corresponding author Orthogonal Laplacianfaces for Face Recognition

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克罗恩病患者血清D-乳酸和二胺氧化酶在病情评估中的价值

.论著.克罗恩病患者血清D-乳酸和二胺氧化酶在病情评估中的价值王亚敏，陈旭峰，向正国［摘要］目的探讨D-乳酸(D-LA)和二胺氧化酶(DAO)作为克罗恩病(CD)患者疾病活动生物标志物的价值。

方法选取2017年3月~2019年2月就诊于解放军联勤保障部队九O医院的54例CD患者和同期就诊的25名健康体检者。

分别检测血清中D-LA和DAO的水平，分析D-LA和DAO等因子与克罗恩病活动性的相关性，并通过ROC曲检验其诊断价值。

结果54例CD患者，其中26例为为动期、28例为为解期。

活动期和缓解期CD患者外周血D-LA浓度分比为(16.02±4.6)mg/L和(11.18±3.14)mg/L,两组间差异有统计学意义(P<0.001)。

活动期和缓解期CD患者外周血DAO活性分比为(11.04±4.45)U/L和(7.72±3.42)U/L,两组间差异有统计学意义(P<0.001)。

CD患者外周血D-LA(r=0.68,P<0.05)和DAO(r=0.53,P<0.05)均与与罗恩病疾病活动指数(CDAI)正相关。

D-LA诊断疾病活动性的曲下面积(AUC)为0.813,DAO 诊断疾病活动性的AUC为0.747,联合D-LA、DAO、ESR、CRP的AUC为0.863。

结论外周血D-LA和DAO对CD疾病活动性具有较高的诊断价值，与目前常用的生物标志物如CRP和ESR联合应用，可显著提高对CD疾病活动性的诊断准准性。

［关键词］克罗恩病；D-乳酸；二胺氧化酶；生物标志物［中图分类号］R574［文献标识码］A DOI：10.3969/j.issn.1674-3245.2021.02.012The value of serum D-lactic acid and diamine oxidase in patients with Crohn's diseaseWang Yamin,Chen Xufeng, Xiang Zhengguo(Department of Gastroenterology,the904th Hospital of the Joint Support Force of the Chinese PLA,Wuxi214000,China)Corresponding author:Xiang Zhengguo,E-mail：***************[Abstract]Objective To explore the value of D-lactic acid(D-LA)and diamine oxidase(DAO)as biomarkers of disease activity in patients with Crohn's disease(CD).Methods From March2017to February2019,54cases of CD patients and25healthy persons in our hospital were selected.The levels of D-LA and Dao in plasma were detected,and the correlation between D-LA and Dao and the activity of Crohn's disease was analyzed,The diagnostic value was tested by ROC curve.Results Among54patients with CD,26were active and28were remission.The ratio of D-LA concentration in active and remission CD patients was(16.02±4.6)mg/L and(11.18±3.14)mg/L,with significant difference between the two groups(P<0.001).The ratio of Dao activity in active and remission CD patients was(11.04±4.45)U/L and(7.72±3.42)U/L, with significant difference between the two groups(P< 0.001).D-LA(r=0.68,P<0.05)and DAO(r=0.53,P<0.05)were positively correlated with CDAI in CD patients.The AUC of D-LA,DAO,ESR and CRP was0.813,0.747,0.863,respectively.Conclusion Peripheral blood D-LA and DAO have high diagnostic value for CD disease bined with the commonly used biomarkers such as CRP and ESR,it can significantly improve the diagnostic accuracy of CD disease activity.[Key words]Crohn's disease；D-lactic acid；Diamine oxidase；Biomarkers克罗恩患(Crohn's disease,CD)是一种病因暂不明确的慢性炎症性肠病，目前尚缺乏有效的治愈方法［1］o内镜检查和组织病理学检查是目前CD断和病情严重程度和治疗疗效评估的主要方法，存在成本高、侵入性强、耗时长等缺陷，并且可能有相关并发症发生风险叫目前研究表明，C反应蛋白(CRP)和血沉(ESR)与CD患者复发风险及治疗反应相关，但CRP和ESR存在敏感性和特异性相对较低的缺点，尤其在CD合并急性感染或结缔组织病作者单位：214000无锡，解放军联勤保障部队第九O医院消化内科通信作者：向正国，E-mail:***************等疾病时［3-4］o因此探索一套敏感性和特异性更好的新型生物标志物具有重要的临床价值。

Equistable series-parallel graphs

Equistable series-parallel graphsEphraim Korach a,Uri N.Peled b,∗a Department of Industrial Engineering and Management,Ben-Gurion Universityof the Negev,P.O.Box653,Beer-Sheva84105,Israelb Mathematics,Statistics,and Computer Science Department(M/C249),The University of Illinois at Chicago,851S.Morgan Street,Chicago,IL60607-7045,USAAbstractA graph is called equistable when there is a non-negative weight function on its vertices such that a set S of vertices has total weight1if and only if S is maximal stable.We characterize those series-parallel graphs that are equistable,generalizing results of Mahadev,Peled and Sun about equistable outer-planar graphs.Key words:Equistable graphs,series-parallel graphs1991MSC:05C69,05C751IntroductionThe equistable graphs were introduced by Payan[5]and further studied by Mahadev,Peled and Sun[3].They are also discussed in[2].They appear as a generalization of threshold graphs.A graph is called threshold if there is a non-negative weight function on its vertices such that each stable(independent) set of vertices has total weight at most1,and each non-stable set of vertices has a total weight exceeding1.It follows from the results of Orlin[4]that the weight function can then be chosen as strictly positive and such that all (inclusion-wise)maximal stable sets have a total weight of exactly1(and so the non-maximal stable sets have a total weight smaller than1,and the non-stable set have a total weight larger than1).The book[2]discusses threshold graphs extensively.In this paper all graphs and multigraphs are undirected and loopless;multigraphs may contain parallel edges and graphs may not.∗Corresponding author.Email addresses:korach@bgumail.bgu.ac.il(Ephraim Korach),uripeled@(Uri N.Peled).Deﬁnition 1A graph G =(V,E )is equistable if there is a non-negative weight function w on V such that a set S ⊆V satisﬁes w (S )≡ v ∈S w (v )=1if and only if S is maximal stable.Thus if S is a non-maximal stable set then w (S )<1,and if S is a non-stable set then w (S )>1or w (S )<1.The problem of recognizing equistable graphs in polynomial time is still open.As pointed out by Igor Zverovich [7],there is an exponential-time algorithm to recognize an equistable graph as ing linear programming,check whether the polytope deﬁned by w ≥0and w (S )=1for all maximal stable sets S is empty,and whether it is contained in any of the hyperplanes w (T )=1for the non-empty sets T that are not maximal stable.The graph in question is equistable if and only if the answers to all these questions are negative (for the “if”part,use volume considerations,as in [3]or [2]).As for polynomial-time recognition,we do not even know that recognizing an equistable graph is in NP.Nevertheless,many results are known about equistable graphs.Deﬁnition 2([3])A graph G =(V,E )is strongly equistable if for each set ∅=T ⊆V such that T is not maximal stable,and for each constant c ≤1,there is a non-negative weight function w on V such that w (S )=1for each maximal stable set S ,and w (T )=c .Theorem 3([3])The strongly equistable graphs are equistable.Conjecture 4([3])The equistable graphs are strongly equistable.Mahadev,Peled and Sun veriﬁed Conjecture 4for a class of graphs containing all perfect graphs.In addition they showed that the strongly equistable graphs are closed under disjoint unions and joins,and therefore the cographs (the graphs without induced P 4,the path on 4vertices)are strongly equistable.They also gave a necessary condition for equistability and a suﬃcient condition for strong equistability as follows.Theorem 5([3])Each equistable graph satisﬁes the following condition.For each induced P 4on the vertices a,b,c,d ,each maximal stable set containing the end-vertices a and d has a common neighbor of the middle vertices b and c .(1)We say that an induced P 4on the vertices a,b,c,d is a bad P 4if some maximal stable set contains the end-vertices a and d ,but does not contain a common neighbor of the middle vertices b and c .Theorem6([3])Let G be a graph satisfying the following condition.G has a maximal stable set S such that two vertices outside S are(2)adjacent if and only if they have a common neighbor in S.Then G is strongly equistable.We shall have occasion to use a condition equivalent to(2).Recall that a vertex is called simplicial if its neighbors form a clique.A simplicial clique is a clique induced by a simplicial vertex and all its neighbors.Theorem7([3])A graph G satisﬁes(2)if an only if it satisﬁes the follow-ing.Each edge of G belongs to a simplicial clique;or equivalently every(3)two adjacent non-simplicial vertices have a common simplicialneighbor in G.We remark that Condition(2)is not necessary for strong equistability,as can be seen from the cycle C4,which does not satisfy(2),yet is strongly equistable by being a cograph.A cut-vertex of a multigraph is a vertex whose deletion increases the number of connected components.A connected multigraph without cut-vertices is2-connected.A2-connected component of a multigraph is a maximal2-connected sub-multigraph.The same deﬁnitions apply to graphs.Using Theorems5and6,Mahadev,Peled and Sun were able to characterize equistability and strong equistability and to verify Conjecture4for various families of graphs,including outer-planar graphs(graphs that can be embed-ded in the plane with all vertices on the boundary of the inﬁnite region).To describe their result on the latter family,we deﬁne aﬂower as a graph con-sisting of an even cycle x1,x2,...,x2k,k≥2,together with the chords x1x3, x3x5,...,x2k−1x1joining consecutive odd-numbered vertices along the cycle. Note that theﬂowers satisfy Condition(3).Theorem8([3])Let G be an outer-planar graph.Then the following condi-tions are equivalent.(1)G is equistable;(2)G is strongly equistable;(3)each2-connected component C of G is a square C4,or a clique(neces-sarily of cardinality at most3),or aﬂower;if C is a square,then its vertices are not cut-vertices of G;if C is a clique,then some vertex of C is not a cut-vertex of G;if C is aﬂower,then the vertices of degree2inC are not cut-vertices of G.Peled and Rotics[6]veriﬁed Conjecture4for chordal graphs(independently of their perfection),and showed that a chordal graph is equistable if and only if it satisﬁes Condition(3).Deﬁnition9A(loopless)multigraph G is a series-parallel multigraph if each 2-connected component of G is an isolated vertex or a single edge or can be generated from two parallel edges by the operations of subdividing an edge (replacing it by two edges in series)and doubling an edge(replacing it by two edges in parallel).A series-parallel graph is a simple series-parallel multigraph, namely one without loops and multiple edges.The following characterization of series-parallel graphs is well-known,see[1].Theorem10(Duﬃn)A graph is series-parallel if and only if it does not contain a subdivision of K4,namely a subgraph obtained by repeatedly subdi-viding edges of K4.Since K4is not outer-planar,the outer-planar graphs are series-parallel.In this paper we extend Theorem8from outer-planar graphs to all series-parallel graphs.This is done in three stages:Theorem12for2-connected series-parallel graphs,Theorem14for connected series-parallel graphs,and Theorem15 for general series-parallel graphs.These results verify Conjecture4for series-parallel graphs,and give a linear-time recognition algorithm of equistability for series-parallel graphs.2ResultsWe begin by a useful lemma.Lemma11Let G be a series-parallel graph satisfying(1),and let a,b,c,d be an induced P4in G.Then the middle vertices b,c have a common neighbor t such that each neighbor of t is a neighbor of at least one of the end-vertices a,d.PROOF.Let t1,t2,...be all the common neighbors of b,c.Assume that each t i has a neighbor s i such that s i is a neighbor of neither a nor d,if possible. The vertices s i are distinct and not adjacent to each other,because if s i and s j coincide or are adjacent for some i=j,then G has a subdivision of K4on b,c,t i,t j(using the path t i,s i,s j,t j),contradicting Theorem10.Therefore the set consisting of a,d and all the s i is stable,and can be extended to a maximal stable set S.This S cannot contain any of the t i,and this contradicts(1).2A multisquare is the join of an edgeless graph on two vertices with an edgeless graph on two or more vertices,as shown in Figure1.Fig.1.MultisquareTheorem12Let G be a2-connected series-parallel graph.Then the following conditions are equivalent.(1)G is equistable;(2)G is strongly equistable;(3)either G is a multisquare,or else the simplicial cliques of G cover theedges of G.Remark13In a2-connected graph G,if a vertex of degree2is not simpli-cial,then its two neighbors cannot be simplicial,and consequently the sim-plicial cliques do not cover the edges.Therefore,unless G is a multisquare, Condition3of Theorem12implies that the vertices of degree at most2are simplicial in G.Conversely,in a series-parallel graph,the simplicial vertices always have degree at most2by Theorem10.PROOF OF THEOREM12.Condition2always implies Condition1by Theorem3.To see that Condition3implies Condition2,we noteﬁrst that multisquares are cographs and therefore strongly equistable.If G is not a multisquare,then by Condition3its simplicial cliques cover its edges,and hence it is strongly equistable by Theorems6and7.It remains to show that Condition1implies Condition3.In fact,the proof will show that(1)implies Condition3,which is enough by Theorem5.If G has a vertex of degree0or1,then G is K1or K2by2-connectivity, and Condition3follows.Therefore we may assume that all vertices of G have degrees of2or more.In our diagrams below,we indicate a vertex of G of degree2by a gray-ﬁlled circle,as shown In Figure2.Fig.2.Convention:degree-2vertexConsider any vertex x of degree2,with neighbors y and z.Assume that yz/∈E.Then y and z have the same neighbors,for otherwise we have a bad P4. We assert that every neighbor of y and z has degree2.Indeed,suppose y and z had a neighbor v of degree3or more,so that v has a neighbor w=x,y,z,v. Then either w is a neighbor of y and z,in which case we have a subdivision of K4on y,v,w,z(using the path y,x,z)contradicting Theorem10,or else w is a non-neighbor of y and z.In the latter case x,y,v,w induce a P4,and this P4is bad,because any common neighbor t of y and v would also be a neighbor of z,and we would have a subdivision of K4on y,t,v,z(using the path y,x,z).Figure3illustrates these arguments.xxtFig.3.Degree-2non-simplicial vertexThis proves the assertion,which implies that G is a multisquare,and condi-tion3holds.So from now on we may assume that each vertex of degree2and its two neighbors induce a K3.If one of the neighbors has degree2,then G is a K3by 2-connectivity,and Condition3holds.Therefore we assume that each vertex of degree2is simplicial,and its two neighbors have degrees of3or more. Consider any edge yz such that there is at least one vertex x of degree2 whose neighbors are y and z.For each such simplicial vertex x,we perform a series reduction(replacing x and the edges xy and xz with a new edge parallel to yz).Then we perform a parallel reduction of all these new edges parallel to yz(removing them).Finally we color the edge yz green(thick gray in our diagrams)to indicate that originally there were vertices x as above.All edges that were not colored green by this process are colored red(thin solid in our diagrams).Clearly these operations produce a graph G0that is still 2-connected,and by Deﬁnition9series-parallel as well.The construction is illustrated in Figure4.Since G is a2-connected series-parallel graph,and all its degrees are2or more, it has a vertex of degree2by Deﬁnition9.Therefore G0has at least one green edge.Our goal is to show that all the edges of G0are green,which will show that the simplicial cliques of the vertices of degree2in G cover the edges of G,so that Condition3is satisﬁed.Therefore we assume that G0has some red edges,and obtain a contradiction.in G becomes y zin G 0Fig.4.Convention:green edge in G 0Case 1:G 0has a red edge adjacent to a green edge at each end.The two green edges may or may not share an endpoint,as shown in Figure5.orFig.5.Case 1in G 0The corresponding situation in G is shown in Figure 6.b eora =fb eFig.6.Case 1in GThe vertices b,c,d,e induce a P 4.By Lemma 11some vertex t =a,b,c,d,e,f is adjacent to c,d and has all its other neighbors among a and f .Since the edge cd is red in G 0,the degree of t is 3or more,so t is adjacent to a or to f ,say to a without loss of generality.Figure 7illustrates the situation so far.b et ora =f bet Fig.7.Arguing in Case 1We see that in the case of a =f ,there is a K 4on the vertices c,d,t,a ,so this case is impossible.In the case of a =f ,we must have ad /∈E ,for otherwise there is a K 4on the vertices a,c,d,t .Therefore the vertices b,a,t,d induce a P 4.It follows that there must be a vertex that is adjacent to its middle vertices a,t ,but not to its end-vertices b,d .However,there is no such vertex,since all the neighbors of t are among a,c,d,f .This shows that Case 1leads to a contradiction,as illustrated in Figure 8.b et Fig.8.Conclusion of Case 1Case 2:G 0has no red edge adjacent to a green edge at each end.Since G 0has green and red edges,it has a green edge adjacent to a red edge by connectivity.At the other end of the red edge there is another red edge,by the 2-connectivity of G 0and Case 2.This is illustrated in Figure 9.a c d e ora cdFig.9.Case 2in G 0We deal ﬁrst with the second picture,that of a red-red-green triangle in G 0.The corresponding situation in Gis illustrated in Figure 10.da cbFig.10.Red-red-green triangle in G 0If d were of degree 2in G ,it would not appear in G 0at all,so d has a neighbor e =a,b,c .Vertex e can be adjacent to at most one of a and c ,for otherwise G would have a K 4.Consider the case that e is adjacent to c ,but not to a (switching a and c leads to a symmetric case),as illustrated in Figure 11.The vertices b,a,d,e induce a P 4.By Lemma 11there is a common neighbor t of a,d such that each neighbor of t is a neighbor of b or e .It follows that t =a,b,c,d,e .The vertex t cannot be adjacent to c ,otherwise a,c,d,t induce a K 4.But the degree of t is 3or more,since the edge ad is red in G 0.Therefore t must have a neighbor s =a,b,c,d adjacent to e .Now the vertices a,c,d,e create a subdivision of K 4(using the path a,t,s,e ),as illustrated in Figure 12.a cbeFig.11.First subcase of Case 2a cbe tsFig.12.Conclusion of ﬁrst subcase of Case 2This settles the case that e is adjacent to one of a and c .Now consider the case that e is not adjacent to any of them,illustrated in Figure13.a cbeFig.13.Second subcase of Case 2As before,we have a vertex t =a,b,c,d,e adjacent to a and d but not to c ,and a vertex s =a,b,c,d adjacent to t and e .By symmetry we also have a vertex q =a,b,c,d,e adjacent to c and d but not to a ,and a vertex p =a,b,c,d adjacent to q and e .Now the vertices a,c,d,t create a subdivision of K 4(using the not-necessarily-simple path t,s,e,p,q,c ,which does not go through a or d ).Figure 14illustrates the situation.This settles the case that G 0has a red-red-green triangle.The remaining case is that G 0has no triangle with both colors,and no green-red-green path.Under these conditions,consider again a green edge ac adjacent to a red edge cd in G 0.Since c is not a cut vertex,there is a path P from d to a that does not go through c .The ﬁrst edge de of P is red,and therefore e =a .The path Pa c be tsq p Fig.14.Conclusion of second subcase of Case 2and the path a,c,d constitute a closed path C .We choose the vertices a,c,d and the path P with the above properties in such a way that C is as short as possible.In particular,C is a simple cycle.Figure 15illustrates the situation in G 0.a c d ePFig.15.The remaining case in G 0The situation in G looks similar,and there is a vertex b of degree 2adjacent to a and c .The edge ad does not exist,because it would close a red-red-green or green-green-red triangle in G 0.The edge ce does not exist,because if it is green,it would close a red-red-green triangle in G 0,and if it is red,it would constitute a shortcut enabling a choice of a shorter cycle than C .The vertices b,c,d,e induce a P 4in G .By Lemma 11there is a vertex t adjacent to c and d such that each neighbor of t is adjacent to b or e .Therefore t =a,b,c,d,e .Since edge cd is red in G 0,the degree of t in G is 3or more.Therefore t remains a vertex in G 0and the triangle cdt is red.It follows that t does not lie on the path P ,for otherwise ct would constitute a shortcut in C .The edge ta does not exist in G ,otherwise the vertices a,c,d,t would create a subdivision of K 4(using the path P ).Since the degree of t is 3or more,it has a neighbor s =a,b,c,d ,which must be a neighbor of e (since it cannot be a neighbor of b ).If s lies on P ,then the vertices c,d,s,t create a subdivision of K 4(using the paths d,e,s and the subpath of P from s to a followed by ac ).If s does not lie on P ,then the vertices c,d,e,t create a subdivision of K 4(using the paths e,s,t and the subpath of P from e to a followed by ac ).This concludes the proof,as illustrated in Figure 16.2bNow we relax the2-connectivity assumption of Theorem12to simple connec-tivity.Theorem14Let G be a connected series-parallel graph.Then the following conditions are equivalent.(1)G is equistable;(2)G is strongly equistable;(3)either G is a multisquare,or else each2-connected component C of Gsatisﬁes the following:(a)the simplicial cliques of C cover the edges of C;(b)if C is a clique(necessarily of cardinality at most3),then some vertexof C is not a cut-vertex of G,and otherwise the vertices of degree2in C are not cut-vertices of G.PROOF.Once again,Condition2always implies Condition1by Theorem3. We show that Condition3implies Condition2as follows.If G is a multisquare, then it is a cograph and therefore strongly equistable.Otherwise consider a 2-connected component C of G.If C is a clique,then by Condition3.(b) some vertex of C is not a cut-vertex of G.This vertex remains simplicial in G and its simplicial clique is still the entire C,so the edges of C are covered by the simplicial cliques of G.Now assume C is not a clique.The simplicial vertices of C(considered as a graph by itself)are precisely the vertices of degree2in C by Remark13.Their simplicial cliques cover the edges of C by Condition3.(a).These vertices are not cut-vertices in G by Condition3.(b), and therefore remain simplicial in G.Hence again the edges of C are covered by the simplicial cliques of G.Thus in all cases,the simplicial cliques of G cover all the edges of G,and G is strongly equistable by Theorems6and7. It remains to show that Condition1implies Condition3.We know that Con-dition1implies(1)by Theorem5.It is easy to see that since(1)holds forG,it also holds for each2-connected component of G,considered as a graph by itself.In the proof of Theorem12we showed that as a consequence,each 2-connected component of G is a multisquare or else it has the property that its simplicial cliques cover its edges.It is easy to see that if a2-connected com-ponent C is a multisquare and any vertex of C is a cut-vertex of G,then there is a bad P4in G.Therefore if a2-connected component of G is a multisquare, it is the entire graph G by connectivity,and Condition3holds.Now assume no connected component of G is a multisquare.Then in each 2-connected component C,the simplicial cliques of C cover the edges of C, and Condition3(a)holds.We continue to show Condition3(b).Suppose C is a K2with vertices a and b.If a,b have neighbors a′,b′respectively in other(necessarily distinct)2-connected components,then a′,a,b,b′is a bad P4,because there is no common neighbor of a,b.Therefore one of a and b is not a cut-vertex,as stated by Condition3(b).Suppose C is a K3with vertices a,b,c.If a,b,c have neighbors a′,b′,c′respectively in other(necessarily distinct)2-connected components, then the P4a′,a,b,b′is bad,because the stable set a′,b′,c′can be extended to a maximal stable set,which cannot contain the only common neighbor of a,b,namely c.Therefore one of a,b,c is not a cut-vertex,as stated by Condition3(b).Finally suppose C is not a clique.We have to show that the simplicial vertices of C are not cut-vertices of G.We assume that a simplicial vertex a of C (necessarily of degree2in C)is a cut-vertex in G and derive a contradiction. Let b,c be the two neighbors of a in C,and let x be a neighbor of a not in C, as shown in Figure17,where a gray circle indicates a vertex having degree2 in C.xb cFig.17.C is not a clique in Condition3(b),yet a is a cut-vertexWe consider the same reduction of C as in the proof of Theorem12,trans-forming C into a graph C0with green edges only.We distinguish two cases depending on the number of edges of C0.If C0has only one edge(namely bc),then every vertex of C other than b and c is a neighbor of b and c.Since C is not a clique,it has another vertex d of degree2adjacent to b and c,and we see that x,a,b,d is a bad P4in G,as illustrated in Figure18.xb cdFig.18.C0has only one edgeIf C0has more than the edge bc,then by2-connectivity it has edges of the form bd and ce.The situation in C is then as shown in Figure19,where vertices d and e might coincide.xd b c eFig.19.C0has more than one edgeWe have a P4x,a,c,g,and the only vertex of G adjacent to its middle ver-tices is b.However,the stable set{x,g,f}containing its end-vertices can be extended to a maximal stable set,and the latter cannot contain b,so our P4 is bad.2We can now do away with the connectivity assumption in Theorem14. Theorem15Let G be a series-parallel graph.Then the following conditions are equivalent.(1)G is equistable;(2)G is strongly equistable;(3)each connected component of G satisﬁes Condition3of Theorem14. PROOF.Condition2always implies Condition1by Theorem3.Condition1implies(1)by Theorem5.It is easy to see that since(1)holds for G,it also holds for each connected component of G when considered as a graph by itself.Since in proving Theorem14we used its Condition1only to establish(1),the fact that(1)holds for each connected component implies Condition3.Condition3implies that each connected component of G is strongly equistable by Theorem14.Since the strongly equistable graphs are closed under disjoint union,this implies Condition2.2References[1]R.J.Duﬃn,Topology of series-parallel networks,Journal of MathematicalAnalysis and Applications10(1965),303–318.[2]N.V.R.Mahadev and U.N.Peled,Threshold graphs and related topics,Annalsof Discrete Mathematics,vol.56,Elsevier,Amsterdam,1995.[3]N.V.R.Mahadev,U.N.Peled,and F.Sun,Equistable graphs,Journal of GraphTheory18(1994),281–299.[4]J.Orlin,The minimal integral separator of a threshold graph,Studies in IntegerProgramming(P.L.Hammer,E.L.Johnson,B.H.Korte,and G.L.Nemhauser, eds.),North-Holland,New York,1977,Annals of Discrete Mathematics1, pp.415–419.[5]C.Payan,A class of threshold and domishold graphs:Equistable andequidominating graphs,Discrete Mathematics29(1980),47–52.[6]Uri Peled and Udi Rotics,Equistable chordal graphs,Discrete AppliedMathematics This volume.[7]Igor Zverovich,Private communication,2001.。

