Representation and abstraction are two of the fundamental concepts of computer science. Together they enable “high-level” programming: without abstraction programming would be tied to machine code; without a machine representation, it would be a pure mathematical exercise. Representation begins with an abstract structure and seeks to find a more concrete one. Abstraction does the reverse: it starts with concrete structures and abstracts away. While formal accounts of representation are easy to find, abstraction is a different matter. In this paper, we provide an analysis of data abstraction based upon some contemporary work in the philosophy of mathematics. The paper contains a mathematical account of how Frege’s approach to abstraction may be interpreted, modified, extended and imported into type theory. We argue that representation and abstraction, while mathematical siblings, are philosophically quite different. A case of special interest concerns the abstract/physical interface which houses both the physical representation of abstract structures and the abstraction of physical systems. This paper is intended to be a contribution to the “philosophy of computer science” . This isThe nature of computational abstraction invokes several of these traditional philosophical categories, and is a common theme in the informal arena of computational discussion . It is sFinding a representation for a given specification is the essence of programming: some goal is specified, and the programming task is to locate a suite of programs that satisfy it. At first gloss, specifications employ abstract concepts that involve little or no process information: specifications say “what has to be done” without saying “how to do it”. Presumably, the latter is the job of actual programs. But this is an over simplification. In practice, “programming” and “specification” are relative terms. In particular, one level of programs can serve as the specification of more concrete ones. For example, Pascal  or MiranIn As we said at the outset, the present paper is a contribution to this general area. This work is theoretical and foundational: there are philosophical and mathematical aspects to the research. But there is no empirical component; there are no experimental results.While there is a good amount of contemporary philosophical work aimed at providing a philosophical foundations for abstraction in mathematics ,19,20,21We provide a conceptual and mathematical analysis of “data abstraction” and “representation” and their relationship. In particular, we provide a type-theoretic approach to Fregean abstraction: abstraction generates new abstract types. We demonstrate that abstraction and representation are related to each other as “congruence” and “homomorphism”. However, there is a philosophical twist in that our treatment of abstraction is not based on the normal construction of “Quotient Types”, but on a method of abstraction that has its origins in Frege , and undRepresentation and abstraction come together in the notion of an “abstract data type” ,7,25, thAn abstract data type defines a class of abstract objects which is completely characterized by the operations available on those objects. This means that an abstract data type can be defined by defining the characterizing operations for that type. According to this, an abstract type is somehow constituted by its collection of operations. There are various interpretations of this , but a mA is the carrier type and A. .Here, But what does it mean to say that a type is completely characterized by “defining” its characterizing functions? There are two kinds of definitions that seem appropriate. An “explicit” definition of a function would be one that defines it in terms of something else, presumably in terms of functions from some other type. For example, we might specify the type of queues by their representation as sequences. So that the queue operations are defined in terms of sequence operations. Subsequently, the properties of the definiendum are fixed by the properties of the definiens. This interpretation is adopted in some approaches to specification . AlternaHowever, similar conceptual points arise for both styles. In particular, under both regimes abstract types define abstract objects. This rules out any account where the functions are characterized by some form of physical implementation in which the objects are physical and the operations mechanical operations on these objects. This would not characterize an abstract type. So, to be clear, the characterization we employ follows a traditional philosophical distinction: abstract types are mathematical objects and non-abstract ones refer to physical structures. But be aware that we shall use the terms “abstract” and “concrete” as relative terms. In particular, “concrete types” maybe be mathematical. In contrast, the term “physical type” is taken only to refer to a physical structures.  that have no analogues with the abstract notion of list: not all physical computations will have abstract analogues. Different levels of abstraction support different notions of computation. Any computation programmable at a more abstract level is representable lower down but not visa-versa. This brings us nicely to the following section.The computer science literature contains a great many informal discussions of the phrase, “level of abstraction” including its wider philosophical application . There iAny approach to abstraction in the Fregean mold faces the threat of paradox ,20. The u and v are permutations of each other.We illustrate matters with the move from list to sets that hides various possible levels of abstraction. Consider the principles y from u. This facilitates the following principle of abstraction: two lists are equivalent if they are permutations of each other. Let Here As indicated by the name, this introduces Bags are permutation independent  (ii) Example 4.The disjoint union of the family of abstract typesis the abstract type, “container”.Explicitly,  cons.While these form a family with just three members, there are other possible “container” types such as Sequences and Arrays, and this analysis can be extended in a straightforward way.Let maybe turned into a representation of B in terms of the disjoint union in the obvious way.So, in particular, we get a representation of We are now in a position to define abstraction over such families.Definition 6.Abstraction over Families. Letbe a disjoint union of the family with equality given by the following abstraction principle.where the new terms take the form whereExample 5.As an example we demonstrate how to abstract sets from containers. Using recursion on the structures we are able to define a congruence relation over and bags .The definitions of the other pairs follow suite: together they define extensional equivalence between the types.How is this related to abstraction relative to a single structure? The congruence relation In particular, consider the special case Here the congruence is restricted to the elements of a single abstract type. This yields a new abstract type:Example 6.In the case of our running example, the abstracted type is isomorphic So, abstracting on a family of containers results in the same type (up to isomorphism) as abstracting from a single member.In fact, generally, such single abstractions are isomorphic to the family abstraction.Theorem 1.For each This justifies the use of our original form of abstraction where a new type is abstracted from an individual type.and and or gates, etc. Complex circuits result from composing simpler ones.We have used the term “abstract” in an ambiguous way. Firstly, we have used the term in a relative sense as a member of an abstract/concrete pair, i.e., one member of a pair is more “abstract” than another. But there is also the absolute sense of the term in which a type is mathematical. So far all types have in this sense been “absolutely” abstract. And this applies to all those we have referred to as “concrete”. Of course, in computer science, at some point in the levels of representation/abstraction, the notion of being “concrete” will give way to the “physical” , where aWhile there are significant differences that emanate from the different natures of abstract and physical devices, the representational/abstraction distinction is still applicable. What then becomes of the processes of representation and abstraction?simple mapping account of computation [Given an abstract typeputation  where eaPhysical representation may be understood in terms of the concepts of technical artifacts ,39,40,41Unfortunately, we inherit all the philosophical concerns of the simple mapping account of the nature of physical computation . In partR on However, there is more going on here than mere extensional agreement that is witnessed by the homomorphism. In particular, this is not the only relationship between physical and abstract devices. Abstracting the abstract device from concrete instances requires the uncovering of a congruence relation. Given a collection of physical devicesP and Q are “equivalent”, if they have the same input/output. They may differ in terms of their size and the other physical properties possessed by electronic circuits. When we abstract on this relation we obtain a data type of “abstract circuits”.This yields an abstract device whose mathematical properties are inherited from the structural properties of the various physical devices, i.e., those that survive the congruence. At this point what is a physical property is abstracted as a mathematical one. This is line with the Wittgenstein perspective that mathematical theorems are ‘hardened’ empirical regularities, upon which the former are supervenient. A mathematical ‘proposition’ functions as if it were an empirical proposition “hardened into a rule” . Such abThe representation/abstraction duality is still present in the physical set-up. In the representational case, the use of the concepts of technical artifacts to conceptualize matters seems appropriate. Not so in the case of abstraction. Abstracting from a collection of physical devices yields an abstract characterization of them. Logically, this creates a new concept; it is not artifact specification  but the We shall return to the abstract/physical case when we have made some more general observations about the differences between representation and abstraction. However, the general point is clear. There is more to the relationship between the physical and abstract devices than their extensional agreement: there is also an intentional aspect that manifest itself as one of either representation or abstraction. This takes some of the sting out of the “pancomputationalism ” claim.We earlier alluded to the relationship between “abstraction” and “representation”. In particular, we stated that the two are related via two standard mathematical notions (“congruence” and “homomorphism”). This provides us with a way of conceptualizing the connections between representation and abstraction, and ensures us that we have a complementary pair of notions.The abstraction process itself begins with a congruence relation and implictly defines a homomorphism via the principle of abstraction. The converse is also true: every homomorphism gives rise to a congruence. The following is routine to check.Theorem 2.Given types Then So formally, But even given the mathematical confluence between the two, there is much more to the relationship between concrete and abstract structures than this mathematical one. We shall get to this shortly but first we need to explore the process of abstraction a little more.Are there abstract types that are, in some sense, as abstract as possible. One motivation for this is pragmatic: a desideratum for specification and design is to isolate and hide