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Der routinemasige Einsatz von „patient reported outcome measurements“ (PROMs) kann die Ausrichtung des Gesundheitssystems an Wert und Nutzen fur Patienten unterstutzen. Die Erhebung von „patient reported experience measurements“ (PREMs) eignet sich, um die Patientenorientierung der Versorgungsprozesse und die gemachte Erfahrung transparent zu gestalten. Beide, PREM und PROM, werden mit Inkrafttreten der Richtlinie zur datengestutzten einrichtungsubergreifenden Qualitatssicherung (DeQS-RL) Bestandteil der Beurteilung der medizinischen Qualitat in Deutschland. Mithilfe von pro Leistungsbereich neu entwickelten Patientenbefragungen werden sie als zusatzliche Quellen fur die gesetzlich verpflichtende Qualitatssicherung herangezogen. Obwohl der Bewertung der Behandlungsqualitat durch die Patienten damit mehr Gewicht verliehen wird, sind bei der Entwicklung und Umsetzung in Orthopadie und Unfallchirurgie Besonderheiten zu berucksichtigen, um eine Fehlinterpretation der Ergebnisse und eine nachfolgende Fehlsteuerung im Gesundheitswesen zu vermeiden.

The routine use of patient reported outcome measurements (PROMs) can support the orientation of healthcare systems towards the value and usefulness for patients. The collation of patient reported experience measurements (PREMs) is suitable for bringing transparency to the patient orientation of healthcare processes and the experience gained. Both PREM and PROM will become an integral component of the assessment of medical quality in Germany when the guidelines for data-supported quality assurance across institutions (DeQS-RL) come into force. By means of newly developed patient surveys per medical service area, they will be used as additional sources for the legally binding quality assurance. Although this gives more weight to the evaluation of the quality of treatment by patients, special features must be taken into account in the development and implementation for orthopedics and trauma surgery in order to avoid misinterpretation of the results and subsequent misguidance in the healthcare system.

The filamentous fungus Penicillium chrysogenum Q176 secretes the antimicrobial proteins (AMPs) PAF and PAFB, which share a compact disulfide-bond mediated, β-fold structure rendering them highly stable. These two AMPs effectively inhibit the growth of human pathogenic fungi in micromolar concentrations and exhibit antiviral potential without causing cytotoxic effects on mammalian cells in vitro and in vivo. The antifungal mechanism of action of both AMPs is closely linked to - but not solely dependent on - the lipid composition of the fungal cell membrane and requires a strictly regulated protein uptake into the cell, indicating that PAF and PAFB are not canonical membrane active proteins. Variations in their antifungal spectrum and their killing dynamics point towards a divergent mode of action related to their physicochemical properties and surface charge distribution. In this review, we relate characteristic features of PAF and PAFB to the current knowledge about other AMPs of different sources. In addition, we present original data that have never been published before to substantiate our assumptions and provide evidences that help to explain and understand better the mechanistic function of PAF and PAFB. Finally, we underline the promising potential of PAF and PAFB as future antifungal therapeutics.

Purpose: To investigate age-related differences in outcomes of critically ill patients with sepsis around the world. Methods: We performed a secondary analysis of data from the prospective ICON audit, in which all adult ( >16 years ) patients admitted to participating ICUs between May 8 and 18, 2012, were included, except admissions for routine postoperative observation. For this sub-analysis, the 10,012 patients with completed age data were included. They were divided into five age groups - 80 years. Sepsis was defined as infection plus at least one organ failure. Results: A total of 2963 patients had sepsis, with similar proportions across the age groups (80 = 30.9%). Hospital mortality increased with age and in patients >80 years was almost twice that of patients 70 years was independently associated with increased risk of dying. Conclusions: The odds for death in ICU patients with sepsis increased with age with the maximal rate of increase occurring between the ages of 71 and 77 years. (C) 2019 Elsevier Inc. All rights reserved.

Background Recent randomized controlled studies have shown improvement in recanalization outcomes when physicians use the latest intra-arterial therapy devices in patients with acute, large-vessel, intracranial occlusions. The goal of this study was to explore how new procedures affected degree of and time to recanalization at a single center over the past 12 years as technology has improved. Methods Patients were included in the study if they had a large or medium intracranial vessel occlusion and had undergone intra-arterial therapy for acute stroke during the period 2002-2013. Therapies were categorized as intra-arterial thrombolysis with tissue plasminogen activator (IA tPA), mechanical thrombectomy using 1st-generation devices (Merci and Penumbra), or mechanical thrombectomy using 2nd-generation devices (stent-trievers). Recanalization was defined using a modified Thrombolysis in Cerebral Infarction (TICI) scale. Results Primary treatment was IA tPA in 24 (12.4%) patients, 1st-generation devices in 128 (66.0%) patients, and 2nd-generation devices in 42 (21.6%) patients. TICI 2b was achieved in 7 (29.2%) patients treated with IA tPA, in 79 (61.7%) patients treated with 1st-generation devices, and in 38 (90.5%) patients treated with 2nd-generation devices. Compared to patients treated with IA tPA, patients treated with 2nd-generation devices were more likely to reach TICI 2b recanalization (odds ratio, 11.66; 95% CI, 1.56-87.01), and they did so in shorter times. Conclusion Technological advances over 12 years in endovascular stroke treatments significantly improved the chance of and reduced time to achieving TICI 2b recanalization in our community hospital. This shows the importance of adopting new technologies in a rapidly evolving field in order to provide the best-practice standard of care for the people of our region.

