Quantifying the Economics of Medical Malpractice - A View from a Civil Law Perspective

Life is full of uncertainties. Legal rules should have a clear intention, motivation and purpose in order to diminish daily uncertainties. However, practice shows that their consequences are complex and hard to predict. For instance, tort law has the general objectives of deterring future negligent behavior and compensating the victims of someone else's negligence. Achieving these goals are particularly difficult in medical malpractice cases. To start with, when patients search for medical care they are typically sick in the first place. In case harm materializes during the treatment, it might be very hard to assess if it was due to substandard medical care or to the patient's poor health conditions. Moreover, the practice of medicine has a positive externality on the society, meaning that the design of legal rules is crucial: for instance, it should not result in physicians avoiding practicing their activity just because they are afraid of being sued even when they acted according to the standard level of care. The empirical literature on medical malpractice has been developing substantially in the past two decades, with the American case being the most studied one. Evidence from civil law tradition countries is more difficult to find. The aim of this thesis is to contribute to the empirical literature on medical malpractice, using two civil law countries as a case-study: Spain and Italy. The goal of this thesis is to investigate, in the first place, some of the consequences of having two separate sub-systems (administrative and civil) coexisting within the same legal system, which is common in civil law tradition countries with a public national health system (such as Spain, France and Portugal). When this holds, different procedures might apply depending on the type of hospital where the injury took place (essentially whether it is a public hospital or a private hospital). Therefore, a patient injured in a public hospital should file a claim in administrative courts while a patient suffering an identical medical accident should file a claim in civil courts. A natural question that the reader might pose is why should both administrative and civil courts decide medical malpractice cases? Moreover, can this specialization of courts influence how judges decide medical malpractice cases? In the past few years, there was a general concern with patient safety, which is currently on the agenda of several national governments. Some initiatives have been taken at the international level, with the aim of preventing harm to patients during treatment and care. A negligently injured patient might present a claim against the health care provider with the aim of being compensated for the economic loss and for pain and suffering. In several European countries, health care is mainly provided by a public national health system, which means that if a patient harmed in a public hospital succeeds in a claim against the hospital, public expenditures increase because the State takes part in the litigation process. This poses a problem in a context of increasing national health expenditures and public debt. In Italy, with the aim of increasing patient safety, some regions implemented a monitoring system on medical malpractice claims. However, if properly implemented, this reform shall also allow for a reduction in medical malpractice insurance costs. This thesis is organized as follows. Chapter 1 provides a review of the empirical literature on medical malpractice, where studies on outcomes and merit of claims, costs and defensive medicine are presented. Chapter 2 presents an empirical analysis of medical malpractice claims arriving to the Spanish Supreme Court. The focus is on reversal rates for civil and administrative decisions. Administrative decisions appealed by the plaintiff have the highest reversal rates. The results show a bias in lower administrative courts, which tend to focus on the State side. We provide a detailed explanation for these results, which can rely on the organization of administrative judges career. Chapter 3 assesses predictors of compensation in medical malpractice cases appealed to the Spanish Supreme Court and investigates the amount of damages attributed to patients. The results show horizontal equity between administrative and civil decisions (controlling for observable case characteristics) and vertical inequity (patients suffering more severe injuries tend to receive higher payouts). In order to execute these analyses, a database of medical malpractice decisions appealed to the Administrative and Civil Chambers of the Spanish Supreme Court from 2006 until 2009 (designated by the Spanish Supreme Court Medical Malpractice Dataset (SSCMMD)) has been created. A description of how the SSCMMD was built and of the Spanish legal system is presented as well. Chapter 4 includes an empirical investigation of the effect of a monitoring system for medical malpractice claims on insurance premiums. In Italy, some regions adopted this policy in different years, while others did not. The study uses data on insurance premiums from Italian public hospitals for the years 2001-2008. This is a significant difference as most of the studies use the insurance company as unit of analysis. Although insurance premiums have risen from 2001 to 2008, the increase was lower for regions adopting a monitoring system for medical claims. Possible implications of this system are also provided. Finally, Chapter 5 discusses the main findings, describes possible future research and concludes.