as many implementation details as possible. Another is located in a more austere interpretation of the notion of abstract data type. Being fixed by the functions of the type could be taken as a demand that the elements of the type are “indiscernible” with respect to the functions of the type, i.e., they fix the notion of equality for the type. To proceed we require following notion.Definition 7.A type  Fully Abstract Structure of a class C of types, of the same signature, if for any Example 7.Consider the class Given this “Galois” style connection between our notions of congruence and homomorphism, we can also characterize fully abstract structures in terms of congruence relations.Theorem 3.A structure Proof. H from Assume that R on G be this isomorphism. Abstraction itself provides a surjective homomorphism F from We know from a previous theorem that, But how do we construct such fully abstract types in a uniform way? This brings the second motivation into the picture. In the next definition we assume that equality Definition 8.Let whereThe first insists that they are indistinguishable as inputs, and the second they are so as outputs. So,  Natural Congruence for which demands that a and For following we have only to observe that any congruence will by definition imply the natural one.Theorem 4.Let (1) (2) If R is any congruence on We may now construct the corresponding abstract type.Definition 9.Let is the Natural Abstraction of In what sense is the natural abstraction fully abstract?Theorem 5.Let (1) The natural abstraction of (2) Every fully abstract type of the class Proof. R on The required homomorphism maps the elements of the given congruence to those of the natural abstraction. For the second part, let Every fully abstract structure is obtained from a natural abstraction, and natural abstractions are those that insist that equality if fixed by the operations. So, fully abstract types become a candidate for a more austere characterization of the notion of abstract data type.While representation and abstraction are mathematically equivalent, in the sense that the notions of “homomorphism” and “congruence relation” are mathematical duals, the activities of representation and abstraction are intentionally quite different. They have different goals and starting points; what governs what is different; what is correct is different.Buried in these remarks are two substantial philosophical differences.One of these concerns their semantic impact. Consider the representation case. The abstract type provides a semantic interpretation for the concrete one in that it provides the correctness conditions for the concrete one: the operations of the concrete type must be in harmony with those of the abstract one. This is fleshed out by the demand that the representation function is a homomorphism. This is a minimalist requirement for the role of semantics: it must supply the conditions of correctness for the use of expressions in the language .In general, a semantic account of a language of any kind must tell us when we are using an expression correctly, and when we are not. The fact that the expression means something implies that there is a whole set of normative truths about my behavior with that expression; namely, that my use of it is correct in application to certain objects and not in application to others…. The normativity of meaning turns out to be, in other words, simply a new name for the familiar fact that, regardless of whether one thinks of meaning in truth-theoretic or assertion-theoretic terms, meaningful expressions possess conditions of correct use. Kripke’s insight was to realize that this observation may be converted into a condition of adequacy on theories of the determination of meaning: any proposed candidate for the property in virtue of which an expression has meaning, must be such as to ground the ’normativity’ of meaning-it ought to be possible to read off from any alleged meaning constituting property of a word, what is the correct use of that word. A semantic account must provide us with an account of what constitutes correct use. Specifically, operations of the concrete type must be correct relative to the corresponding operations of the abstract one. In this sense the representation has a semantic function.the direction of a’ and ‘the direction of b’ refer to the same entity if and only if the lines a and b are parallel. In other words, an understanding of the concept of a direction presupposes an understanding of the concept of parallelism, but not vice-versa. This is the perspective of semantic abstractionism [Abstraction principles also have semantic significance: the semantic interpretation of the functional expressions on the left hand side would appear to be given by the congruence relations on the right hand side, i.e., the latter are semantically prior to the functional expression on the left. For example, in order to understand the term ‘ctionism ,23. Rougctionism  who docuWhile both representation and abstraction have a semantic component, the correctness conditions are reversed. For representation, it is the abstract type that provides the correctness conditions for the concrete one. For abstraction, it is the concrete type that furnishes the semantic interpretation for the abstract one.The most obvious difference between representation and abstraction concerns their underlying ontological assumptions. In the representational case, the construction of a homomorphism from the concrete to the abstract presupposes that both data types already exist. In contrast, in the abstraction scenario, the abstract structure is ontologically dependent upon the more concrete one: it is created from it by abstraction. Abstraction principles are taken to introduce new terms referring to sui-generis objects, and thereby provide a mechanism for the creation of new abstract types. In our example, finite sets are introduced via abstraction from finite lists. However, in the case of representation, no new objects with their types are introduced. We are given both structures ahead of time.This ontological difference between representation and abstraction can be further illustrated by considering the the way these notions are employed in set theory . We illun is a member of Benacerraf’s identification problem [The abstractionist approach is entirely different. First notice that representations are not intended to be definitions, and there are good reasons for not so taking them. There is an immediate concern: which one do we chose? Do we select the Von-Neumann or Zermelo numerals—or one of the other myriad of possibilities? Each of them attributes a different collection of set-theoretic, non-arithmetic, properties to numbers. For example, Zermelo and Von-Neumann differ on whether  problem . AccordiAll this is a criticism only of the definitional perspective. From the representational one, multiple representations are not surprising, indeed they are to be welcomed since the aim of specification is to jettison or hide many of the incidental properties that give rise to such multiplicity. Generally, for abstract types, we would expect the representations to have additional properties and operations that go beyond the abstract version.Dedekind  earlier The real numbers should not be identified with the corresponding cuts because those cuts have “wrong properties”; namely, as sets they contain elements, something that seems “foreign” to the real numbers themselves. Similarly, the natural numbers should not be ascribed set-theoretic or other “foreign” properties; they too should be conceived of “purely arithmetically”. If one wishes to pursue your approach I should advise not to take the class itself  as the number , but rather something new (corresponding to this class), something the mind creates.Dedekind is alluding to the creation of new things, and here abstraction comes to the fore. One interpretation of this is that numbers are to be abstracted: we need to abstract away from all the idiosyncratic properties of the various set-theoretic definitions, and just leave the numerical structure. To see how, consider an indexed family of possible numerical structures.However, the elements of rs. (See  who emplrs. (See . From thrs. (See .) AbstraWhile we have employed a set-theoretic framework for our exposition, the use of set theory as the appropriate medium for the formalization of computational notions is not unproblematic. The arguments of  would apT be a formal theory of an informal body of mathematics M.However, it is not just the data items themselves that raise issues. Feferman  introducT is “adequate” for M, if every concept, argument, and result of M is represented by a (basic or defined) concept, proof, and a theorem, respectively, of T.T is “faithful” to M, if every basic concept of T corresponds to a basic concept of M and every axiom and rule of T corresponds to or is implicit in the assumptions and reasoning followed in M .The Zermelo–Fraekel set theory does not provide a faithful formalization of the computer science notion of type. The primary purpose of the latter is a way of classifying the objects of the language: it acts as barrier to semantic nonsense. Furthermore, for practical reasons, type membership must be a decidable judgment: we require a type-checker to be part of the implementation of the language. While set theory is an adequate formalization of the computational notion of type, it is not faithful: it goes beyond the reasoning associated with the role of types.This argues for a more radical approach in which the computational notion of type is taken as the fundamental one. Indeed, this is implicit in our informal development which took place against the backdrop of functional programming ,15. To fAbstraction and representation are two of the fundamental notions of contemporary computer science. While they are mathematically dual notions they are philosophically quite different.While they both have semantic import, they differ in terms of what provides the semantic interpretation of what. For abstraction, the source type provides the semantic foundations for the abstracted one by supplying its equality conditions. For representation, the abstract type supplies the correctness conditions for the source type acting as a representation.Ontologically, they differ in that representation assumes that both structures are in place, whereas abstraction brings new structures into being. Abstraction generates new types, representation enables their use in computation by supplying a more concrete representation.These differences apply equally well to the case where one of the data types is physical. This demonstrates that the relationship between the physical and abstract types goes beyond extensional agreement: it brings an intentional aspect that is materialized by the intentions to locate a representation for one type in another or abstract a new type from an existing one—or a family of such.


Drosophila Plc21C is involved in calcium wave propagation during egg activation. microPublication Biology. 10.17912/micropub.biology.000235For Hu, Q; Vélez-Avilés, AN; Wolfner, MF (2020). Authors requested to correct an omission in their funding acknowledgement:“NIH grant R21-HD088744 (to MFW). NSF Grant 1428922 funding (for the shared Zeiss Elyra Super Resolution Microscope).”The authors correct the funding report to read:“NIH grant R21-HD088744 (to MFW). NSF Grant 1428922 funding (for the shared Zeiss Elyra Super Resolution Microscope). For ANVA: partial support from Cornell’s Department of Molecular Biology and Genetics and its NSF-funded REU program (funded on NSF REU DBI-1659534), and partial support from the Society of Developmental Biology’s Choose Development! Program, which is funded by NSF .”This omission has been corrected online.