Grosunfalle spielen bei Grosschadensereignissen unterhalb der Katastrophenschwelle eine wesentliche Rolle. Sie werden zunachst mit den Mitteln des regularen ortlichen Rettungsdienstes beschickt. Eine adaquate Bewaltigung mit dem Ziel, das Qualitatsniveau von Individualmedizin, nicht von Katastrophenmedizin zu erreichen, gelingt letztlich jedoch fast immer nur unter Einbindung uberregionaler rettungsdienstlicher Ressourcen 1 . Dadurch sind die fur den Einsatz verantwortlichen ortlichen rettungsdienstlichen Strukturen haufig mit sehr unterschiedlichen Fuhrungs-, Ausrustungs- und Kommunikationsstrukturen konfrontiert. Auf der Seite der Ortsfremden kommt zur Problematik der notwendigen Integration der Mangel an Ortskenntnissen der Einsatzstelle, der ortlichen und uberortlichen Krankenhausstruktur sowie der Zufahrtswege zu den Krankenhausern hinzu. Die wesentliche Problematik bei der Bewaltigung von Grosunfallen lag in den 70er- und 80er-Jahren des 20. Jahrhunderts in einem bestehenden Missverhaltnis zwischen der notwendigen und der vorhandenen Anzahl hierfur qualifizierter Helfer 2 sowie in vielen Fallen an fehlender Ausrustung fur den Massenanfall von Verletzten. Durch verbesserte Ausbildung und damit Qualifikation fur den Grosschadensfall sowohl der Notarzte als auch der Rettungsassistenten, differenziertere und besser trainierte Fuhrungsstrukturen sowie Vorhaltung von flexibler, mehr auf Grosunfalle als auf Katastrophen ausgerichtete Ausrustung haben sich die Schwerpunkte und Problemstellungen verschoben. Drei hochst unterschiedliche, zwar in ihrer Dimension seltene, aber in Art und Form eher alltagliche Unfallszenarien mogen dieses verdeutlichen.

Am 24. Juli 2010 fand in Duisburg eine Musikveranstaltung mit der Bezeichnung „Loveparade“ statt, zu der etwa 500.000 Gaste erwartet wurden. Im Verlauf des fruhen Abends kam es zu einem Ungluck, bei dem 21 Menschen starben und mehrere Hundert verletzt wurden. Im vorliegenden Beitrag werden die monatelangen Vorbereitungen des Sanitats- und Rettungsdienstes beschrieben, und es wird der Verlauf des Einsatzes mit uber 1600 Einsatzkraften aus ganz Deutschland dargestellt. Ein besonderer Fokus liegt in der Beschreibung des Massenunfalls im Tunnel am fruhen Abend dieses Tages.

Der tragische Verlauf der Loveparade 2010 hat starke offentliche Aufmerksamkeit erregt. Bei steigender Frequenz ahnlicher Grosveranstaltungen werden zunehmend Kliniken und Praxen mit der Vorbereitung und Reaktion auf unvorhergesehene Ereignisse konfrontiert. Verbindliche arztliche Leitlinien bestehen nicht, so dass bei jeder Veranstaltung erneut Grundsatzliches diskutiert wird. Ziel dieses Beitrags ist es, die Erfahrungen der an der Loveparade beteiligten Kliniken und Ambulanzen strukturiert auszuwerten, um daraus sinnvolle, fur Kliniken und Praxen anwendbare Masnahmen abzuleiten. Die strukturierte Analyse der Daten zur Vorbereitung der Patientenstrome und der Patientenstatistik aller beteiligten Kliniken ergab ein Profil, aus dem die Notwendigkeit zur Vorhaltung von Personal, Raumlichkeiten und Material resultiert. Zusatzlich erfolgten eine Konsensuskonferenz nach der Veranstaltung und Einzelinterviews mit den Klinikkoordinatoren, um Vorbereitungen und Masnahmen zu bewerten und sinnvolle von nicht sinnvollen Masnahmen zu trennen. Es werden personelle, logistische und raumliche Masnahmen aus der konkreten Anwendung beschrieben. Sinnvolle Masnahmen zu Vorbereitung und Bewaltigung der aufgetretenen Massenpanik werden analysiert und detailliert dargelegt, sowie konkrete Probleme benannt und Losungsmoglichkeiten besprochen. Es resultiert ein qualitativer Katalog, der Planung und Vorbereitung zukunftiger Veranstaltungen unterstutzen kann. Mit konkreten Erfahrungen aus der Loveparade 2010 lassen sich Vorbereitungen zu Grosveranstaltungen optimieren und Notfallplane uberprufen. Eine koordinierte Zusammenarbeit aller Beteiligten ist notwendig.

Die Krankenhausnotaufnahme ist ein entscheidendes Bindeglied in der Rettungskette, das gerade auch in ausergewohnlichen Situationen von zentraler Bedeutung ist. Am Beispiel der Loveparade 2010 werden Moglichkeiten in Planung und Reaktion bei einem Massenanfall von Verletzten (MANV) beschrieben und diskutiert. Zur Abschatzung der Belastung der Notaufnahmen der 4 am starksten betroffenen Kliniken wurden die Patienten anhand der ICD-Daten retrospektiv in das Manchester Triage-System eingeteilt, dabei wurde die Notwendigkeit einer Schockraumbehandlung festgestellt. Die Ergebnisse, die speziellen Probleme des Ungluckstags und die Losungen wurden in einer qualifizierten Diskussion der beteiligten Notaufnahmen und des Rettungsdienstes evaluiert. Daraus resultierte ein quantitatives und qualitatives Belastungsprofil der Notaufnahmen. Die 4 in die Auswertung einbezogenen Kliniken behandelten 388 Patienten. Bei kurzer Entfernung zum Unglucksort wachst der Anteil ambulanter Patienten und die Hauptbelastung tritt fruh nach dem Ungluck auf; bei groserer Entfernung werden mehr stationare Patienten behandelt und die Belastung verlagert sich zeitlich nach hinten. Eckdaten zur Kapazitatsplanung werden vorgestellt und die zentralen Probleme diskutiert. Zentrale Notaufnahmen stehen im Fokus der Vorbereitungen fur Grosveranstaltungen. Die vorgestellten Masnahmen waren geeignet, geplante und ungeplante Patientenstrome zu kontrollieren und eine fachgerechte Versorgung zu gewahrleisten.