10 Å cryo-EM structure of Drosophila melanogaster hexamerin and Limulus polyphemus hemocyanin

In the present study, the quaternary structures of Drosophila melanogaster hexamerin LSP-2 and Limulus polyphemus hemocyanin, both proteins from the hemocyanin superfamily, were elucidated to a 10 Å resolution with the technique of cryo-EM 3D-reconstruction. Furthermore, molecular modelling and rigid-body fitting allowed a detailed insight into the cryo-EM structures at atomic level. The results are summarised as follows: Hexamerin 1. The cryo-EM structure of Drosophila melanogaster hexamerin LSP-2 is the first quaternary structure of a protein from the group of the insect storage proteins. 2. The hexamerin LSP-2 is a hexamer of six bean-shaped subunits that occupy the corners of a trigonal antiprism, yielding a D3 (32) point-group symmetry. 3. Molecular modelling and rigid-body fitting of the hexamerin LSP-2 sequence showed a significant correlation between amino acid inserts in the primary structure and additional masses of the cryo-EM structure that are not present in the published quaternary structures of chelicerate and crustacean hemocyanins. 4. The cryo-EM structure of Drosophila melanogaster hexamerin LSP-2 confirms that the arthropod hexameric structure is applicable to insect storage proteins. Hemocyanin 1. The cryo-EM structure of the 8×6mer Limulus polyphemus hemocyanin is the highest resolved quaternary structure of an oligo-hexameric arthropod hemocyanin so far. 2. The hemocyanin is build of 48 bean-shaped subunits which are arranged in eight hexamers, yielding an 8×6mer with a D2 (222) point-group symmetry. The 'basic building blocks' are four 2×6mers that form two 4×6mers in an anti-parallel manner, latter aggregate 'face-to-face' to the 8×6mer. 3. The morphology of the 8×6mer was gauged and described very precisely on the basis of the cryo-EM structure. 4. Based on earlier topology studies of the eight different subunit types of Limulus polyphemus hemocyanin, eleven types of interhexamer interfaces have been identified that in the native 8×6mer sum up to 46 inter-hexamer bridges - 24 within the four 2×6mers, 10 to establish the two 4×6mers, and 12 to assemble the two 4×6mers into an 8×6mer. 5. Molecular modelling and rigid-body fitting of Limulus polyphemus and orthologous Erypelma californicum sequences allowed to assign very few amino acids to each of these interfaces. These amino acids now serve as candidates for the chemical bonds between the eight hexamers. 6. Most of the inter-hexamer contacts are conspicuously histidine-rich and evince constellations of amino acids that could constitute the basis for the allosteric interactions between the hexamers. 7. The cryo-EM structure of Limulus polyphemus hemocyanin opens the door to a fundamental understanding of the function of this highly cooperative protein.

Pseudodifferential analysis in Psi*-algebras on transmission spaces, infinite solving ideal chains and K-theory for conformally compact spaces