The equilibrium of the spirocyclization is environmentally sensitive and can be directly measured by determining the ratio of red to green fluorescence, thereby enabling the generation of ratiometric fluorescent probes and biosensors. Specifically, we developed a ratiometric biosensor for imaging calcium ions (Ca 2+) in living cells and a bioassay for the quantification of NADPH.Environmentally sensitive color‐shifting fluorophores that reversibly switch between a green and red fluorescent form were developed. The equilibrium of the spirocyclization is environmentally sensitive, thereby enabling the generation of ratiometric fluorescent probes and biosensors, including probes for imaging calcium ions (Ca Studying biological processes in living cells through fluorescence imaging depends on the availability of suitable fluorescent probes. Rhodamines are very bright and photostable fluorophores and currently represent the most prominent class of fluorophores for the development of such probes.color‐shifting fluorophores (CSFs) based on spirocyclization, which exist in a dynamic and environmentally sensitive equilibrium between a green and a red fluorescent form. By coupling these CSFs to ligands or proteins, they enable the design of a new type of ratiometric fluorescent probes for biosensing with large dynamic ranges. Such ratiometric sensors have the advantage that their readout is independent of (fluctuations in) sensor concentration.While the absence of fluorescence of the spirocyclic form of rhodamines has been exploited for the creation of numerous (fluorogenic) probes,3, 4 o1) consisting of a coumarin and a benzopyrylium moiety  and the red color of the larger π‐conjugated structure , respectively. However, fluorophore 1 mainly exists in its red zwitterionic form in water , and thus would not allow the generation of CSFs. We therefore attempted to push the equilibrium towards the green spirocyclic state by replacing the carboxyl group of 1 by electron‐deficient amides such as acyl cyanamide (2), acyl sulfonamide (3) and acyl sulfamide (4) , acyl sulfonamide (3) and acyl sulfamide (4) allowed to stepwise increase the D50 value .Our attempts to create CFSs was inspired by previous work on hybrid fluorophores oxy)ethoxy)ethan‐1‐amine] with 1–4 . Notably, probe 8 carrying a N,N‐dimethylsulfonamide moiety showed the largest shift in color upon HaloTag7 labeling .To probe the environmental sensitivity of CSFs towards proteins, we employed HaloTag7, a widely used self‐labeling protein tag,g Figure  with 648g Figure . In vitr2+) indicator.2+‐binding domain into the structure of HaloTag7 resulted in chimera in which calcium‐binding affected the equilibrium of spirocyclization of a HaloTag‐bound rhodamine and thereby its fluorescence intensity. We hypothesized that replacement of single‐channel fluorophores by CFSs could offer a ratiometric Ca2+ sensor  or a troponin domain, both known to undergo large conformational change upon Ca2+ binding.8, Ca2+ responsive green  and red fluorescence  . Sensor titration with Ca2+ showed a 14.1‐fold ratiometric fluorescence signal change with a c50 value of 363±14 nM for Ca2+   Figure . For thi) Figure . TitratiM Figure , S8. Thi2+ sensing domain (rHCaMP), these CSF allowed for fluorescence ratiometric measurement of Ca2+ in vitro and in cellulo. CSFs coupled to different protein ligands resulted in probes with up to 2400‐fold fluorescence ratio changes upon target binding. CSFs thus represent a new platform for the generation of ratiometric fluorescent probes, biosensors and bioassays.In summary, we report novel environmentally sensitive fluorophores that reversibly switch between a green fluorescent spirocyclic form and red fluorescent zwitterionic form. Coupled to an engineered fusion of HaloTag7 with a CaK.J. and L.W. are inventors on a patent filed by the Max Planck Society.As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.SupplementaryClick here for additional data file.


The volume effect of iso-oncotic colloid is supposedly larger than crystalloid, but such differences are dependent on clinical context. The purpose of this single center observational study was to compare the volume and hemodynamic effects of crystalloid solution and colloid solution during surgical manipulation in patients undergoing major abdominal surgery.Subjects undergoing abdominal surgery for malignancies with intraoperative goal-directed fluid management were enrolled in this observational study. Fluid challenges consisted with 250 ml of either bicarbonate Ringer solution, 6% hydroxyethyl starch or 5% albumin were provided to maintain optimal stroke volume index. Hematocrit derived-plasma volume and colloid osmotic pressure was determined immediately before and 30 min after the fluid challenge. Data were expressed as median (IQR) and statistically compared with Kruskal-Wallis test.One hundred thirty-nine fluid challenges in 65 patients were analyzed. Bicarbonate Ringer solution, 6% hydroxyethyl starch and 5% albumin were administered in 42, 49 and 48 instances, respectively. Plasma volume increased 7.3 (3.6–10.0) % and 6.3 (1.4–8.8) % 30 min after the fluid challenge with 6% hydroxyethyl starch and 5% albumin and these values are significantly larger than the value with bicarbonate Ringer solution (1.0 (− 2.7–2.3) %) Colloid osmotic pressure increased 0.6 (0.2–1.2) mmHg after the fluid challenge with 6% hydroxyethyl starch and 0.7(0.2–1.3) mmHg with 5% albumin but decreased 0.6 (0.2–1.2) mmHg after the fluid challenge with bicarbonate Ringer solution. The area under the curve of stroke volume index after fluid challenge was significantly larger after 6% hydroxyethyl starch or 5% albumin compared to bicarbonate Ringer solution.Fluid challenge with 6% hydroxyethyl starch and 5% albumin showed significantly larger volume and hemodynamic effects compared to bicarbonate Ringer solution during gastrointestinal surgery.UMIN000017964. Registered July 01, 2015.UMIN Clinical Trial Registry  Recent investigations have demonstrated the benefits of intraoperative goal-directed fluid management . AlthougThe purpose of this study was to compare the volume and hemodynamic effects of crystalloid, HES and Alb during intraoperative goal-directed fluid management in patients undergoing major abdominal surgery.www.umin.ac.jp/ctr; UMIN000017964). During 18-month study period, we enrolled patients scheduled to undergo major, elective abdominal surgery for gastrointestinal, gynecological, or urological malignancies at Toho University Ohashi Medical Center. Patients were excluded from the study if they were younger than 20 years, were pregnant, had an arrhythmia, or underwent a laparoscopic procedure.This prospective observational study was approved by the Ethics Committee of Toho University Ohashi Medical Center  and written informed consent was obtained from all subjects participating in this study. This study was registered prior to patient enrollment at UMIN Clinical Trial Registry  [− 1 h− 1. Either the left or right radial artery was cannulated with a 22-gauge Teflon catheter , and stroke volume was continuously measured by non-calibrated arterial pulse contour analysis . Air bubbles were removed from the line and the arterial catheter was carefully fixed at the wrist to prevent arterial waveform distortion. A central venous catheter was inserted when clinically necessary. The protocol of goal-directed fluid management used in this study was a modification of our previously reported protocol [− 2 was used to the target of intraoperative hemodynamic target but target SVI up to 40 ml m− 2 is allowed dependent on the attending anesthesiologist discretion. Fluid challenges consisted of 250 ml of either BRS, 6% saline-based hydroxyethyl starch 130/0.4 , or 5% albumin . Each fluid challenge consisted of rapid injection of 250 ml fluid using a 50-ml syringe [Prior to anesthesia induction, all study patients received an epidural catheter at mid to low thoracic level. General anesthesia was induced with combination of propofol, rocuronium, fentanyl and maintained with sevoflurane and remifentanil combined with intermittent rocuronium administration. Initially, 6 to 8 ml of 0.375% of ropivacaine was intermittently administered via epidural catheter. The timing and the dose of supplemental epidural ropivacaine were at the discretion of the attending anesthesiologists. Postoperatively, 0.2% ropivacaine supplemented with fentanyl was continuously administered via epidural catheter with elastometric pump. Patients were mechanically ventilated with a fixed tidal volume of 8 ml kg, Japan)  was admiprotocol  and is sprotocol . Basical syringe  and a tyImmediately before each fluid challenge, heparinized arterial blood was collected to determine the hematocrit (Hct) and plasma colloid osmotic pressure (COP). Hct was measured using a standard blood gas analyzer . After centrifugation, plasma COP was measured using a colloid osmometer  with a semi-permeable membrane with a 30-kDa cutoff (SS-030). COP analysis was repeated 30 min after the start of each fluid challenge. This interval was based on our previous study wherein we found that the intraoperative volume effect of crystalloid disappears after about 30 min . This inIn order to eliminate the confounding effects of blood loss and changes in vascular capacitance on the evaluation of volume effect, fluid challenges were excluded if they were concomitant with measurable blood loss, within 2 h after an epidural bolus injection of local anesthetic, vascular clamping/declamping, bolus administration or dose changes in the continuous infusion of vasoactive drugs, and if an additional fluid challenge was required during the 30-min observation period. The change of plasma volume caused by each fluid challenge was evaluated using the following formula :\documeThe hemodynamic effects of each fluid challenge were evaluated as follows. First, the trend of SVI was examined offline and the peak and duration of the SVI change caused by each fluid challenge were determined by two authors who were not involved in the intraoperative management (DT and YK). Then, the time to peak SVI, maximal SVI change, area under the curve of SVI change above baseline, and mean arterial pressure (MAP) change at the time of maximal SVI change were determined and compared.P < 0.05 was considered statistically significant. In this study, we hypothesized that the volume effect of colloid would be 50% larger than the volume effect of crystalloid. Based on this hypothesis, we estimated that 40 measurements for each fluid type were needed to achieve a beta error less than 0.8 and an alpha error of 0.05.Statistical analysis was performed with customized version of R software, ver. 3.4.4   and PrisThe flow of patients and data analysis is summarized in Fig. 2 between the volume effect after BRS, HES and Alb was 0.09, 0.17 and 0.02, respectively).The median increase in plasma volume 30 min after fluid challenge was 7.3%  with HES and 6.3%  with Alb. Conversely, the median increase in plasma after fluid challenge with BRS was only 1.0% . Thus, the volume effects 30 min after fluid challenge with HES and Alb were significantly greater than with BRS; however, there was no significant difference between the volume effects of HES and Alb  with BRS, 8 ml m− 2  with HES, and 5 ml m− 2  with Alb. The maximal SVI was significantly higher after fluid challenge with HES than with BRS or Alb (p < 0.0001). After the fluid challenges, the median area under the curve of SVI was 26 ml m− 2  with BRS, 107 ml m− 2  with HES, and 80 ml m− 2  with Alb; notably, the SVI was significantly higher after fluid challenge with HES or Alb than with BRS (p < 0.0001). The median MAP increase at the time of peak SVI was 2.5 mmHg  with BRS, 6 mmHg  with HES, and 4 mmHg  with Alb; however, there were no significant differences in the MAP increase between the three study fluids.The course of SVI after fluid challenge with each fluid is demonstrated in Fig. In this study, we compared the volume and hemodynamic effects of fluid challenges with crystalloid, 6% HES 130/0.4, and 5% Alb during surgical manipulation in patients undergoing major abdominal surgery. We found greater hemodilution, as well as a larger increase in COP and SVI, after fluid challenges with HES and Alb than with crystalloid.