might be indicative of minor metabolic disturbance caused byfleroxacin.Also,theslightFIG.4.Severe phospholipidosis(A)and acute tubular necrosis(B)induced by a10-day exposure to gentamicin(40mg/kg/12h).Comparison of panel A with Fig. 3C clearly reveals the progression of lysosomal alteration with the duration of treatment.In panel B,prominent signs of phospholipidosis(arrowheads)can still be observed in the vicinity of a necrotic tubule(NT).Plastic sections were stained with toluidine blue.Magnification,ϫ746.FIG.3.Light microscopy appearance of renal cortex in rats treated for4days withfleroxacin(25mg/kg/12h)(B),gentamicin(40mg/kg/12h)(C),or a combination of both antibiotics(D).A control animal is included for comparison(A).Dosing protocols and preparation of morphological specimens are detailed in Materials and Methods.Lysosomes are particularly conspicuous in proximal tubules(P in panel A)and much less apparent in distal tubules(D in panel A)or collecting ducts(CD in panel B).No visible change in lysosome morphology can be seen after exposure tofleroxacin alone(compare panel B with panel A).By contrast,gentamicin administration causes a marked enlargement of lysosomes,which also become heterogeneous and irregular in shape(C).Fleroxacin administered in combination with gentamicin substantially reduces the degree of lysosomal alteration caused by the latter antibiotic(compare panel C with panel D).Plastic sections were stained with toluidine blue.Magnification,ca.ϫ724.V OL.41,1997FLEROXACIN AND GENTAMICIN NEPHROTOXICITY1241decrease of DNA synthesis in the renal cortex of animals treated with fleroxacin alone compared to sham-treated rats might be due in part to an effect of fleroxacin on the eucaryotic topoisomerase II,a gyrase-like enzyme found in mammaliancells.It has been reported elsewhere that quinolones inhibit the replication of mitochondrial DNA in mammalian cells in a dose-related manner (29).However,Barrett et al.(3)and Hussy et al.(22)have demonstrated that the affinity of fleroxa-cin for eucaryotic topoisomerase II is much lower than that for bacterial gyrase,despite the fact that fleroxacin affinity for DNA gyrase is one of the highest among quinolones and sur-passed only by that of ofloxacin (21).Nonetheless,a possible effect of fleroxacin on unscheduled DNA synthesis in renal cortex might occur and cause an apparent or actual decrease in the rate of cell proliferation associated with tubular regenera-tion.Protection against aminoglycoside-induced nephrotoxicity has been demonstrated for many antibiotics or chemical com-pounds.Actually,several antimicrobials,including ceftriaxone (5),ticarcillin (12),carbenicillin (9),latamoxef (23),and dapto-mycin (6,11,40,42),as well as compounds such as poly-L -as-partic acid (4,17),act as modifiers of aminoglycoside nephrotox-icity.This protection occurs with or without a reduction in the uptake of the aminoglycosides,suggesting different mechanisms of protection.Studies performed in our laboratory have re-vealed that daptomycin might reduce tobramycin nephrotoxicity by forming an electrostatic complex with the aminoglycoside (6,11,40),whereas ceftriaxone seems to prevent tobramycin from binding to the brush border membrane,consequentlyFIG.5.Morphometric analysis of proximal tubular cell lysosomes.Animals were treated with saline (NaCl;0.9%)or gentamicin at a dose of 10or 40mg/kg/12h combined with either saline or fleroxacin at a dose of 25mg/kg/12h during 4and 10days.ء,significantly different from all groups (P Ͻ0.01);ءء,significantly different from saline,fleroxacin,and gentamicin (10mg/kg)-fleroxa-cin (P Ͻ0.05);§,significantly different from saline and fleroxacin (P Ͻ0.01).FIG.6.Total histopathologic nephrotoxicity scores (calculations are detailed in Materials and Methods).Animals were treated during 10days with saline (NaCl;0.9%)or gentamicin at a dose of 10or 40mg/kg/12h combined with either saline or fleroxacin at a dose of 25mg/kg/12h during 10days.ء,significantly different from saline-and fleroxacin-treated rats (P Ͻ0.05);ءء,significantly different from all groups (P Ͻ0.05);¥,significantly different from all groups (P Ͻ0.05).FIG.7.Effects of fleroxacin on gentamicin-induced renal dysfunction as measured by BUN and serum creatinine.Animals were treated with saline (NaCl;0.9%)or gentamicin at doses of 10and 40mg/kg/12h combined with either saline or fleroxacin at a dose of 25mg/kg/12h during 10days.