The present thesis is a contribution to the theory of algebras of pseudodifferential operators on singular settings. In particular, we focus on the $b$-calculus and the calculus on conformally compact spaces in the sense of Mazzeo and Melrose in connection with the notion of spectral invariant transmission operator algebras. We summarize results given by Gramsch et. al. on the construction of $Psi_0$-and $Psi*$-algebras and the corresponding scales of generalized Sobolev spaces using commutators of certain closed operators and derivations. In the case of a manifold with corners $Z$ we construct a $Psi*$-completion $A_b(Z,{}^bOmega^{1/2})$ of the algebra of zero order $b$-pseudodifferential operators $Psi_{b,cl}(Z, {}^bOmega^{1/2})$ in the corresponding $C*$-closure $B(Z,{}^bOmega^{12})hookrightarrow L(L^2(Z,{}^bOmega^{1/2}))$. The construction will also provide that localised to the (smooth) interior of Z the operators in the $A_b(Z, {}^bOmega^{1/2})$ can be represented as ordinary pseudodifferential operators. In connection with the notion of solvable $C*$-algebras - introduced by Dynin - we calculate the length of the $C*$-closure of $Psi_{b,cl}^0(F,{}^bOmega^{1/2},R^{E(F)})$ in $B(F,{}^bOmega^{1/2}),R^{E(F)})$ by localizing $B(Z, {}^bOmega^{1/2})$ along the boundary face $F$ using the (extended) indical familiy $I^B_{FZ}$. Moreover, we discuss how one can localise a certain solving ideal chain of $B(Z, {}^bOmega^{1/2})$ in neighbourhoods $U_p$ of arbitrary points $pin Z$. This localisation process will recover the singular structure of $U_p$; further, the induced length function $l_p$ is shown to be upper semi-continuous. We give construction methods for $Psi*$- and $C*$-algebras admitting only infinite long solving ideal chains. These algebras will first be realized as unconnected direct sums of (solvable) $C*$-algebras and then refined such that the resulting algebras have arcwise connected spaces of one dimensional representations. In addition, we recall the notion of transmission algebras on manifolds with corners $(Z_i)_{iin N}$ following an idea of Ali Mehmeti, Gramsch et. al. Thereby, we connect the underlying $C^infty$-function spaces using point evaluations in the smooth parts of the $Z_i$ and use generalized Laplacians to generate an appropriate scale of Sobolev spaces. Moreover, it is possible to associate generalized (solving) ideal chains to these algebras, such that to every $ninN$ there exists an ideal chain of length $n$ within the algebra. Finally, we discuss the $K$-theory for algebras of pseudodifferential operators on conformally compact manifolds $X$ and give an index theorem for these operators. In addition, we prove that the Dirac-operator associated to the metric of a conformally compact manifold $X$ is not a Fredholm operator.

Effects of Global Warming on Berry Composition of cv. Sangiovese: Biochemical and Molecular Aspects and Agronomical Adaptation Approaches

Wine grape must deal with serious problems due to the unfavorable climatic conditions resulted from global warming. High temperatures result in oxidative damages to grape vines. The excessive elevated temperatures are critical for grapevine productivity and survival and contribute to degradation of grape and wine quality and yield. Elevated temperature can negatively affect anthocyanin accumulation in red grape. Particularly, cv. Sangiovese was identified to be very sensitive to such condition. The quantitative real-time PCR analysis showed that flavonoid biosynthetic genes were slightly repressed by high temperature. Also, the heat stress repressed the expression of the transcription factor “VvMYBA1” that activates the expression of UFGT. Moreover, high temperatures had repressing effects on the activity of the flavonoids biosynthetic enzymes “PAL” and “UFGT”.Anthocyanin accumulation in berry skin is due to the balance between its synthesis and oxidation. In grape cv. Sangiovese, the gene transcription and activity of peroxidases enzyme was elevated by heat stress as a defensive mechanism of ROS-scavenging. Among many isoforms of peroxidases genes, one gene (POD 1) was induced in Sangiovese under thermal stress condition. This gene was isolated and evaluated via the technique of genes transformation from grape to Petunia. Reduction in anthocyanins concentration and higher enzymatic activity of peroxidase was observed in POD 1 transformed Petunia after heat shock compared to untrasformed control. Moreover, in wine producing regions, it is inevitable for the grape growers to adopt some adaptive strategies to alleviate grape damages to abiotic stresses. Therefore, in this thesis, the technique of post veraison trimming was done to improve the coupling of phenolic and sugar ripening in Vitis vinifera L. cultivar Sangiovese. Trimming after veraison showed to be executable to slow down the rate of sugar accumulation in grape (to decrease the alcohol potential in wines) without evolution of the main berry flavonoids compounds.