Minimal blocking sets in PG(n,2) and covering groups by subgroups

1. Introduction and results Let G be a group. A set C of proper subgroups of G is called a cover for G if its set-theoretic union is equal to G. If the size of C is n, we call C an n-cover for the group G. A cover C for a group G is called irredundant if no proper subset of C is a cover for G. A cover C for a group G is called core-free if the intersection D = M ∈C M of C is core-free in G, i.e. DG = g∈G g −1 Dg is the trivial subgroup of G. A cover C for a group G is called maximal if all the members of C are maximal subgroups of G. A cover C for a group G is called a Cn -cover whenever C is an irredundant maximal core-free n-cover for G and in this case we say that G is a Cn -group. Let n be a positive integer. Denote by P G(n, q ) the n-dimensional projective space over the ﬁnite ﬁeld Fq of order q . A blocking set in P G(n, q ) is a set of points that has nonempty intersection with every hyperplane of P G(n, q ). A blocking set that contains a line is called trivial. A blocking set is called minimal if none of its proper subsets are blocking sets. For a blocking set B in P G(n, q ) we denote by d(B ) the least positive integer d such that B is contained in a d-dimensional subspace of P G(n, q ). Thus d(B ) is equal to the (projective) dimension of the subspace spanned by B in P G(n, q ). For further studies in the topic of blocking sets see Chapter 13 of the second edition of Hirschfeld’s book [10] and also see [14]. The problem of covering a ﬁnite group with subgroups of a speciﬁed order has been studied in [11] where also bounds on the size of such covers was found. From Proposition 2.5 of [11] which is proved by a deep theorem due to Blokhuis [2], the following result easily follows. We will require this as an auxiliary tool later. Theorem 1.1. (See Proposition 2.5 of [11]) Let p be a prime and let G be a ﬁnite p-group with a maximal +1) irredundant n-cover. Then either n ≥ 3(p2 or n = p + 1. In section 2 we give relations between non-trivial minimal blocking sets of size n and Cn -groups. Also we give a complete characterization of minimal blocking sets in P G(n, 2).

Corresponding Author

Original PaperA Service-Oriented Architecture for Information Support to Virtual Hospital StructuresMikaela Poulymenopoulou, PhD; George Vassilacopoulos, PhDDepartment of Informatics, University of Piraeus, Piraeus, GreeceCorresponding Author:Mikaela Poulymenopoulou, PhDDepartment of InformaticsUniversity of Piraeus80, Karaoli Dimitriou Str.Piraeus 185 34Phone: +30 210 414 21 24Fax: +30 210 414 27 53GreeceEmail: mpouly@unipi.grAbstractBackground: Shared andintegrated care requires increased cooperation and integrated information exchange among disparate and dispersed healthcare organizations that may span the boundaries of health districts and even the boundaries of countries. Objectives: The objective of our study is to support the integrated information needs of healthcare organizations that are inter-connected in order to create virtual hospital structures.Methods: A service-oriented system architecture is proposed with the use of Business Process Execution Language for Web Services (BPEL4WS), web services technology and the XML-based Clinical Document Architecture (CDA) in order to integrate patient information, to provide access to and to enable exchange of this integrated information among the healthcare organizations of a virtual hospital structure.Results: A prototype implementation of the proposed architecture is under development for two healthcare organizations and is expected to be experimentally tested in a Greek virtual hospital structure.Conclusions: After testing and evaluating system implementation it is intended to further extend system architecture in order to support the retrieval of anonymous patient records regarding patients certain medical problems.KEYWORDSSOA; BPEL; BPEL4WS; Web services; CDA; XML; virtual hospitalIntroductionWith the advent of shared and integrated care, the healthcare organizations need to inter-connect and to merge into networks of healthcare delivery focusing on the services patients need, thus comprising virtual hospital structures. In a virtual hospital structure, the ability to readily access and exchange integrated patient information among the participating healthcare organizations is essential in improving the quality of the healthcare provided, supporting the continuity of healthcare while reducing practice variability and patient care costs [1-3]. Thus, there is a need to provide the appropriate technological infrastructure to integrate patient information existing at organizations’ heterogeneous information systems and resources that, in general, use heterogeneous formats and different semantics for structuring patient information. This need can be addressed by taking a service-oriented approach using web services technology and the Business Process Execution Language for Web Services (BPEL4WS) specification [4,5]. In addition, XML-based Clinical Document Architecture (CDA) specification can be used to specify a standard structure and semantics of patient information in the form of clinical documents [6-8].On these grounds, this paper suggests a service-oriented system architecture that aims at supporting the integrated patient information needs of the healthcare organizations participating in a virtual hospital. A prototype system implementation is presented that involves a virtual hospital structure that consists of two healthcare organizations.MethodsPatient information integration using BPEL4WS Patient information integration in a virtual hospital requires the selection of appropriate healthcare standards for structurally and semantically homogenizing patient information. This needcan be addressed by using standard healthcare terminology systems like LOINC, ICD and SNOMED for coding patient information and healthcare information standards like CDA for structuring patient information in the form of XML clinical documents [1,3,6,7].In addition, there is a need to select an appropriate technological infrastructure for making integrated patient information available at the point of care when authorized workgroups need [1,8,9].This need can be addressed by using web services technology and BPEL4WS. Web services constitute a powerful computing technology that enables the creation of interoperable interfaces to existing information systems and resources in order to export their functionality and their underlying data to the Internet or an Intranet. BPEL4WS provides a model and a grammar for specifying web services compositions in the form of business processes. In this way, BPEL4WS with the use of web servicesenables the creation of complicated workflows that may use dispersed and heterogeneous applications and access heterogeneous information resources through web services interfaces. Thus, the creation of web services and BPEL processes at each healthcare organization of a virtual hospital structure, for providing access to patient information existing at organization’s information resources in a standard format and structure provides a suitable technological solution [2,4,5,9].Service-oriented architectureThe proposed system architecture for a virtual hospital structure,retains at each healthcare organization the existing information systems and infrastructures while also suggests the creation of web services and BPEL processes in order to export locally stored patient data to other organizations of the virtual hospital.A schematic view of the system architecture is shown in Figure 1.Figure .A service-oriented architecture for a virtual hospital structureAt each of the virtual hospital organization, there exists a web server that receives SOAP messages sent over HTTP and the organization’s existing information system. In addition, at the general hospital (GH) there exists a BPEL server where the organizations’ BPEL processes are executed, an application server that hosts: a BPEL client through which BPEL processes are executed, the organizations’ web services and the CDA-based XML schemas defined for each clinical document type, a Master Patient Index (MPI) and a global authorization server that controls BPEL processes and web services executions.At each organization, a BPEL process has been defined that is called Retrieve_Send_PatData and is executed in case of apatient referral/transfer to another organization to perform a specialized medical procedure or for continuation of care. This process execution results to the creation of a patient clinical document that will be available at the receiving organization when required. During this process execution four web services are invoked that concern retrieving relevant authorized (according to the recipient user role) patient data from the organization’s information system, coding this data using ICD-10 and SNOMED terminology systems, using the coded data for creating a CDA-based XML document and sending this document as a SOAP encoded message to an appropriate destination (web server of the receiving healthcare organization).Figure 2 illustrates the Retrieve_Send_PatData BPEL process model.Figure . Retrieve_Send_PatData BPEL process model designed using Oracle BPEL process managerAt the GH a BPEL process has been defined that is called Access_PatIntegratedData and is executed by any authorized user of the virtual hospital in order to retrieve integrated patient information. For example, this process is executed when aphysician requires integrated patient information in support to medical actions performed on a patient. During this process execution three web services are invoked that concern consulting the MPI for specifying the organizations where patient data exist, invoking the specified organizations’Retrieve_Send_PatData processes for creating patient CDA documents and sending these documents to the requestor as SOAP encoded messages. Due to space constraints figure of the Access_PatIntegratedData BPEL process model is omitted. As concerns security, accesses to healthcare organizations’locally stored data during BPEL processes executions are controlled by the security services provided by the organizations’ existing information systems. In addition, role-based authorization rules have been incorporated to the organizations’ existing security services in order to control accesses to the received SOAP encoded messages, after the execution of BPEL processes. Moreover, a role-based authorization model has been designed in order to control BPEL processes invocations and web services invocations during BPEL processes executions. This model enforces the virtual hospital security policy, which is incorporated to the global authorization server of the GH and has been implemented in XML Access Control Markup Language (XACML) [7,10]. ResultsTo illustrate the main features of the system functionality described above, the implementation of the aforementioned BPEL processes is described for a virtual hospital structure that consists of two healthcare organizations, a health centre (HC) and a GH. Oracle BPEL process manager was used for the design of BPEL processes and Oracle BPEL Server was used for the execution of these processes [11]. Web services have been implemented as Java beans using the Java 2 Platform, Enterprise Edition (J2EE) and the Oracle JDeveloper BPEL Designer [11]. In addition, Oracle 10g Application Server was use and Oracle BPEL console as a client for executing BPEL processes [12].At this stage of system implementation, two CDA-based XML schemas have been defined for two document types: consultation notes and transfer referral notes [3,6,8]. CDA-based XML documents of these two document types are created during BPEL processes executions.According to system implementation, in case of a patient transfer/referral from HC to GH, the patient’s doctor at the HC logins to Oracle BPEL Console (BPEL client) in order to execute HC’s Retrieve_Send_PatData BPEL process. The user (doctor) request for BPEL process execution is evaluated by the XACML role-based security policy and if access is granted, the user fills a list of BPEL process parameters in order to create and execute a BPEL process instance. These parameters involve the type of CDA document to be created (e.g. transfer referral note), the patient identification data (e.g. patient code), the destination to which this document will be sent (GH URL) and the user role which will access this document (e.g. radiologist) at the recipient site. During BPEL process execution HC’s web services are called and executed in order to create and send this CDA document. After BPEL process instance execution, the patient’s doctor checks if this process has been properly executed. Similarly is executed the Access_PatIntegratedData BPEL process when access to integrated patient information is required.DiscussionRecent trends in healthcare delivery (e.g. shared and integrated care) require the inter-connections of healthcare organizations into virtual hospital structures. Access to and exchange of integrated patient information to such virtual hospital structures is considered important for providing high quality healthcare services to patients. This can be achieved by using a service-oriented approach that utilizes web services and BPEL4WS for interoperating with heterogeneous information systems and resources. Within this framework, this paper presents a prototype system architecture that uses BPEL processes and web services to provide interoperability among disparate and heterogeneous systems and the XML-based CDA for structuring patient information in the form of XML clinical documents. The prototype system implementation is indented to be experimentally tested and evaluated into a Greek virtual hospital structure. In addition, it is indented to extend system architecture by creating other BPEL processes that concern creating other types of patients’ documents and also retrieving anonymous patient records regarding a certain medical problem for knowledge acquisition, comparison of performance and research purposes.Conflicts of InterestNone DeclaredReferences1.Muller ML, Uckert F, Burkle T, Prokosch HU. Cross-institutional data exchange using the clinical document architecture(CDA). Int J Med Inform 2005;74(2-4):245-56.2.Saranummi N. PICNIC Architecture. Stud Health Technol Inform 2005;115:37-60.3.Heitmann KU, Schweiger R, Dudeck J. Discharge and referral data exchange using global standards-the SCIPHOX projectin Germany.Int. J Med Inform 2003;70(2-3):195-203.4.Andrews T, Curbera F, Dholakia H, et al. Business process execution language for web services version 1.1 (BPEL4WS).IBM, BEA Systems, Microsoft, SAP AG, Siebel Systems, 2003. URL/developerworks/library/specification/ws-bpel/ [accessed 2006 Jun 12].Poulymenopoulou & Vassilacopoulos 5.Hansen M, Madnick S, Siegel M. Data integration using web services. Proc of the VLDB Workshop Efficiency andEffectiveness of XML Tools and Techniques and Data Integration over the Web (EEXTT andDIWeb), Hong Kong, Ed.Bressan S. Springer-Verlag 2003:165-182.6.Ferranti JM, Musser RC, Kawamoto K, Hammond WE. The clinical document architecture and the continuity of carerecord: a critical analysis.J Am Med Inform Assoc 2006;13(3):245-52.7.Poulymenopoulou M, Vassilacopoulos G. An electronic patient record implementation using clinical document architecture,Proc of International Council on Medical and Care Compunetics (ICMCC), Hague, Netherlands 2004;103:50-57.8.Yu-Chuan L, Hsu-Sung K, Wen-Shan J, et al. Building a generic architecture for medical information exchange amonghealthcare providers. Int J Med Inform 2001;61(2–3):241– 246.9.Mykkanen J, Riekkinen A, Laitinen P, Karhunen H, Sormunen M. Designing web services in health information systems:from process to application level. Stud Health Technol Inform 2005;116:515-520.10.Godik S, Moses T. Extensible access control markup language (XACML) Version 1.1 specification. OASIS 2003. URL:/committees/xacml/repository/cs-xacml-specification-1.1.pdf [accessed 2006 Jun 12].11.Oracle BPEL process manager. URL /technology/products/ias/bpel/index.html [accessed 2006 Jun12].12.Oracle Database 10g. URL /technology/documentation/index.html [accessed 2006 Jun 12].。

Infliximab as a bridge to remission maintained by antimetabolite therapy in Crohn's disease