− 1 bolus over 5 min was adequate to reliably discriminate fluid responders from non-responders in post-cardiac surgical patients [The current study has two distinct features. First, all fluid challenges were rapid (finishing in less than 30 min). A meta-analysis by Toscani et al. revealed that fluid challenges that finished in less than 30 min resulted in a higher proportion of responders compared with fluid challenges that took longer than 30 min . Aya et patients . Furtherpatients , 23, andpatients –26. ThusIncreases in plasma volume were sustained for at least 30 min after fluid challenge with HES or Alb, but not with BRS. In patients undergoing major abdominal surgery, intravascular volume may be continuously lost to the interstitial space due to surgical stress and inflammation, as well as to the environment through evaporative loss. These findings suggest that, despite these fluid shifts, a significant proportion of administered HES or Alb remains intravascular, whereas a significant amount of administered BRS is lost from the vasculature after 30 min. Joosten and the colleagues analyzed the data of existing trial and found that the initial hemodynamic change during fluid challenge is independent of the types of fluid . They spSince fluid administration is generally guided by either subjective decision of the attending anesthesia providers or objective hemodynamic parameters, the difference in volume effects between crystalloid and colloid in many clinical studies likely reflects differences in hemodynamic effects. Unfortunately, reports with detailed hemodynamic profiles after fluid challenges are rare. Aya et al. reported that cardiac output peaked 1 min after fluid challenge with 250 ml crystalloid in postoperative ICU patients and the effect was sustained for about 10 min after the completion of the fluid challenge . Gandos We believe that the results of this study have clinical implications. HES was not associated with the improvement of the majority of the outcomes despite the lower fluid requirement in the recent large-scale randomized trial. Instead, the authors found increased incidence of low-stage AKI and concluded that use of HES is not supported . HoweverThis study has several limitations. First, the context of each fluid challenge significantly affects data interpretation. We tried to minimize the influence of factors such as blood loss, changes in vascular compliance , and surgical manipulation. Nevertheless, such adjustments still remain subjective and cannot preclude the presence of confounding factors. The robust results found in this study suggest that the volume effects and subsequent hemodynamic effects of the study fluids are real. Second, COP was determined using a semipermeable filter with a cut-off value of 30 kDa. The renal excretion threshold is around 50 kDa ; therefoIn conclusion, this study showed that the increase in plasma volume after rapid injection of crystalloid during major abdominal surgery was almost completely lost after 30 min. Conversely, rapid injection of both HES and Alb resulted in significantly greater increases in plasma volume and COP compared with BRS. Moreover, increases in plasma volume were accompanied by concomitant increases in stroke volume. These results correspond well with the results of other recent studies and confirm that colloid can reduce the total fluid input during goal-directed fluid management.


Optimized fluid management is a key component of enhanced recovery (ERAS) pathways. Implementation is challenging for pancreatoduodenectomy (PD) and clear guidance is missing in the respective protocol. The aim of this retrospective study was to evaluate the influence of perioperative intravenous (IV) fluid administration on postoperative complications. 164 consecutive patients undergoing PD within ERAS between October 2012 and June 2017 were included. Perioperative IV fluid and morbidity (Clavien classification and comprehensive complication index (CCI)) were assessed. A threshold of more than 4400 ml IV fluid during the first 24 h could be identified to predict occurrence of complications (area under ROC curve 0.71), with a positive and negative predictive value of 93 and 23% respectively. More than 4400 ml intravenous fluids during the first 24 h was an independent predictor of overall postoperative complications . Patients receiving ≥ 4400 ml were associated with increased overall complications , especially pulmonary complications , as well as a higher median CCI . This threshold of 4400 ml intravenous fluid might be a useful indicator for the management following pancreatoduodenectomy. These interventions still have a high morbidity and patients may need a delay up to 6 month to reach their preoperative quality of life4. In an effort to improve those outcomes, the concept of enhanced recovery (ERAS) is increasingly recommended for pancreatic surgery. ERAS pathway aims to reduce the surgical stress in order to shorten patient’s recovery and works in pancreatic surgery6. One of the cornerstone of enhanced recovery is balanced fluid therapy with avoidance of fluid overload. Uncontrolled perioperative fluid administration has potential deleterious impact on postoperative outcome. While fluid overload may lead to interstitial edema, hypovolemia may result in renal dysfunction. For these reasons, implementation of an enhanced recovery protocol for PD is challenging7 and specific guidance on defining fluid balance for PD are required.The outcomes following pancreatoduodenectomy (PD) have improved, with a drastic fall of postoperative mortality from 15 to 20% in the 80sThis study aimed to assess the potential impact of perioperative fluid administration on postoperative outcomes after PD within an ERAS protocol.A total of 178 consecutive patients underwent pancreatoduodenectomy in our institution during the study period. As 14 patients refused the use of their data, 164 patients were included in the analysis. Patients demographics and surgical characteristics are detailed in Table The median total amount of IV fluids POD 0 was 5005 ml (IQR 3963–6124). The median intraoperative IV fluid was 3500 ml (IQR 2575–4500) and was composed by crystalloids  and colloids . The median intraoperative infusion rate was 9 ml/kg/h (IQR 7–11). The amount of IV fluids POD 0 was composed by the addition of intraoperative, and postoperative IV fluids, and both were higher in patients with complications (3500 ml (IQR: 2712–4500) vs 3000 ml (IQR 2000–3687); p value 0.034, and 1400 ml (IQR 1100–1860) vs 1165 (IQR 770–1605); p value 0.024, respectively).As postoperative complications were higher in patients with increased perioperative fluids, the potential correlation between perioperative fluids and postoperative complications was assessed. As presented in Fig. Fig. ). The Area Under the Curve (AUC) was 0.71 (95% CI 0.59–0.83), which is above the 0.70 cut-off indicating moderate accuracy8. The optimal threshold of IV fluids POD 0 as predictor of complications was set at 4400 ml. This threshold provided a sensitivity of 69% and a specificity of 63% with a positive predictive value of 93% and a negative predictive value of 23%. The ROC curve analysis for IV fluids POD 0 and major complications was not contributive (AUC = 0.55). Further ROC curve analyses of IV fluids on POD taking account the body weight (ml/kg/24 h) found an AUC of 0.69 for overall complications and an AUC of 0.49 for major complications. When considering the infusion rate of intraoperative fluids (ml/kg/h) the AUC for overall and major complications were 0.58 and 0.42, respectively.In order to identify a critical threshold, a ROC curve analysis of IV fluids POD 0 (ml/24 h) and overall complications was performed , in comparison of 14 ml/kg/h for Eng et al., and corresponding to a restrictive fluid administration (< 10 ml/kg/h)13, although no standard definition exists. The rate of renal failure in the present study  was in accordance to the 7% rate reported by Weinberg et al.9. Other parameters were comparable with the literature: similar demographics in term of age , gender , mean BMI (25.6 kg/m2 versus 25.8 kg/m212 to 26 kg/m29). As in most studies, a large majority of patients had malignant tumor as indication for PD (86% versus 73.4%10 to 88%12). The ASA score may be lower in the present study with 33.5% of patients with ASA-score of 3 or 4, which ranged from 34.510 to 89.5%12 in other studies. In term of operative parameter, the mean operative time tend to be lower in our data (335 min versus 420 min9 to 445 min11) but with similar vascular resection rate  and blood loss (median blood loss 440 ml versus 350 ml9 to 909 ml11).Comparison between studies on fluid therapy in PD is difficult because of the various definition of fluids  and heterogeneous data. Moreover, most studies did not encompass the use of a systematic enhanced recovery protocol. Nevertheless, our center has a more restrictive fluid administration as in some other centers with a median intraoperative fluid administration of 3500 ml in comparison to 6000 ml for Kulemann et al.18, a multicenter international trial of cardiac output-guided fluid therapy with low-dose inotrope infusion compared with usual care in patients undergoing major elective gastrointestinal surgery. Meantime, a threshold of perioperative IV fluid is a simple and reproducible way to estimate the fluid balance. The ROC analysis identified a threshold of 4400 ml perioperative fluid for complications. Previously, specific thresholds for perioperative IV fluid were identified, for example for open colorectal surgery (> 3500 ml)19 or loop ileostomy closure (> 1700 ml)20. Although the above mentioned threshold of 3500 ml for perioperative fluids was determined for open colorectal surgery, it was previously used by extrapolation for pancreatodudenectomy7. Data for pancreatic resection are sparse and Bruns et al. identified a ratio (infusion rate/glomerula function rate) of 0.15 as predictive of pancreatic fistula21. Available data for liver surgery identified a threshold of an increased weight of 3.5 kg on the second postoperative day which was associated with increased major complications22, but no specific data on fluids were provided. In the present study, the weight difference did not vary between patients with or without complications, possibly indicating that fluid balance evaluation is a complex process.As avoiding fluid overload might improve postoperative outcome after PD, the way to achieve this euvolemia is