ء,signifi-cantly different from all groups (P Ͻ0.01);ءء,significantly different from all groups (P Ͻ0.05).1242BEAUCHAMP ET AL.A NTIMICROB .A GENTS C HEMOTHER .reducing its uptake by the proximal tubular cells (5).On the other hand,poly-L -aspartic acid protects against aminoglyco-side nephrotoxicity by forming complexes at acidic pH and pre-venting phospholipid overloading in lysosomes,even though it does not diminish but rather increases aminoglycoside accu-mulation (4).To our knowledge,fleroxacin is the first quinolone antibiotic reported to offer protection against aminoglycoside-induced nephrotoxicity.To some extent,this protection could result from the fact that fleroxacin reduces intracortical accumula-tion of gentamicin,consequently decreasing cell injury,tubular necrosis,and renal dysfunction induced by gentamicin.The mechanism by which fleroxacin reduces gentamicin accumula-tion remains unknown,but one can suppose that fleroxacin and gentamicin compete for similar binding sites or interact with each other in such a way that gentamicin reabsorption by proximal tubular cells is decreased or prevented.It is also conceivable that gentamicin,after its reabsorption,is actively excreted from the proximal tubular cells via a stim-ulation of exocytosis.It would explain the increase in the uri-nary excretion of -Gal,NAG,and ␥-GT observed when fleroxacin is administered in combination with gentamicin.One might even consider the possibility that interactions be-tween fleroxacin and gentamicin enhance the exocytic activityin proximal tubular cells,resulting in a higher excretion of urinary enzymes.In this respect,it is worth noting that fleroxa-cin injected alone into animals increases significantly the ac-tivity of sphingomyelinase,a lysosomal enzyme which is less inhibited when the combination fleroxacin-gentamicin is used compared with gentamicin alone.Since fleroxacin and genta-micin are both reabsorbed by proximal tubular cells,an inter-action between these drugs at the brush border membrane level may modulate membrane structure and physiological state,causing a depolarization and resulting in an increase of intracytosolic Ca 2ϩ.It is well known that this last event triggers the exocytosis process.This hypothesis might provide an ex-planation for the increased urinary excretion of -Gal,NAG,and ␥-GT observed in the present study.The nature of the interaction between fleroxacin and gentamicin remains un-known even though it can be assumed that their respective anionic and cationic natures are involved.Additional studies are warranted in order to test these assumptions,such as the measurement of gentamicin urinary excretion,the examination of gentamicin and fleroxacin interactions with brush border membranes,and the effect of treatment on intracellular Ca 2ϩ.FIG.8.Regenerative hyperplasia in renal cortex after treatment with genta-micin and/or fleroxacin.Animals were treated with saline (NaCl;0.9%)or gen-tamicin at doses of 10and 40mg/kg/12h combined with either saline or fleroxa-cin at a dose of 25mg/kg/12h during 4and 10days.ء,significantly different from animals treated with saline and fleroxacin (P Ͻ0.05);ءء,significantly different from all groups (P Ͻ0.01);ءءء,significantly different from all groups (P Ͻ0.01).FIG.9.Effects of fleroxacin on gentamicin-induced urinary excretion of NAG.Animals were treated with saline (NaCl;0.9%)or gentamicin at doses of 10(upper panel)and 40(lower panel)mg/kg/12h combined with either saline or fleroxacin at a dose of 25mg/kg/12h during 4and 10days.ء,significantly different from saline and gentamicin at 40mg/kg (P Ͻ0.05);ءء,significantly different from saline,fleroxacin,and gentamicin at 40mg/kg (P Ͻ0.01);¥,significantly different from saline,fleroxacin,and fleroxacin-gentamicin at 40mg/kg (P Ͻ0.05).V OL .41,1997FLEROXACIN AND GENTAMICIN NEPHROTOXICITY 1243。
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Z (Λ, G, M ) =
Riem(M )/Dif f (M )
D [g(M )]e−Sg [Λ,G,Σ]
(1)
where Sg [Λ, G, Σ] is the Einstein-Hilbert action associated with the Riemannian manifold (M, g), viz.,
