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Background: Hypocoagulability and impaired platelet function have been associated with a high risk of death in sepsis. The aim of this cohort study was to determine whether sepsis-induced hypocoagulability and platelet dysfunction (assessed by ROTEM® and MULTIPLATE®, respectively) are increased in sepsis patients who died within 28 days after diagnosis compared with patients who died between 29 and 90 days after diagnosis., Methods: Consecutive patients admitted to the intensive care unit of Padova University Hospital from March 2015 to March 2018 for severe sepsis were considered. We collected blood samples from all patients to determine ROTEM® and MULTIPLATE® parameters. Each enrolled patient underwent a 90-day follow-up and the mortality rate was recorded., Results: Of 120 patients, 36 (30%) died within 28 days post-diagnosis (Group A), 23 (19%) died between days 29 and 90 post-diagnosis (Group B), and 61 (51%) were alive after 90 days (survivors). The clotting time in the ROTEM® test and clot formation time in the EXTEM test were significantly more prolonged in Group A than in B. Both groups showed a significantly higher hypocoagulability than survivors in the EXTEM test. MULTIPLATE® platelet function analysis showed that platelet function was significantly lower in Group A than in Group B., Conclusions: The present study showed that the combination of thromboelastometry and impedance aggregometry may help identifying sepsis patients at high risk of short-term death. Larger studies are warranted to corroborate our results.

Background: Microparticles (MP) have been largely studied as potential biomarkers in septic shock (SS) though their biological and clinical relevance is still unclear. This case-control study describes the trend of various MP subtypes during SS to evaluate their possible association with severity of illness and sepsis-related complications (disseminated intravascular coagulation [DIC] and acute kidney injury [AKI])., Methods: Forty patients admitted to the Intensive Care Unit with SS and 40 matched healthy volunteers were recruited. AnnexinV+, E-selectin+, thrombomodulin (TM+), leukocyte-derived (CD45+, CD36+) and platelet-derived MP (PMP-expressed as PMP/platelets ratio) were measured by flow-cytometry at baseline, on day 1, 3 and 7 after diagnosis. Severity of illness was assessed by Sequential Organ Failure Assessment Score, duration of vasoactive support and mechanical ventilation. Sepsis-related complications were considered., Results: Overall, septic patients showed higher levels of all MP considered compared to controls. TM+MP were significantly lower in more severe sepsis, while CD36+MP and PMP/platelets ratio were significantly increased in patients requiring longer vasoactive support and mechanical ventilation. As for sepsis-related complications, a higher PMP/platelets ratio in patients who developed DIC and increased E-selectin+MP in subjects who developed AKI were observed. PMP/platelets ratio at baseline was significantly associated with longer vasoactive support (OR=1.59 [1.05-2.42]), longer mechanical ventilation (OR=1.6 [1.06-2.42]) and DIC occurrence (OR=1.45 [1.08-1.96])., Conclusions: A global response through extra-vesiculation of endothelial cells, leukocytes and platelets during the early stages of SS was confirmed. The cellular activation was detected until day 3 after diagnosis. PMP/platelets ratio at diagnosis may be useful to evaluate SS severity and DIC occurrence.