SummaryStreptococcus pyogenes is the causative agent in a wide range of diseases in humans. Thrombin-activatable fibrinolysis inhibitor (TAFI) binds to collagen-like proteins SclA and SclB at the surface of S. pyogenes. Activation of TAFI at this surface redirects inflammation from a transient to chronic state by modulation of the kallikrein/kinin system. We investigated TAFI binding characteristics to SclA/SclB. Thirty-four overlapping TAFI peptides of ∼20 amino acids were generated. Two of these peptides (P18: residues G205-S221, and P19: R214-D232) specifically bound to SclA/SclB with high affinity, and competed in a dose-dependent manner with TAFI binding to SclA/SclB. In another series of experiments, the binding properties of activated TAFI (TAFIa) to SclA/SclB were studied with a quadruple TAFI mutant (TAFI-IIYQ) that after activation is a 70-fold more stable enzyme than wild-type TAFIa. TAFI and TAFI-IIYQ bound to the bacterial proteins with similar affinities. The rate of dissociation was different between the proenzyme (both TAFI and TAFI-IIYQ) and the stable enzyme TAFIa-IIYQ. TAFIa-IIYQ bound to SclA/ SclB, but dissociated faster than TAFI-IIYQ. In conclusion, the bacterial proteins SclA and SclB bind to a TAFI fragment encompassing residues G205-D232. Binding of TAFI to the bacteria may allow activation of TAFI, whereafter the enzyme easily dissociates.

Dipeptides are obtained optically pure and in good yield by boiling equivalent amounts of N-acylamino-acids and amino-ester hydrochlorides with ethoxyethyne in ethyl acetate containing 0.5% of water. For the preparation of higher peptides it is preferable to add the amino-component not as hydrochloride but as free ester, because otherwise partial racemisation may occur. By means of this method the hexapeptide, pro-val-lys-val-tyr-pro, a sequence present in β-corticotropin, has been prepared.

Introduction: One of the major complications in patients with diabetes mellitus is impaired wound healing. The fibrinolytic system is involved in parts of the wound healing process and deficiency of thrombin-activatable fibrinolysis inhibitor (TAFI) results in delayed wound closure. Moreover, levels of TAFI are affected by diabetes mellitus. The aim of this study was to elucidate the effect of hyperglycaemia on TAFI and to determine the effect of deficiency of TAFI on wound healing under hyperglycaemic conditions. Materials and methods: Hyperglycaemia was induced with streptozotocin (STZ) and used as a model for diabetes mellitus. TAFI plasma levels and TAFI gene expression in the liver were determined. Incisional and excisional wound healing were studied in non-treated and STZ-treated wild-type and TAFI-deficient mice. Wound closure was scored daily as open or closed. Results: Mice treated with STZ showed hyperglycaemia, and TAFI plasma levels and TAFI gene expression were increased in diabetic mice. TAFI-deficient mice and diabetic wild-type and diabetic TAFI-deficient mice showed delayed wound healing of incisional wounds. No differences were observed between diabetic and non-diabetic TAFI-deficient mice and between diabetic wild-type and diabetic TAFI-deficient mice. Conclusions: This study illustrated that TAFI was affected by hyperglycaemia and confirmed that TAFI is involved in wound healing. No additional effect was observed under hyperglycaemic conditions, indicating that deficiency of TAFI did not have an additive or synergistic effect in diabetic wound healing. Further research has to elucidate if TAFI and hyperglycemia affect wound healing via similar mechanisms. (C) 2010 Elsevier Ltd. All rights reserved

Thrombin-activatable fibrinolysis inhibitor (TAFI) provides an important molecular link between the coagulation and fibrinolytic systems. In this review, recent major advances in TAFI research, including the elucidation of crystal structures, the development of small inhibitors and the role of TAFI in systems other than hemostasis, are described and discussed.

The complication rate of conventional plate osteosynthesis (CPO) of periprosthetic femoral fractures above total knee arthroplasties (TKA) is high. Indirect reduction techniques were introduced to reduce surgical dissection at the fracture site. Twenty-one patients (4 men and 17 women) with femoral fractures above well-fixed total knee arthroplasties were consecutively treated with the indirect reduction technique. AO/ASIF (Arbeitsgemeinschaft fur Osteosynthesefragen/Association for the Study of the Problems of Internal Fixation) Type 33A fractures were included. The mean age was 78 years (range, 67–94 years). Four fractures were stabilised with bone grafts, three in combination with bone cement. Nineteen of the patients were seen at a 1-year follow-up, 15 were seen after a long-term follow-up of 9 years (range, 7–12 years). There was only one implant failure in a comminuted fracture with severe osteoporosis, no infection, and no non-union. At the 1-year follow-up malalignment of 5° varus occurred in one patient. The mean range of motion of the eighteen patients was 98° (range, 65–110°). The mean knee society score was 74 (range, 62–84), the mean function score was 52 (range, 39–72). At the long-term follow-up, the mean range of motion of the patients was 101° (range, 65–115°). The mean knee society score was 77 (range, 65–88), the mean function score was 55 (range, 40–75). Our results suggest the 95° condylar blade plate in the indirect reduction technique is still a good implant with good long-term results. It works best in proximal fractures when there is minimal comminution of the distal fragment in the hands of an experienced trauma surgeon. Knee function and range of motion increased less over time.