still matter of debate. Goal directed fluid therapy requires cardiac output monitoring that may be invasive and lacks easily identifiable target. For these reasons it is a challenging measure to implement in daily clinical practice. Further guidance are awaited from the OPTIMISE II trial11. The meta-analysis of Garland et al23 found no difference between restrictive and liberal fluid therapy on overall morbidity  and pulmonary complications . While causes of postoperative respiratory complications are multifactorial, a recent systematic review24 identified enhanced recovery  and goal directed therapy  among other interventions as effective measure to reduce their occurrence. Postoperative pulmonary complications are probably also related to other complications, but the study design as well as the lack of date of occurrence of each complications prevented to conduct a separate detailed analysis of predictive factors, including other complications, of pulmonary complications. As enhanced recovery also encloses goal-directed fluid therapy, the direct effect of fluid management is difficult to isolate. The threshold of 4400 ml would be more on the restrictive side as opposed to the liberal side when considering the various cut-offs reported in the systematic review on fluid regimens in pancreatoduodenectomy by Garland et al23. A fear of a too restrictive fluid regimen is potential tissue hypoperfusion leading to an increased rate of renal failure or altered wound healing. For example, the RELIEF  trial observed an increased rate of acute kidney injury associated with restrictive fluid therapy  among high risk patient undergoing major abdominal surgery25. Of notice, in the RELIEF trial the median intravenous fluid during and up-to 24 h surgery was 3700 ml in the restrictive group and 6100 ml in the liberal group. In the present study no increased renal failure was observed in patients receiving less than 4400 ml.Noteworthy, the 4400 ml threshold was related to increased complications and length of stay. Especially postoperative minor pulmonary complications were increased in patients receiving 4400 ml or more. Similarly, Eng et al. reported an increased rate of pulmonary complications  related to intraoperative infusion when comparing patients receiving more or less than 13.95 ml/kg/h23 who reported in a meta-analysis no significant difference in occurrence of delayed gastric emptying or pancreatic fistula when comparing restrictive to liberal fluid therapy in PD patients. However, some retrospective studies not included in the abovementioned meta-analysis28 were suggesting an increase in pancreatic fistulas associated with excessive fluid. Moreover, a study from Bannone et al. reported an increased incidence of postoperative acute pancreatitis and pancreatic fistula in high-risk patients after pancreatoduodenectomy with an intraoperative fluid administration of ≤ 3 ml/kg/h29. In the present study, the median intraoperative fluid administration was 9 ml/kg/h and no increased rate of pancreatic fistula was observed between both groups.Regarding pancreatic-specific complications such as delayed gastric emptying and pancreatic fistula, the present study did not observed increased risk associated with increased perioperative fluid infusion. This is in line with Garland et al.7. However, in order to avoid redundancy with previously published results7, this study focused on fluid management and impact of ERAS compliance was not assessed here. In addition, the amount of IV fluid administered in the first 24 h of surgery is not an entirely modifiable factor, as it is closely related to patient’s comorbidity, disease’s prognosis and surgery’s extent.Limitations of the present study are inherent to the retrospective analysis and to the limited study sample obtained in a single center. Moreover, enhanced recovery relies on compliance to protocol elements, including fluid management, which has altogether a strong influence on the postoperative outcomeIn order to validate and generalize this threshold of 4400 ml iv fluids on POD 0 and associated findings, further study including PD performed within an enhanced recovery setting need to be conducted. Once available, this will provide useful guidance on how to refine fluid management of patients undergoing PD to avoid both fluid overload and kidney insufficiency.In conclusion, the present study emphasizes the potential deleterious consequence of fluid overload especially on pulmonary complications. A threshold for perioperative intravenous fluid at 4400 ml might be a useful indicator in the management after pancreatoduodenectomy within an enhanced recovery pathway.7. Patients younger than 18 years old, and those who were opposed to the use of their data were not included. The study protocol was approved by the Institutional Review Board (CER-VD # 2016-01815) and patients gave informed consent. This study was reported in accordance with the STROBE guidelines30.This retrospective cohort study included all consecutive patients undergoing elective PD within an ERAS program in a tertiary referral centre , Switzerland) between October 2012 and June 2017. This cohort of patients was previously included and merged with data of three other institutions in a multicentre study5 and was previously detailed7. During the surgery, an infusion of Ringer Lactate at a rate of 3-5 ml/kg/h was initiated and bolus of 500 ml were given in case of decreased cardiac output  or increased lactate with a minimal diuresis set at 0.5 ml/kg/h. Vasopressors were liberally used during and after the operation to counterbalance the vasodilator effect of epidural. In the postoperative period, an infusion of 1000 ml/24 h of Ringer Lactate was instilled, with 250 ml bolus of Physiogel in case of diuresis less than 2 ml/kg/4 h. Free oral drinks were encouraged from the day of surgery. Preoperative and demographic characteristics, intraoperative data and postoperative outcomes were prospectively collected using the ERAS Interactive Audit System (EIAS). The postoperative follow-up was 30 days.The enhanced recovery protocol for PD was initiated in October 2012 according to the ERAS guidelinesPerioperative fluids were defined as intravenous (IV) infusion, including crystalloids, colloids and blood products given during the first 24 h of surgery (postoperative day 0: POD 0). The total IV volume administration on POD 0 (IV fluids POD 0) was used as parameter to define critical threshold.31. Grade I and II were defined as minor and grade IIIa to IVb as major complications. Grade V was reported as mortality. The Comprehensive Complication Index32 (CCI) was calculated to obtain a continuous morbidity scale. Complications, including postoperative pulmonary complications were reported according to the EPCO  definitions33. Accordingly, postoperative pulmonary complications included respiratory infection , respiratory failure , pleural effusion (demonstrated by chest radiograph), atelectasis (lung opacification with shift toward affected area and compensatory over-inflation in the adjacent non-atelectatic lung), pneumothorax , bronchospasm (newly detected expiratory wheezing treated with bronchodilators) and aspiration pneumonitis .Descriptive statistics for categorical variables were reported as numbers and percentages, while continuous variables reported as median and interquartile ranges (IQR) or mean and standard deviations (SD). Categorical variables were compared with the Chi-Square or Fisher’s exact test. The Student’s t test and Mann–Whitney U test were used for continuous normally and non normally distributed data, respectively. Correlation between CCI and perioperative fluids was assessed by the Spearman’s test. The diagnostic ability was illustrated by a receiver operating characteristic (ROC) curve. An area under the curve (AUC) of > 0.7 was considered statistically significant. Threshold was identified according to the Youden index. Potential predictors of overall and major complications were assessed by binary logistic regression analysis and multiple logistic regression analysis was further performed including all previous independent variables with a


As demonstration, the prognostic value of 51 previously reported survival associated biomarkers, such as PROM1  and CXCR4 , were confirmed in OSgbm. In summary, OSgbm allows users to evaluate and develop prognostic biomarkers of GBM. The web server of OSgbm is available at http://bioinfo.henu.edu.cn/GBM/GBMList.jsp.Glioblastoma (GBM) is the most common malignant tumor of the central nervous system. GBM causes poor clinical outcome and high mortality rate, mainly due to the lack of effective targeted therapy and prognostic biomarkers. Here, we developed a user-friendly Online Survival analysis web server for GlioBlastoMa, abbreviated OSgbm, to assess the prognostic value of candidate genes. Currently, OSgbm contains 684 samples with transcriptome profiles and clinical information from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Chinese Glioma Genome Atlas (CGGA). The survival analysis results can be graphically presented by Kaplan-Meier (KM) plot with Hazard ratio (HR) and log-rank  Glioblastoma (GBM) is the most common malignant tumor of the central nervous system (CNS) and causes a high mortality rate . AlthougIDH and PTEN, and expression variation of gene CD133 . Second, four cohorts (≥30 cases) with available gene expression profiles and clinical survival information were collected from GEO database (http://www.ncbi.nlm.nih.gov/geo/). Third, two GBM cohorts were gathered from CGGA (http://www.cgga.org.cn/). After an initial filtration and quality check , 153 samples from TCGA, 276 samples from GEO, and 255 samples from CGGA were included for the following database and web server construction. The histology of recurrent GBM (rGBM) were included in GSE7696 (10 samples), GSE42669 (11 samples), CGGAarray (9 samples) and CGGAseq (22 samples) datasets. Two CGGA datasets also included 20 samples of secondary GBM (sGBM).GBM datasets are from three major data sources. First, level-3 gene expression profiling data (HiSeqV2) and clinical information of GBM samples were downloaded from TCGA on April 2018  architecture as we previously described . The genA PubMed search was performed to identify previously reported GBM prognostic biomarkers, using keywords ‘glioblastoma’, ‘survival’ and ‘biomarker’. Totally, 53 prognostic biomarkers were identified from 2013 publications. The flow chart of biomarker collection was showed in In OSgbm, we included a total of 684 unique GBM samples from seven datasets, including one TCGA cohort, four GEO cohorts and two CGGA cohorts. The survival information includes overall survival (OS), disease specific survival (DSS), disease free interval (DFI) and progression free interval (PFI) . The conp value.The main function of OSgbm web server is to evaluate and determine the prognostic value of the quested genes. The users start by typing the gene symbol and choosing one dataset of interest or the combined dataset with pooling all the datasets together. To measure the association between a quested gene and survival, GBM samples are categorized according to the median  of the selected gene, and KM analysis is used to compare the outcomes between groups . The useIGF1R and PCBP2) display significant prognostic values in OSgbm, but is contradictory to what was reported in the literatures. Both