Background: Sugammadex, which is used to reverse rocuronium-induced neuromuscular blockade, has a limited and transient effect on activated partial thromboplastin time and prothrombin time. However, no data are available on the effects of sugammadex on coagulation in morbidly obese patients, as assessed by rotational thromboelastometry (ROTEM®)., Methods: Sixty patients received sugammadex 2 mg/kg or 4 mg/kg to reverse moderate or deep rocuronium-induced neuromuscular blockade (N.=30/group) at the end of surgery under desflurane anesthesia. Arterial blood samples were collected before and 3 min and 30 min after sugammadex administration for ROTEM® analysis, including measurements of clotting time (CT), clot formation time, α angle, and maximum clot firmness in INTEM, EXTEM, and FIBTEM assays. Major and minor bleeding events were also monitored during the postoperative period., Results: Sugammadex 2 and 4 mg/kg has a limited and transient (<30 min) effect on INTEM CTs of 7.7% (P=0.04) and 10.7% (P<0.0001), respectively. There were no relevant effects on other ROTEM® parameters. A multivariate analysis indicated a significant effect of total sugammadex dose (<250, 250-500, >500 mg) on the INTEM CT (P=0.002). A regression analysis showed a positive relationship between sugammadex dose and INTEM CT value at 3 min after administration (coefficient = 0.052 s; 95% CI: 0.005-0.098 s; P=0.03). No major or minor bleeding events were observed in either group during the postoperative period., Conclusions: Sugammadex produces a slight effect on coagulation in morbidly obese patients, without increasing the risk for postoperative bleeding.

Background: Univentricular congenital heart defects require open-heart surgery soon after birth, and are associated with risk of brain injury and poor neurologic outcome., Methods: This is a prospective, observational study on children undergoing cardiac surgery. Plasma glial fibrillary acidic protein (GFAP), as an early marker of brain injury, was measured by ELISA at the end of anaesthesia induction, initiation of cardiopulmonary bypass (CPB), the end of cooling, the end of rewarming, the end of CPB, and after protamine administration. We recorded clinical and surgical parameters to assess which CPB phase and clinical parameters were associated with a GFAP increase., Results: We studied 13 children less than 50 months of age: 8 underwent Norwood or Damus-Kaye-Stansel palliation (group 1) and 5 underwent Fontan procedure (group 2). A GFAP increase was only observed in group 1, with the highest median value at the end of rewarming. No quantifiable levels of GFAP were measured at pre-bypass and the start of CPB stages in all patients. End of cooling and CPB-end GFAP, GFAP maximum value, and GFAP area under the curve all correlated with the CPB time spent at a cerebral regional saturation < 45% (P = 0.021, 0.028, 0.007, 0.021, respectively)., Conclusions: Children with univentricular heart defects exhibit a CPB plasma-GFAP increase only after stage 1 palliation. The maximum GFAP increase occurred at the end of rewarming. Further studies are needed to identify which clinical or surgical parameter(s) could reflect a GFAP increase during surgery for congenital heart defects, and whether GFAP levels correlate with the neurologic outcome., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Activation of the clotting cascade is central in acute xenograft rejection (AHXR) that occurs when pig organs are transplanted into primates. The coagulopathy reported in this model is a very complex process that involves simultaneously coagulation factors, platelets and phospholipid-bearing cells (i.e., leukocytes, red blood cells, and endothelial cells). Choosing whole blood for coagulation analysis theoretically appears more favorable compared with plasma. Whole blood rotation thromboelastometry (ROTEM(®) ) is a point-of-care global coagulation analyzer able to evaluate the characteristics of clot formation and lysis by dynamic monitoring. The aim of this study was to record thromboelastographic profiles, performed by ROTEM(®) , in a series of immunosuppressed nephrectomized primates that received a life-supporting kidney., Methods: Of the eight primates, n = 4 received a pig kidney transgenic for human decay-accelerating factor (hDAF/Gal+); n = 2, an α 1,3-galactosyltransferase gene-knockout (GT-KO) pig kidney transgenic for human CD39, CD55, CD59 and fucosyltransferase (HTF); and n = 2, a GT-KO pig kidney transgenic for hDAF. Blood samples were collected before and at least once per week after transplantation till euthanasia. Intrinsic (INTEM) and extrinsic (EXTEM) coagulation pathways and the function of fibrinogen (FIBTEM) were evaluated. Thromboelastographic parameters considered were clotting time (CT, seconds) and clot formation time (CFT, seconds) in INTEM and EXTEM and maximum clot firmness (MCF, mm) in FIBTEM. The correlations between CT in INTEM and activated partial thromboplastin time (aPTT), CT in EXTEM and PT, CFT in INTEM and EXTEM, and platelet counts and MCF in FIBTEM and fibrinogen plasma levels were also considered., Results: In all animals, thromboelastographic profiles showed progressive prolongation of CT (activation of coagulative cascade) in INTEM. A close correspondence was observed between (i) the prolongation of the CFT values (propagation of clot formation), both in INTEM and EXTEM, and the decrease in platelet counts; (ii) the reduction in MCF values (clot firmness) ​​in FIBTEM and the decrease in fibrinogen plasma levels. No concordance between CT in INTEM and aPTT and between CT in EXTEM and PT was observed., Conclusions: Our study demonstrated that ROTEM(®) analyzer could be a useful and complementary tool to study the consumptive coagulopathy, either "compensated" or "non-compensated," that takes place when transgenic pig kidneys are transplanted into primates. Larger and prospective studies are needed to confirm our results and to evaluate the role of ROTEM(®) to guide the management of consumptive coagulopathy in order to prolong the survival of the transplanted organ., (© 2013 John Wiley & Sons A/S.)