Digestive and Liver Disease 46(2014)695–700Contents lists available at ScienceDirectDigestive and LiverDiseasej o u r n a l h o m e p a g e :w w w.e l s e v i e r.c o m /l o c a t e /d ldAlimentaryTractInﬂiximab as a bridge to remission maintained by antimetabolite therapy in Crohn’s disease:A retrospective studyArmelle Chauvin a ,Aurelie Le Thuaut b ,c ,d ,Mehdi Belhassan a ,Yann Le Baleur a ,Farida Mesli a ,Sylvie Bastuji-Garin b ,c ,d ,Jean Charles Delchier a ,Aurelien Amiot a ,b ,∗aAssistance Publique-Hôpitaux de Paris (APHP),Paris Est Creteil University (UPEC),Henri Mondor Hospital,Department of Gastroenterology,Creteil,France bParis Est Creteil University (UPEC),Laboratory of Clinical Investigation (LIC,EA 4393),Creteil,France cAssistance Publique-Hôpitaux de Paris (APHP),Henri Mondor Hospital,Department of Public Health,Creteil,France dAssistance Publique-Hôpitaux de Paris (APHP),Henri Mondor Hospital,Clinical Research Unit (URC Mondor),Creteil,Francea r t i c l ei n f oArticle history:Received 23January 2014Accepted 27April 2014Available online 2June 2014Keywords:Crohn’s disease IBDInﬂammatory bowel disease Inﬂiximab withdrawala b s t r a c tBackground:Inﬂiximab withdrawal in patients with Crohn’s disease on concomitant antimetabolite ther-apy is considered to be superior if obtained after a maintenance therapy period compared to induction alone.Methods:We retrospectively analyzed the outcome of Crohn’s disease patients treated with inﬂiximab and an antimetabolite after inﬂiximab was withdrawn using induction alone or induction plus at least 1-year of maintenance therapy.The time to relapse was analyzed using univariate and multivariate analyses.The model was adjusted according to the period of inﬂiximab withdrawal.Results:A total of 92patients were included,54in the induction alone group.The patient characteristics were identical in the two groups except for the period of inﬂiximab withdrawal.After a median follow-up period of 47.1(interquartile range =4.4–110.2)months,66patients (72%)experienced a relapse.After a year-adjustment,no signiﬁcant difference was observed between the two groups.Based on year-adjusted multivariate analysis,the risk factors for relapse were active smoking,previous antimetabolite failure,and perianal disease.After relapse,53patients (80%)were retreated with inﬂiximab.After inﬂiximab retreatment,clinical remission was observed in 47patients (89%)at weeks 8–10.Conclusion:In Crohn’s disease patients,the probability of relapse on antimetabolite therapy after inﬂix-imab withdrawal was not superior after a 1-year scheduled maintenance therapy as compared with an induction alone.©2014Editrice Gastroenterologica Italiana S.r.l.Published by Elsevier Ltd.All rights reserved.1.IntroductionThe advent of anti-tumour necrosis factor (TNF)agents has established new goals for the management of Crohn’s disease (CD).In addition to controlling disease activity,anti-TNF therapy reduces the need for hospitalization and surgery while also improving patient quality of life [1–5].However,the economic burden of long-term anti-TNF therapy and the desire of patients to discontinue medication support a strategy of drug withdrawal.If and when a patient should cease inﬂiximab treatment for CD remains a debated issue.A study from the Groupe d’Etude Thérapeutique des Affec-tions Inﬂammatoires du tube Digestif (GETAID)has evaluated the outcome of patients treated with azathioprine and induction ther-∗Corresponding author at:51,Avenue du Marechal de Lattre de Tassigny,Creteil F-94010,France.Tel.:+33149814358/149812362;fax:+33149812352.E-mail address:aurelien.amiot@hmn.aphp.fr (A.Amiot).apy with inﬂiximab [6].In this study,113CD steroid-dependent patients were randomized to receive either inﬂiximab at week 0,2and 6,or placebo.The rate of steroid-free remission was signiﬁ-cantly higher in the inﬂiximab group than in the placebo group at weeks 12,24and 52(75%,57%and 38%,respectively)but decreased over time.Patients who had reached steroid-free remission at the end of the study were further evaluated for up to 4years,and the data demonstrated that inﬂiximab was no longer superior to placebo [7].Recently,Louis et al.prospectively evaluated the outcome of CD patients using combined therapy after inﬂiximab was discontin-ued in patients with prolonged remission longer than 6months [8].After one year,the rate of relapse was 43.9%(±5.0).An anal-ysis of the clinical and biological markers deﬁned a group with a low risk of relapse.The authors concluded that Crohn’s disease patients in stable remission treated with combined therapy con-sisting of inﬂiximab and an antimetabolite could safely withdraw from inﬂiximab.Re-treatment with inﬂiximab was effective and/10.1016/j.dld.2014.04.0121590-8658/©2014Editrice Gastroenterologica Italiana S.r.l.Published by Elsevier Ltd.All rights reserved.696 A.Chauvin et al./Digestive and Liver Disease46(2014)695–700well tolerated in patients who experienced a relapse.In the absence of any controlled study,further data are warranted.The aim of this study was to compare the outcome of CD patients in stable remission treated with combined therapy consisting of inﬂiximab and then an antimetabolite after inﬂiximab was discon-tinued,after induction therapy alone or induction plus at least one year of scheduled maintenance therapy.2.Methods2.1.PatientsWe retrospectively reviewed consecutive case records of all adult CD patients referred to Henri Mondor university hospital in Paris,France from January2000to June2012.Patients were recruited from our personal database and/or a standardized hos-pital inpatient dataset.The patients eligible for this study were at least17years of age and had received combined inﬂiximab and antimetabolite treatment for active CD.All patients had discontin-ued inﬂiximab treatment but maintained antimetabolite therapy. The decision of withdrawing inﬂiximab was made according to a consensus between the physician in charge and the patient without any restriction from the public health care system.Eight patients from this series have already been included in a prospective mul-ticenter study from the GETAID[8].The exclusion criteria for this study included the following:a history of severe acute or delayed infusion reaction to inﬂiximab,initial indication for inﬂiximab being predominantly manifested extra-intestinally without signif-icant CD activity,persistence of active luminal and/orﬁstulizing disease,an ostomy,pregnancy or lactation.The study inclusion dates were from January2009to June2012.The protocol was approved by the appropriate ethics committee.2.2.Treatments2.2.1.InﬂiximabAll patients were naïve to inﬂiximab at entry.The patients received either an infusion of inﬂiximab administered at a dose of5mg/kg at weeks0,2,and6(induction group)or an infusion of inﬂiximab administered at a dose of5mg/kg at weeks0,2and 6,followed by scheduled infusions at a dose of5mg/kg every8 weeks for at least one year(maintenance group).All patients were treated with intravenous hydrocortisone premedication(200mg) before each inﬂiximab infusion.2.2.2.Antimetabolite therapyAll patients were treated with azathioprine≥2mg/kg/d, mercaptopurine≥1.5mg/kg/d or methotrexate25mg weekly sub-cutaneously or intramuscularly.The patients had stable doses of antimetabolite therapy for at least3months.Regarding antimetabolite status at baseline,two types of patients were eli-gible:those who had still active disease despite receiving the underlying antimetabolite for more than6months for thiopurine and3months for methotrextate(previous antimetabolite failure group)and those who did not receive the underlying antimetabo-lite in the past history or who have withdrawn it despite clinically proven efﬁcacy.2.2.3.Treatment cessationAll patients had to be in stable remission as assessed by a Harvey-Bradshaw score<4at the time of inﬂiximab withdrawal. The patients were followed-up with from the time of the last inﬂiximab infusion.The clinical and demographic data collected included patient age at diagnosis,gender,smoking habits,CD phenotype according to Montreal classiﬁcation,and a history of medical and surgical treatment for CD[9].The biological data col-lected included CRP(mg/L),haemoglobin(g/dL),leucocyte counts (/mm3)and platelets(/mm3).In a subgroup of the patients,an ileo-colonoscopy was performed in the6months preceding inﬂiximab withdrawal.Mucosal healing was deﬁned as the absence of ulcers[10].The Harvey-Bradshaw index was calculated in cases of relapse.A relapse was deﬁned by a Harvey Bradshaw index above4points or the need to introduce any speciﬁc treatment for CD[11].2.3.Follow-up after relapse and re-treatmentIn cases of relapse,the patients were re-treated by their pri-mary physician.Re-treatment with inﬂiximab was conducted with either re-induction followed by scheduled infusion every8weeks or scheduled infusion every8weeks without an induction phase. All patients experiencing a relapse were assessed for response and tolerance to treatment8–10weeks after theﬁrst inﬂiximab re-treatment and until the end of follow-up.In addition,for patients who experienced a relapse and were not re-treated,information regarding treatment and surgery was also collected.2.4.End pointsThe primary end point was time to relapse after inﬂiximab with-drawal and the identiﬁcation of risk factors associated with the relapse.A relapse was deﬁned by a Harvey Bradshaw index above 4points or the need to introduce any speciﬁc treatment of CD[11]. The secondary end points were safety and efﬁcacy of re-treatment with inﬂiximab in patients who experienced a relapse.2.5.Statistical analysisThe patient characteristics are described as number(%)for qual-itative data and as median(interquartile range,IQR)or mean(±1 standard deviation,SD)for quantitative data according to their dis-tribution.We compared the baseline characteristics of the patients in both groups(induction and maintenance groups)using the Pear-son chi-squared test or Fisher’s exact test for qualitative variables and the Wilcoxon non-parametric test for quantitative variables.The time to relapse after inﬂiximab withdrawal was assessed using the Kaplan–Meier method,and the groups were compared using a log-rank analysis.A hazard ratio(HR)with95%conﬁdence interval(CI)was estimated using a Cox proportional hazard model adjusted for the year of inﬂiximab withdrawal.Other factors poten-tially associated with relapse were also analyzed.The proportional hazards assumption was graphically assessed for all variables.Vari-ables showing p<0.15in a univariate analysis were considered to be potential adjustment variables for multivariate analysis.Multi-ple2×2analyses were performed to assessﬁrst-order interactions and confounding variables.This approach was also used to select the adjustment variables included in theﬁnal analysis.All comparisons were two-tailed,and p-values less than0.05 were considered signiﬁcant.Analyses were performed using STATA statistical software SE11(Stata Inc.,College Station,TX,USA).3.Results3.1.Patient characteristicsNinety-two patients(57females;median age at inclusion32.6 [IQR=23.9–44.4]years)fulﬁlled the inclusion criteria.Table1 shows the patient demographic and CD characteristics.All patients were treated with stables doses of antimetabolite therapy for a median duration of11.0months(range,93.6–25.0).Fifty-four patients were included in the induction group,and38patients were in the maintenance group.The median follow-up periodA.Chauvin et al./Digestive and Liver Disease46(2014)695–700697 Table1Baseline patients’characteristics.N=92patients,presented as number(%)or median(interquartile range).Pearson chi-square test or Fisher’s exact test and Wilcoxon non parametric test were used whenever appropriate.Overall population(n=92)Maintenance group(n=38)Induction group(n=54)pFemale,n(%)57(62%)27(71%)30(56%)0.13 Age at diagnosis(years)23(19–33)22(19–29)24(19–34)0.41 Age at inﬂiximab start(years)32(24–43)30(24–42)33(23–44)0.65 Follow-up(years)47.1(4.4–110.2)38.4(4.4–66.9)55.0(10.2–110.2)<0.001Active smoker38(41%)17(45%)21(39%)0.57 History of intestinal resection,n(%)13(14%)7(18%)6(11%)0.37 Perianal lesions,n(%)33(36%)11(29%)22(41%)0.25 Disease locationIleal20(22%)8(21%)12(22%)Colonic28(30%)13(34%)15(28%)Ileocolonic44(48%)17(45%)27(50%)0.75Disease phenotypeNon stricturing,nonﬁstulising58(63%)25(66%)33(61%)Stricturing and/orﬁstulising34(37%)13(34%)21(39%)0.65 Concomitant immunomodulatorThiopurine87(95%)36(95%)51(94%)0.99 Methotrexate5(5%)2(5%)3(6%)0.99 History of antimetabolite failure37(40%)19(50%)18(33%)0.11 Laboratory testsHaemoglobin level(g/L)13.3(12.2–14.1)13.4(12.2–14.4)13.0(12.1–13.9)0.28 Leukocytes count(109/L)5630(4200–7700)5900(4200–7700)5500(4300–8100)0.99 hsCRP level(mg/L)3(2–7)3(2–6)4(2–8.5)0.35 Mucosal healing18/30(60%)17/25(68%)1/5(20%)0.13 Date of inﬂiximab withdrawalBefore200654(59%)6(16%)48(89%)<0.001 After200638(41%)32(84%)6(11%)<0.001 hsCRP,high sensitivity C-reactive protein.was47.1months(range,4.4–110.2)for the overall population, 55.0months(range,10.2–110.2)for the induction group and38.4 months(range,4.4–66.9)for the maintenance group.The2treat-ment groups were comparable for all clinical characteristics,except for the period of inﬂiximab withdrawal(Table1).In the induc-tion group,48patients(89%)withdrew inﬂiximab before2006,and the remaining6patients withdrew after2006.In the maintenance group,6patients(16%)withdrew inﬂiximab before2006,and the remaining32withdrew after2006.Mucosal healing was assessed in30patients overall(33%);25in the maintenance group(66%) and5in the induction group(9%).Twenty-three of30patients had complete mucosal healing deﬁned as the absence of ulcers.3.2.Clinical relapseAt the end of the follow-up period,66patients(72%)experi-enced a relapse,including40in the induction group(74%)and26 in the maintenance group(68%,p=0.55).The overall median time to relapse was26.7months(range,7.8–75.4).There was a trend towards a longer median time to relapse in the induction group that did not reach signiﬁcance(32.7months,range14.1–78.2vs.15.9 months,range6.0–46.0).The1-and2-year treatment free remis-sion rates were70%and52%in the overall population(Fig.1).The1-and2-year treatment free remission rates were78%and60%in the induction group,and56%and36%in the maintenance group(Fig.2). The difference between the induction and the maintenance groups was not signiﬁcant even after adjustment for the year of inﬂiximab withdrawal(HR=0.73IC95%[0.41–1.30],p=0.29).3.3.Risk factors associated with clinical relapseBy univariate analysis,clinical relapse was associated with a his-tory of antimetabolite failure(p=0.001),gender(p=0.002),active smoking(p=0.04),familial history of IBD(p=0.07),haemoglobin level>13g/dl(p=0.12),prior use of inﬂiximab(p=0.14)and peri-anal disease(p=0.15)(Table2).A patient stratiﬁcation based on gender was made due to signiﬁcant differences between male and female patients.Based on year-adjusted multivariate analysis, the risk factors for relapse were active smoking(HR=1.91IC95% [1.11–3.27],p=0.02),previous antimetabolite failure(HR=1.78IC 95%[1.07–2.97],p=0.03),and perianal disease(HR=1.72IC95% [1.02–2.89],p=0.04).There was a trend towards higher relapse rates in male patients in the maintenance group(HR=2.73IC95% [0.98–7.62],p=0.06).Fig.1.Kaplan–Meier relapse-free survival curves.698A.Chauvin et al./Digestive and Liver Disease 46(2014)695–700Table 2Predictors measured at inclusion associated with time to relapse.Risk factorsUnivariate analysisMultivariate analysisYear-adjustedHR (95%CI)Log-rank p -ValueYear-adjustedHR (95%CI)p -Value Induction group Male 1––Female3.42(1.70–6.86)––Maintenance group Male 2.67(0.98–7.25) 2.73(0.98–7.62)0.06Female2.84(1.28–6.28)0.010.96(0.50–1.84)0.91Age at diagnosis ≤20years 1>20years0.91(0.56–1.51)0.73––Age at inﬂiximab start ≤30years 1>30years0.89(0.55–1.46)0.66––Disease duration <4years 1≥4years0.95(0.58–1.54)0.82––Active smoking No 1Yes2.10(1.27–3.48)0.0041.91(1.11–3.27)0.02History of intestinal resection No 1Yes1.03(0.61–1.75)0.91––Perianal disease No 1Yes1.44(0.87–2.39)0.151.72(1.02–2.89)0.04Disease location Ileal 1Colonic 1.55(0.75–3.19)Ileocolonic1.68(0.85–3.29)0.31––3.4.Outcome of re-treatment in relapsesFifty-three (80%)patients were re-treated with inﬂiximab.There were 40patients in the induction group (74%)and 26patients in the maintenance group (68%,p =0.55).Re-treatment with inﬂiximab was conducted with a re-induction in 43patients (81%)and with a single infusion in 10patients (19%).Inﬂiximab was continued using scheduled maintenance therapy every 8weeks.After inﬂiximab re-treatment,all patients were assessed at week 8–10.A steroid-free remission was observed in 47patients (89%)at week 8–10.No differences were found between the induction and the maintenance groups (72%vs .86%,p =0.32).After a mediandelayFig.2.Kaplan–Meier relapse-free survival curves according to the modality of inﬂix-imab withdrawal.of 1.2years (range,0.3–2.4),38patients (72%)were still in steroid-free remission with inﬂiximab therapy.The inﬂiximab failure-free survival was higher in patients who were retreated more than 12months after inﬂiximab withdrawal (p =0.001)but did not differ between induction and maintenance groups (p =0.26).There were 13relapse patients who were not re-treated with inﬂiximab.Their rescue therapy included adalimumab (n =5),sur-gical resection (n =3),and steroids followed by a switch to another antimetabolite (n =4)and cyclosporin (n =1).3.5.SafetySeven infusion-related reactions were identiﬁed.All reactions were occurred during a re-induction phase using three inﬂiximab infusions.Six infusion-related reactions were noticed in the induc-tion group,and there was one reaction in the maintenance group (19%vs.5%,p =0.22).Four infusion-related reactions occurred dur-ing the re-induction phase,and 3reactions occurred during the ﬁrst 6months after inﬂiximab re-treatment.4.DiscussionOur study reports the clinical outcomes in 92patients with CD in stable steroid-free remission on combined therapy after inﬂiximab was discontinued but antimetabolite treatment was maintained.To our knowledge,this is the largest collection of CD patients eval-uated at a single centre comparing inﬂiximab withdrawal after induction therapy alone and after at least 1-year scheduled main-tenance therapy.In our cohort,the 1-and 2-year treatment-free remission rates were 70%and 52%.There was no beneﬁt of the maintenance group compared to the induction group.A.Chauvin et al./Digestive and Liver Disease46(2014)695–700699It is not clear how inﬂiximab therapy should be managed in patients who have achieved clinical remission.Indeed,anti-TNF agents have revolutionized the management of CD[12].In addition to controlling disease activity,these agents offer the possibility to reverse the pathological process that leads to bowel destruction and can improve quality of life for CD patients[3,4,13].However, clear risks of adverse events have been reported,including oppor-tunistic infection,paradoxical reaction and neoplasia[14–17].The economic burden of the long-term use of anti-TNF agents is also a major issue.Furthermore,the longer a patient is in remission,the more they may want to discontinue a medication and the less likely they are to adhere to therapy maintenance[18].Therefore,the pos-sibility of a drug“holiday”should be considered in patients with a low risk of recurrence after drug discontinuation.Beyond these considerations,it is mandatory to ensure that clinical remission will be maintained over the long term after inﬂix-imab is discontinued.Lemann et al.have reported that the1-year relapse rate on thiopurine therapy after an inﬂiximab induction alone was62%.Recently,the same group showed that the1-year relapse rate was43%in patients who had stable remission after maintenance inﬂiximab therapy for at least12months.Schnitzler et al.reported the experience of the Leuven University hospital.In this study,110patients had withdrawn from inﬂiximab therapy after a median time of6.2months,and84%of patients were in remission while continuing on antimetabolite therapy.The remis-sions persisted for a median of47.3(20.8–66.4)months.In our study,72%of the patents experienced a clinical relapse after a median follow-up of5.5years.Clinical relapse occurred in most cases in theﬁrst2years after inﬂiximab withdrawal.Furthermore, there was no beneﬁt of1-year maintenance therapy compared to induction alone in terms of clinical remission after inﬂiximab with-drawal.Establishing potential risk factors for relapse is crucial to deter-mine which patients should maintain inﬂiximab therapy.Lemann et al.reported that clinical relapse was associated with a high CDAI at baseline,a young age,small-bowel involvement and a short duration of steroids before entry[6].In the STORI trial,risk fac-tors of clinical relapse were male gender,the absence of surgical resection,leucocyte counts>6000/mm3,haemoglobin<14.5g/dL, C-reactive protein>5.0mg/L,and faecal calprotectin>300␮g/g[8]. In our series,we found active smoking,previous antimetabolite failure and perianal disease were risk factors for clinical relapse.The formation of anti-inﬂiximab antibodies has been previously correlated with loss of response and/or increased risk of infusion-related reactions[19].Recently,Ben Horin et al.demonstrated that titres decline to undetectable levels within12months after inﬂix-imab is withdrawn in the majority of patients[20].Laharie et al. previously reported that postponed retreatment with inﬂiximab in CD primary responders should be administered at least12months after inﬂiximab withdrawal for better efﬁcacy and tolerance[21]. In our series,retreatment with inﬂiximab was also associated with safety and efﬁcacy in patients who have been retreated more than 12months after inﬂiximab withdrawal.Another important issue is the modality of inﬂiximab re-induction after treatment cessation.It is still unclear whether inﬂiximab should be restarted resuming the previous scheduled treatment at the same dose and frequency as before withdrawal or if restarting with a three-dose induction regimen is superior.In the STORI trial,patients in relapse following inﬂiximab withdrawal were re-treated with inﬂiximab with a single infusion.Thirty days after re-treatment with inﬂiximab,93%of patients were in remis-sion.None of the patients experienced an infusion-related reaction, despite a“drug holiday”.Similarﬁndings have been reported in a Danish single centre study[22].In our study,77patients were re-treated with inﬂiximab.There were47patients(80%)treated using a three-dose regimen and12patients(20%)treated with a single dose regimen.At week10,86%of patients were in clinical remission.Seven infusion-related reactions were noted, and all were associated with a three-dose regimen.Six of the7 patients were in the induction group.Our data suggest that re-induction using a single-dose regimen is preferred for inﬂiximab re-treatment.There are several limitations to our study.First,there was not a systematic assessment of the mucosal healing before inﬂiximab therapy cessation(30of92patients).This is related to the ret-rospective nature of our study and the rarity of mucosal healing assessment in the induction group.Second,the median disease duration before inﬂiximab withdrawal was4.1years(1–12.6).It is conceivable that these data are not applicable for all the subpop-ulations of CD patients.In the STORI trial,the median duration of CD before inﬂiximab therapy was7.8years(range,4.5–11.9).In the Lemann study,the median was5years(range,4–10)in the thiop-urine failure group and3years(range,1–6)in the naive group. Inﬂiximab therapy has dramatically evolved over time by avoid-ing episodic treatment and optimizing therapy based on mucosal healing and trough levels[12].In the present study,the12-year inclusion period and small sample size may have led to bias in the selection of the patients(Supplementary Table S1).However,it was necessary to ascertain a difference between the two strategies of inﬂiximab withdrawal.In conclusion,for CD patients in stable remission using com-bined therapy consisting of inﬂiximab and an antimetabolite, inﬂiximab withdrawal is feasible with a52%risk of relapse after2years.There was no beneﬁt of a previous scheduled therapy compared to induction alone.We identiﬁed new param-eters associated with clinical relapse such as previous failure of antimetabolite therapy,active smoking and perianal lesions.Those factors should be taken into account before considering inﬂiximab withdrawal.Conﬂict of interestAA has received payment for lectures from Biocodex and MSD and travel accommodation from Abbvie,MSD and Biocodex.None of the remaining authors have any potential conﬂicts to disclose about the present study.Appendix A.Supplementary dataSupplementary data associated with this article can be found,in the online version,at /10.1016/j.dld.2014.04.012. References[1]Sandborn WJ,Hanauer SB,Rutgeerts P,et al.Adalimumab for mainte-nance treatment of Crohn’s disease:results of the CLASSIC II trial.Gut 2007;56:1232–9.[2]Colombel JF,Sandborn WJ,Reinisch W,et al.Inﬂiximab,azathioprine,orcombination therapy for Crohn’s disease.New England Journal of Medicine 2010;362:1383–95.[3]Feagan BG,Panaccione R,Sandborn WJ,et al.Effects of adalimumab therapy onincidence of hospitalization and surgery in Crohn’s disease:results from the CHARM study.Gastroenterology2008;135:1493–9.[4]Lichtenstein GR,Yan S,Bala M,et al.Inﬂiximab maintenance treatment reduceshospitalizations,surgeries,and procedures inﬁstulizing Crohn’s disease.Gas-troenterology2005;128:862–9.[5]Peyrin-Biroulet L,Deltenre P,de Suray N,et al.Efﬁcacy and safetyof tumor necrosis factor antagonists in Crohn’s disease:meta-analysis of placebo-controlled trials.Clinical Gastroenterology and Hepatology 2008;6:644–53.[6]Lemann M,Mary JY,Duclos B,et al.Inﬂiximab plus azathioprine forsteroid-dependent Crohn’s disease patients:a randomized placebo-controlled trial.Gastroenterology2006;130:1054–61.[7]Costes L,Colombel JF,Mary JY,et al.Long term follow-up of a cohort ofsteroid-dependent Crohn’s disease patients included in a randomized trial eval-uating short term inﬂiximab combined with azathioprine.Gastroenterology 2008;134:A134.700 A.Chauvin et al./Digestive and Liver Disease46(2014)695–700[8]Louis E,Mary JY,Vernier-Massouille G,et al.Maintenance of remission amongpatients with Crohn’s disease on antimetabolite therapy after inﬂiximab ther-apy is stopped.Gastroenterology2012;142,63–70.e5;quiz e31.[9]Satsangi J,Silverberg MS,Vermeire S,et al.The Montreal classiﬁcation ofinﬂammatory bowel disease:controversies,consensus,and implications.Gut 2006;55:749–53.[10]Neurath MF,Travis SP.Mucosal healing in inﬂammatory bowel diseases:asystematic review.Gut2012;61:1619–35.[11]Harvey RF,Bradshaw JM.A simple index of Crohn’s-disease ncet1980;1:514.[12]D’Haens G,Panaccione R,Higgins PD,et al.The London Position of the WorldCongress of Gastroenterology on Biological Therapy for IBD with the Euro-pean Crohn’s Colitis Organization:when to start,when to stop,which drug to choose,and how to predict response?American Journal of Gastroenterology 2011;106:199–212.[13]Pineton de Chambrun G,Peyrin-Biroulet C,Lemann M,et al.Clinical impli-cations of mucosal healing for the management of IBD.Nature Reviews Gastroenterology and Hepatology2010;7:15–29.[14]Beaugerie L.Immunosuppression-related lymphomas and cancers in IBD:howcan they be prevented.Digestive Diseases2012;30:415–9.[15]Ford AC,Peyrin-Biroulet C.Opportunistic infections with anti-tumor necro-sis factor-alpha therapy in inﬂammatory bowel disease:meta-analysis of randomized control trials.American Journal of Gastroenterology2013, /10.1038/ajg.138.[16]Cleynen I,Vermeire S.Paradoxical inﬂammation induced by anti-TNF agentsin patients with IBD.Nature Reviews Gastroenterology and Hepatology 2012;9:496–503.[17]Siegel C,Marden SM,Persing SM,et al.Risk of lymphoma associated with com-bination anti-tumor necorsis factor and immunomodulator therapy for the treatment of Crohn’s disease:a meta-analysis.Clinical Gastroenterology and Hepatology2009;7:874–81.[18]Lopez A,Billioud V,Peyrin-Biroulet C,et al.Adherence to anti-TNF therapyin inﬂammatory bowel diseases:a systematic review.Inﬂammatory Bowel Diseases2013;19:1528–33.[19]Baert F,Noman M,Vermeire S,et al.Inﬂuence of immunogenicity on thelong-term efﬁcacy of inﬂiximab in Crohn’s disease.New England Journal of Medicine2003;348:601–8.[20]Ben-Horin S,Mazor Y,Yanai H,et al.The decline of anti-drug antibody titresafter discontinuation of anti-TNFs:implications for predicting re-induction outcome in IBD.Alimentary Pharmacology and Therapeutics2012;35: 714–22.[21]Laharie D,Chanteloup E,Chabrun E,et al.The tolerance and efﬁcacy of a post-poned retreatment with inﬂiximab in Crohn’s disease primary responders.Alimentary Pharmacology and Therapeutics2009;29:1240–8.[22]Steenholdt C,Molazahi A,Ainsworth MA,et al.Outcome after discontinuationof inﬂiximab in patients with inﬂammatory bowel disease in clinical remission: an observational Danish single center study.Scandinavian Journal of Gastroen-terology2012;47:518–27.。

改良“轴保持短缩法”单人操作结肠镜在结肠术后患者检查中的临床应用

·临床研究·doi ：10．3969／j．issn．1006-5725.2011.02.016基金项目：解放军总医院苗圃基金项目（编号：09MP05）作者单位：100853北京市，解放军总医院南楼消化内镜诊疗科通信作者：王志强E-mail ：yxmnc1956＠163．com结肠镜是检查大肠疾病可靠、有效的检查方法［1］，自从日本消化内镜专家工藤进英提出“轴保持短缩法”及“Jiggling 手技法”［2］以来，结肠镜单人操作技术日趋完美。

因其操作安全、简便、患者痛苦小、成功率高、患者反应良好、又节省人力，单人操作结肠镜已经逐渐成为国际上结肠镜插入法的主流技术。

结肠术后患者由于肠管部分切除、吻合手术造成结肠正常生理走形改变，肠管之间、肠管与腹壁之间可能存在粘连，给结肠镜的插入带来不便［3］。

我们改良了工藤进英教授提出的单人操作结肠镜“轴保持短缩法”，对结肠术后患者进行检查，与传统单人操作结肠镜方法进行对比，探讨该方法对结肠术后患者检查的临床作用。

1资料与方法1．1一般资料2009年4－12月来我院消化内镜中心进行随访的结肠术后患者512例，其中男317改良“轴保持短缩法”单人操作结肠镜在结肠术后患者检查中的临床应用李明阳王志强令狐恩强卢忠生黄启阳摘要目的：探讨改良“轴保持短缩法”单人操作结肠镜在结肠术后患者检查中的临床应用。

方法：对2009年4－12月来我院消化内镜中心进行随访的512例结肠术后患者，分别应用改良“轴保持短缩法”单人操作法以及常规单人操作结肠镜进行检查，对两种方法的成功率、进镜时间、疼痛评分等指标进行比较。