1 2
email ambjorn@nbi.dk. Supported by a MaPhySto-grant email carfora@pv.infn.it; carfora@sissa.it 3 email gabri@sissa.it 4 marzuoli@pv.infn.it
1
1
Introduction
about which the reader can find abundant literature, and simply recall that in the Dynamical Triangulations approach to quantum gravity one attempts to give meaning to (1) by replacing the continuum Riemannian manifold (M, g) with a Piecewise-Linear manifold (still denoted by M ) endowed with a triangulation Ta → M generated by gluing a (large) number of equilateral n-simplices σ n . One approximates Riemannian structures by means of such triangulated manifolds by using a representative metric where each simplex σ n is a Euclidean equilateral simplex with sides of length a, (typically we set a = 1). This metric is locally Euclidean everywhere on the P L-manifold except near the (n − 2) sub-simplices σ n−2 , (the bones), where the sum of the dihedral angles, θ (σ n ), of the incident σ n ’s is in excess (negative curvature) or in defect (positive curvature) with respect to the 2π flatness constraint, the corresponding deficit angle r being defined by r = 2π − σn θ (σ n ). If K n−2 denotes the (n − 2)-skeleton of T → M n , then M n \K n−2 is a flat Riemannian manifold, and any point in the interior of an r - simplex σ r has a neighborhood homeomorphic to B r × C (link(σ r )), where B r denotes the ball in Rn and C (link(σ r )) is the cone over the link link(σ r ), (the product link(σ r ) × [0, 1] with link(σ r ) × {1} identified to a point). Note that for dynamical triangulations the deficit angles are generated by the string of inteNn−2 −1 providing the numbers of top-dimensional gers, the curvature assignments, {q (k)}k=0 simplices incident on the Nn−2 distinct bones, viz., r (i) = 2π − q (i) arccos(1/n). By specializing to this setting the standard Regge calculus, the formal path integration (1) is replaced on a dynamically triangulated PL manifold M , (of fixed topology), by the (grand-canonical) partition function [3],[2],[4] Z [kn−2 , kn ] = 1 −kn Nn +kn−2 Nn−2 e C T ∈T (M ) T (3)
c b
a
Abstract We estimate analytically the critical coupling separating the weak and the strong coupling crit ≃ 1.3093. By carrying out regime in 4D simplicial quantum gravity to be located at k2 a detailed geometrical analysis of the strong coupling phase we argue that the distribution of dynamical triangulations with singular vertices and singular edges, dominating in such a regime, is characterized by distinct sub-dominating peaks. The presence of such crit (N = 32000) ≃ 1.25795, peaks generates volume dependent pseudo-critical points: k2 4 crit (N = 48000) ≃ 1.26752, k crit (N = 64000) ≃ 1.27466, etc., which appear in good k2 4 4 2 agreement with available Monte Carlo data. Under a certain scaling hypothesis we analytically characterize the (canonical) average value, c1 (N4 ; k2 ) =< N0 > /N4 , and the 2 > − < N >2 )/N , associated with the vertex distribususceptibility, c2 (N4 ; k2 ) = (< N0 0 4 tion of the 4-D triangulations considered. Again, the resulting analytical expressions are found in quite a good agreement with their Monte Carlo counterparts.
Sg [Λ, G, Σ] = Λ
M
√ dn ξ g −
1 16πG
M
√ dn ξ g R
(2)
and D [g(M )] is some a priori distribution on Riem(M )/Dif f (M ) describing the strong coupling statistics (Λ → 0, G → ∞) of the set of Riemannian manifolds {(M, g)} considered. We avoid here discussing well-known specific pathologies in dealing with (1) and 2
arXiv:hBiblioteka p-lat/9806035v2 5 Nov 1998
The Niels Bohr Institute, Blegdamsvej 17, DK-2100 Copenhagen Ø, Denmark, Dipartimento di Fisica Nucleare e Teorica, Universit` a degli Studi di Pavia, via A. Bassi 6, I-27100 Pavia, Italy, and Istituto Nazionale di Fisica Nucleare, Sezione di Pavia, via A. Bassi 6, I-27100 Pavia, Italy S.I.S.S.A.-I.S.A.S., Via Beirut 2-4, 34013 Trieste, Italy
1.1
The Model
Let M be a closed n-dimensional, (n ≥ 2), manifold of given topology. Let Riem(M ) and Dif f (M ) respectively denote the space of Riemannian metrics g on M , and the group of diffeomorphisms on M . In the continuum formulation of Euclidean quantum gravity one attempts to give meaning to a formal path integration over Dif f (M ) equivalence classes of metrics in Riem(M ):