of them were shown as favorable prognostic biomarkers in OSgbm but were reported to be unfavorable GBM prognostic biomarkers in previous reports  , while the race reported in literature for IGF1R is European. As a result, it will be necessary to validate the prognostic performance of IGF1R and PCBP2 in a larger independent cohort of glioblastoma.The development of prognostic biomarkers is important for guiding the treatments especially for therapy-resistant GBM patients. In our work, we developed a new web server, OSgbm, to help researchers to evaluate the prognostic value of a given gene for GBM patients. OSgbm is easy to use and requires no special skills (such as bioinformatics training). With filtering by one or several clinical confounding factors provided in OSgbm, users can also evaluate the prognostic value of their interested genes according to their special needs. The function and performance tests of OSgbm web server showed that 96% (51 out of 53) of previously reported prognostic biomarkers could be confirmed in OSgbm, which indicates that these biomarkers validated in independent cohorts have the potency of translating to clinical applications, and also indicates the well performance of OSgbm. Nevertheless, there are two genes including emistry) . For exaIn conclusion, OSgbm is a user-friendly web server to help researchers and clinicians to identify suitable prognostic biomarkers in GBM. Furthermore, we will keep update the database of OSgbm to collect more and more GBM datasets when new GBM dataset is available, and will implement the multivariate cox proportional hazards model into OSgbm for the purpose of adjustment for the confounding clinical factors, and we also encourage users to contact us to upload their own data into OSgbm.All datasets for this study are included in the article/XG conceived and directed the project. HD and QW collected data and developed the web server. HD, NL, JL, LG, MY, GZ, YA, FW, LX, and YL performed data analysis. WZ, HZ, and MZ contributed to data analysis and paper writing. XG and HD wrote the manuscript with the assistance and approval of all authors.Author MZ is employed by company of Nanjing Jiliang Biotechnology Co., Ltd.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Pituicytoma is a rare pituitary non-neuroendocrine tumour. The awareness of pituitary non-neuroendocrine tumours has gradually increased over the past several decades, but the knowledge of some histological variants of the tumours is limited, particularly in clinicopathological significance. Here, we report a rare case of pituicytoma variant.A 71-year-old man presented with sudden symptoms of stroke including urinary incontinence, weakness in right lower limb, and trouble speaking. Physical examinations showed a right facial paralysis. The radiological examinations eventually found a 1.7 × 1.4 × 1.3 cm sellar occupied lesion. After symptomatic treatment improved the symptoms, the patient underwent transsphenoidal resection of the pituitary mass. Histologically, the tumour contained hypocellular area and hypercellular area. The hypocellular area showed elongated spindle cells arranged in a fascicular pattern around small vessels and scattered Herring bodies; the hypercellular area showed a large number of pseudorosettes. Immunohistochemistrically, the tumour cells were positive for thyroid transcription factor-1, S100, and neuron-specific enolase. Neurofilament only showed a little positive in the hypocellular area, and silver impregnation was only noted in a perivascular distribution. The patient had no recurrence 4 months after the surgery.The rare variant of pituicytoma has a favourable prognosis. Moreover, it needs to be distinguished pituicytomas with pseudorosettes from ependymomas because of different prognosis. Lastly, Herring bodies may occasionally be seen in the pituicytoma, which could be a potential diagnostic pitfall. The most common pituitary tumour is pituitary adenoma that is a neuroendocrine tumour, whereas pituitary non-neuroendocrine tumours are rare and include pituicytoma, spindle cell oncocytoma (SCO), granular cell tumour (GCT), and gangliocytoma according to the 2016 WHO classification of tumours of the central nervous system (CNS). The former three tumours have been found to arise from pituicytes and may constitute a spectrum of a single nosological entity because they are positive for thyroid transcription factor 1 (TTF1), a specific histogenetic marker of pituicytes [This patient was a 71-year-old man with a history of grade 2 hypertension for 30 years, and he presented with dizziness for a week. As sudden urinary incontinence, weakness in right lower limb, and trouble speaking, he underwent an emergency non-enhanced head computed tomography (CT) examination. The CT examination showed a slightly low-density area in the left frontal lobe and the left temporal lobe, which raised a suspicion for acute infarctions. The following contrast-enhanced head CT and magnetic resonance imaging (MRI) examinations showed no infarction, but a 1.7 × 1.4 × 1.3 cm sellar occupied lesion with heterogeneous enhancement (Fig. The greyish-white colour resected specimen was about 1.5 cm in diameter. Histologically, this tumour contained hypocellular and hypercellular areas that showed apparent geographical separation Fig. a. The hyDiligent clinical correlation, together with some appropriate immunohistochemical panel, is generally sufficient to reach the correct diagnosis of a rare tumour with an unusual morphology. Clinically, the symptoms of stroke pushed the radiologist to focus on looking for some suspicious cerebrovascular disease manifestation on the non-enhanced CT scan, resulting in missing the apparent lesion showed on the following contrast-enhanced CT and MRI examination: sellar tumour. Immunohistochemistrically, the tumour cells were positive for TTF1, S100, and NSE. According to the 2016 WHO classification of tumours of CNS, the tumour should fall within pituitary non-neuroendocrine TTF1-expressing tumours. Among the umbrella term encompassing pituicytoma, GCT, and SCO, pituicytoma was eventually picked out to diagnose the sellar tumour based on the following analyses.GCT and SCO have been referred to constitute pituicytomas that are composed of tumour cells with lysosome-rich and mitochondrion-rich cytoplasm, respectively . The lysThis pituicytoma rarely contains two different morphological areas. In the hypercellular area, a large number of pseudorosettes are reminiscent of ependymoma. The pattern presented in sellar tumours has been described in some literature, but the nomenclature is not well established owing to limited understanding of them, with different studies referring to the tumour as “ependymoma” or “pituicytoma with an ependymoma-like component” –13. CompHerring bodies, dilated terminal portions of neurosecretory axons from the hypothalamus and stored antidiuretic hormone and oxytocin, are regarded as a useful diagnostic clue of neurohypophysis according to the 2016 WHO classification. However, Herring bodies have been described in at least four cases of pituicytoma, including ours , 17, 18.In conclusion, the rare variant of pituicytoma has a favourable prognosis. Moreover, it is necessary to distinguish the pituicytoma with pseudorosettes from the ependymoma because of different prognosis. Lastly, Herring bodies can occasionally be seen in a pituicytoma, which is a potential diagnostic pitfall.


Tumour growth is not solely driven by tumour cell-intrinsic mechanisms, but also depends on paracrine signals provided by the tumour micro-environment. These signals comprise cytokines and growth factors that are synthesized as trans-membrane proteins and need to be liberated by limited proteolysis also termed ectodomain shedding. Members of the family of A disintegrin and metalloproteases (ADAM) are major mediators of ectodomain shedding and therefore initiators of paracrine signal transduction. In this review, we summarize the current knowledge on how ADAM proteases on tumour cells but also on cells of the tumour micro-environment contribute to the formation of gastrointestinal tumours, and discuss how these processes can be exploited pharmacologically. Gastrointestinal organs are composed of highly complex tissue and most of these tissues are constantly replenished by the proliferation and differentiation of multi-potent tissue stem cells. These processes are regulated by paracrine signals provided by cells of the stem cell niche. Moreover, signals emitted from inflammatory cells recruited to damaged or infected tissue contribute to the mobilisation of tissue stem cells, regeneration and remodelling of the damaged tissue. Several paracrine signal proteins are synthesized as membrane-bound proteins and need to be proteolytically processed to give rise to soluble factors that then can act in a paracrine or even an endocrine fashion. Additionally, receptor molecules and proteins of the extracellular matrix are subject to proteolytic remodelling. Members of the A disintegrin and metalloprotease (ADAM) family are involved in all these processes. Aberrant activation of paracrine signal transduction is key to the development of gastrointestinal tumours and it is therefore not surprising that ADAM proteases play a decisive role in gastrointestinal tumorigenesis. Here, we give an overview of ADAM protease biology and the current knowledge regarding their tumour-promoting role in gastrointestinal malignancies. We further discuss how ADAM proteases can be therapeutically targeted for the treatment of gastrointestinal cancers.Limited ectodomain proteolysis is a regulatory mechanism mediated by proteases that converts membrane-bound proteins irreversibly into their soluble isoforms. The family of A disintegrin and metalloproteases (ADAMs) consists of 21 members  with 13 Proteolytic activity of ADAM proteases can either be constitutive or activated by signal transduction pathways. Regulation of ADAM protease activity is best described for the family members ADAM10 and ADAM17. Members of the membrane multi-pass families inactive rhomboids (iRhoms) ,10 and tThe rhomboid family comprises several transmembrane proteins that are evolutionarily conserved. The inactive rhomboid members lack the amino-acid residues that are indispensable for catalytic activity.rhomboid family member (RHBDF) 2 gene. iRhom2 is localized in the ER and shuttles ADAM17 from the ER to the Golgi apparatus . PDGFRβ was previously shown to induce ADAM17 activation . . 111]. I+ breast cancer, large B-cell non-Hodgkin lymphoma . . 129]. FThere is now a growing body of evidence that members of the ADAM protease family are over-expressed on tumour cells and are correlated with tumour formation and the progression of gastrointestinal tumours (summarized in Given the fact that ADAM proteases generate paracrine signals, the role of ADAM proteases in the tumour microenvironment needs more attention. Cell type-specific gene targeting in mouse models of cancer combined with unbiased proteomic substrate identification will improve our understanding of how ADAM proteases shape the tumour microenvironment and promote tumour metastasis. This will also help to design tissue-specific ADAM protease inhibitors or to target ADAM-mediated novel tumour cell vulnerabilities, with the aim to reduce the severe side effects encountered with current ADAM protease inhibitors.