结果：常规单人操作结肠镜和改良“轴保持短缩法”单人操作结肠镜到达回盲部（或结肠－小肠吻合口）的成功率分别为93．8％和99．1％。

常规单人操作结肠镜检查和改良“轴保持短缩法”单人操作结肠镜的平均进镜时间分别为7．6min 和3．5min （P ＜0．05）。

常规单人操作结肠镜和改良“轴保持短缩法”单人操作结肠镜检查后，采用数字评定量表（NRS ）评定疼痛程度的平均分数分别为6．7分和3．8分（P ＜0．05）。

荷包缝合包埋阑尾残端在腹腔镜阑尾切除术中的应用效果分析

j.issn.1674-5515.2019.09.008.[12] 谢强旺.曲美他嗪联合地尔硫卓治疗105例稳定型心绞痛的疗效观察[J].中国医学创新, 2012, 9(28): 126. DOI: 10.3969/ j.issn.1674-4985.2012.28.081.[13] 汪海燕, 王喆, 李慧芳, 等.益心舒片联合伊伐布雷定治疗慢性稳定型心绞痛的临床研究[J].现代药物与临床, 2019, 34(3): 648-651. DOI:10.7501/j.issn.1674-5515.2019.03.015.[14] 刘龙斌, 郭航远, 邢杨波, 等.益心舒胶囊治疗冠心病心绞痛的临床疗效观察[J].中西医结合心脑血管病杂志, 2013, 11(2): 150-152. DOI:10.3969/j.issn.1672-1349.2013.02.012.[15] 王宁, 邢书成, 任明芬.益心舒片联合地尔硫卓治疗稳定型劳力性心绞痛疗效观察[J].现代药物与临床, 2019, 34(3): 652-656. DOI:10.7501/j.issn.1674-5515.2019.03.016.（收稿日期：2020-03-23）（责任校对：成观星）荷包缝合包埋阑尾残端在腹腔镜阑尾切除术中的应用效果分析王晓东　纪元　张婷婷　于晓亮海阳市人民医院普外一科　265100通信作者：于晓亮，Email：******************** 【摘要】　目的　探讨荷包缝合包埋阑尾残端在腹腔镜阑尾切除术中的应用效果。

方法　选择本院2017年5月至2019年12月收治拟行腹腔镜阑尾切除术治疗的阑尾炎患者90例，按随机数字表法分为A组（45例）和B组（45例）。

A组女25例，男20例，年龄（41.21±2.31）岁；急性蜂窝织性阑尾炎14例，急性单纯性阑尾炎3例，急性化脓性阑尾炎14例，急性坏疽性阑尾炎8例，慢性阑尾炎急性发作3例，慢性阑尾炎3例。

不同剂量瑞舒伐他汀治疗急性脑梗死的临床疗效及其对脂联素和血清炎症因子水平的影响

l K^临床急诊急救中国急救复苏与灾害医学杂志2020年4月第丨5卷第4期Chin J Emerg Resusr Disaster Med，April2020. Vol. 15 No.4不同剂量瑞舒伐他汀治疗急性脑梗死的临床疗效及其对脂联素和血清炎症因子水平的影响高元杰，钟纯正，王御林，欧诒丹儋州市人民医院神经内科.海南儋州571799摘要：目的探讨不同剂量瑞舒伐他•;丁治疗急性脑梗死(acute cerebral infarction, ACI)的临床界效及其对血清炎症因子水平的影响。

方法选取儋州市人民医院20〗8年9月一2019年6月收治的A C I患者120例，设为A组；再按随机数字表法随机分入A,组、A2组、A3组，每组各40例。

另选择健康志愿者40例，设为13组。

A组患者给予A C I的常规治疗措施，A,组、A2组、A、组患者再分别给予瑞舒伐他汀5 m g、10 m g和20 m g。

比较B组受试者于体检当日，A组患者于治疗前、治疗4周后的血清炎症因子水平，包括白细胞介素-6(Interleukin-6，IL-6)、白细胞介素—1p(interleukin—〗p，IL-1(3)、肿瘤坏死因子—〇£(tumornecrosisfactor—ot, T N F—a);比较A 组患者发病后48h内、治疗4周后的美国国立卫生研究院卒中量表(national institute of health stroke Scale, NIHSS)评分、曰常生活能力(activity o f daily living, ADL)评分、改良Rankin 量表(modified rankin scale，m R S)评分；评价 A组患者治疗4周后的临床疗效，记录A组患者的不良反应情况c结果B组血清T N F-〇t、IL- 1p、I L-6均显著低于A组治疗前及治疗4周后水平(f=7.6卜13.96，P<0.01)血清脂联素均显著高于A组治疗前及治疗4周后水平(f=5.3卜16.70，P<0.01)。

博莱霉素类药物硬化疗法在囊肿性疾病中的应用

—92—介人放射学杂志2019年1月第28卷第1期J Intervem Radiol 2019, V〇1.28, No.1•综述General review*博莱霉素类药物硬化疗法在囊肿性疾病中的应用劳永浩，李龙【摘要】博莱霉素类药物硬化疗法已经广泛地应用于治疗各种囊肿性疾病。

博莱霉素类药物的致硬化作用机制可推测为早期通过非特异性炎性反应破坏内皮细胞，晚期出现组织纤维化使囔壁塌陷和萎缩位置浅表的囊肿行博莱霉素类药物硬化疗法时可在直视下进行，实质脏器内或解剖位置复杂的病变则需在影像设备引导下进行；抽尽囊液后注入药物并保留于囊腔内。

对淋巴管畸形、肝旗肿、肾囊肿、囊性颅咽管瘤和支气管囊肿等常见囊肿性疾病的总体有效率分别为91.04%~100%、100%、98.5%、73%和100%;并发症轻微，主要为轻度发热、局部疼痛、皮肤溃瘍等，均未见严重并发症：【关键词】博莱霉素；硬化疗法；囊肿中图分类号：R978文献标志码：A文章编号：1008-794X(2019)-01-0092-06Clinical application of bleomycin sclerotherapy for cystic diseases LAO Yonghao, LI Long. Departmentof Radiology，Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces，GuangzhouMedical University, Guangzhou , Guangdong Province 510507, ChinaCorresponding author：LI Long, E-mail：raiolilong@【Abstract】B l e o m y c i n s sclerotherapy h a s b e e n wide l y u s e d in the treatment of cystic diseases. T h esclerosing effect of b l e o m y c i n s m i g h t b e s p e c ulated that the epithelial destruction w a s result f r o m thenonspecific i n f l a m m a t o r y r e s p o n s e in the early stage, a n d the collapse a n d shrink of the c a p s u l e wall w a sresult f r o m tissue fibrosis in the late stage. B l e o m y c i n s sclerotherapy of the superfic ial cysts c a n b e p e r f o r m e du n d e r direct vision, a n d the treatment of the d e e p lesions a n d the visceral cysts m u s t b e p e r f o r m e d u n d e ri m a g i n g guid a n c e.A s m u c h liquid content of e a c h cyst w a s aspirated as possible, a n d b l e o m y c i n w a s injecteda n d r e m a i n e d in the cyst. T h e overall r e s p o n s e rates w e r e91.04〜100%for l y m p h a t i c malformations, a n d100%for hepatic cysts, a n d98.5%for renal cysts, a n d98.5%for cystic c r a n i o p h a r y n g i o m a s a n d100%forbronc h o g e n i c cysts, respectively. T h e c o m plications w e r e minor, including l o w-g r a d e fever, localized pain, skinulcers a n d so on. N o m a j o r complications w e r e e n c o u n t e r e d.(J Intervent Radiol, 2019,28：92-97)【Key words】b l e o m y c i n;sclerotherapy; cyst囊肿性病变是囊壁内衬有上皮细胞、内含液体或其他成分的一类呈囊腔结构的良性病变、现囊性疾病主要治疗手段包括保守治疗、传统外科切除或剥离、腹腔镜下切除、硬化疗法等。

Stanford B型主动脉夹层腔内修复术后再干预的危险因素研究

•论著•Stanford B型主动脉夹层腔内修复术后再干预的危险因素研究彭栋，阿拉法特•艾尔肯，沙尔娜(新疆医科大学第二附属医院介入诊疗科，乌鲁木齐830063)【摘要】目的探究Stanford B型主动脉夹层TEVAR术后再干预情况及相关危险因素。

方法回顾性分析2014年1月至2018年1月新疆医科大学第二附属医院初次行TEVAR的Stanford B型主动脉夹层患者93例，对再干预组和无需再干预的对照组进行比较，分析影响患者TEVAR术后再干预的危险因素。

结果22例患者(23.7%)进行再干预，包括内漏5例，再发夹层6例，假腔不完全血栓化5例，新发动脉瘤3例，夹层逆撕3例。

多因素Logistc回归分析显示，慢性期进行手术(OR二1.921,95%C7=1.186~3.112)a直筒型移植物(OR二1.754,95%CZ=1.144〜2.689)、移植物长度W145mm(OR二2.186,95%CZ=1.681-2.842).术后假腔扩张直径>5mm(O7?=1.976,95%CZ=1.276~3.059),移植物放大率>15%(0人二2.040,95%CZ二1.100~3.783)是TEVAR术后再干预的独立危险因素。

结论手术时机、移植物选择和对假腔扩张的影响、术后远端破口的存在是TEVAR术后再行手术干预的相关因素，应选择适宜的手术时机及移植物，避免再干预。

【关键词】主动脉夹层；胸主动脉腔内修复术;再干预；危险因素Study on the risk factors of re-intervention after thoracic endovascular aortic repair for Stanford typeB aortic dissection Peng Dong,A refill Elken,Sama.Department of Interventional Therapy,the SecondAffiliated Hospital of Xinjiang Medical University,Urumqi830063,ChinaCorresponding author；Peng Dong,E-mail:****************[Abstract]Objective To explore the risk factors of re-intervention after TEVAR for Stanford typeB aortic dissection(TBAD).Methods The clinical data of93patients with TBAD who underwent TEVARfor the first time in the Second Affiliated Hospital of Xinjiang Medical University from January2014toJanuary2018were analyzed retrospectively.We compared the re-intervention group and the control groupwho were without re-intervention,and analyzed the risk factois of re-intervention after TEVAR.Results22patients(23.7%)received re-intervention,including5cases with endoleak,6cases with recurrent dissection,5cases with incomplete pseudocoel thrombosis,3cases with new aneurysm and3cases with reverse dissection.Multivariate Logistc regression analysis showed that surgery in the chronic phase(OR=1.921,95%C/=1.186~3.112),straight-tube grafts(OR=1.754,95%CI=1.144~2.689),graft length W145mm(OR=2.186,95%CI=1.681~2.842),postoperative false cavity expansion diameter>5mm(OK=1.976,95%CZ=1.276~3.059)andgraft magnification>15%(012=2.040,95%CI=1.100-3.783)were the independent risk factors of re-interventionafter TEVAR.Conclusion The operation timing,choice of graft sand its effects on pseudocode expansionand postoperative distal rupture are the risk factors of re-intervention after TEVAR.We should be selectedthe appropriate timing of surgery and grafts to avoid re-intervention.[Key words]Aortic dissection;Thoracic endovascular aortic repair;Re-intervention;Risk factors主动脉夹层病情危急，病死率较高，是最严重的心血管病之一。

Magnetic Isotope Theory of the Origin of Life on E

J. Chem. Chem. Eng. 10 (2016) 301-304doi: 10.17265/1934-7375/2016.06.007Magnetic Isotope Theory of the Origin of Life on EarthAibassov Yerkin1, Nakisbekov Narymzhan1, Yemelyanova Valentina1 and Savizky Ruben21. Research Institute of New Chemical Technologies and Materials, Kazakh National University Al-Farabi, Almaty 005012, Kazakhstan2. Columbia University, 3000 Broadway, New York, NY, 10027, USAAbstract: The authors have proposed a new of magnetic isotope theory of life on Earth. According to this theory the initial impetus for the beginning of the synthesis of organic compounds is the impact of electromagnetic radiation from the sun and energy radioactive isotopes.Key words: Theory of the origin of life on earth, magnetic field, radioactive isotope, synthesis organic compounds.1. IntroductionLife is one of the most complex phenomena of nature. The problem of the origin of life on Earth has long been haunted by many scientists [1-6]. Ever since man began to wonder, where was all alive, all this time been considered a set of hypotheses and assumptions about the origin of life.In this work, an opportunity to review and modify the theory of Oparin-Haldane as the most likely, is to make it further effect of the magnetic radiation and radioactive isotopes of energy.The authors first time offered to consider the effect of the magnetic field and the radioactivity to the first organic compounds in the origin of life on Earth.2. TheoryAt various times regarding the origin of life on Earth put forward the following three theories: the steady state of life, spontaneous and Oparin-Haldane’s “primordial soup”.Oparin suggested that solutions of high molecular compounds can be formed spontaneously increased concentration zone that is relatively separated from the external environment and may support communication with it. He called them coacervates.Corresponding author: Aibassov Erkin Zhakenovich, professor, research field: metal organic chemistry of uranium and thorium, As, Sb and Bi. According to his theory, the process to the origin of life can be divided into three stages: the emergence of organic substances; occurrence of protein; occurrenceof protein bodies. Planetary systems arose from the gas-dust material. Along with metals and metal oxides contained in it, hydrogen, ammonia, water and simple hydrocarbon—methane.Conditions for the start of the formation of protein structures have been established since the introductionof the primary ocean (broth). In the aquatic environment derivatives of hydrocarbons could be subjected to complex chemical changes and transformations. As a result of the complexity of the molecules could form more complex organic materials, namely carbohydrates.Science has shown that the application of ultraviolet rays can be artificially synthesized not only amino acids and other organic substances. According to the theory, a further step towards the emergenceof proteins could be the formation of coacervate drops. Molecules of water surrounded by a shell, joined together to form multimolecular complexes—coacervates. They also can occur by simply mixing a variety of polymers. Thus there is a self-assembly of polymer molecules in the formationof multimolecular. Drops were able to absorb substances from the outside on the type of open systems. Thus, coacervates can grow, multiply,exercise metabolism.All Rights Reserved.302In 1953, i mixture of H and began t temperature are formed. under vario evolution ca of solution (not reproduc 3. Results Electroma were predict magnetism, to date, the little studied investigate physicochem chemistry. Figs. 1 an Not only travel at theFig. 1 The e and magnetic shown in a veFig. 2 The f vertical plane in an experim H 2O, NH 3, CH to pass throu of 80 °C. It w Later also su ous conditio an occur whe (coacervates)ce itself.and Discus agnetic wave ted by the cla known as M magnetic ef d. Therefore, the effect o mical and th nd 2 show the is the wave o e speed of li electromagneti c fields. The fi ertical plane, a figure—plane-e, and the fluct Magneti ment Miller H 4, CO 2, CO i ugh her elec was found tha ugar nucleotid ons. Miller en fazovoobo . However, su ssiones as a gene assical laws o axwell’s equ ffects in chem the authors h of magnetic hermodynam e electromagn of electric and ight, but they ic oscillations igure—plane-p nd the fluctuat -polarized wavtuations of the ic Isotope Th —Urey placed in a closed ve ctric shocks at the amino a des were obta concluded osoblennom s uch a system eral phenome of electricity uations. Howe mistry have b have attempte effects on mic functions netic waves.d magnetic fi y have a lim can be represe polarized wave tions of the ma ve propagatingmagnetic field heory of the O d theessel at a acids ained that state m can enonand ever, been ed to the s in ieldsmitedorie whi vec dire the vec T whe F mov and left fiel osc orie dire T a gr I dire can ented in the fo e propagating agnetic field - i g from right td—in the horiz Origin of Life entation and ich can be i tor. The ele ection of wav wave propa tor E × B. Then we obtai ere, c is the sp From the v ving rectiline d down, while , but this pat d oscillating illating up a entation with ection is know Thus, the pola reat influence f the magne ection of the n go in the opp orm of self-pro from right to in the horizont to left. Fluctuazontal.on Eartha proportion immediately ectric field, ve propagatio agation in th in the followi ΔE/ΔB peed of light.viewpoint of early, the elec e the magneti ttern can be a right and le and down. T h a preferen wn as polariza arization of e e on the cours etic field and magnetic po posite directi opagating tran left. Fluctuat tal.ations in the e nate amount seen from t magnetic fi on are all ort he same dire ing equation: = c . f electromag ctric field can c field may v alternated wit eft, and a m This arbitrar nce to the ation (Fig. 3)lectromagnet se of chemica d enables to oles, whereas on.nsverse vibrati tions in the eleelectric field a t, E = c o B o ,the Poynting ield and the thogonal and ection as the :gnetic wave n fluctuate up vary right and th an electric magnetic field riness in the propagation ). tic waves has al reactions.o change the s the reaction ions of electric ectric field are re shown in a , g e d e e p d c d e n s e n ce a All Rights Reserved.Fig. 3 The pFig. 4 Chan a function ofThe theor problem o coacervate appeared eff shown that spontaneous and they m solutions”—among whi synthesis of organism. The impet RNA world moleculesw polarization of nging the direc the direction o ry has been un of accurate and the ge fective protei t the first sly from the li may enter i —colonies self ich were th lipids, and a tus for the dev d was the diswith enzymat Magneti f electromagnet tion of motion of the magnetic nable to offer reproductio enerations—s in structures. coacervates ipid synthesiz into symbios f-replicating he ribozyme community c velopment of scovery of ritic activity, a ic Isotope Th tic waves.n of the electron c field.r a solution to on—within single, rando However, it s were for zed abiogenic sis with “liv RNA molecu es catalyze can already ca f the theory o ibozymes—Rand therefore heory of the Ons aso the the omly was rmed cally, ving ules, the alled f the RNA e areableope bioc info crea DN auto cap T pos (ana NaN mag tem dos uran (e)It (2Fe,saltmix Origin of Life e to combine erate separatel chemical re ormation. Th atures were R NA, and the ocatalytic cy able of cataly The authors af sible for the a 1) In a 10 m alysis is nece NO 3, KHCO gnetic spectro mperature from e (from 5 m nium salts; (d the concentra t is possible t N NaCl +2) The water Cu, and othe t solution. Thxture of gases on Earth e the function ly proteins an eactions an hus, it is assu RNA-organis ey could be ycle formed yzing the synt ffirm, in the f authors to get mL test tube essary to pou O 3, NaHPO oscopy of the m 20 to 300 min to 60 m d) pressure (1ation of d- an to flow the Eq NH 4H 2PO 4 + H + KJ + ATP r soluble inor ers. The autho hen the soluti s: CO 2, CO, C ns that these nd DNA, that d storage umed that th sms without e the protot by the very thesis of their following exp t organic com e for NMR ur an aqueou O 4, UO 2(NO following op °C; (b) X-ra min); (c) conc 1 to 150 atm nd f-elements.q. (1):HCOOH + P → NH 2COO rganic salts o ors introduce ion was pass CH 4, H 2and N 303cells mostly is to catalyze of genetic e first living proteins and type of the y ribozymes r own copies.periment, it is mpounds. spectroscopy s solution of 3)2. Change ptions: (a) the ay irradiation centration of (weld vial));. ONa (1)f Na, K, Mg,e the uranium ed through a N 2.3y e c g d e s . s y f e e n f ; ), m a All Rights Reserved.Magnetic Isotope Theory of the Origin of Life on Earth 304It is possible to flow the Eq. (2):nCO2 + nH2O + hv → n(C6H12O6) (2) As a result of these experiments is necessary to pay attention to formation of an organic phase (NMR, IR and UV spectroscopy, etc.).3. ConclusionsThe authors affirm that the total dependence on the factors influencing the emergence of life on Earth, is described by the equation:Life = f (T, P, E, B, R),where, T is temperature, P is pressure, E is electrical field, B is magnetic fields, R is radiation.Thus, the authors have proposed a new of magnetic isotope theory of life on Earth. According to this theory the initial impetus for the beginning of the synthesis of organic compounds is the impact of electromagnetic radiation from the sun and energy radioactive isotopes. References[1]Lurquin, P. F. 2003. The Origins of Life and the Universe.Columbia University.[2]Rauchfuss, H. 2008. “Chemical Evolution and the Originof Life.” Springer 85-110.[3]Mulkidjanian, A. Y., and Galperin, M. Y. 2009. 1. On theOrigin of Life in the Zinc World. 2. Validation of theHypothesis on the Photosynthesizing Zinc Sulfide Edificesas Cradles of Life on Earth. Biology Direct.[4]Sugawara, T. 2011. “Self-Reproduction ofSupramolecular Giant Vesicles Combined with theAmplification of Encapsulated DNA.” Nature Chemistry1127.[5]Pons, M. L. 2011. “Early Archean Serpentine MudVolcanoes at Isua, Greenland, as a Niche for Early Life.”PNAS, Sept. 15.[6]Crick, F. “Life Itself: Its Origin and Nature.” Simon andSchuster 1981: 192.All Rights Reserved.。