Die Aufhebung von Schutzgebieten nach dem Landschafts- und Naturschutzrecht

Seit einiger Zeit mehren sich Befürchtungen, dass Umweltpolitik und Umweltrecht im Zuge von Globalisierung und konjunkturellen Krisen in die Defensive geraten und in der Hochphase der Ökologiebewegung entwickelte Umweltstandards zurückgeschraubt werden. Dies wirkt sich unter anderem auf den Objekt- und Flächenschutz des Landschafts- und Naturschutzrechts in Form der Ausweisung von Schutzgebieten aus. In einigen Bundesländern ist bereits eine Tendenz zur Aufhebung von Schutzgebieten zu beobachten. rnDie Aufhebung unter Schutz gestellter Gebiete ist bisher gesetzlich nicht geregelt, was vom Verfasser dieser Arbeit zum Anlass genommen wird, die Anforderungen an die Aufhebung von Schutzgebieten näher zu untersuchen. Dabei wird zunächst kurz erläutert, ob die Aufhebung der Unterschutzstellung rechtlich und tatsächlich grundsätzlich möglich ist. Anschließend werden die rechtlichen Anforderungen, die an die Aufhebung von Schutzgebieten zu stellen sind, umfassend untersucht. Die Untersuchung erstreckt sich auf das europäische Gemeinschaftsrecht, das Bundes- und Landesverfassungsrecht, das Bundesnaturschutzgesetz, den Einigungsvertrag, das Gesetz über die Umweltverträglichkeitsprüfung sowie das Völkerrecht. Dabei wird der Frage nachgegangen, welche einzelnen Normen welcher Gesetze bei der Aufhebung von Schutzgebieten betroffen werden und zu berücksichtigen sind. Soweit die untersuchten Vorschriften selbst keine speziellen und abschließenden naturschutzfachlichen Bewertungskriterien enthalten, werden allgemeine naturschutzfachliche Bewertungskriterien erörtert, die es erlauben sollen, Maßstäbe zu entwickeln, die bei der Frage nach der Rechtmäßigkeit der Aufhebung von Schutzgebieten herangezogen werden können. rnIm Anschluss an die Untersuchung der materiell-rechtlichen Anforderungen werden verfahrensrechtlichen Aspekte sowie die Frage erörtert, durch wen und auf welche Art und Weise die Rechtmäßigkeit der Aufhebung eines Schutzgebietes letztlich überprüft werden kann. Abschließend werden vom Verfasser noch einige Vorschläge unterbreitet, wie die bestehenden Anforderungen an die Aufhebung von Schutzgebieten durch Gesetzesänderungen deutlicher ausgestaltet und die Einhaltung dieser Anforderungen wirksamer überprüft werden könnten.rn

Politiche attive del lavoro e ammortizzatori sociali in deroga: misure difensive o di promozione delle capacità?

Il tema generale del dottorato di ricerca è l'analisi delle politiche di attivazione in Italia durante la crisi economica. La combinazione di politiche attive e passive del lavoro viene interpretata ricorrendo al quadro teorico proposto da Amartya Sen e basato sul concetto di capability. Abbiamo considerato le misure nazionali e regionali nel quadro delle linee guida europee e analizzato le tendenze verso l'empowerment dei beneficiari di politiche del lavoro attraverso il concetto di capability proposto da Sen. La ricerca empirica ha utilizzato diversi strumenti per la raccolta dei dati: focus group, un questionario inviato ad un campione di 1.200 lavoratori, e interviste.

Per un atlante dei castelli dell’Emilia Romagna: Rubiera, Salvaterra, Dinazzano e la difesa del confine orientale

Il lavoro è stato strutturato in due parti distinte. La prima riguarda il riordino delle informazioni contenute nella Banca Dati sui Castelli dell’Emilia Romagna ultimata nel 2004, arricchendo le informazioni con nuove fonti sia edite che inedite e fotografie, mettendo poi tutti i dati online sul sito Geologia Storia Turismo della Regione Emilia Romagna. La seconda parte ha riguardato invece l’analisi dell’area reggiana e, in particolare, di tre castelli: Rubiera, Salvaterra e Dinazzano che, a partire dalla fine del XII secolo, hanno costituito quella che è stata definita la Cintura sul Secchia, una vera e propria catena difensiva costruita dal comune di Reggio Emilia a protezione del suo confine orientale, quello con Modena. Nella prima parte si è predisposto l’avvio di un Atlante dei castelli esistenti e scomparsi dell’Emilia Romagna, strutturato provincia per provincia, con corredo di piante e grafici che indicano la consistenza del fenomeno nelle diverse aree della Regione; poi, per l’area reggiana, si è completata la disamina con una serie di grafici che mettono in luce la dislocazione per aree, la localizzazione sicura dei castelli in rapporto alla loro condizione attuale e la densità per aree del fenomeno. Infine si sono inserite informazioni ricavate da materiale inedito per verificare possibili sviluppi della Banca Dati. La seconda parte ha ricostruito non solo le vicende storico-costruttive dei castelli di Rubiera, Salvaterra e Dinazzano, ma ha approfondito anche la genesi e l’evoluzione di questo progetto di difesa territoriale: studiare questo progetto significa capire come il comune di Reggio Emilia, nell’arco di oltre un secolo, ha governato i propri castelli, come ne ha organizzato la difesa e la manutenzione e come ne ha progettato il popolamento.