Re less than 200, power-law index n ranging from 0.5 to 1.5 and consistency index K varying from 0.001 to 0.5 to explore heat transfer and flow structure of shear-thinning fluid and shear-thickening fluid. Results indicate that with the increase of n, K for a given Re, wall Nusselt number increases mainly attributing to the increase of inlet velocity U. For a given inlet velocity, wall Nusselt number decreases with the increase of n and K, which mainly attributes to the increase of apparent viscosity and the reduction of momentum diffusion. For the same Re, U and Pr, wall Nusselt number decreases with the increase of n. Among the study of industrial power-law shear-thinning fluid, CMC solution with 100 ppm shows the best heat transfer performance at a given velocity. Moreover, new correlation of Nusselt number about industrial fluid is proposed. In general, for the heat transfer of laminar confined impinging jet, it is best to use the working fluid with low viscosity.Heat transfer performances and flow structures of laminar impinging slot jets with power-law non-Newtonian fluids and corresponding typical industrial fluids (Carboxyl Methyl Cellulose (CMC) solutions and Xanthangum (XG) solutions) have been studied in this work. Investigations are performed for Reynolds number  Heat transfer enhancement technologies have drawn much more attentions in recent years for the intense demand in the industrial fields. Generally, the machining of rough or extended surfaces and vortex generators, as well as the promotion of working fluid properties is considered as the passive methods. While the active methods such as forced channel flow, impinging jets, mechanical vibration and electromagnetic field consume extra energy.2O3-Water nanofluids. They found that the average Nusselt number increases with the variations of nanoparticle volume concentration (φ). From the previous literatures, it can be concluded that combinations of several heat transfer enhancement technologies have become one heated topic. Impinging jets with unconventional working fluid seems to be potential for strengthening heat transfer.Among these heat transfer enhancement methods, impinging jets have the highest known single phase local heat transfer rate but low drop pressure, which is attractive for electronic thermal management . Basic pRe. Hooshmand et al. [2 nanoparticles, exhibiting pseudoplastic behavior. Overall, non-Newtonian fluid whose viscosity is sensitive to shear strain rate may be effective on impinging jets with manifest shear flow.Non-Newtonian fluid has drawn some attentions in recent years for its obvious advantages of drag reduction and heat transfer enhancement in channel flow ,16,17,18d et al.  numericad et al.  theoretid et al.  discussed et al.  studied d et al.  employedd et al.  numericad et al.  investign, consistency index K and inlet velocity u. Moreover, industrial-fluid solutions such as CMC and xanthane are also examined. By this study, several variation tendencies of Nusselt number with diverse physical parameters can be obtained so that the desirable working fluid can be found.In the review of published literatures, the combination studies of impinging jets and non-Newtonian fluid are necessary for heat transfer enhancement and the researches especially for the studies of the heat transfer characters on a confined impinging slot jet by employing power-law liquid are relatively few. More work is still needed to obtain better heat transfer performance. In this study, a confined impinging slot jet was numerically investigated considering the effects of power-law index ijτ is the viscous stress tensor and subscripts i and j represent the normal direction of action surface and direction of the stress component on the aforementioned surface, respectively. T is the temperature. u and v are the velocity. x and y are the Cartesian coordinates. ρ, pc and λ are the fluid density, specific heat and thermal conductivity, separately. Moreover, the pressure terms are additionally included in the normal stress tensor iiτ.In the study, non-Newtonian fluid which behaves as temperature is independent of power-law fluid was selected as the working fluid. Governing equations of continuity, momentum and energy of the steady, laminar and incompressible flow in a Cartesian reference frame are given as follows .(1)∂u∂xW = 0.0062 mm. Uniform velocity U ranges from 0.02 m/s to 0.1 m/s and the uniform temperature is j =T 293 K. Normally, the isothermal target surface temperature is Twall = 313 K. H represents the distance between jet exit and the target surface. L is the plate length, respectively. In our study, the H/W is fixed to be 4 and L/W is fixed to be 100.The physical model of the confined slot impinging jet is similar to that of . As seenn and 1000 Pa·sn, respectively. Various power-law liquids can be obtained by changing power-law index n, ranging from 0.5 to 1.5 and consistency index K, ranging from 0.001 to 0.5. The fluid density, specific heat and thermal conductivity are assumed to be constant under jT = 293 K condition in −6.The numerical simulation was conducted with Fluent. A second-order upwind scheme and the SIMPLE algorithm are employed to simulate the steady-state laminar flow. Material properties of the working fluid are created by using the non-Newtonian power-law fluid model. The minimum and the maximum viscosity are set at 0 Pa·sThe apparent temperature independent dynamic viscosity η of the power-law fluid is given byK is the consistency index; n is the power-law index which determines the class of the fluid; γ is the shear strain rate. As n = 1, the fluid is Newtonian fluid; as n < 1, the fluid viscosity decreases with the increase shear strain rate, exhibiting pseudo-plastics (shear-thinning) behavior; as n > 1, the fluid whose viscosity increases with the increase shear strain rate is the dilatant (shear-thickening) fluid.Here, U is the inlet velocity, W is the jet exit width, ρ, pc and λ denote the fluid density, specific heat and thermal conductivity, respectively.Furthermore, the Reynolds number and Prandtl number  are defiThe heat transfer performance is characterized by Nusselt numbers, expressed ash is the heat transfer coefficient which is defined asq is the heat flux, wT is the temperature of the target surface and jT represents the temperature of the jet.Here, Pumping power  is definQ is the volume flow rate, ∆tP is the difference of total pressure between the inlet and outlet cross-section.Here, U = 0.016 m/s, Re = 100, H/W = 4, n = 1, K = 9.93 × 10−4 Pa·s. As seen in Nuave of the whole plate is 0.054%, which is small enough. To guarantee the accuracy of results and reduce the computational resource cost, grid 3 is chosen for the following study. The grid diagram and magnification of refined grids near the impingement region and the walls are shown in The grid independence check is carried out by testing four different grids under n = 1, K = 9.93 × 10−4 Pa·s, inlet velocity ranging from 0.016 m/s to 0.032 m/s, Re ranging from 100 to 200 and H/W = 4. As observed in Nux/Nu0 distributions show a good agreement with that of the literature [Nux and Nu0 represent local Nusselt number and Nusselt number at the stagnation point, respectively. Therefore, the numerical method simulating the power-law liquid impinging jet can be employed in the following investigations.The impinging jet using special non-Newtonian liquid pure water as the working fluid is employed to validate the simulation results with the available data given in . The samK ranges from 0.001 to 0.5, which varies in a large scale in order to simulate extensive fluid in nature, the associated results show large variable ranges. As shown in Nuave is influenced by Reynolds number Re, power-law index n and consistency index K, simultaneously. Nuave increases with Re. For a fixed Reynolds number, Nuave increases with the increase of power-law index n and consistency index K, respectively. U calculated via Equation (6). It can be seen that the conditions with high Nuave tend to get high inlet velocity. The increase of Nuave mainly attribute to the increase of inlet velocity U.In order to simulate extensive fluid in nature, n = 1.2 is larger than that of n = 0.8 for a fixed Re = 100. x/W is about equal to 7, the wall jet turns its direction upward because of the vortex which is near the impinged wall. As x/W is larger than 25, the shear flow runs parallel and the flow is out of the domain exit. So, for shear-thinning fluid (n = 0.8), the apparent viscosity of shear-layer is lower than that of the potential core. The apparent viscosity is largely away from the center of the domain, while the shear-thickening fluid (n = 1.2) shows the opposite distribution.From Re = 100, the formation of the main re-circulating vortex near the jet inlet and secondary vortices on the impinged wall can be observed. Compared with Re = 100, the flow structure of Re = 200 changes significantly. The main re-circulating vortex is split into two main cores and a new vortex is generated near the jet inlet. Secondary vortex on the lower wall is stretched to the lateral exit along the lower wall. When Re increases further, the flow structure becomes more complex so that the flow becomes unsteady and unsymmetrical with complicated vortices.As shown in U. Therefore, it is better to compare the different working fluid based on the same inlet velocity if the pumping power is considered.What’s more, the differences of total pressure between the inlet and outlet cross-section is in a wide range, which mainly are affected by inlet velocity Nuave with power-law index n for various consistency index K at the same inlet velocity U. It can be seen that Nuave decreases with an increase of power-law index n and K, respectively. When K is larger than 0.05, the effects on Nuave for different K are insignificant, which mainly attribute to the small differences of Re.n and K on jet flow are manifested mainly by influencing the apparent viscosity. From Equation (5), the apparent viscosity η increases with n under the same K condition. When n is identical, the apparent viscosity η increases with K. As seen in K for the increasing apparent viscosity. Furthermore, the center velocity decays quickly with the increase of K, which is not good for the heat transfer.The effects of n < 1 with large K such as