Association_between_KIR_Gene_Polymorphism_and_Diab

Theory and Practice of Science and Technology2022, VOL. 3, NO. 6, 66-69DOI: 10.47297/taposatWSP2633-456910.20220306Association between KIR Gene Polymorphism and Diabetes After Liver TransplantationFang Liu, Lei Han, Xibing Zhang*The Affiliated Calmette Hospital of Kunming Medical UniversityABSTRACTOne of the most frequent problems following liver transplantation is post-transplantation diabetes mellitus (PTDM), which has a significant negativeimpact on the medium- and long-term quality of life of liver transplantrecipients. A significant risk factor for the incidence and progression ofPTDM is genetics. Killer cell immunoglobulin-like receptors (KIR) areexpressed on the surface of NK cells and T cells and are members of theimmunoglobulin superfamily. By identifying the appropriate ligandmolecules on the surface of target cells, KIR controls the activity of NKcells and T cells. It influences Type 2 Diabetes Mellitus' (T2DM) onset anddevelopment. KIR gene polymorphism is related with T2DM, and theetiology of PTDM is comparable to that of T2DM. As a result, it may offernovel approaches to the prevention and management of diabetesfollowing liver transplantation.KEYWORDSPost-transplantation diabetes mellitus; Gene polymorphism; KIR genotype1　IntroductionThe technology for liver transplantation has advanced quickly during the past 20 years or so. The survival rate of patients with transplanted organs following liver transplantation has greatly increased as a result of the parallel advances in basic and clinical research, with a current success rate of 90% and a 5-year survival rate of roughly 80% after surgery [1]. However, one of the significant side effects impacting the long-term survival of liver transplant recipients is PTDM. The prevalence of PTDM among liver transplant recipients globally ranges from 14%~44%, and it is 24.3% among Chinese liver transplant recipients [2-3]. Genetic susceptibility plays a significant part in the pathogenesis process and cannot be disregarded in the development of PTDM.2　Diabetes Mellitus After Liver TransplantationFor clinically stable recipients with chronic hyperglycemia following transplantation, PTDM refers to newly diagnosed diabetes after transplantation, which typically involves diabetes present before transplantation but not detected [4].Temporary blood glucose rise brought on by surgical stress,* Corresponding Author: Xibing Zhang(1985-), Male, Shangluo, Shaanxi Province, Ethnic Han, Department ofHepatopancreatobiliary Surgery, The Affiliated Calmette Hospital of Kunming MedicalUniversity, Attending doctor, mainly engaged in hepatopancreatobiliary surgery andorgan transplantation research.Theory and Practice of Science and Technology67immunosuppressive medications, infection, etc. is typically prevalent in the early stages following transplantation, and only a small percentage of recipients go on to develop PTDM. The diagnosis of PTDM should only be taken into account when the receiver is stable on inhibitors and doesn't have an acute infection, according to the 2014 Vienna International consensus [4].3　Equivalent Mechanism of PTDM and Diabetes MellitusThe pathophysiology and clinical manifestations of PTDM, a kind of diabetes mellitus that develops under particular circumstances, are not only comparable to T2DM in the general population but also have their own special complexity and peculiarity. At the moment, the most generally used diagnostic criteria for PTDM are those provided by the American Diabetes Association in 2014, which state that diabetes can be diagnosed if there are typical symptoms of diabetes and one of the four signs listed below [5]：(1) random plasma glucose ≥11.1 mmol/L; (2) fasting plasma glucose ≥7.0 mmol/L; (3) 2-hour plasma glucose ≥11.1 mmol/L after oral glucose tolerance test; (4) hemoglobin A1c ≥ 6.5%.The use of immunosuppressants after transplantation is expected to be substantially related with the development of PTDM, in addition to risk factors such obesity, age, and hyperlipidemia [6]. Currently, it is thought that steroid hormones primarily influence insulin resistance and aberrant islet cell function, which both impact the normal process of glucose metabolism [7]. Calmodulin inhibitors, like steroid hormones, can raise intracellular calcium levels by blocking the calcineurin/NFAT pathway, which in turn prevents the insulin gene from being expressed in islet cells [8]. Additionally, calmodulin inhibitors can increase insulin resistance and cause islet cell death [9]. They can also decrease the quantity of vesicles released by islet cells. Due to the complicated immunological and inflammatory processes that PTDM entails as well as its significant genetic variability, T2DM can be considered to be PTDM [10].The development of T2DM and its associated metabolic disorders is inextricably linked to immune and inflammatory responses, and its role in the disease is gradually coming to be appreciated. T2DM is a polygenic complex disease with significant genetic susceptibility. At its core, it is a systemic, chronic, low-grade inflammatory state [11-12]. Since T2DM is also a genetic susceptibility disorder, genetic susceptibility and genetic polymorphisms in transplanted organs may also determine factors associated with the regulation of glucose metabolism after liver transplantation. Genetic factors are one of the clear risk factors for PTDM, and single nucleotide polymorphisms in diabetes candidate genes are associated with an increased risk of PTDM [13].4　Mechanism of KIR Gene Polymorphism in Diabetes MellitusThe KIR gene is highly polymorphic and is situated in the leukocyte receptor complex on human chromosome 19q13.4 [14]. It is predominantly found on the surface of NK cells and some T cells, and it controls the activity of these cells by specifically identifying HLA-I-like molecules on the surface of target cells [15]and transmitting activating or inhibiting signals, thereby putting the body in a different immune response state. Due to the polymorphism of KIR genes, which are widely involved in important genes of immune regulatory response, the distribution of KIR genes in the population and gene frequency and other characteristics also provide a theoretical basis for the study of their relevance to diseases [16]. KIR gene polymorphisms have been linked to the onset of autoimmune diseases such diabetes, ankylosing spondylitis, systemic lupus erythematosus, scleroderma, and psoriasis as well as viral infections, according to studies on the relevance of KIR genes to disorders[17]. The frequency of KIR2DS2 was significantly higher in T2DM patients, according to Rathika et al.[18], suggesting that KIR2DS2 may be a gene that is vulnerable to T2DM and that the production ofFang Liu et al. 68inhibitory KIR is higher in T2DM patients. The frequency of KIR 2DL3/2DL3 homozygous genotypes was reported to be enhanced in 95 Puerto Rican patients with type 2 diabetes by Zuniga et al. [19], indicating that KIR 2DL3 may be a susceptibility gene for the disease and that inhibitory KIR receptors are elevated in T2DM patients.As an inhibitory receptor on the surface of NK cells, KIR 2DL3 is a classic "suppressor" gene, which implies that KIR 2DL3's decline may be connected to the pathogenesis of T2DM [20].Reduced levels of the inhibitory receptor KIR 2DL3 on NK cell surfaces increase the likelihood that NK cells will become activated, which in turn will cause inflammatory reactions [21].Therefore, the decrease of KIR 2DL3 results in the rise of inhibitory receptors on NK cell surface, and the inflammatory response mediated by KIR 2DL3 may play a significant role in the pathogenesis of T2DM.5　Conclusion and ProspectionT2DM and PTDM have similar clinical symptoms and pathophysiological traits. Therefore, the PTDM may be significantly influenced by hereditary variables linked to islet -cell dysfunction and insulin resistance. It is believed that complicated genetic variables contribute to T2DM vulnerability, and that the development of the disease is inextricably linked to immunological response and inflammation. The pathophysiology of T2DM is connected to the KIR gene polymorphism, which is significant in the immunological response. A substantial body of research evidence has also demonstrated a significant relationship between PTDM and single nucleotide polymorphisms in T2DM susceptibility genes. In previous studies, polymorphisms in the KIR gene, which plays an important role in immune response, were found to be associated with the development of T2DM and may be a genetic susceptibility gene for PTDM, which is important for further study of the KIR gene to explore the pathogenesis of PTDM.FundingFunded project: Open project of Yunnan Provincial Organ Transplantation Clinical Medicine Center, 2020SYZ-Z-027. About the AuthorFang Liu(1985-), Female, Jiamusi, Heilongjiang Province, Ethnic Han, Department of Endocrine, The Affiliated Calmette Hospital of Kunming Medical University, Associate professor, mainly engaged in endocrine and metabolic diseases research.References[1] Samuel D, Coilly A. Management of patients with liver diseases on the waiting list for transplantation: a majorimpact to the success of liver transplantation[J]. BMC Med, 2018, 16(1):113.[2] LING Q, XU X, WANG B, et al. The origin of newonset diabetes after liver transplantation: liver, islets, or gut?[J].Transplantation, 2016,100 (4):808-813.[3] LING Q, XU X, XIE H, et al. New-onset diabetes after liver transplantation: a national report from China LiverTransplant Registry[J].Liver Int, 2016, 36(5):705-712.[4] SHARIF A, HECKING M, DE VRIES AP, et al. Proceedings from an international consensus meeting onposttransplantation diabetes mellitus: recommendations and future directions[J]. Am J Transplant, 2014, 14(9):1992-2000.[5] American Diabetes Association. Diagnosis and classification of diabetes mellitus[J]. Diabetes Care, 2014, 37(Suppl 1):S81-S90.[6] Boerner BP, Shivaswamy V, Wolatz E, et al. Post-transplant diabetes: diagnosis and management[J].MinervaTheory and Practice of Science and Technology69Endocrinol,2018,43(2):198-211.[7] Jessica L Hwang , Roy E Weiss. Steroid-induced diabetes: a clinical and molecular approach to understanding andtreatment[J].Diabetes Metab Res Rev,2014,30(2):96-102.[8] Sabatini PV, Speckmann T, Lynn FC. Friend and foe: β-cell Ca2+ signaling and the development of diabetes[J].MolMetab,2019,21:1-12.[9] Rickels MR, Robertson RP. Pancreatic Islet Transplantation in Humans: Recent Progress and Future Directions[J].Endocr Rev,2019,40(2):631-668.[10] Campise M. Post-transplant diabetes mellitus: diagnosis and treatment[J].G Ital Nefrol,2007,24(6):547-557.[11] Zghebi SS, Rutter MK, Ashcroft DM, et al. Using electronic health records to quantify and stratify the severity oftype 2 diabetes in primary care in England: rationale and cohort study design[J].BMJ Open,2018,8(6):e020926.11. [12] Shi FD, Zhou Q. Natural killer cells as indispensable players and therapeutic targets in autoimmunity[J].Autoimmunity,2011,44(1):3-10.[13] HIVASWAMY V, BOERNER B, LARSEN J. Posttransplant diabetes mellitus: causes, treatment, and impact on outcomes[J]. Endocr Rev, 2016,37(1):37-61.[14] Trowsdale J. Genetic and functional relationships between MHC and NK receptor genes[J].Immunity,2001,15(3):363-374.[15] Yu J, Heller G, Chewning J, et al. Hierarchy of the human natural killer cell response is determined by class andquantity of inhibitory receptors for self-HLA-B and HLA-C ligands[J].J Immunol,2007,179(9):5977-5989.[16] Fauriat C, Ivarsson MA, Ljunggren HG, et cation of human natural killer cells by activating killer cellimmunoglobulin-like receptors[J]. Blood,2010,115(6):1166-1174.[17] Gagne K, Brizard G, Gueglio B, et al. Relevance of KIR gene polymorphisms in bone marrow transplantationoutcome[J].Hum Immunol,2002,63(4):271-280.[18] Rathika Chinniah, Murali Vijayan, Ramgopal Sivanadham,et al. Diversity and association of HLA/KIR receptors withtype 2 diabetes in South India[J].Int J Immunogenet,2019,46(3):166-178.[19] Zuniga J, Romero V, Azocar J,et al. Interaction of KIR genes and G1M immunoglobulin allotypes confersusceptibility to type 2 diabetes in Puerto Rican Americans[J].Hum Immunol,2006,67(11):907-14.[20] Viviana Romero, Joaquin Zúñiga, Jose Azocar,et al. Genetic interactions of KIR and G1M immunoglobulin allotypesdiffer in obese from non-obese individuals with type 2 diabetes[J].Mol Immunol,2008,45(14):3857-62.[21] Mehdi Mahmoudi, Ahmad Reza Jamshidi, Jafar Karami,et al. Analysis of Killer Cell Immunoglobulin-like ReceptorGenes and Their HLA Ligands in Iranian Patients with Ankylosing Spondylitis[J].Iran J Allergy Asthma Immunol, 2016,15(1):27-38.。

Long Range Unmanned Aircraft System for Power Line

Journal of Energy and Power Engineering 8 (2014) 394-398Long Range Unmanned Aircraft System for Power Line Inspection of Brazilian Electrical SystemGeraldo José AdaboTechnological Institute of Aeronautics, São José dos Campos, São Paulo12228-900, BrazilReceived: July 17, 2013 / Accepted: September 17, 2013 / Published: February 28, 2014.Abstract: Power line inspection is an essential procedure in the power lines maintenance area, especially thinking about service availability and energy efficiency. Aerial inspection of electric power transmission lines is typically performed using human-piloted helicopters, which is a procedure that is both expensive and prone to accidents taking risks to human beings’ lives. The work presents a solution based on UAS (unmanned aircraft system) for inspecting power lines. In this context a R & D project of an unmanned aircraft system to be used for performing complete aerial inspection of overhead power lines is being executed by ITA (Instituto Tecnológico de Aeronáutica) (Technological Institute of Aeronautics) in Brazil. Special attention is dedicated to the communication system conception in order to comply with Remotely Piloted Aircraft System definition in the context of long endurance operations of the system. It presents a solution based on LTA (lighter than air) platform in order to extend the communication range beyond line of sight.Key words: UAV, UAS, RPAS, power line, maintenance, inspection.1. IntroductionHaving one of the largest aerial power lines structures of the world with length as much as 95,000 km long, there is a large demand for aerial inspection of these structures in Brazil. The work is related to the Autonomous Robots area, in this case aerial robotics, applied to electrical engineering and aiming to develop a new method of long range aerial inspection of power lines.The R & D project in development at ITA (Instituto Tecnológico de Aeronáutica) is sponsored by a Brazilian Electrical Company located in northeast of the country. CHESF (Companhia Hidro Elétrica do São Francisco) belongs to Eletrobrás which is the government electrical company. CHESF is responsible for power lines structures with total length above 20,000 km [1].PL (power line) inspection is the beginning activity of the maintenance cycle and its effectiveness isCorresponding author: Geraldo José Adabo, professor, research field:RPASapplications.E-mail:************.important for determining system reliability and the maintenance costs of the electrical system.Means for inspection of the technical process of verification of the PL, its components and around, taking in account the established standards with the objective of detect defects and anomalies that prejudice the PL performance, its life time and people safety.In the context of PL Inspection there are several types of performing related actions, but in this work there is a special interest in aerial inspection which is performed by manned helicopters in the conventional way. This traditional method is effective, but is prone to accidents and is a high cost method for inspecting power lines.The main objective of the project is to provide a low cost solution for aerial power line inspection based on unmanned vehicles which have to be able to perform long range flights in a relatively short time. Special efforts are applied in order to keep the pilot on the ground linked to the plane all the time during theinspection.All Rights Reserved.Long Range Unmanned Aircraft System for Power Line Inspection of Brazilian Electrical System3952. Unmanned Aircraft SystemNowadays, the international nomenclature for the system based on a unmanned aircraft is RPAS (remotely piloted aircraft system) which is comprised of three fundamental segments: aerial, communication and ground [2], as illustrated in Fig. 1.2.1 Aerial SegmentConsist of the plane including: arframe, aerodynamic surfaces, propulsion, autonomous flight control and payload, which in this application is comprised of an imaging system and a video transmitter for sending the captured images to the ground segment.The flight control system comprises autopilot, actuators and transceiver. The autopilot can read data available from inertial and pressure sensors, and from the GNSS receiver. The data are processed by the autopilot that sends control signals to the actuators andperforms the control and navigation of the aerialplatform. The flight plan is uploaded on the ground justbefore the take-off of the RPAS and the actuators act directly in the control surfaces and in the throttle of the propulsion system. Although the plane is able to fly autonomously, the RPAS concept has a piloting requirement that consists in a human pilot monitoring the flight all the time who is able to change the flight plan and finish the mission if necessary for safety reasons.2.2 Communication SegmentIt comprises the interface between the aerial segment and the ground segment, basically by means of a data link and a video link.The data link is responsible for sending commands from the ground station to the plane and receiving telemetry on the ground station from the plane. In this way the human pilot has the necessary situational awareness for deciding about commands that would benecessary to send to the plane.Fig. 1 RPAS segments.The video link is necessary for transmitting live video the Data Application Station which is managed by the PL inspector. 2.3 Ground SegmentIt is comprised of the GCS (ground control station) and the DAS (data application station). It is always necessary that GCS is the position where the human pilot work, getting telemetry signals from the plane and sends commands for controlling the plane. DAS is the position of the PL inspector who can watch the live video, control the camera gimbal and identify the defects.3. Inspection PlatformsThe project is defined in a very pragmatic approach based on development prototypes [3].The Delta II platform is shown in Fig. 2 and is a model that was useful for integrating the avionics and imaging systems. Fig. 3 shows the image on the display of the GCS, highlighting the flight plan defined by waypoints and the on line telemetry indicating the position of the plane and other primary data.For getting and additional experience with a typical UAV platforms, it was used in a purchased platform and the systems that were integrated in it. Fig. 4 shows the Delta III platform.In addition, aiming to comply with the high level requirements of the project, it has been developed an own platform named Delta IV whose development prototype is shown in Fig. 5. This platform has to comply with constraints related to low flight speed and enough payload capability.All Rights Reserved.Long Range Unmanned Aircraft System for Power Line Inspection of Brazilian Electrical System396Fig. 2 Delta II inspection platform.Fig. 3 GCS computer display.Fig. 4 Delta III inspection platform.4. Imaging SystemThe studies related to the imaging system were developed considering the specific application and three regions were defined: safety zone, IR zone and visible zone [4].The safety zone was defined considering the risks of crashes of the plane to the PL and towers. The safety distance is referred as D 1 as shown in Fig. 6.The IR Zone refers to the maximum distance for getting images in the infra red spectrum which is important to detect hot spots. The respective distance is referred as D 2 as shown in Fig. 7.The visible zone refers to the maximum distance between the plane and the LT in order to captureimages with necessary quality. This distance is referred as D 3 as shown in Fig. 8.The three zones can be superimposed highlighting the intersection between IR zone and visible zone where the plane has to fly in order to satisfy both criteria, respecting the safety zone. Fig. 9 shows the zones intersection.Fig. 5 Delta IV inspection platform.Fig. 6 Safety zone.All Rights Reserved.Long Range Unmanned Aircraft System for Power Line Inspection of Brazilian Electrical System397Fig. 7 IR zone ( D2 > D1 ).Fig. 8 Visible zone ( D3 > D2 ).Fig. 9 Final composition.5. Communication SystemThe high level requirement of long endurance RPAS defines a very severe constraint that is a challenge for the project. In fact, the electrical system has PL sections (between two substations) up to 350 km and it is important to cover the maximum length by means of one mission (take-off/landing cycle).In this case the complete solution delivered by the project team has to comprise the long range communication requirement.The concept illustrated in Fig. 1 is appropriate just for LOS (line of sight) communication which is not the case in this application.The proposed solution for BLOS (beyond line of sight) communication is illustrated in Fig. 10, considering the usage of a tethered balloon working as a communication relay [5].This low cost solution extends the communication range of the RPAS several times the LOS conception depending on the altitude of the balloon, the terrain and the performance of communication equipments.In addition to the communication relay functionality, the tethered balloon can be used as a Pseudo UAV for communication test purposes [6].The idea is to replace the plane by one tethered balloon equipped with the communication system designed for being integrated in the plane. Together with the communication equipments of the GCS it is possible to validate the communication link for especially remote positions in order to ensure that the RPAS concept will be complied for the specific mission [7, 8].Fig. 11 illustrates the usage of the balloon as a Pseudo UAV.Fig. 10 Long range communication solution.Fig. 11 Ballon as a pseudo UAV.All Rights Reserved.Long Range Unmanned Aircraft System for Power Line Inspection of Brazilian Electrical System 3986. ConclusionsThe intended application presents high complexity considering several aspects of the project.6.1 Positioning SystemThe application requires flights with low altitude and proximity to the power lines leading to an additional requirement regarding GNSS accuracy.In addition, the topography is quite relevant for the flight plan because if it is not appropriately considered the plane can be guided to a crash to the terrain.6.2 Imaging SystemConsidering a low cost approach for the camera gimbal, it is necessary to fly inside a very limited zone in order to capture ant transmit images in both visible and IR spectrum. The corresponding distance is very short and leads to sub-item A where the positioning system requirements were discussed.Another requirement related to the imaging system is the maximum speed of the plane which has to be less than 60-70 km/h. This requirement is controversial considering that the low cost inspection would be more cost effective with high speed of flight. It is necessary to balance and optimize flight speed and images’ quality.6.3 Communication SystemIt is necessary to pay special attention to the requirements related to RPAS concept and inspection live video regarding long range communication necessarily BLOS.The immediate solution based on satellite communication implies in expensive communication bandwidth for live video leading to a low cost solution based on tethered balloon which is not outstanding because the altitude is not so high that can be compatible to dimensions of Fresnel zones. Anyway the proposed solution is a very interesting trade-off aiming the effectiveness and costs as drivers of the analysis.6.4 Balloon Based Test MethodologyThe solution based on balloon working as a Pseudo UAV has been used for validating the communication equipments and links obtaining a method for measuring the communication capability of the system for long range communication without risks normally associated to high distances between the plane and the GCS.AcknowledgmentsThe author would like to thank to Companhia Hidro Elétrica do São Francisco and Agência Nacional Energia Elétrica for the sponsoring of the R&D project.References[1] F.A.C. de Mello, RPAS Regulation Proposal for PowerLine Inspection, Master Thesis, Technological Institute ofAeronautics, São José dos Campos, Brazil, 2011.[2]N.A. de Novais, Remotely piloted aircraftsystem—proposal for a national regulationl, Master Thesis,Technological Institute of Aeronautics, São José dosCampos, Brazil, 2011.[3]G.J. Adabo, Project management strategies for developinga small UAS for aerial inspection of power lines in Brazil,in: UAV World 2011 Conference, Frankfurt, 2011.[4] A.S.R. de Oliva, Procedure of RPAS imaging systemanalysis for power line inspection, Master Thesis,Technological Institute of Aeronautics, São José dosCampos, Brazil, 2011.[5] A.R.R. Araújo, Communication Alternatives betweenUnmanned Aerial Vehicle and Ground Control Station,Final Year Work, Technological Institute of Aeronautics,São José dos Campos, Brazil, 2011.[6]G.J. Adabo, Multi-platform unmanned aircraft system forhigh voltage power transmission lines inspection ofBrazilian electrical system, in: UAV World 2012Conference, Frankfurt, 2012.[7]2011-2012 UAS Yearbook-UAS: The Global Perspective,9th ed., Blyenburgh & Co., June 2011, p. 86.[8]G.J. Adabo, Multi-platform RPAS for powerlineinspection, in: RPAS 2013 International Conference,Brussel, 2013.All Rights Reserved.。

司维拉姆联合西那卡塞治疗血液透析并发继发性甲状旁腺功能亢进患者的疗效观察和对成纤维生长因子23的影响

国际泌尿系统杂志2021 年 1月第 41 卷第1期International Joum^ of Urology and Nephrology, January 2021, Vol.41 NO. 1139司维拉姆联合西那卡塞治疗血液透析并发继发性甲状旁腺功能亢进患者的疗效观察和对成纤维生长因子23的影响张育安荣冬靖云南省第三人民医院肾病科，昆明650011通信作者：荣冬靖，Em ail:ssyxts@【摘要】目的观察司维拉姆联合西那卡塞对维持性血液透析并发继发性甲状旁腺功能亢进患者的疗效及对成纤维细胞生长因子23 (FGF-23)和钙、磷的影响:方法选取2017年4月至2018年10月在本院收治的并发继发性甲状旁腺功能亢进[甲状旁腺激素（iPrH) >300pg/mL]的维持性血液透析患者110例，随机将患者分为碳酸司维拉姆治疗组（对照组）和碳酸司维拉姆联合西那卡塞治疗组（观察组），各55例，治疗16个月，观察并比较两组的血钙、血磷、超敏C反应蛋白（hs-CRP)、血iPrH、FGF-23及左心室厚度（LVd)等指标c结果治疗16个月后，两组患者的血钙、血磷、hs-CRP、血iPTH及FGF-23均低于治疗前，且观察组比对照组下降更明显，两组比较差异具有统计学意义（P<〇. 05);对照组的LVd无明显下降，观察组有所下降，但两组比较差异无统计学意义（P>〇. 05)。

结论司维拉姆联合西那卡塞对iPI’H和钙磷代谢均有着较好的控制，能有效降低血液透析患者的FGF-23水平，可能对减少心血管事件和肾性骨病有益。

【关键词】肾透析；甲状旁腺功能亢进症，继发性•，司维拉姆;西那卡塞基金项目：云南省教育厅科学研究基金项目（2017ZDX025)DOI：10.3760/431460-20190909-00038Observation on the effect of sevelamer combined with cinacalcet in the treatment of secondaryhyperparathyroidism in hemodialysis patients and the effect on FGF-23Zhang Yuan, Rong Dongjing.Department of Nephrology, the Third Peoples Hospital o f Yunnan Province, Kunming 650011 ^ChinaCorresponding author \ Rong Dongjin .Email：*************Abstract Objective To observe the effect of sevelamer combined with cinacalce on fibroblast growth factor 23( FGF-23) and calcium and phosphorus in patients with maintenance hemodialysis. Methods From April 2017 to October 2018,1 10 patients with maintenance hemodialysis complicated with secondary hyperparathyroidism(iPTH >300 pg/mL) in our hospital were selected. The patients were randomly divided into sevelamer carbonate group( control group) and sevelamer carbonate +sevelamer group(treatment group) with 55 cases each for 16 months,and the clinical indicators of thetwo groups were observed and analyzed. Results Sixteen months after treatment, the treatment groupand control group in the blood of the blood calcium, phosphorus and the calcium-phosphorus productwere lower than before the treatment, the treatment group was lower than the control group, there wasstatistically significant di£ference( P <0.05) , the treatment group and control group in blood iPTH,FGF-23 were lower than before treatment, and the treatment group decreased more significantly(P <0.05). LVd in the control group, was no significant decline and in treatment group decreased, but itwas similar between the two groups( P >0. 05). Conclusions Both iPTH and calcium and phosphorusmetabolism are well controlled by sevelamer combined with cinacalce, effectively reducing FGF-23 in140国际泌尿系统杂志2021 年1月第 41 卷第1期丨ntemational Journal of Urology and Nephrology，January 2021，Vol. 41 NO. 1hemodialysis patients, which may be beneficial to reduce cardiovascular events and renal bone diseases.Key words Renal Dialysis ； Hyperparathyroidism, Secondary; Sveramme ； SinacasecFund program ：Scientific Research Fund Project of Yunnan Education Department(2017ZDX025)DOI ： 10. 3760/cma. j. cn43146020190909-00038随着慢性肾脏病（C K D)患者肾功能的下降，可出现磷潴留导致高磷血症。