Background: Thrombin-activatable fibrinolysis inhibitor (TAFI) is a 56-kDa procarboxypeptidase. Proteolytic enzymes activate TAFI into TAFIa, an inhibitor of fibrinolysis, by cleaving off the N-terminal activation peptide (amino acids 1-92), from the enzyme moiety. Activated TAFI is unstable, with a half-life of approximately 10 min at 37 degrees C. So far, it is unknown whether the activation peptide is released or remains attached to the catalytic domain, and whether it influences TAFIa's properties. The current study was performed to clarify these issues. Methods: TAFI was activated, and the activity and half-life of the enzyme were determined in the presence and absence of the activation peptide. Results: TAFIa was active both before and after removal of the activation peptide, and the half-life of TAFIa was identical in the two preparations. Furthermore, we observed that intrinsically inactivated TAFIa (TAFIai) aggregated into large, insoluble complexes that could be removed by centrifugation. Conclusions: The data presented in this article show that the activation peptide of TAFI is not required for TAFIa activity and that the activation peptide has no effect on the stability of the enzyme. These results are in favour of a model in which the activation peptide solely stabilizes the structure of the proenzyme. After activation of TAFI and subsequent breakage of interactions between the activation peptide and the catalytic domain, the activation peptide is no longer capable of performing this stabilizing task, and the integrity of the catalytic domain is lost rapidly. The resulting TAFIai is more prone to proteolysis and aggregation. (Less)

The Less Invasive Stabilization System (LISS) is an internal fixator, which combines closed reduction of the diaphysis or metaphysis of distal femur fractures with locked unicortical screw fixation.In a retrospective consecutive study, 50 patients with Association for the Study of the Problems of Internal Fixation/Orthopaedic Trauma Association (AO/OTA) type 33-A1 to 33-C3 fractures were treated with the LISS between January 1999 and December 2003. Final results were assessed using the functional score of Neer after a median follow-up of 29 months (15-48 months).Fifteen male and 16 female patients were followed up. The mean age was 49 years (17-90 years). Deep wound infection was seen in one patient (3%) and malpositioning with cutting-out of the proximal screws was in two patients (6%). All other fractures healed uneventfully without bone graft requirements after a mean of 12 weeks (7-20 weeks). A revised osteosynthesis was performed for correction of a valgus deformity of 20 degrees after 4 months. There was no difference in leg length exceeding 2 cm. One patient had a valgus deformity of 10 degrees combined with a rotational deformity of 10 degrees. Range of motion of the knee joint was120 degrees in 15 patients (48%); 12 (39%) had a range of motion between 90 degrees and 120 degrees and 4 (13%) between 70 degrees and 90 degrees. The function according to the Neer score was excellent in 15 (48%), good in 10 patients (32%), and fair in 6 patients (20%). The mean Neer score was 80 (60-100).The LISS promotes early mobilization and rapid rates of bony and clinical healing without bone grafting with low rates of infection.

Nach Verletzungen des Kniegelenkes bleiben nicht selten Storungen der Gelenkfunktion bestehen, die durch Veranderungen im neuromuskularen Zusammenspiel bedingt sein konnen. Es wurden 31 gesunde Personen (16 Frauen, 15 Manner) untersucht. Die Untersuchung des M. quadriceps femoris erfolgte mittels EMG-Interferenzmapping unter definierten isokinetischen Untersuchungsbedingungen (90° Flexion bis 0° Extension im Kniegelenk) bei Maximalkraft mit Winkelgeschwindigkeiten von 60°/s und 180°/s. Das identifizierte Muster der neuromuskularen Ansteuerung des M. quadriceps femoris zeigte deutliche Geschlechtsunterschiede. Bei den Frauen war das Aktivitatsmaximum vor allem uber dem M. vastus medialis und dem M. rectus femoris lokalisiert, bei den Mannern war das Aktivitatsmaximum immer uber dem M. vastus medialis nachweisbar. Mit zunehmender Streckung wanderte das Aktivitatsmaximum bei den Frauen nach distal, bei den Mannern kamen relevante Aktivitaten des M. rectus femoris hinzu. Eine geschlechtsspezifische Beurteilung des neuromuskularen Aktivierungsverhaltens der Kniestreckermuskulatur erscheint notwendig.

Bacteria-controlled regulation of host responses to infection is an important virulence mechanism that has been demonstrated to contribute to disease progression. Here we report that the human pathogen Streptococcus pyogenes employs the procarboxypeptidase TAFI (thrombin-activatable fibrinolysis inhibitor) to modulate the kallikrein/kinin system. To this end, bacteria initiate a chain of events starting with the recruitment and activation of TAFI. This is followed by the assembly and induction of the contact system at the streptococcal surface, eventually triggering the release of bradykinin (BK). BK is then carboxyterminally truncated by activated TAFI, which converts the peptide from a kinin B2 receptor ligand to a kinin B1 receptor (B1R) agonist. Finally, we show that streptococcal supernatants indirectly amplify the B1R response as they act on peripheral blood mononuclear cells to secrete inflammatory cytokines that in turn stimulate upregulation of the B1R on human fibroblasts. Taken together our findings implicate a critical and novel role for streptococci-bound TAFI, as it processes BK to a B1R agonist at the bacterial surface and thereby may redirect inflammation from a transient to a chronic state.

Thrombin-activatable fibrinolysis inhibitor (TAFI) is a pro-metallocarboxypeptidase that can be proteolytically activated (TAFIa). TAFIa is unique among carboxypeptidases in that it spontaneously inactivates with a short half-life, a property that is crucial for its role in controlling blood clot lysis. We studied the intrinsic instability of TAFIa by solving crystal structures of TAFI, a TAFI inhibitor (GEMSA) complex and a quadruple TAFI mutant (70-fold more stable active enzyme). The crystal structures show that TAFIa stability is directly related to the dynamics of a 55-residue segment (residues 296-350) that includes residues of the active site wall. Dynamics of this flap are markedly reduced by the inhibitor GEMSA, a known stabilizer of TAFIa, and stabilizing mutations. Our data provide the structural basis for a model of TAFI auto-regulation: in zymogen TAFI the dynamic flap is stabilized by interactions with the activation peptide. Release of the activation peptide increases dynamic flap mobility and in time this leads to conformational changes that disrupt the catalytic site and expose a cryptic thrombin-cleavage site present at Arg302. This represents a novel mechanism of enzyme control that enables TAFI to regulate its activity in plasma in the absence of specific inhibitors.