Medical Malpractice in Public Healthcare Systems: An Empirical Investigation of Scheduled Damages

In the last decades, medical malpractice has been framed as one of the most critical issues for healthcare providers and health policy, holding a central role on both the policy agenda and public debate. The Law and Economics literature has devoted much attention to medical malpractice and to the investigation of the impact of malpractice reforms. Nonetheless, some reforms have been much less empirically studied as in the case of schedules, and their effects remain highly debated. The present work seeks to contribute to the study of medical malpractice and of schedules of noneconomic damages in a civil law country with a public national health system, using Italy as case study. Besides considering schedules and exploiting a quasi-experimental setting, the novelty of our contribution consists in the inclusion of the performance of the judiciary (measured as courts’ civil backlog) in the empirical analysis. The empirical analysis is twofold. First, it investigates how limiting compensations for pain and suffering through schedules impacts on the malpractice insurance market in terms of presence of private insurers and of premiums applied. Second, it examines whether, and to what extent, healthcare providers react to the implementation of this policy in terms of both levels and composition of the medical treatments offered. Our findings show that the introduction of schedules increases the presence of insurers only in inefficient courts, while it does not produce significant effects on paid premiums. Judicial inefficiency is attractive to insurers for average values of schedules penetration of the market, with an increasing positive impact of inefficiency as the territorial coverage of schedules increases. Moreover, the implementation of schedules tends to reduce the use of defensive practices on the part of clinicians, but the magnitude of this impact is ultimately determined by the actual degree of backlog of the court implementing schedules.

Il consenso informato come strumento di esercizio del diritto alla salute per i pazienti stranieri?

L’elaborato propone una riflessione rispetto all’atto giuridico del consenso informato quale strumento garante dell’esercizio del diritto alla salute per i migranti. Attraverso una riflessione antropologica rispetto alla natura, alla costruzione e alla logica dei diritti universali, verranno analizzate le normative nazionali, europee ed internazionali a tutela del diritto alla salute per i migranti; l’obiettivo della ricerca è indagare l’eventuale scarto tra normative e politiche garantiste nei confronti della salute migrante e l’esistenza di barriere strutturali che impediscono un pieno esercizio del diritto alla salute. L’ipotesi di ricerca si basa sulla reale capacità performativa del consenso informato, proposto solitamente sia come strumento volto ad assicurare la piena professionalità dell’operatore sanitario nell’informare il paziente circa i rischi e i benefici di un determinato trattamento sanitario, sia come garante del principio di autonomia. La ricerca, attraverso un’analisi quanti-qualitativa, ha interrogato il proprio campo, rappresentato da un reparto di ginecologia ed ostetrica, rispetto alle modalità pratiche di porre in essere la firma nei moduli del consenso informato, con particolare attenzione alle specificità proprie delle pazienti migranti. Attraverso l’osservazione partecipante è stato quindi possibile riflettere su aspetti rilevanti, quali le dinamiche quotidiane che vengono a crearsi tra personale sanitario e pazienti, le caratteristiche e i limiti del servizio di mediazione sanitaria, le azioni pratiche della medicina difensiva. In questo senso il tema del “consenso informato”, indagato facendo interagire discipline quali l’antropologia, la bioetica, la filosofia e la sociologia, si è posto sia come lente di lettura privilegiata per comprendere le dinamiche relazionali ad oggi esistenti tra professionisti sanitari e popolazione migrante, ancora vittima di diseguaglianze strutturali, ma altresì come “innesco potenziale” di nuove modalità di intendere la relazione medico-paziente.