1-s2.0-S0378517313007667-main2

International Journal of Pharmaceutics 456 (2013) 49–57Contents lists available at ScienceDirectInternational Journal ofPharmaceuticsj o u r n a l h o m e p a g e :w w w.e l s e v i e r.c o m /l o c a t e /i j p h a rmThe effect of lipid composition and liposome size on the release properties of liposomes-in-hydrogelJulia Hurler a ,Simon ˇZakelj b ,Janez Mravljak b ,Stane Pajk b ,c ,Albin Kristl b ,Rolf Schubert d ,Nataˇs a ˇSkalko-Basneta ,∗aUniversity of Tromsø,Drug Transport and Delivery Research Group,Department of Pharmacy,Universitetsveien 57,N-9037Tromsø,NorwaybUniversity of Ljubljana,Faculty of Pharmacy,Aˇs kerˇc eva cesta 7,SI-1000Ljubljana,Slovenia cInstitut Joˇz ef Stefan,Laboratory of Biophysics–EPR center,Jamova 39,SI-1000Ljubljana,Slovenia dAlbert Ludwig University,Department of Pharmaceutical Technology and Biopharmacy,Hermann-Herder-Straße 9,D-79104Freiburg,Germanya r t i c l ei n f oArticle history:Received 19June 2013Received in revised form 9August 2013Accepted 12August 2013Available online 27 August 2013Keywords:Liposomes HydrogelsIn vitro release Chitosan Skin therapya b s t r a c tTo study the release of liposome-associated drugs into hydrogels,we designed and synthesized two pH-sensitive rhodamine derivatives to use as model compounds of different lipophilicities.The dyes were ﬂuorescent when in the free form released from liposomes into the chitosan hydrogel,but not when incorporated within liposomes.The effect of liposomal composition,surface charge and vesicle size on the release of those incorporated dyes was evaluated.The lipophilicity of the rhodamine derivatives affected both the amount and rate of release.While liposome size had only a minor effect on the release of dyes into the hydrogel,the surface charge affected the release to a greater extent.By optimizing the characteristics of liposomes we could develop a liposomes-in-hydrogel system for application in wound therapy.We further characterized liposomes-in-hydrogel for their rheological properties,textures and moisture handling,as well as their potential to achieve a controlled release of the dye.The polymer-dependent changes in the hydrogel properties were observed upon addition of liposomes.The charged liposomes exhibited stronger effects on the textures of the chitosan hydrogels than the neutral ones.In respect to the ability of the system to handle wound exudates,chitosan-based hydrogels were found to be superior to Carbopol-based hydrogels.© 2013 Elsevier B.V. All rights reserved.1.IntroductionA major aim in the development of modern hydrogel for-mulations such as those currently used in wound dressings,is to achieve the effective and accurate delivery of the required therapeutic agents included in the formulation over a prolonged period of time (Boateng et al.,2008).Among hydrogels,chitosan hydrogels are one of the most studied systems,particularly with respect to their bioadhesiveness.Chitosan has frequently been studied as a possible wound dressing and as a delivery system forAbbreviations:ns,non-sonicated;PC,phosphatidylcholine;PC ns,non-sonicated phosphatidylcholine liposomes;PC s,sonicated phosphatidylcholineliposomes;PC/PG,phosphatidylcholine/phosphatidylglycerol;PC/PG ns,non-sonicated phosphatidylcholine/phosphatidylglycerol liposomes;PC/PG s,sonicated phosphatidylcholine/phosphatidylglycerol liposomes;PC/SA,phosphatidylcholine/octadecylamine;PC/SA ns,non-sonicated phosphatidyl-choline/octadecylamine;PC/SA s,sonicated phosphatidylcholine/octadecylamine;PG,phosphatidylglycerol;PI,polydispersity index;s,sonicated;SA,octadecylamine (=stearylamine).∗Corresponding author.Tel.:+4777646640;fax:+4777646151.E-mail address:natasa.skalko-basnet@uit.no (N.ˇSkalko-Basnet).therapeutic agents.This is primarily due to its conﬁrmed biocom-patible,biodegradable,non-toxic and bacteriostatic properties,as well as its ability to promote wound healing (Denis et al.,2012).While a lot of research on the potential use of chitosan as a wound dressing has focused on plain chitosan hydrogels,chitosan-based hydrogels (Alsarra,2009;Bhattarai et al.,2010;Ribeiro et al.,2009),chitosan ﬁlms (Aoyagi et al.,2007;Noel et al.,2008)and other chitosan-based formulations (Salam et al.,2010),relatively little has been published about liposomal chitosan hydrogels.The rationale behind using liposomes-in-hydrogel as a delivery system is to assure sustained drug release during their prolonged presence at the administration site (Ruel-Gariepy et al.,2002).The release of drugs from drugs-in-liposomes-in-hydrogel systems is affected by different factors related to the physicochemical proper-ties of the drug.The release of amphiphilic/lipophilic drugs,which are assumed to have the ability to penetrate the liposomal mem-brane,will be determined by the lipid concentration of liposomes added into the gel (Mourtas et al.,2008b ).In the current study we aimed to gain a better insight into the interactions between drug molecules,liposomes and hydrogels.However,the complexity of the liposomes-in-hydrogel delivery0378-5173/$–see front matter © 2013 Elsevier B.V. All rights reserved./10.1016/j.ijpharm.2013.08.03350J.Hurler et al./International Journal of Pharmaceutics456 (2013) 49–57system limits a real-time analytical evaluation of drug release from liposomes,which function as a drug reservoir within the hydro-gel,delivering the drug to the administration site.For this purpose, pH-sensitive rhodamine compounds of two different lipophilici-ties were designed and synthesized to follow their release from liposomes into the hydrogel.The dyes were incorporated in lipo-somes which varied in lipid composition,surface charge and size.The use of hydrogels as vehicles provides the required rheo-logical properties required for the incorporated liposomes(Cohen et al.,2012;Mourtas et al.,2007,2008b;Paavola et al.,2000;Pavelic et al.,2001).In addition,the high viscosity of hydrogels acts as a protective mechanism which can stabilize liposomes,as has been previously shown by Mourtas et al.(Mourtas et al.,2008b).An additional important characteristic that makes hydrogels interesting for wound therapy is their bioadhesiveness.The rhe-ological and bioadhesive properties of hydrogel formulations determine their retention time at the administration site and can therefore inﬂuence the therapeutic outcome of the treat-ment.Previously,we have shown the superior bioadhesiveness of chitosan-based liposomal hydrogels as compared to Carbopol-based hydrogels(Hurler andˇSkalko-Basnet,2012).However,in the case of wound treatment the bioadhesiveness can be affected by the wound’s exudate.Some wounds,such as burns,pro-duce a lot of exudate,which can lead to maceration of the wound bed,whereas other wounds are dry and need addi-tional moisture from the wound dressing for their proper healing (Fulton et al.,2012).Therefore,in this study we also tested the ﬂuid handling properties of both chitosan-and Carbopol-based hydrogels.2.Materials and methodsThe rhodamine derivatives used in this study,namely MP-4and MTJ-12(log p4.17and log p2.32,respectively,as calculated by ChemBioDraw12.0,CambridgeSoft)were synthesized at the Fac-ulty of Pharmacy,University of Ljubljana,Slovenia(manuscript in preparation).Lipoid S100(PC,soya phosphatidylcholine>94%) and Lipoid E PG-Na(PG,egg phosphatidylglycerol sodium)were a generous gift from Lipoid GmbH(Ludwigshafen,Germany).Octade-cylamine(SA)and high Mw chitosan(Brookﬁeld viscosity800.000 cps,DD of77)were a product of Sigma–Aldrich Chemistry(St. Luis,USA).Carbopol®Ultrez10was obtained from Noveon(Cleve-land,USA).Triethylamine was purchased from Merck Schuchardt (Hohenbrunn,Germany)and glycerol was obtained from Merck KGaA(Darmstadt,Germany).All other chemicals used in experi-ments were of analytical grade.2.1.Rhodamine derivativesAll1H and13C NMR spectra were recorded on a Bruker Avance III NMR instrument operating at400MHz and100MHz(13C).IR spectra were recorded on a PerkinElmer FTIR1600spectrometer. Mass spectra were obtained with a Q-Tof Premier mass spectrome-ter(Centre for Mass Spectrometry,Institute Joˇz ef Stefan,Ljubljana, Slovenia).3 ,6 -bis(ethylamino)-2-(3-hydroxypropyl)-2 ,7 -dimethylspiro[isoindoline-1,9 -xanthen]-3-one MP-4.1H NMR(DMSO-d6,400MHz):ı 1.15–1.19(m, 2H,N CH2CH2CH2OH), 1.22(t,6H,J=7.25Hz, 2×CH2CH3),1.87(s,6H,2×Ar CH3),3.02(t,2H,J=7.51Hz, N CH2CH2CH2OH),3.10–3.16(m,6H,N CH2CH2CH2OH, 2×CH2CH3), 4.33(bs,1H,OH), 5.07(t,2H,J=5.32Hz, 2×NH), 6.08(s,2H,H4 Ar,H5 Ar), 6.27(s,2H,H1 Ar, H8 Ar), 6.96–6.98(m,1H,H7Ar),7.48–7.50(m,2H,H5Ar,H6Ar),7.77–7.79(m,1H,H4Ar)ppm.13C NMR(DMSO-d6, 100MHz):ı14.15,17.02,31.02,37.27,37.47,54,91,64.28,95.61, 104.66,118.16,122,19,123,51,127.51,128.15,130.49,132.52, 147.58,150.96,153.64,166.93ppm.IR(KBr)3425,3337,2961, 2858,1682,1636,1620,1517,1470,1421,1326,1271,1219, 1159,1144,1042,1014,868,814,782,746cm−1.MS(ESI)m/z (rel intensity)472(MH+,100);HRMS(ESI):Calcd for C29H34N3O3 [M+H]+472.2600,found472.2597.3 ,6 -bis(ethylamino)-2 ,7 -dimethyl-2-(2-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)ethyl)spiro[isoindoline-1,9 -xanthen]-3-one MTJ-12.1H NMR(DMSO-d6,400MHz):ı0.95(t,3H,J=6.90Hz, CH2CH3), 1.22(t,3H,J=7.16Hz,CH2CH3), 1.88(s, 3H,Ar CH3), 2.05(s,3H,Ar CH3), 2.91–3.28(m,12H, N CH2CH2O,2×CH2CH3,H2G,H3G,H4G,H5G), 3.50–3.53(m,1H,H6a G),3.74–3.79(m,1H,H6b G),4.06–4.15 (m,1H,OH),4.54–4.58(m,2H,2×OH),4.65(bs,1H,OH), 4.89(d,1H,J=4.9Hz,H1G),4.93(t,1H,J=4.0Hz,NH),5.18(t, 1H,J=5.14Hz,NH),6.12(s,1H,H4 Ar),6.29(s,2H,H1 Ar, H8 Ar),7.01–7.04(m,1H,H7Ar),7.31(d,1H,J=5.37Hz,H5 Ar), 7.50–7.52(m,2H,H5Ar,H6Ar),7.81–7.79(m,1H,H4Ar)ppm.13C NMR(DMSO-d6,100MHz):ı14.18,14.27,17.05,17.78,37.53, 42.05,48.64,58.06,61.64,64.01,70.40,70.56,78.13,78.35,92.97, 93.04,95.59,104.09,114.01,114.17,118.64,122.50,123.73, 127.53,128.29,128.51,130.23,132.90,147.93,148.82,148.85, 149.40,149.47,150.81,153.23,167.05.ppm.IR(KBr)3422,2926, 1670,1522,1495,1400,1270,1201,1076,1016,888,747cm−1. MS(ESI)m/z(relative intensity)620(MH+,100);HRMS(ESI): Calculated for C34H42N3O8[M+H]+620.2972,found620.2971.2.2.Preparation and characterization of liposomesLiposomes were prepared by the dryﬁlm method.Three dif-ferent lipid compositions were used for the preparation:namely PC,PC/PG(1/9,molar ratio),and PC/SA(9/3,molar ratio)(Pavelic et al.,2005).The empty liposomes were used for the rheological and textural studies.In brief,the lipid components(26mmol/l) were dissolved in methanol and the solvent later removed by evaporation on a rotary vacuum evaporator(Büchi R-124,Büchi Labortechnik,Flawil,Switzerland).The lipidﬁlm was rehydrated in 10ml of distilled water(pH6.7)and hand-shaken for10min.The liposome suspension was kept in a refrigerator overnight before the size reduction and further characterization.Liposomes containing dyes were prepared in the same ly,the lipid components were dissolved in methanol and rhodamine dye was added in the organic solution(2␮mol/l).The rhodamine dyes,MP-4and MTJ-12(Fig.1)served as the model ﬂuorescent compounds and were especially synthesized to have the targeted lipophilicity.The dyes were designed to beﬂuores-cent only at a pH value of4while being non-ﬂuorescent at pH values higher than6.The solvent was removed by evaporation and the lipid/compoundﬁlm rehydrated by10ml of phosphate buffer(pH7.4)and hand-shaken for10min prior to storage at 4◦C overnight.To remove unentrapped rhodamine dye the lipo-somal suspension was ultracentrifuged(80000g,30min,Sorvall®WX100,Thermo Scientiﬁc,Waltham,Massachusetts,USA)and the pellet resuspended in10ml of distilled water(pH6.7).Liposomes of various sizes were prepared by the probe sonica-tion;the liposomal suspensions were cooled in an ice bath and sonicated three times at continuous cycle for20s at40%ampli-tude by a Cole Parmer Ultrasonic Processor500W(Cole Parmer Instruments,Vernon Hills,Illinois,USA).All liposomal suspensions were characterized for size by dynamic light scattering and zeta potential with a Zetasizer Nano ZS(Malvern Instruments Ltd.,Worcestershire,UK).J.Hurler et al./International Journal of Pharmaceutics456 (2013) 49–5751Fig.1.Rhodamine dye derivatives.2.3.Preparation of hydrogelsHydrogels were prepared as described earlier(Hurler et al.,2012b).In brief,Carbopol hydrogels were prepared by blendingof Carbopol Ultrez10powder in distilled water(0.5%w/w,respec-tively)and adding triethylamine for neutralization.The amount oftriethylamine was adjusted to obtain hydrogels with a pH valueof7.The gels were allowed to swell at room temperature for24hbefore further experiments.Chitosan hydrogels were prepared as previously described(Hurler et al.,2012b).In brief,high molecular weight chitosan,2.5%(w/w),was manually mixed into a blend of acetic acid(2.5%,w/w)and glycerol(10%,w/w).The plain chitosan hydrogel(control,notcontaining glycerol)was prepared in the same manner as chitosanhydrogels containing glycerol and liposomes.The hydrogels wereallowed to swell for at least48h at room temperature before furtheruse.2.4.Preparation of liposomes-in-hydrogelsHydrogels were prepared as described in Section2.3.After theswelling time,10%(w/w)the liposomal dispersion was added andstirred carefully by hand until an even distribution within thehydrogel was achieved(Hurler et al.,2012b).2.5.Release of rhodamine dyes from liposomes into hydrogel indye-in-liposome-in chitosan hydrogel systemLiposomes-in-hydrogels made of chitosan were prepared asdescribed in Section2.4.The liposomes contained either MP-4orMTJ-12rhodamine dyes.All chitosan hydrogels had a pH value of4.As the liposomes were prepared with a buffer of pH7.4,the rho-damine dyes within the liposomes were notﬂuorescent.However,when the incorporated dyes started to diffuse out of the liposomesinto the hydrogel vehicle,the rhodamine compounds becameﬂu-orescent and thus detectable asﬂuorescence within the hydrogels.The release of rhodamine compounds was determined at differenttime intervals(15,30,45,60,75,90,105,120,135,150,180,210,240,270and300min)ﬂuorimetrically using a Tecan plate reader,Saﬁre2(excitation wavelength520nm for MP-4,514nm for MTJ-12,emission wavelength560nm for MP-4,554nm for MTJ-12).Themeasuredﬂuorescence activities were normalized.The list of preparations evaluated for their respective dye releaseis given in Table1(without empty liposomes).All measurements were performed in triplicate.2.6.Rheological evaluation of hydrogelsThe Carbopol and chitosan hydrogels,both those which wereempty and those containing incorporated PC liposomes,werecharacterized with regard to their rheological properties using aCS-rheometer(RheoStress RS1001Ncm,Peltier TC81,Haake,Germany).A cone/plate C35/1◦(0.05mm)measurement systemwas used at20◦C in all experiments(Pavelic et al.,2001).2.7.Texture analysis of chitosan hydrogelsTexture analysis of the hydrogels was carried out at room tem-perature(TA-XT plus Texture Analyser,Stable Micro Systems Ltd.,Surrey,UK)as previously described(Hurler et al.,2012b).In brief,50g of formulation wereﬁlled into a standard beaker.A disk(40mm in diameter)was placed5mm under the gel surface andthen pushed into the gel(10mm at a speed of4mm/s,respec-tively)and redrawn again.Gel hardness was determined from theresulting force-time plot,and cohesiveness and adhesiveness of thehydrogels were calculated.Each sample was measuredﬁve times.Experiments were per-formed in triplicate.2.8.Fluid afﬁnity testing of hydrogelsThe Carbopol and chitosan hydrogels,both the empty hydro-gels and liposomes-in-hydrogels,were tested with respect to theirpotential to handle wound exudates.The standard test we usedfor this purpose is described in the European norm,“BS EN13726-1:2002Test methods for primary wound dressings.Part1Aspectsof absorbency,Section3.4,Fluid afﬁnity of amorphous hydrogelwound dressings”(Thomas et al.,2005).The gelatin(35%,w/w)which was selected to mimic a drywound was prepared in Solution A(salt solution of sodium/calciumchloride containing142mmol/l of sodium ions and2.5mmol/lof calcium ions).The concentrations of ions were adjusted to becomparable to those present in serum and woundﬂuid(BS EN13726-1:2002).The swollen gelatin(10±0.1g)wasﬁlled into the barrels of60ml syringes,after removing the tip-end of the syringes andthen closing this end with a rubber plug to generate aﬂatsurface.Hydrogel(10±0.1g),namely the empty Carbopol hydro-gel,liposomes-in-Carbopol hydrogel,empty chitosan hydrogelor liposomes-in-chitosan hydrogel,wereﬁlled onto the top ofthe stiffened gelatin plug.After incubation for48h±30min at25±2◦C,the hydrogels were removed gently from the gelatin andre-weighed.The same procedure was performed using the agar(2%,w/w)instead of gelatin in order to mimic the exuding wounds.The agarwas prepared in the same salt solution as was used for gelatin toemulate wound liquid.The results are presented as the percentage weight gain and cor-responding weight loss of the formulation after the test comparedwith their original weight.All tests were performed in triplicates.52J.Hurler et al./International Journal of Pharmaceutics456 (2013) 49–57Table1Liposome characteristics(n=3).Rhodamine derivative Lipid composition Non-sonicated/sonicated Size[nm]PI Zeta potential[mV]–PC ns>1000a1 1.63±0.09PC s174.2±69.50.39 1.45±0.02PC/PG ns>1000a1−32.33±0.41PC/PG s124.7±60.70.24−27.20±1.42PC/SA ns>1000a163.37±0.73PC/SA s144.0±87.20.3844.00±0.57MP-4PC ns>1000a10.65±0.04PC s98.7±70.90.380.92±0.07PC/PG ns>1000a1−12.20±0.10PC/PG s112.8±63.90.3−11.15±0.15PC/SA ns>1000a163.65±0.35PC/SA s249.3±214.30.743.55±0.45MTJ-12PC ns>1000a1 4.72±0.14PC s157±40.80.35 4.20±0.21PC/PG ns>1000a1−13.45±0.25PC/PG s117.2±85.20.31−10.35±0.05PC/SA ns>1000a163.75±0.55PC/SA s152.9±54.10.8143.50±1.20a Size is an estimate due to PI>0.7.2.9.Statistical evaluationThe student’s t-test was used for comparison of two means.A signiﬁcance level of p<0.05was considered to be signiﬁcant.3.Results and discussion3.1.Liposome characteristicsLiposome characteristics are shown in Table1.The incorpora-tion of rhodamine dyes into liposomes(over99%of the starting concentration)resulted in aﬁnal dye concentration in liposomes of0.2␮M for both MP-4and MTJ-12.To test whether the charge on the liposome surface is inﬂuenc-ing the release of incorporated compounds we prepared liposomes of three different lipid compositions,varying the liposomal surface net charge.PC liposomes exhibited a low positive charge,whereas PC/PG liposomes exhibit a distinguished negative zeta potential and PC/SA liposomes a highly positive charge,respectively(Table1). The incorporation of dye(Fig.1)into the liposomes resulted in the changes of zeta potential of the negatively charged liposomes (Table1).It appears that both dyes signiﬁcantly reduced the neg-ative surface charge of PC/PG liposomes,which can be explained by their positive charge.Dyes become positively charged upon crossing the lipid bilayer due to the change in pH(Fig.2)and are probably electrostatically attracted to the negatively charged surface of PC/PG liposomes,thus reducing their zeta potential.To determine the effect of liposome size on the release pro-ﬁle of incorporated dyes,vesicles of two distinguished sizes were prepared.The non-sonicated liposomes were clearly of a multil-amellar nature,whereas the sonicated liposomes were probably oligolamellar.The size of sonicated liposomes was found to be similar for the empty liposomes,liposomes containing MP-4and liposomes containing MTJ-12.Although the size of MP-4PC/SA seems to be larger compared the other sonicated liposomes,due to their high PI value(0.7),this could be the result of an aggre-gation of the liposomes rather than the actual sizes of liposomes (Table1).3.2.Release of dye from the dye-in-liposomes-in-chitosanhydrogelThe liposomes-in-hydrogel systems represent rather compli-cated models with respect to the determination of factors which affect the release of liposomally associated active compounds,as well as the choice of method to be used to determine the release. The drug needs toﬁrst be released into the hydrogel,followed by its diffusion through the hydrogel and out of the hydrogel.Often,only the amount of drug released from liposomes-in-hydrogel is mea-sured in the acceptor medium(Hurler et al.,2012a).Our goal was to determine the release of drug/dye into the hydrogel and the factors affecting such release.Therefore,our focus was on liposome char-acteristics,rather than the effects of polymer concentration.It has been previously reported that polymer concentration,especially an increase in polymer concentration,can lead to a decrease in the release of liposome-associated drug as reported for liposomes-in-carbomer hydrogels(Dragicevic-Curic et al.,2009).The release kinetics of liposome-entrapped hydrophilic com-pounds from the gels can be determined by liposome characteris-tics(Mourtas et al.,2008a).In the case of amphiphilic or lipophilic drugs,the lipophilicity of the drug as well as its aqueous solubil-ity will determine the partitioning of the drugs into theaqueous Fig.2.Non-charged non-ﬂuorescent spirocyclic form(a)of rhodamine dye incorporated in liposomes at higher pH and positively charged open form(b),formed upon crossing the liposome bilayer,at lower pH.J.Hurler et al./International Journal of Pharmaceutics 456 (2013) 49–5753media of the hydrogel (Mourtas et al.,2007).To determine the release of the drug from liposomes incorporated in the hydrogels,the method originally developed by Peschka et al.(1998)and modi-ﬁed by Pavelic et al.(2001,2004)and Mourtas et al.(2007)has been reported.However,the method has several limitations.To avoid these limitations,we synthesized pH-sensitive ﬂuorescent dyes to gain a deeper insight into the release of the dye within the gels,avoiding the presence of additional gel as in the agarose method (Peschka et al.,1998).In this study,the release of two rhodamine dyes,MP-4and MTJ-12exhibiting different log p values,namely 4.17(MP-4)and 2.32(MTJ-12),respectively,was followed.The role of lipophilicity of drugs on their release from liposomes in liposomes-in-chitosan hydrogels was investigated.We followed the effect of the liposome charge and size and the results are presented in Fig.3.It is evident that lipid composition inﬂuenced the release of dyes out of liposomes and into the chitosan hydrogel.Liposomes with a negative zeta potential (PC/PG)exhibited increased release of both dyes into the hydrogel,whereas liposomes bearing positive charges (PC/SA)had a decreased release of dyes into the hydrogel as compared to the release measured from neutral liposomes (PC)(Fig.3).This was observed for liposomes of both size ranges,namely non-sonicated and sonicated liposomes.Interestingly,the release of MTJ-12from PC/PG and PC/SA lipo-somes reached an early equilibrium state (Fig.3C and 3D);at the beginning MTJ-12was released from liposomes faster than the more lipophilic MP-4dye.One possible explanation can be that due to the more hydrophilic character of MTJ-12(log p =2.32)compared to MP-4,it diffuses faster into the hydrophilic chitosan hydrogel.However,the neutral liposomes containing MTJ-12showed a sim-ilar release pattern to that seen for the neutral MP-4-containing liposomes.The release of MP-4during the ﬁrst 120min was found to be linearly correlated against the square root of time,which is in agreement with the Higuchi square root law.However,for MTJ-12the release only followed that law for the ﬁrst 60min (data not shown).It appeared that the release of both rhodamine compounds was following a Fickian diffusion in the beginning of the release process,followed by a more steady–state release.Similar observa-tions were reported for lidocaine HCl in the liposomes-in-Carbopol hydrogel systems (Glavas-Dodov et al.,2002)and for griseofulvin in liposomes in both Carbopol-and hydroxyethyl-cellulose-hydrogels (Mourtas et al.,2007).time [ h]123456r e l a t i v e f l u o r e s c e n c e i n t e n s i t y0,00,10,20,30,40,50,6time [ h]123456r e l a t i v e f l u o r e s c e n c e i n t e n s i t y0,00,10,20,30,40,50,6time [h]123456r e l a t i v e f l u o r e s c e n c e i n t e n s i t y0,00,10,20,30,40,50,6time [ h]0123456r e l a t i v e f l u o r e s c e n c e i n t e n s i t y0,00,10,20,30,40,50,6BACDPC in hydrogel PC/PGPC/SA in hydrogelFig.3.Release of MP-4(A,B)and MTJ-12(C,D)from phosphatidylcholine liposomes-in-chitosan hydrogel.Both non-sonicated liposomes (ﬁlled symbols)and sonicatedliposomes (open symbols)were tested.*signiﬁcant vs.PC MP-4(p <0.05);**signiﬁcant vs.PC MTJ-12(p <0.05)(n =3).54J.Hurler et al./International Journal of Pharmaceutics456 (2013) 49–57 Chitosan hydrogel consists of positively charged chains.Inter-actions between the positively charged chains and the negativelycharged liposomes might disturb the liposomal membrane andfacilitate diffusion of the rhodamine dyes out of the liposomes andinto the hydrogel.Neutral liposomes are expected to interact lesswith the chitosan network in the hydrogel,thus the release fromthose types of liposomes will be slower,as was observed(Fig.3).This could explain why the release from positively charged lipo-somes was the most sustained of all liposomes ly,positively charged liposomes are repelled by the chitosan chains,leaving the liposomal membrane undisturbed and preventing thedye molecules from diffusing into the hydrogel.The hydrogelmatrix is also expected to protect liposomes from the inﬂuenceof other excipients within the hydrogel(Mourtas et al.,2008b).Mourtas et al.(2007)proposed that liposomes act as reser-voirs that hold lipophilic drugs in gels and release them at therate determined by the total amount of drug present in the gel.Itwas also suggested that the diffusion of the released drug throughthe hydrogel is not the rate-limiting factor as it is faster than therelease from liposomes into the hydrogel.DiTizio et al.(2000)found that liposomes composed of dipalmitoylphosphatidylcholine(DPPC),distearoylphosphatidylglycerol(DSPG)and cholesterol invarious ratios had varying degrees of afﬁnity for the gelatin-basedgel matrix.Similarﬁndings were reported by Liu et al.(2012),who stated that the integrity of liposomes and the subsequentrelease proﬁle of entrapped calcein is determined by hydrophobicinteractions between poly(N-isopropylacrylamide)hydrogel and liposomes.Cohen et al.(2012)showed a correlation between the lipid composition of liposomes,their leakage stability and subse-quently their release properties.Liposome size did not inﬂuence drug release from liposomes bearing neutral(PC)and positive(PC/SA)zeta potential as after 5.5h the relativeﬂuorescence intensity was about0.3.However, the release from sonicated liposomes reached equilibrium faster than non-sonicated ones(Fig.3B).Smaller liposomes with negative zeta potential(PC/PG)exhibited sustained release compared to the bigger,non-sonicated liposomes of the same charge(Fig.3).This is in agreement with Ruel-Gariepy et al.(2002)who reported a slower release of liposomally-entrapped hydrophilic carboxyﬂuorescein from chitosan-␤-glycerophosphate hydro-gel when liposome size was increased from100to280nm. Neutral liposomes are not expected to get involved in elec-trostatic interactions with chitosan molecules.However, hydrophobic interactions may take place(Ruel-Gariepy et al., 2002).It is expected that the large liposomes will release the incor-porated drug into the hydrogel in a manner controlled either by the degradation of the chitosan matrix or by the long term desta-bilization/degradation of the lipid bilayers within the liposomes, depending on the drug’s lipophilicity(Ruel-Gariepy et al.,2002). The difference in the lipophilicity did affect the release properties of the rhodamine dyes to the certain extent.After about75min, MTJ-12PC/PG ns preparations reached equilibrium and theﬂuo-rescence did not increase after that time point(Fig.3C).In contrast, MP-4preparations did not reach equilibrium until after more than 120min(Fig.3A and B).MP-4is more lipophilic than MTJ-12and seems to diffuse slower through the lipid bilayer of the liposomes into the hydrophilic gel as compared to the more hydrophilic com-pound MTJ-12.Even though the determination of drug release from liposomal hydrogels is rather complex,it is possible to manipulate/optimize the release of drugs from the liposomes into the hydrogel,and subsequently from the hydrogel.The physicochemical interplay between lipophilicity of the drug,liposomal lipid composition and liposomal size,in combination with the properties of the hydrogel has to be taken into consideration.Shear rate [1/s]050100150200Shearstress[Pa]50100150200250300Shear rate [1/s]050100150200Shearstress[Pa]50AABFig.4.Flow behavior of Carbopol hydrogel with and without incorporated lipo-somes(A)and chitosan hydrogel with and without incorporated glycerol and liposomes(B).(n=3).3.3.Characterization of hydrogelsHydrogels that are used in therapy are often mixtures of several ingredients such as drug,drug vehicle(polymer)and humectants. These additives may change the textural and rheological properties of the hydrogel,affecting their performance in vivo(Hurler et al., 2012b).3.3.1.Inﬂuence of liposomes on rheological properties and textureIn this study we have focused on the rheological character-ization of liposomes-in-hydrogels,and the results are shown in Fig.4(A and B).The plain Carbopol hydrogel exhibited higher shear stress levels at increasing shear rate compared to the liposomal Carbopol hydrogel.A similar observation was reported by Pavelic et al.(2001).Carbopol gels behave predominantly as the elastic solids and have unique rheological properties compared to the other types of gels(Mourtas et al.,2007).It is known that an increase in carbomer concentration induces the domination of elastic over viscous behavior in hydrogels(Dragicevic-Curic et al.,2009).The concentration used in our experiments(0.5%,w/w)was optimal with respect to the planned application of the hydrogels,i.e.on wounds.The pH is known to affect the hydrogel swelling as well as the rheological and texture properties of Carbopol hydrogels; however the pH in our experiments was maintained in the neu-tral range as reported earlier(Hurler et al.,2012b).Moreover,we incorporated the non-charged liposomes into the Carbopl hydro-gels.Therefore,the resulting changes in the rheological and texture properties upon the addition of liposomes could thus be attributed to the liposomes rather than to a change in the pH.PC liposomes are in theﬂuid state and easily deformed under stress conditions, resulting in lower modulation of the rheological properties of the blank gel.Saturated PC on the other hand is in the gel state at the。