Since 1998, new mate trees were identified in five plantations in Misiones, Argentina, through mass selection. Emphasis was put on capturing genes related to caffeine, theobromine, saponin, twig color, anthocyanin, waxiness, leaf chlorophyll, and leaf thickness, characteristics that influence mate leaf quality in the drinking vessel or in the bombilla. Subsequently, saponin content of mate leaves was positively correlated with leaf thickness, anthocyanin, waxiness, and leaf chlorophyll. Saponin content was negatively, though slightly, related to caffeine content. A cluster analysis was used to distinguish the desired quality ideotypes, retaining good variability of the origins among the quality groups. The major consumer categories proposed were Gaucho for traditional consumption, Tango for urban consumption and Middle-East as an alternative for green tea. Seed gardens were organized accordingly to ensure market quality.

Summary Background Thrombin-activatable fibrinolysis inhibitor (TAFI) is a risk factor for coronary heart disease. TAFI is proteolytically activated by thrombin, the thrombin-thrombomodulin complex and plasmin. Once active, it dampens fibrinolysis and inflammation. The aim of this study was to generate TAFI-derived peptides that specifically modulate TAFI activation and activity. Methods Thirty-four overlapping TAFI peptides, and modifications thereof, were synthesized. The effects of these peptides on TAFI activation and TAFIa activity were determined. In addition, the binding of the peptides to thrombin were determined. Results Four peptides (peptides 2, 18, 19 and 34) inhibited TAFI activation and two peptides (peptides 14 and 24) inhibited TAFIa activity directly. Peptide 2 (Arg12-Glu28) and peptide 34 (Cys383-Val401) inhibited TAFI activation by the thrombin-thrombomodulin complex with IC50 values of 7.3 ± 1.8 and 6.1 ± 0.9 μm, respectively. However, no inhibition was observed in the absence of thrombomodulin. This suggests that the regions Arg12-Glu28 and Cys383-Val401 in TAFI are involved in thrombomodulin-mediated TAFI activation. Peptide 18 (Gly205-Ser221) and peptide 19 (Arg214-Asp232) inhibited TAFI activation by thrombin and the thrombin-thrombomodulin complex. Furthermore, these peptides bound to thrombin (KD: 1.5 ± 0.4 and 0.52 ± 0.07 μm for peptides 18 and 19, respectively), suggesting that Gly205-Asp232 of TAFI is involved in binding to thrombin. Peptide 14 (His159-His175) inhibited TAFIa activity. The inhibition was TAFIa specific, because no effect on the homologous enzyme carboxypeptidase B was observed. Conclusions Thrombin-activatable fibrinolysis inhibitor-derived peptides show promise as new tools to modulate TAFI activation and TAFIa activity. Furthermore, these peptides revealed potential binding sites on TAFI for thrombin and the thrombin-thrombomodulin complex.

The purpose of the study was to evaluate tamoxifen-associated changes in the vagina and uterus in postmenopausal breast cancer patients. Between June 1994 and December 1998, 45 patients enrolled in a prospective study before commencing tamoxifen therapy. Patients with endometrial thickness5 mm or neoplasia were excluded. Transvaginal ultrasonography, vaginal maturation indexes (VMI), and endometrial biopsy were performed at baseline and repeated at 6 months (n= 42), 1 year (n= 39), 2 years (n= 32), 3 years (n= 26), 4 years (n= 19), and 5 years (n= 15). For the 39 patients followed for 1 year, VMI (% parabasal/intermediate/superficial) was 21/71/8 at baseline compared with 1/90/9 at 1 year (P value = 0.0008/0.001/0.78). At baseline, mean endometrial thickness and uterine volume were 2.6 mm and 64 cm(3), respectively, compared with 5.8 mm and 84 cm(3) at 1 year (P= 0.0002, 0.002). At baseline, 80% of patients had atrophic endometrium and 9% proliferative endometrium compared with 61% and 26% at 1 year, respectively (P= 0.04). No cases of endometrial hyperplasia or adenocarcinoma were detected. Findings observed at 6 months persisted through 5 years of follow-up. Tamoxifen exerts a weak estrogenic effect on the vagina and uterus in highly prescreened postmenopausal women without preexisting endometrial pathology.

Summary. Objective: To elucidate the mechanism and the binding regions of monoclonal antibodies (MA) that interfere with thrombin-activatable fibrinolysis inhibitor (TAFI)/activated thrombin-activatable fibrinolysis inhibitor (TAFIa) activity. Results: Of 42 MA, 19 interfere with the TAFI activation/ TAFIa activity resulting in an inhibition of up to 92%. Characterization of the mechanism of inhibition revealed that 14 MA blocked the activation of TAFI by thrombin/thrombomodulin completely whereas five MA interfered directly with the enzymatic activity of TAFIa. Surprisingly, the former, except one, induced a significant reduction of clot lysis time whereas the latter did not. Affinity studies using a human/ murine TAFI chimer revealed that the binding region of the 14 activation blocking MA is located between AA1 and AA67. MA that inhibit exclusively the activation of TAFI by thrombin/thrombomodulin bind to Gly 66 . A MA that inhibits the activation of TAFI by both thrombin/thrombomodulin and plasmin binds to Val 41 . The MA that interfere with the enzymatic activity bind to the TAFIa moiety. Conclusions: The current study reveals at least three different putative molecular targets in the search for pharmacologically active compounds to modulate TAFIa activity.