n = 0.5 and K = 0.5, the heat transfer performance is not better than that when n > 1 with small K such as n = 1.5 and K = 0.001, which is connected with the apparent viscosity. η with shear strain rate for a specific case. When U = 0.02 m/s, the calculated maximum shear strain rate is about 110 s−1. Under this condition, shear-thickening fluid is better using as heat transfer working fluid due to the shear strain rate is less than 500 s−1. So, when the pumping power is fixed, it is better to adopt fluid with small apparent viscosity for good heat transfer enhancement.When n. When n < 1, the local Nusselt number does not attain the peak at the stagnation point. What’s more, with the decrease of n, the deviation between the stagnation Nusselt number and the maximum value increases. When n is not less than 1, the local Nusselt number reaches the maximum at the stagnation point.Pr, K can be defined as:According to the definition of Then, putting Equation (11) into Equation (6), we can get it as follows:Pr and U are the constants, the same Re is obtained. By changing n and K which are based on the same Pr, different fictitious power-law fluid could be got, as displayed in n. Furthermore, variations of apparent viscosity of five fictitious fluids are exhibited in n, the apparent viscosity increases on the whole.So, when n under the condition of Re = 144.5, Pr = 30 and U = 0.1 m/s. With the identical U, Re and Pr, fluid with low viscosity tends to have better heat transfer performance.n and consistency index K for different concentrations is listed in The polymer aqueous solutions of CMC and XG represent shear-thinning behavior, which are employed in this study. Their physical properties except the dynamic viscosity are considered as the same as that of water at 293 K for low temperature difference and concentration. The dynamic viscosity changes with shear strain rate according to the rule of the power-law exponent. The power-law index Nuave decreases and then increases with the increase of n under various U conditions. Because when U is larger than 0.05 m/s, the Re of pure water is larger than 309, the flow is unsteady, which is beyond our study. So, the industrial shear-thinning fluids are compared with pure water only when U = 0.02 m/s. Pure water has better heat transfer performance which mainly attributes to its low viscosity. As seen in −1) in this study is about 0.003 Pa·sn, which is larger than that of pure water of 0.000993 Pa·sn. Moreover, CMC solution with 100 ppm concentration shows the best heat transfer performance among the industrial shear-thinning fluids in this study.It can be seen from Nuave is given based on the industrial fluids results obtained in the present work, because the given fictitious fluid is in a wide range which is difficult to fit a correlation. The correlation formula with five undetermined coefficients is expressed as [Correlation of essed as :(13)NuavA, B, C, D, E and RMSE (Root Mean Square Error).The simulation results are compared with fitting results. Their maximum deviation is 8.7%, as displayed in Heat transfer of fictitious and industrial power-law non-Newtonian fluid in laminar confined impinging jet is investigated. The main conclusions obtained are as follows.(1)n and K, respectively, which mainly attributes to the increase of inlet velocity. With the increase of Re, the average Nusselt number increases and the flow becomes complex with more vortices.For a given Reynolds number, the average Nusselt number increases with (2)n.For the given Reynolds number, Prandtl number and inlet velocity, the average Nusselt number decreases with the increase of (3)Nuave is proposed.Industrial shear-thinning fluids are investigated, which is not better than pure water at the given inlet velocity due to the high viscosity under the shear strain rate in this study. Among these shear-thinning fluids studied in this paper, CMC solution with 100 ppm concentration shows the best heat transfer performance. What’s more, a correlation of (4)For laminar confined impinging jet at a given inlet velocity, application of non-Newtonian fluid has no significant influence on heat transfer enhancement. To obtain good heat transfer enhancement, fluid with low viscosity is the reasonable choice. Moreover, turbulent impinging jets with non-Newtonian fluid need more future research.


Although the detrimental effects of excessive perioperative fluid administration are generally well established, data in the setting of cardiac surgery remain less robust.  In this retrospective single-center observational study, the total fluid balance in the first 12 hours during and after surgery was evaluated. Primary endpoint was the relationship between total fluid balance and the incidence of prolonged mechanical ventilation. For this purpose, data were divided into quartiles (Q); prolonged mechanical ventilation and prolonged length of stay (LOS) in the ICU were defined as Q4. Secondary endpoints were prolonged LOS in the ICU, incidence of acute kidney injury , and ICU mortality. p < 0.001). In addition, patients in Q4 of the fluid balance had a significantly longer LOS in the ICU, as well as a higher incidence of AKI and ICU mortality. In a multivariate analysis, Q4 of the fluid balance was independently associated with prolonged mechanical ventilation  and prolonged LOS in the ICU , but not with the incidence of AKI or ICU mortality.  In a 3-year period, 748 patients were included. In a univariate analysis, the median duration of mechanical ventilation was 2.9 h [2.4–3.7] in Q1 of the fluid balance and increased significantly to 4.7 h [3.1–9.2] in Q4 of the fluid balance ( Perioperative fluid administration in cardiac surgery patients was independently associated with prolonged mechanical ventilation and prolonged LOS in the ICU. In critical care, there is growing concern about the potential detrimental effects of fluid administration . AlthougIn this study, we aimed to determine whether the fluid balance is independently associated with the time to extubation following cardiac surgery.th International Symposium on Intensive care and Emergency Medicine , unless stated otherwise. The data were tested for normal distribution using the Kolmogorov–Smirnov test. In case of abnormal distribution, an applicable nonparametric test  was used to detect differences between groups. If significant differences were detected, a Mann–Whitney Due to the lack of specific knowledge on the distribution of fluid balance, a proper power analysis was impossible. A sample size of 750 patients was deemed sufficient in accordance with the previous literature .th percentiles as cutoff values. Baseline characteristics with a p value <0.25 in the univariate analysis were included in the model.A multivariate linear regression analysis was performed using the backward Likelihood Ratio (LR) method. Continuous variables were transformed into binominal variables , using the 75Ideally, before conducting the multivariate linear regression analysis, correction for missing data should be performed. However, this was the case in less than 2% of the patient population, excluding 10 out of a total of 750 patients. Therefore, it was decided not to perform a procedure for multiple imputations.A total of 750 patients were included in this study. Two patients were excluded afterwards due to incorrect reason for admission. The mean age was 68 ± 10 years, and 71.3% were male. The total fluid balance ranged from −2.6 to 11.0 L. The baseline characteristics are summarized in Perioperative characteristics are summarized in p < 0.001, p < 0.001). In a multivariate analysis, the fluid balance remained an independent risk factor for prolonged mechanical ventilation  had significantly longer duration of mechanical ventilation compared to patients in the other quartiles of fluid balance . The medtilation .p < 0.001). The incidence of AKI was 0.5% in Q1 of the fluid balance and increased significantly to 4.8% in Q4 of the fluid balance (p < 0.007). ICU mortality was 0.5% in Q1 of the fluid balance and increased significantly to 3.2% in Q4 of the fluid balance (p < 0.025). Although absolute mortality was lower in Q3 as compared to Q1 and Q2, this was not statistically significant. Furthermore, a moderately but significantly higher CVP was observed in Q4. After multivariate analysis, Q4 of the total fluid balance remained an independent risk factor for prolonged mechanical ventilation and LOS in the ICU, but not for the incidence of AKI or ICU mortality  had a significantly longer LOS in the ICU , as wellortality .In this study, there was an independent association between fluid administration and the incidence of prolonged mechanical ventilation. Although the absolute difference in median duration of mechanical ventilation between Q1 and Q4 is “only” 1.8 hours, A potential explanation is the extravasation of fluid into the extracellular compartment, driven by increased hydrostatic pressure. This extravasation may result in pulmonary edema and decreased pulmonary function and, finally, prolong the duration of mechanical ventilation , 15–18. The observed detrimental effects of fluid overload on LOS in the ICU in this study are consistent with previous studies , 14, 20.The present study had several limitations. Due to the retrospective and single-centered design, the inevitable evaluation over time carries the potential of unrecognized biases, and the potential for generalization to other settings is limited. Additionally, severity of illness, hemodynamic monitoring techniques and endpoints, fluid management protocols, and postoperative complications may be possible confounders and may not be fully accounted for in this retrospective analysis. Although the study lacks an a priori sample size calculation, post hoc sample size calculation reveals that as little as 5 patients per group would be sufficient to detect a significant difference in the primary endpoint between Q1 and Q4.Ideally, a large randomized controlled trial of a fluid restricted versus liberal fluid strategy would be needed to definitively determine the cause-effect relationship of fluid overload on attributable to morbidity after cardiac surgery.Perioperative fluid administration in cardiac surgery patients was independently associated with prolonged mechanical ventilation and prolonged LOS in the ICU.