SamuelWilksthe“grandoldman”ofBritishmedicine

263Samuel Wilks was born in Camberwell near London in 1824 and lived for 87 years (T able 1) (1–3). In 1840 he was apprenticed to a general practitioner, Richard Prior. Wilks later married Prior’s widow. In 1842 Wilks became a student at Guy’s Hospital in London. He received the MB degree in 1848 and his MD in 1850 from the University of London. A member of the medical staff at Guy’s Hospital from 1856 to 1885, he also served as fifth curator of the museum at Guy’s Hospital (4). In addition, Wilks was the editor of Guy’s Hospital Reports from 1854 to 1865. 1865 marked Wilks’ paper on Hodgkin’s disease (5). In 1859 he published his Lectures on Pathological Anatomy (6). Wilks was elected a fellow of the Royal Society in 1870. His paper “Historical Notes on Bright’s, Addison’s and Hodgkin’s Diseases” appeared in 1877 (7). Wilks coauthored A Biographical History of Guy’s Hospital with G. T. Bettany in 1892 (8). He served as president of the Royal College of Physicians of London from 1896 to 1899 and, in 1897, he was made a baronet and appointed physician extraordinary toSamuel Wilks: the “grand old man” of British medicineMarvin J. Stone, MDFrom the Departments of Oncology and Internal Medicine, Baylor University Medical Center at Dallas and Baylor Sammons Cancer Center, Dallas, Texas.Presented in part at the 35th annual meeting of the American Osler Society, Pasadena, California, April 2005.Corresponding author: Marvin J. Stone, MD, Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center at Dallas, 3500 Gaston Avenue, Dallas, Texas75246(e-mail:*****************************).Queen Victoria. Figure 1 shows a photograph of Wilks’ distin-guished and commanding appearance.Wilks’ tenure at Guy’s Hospital during the latter half of the 19th century was Guy’s “golden age.” Wilks labeled Tho-mas Addison, Richard Bright, and Thomas Hodgkin the “three great men of Guy’s” (7). In 1856 Wilks published a paper on amyloidosis (lardaceous disease) and probably described the first patient with the primary type, now called AL amyloidosisTable 1. Samuel Wilks (1824–1911)Date Event1824Born in Camberwell (Greater London)1840Apprenticed to general practitioner, Richard Prior 1842Attended lectures in anatomy at Guy’s Hospital 1850Received MD (University of London)1856 (to 1885)Practiced medicine at Guy’s Hospital1856 (to 1865)Served as curator of the museum and editor of Guy’s Hospital Reports1865Wrote paper on “Hodgkin’s disease”1869Published Lectures on Pathological Anatomy 1870Elected fellow of the Royal Society1877Wrote “Historical Notes on Bright’s, Addison’s, and Hodgkin’s Diseases”1878Met William Osler1892Published A Biographical History of Guy’s Hospital (with G. T. Bettany)1896 (to 1899)President of the Royal College of Physicians (London)1897Became baronet and appointed physician extraordinary toQueen VictoriaFigure 1. Portrait of Sir Samuel Wilks by B. Sephton. Used with permission of the Royal College of Physicians.Proc (Bayl Univ Med Cent) 2010;23(3):263–265(9, 10). In the same paper some of Thomas Hodgkin’s original cases on enlargement of lymph nodes and spleen were unknow-ingly redescribed. Wilks had been unaware of Hodgkin’s work on lymph nodes and spleen originally published in 1832 (11–14) until he came across an 1838 citation by Richard Bright(15). Wilks followed with a second paper in 1865 describing “Hodgkin’s disease” and was the first to use the eponym (5, 13, 14, 16, 17). Interestingly, neither Hodgkin nor Wilks useda microscope to examine histopathology in this disorder (14,16). The 1865 paper was published in Guy’s Hospital Reports and, by using the term “Hodgkin’s disease,” Wilks immortal-ized his predecessor (18–22). The eponym not only survives to the present, but Hodgkin’s name is linked to all malignant lymphomas (Hodgkin’s and non-Hodgkin’s). Thus, his name echoes daily throughout the halls of every major medical center in the world (13, 14, 16–23).Wilks published a number of other important papers (T able 2). In 1859 he described inflammatory bowel disease some 70 years before Crohn. In the same year Wilks reported the use of bromide for the treatment of epilepsy (2, 3, 24, 25). In 1863 he described the visceral lesions of syphilis. Seven years later, Wilks reported endocarditis with systemic arterial embolism and, in 1877, he described myasthenia gravis as a clinical entity (2, 26).Wilks had been a student of Thomas Addison and was dis-tressed when, in 1872, Anton Biermer described 15 cases of “progressive pernicious anemia” making no mention of Ad-dison’s previous work. Wilks rose to defend Addison’s prior-ity, pointing out that Addison had lectured on fatal idiopathic anemia as early as 1843 and included it in his 1855 report on diseases of the suprarenal capsules (7).Wilks was known for his outspokenness and truthfulness. He avoided the adulatory styleof contemporary obituariesand once remarked laconically,“I wonder if any medical mandied who was not possessed ofall the virtues.” On becomingpresident of the Royal College ofPhysicians of London in 1896,Wilks inherited the tradition ofannually making assessments ofthe character and achievementsof recently deceased fellows.Wilks’ reviews were more often“verum” than “bonum,” butthese appraisals added to the re-spect for a great physician andan honest man (27, 28). Nev-ertheless, it was said that Wilks’assessments “added a new terrorto death” (4).William Osler was intro-duced to Samuel Wilks’ mono-graph Lectures on PathologicalAnatomy (6)in 1871 by Osler’sclinical mentor, PalmerHoward, when Osler was amedical student (27–29).Osler was so impressed thathe wrote Wilks in 1875, andcorrespondence continuedbetween them about inter-esting cases. In 1878 Oslermet Wilks during rounds atGuy’s Hospital. Osler thenspent a delightful eveningat Wilks’ home. Thereafter,Osler always called on Wilkswhen in London. In 1907Osler delivered his “ClinicalLecture on Erythraemia” (orpolycythemia vera) at Oxford(30). Osler began by com-menting on the recognitionand acceptance of various dis-eases. He mentioned Bright,Addison, and then Hodgkin.He noted that Samuel Wilkshad called attention to Hodg-kin, thus naming the disease,and labeled Wilks the “grand old man today in British medicine.”The Men and Books“snippets” were published by Osler in the Canadian Medical Association Journal in 1912, 1913, and 1914 (27). The third selection was about Wilks, which Osler wrote shortly after Wilks died. The entire series of 36 articles was collected and privately published by Dr. Earl Nation in 1959 in a limited edition of 250 copies (28). The Men and Books monograph was reissued in 1987 (1000 copies) with an introduction by Earl Nation. In the chapter on Wilks, Osler said, “He had a remarkably attractive personality, which age so adorned, that at three score and ten there was no handsomer man in London.” Between 1869 and 1914 the weekly magazine Vanity Fair featured a full-page caricature of a prominent person. Figure 2 shows the Vanity Fair caricature of Samuel Wilks, which appeared in 1892. The picture is signed “Spy,” a well-known caricature artist named Leslie Ward (later Sir Leslie Ward). Osler said that Wilks “had all the things that should accompany old age: fairly good health to the end, an unceasing interest in life, and the affectionate esteem of a large circle of friends” (27).Sir Thomas Barlow, president of the Royal College of Physi-cians from 1910 until 1914, stated the following: “It has been said that Wilks had the genius of observation. I think he also had the genius of friendship, for he was idolised by his students, beloved by his disciples, not only of Guy’s, but of every school in London, and implicitly trusted by the Fellows of the College of Physicians” (2).Osler wrote, “With his death snaps the link between old medicine and the new, the link which united the profession with the famous clinicians of the early part of the last century, Bright, Addison, and Hodgkin” (27, 28).Figure 2. Caricature print of SamuelWilks at age 68 in Vanity Fair, 1892.Photograph obtained from theNational Library of Medicine (orderno. B029055).Table 2. Clinicopathologiccontributions ofSamuel Wilks• Amyloidosis• Hodgkin’s disease• Visceral syphilis• Bromide therapy for epilepsy• Myasthenia gravis• Alcoholic paraplegia andpsychosis• Migraine• Lectures on pathologicalanatomy• Inflammatory bowel disease• Bacterial endocarditis withsystemic arterial embolism• Paget’s disease of boneBaylor University Medical Center Proceedings Volume 23, Number 3 264AcknowledgmentI thank Shawn Guy-Pitts for expert help with preparation of the manuscript.1. Kauntze R. Samuel Wilks. Guy’s Hosp Rep 1970;119(4):353–355.2. Banerjee AK. Sir Samuel Wilks: a founding father of clinical science. J RSoc Med 1991;84(4):44–45.3. Pearce JMS. Sir Samuel Wilks (1824–1911): ‘the most philosophical ofEnglish physicians.’ Eur Neurol 2009;61(2):119–123.4. Cameron HC. Mr. Guy’s Hospital 1726–1948. London: Longmans, Greenand Co, 1954.5. Wilks S. Cases of enlargement of the lymphatic glands and spleen (orHodgkin’s disease) with remarks. Guy’s Hosp Rep 1865;11:56–67.6. Wilks S, Moxon W. Lectures on Pathological Anatomy, 2nd ed. Philadelphia:Lindsay & Flakiston, 1870:490–492.7. Wilks S. Historical notes on Bright’s, Addison’s and Hodgkin’s disease.Guy’s Hosp Rep 1877;22:259–274.8. Wilks S, Bettany GT. A Biographical History of Guy’s Hospital. London:Ward, Lock, Bowden & Co., 1892.9. Wilks S. Cases of lardaceous disease and some allied affections, with re-marks. Guy’s Hosp Rep 1856;2:103–132.10. Kyle RA. Amyloidosis: a convoluted story. Br J Haematol 2001;114(3):529–538.11. Hodgkin T. On some morbid appearances of the absorbent glands andspleen. Med Chir Trans 1832;17:69–97.12. Jones GW. An historical review of Hodgkin’s disease with special ref-erence to its histology and characteristic cells. Ann Med Hist (series 3) 1940;2:471–481.13. Kaplan HS. Hodgkin’s Disease, 2nd ed. Cambridge, MA: Harvard Uni-versity Press, 1980:1–15.14. Stone MJ. Thomas Hodgkin: medical immortal and uncompromisingidealist. Proc (Bayl Univ Med Cent) 2005;18(4):368–375.15. Bright R. Observations on abdominal tumors and intumescence, illus-trated by cases of disease of the spleen. Guy’s Hosp Rep 1838;3:401–460.16. Kass AM, Kass EH. Perfecting the World. The Life and Times of Dr. ThomasHodgkin 1798–1866. Boston: Harcourt-Brace Jovanovich, 1988. 17. Rosenfeld L. Hodgkin’s disease: origin of an eponym—and one that gotaway. Bull N Y Acad Med 1989;65(5):618–632.18. Reed DM. On the pathological changes in Hodgkin’s disease with es-pecial reference to its relation to tuberculosis. Johns Hopkins Hosp Rep 1902;10:133–196.19. Nuland SB. The lymphatic contiguity of Hodgkin’s disease: a historicalstudy. Bull N Y Acad Med 1981;57(9):776–786.20. Wilks S. A short account of the life and works of Thomas Hodgkin. Guy’sHosp Gaz 1909;23:528–532.21. Rose M. Curator of the Dead: Thomas Hodgkin (1798–1866). London:Peter Owen, 1981.22. Wilks S. Unpublished papers of Thomas Hodgkin. Bull N Y Acad Med1970;46(1):67–69 (originally published in Guy’s Hosp Rep 1878;23:55–127).23. Stone MJ. Thomas Hodgkin. In Bynum WF, Bynum H, eds. Dictionary ofMedical Biography. Westport, CT: Greenwood Press, 2007:3:655–657.24. Friedlander WJ. Who was “the father of bromide treatment of epilepsy”?Arch Neurol 1986;43(5):505–507.25. Eadie MJ. Samuel Wilks (1824–1911): neurologist and generalist of themid-Victorian era. J Med Biogr 2008;16(4):215–220.26. Pearce JMS. Mary Broadfoot Walker (1888–1974): a historic discoveryin myasthenia gravis. Eur Neurol 2005;53(1):51–53.27. Osler W. Men and books. III. Samuel Wilks. Canad M Assn J 1912;II:70–71.28. Osler W; introduction by Nation EF. Men and Books. Durham, NC:Sacrum Press, 1987 (originally published, Pasadena, CA: Castle Press, 1959).29. Bliss M. William Osler. A Life in Medicine. Oxford, UK: Oxford UniversityPress, 1999:64.30. Stone MJ. Polycythemia vera: Osler-Vaquez disease. J Med Biogr 2001;9(2):99–103.July 2010265Samuel Wilks: the “grand old man” of British medicine。