Thrombin activates thrombin-activatable fibrinolysis inhibitor (TAFI) that removes C-terminal lysines or arginines. The activity of active TAFI (TAFIa) is lost rapidly. TAFIa is not inactivated by proteolysis but converted to an inactive state by a conformational transition. Numerous polymorphisms were identified in the TAFI gene. The TAFI-325Ile variant seems to influence TAFI levels. TAFIa retards plasmin formation and makes plasmin more susceptible to inhibition by antiplasmin; it prevents the conversion of the fibrin fragment DD(E) to fragment DD that impairs fibrin polymerization. The complement-derived factors C3a and C5a as well as bradykinin are further substrates for TAFIa. Elevated TAFI levels were associated with an increased risk of venous thrombosis. TAFI deficiency has been shown to be associated with an enhanced leucocyte migration. The absence of TAFI results in delayed wound healing with disturbed keratinocyte migration. Pro-inflammatory properties of osteopontin are downregulated by TAFIa. Hence, TAFI plays a role – besides in regulation of fibrinolysis – in wound healing, angiogenesis, and inflammation.

The project group "Central Trial Support" of the German Competence Network Pediatric Oncology and Haematology supports the members of the Society of Pediatric Oncology and Haematology in their effort to cope with the growing statutory, ethical and administrative requirements for therapy optimization studies (investigator-initiated, non-profit clinical trials). By these quality improvement measures the studies will become more revisable and reliable, but at the same time their processing will become more and more complex. The basic instrument of the project group "Central Trial Support" will be the so-called "Quality House" which has been built up in order to improve the performance of the associated study centres and to help put a systematic quality management system into practice. The "Quality House Pediatric Oncology" comprises detailed descriptions of the activities of all trial center co-workers. Its process map details all operational sequences which constitute an efficiently performing trial center. The so-called value adding processes are explained step by step, and the associated specific tasks are assigned to each respective co-worker. At each process step, the person in charge will have explanatory descriptions at her/his disposal and - if necessary - further problem solving means as well as references to possible optimization measures (e. g. Standard Operating Procedures and other documents). The German Competence Network Pediatric Oncology and Haematology will be implementing this electronic quality management system in trial centers which will convince both sponsors and authorities of the compliance with requirements and standards.

Although there has been remarkable progress and momentum toward achieving smoke-free pregnancies in the United States since 1990, concerted action is needed to close the remaining gaps in treatment and prevention so that we can reach the Healthy People 2010 goal for pregnant smokers: a prevalence of 1% or less. This need for action led to the formation of the National Partnership to Help Pregnant Smokers Quit, a collaboration among more than 50 organizations and agencies, public and private, that have joined forces to help pregnant smokers quit by providing proven clinical and community-based interventions to every pregnant smoker. This article summarizes the action plan developed by the partnership, the strategies it outlines, and some of the actions taken by partners over the past year to put the plan into action. Action is planned and progress is being made in five strategic areas: offering help through the health care system; using the media effectively; harnessing community and worksite resources; promoting policies known to increase smoking cessation efforts and successes; and expanding national research, surveillance, and evaluation efforts.

The coagulation system is a potent mechanism that prevents blood loss after vascular injury. It consists of a number of linked enzymatic reactions resulting in thrombin generation. Thrombin converts soluble fibrinogen into a fibrin clot. The clot is subsequently removed by the fibrinolytic system upon wound healing. Thrombin-activatable fibrinolysis inhibitor (TAFI), which is identical to the previously identified proteins procarboxypeptidase B, R, and U, forms a link between blood coagulation and fibrinolysis. TAFI circulates as an inactive proenzyme in the bloodstream, and becomes activated during blood clotting. The active form, TAFIa, inhibits fibrinolysis by cleaving off C-terminal lysine residues from partially degraded fibrin that stimulates the tissue-type plasminogen activator-mediated conversion of plasminogen to plasmin. Consequently, removal of these lysines leads to less plasmin formation and subsequently to protection of the fibrin clot from break down. Moreover, TAFI may also play a role in other processes such as, inflammation and tissue repair. In this review, recent developments in TAFI research are discussed.

Activated thrombin-activable fibrinolysis inhibitor (TAFIa) is a carboxypeptidase B that can down-regulate fibrinolysis. TAFIa is a labile enzyme that can be inactivated by conformational instability or proteolysis. TAFI is approximately 40% identical to pancreatic carboxypeptidase B (CPB). In contrast to TAFIa, pancreatic CPB is a stable protease. We hypothesized that regions or residues that are not conserved in TAFIa compared with pancreatic CPB play a role in the conformational instability of TAFIa and that replacement of these non-conserved residues with residues of pancreatic CPB would lead to a TAFIa molecule with an increased stability. Therefore, we have expressed, purified, and characterized two TAFI-CPB chimeras: TAFI-CPB-(293-333) and TAFI-CPB-(293-401). TAFI-CPB-(293-333) could be activated by thrombin-thrombomodulin, but not as efficiently as wild-type TAFI. After activation, this mutant was unstable and was hardly able to prolong clot lysis of TAFI-deficient plasma. Binding of TAFI-CPB-(293-333) to both plasminogen and fibrinogen was normal compared with wild-type TAFI. TAFI-CPB-(293-401) could be activated by thrombin-thrombomodulin, although at a lower rate compared with wild-type TAFI. The activated mutant displayed a markedly prolonged half-life of 1.5 h. Plasmin could both activate and inactivate this chimera. Interestingly, this chimera did not bind to plasminogen or fibrinogen. TAFI-CPB-(293-401) could prolong the clot lysis time in TAFI-deficient plasma, although not as efficiently as wild-type TAFI. In conclusion, by replacing a region in TAFI with the corresponding region in pancreatic CPB, we were able to generate a TAFIa form with a highly stable activity.