Modelli e strumenti di supporto alla scelta informata del paziente: un argine alla medicina difensiva

L’aumento esponenziale del contenzioso medico-legale – originatosi negli USA negli anni Sessanta in proporzioni tali da far parlare di medical liability crisis, e sviluppatosi in Italia a partire dalla metà degli anni Ottanta – ha comportato e continua a comportare, unitamente ad altre conseguenze negative, il ricorso sempre più frequente dei sanitari alle pratiche di medicina difensiva, con elevatissimi costi a carico del Servizio Sanitario Nazionale dovuti alla sovrabbondanza di trattamenti e ricoveri inutili e di procedure diagnostiche invasive non necessarie, peraltro produttive di stress emotivo nei pazienti. La causa dell’aumento della litigiosità deve essere ricercata in buona parte nella relazione medico-paziente, in particolar modo con riferimento al momento informativo che precede l’acquisizione del consenso informato al trattamento clinico. In Italia, i limiti che per lo più caratterizzano gli studi riguardanti il consenso informato derivano principalmente dal fatto che essi tendono a focalizzarsi unicamente sulla componente scritta del medesimo. Il fulcro del consenso informato, invece, deve ritenersi rappresentato da una comunicazione tra sanitario e paziente relativa ad un trattamento proposto ed alle possibili alternative, alla non sottoposizione ad alcun trattamento e ai rischi e benefici di ciascuna di queste opzioni. In un tale contesto il tema della comunicazione tra il professionista e la persona assistita sta suscitando interesse poiché ci si aspetta che esso conduca a miglioramenti degli outcome dei pazienti e alla diminuzione delle denunce da parte di questi ultimi per casi di responsabilità sanitaria. La maggiore attenzione al rapporto medico - paziente ha fatto emergere il bisogno di migliorare e potenziare le abilità comunicative dei medici, in un’ottica in cui il momento comunicativo possa essere percepito dal professionista come fulcro del rapporto medico-paziente, nella prospettiva di una elaborazione di strategie di prevenzione e contrasto ai fenomeni di medicina difensiva.

La sanità mediata: il rapporto medico-paziente dentro e fuori lo schermo televisivo

L’obiettivo di questa tesi è rilevare se e quanto i medical dramas abbiano contribuito a ridefinire conoscenze, aspettative e pratiche dei telespettatori/pazienti rispetto a questioni concernenti la salute e il loro ruolo all’interno della relazione medico-paziente. Grazie ad un lavoro di campo, fatto di questionari e interviste con utenti, operatori della sanità di Centro e Nord Italia e studenti di Medicina, sono state poi registrate le modalità di interazione che i protagonisti della scena della cura dichiarano di sperimentare quotidianamente. Ciò ha permesso di rendere conto delle trasformazioni più recenti della professione medica e di come viene elaborato oggi il sapere sulla malattia da parte dei soggetti implicati, fra tecnicismi, atteggiamenti difensivi, sfiducia e affidamento. La tesi restituisce anche alcune modalità sperimentali di interazione fra pazienti e medici, messe in atto in contesti locali, che testimoniano l’esigenza di approdare a un sapere partecipato delle relazioni di cura. Infine, raccogliendo la sfida posta dalle medical humanities, immagina un utilizzo del medical drama nella formazione degli studenti di medicina per l’apprendimento di competenze narrative necessarie ad una pratica medica più umana e efficace.

La prova penale nelle indagini difensive. Analisi comparata degli strumenti processuali concessi alla difesa nei sistemi italiano e statunitense.