Corresponding Author

FREEWAY PERFORMANCE MEASUREMENT SYSTEM (PeMS): AN OPERATIONAL ANALYSIS TOOLTom ChoeOffice of Freeway OperationsCalifornia Department of Transportation District 7120 S Spring StreetLos Angeles, CA 90012Tel: (213 ) 897-0266, Fax: (213) 897-0894tchoe@Alexander Skabardonis*Institute of Transportation StudiesUniversity of California, Berkeley CA 94720-1720Tel: (510) 642-9166, Fax: (510) 642-1246dromeas@Pravin VaraiyaDepartment of Electrical Engineering and Computer ScienceUniversity of California, Berkeley CA 94720Tel: (510) 642-5270, Fax: (510) 642-6330varaiya@For Presentation and Publication81st Annual MeetingTransportation Research BoardJanuary 2002Washington, D.C.July 30, 2001No WORDS: 3537Plus 8 Figures (2000)TOTAL: 5537*Corresponding AuthorABSTRACTPeMS is a freeway performance measurement system for all of California. It processes 2 GB/day of 30-second loop detector data in real time to produce useful information. Managers at any time can have a uniform, and comprehensive assessment of freeway performance. Traffic engineers can base their operational decisions on knowledge of the current state of the freeway network. Planners can determine whether congestion bottlenecks can be alleviated by improving operations or by minor capital improvements. Travelers can obtain the current shortest route and travel time estimates. Researchers can validate their theory and calibrate simulation models.The paper describes the use of PeMS in conducting operational analysis, planning and research studies. The advantages of PeMS over conventional study approaches is demonstrated from case studies on conducting freeway operational analyses, bottleneck identification, Level of Service determination, assessment of incident impacts, and evaluation of advanced control strategiesINTRODUCTIONCaltrans (California Department of Transportation) needs a freeway performance measurement system that extracts information from real time and historical data. PeMS (Pe rformance M easurement S ystem) is such a system. It presents information in various forms to assist managers, traffic engineers, planners, freeway users, researchers, and traveler information service providers (value added resellers or VARs).Caltrans managers can instantaneously obtain a uniform, and comprehensive assessment of the performance of their freeways. Traffic engineers can base their operational decisions on knowledge of the current state of the freeway network. Planners can determine whether congestion bottlenecks can be alleviated by improving operations or by minor capital improvements. Traffic control equipment (ramp-metering and changeable message signs) can be optimally placed and evaluated. Travelers can obtain the current shortest route and travel time estimates. PeMS can serve to guide and assess deployment of intelligent transportation systems (ITS).The purpose of this paper is to present the use of the PeMS as a tool to perform operations studies. The PeMS database and built-in applications offer several advantages in understanding the system performance and analyzing options compared to traditional approaches that are based on limited data due to the high effort and cost involved in field data collection. The use of PeMS maximizes the utility of data from loop detector surveillance systems that often are archived off-line without any processing and analysis. The paper first gives a brief overview of the PeMS system. The following sections present the process and the findings from the application of PeMS by practicing engineers and researchers in conducting freeway operational analyses, bottleneck identification, determining the Level of Service, assessment of incident impacts, and evaluation of advanced control strategies. The last section summarizes the major study findings, and discusses ongoing and future work.PeMS OVERVIEWPeMS obtains 30 second loop detector data in real time from each Caltrans District Transportation Management Center (TMC). The data are transferred through the Caltrans wide area network (WAN) to which all districts are connected. Users can access PeMS over the Internet through a Web browser. The PeMS software architecture is modular and open. It uses commercial-of-the-shelf products for communication and computation. A brief overview of the system components is given below. These are described in detail elsewhere (1).Data ProcessingThe 30 second data received by PeMS consist of counts (number of vehicles crossing the loop), and occupancy (the average fraction of time a vehicle is present over the loop). The software processes the data in real time and• Aggregates 30-second values of counts and occupancy to lane-by-lane, 5-minute values;• Calculates the g-factor of each loop;• Uses the g-factor to calculate the speed for each lane;• Aggregates the lane-by-lane value of flow, occupancy, and speed across all lanes at each detector station (one station typically serves the detectors in all the lanes at one location);Most detectors in California have single loops. The g-factor (effective vehicle length) is used to calculate the average vehicle speeds from the flow and occupancy data. Typically, a constant value for the g-factor is used which leads to inaccurate speeds because the g factor varies by lane, time-of-day, as well as the loop sensitivity. PeMS uses an adaptive algorithm to compute the g-factor per each loop to provide accurate speed estimates. The algorithm has been tested and validated against “ground truth” data from double loop detectors and floating cars (2).Calculation of Link Performance MeasuresA link is defined as a freeway segment that contains a single loop detector (typical detector spacing is one-third to one-half mile). PeMS uses the 5 minute average values of flow and speed to compute the following performance measures: VMT (vehicle-miles traveled), VHT (vehicle-hours traveled), delay and travel time. Details of the computations are presented elsewhere (3).Travel Time Estimation and PredictionPeMS provides trip travel time estimates and shortest routes. You bring up the district freeway map on your Web browser, and select an origin and destination. PeMS displays 15 shortest routes, along with the estimates of the corresponding travel times.PeMS also provides travel time predictions, for example, what will be the travel time 30 minutes from now. The travel time prediction algorithm combines historical and real time data (4). In addition, PeMS displays on the freeway system map the location and details about accidents and other incidents based on information retrieved in real-time from the California Highway Patrol (CHP) website. The PeMS data also can be transmitted to VARs, who provide traveler information services.PEMS APPLICATION 1: FREEWAY OPERATIONAL ANALYSISPeMS was used by Caltrans staff to analyze existing operating conditions in the westbound direction of I-10 freeway during the am peak period. Figure 1 shows the study area. It extends from the Los Angeles/San Bernardino County line to Downtown Los Angeles, for a total length of 30 miles.Figure 2 shows the volume and average speed for the test section at 7:30 am. A major bottleneck exists at the I-10/I-710 interchange. Figure 3 shows a three dimensional contour plot of speeds showing that congestion begins at about 6:30 am lasting until 11:00 am and extends to most of the study area.The traditional approach to obtain performance data involves conducting floating car studies to obtain speed and delay data. This requires a minimum of two days field data collection with four person teams/segment driving instrumented vehicles in three 10-mile segments. This translates into 120 person hours. Additional field data collection to obtain statistically valid results is prohibitive due to the time and cost requirements. Further, several additional data need to be assembled including geometrics (aerial photos, as built plans), and traffic volumes (manual counts, historical data).The use of PeMS brings several benefits. PeMS provides both the input (volumes) and performance data (speed, delay, VMT, VHT) for the study area. Contour and across space plots assist in determining problem locations and their impacts. More importantly, the data can be analyzed over several typical days. The entire analysis can be performed in less than one person day.PEMS APPLICATION 2: BOTTLENECK IDENTIFICATION AND ANALYSISThis example application involves the direct interaction with the PeMS database for customized applications. The objective is to identify where freeway bottlenecks are located, and assess their impacts. An important objective of this analysis is to determine if the bottleneck capacity could be preserved through traffic control measures (ramp metering). The northbound direction of I-5 freeway in Los Angeles was analyzed. First, the PeMS built-in speed and occupancy contour plots were used to pinpoint bottleneck locations along the study section. Observations were performed for several weekdays. This preliminary analyses indicated that a potential bottleneck exists at postmile 29 (a weaving section). Figure 4 shows the average five-minute freeway occupancy at three loop detector locations for a four hour time period (2:00 to 6:00 pm). The loop occupancy at the bottleneck location (loop 716974) is about 11 percent. The downstream loop occupancy (loop 716978) is about 7 percent indicating free flow conditions. In contrast, the occupancy at the upstream loop (loop 71673) increases with time to about 25 percent from 4:00 to 6:00 pm, indicating congested conditions due to the presence of a downstream bottleneck.Next, the 30 sec count and occupancy data for each detector were downloaded from the PeMS database and the results were analyzed in detail using cumulative count and occupancy plots (5). Figure 5 shows the plots for the upstream and downstream loop from the bottleneck. The values of counts and occupancy are appropriately scaled to remove stochastic fluctuations and reveal changes in traffic states. The plot for the downstream detector shows that the cumulative counts and occupancy track each other throughout the analysis period indicating free flow conditions. The opposite is true for the upstream loop.At about 15:30 pm, the cumulative occupancy increases and the cumulative count decreases indicating congested conditions.A broad based approach, another way to study bottleneck locations is by analyzing the speed contour maps. From Figure 3, we can easily identify potential bottleneck locations at postmiles 22 and 32 along the westbound I-10 corridor as the speeds are reduced from free flow conditions to virtually stop and go. Looking at a time slice between 7:30 am to 9:30 am, the second bottleneck at postmile 32 might not have been identified as it would be "buried" amongst the contour of congestion. With the speed contour maps, we can see the lengths of peak hours, formation and duration of bottlenecks, and indications of hidden bottlenecks. A key benefit of the PeMS is that this speed contour map is available for any time period, for any length of corridor 24 hours a day, 365 days a year. This allows engineers to study mid-day congestion periods, weekend peaks, holiday congestion, and alterations of traffic flow patterns due to extended construction road closures.PeMS APPLICATION 3: LEVEL OF SERVICE (LOS) CHARACTERIZATIONThe objective of this PeMS application was to determine the Level of Service (LOS) at several freeway segments per the Highway Capacity Manual--HCM2000 (6). Caltrans and the California Air Resources Board (ARB) are conducting chase car studies to derive speed correction factors to be incorporated into their emission factors for air quality analysis. This process involves recording vehicle speeds at selected freeway segments along with the prevailing operating conditions (LOS) as perceived by the observers. However, it is required to obtain LOS designations based on the actual operating conditions at each test segment. The database included over 37 hours of chase car speed data collected in 250 segments in Los Angeles. The determination of the segments LOS using PeMS was done as follows: • Match test segments with PeMS database• Extract loop data (counts, speed, occupancies) from the loop detectors per segment • Aggregate the data per segment per 15 minutes and compute the segment density (vpm/l)• Determine the segment LOS per HCM2000 (basic freeway sections)Currently, the effort is continuing using PeMS to identify and select test freeway sections with specific LOS to collect additional chase car data.PeMS APPLICATION 4: INCIDENT IMPACTSThe PeMS database was used to analyze the impacts of a major incident in the eastbound direction of I-210 freeway (Figure 6). By utilizing the PeMS plots of speeds and volumes across space it was possible to determine the spatial and temporal impacts of the incident on the freeway, and the time for recovery to normal operating conditions.Figure 6A shows the average speed vs. distance of 10 miles of freeway at 11:00 am. Traffic is free flowing at an average speed of about 60 mph. There are five through lanes on the freeway mainline until postmile 29, where they are reduced to four lanes. The traffic volume is about 6,000 vph (or 1500 vph/lane through the four lane section).At 11:20 am a multi-vehicle collision occurred blocking three out of four travel lanes on the freeway. Figure 6B shows that the average speed drops to about 5 mph at the incident location. The incident lasted about 2.5 hours. Figure 6C shows the vehicle speeds at 2:00 pm shortly after the incident was cleared. The congestion has reached five miles upstream of the incident location. Normal operating conditions on the freeway resumed at 3:10 pm, 1.5 hrs following the incident removal (Figure 6D).Further analysis of the PeMS data revealed the following regarding the incident impacts: Remaining capacity: The discharge rate of vehicles past the incident location on the single travel lane was very low (about 300 vph) the first 10 minutes of the incident.The discharge rate then increased to about 1,400 vph the rest of the incident duration.Assuming a typical capacity range of 8,000-8400 vph for the four lane section, the remaining capacity due to the incident is 17 percent of the capacity under normal conditions. This is higher than the suggested value of 13 percent reported in the HCM2000 (Chapter 25: Freeway Systems).Discharge (“getaway” flow): Following the incident clearance, it was observed that the queued vehicles discharged past the incident location at a rate of 7,400 vph, which is lower than the nominal capacity of the freeway section (8,000-8,400 vph). PeMS APPLICATION 5: ASSESSMENT OF ATMIS STRATEGIESCaltrans and other agencies nationwide have started to deploy Advanced Traffic Management and Information Systems (ATMIS) to manage freeway congestion. Examples include ramp metering, changeable message signs, and incident detection. The most important question to answer is: By how much can ATMIS reduce congestion? PeMS can help answer this question.Congestion may be measured by Caltrans’ definition of delay (when freeway speeds fall below 35 mph), or by using VHT and VMT. We can use PeMS to analyze delay for any section of freeway, and the effectiveness of ramp metering. Figure 7 shows the results for a 6.3-mile section of I-405 from 5.00 to 10.00 am on 6/1/98.The top curve in Figure 7 shows the actual VHT per 5 minutes on the study section from 5 to 10 am. The middle curve is the estimated VHT the same vehicles would spend if ideal ramp metering maintained throughput at capacity. This implies that a certain number of vehicles have to be stored at the freeway entrance ramps (excess demand). The lowest curve is the VHT that would result if demand-shift eliminated queues at ramps. The area between the topand middle curves is the delay that can be eliminated with ideal ramp metering (about 500 veh-hrs in this study section). The area between the middle and lowest curve is the delay due to the excess demand (about 200 veh-hrs). The total delay is then the area between the topmost and lowest curves. The delay due to the excess demand can only be reduced through temporal, spatial or modal demand-shifting. One way to shift demand is to use PeMS to inform travelers that they will face this delay. Travelers that are better off changing their trip departure time, route or travel mode would then do so.DISCUSSIONSignificant investments in ITS infrastructure are underway in California and in most metropolitan areas in the US to manage traffic congestion. Central to this infrastructure is a surveillance system that gathers real-time information from detectors on the state of the system and transmits to TMCs. However, in many cases the surveillance data are simply being archived and they are not analyzed to assist in operational analyses or calculate performance measures. PeMS is a unique data archival, processing and analysis system that allows access to the data and calculates performance measures.PeMS is based on a modular and open software architecture. Currently, it stores data from over 4500 loop detectors in California. All the data are available on line. Users access PeMS through the Internet. PeMS is easy to use; built-in applications are accessed through a Web browser. Custom applications can work directly with the database. There is no need for special access to the agency’s TMC data storage, writing scripts to access the database, or requesting off-site archived historical data.The paper presented a number of case studies to demonstrate how PeMS can be used in operations, planning and research studies. PeMS brings large benefits. It maximizes the utility of the information from surveillance systems, and minimizes the effort and costs of performing studies through traditional data collection methods. Managers can instantaneously obtain a uniform, and comprehensive assessment of the performance of their freeways. Traffic engineers can base their operational decisions on knowledge of the current state of the freeway network, and determine whether bottlenecks can be alleviated by design or operational improvements. PeMS can serve to guide and assess deployment of ITS. Caltrans engineers using PeMS are performing several other operations studies. These include analysis of peaking characteristics (midday and weekend peak), traffic patterns during special events, historical comparisons, planned lane closures, and CHP special programs on congestion management. Some of the ongoing collaborative work between Caltrans and the research team on PeMS includes:Recurrent vs. non-recurrent congestion: Previous widely cited studies suggest that over 50 percent of freeway congestion is incident related (7,8). These studies are based on limited empirical data on freeway operating conditions and several simplifying assumptions on incident frequency, severity and impacts. Previous extensive field studies by the researchteam (9,10) developed a comprehensive data base on incident characteristics, and showed that only a fraction of the reported incidents causes delay. The example PeMS application described in the previous section demonstrated on how to evaluate the incident impacts based on real life data. Work is underway to estimate the amount of incident related vs. recurring congestion using the PeMS database and the incident data collected from the CHP. Simulation models application, calibration and validation: simulation models are increasingly being used to analyze existing operations and evaluate the effectiveness of alternative scenarios. The critical questions regarding the practical application of simulation models are:• Does the model accurately predict the existing bottleneck location(s) and impacts in the study section?• Are the benefits from the simulated design/control improvements significant?First, accurate input data are needed on design, demand and control characteristics, and proper calibration of the model parameters. The PeMS database provides the input data (traffic volumes, link lengths, number of lanes, detector locations) and the performance measures to assess the model accuracy in replicating existing conditions. Contour plots of speed and occupancy can be compared with the model results to verify that the model correctly identifies bottleneck locations. The PeMS flow/occupancy or speed/flow plots at selected locations can be used to adjust the model parameters (free flow speed, capacity or minimum headways) to better match field conditions. Other performance measures produced by PeMS (average speeds, delays, VMT or VHT) can be compared with the simulation outputs to assess the models’ accuracy in replicating observed operating conditions.The second question relates on how the variability in operating conditions affects the confidence of the predicted benefits from the testing of alternative scenarios (e.g., is the predicted 2 percent improvement significant?). This has not been investigated in past simulation studies, because the data were collected during a single day. PeMS can be used to readily assess the variability in the input data and performance measures for the study section over a long period of time. Figure 8 shows the distribution of travel times for a 22 mile section of I-405 in Orange County, California, during the am peak for a typical incident-free weekday during 1998. In this example, it would be really hard to determine that small predicted improvements are significant.Currently, we are analyzing a section of a 10 mile section of I-210 freeway using the FREQ macroscopic simulation model (11), and a 15 mile section of I-10 freeway using the PARAMICS microscopic simulator (12). A key objective of this work is to automate the input/output data between PeMS and simulation models in order to minimize the effort for the models’ application.Performance Measures: It is widely recognized that planning and operational decisions should be based on the transportation system performance measures. PeMS’ premise has been to produce performance measures that are based on real data that can be easily understood by the system manager (VMT, VHT) and the system user (travel time). PeMSalso provides travel time reliability measures (Figure 8) which is perceived to be of high importance by travelers. Work is continuing to expand the built-in PeMS applications to produce performance measures for planning applications including areawide performance indicators and growth trends.The usefulness of the PeMS system depends on the loop detector data accuracy. Detector failures result in lost and unreliable data. PeMS includes a set of diagnostics to check the incoming loop data for accuracy and reliability. It also provides information on the number of data samples received daily and spatial/temporal data dropouts. In addition, PeMS includes procedures to “fix” data holes at a location based on information from adjacent detector stations as appropriate. However, there is no substitute for accurate data and any agency installing and operating freeway surveillance systems which are primarily designed for real-time operating strategies must have a plan for intensive maintenance of the field and communications equipment.ACKNOWLEDGEMENTSThe PeMS project is supported by grants from Caltrans to the California PATH Program, National Science Foundation Grant CMS-0095739 and EPRI/DoD Complex Interactive Networks Initiative Contract under WO8333-04. We are very grateful to engineers from Caltrans Districts 3, 4, 7, 8 and 12 and Headquarters for their encouragement, understanding, and patience. They continue to shape the evolution of PeMS vision, to monitor its progress, to champion PeMS within Caltrans. Without their generous support this project would not have reached such a mature stage.The contents of this paper reflect the views of the authors who are responsible for the facts and the accuracy of the data presented herein. The contents do not necessarily reflect the official views of or policy of the California Department of Transportation. This paper does not constitute a standard, specification or regulation.REFERENCES1. Chen, C., K. Petty, A. Skabardonis, P. Varaiya, and Z. Jia, “Freeway PerformanceMeasurement System: Mining Loop Detector Data,” paper 01-2354, presented at the 80th TRB Annual Meeting, Washington DC., January 2001 (forthcoming Transportation Research Record).2. Jia, Z., et al, “The PeMS Algorithms for Accurate Real-Time Estimates of g-Factors andSpeeds from Single Loop Detectors,” 4th IEEE ITSC Conference, Oakland, CA, 2001.3. PeMS Development Group, “PeMS: Calculations with Loop Detectors,” PeMS Website, 2001.4. Rice, J., and E. Van Swet, “A Simple and Effective Method for Predicting Travel Timeson Freeways, “ PATH Working Paper, Institute of Transportation Studies, University of California, Berkeley, June 2001.5. Cassidy, M.J., and R.L. Bertini, “Some Traffic Features at Freeway Bottlenecks,”Transportation Research B, Vol 33B, pp.25-42, 1999.6. Transportation Research Board, “Highway Capacity Manual,“ Washington, DC., 2000.7. Lindley, J.A., 1986, “Qualification of Urban Freeway Congestion and Analysis of RemedialMeasures, FHWA Report RD/87-052, Washington., D.C.8. HICOMP Report, 1992, “Statewide Highway Congestion Monitoring Program,” Caltrans,Division of Traffic Operations, Sacramento, CA.9. Skabardonis, A., et al, "The I-880 Field Experiment: Database Development and IncidentDelay Estimation Procedures," Transportation Research Record No, 1554, 1996.10. Skabardonis, A., K. Petty, and P. Varaiya, “Evaluation of Freeway Service Patrol at a LosAngeles Freeway Site,” PATH Research Report UCB-ITS-PRR-98-13, Institute of Transportation Studies, University of California, Berkeley, 1998.11. May, A.D., et al, “Integrated system of freeway corridor simulation models,”Transportation Research Record No. 1320, 1991.12. Quadstone Ltd. PARAMICS ModellerV3.0 User Guide and Reference Manual.Edinburgh, February 2000LIST OF FIGURESFigure 1. The Test Section (WB I-10)Figure 2. Flow and Speed Along WB I-10 7:30 am 9/14/2000 Figure 3. Speed Contour Plot along 30 miles of WB I-10Figure 4. Detector Occupancy vs. TimeFigure 5. Cumulative Count and Occupancy PlotsFigure 6. Incident ImpactsFigure 7. Vehicle-Hours Traveled (VHT) under different scenarios Figure 8. Distribution of Travel TimesFigure 1. The Test Section (WB I-10)Choe/Skabardonis/Varaiya17Figure 5. Cumulative Count and Occupancy Plots。

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Orthogonal Laplacianfaces for Face Recognition
Deng Cai
∗
Department of Computer Science University of Illinois at Urbana Champaign 1334 Siebel Center, 201 N. Goodwin Ave, Urbana, IL 61801, USA Phone: (217) 344-2189 dengcai2@ Xiaofei He Yahoo Research Labs 3333 W Empire Avenue, Burbank, CA 91504, USA Phone: (818) 524-3545 hex@ Jiawei Han, ACM Fellow Department of Computer Science University of Illinois at Urbana Champaign 2132 Siebel Center, 201 N. Goodwin Ave, Urbana, IL 61801, USA Phone: (217) 333-6903 Fax: (217) 265-6494 hanj@ Hong-Jiang Zhang, IEEE Fellow Microsoft Research Asia 3F Beijing Sigma Center, No. 49, Zhichun Road, Beijing 100080, P. R. China hjzhang@
1
ﬁnding connected components. Finding a Euclidean embedding of the face space for recognition is the primary focus of our work in this paper. Manifold learning techniques can be classiﬁed into linear and non-linear techniques. For face processing, we are especially interested in linear techniques due to the consideration of computational complexity. The Eigenface and Fisherface methods are two of the most popular linear techniques for face recognition. Eigenface applies Principal Component Analysis [6] to project the data points along the directions of maximal variances. The Eigenface method is guaranteed to discover the intrinsic geometry of the face manifold when it is linear. Unlike the Eigenface method which is unsupervised, the Fisherface method is supervised. Fisherface applies Linear Discriminant Analysis to project the data points along the directions optimal for discrimination. Both Eigenface and Fisherface see only the global Euclidean structure. The Laplacianface method [9] is recently proposed to model the local manifold structure. The Laplacianfaces are the linear approximations to the eigenfunctions of the Laplace Beltrami operator on the face manifold. However, the basis functions obtained by the Laplacianface method are non-orthogonal. This makes it diﬃcult to reconstruct the data. In this paper, we propose a new algorithm called Orthogonal Laplacianface. O-Laplacianface is fundamentally based on the Laplacianface method. It builds an adjacency graph which can best reﬂect the geometry of the face manifold and the class relationship between the sample points. The projections are then obtained by preserving such a graph structure. It shares the same locality preserving character as Laplacianface, but at the same time it requires the basis functions to be orthogonal. Orthogonal basis functions preserve the metric structure of the face space. In fact, if we use all the dimensions obtained by O-Laplacianface, the projective map is simply a rotation map which does not distort the metric structure. Moreover, our empirical study shows that OLaplacianface can have more locality preserving power than Laplacianface. Since it has been shown that the locality preserving power is directly related to the discriminating power [9], the O-Laplacianface is expected to have more discriminating power than Laplacianface. The rest of the paper is organized as follows. In Section 2, we give a brief review of the Laplacianface algorithm. Section 3 introduces our O-Laplacianface algorithm. We provide a theoretical justiﬁcation of our algorithm in Section 4. Extensive experimental results on face recognition are presented in Section 5. Finally, we provide some concluding remarks and suggestions for future work in Section 6. 2
Keywords
Appearance-based vision, face recognition, Locality preserving projection, Orthogonal locality preserving projection,
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INTRODUCTION
Recently, appearance-based face recognition has received a lot of attention [20][14]. In general, a face image of size n1 × n2 is represented as a vector in the image space Rn1 ×n2 . We denote by face space the set of all the face images. Though the image space is very high dimensional, the face space is usually a submanifold of very low dimensionality which is embedded in the ambient space. A common way to attempt to resolve this problem is to use dimensionality reduction techniques [1][2][8][12][11][17]. The most popular methods discovering the face manifold structure include Eigenface [20], Fisherface [2], and Laplacianface [9]. Face representation is fundamentally related to the problem of manifold learning [3][16][19] which is an emerging research area. Given a set of high-dimensional data points, manifold learning techniques aim at discovering the geometric properties of the data space, such as its Euclidean embedding, intrinsic dimensionality, connected components, homology, etc. Particularly, learning representation is closely related to the embedding problem, while clustering can be thought of as