Marked differences regarding both caffeine and theobromine contents of mate leaves (Ilex paraguariensis) were found among 230 mass selected candidate trees distributed across 5 plantations in the region of Misiones, Argentina. In the vast majority of the analyzed samples, the caffeine concentrations ranged within the established limits for mate leaves, however theobromine contents (average content 0.96%) generally surpassed literature figures so far published [4,10]. By means of a simple cluster analysis using “group average” as the clustering algorithm, the samples were divided into eight different groups according to the contents of both purine alkaloids. Based upon this division it will be possible to pick appropriate genotypes for breeding ideotypes which meet more precisely the different specific consumer expectations.

PURPOSE Some operators use the lack of point tenderness over compression fractures to exclude patients from undergoing percutaneous vertebroplasty procedures. The purpose of this study was to determine whether this lack of tenderness portends a poorer clinical outcome after vertebroplasty than is achieved in patients with such tenderness. MATERIALS AND METHODS The authors conducted a retrospective review of consecutive percutaneous vertebroplasty procedures performed at their institution to define two populations. Group 1 included 90 patients with tenderness to palpation over the spinous process of the fractured vertebra, whereas group 2 included 10 patients without such tenderness. This second group presented with back pain and demonstrated tenderness distant from the fracture ( n = 5), tenderness lateral to the fracture ( n = 4), or no focal tenderness at all ( n = 1). All were treated because of edema seen on magnetic resonance (MR) imaging and/or increased activity on bone scan. Clinical outcomes were assessed by quantitative measurements of preand postoperative levels of pain (11-point scale) and mobility (five-point scale). RESULTS Pain improvement of three points or greater occurred in 77 of the 85 patients (91%) in group 1 who complied with follow-up and nine of nine such patients (100%) in group 2, with mean postoperative pain levels of 1.82 and 0.33 points, respectively ( P = .14). Forty of 45 patients (89%) in group 1 with impaired preoperative mobility reported improvement postoperatively, as did two of three such patients (67%) in group 2. Mean levels of postoperative impaired mobility for groups 1 and 2 were 0.27 and 0.67 points, respectively ( P = .27). CONCLUSION Pain on palpation over the fractured vertebra is not a necessary requirement in selecting patients who will benefit from percutaneous vertebroplasty. Other factors, such as MR evidence of edema or increased uptake on bone scan, should be weighed considerably in the decision to treat a patient.

Activated thrombin-activatable fibrinolysis inhibitor (TAFIa) attenuates the fibrin cofactor function of tissue-type plasminogen activator-mediated plasmin formation and subsequently fibrin degradation. In the present study, we focused on the role of plasmin in the regulation of TAFIa activity. Upon incubation with plasmin, TAFIa activity was generated, which was unstable at 37 degrees C. Analysis of the cleavage pattern showed that TAFI was cleaved at Arg(92), releasing the activation peptide from the 35.8-kDa catalytic domain. The presence of the 35.8-kDa fragment paralleled the time course of generation and loss of TAFIa activity. This suggested that, in the presence of plasmin, TAFIa is probably inactivated by proteolysis rather than by conformational instability. TAFI was also cleaved at Arg(302), Lys(327), and Arg(330), resulting in a approximately 44.3-kDa fragment and several smaller fragments. The 44.3-kDa fragment is no longer activatable since it lacks part of the catalytic center. We concluded that plasmin can cleave at several sites in TAFI and that this contributes to the regulation of TAFI and TAFIa.

In order to start a genetic improvement program for quality in the Mate crop (Ilex paraguariensis), it was attempted to estimate the actual genetic parameters of caffeine, theobromine and related quality traits, using available progeny tests in Misiones, Argentina. Using cluster analysis, eight groups of similar characteristics could be identified, and individual within full-sib family selection for quality was performed. Additive effects were strong for caffeine but weak for theobromine. Co-heritability between caffeine and theobromine was positive, suggesting that additive genetic correlations and dominance correlations are concurring. The strong influence of paternal progenitors regarding caffeine needs more research.

PURPOSE To test the hypothesis that articles published as "preliminary" or "pilot" reports are followed by more definitive publications in only a minority of cases. METHOD A survey of Medline was performed for reports published in 1992 in journals listed in the Abridged Index Medicus that had the word "preliminary" or "pilot" in the title. For identified reports, a Medline search of publications in 1992 through 1999 was performed, using lead author's name, second author's name, and senior (last) author's name, and at least one keyword based on the publication title. Preliminary and pilot publications were subdivided by type of study (controlled clinical study, case series, laboratory or nonclinical) and by the report of either positive or negative results. Rates of publication based on study design and publication bias were compared using the chi-square test for statistical significance. RESULTS The rate of publication of follow-up reports within seven years of the initial publication was 27%. Follow-up studies of controlled clinical studies (40%) were published more frequently than were those of laboratory or nonclinical studies (31%) or case series (22%), but these differences were not significant (p >.10). There was no statistically significant difference in follow-up publication rates based on publication bias. CONCLUSION Only 27% of studies published as preliminary or pilot reports were subsequently followed by a more definitive publication. While the words preliminary and pilot suggest that publication of further, refined work is pending, this is often not the case.

Of all the technical triumphs of the 20th Century, the flight of the first airplane by the Wright Brothers is probably the best known and revered by people of all ages. It is strange but true that, prior to this project, very little was known about the flight characteristics of the 1903 Wright Flyer, the first successful airplane. Replicas have been built and flights attempted, but no one has been able to repeat or exceed the 59-second flight by Wilbur Wright on Dec 17, 1903. The Los Angeles Section of the American Institute of Aeronautics and Astronautics (AIAA) organized the Wright Flyer Project for the purpose of building and flying a replica of the machine, applying modern methods of test and analysis to yield a quantitative database documenting the flight characteristics of the first aircraft to fly. This effort, which began two decades ago and is now coming to fruition is described in this paper.