L’elaborato si occupa di fare il punto in materia di indagini difensive a tre lustri dall’entrata in vigore della legge n. 397/2000, epilogo di un lungo processo evolutivo che ha visto da un lato, una gestazione faticosa e travagliata, dall’altro, un prodotto normativo accolto dagli operatori in un contesto di scetticismo generale. In un panorama normativo e giurisprudenziale in continua evoluzione, i paradigmi dettati dagli artt. 24 e 111 della Costituzione, in tema di diritto alla difesa e di formazione della prova penale secondo il principio del contraddittorio tra le parti, in condizioni di parità, richiedono che il sistema giustizia offra sia all’indagato che all’imputato sufficienti strumenti difensivi. Tenuto conto delle diversità che caratterizzano naturalmente i ruoli dell’accusa e della difesa che impongono asimmetrie genetiche inevitabili, l’obiettivo della ricerca consiste nella disamina degli strumenti idonei a garantire il diritto alla prova della difesa in ogni stato e grado del procedimento, nel tentativo di realizzare compiutamente il principio di parità accusa - difesa nel processo penale. La ricerca si dipana attraverso tre direttrici: l’analisi dello statuto sulle investigazioni difensive nella sua evoluzione storica sino ai giorni nostri, lo studio della prova penale nel sistema americano e, infine, in alcune considerazioni finali espresse in chiave comparatistica. Le suggestioni proposte sono caratterizzate da un denominatore comune, ovvero dal presupposto che per contraddire è necessario conoscere e che solo per tale via sia possibile, finalmente, riconoscere il diritto di difendersi indagando.

Paracrine factors secreted by endothelial progenitor cells prevent oxidative stress-induced apoptosis of mature endothelial cells

Endothelial progenitor cells (EPC) play a fundamental role in tissue regeneration and vascular repair. Current research suggests that EPC are more resistant to oxidative stress as compared to differentiated endothelial cells. Here we hypothesized that EPC not only possess the ability to protect themselves against oxidative stress but also confer this protection upon differentiated endothelial cells by release of paracrine factors. To test this hypothesis, HUVEC incubated with conditioned medium obtained from early EPC cultures (EPC-CM) were exposed to H2O2 to assess the accumulation of intracellular ROS, extent of apoptosis and endothelial cell functionality. Under oxidative stress conditions HUVEC treated with EPC-CM exhibited substantially lower levels of intracellular oxidative stress (0.2+/-0.02 vs. 0.4+/-0.03 relative fluorescence units, p<0.05) compared to control medium. Moreover, the incubation with EPC-CM elevated the expression level of antioxidant enzymes in HUVEC (catalase: 2.6+/-0.4; copper/zinc superoxide dismutase (Cu/ZnSOD): 1.6+/-0.1; manganese superoxide dismutase (MnSOD): 1.4+/-0.1-fold increase compared to control, all p<0.05). Furthermore, EPC-CM had the distinct potential to reverse the functional impairment of HUVEC as measured by their capability to form tubular structures in vitro. Finally, incubation of HUVEC with EPC-CM resulted in a significant reduction of apoptosis (0.34+/-0.01 vs. 1.52+/-0.12 relative fluorescence units, p<0.01) accompanied by an increased expression ratio of the anti/pro-apoptotic factors Bcl-2/Bax to 2.9+/-0.7-fold (compared to control, p<0.05). Most importantly, neutralization of selected cytokines such as VEGF, HGF, IL-8 and MMP-9 did not significantly reverse the cyto-protective effect of EPC-CM (p>0.05), suggesting that soluble factors secreted by EPC, possibly via broad synergistic actions, exert strong cyto-protective properties on differentiated endothelium through modulation of intracellular antioxidant defensive mechanisms and pro-survival signals.

What Lies Beneath

With “What Lies Beneath,” I attempt to illustrate, through a series of poems, an exploration of the subjects, images, and emotions that have colored my experience both at Bucknell and my home in North Carolina for the past four years. A large portion of the collection, however, does not address the more tangible elements of my life but rather the corners of my imagination, my dreamscape, and the absences that influence them.

Ordering CT pulmonary angiography to exclude pulmonary embolism: defense versus evidence in the emergency room

To identify reasons for ordering computed tomography pulmonary angiography (CTPA), to identify the frequency of reasons for CTPA reflecting defensive behavior and evidence-based behavior, and to identify the impact of defensive medicine and of training about diagnosing pulmonary embolism (PE) on positive results of CTPA.