Abstract —Elevated levels of lipoprotein(a) [Lp(a)] and the presence of small isoforms of apolipoprotein(a) [apo(a)] have been associated with coronary artery disease (CAD) in whites but not in African Americans. Because of marked race/ethnicity differences in the distribution of Lp(a) levels across apo(a) sizes, we tested the hypothesis that apo(a) isoform size determines the association between Lp(a) and CAD. We related Lp(a) levels, apo(a) isoforms, and the levels of Lp(a) associated with different apo(a) isoforms to the presence of CAD (≥50% stenosis) in 576 white and African American men and women. Only in white men were Lp(a) levels significantly higher among patients with CAD than in those without CAD (28.4 versus 16.5 mg/dL, respectively; P =0.004), and only in this group was the presence of small apo(a) isoforms (P =0.043). Elevated Lp(a) levels (≥30 mg/dL) were found in 26% of whites and 68% of African Americans, and of those, 80% of whites but only 26% of African Americans had a small apo(a) isoform. Elevated Lp(a) levels with small apo(a) isoforms were significantly associated with CAD ( P

We report our experience with the use of the antifibrinolytic agent epsilon-aminocaproic acid (EACA), Amicar, as an adjuvant to endovascular treatment of cranial arteriovenous fistulae. We also review applications of antifibrinolytic agents to neurovascular disorders and discuss the mechanism of action, dosing strategy, contraindications, and possible complications associated with the use of EACA. We identified 13 patients with cranial arteriovenous fistulae (five direct carotid cavernous fistulae [CCF], seven dural arteriovenous fistulae [DAVF], and one vein of Galen malformation) who received EACA as an adjunct to endovascular treatment. In all cases embolic coils were the primary embolic agent. We reviewed the modes of initial endovascular therapy and angiographic findings immediately thereafter and the response to EACA. Two direct CCF and two DAVF were completely thrombosed on follow-up angiography, and two DAVF demonstrated diminished flow after EACA therapy. Seven fistulae did not respond to EACA. Four of eight tightly coiled fistulae thrombosed, while none of five loosely coiled fistulae thrombosed. None of four cases with a residual fistula separate from the coil mass underwent thrombosis with EACA, while four of nine cases without a separate fistula thrombosed. There was no morbidity related to EACA therapy. EACA may thus be useful as an adjunct to endovascular treatment of cranial arteriovenous fistulae. Loose or incomplete coil packing of the fistula predicts a poor response to EACA therapy.

SummaryBased on in vitro studies, thrombin-activatable fibrinolysis inhibitor (TAFI) has been hypothesized as a link between coagulation and fibrinolysis, but the physiological role of TAFI in vivo has not yet been established. To anticipate on the availability of genetically modified mouse models, we studied the endogenous expression of TAFI in mice. Functional TAFI was found in mouse plasma. TAFI mRNA was only detectable in the liver, showing a hepatocyte-specific expression with a pericentral lobular distribution pattern. The murine TAFI cDNA was cloned and sequenced. The deduced amino acid sequence revealed that murine TAFI is highly identical to human TAFI. The murine cDNA was stably expressed and the activated recombinant protein was functionally active; it converted the substrate hippuryl-arginine, and prolonged the clot lysis time of TAFI depleted plasma. We conclude that mice have functional TAFI in plasma, which is highly similar to human TAFI. Therefore, genetically modified mice may provide useful models to study the role of TAFI in vivo. Abbreviations: TAFI, thrombin-activatable fibrinolysis inhibitor; CPI, carboxypeptidase inhibitor from potato tubers; CPN, carboxypeptidase N; t-PA, tissue-type plasminogen activator; PPACK, H-D-Phe-Pro-Arg-chloromethylketone.

Als„Marjolin Ulcus“ bezeichnet man maligne Transformationen chronischer Wunden insbesondere nach Verbrennungstraumen. Die Latenzzeit zwischen dem Primartrauma und der malignen Transformation betragt etwa 30 Jahre. Das„Marjolin Ulcus“ zeichnet sich durch ein aggressiveres Verhalten gegenuber anderen Plattenepithelkarzinomen aus. In einem Fall eines 65 jahrigen Patienten mit der Lasion am rechten Handrucken und regionalen Lymphknotenmetastasen berichten wir uber die kombinierte Strahlen- und chirurgische Therapie. Der ausgedehnte Weichteildefekt nach entsprechend breiter lokaler Exzision wurde mit einem retrograd gestielten A. radialis-Lappen gedeckt.

The volatile oil compositions of Eucalyptus camaldulensis var. brevirostris leaves obtained by hydrodistillation (HD) and supercritical fluid extraction methods (SFE) were analysed qualitatively and quantitatively by GLC-MS. Ninety different components were separated and most of them identified. In both extracts the main constituents were found to be β-phellandrene (8.94 and 4.09%), p–cymene (24.01 and 10.61%), cryptone (12.71 and 9.82%) and spathulenol (14.43 and 13.14%). The yield of the monoterpene hydrocarbons in HD oil (0.288 g/100 g fresh leaves) was slightly higher compared with that in the SFE extract (0.242 g/100 g fresh leaves). The SFE extract possessed higher concentrations of the sesquiterpenes, light oxygenated compounds and heavy oxygenated compounds than the HD oil. The relationship between the antioxidant activity and chemical composition of the extracted oils was investigated. The significant amounts of p–cymen-7-ol and thymol are responsible for the antioxidative activity of both extracts. The concentration of both compounds, but especially that of p–cymen-7-ol (2.25%), is higher in the SFE extract. This corresponds with the higher antioxidative activity of the SFE compared with the HD extract. p–Cymen-7-ol, a compound newly identified in leaves of Eucalyptus species, exhibited superior antioxidant activity in comparison with that of butylated hydroxyanisole.