Severe factor V (FV) deficiency (parahaemophilia) is a rare congenital hemorrhagic disorder characterized by very low or undetectable plasma FV levels and bleeding phenotype ranging from mild to severe. We evaluated whole blood (WB) rotation thromboelastometry (ROTEM) in parahaemophilia patients and the contribution of intraplatelets FV, if any, to clot formation. Standard ROTEM(®) assays were performed in WB from nine parahaemophilia patients and 50 healthy controls. In addition, platelets poor plasma from one parahaemophilia patient (PPP-Pt) or normal subjects (PPP-N) was reconstituted with washed platelets obtained either from one patient with parahaemophilia (Plts-Pt) or normal subjects (Plts-N) and ROTEM assays were performed in platelets rich plasma (PRP) samples. There was a prolongation of the WB clotting time (CT) in all assays in patients as compared with controls. However, maximum clot firmness (MCF) was similar in patients and controls. ROTEM in PPP-Pt showed both a prolongation of CT and a reduction of MCF as compared with PPP-N. The addition of either Plts-Pt or Plts-N to PPP-Pt resulted in similar increase in MCF and a decrease of CT which was more evident for PPP-Pt + Plts-N than PPP-Pt + Plts-Pt. In contrast, the addition of Plts-Pt or Plts-N to PPP-N had superimposable effects on both CT and MCF. In parahaemophilia patients, WB ROTEM(®) presents mainly with prolongation of CT and no relevant effect on MCF. Residual intraplatelets FV in parahaemophilia contributes significantly to thrombin generation as shown in artificially reconstituted PRP models., (© 2011 Blackwell Publishing Ltd.)

Background: The role potential of recombinant human activated protein C (rhaPC), a recently developed molecule with anticoagulant and antiinflammatory properties, in prolonging survival in immunosuppressed primate recipients of porcine renal xenografts has been evaluated., Methods: rhaPC was administered daily for 5 days (24 μg/kg/hr; group A; n = 3) or throughout the postoperative period (8-24 μg/kg/hr; group B; n = 2; or 24-48 μg/kg/hr; group C; n = 4). Animals in group D (n = 2) received rhaPC daily (24 μg/kg/hr) combined with recombinant human antithrombin (84 U/kg every 8 hr). Two animals served as control (group E)., Results: The results indicate that rhaPC is protective against fibrin deposition early after transplantation but does not prevent fibrin deposition and the occurrence of acute humoral xenograft rejection (AHXR) later on. Animals in the study survived between 8 and 55 days. At the dose used, rhaPC is able to prevent fibrin deposition in the graft in the first 2 weeks after xenotransplantation, except when it is administered in conjunction with antithrombin. However, rhaPC did not prevent the eventual occurrence of AHXR in primate recipients of porcine xenografts., Conclusions: In this pig to primate model, rhaPC confers a short advantage in the prevention of early perioperative xenograft damage but does not represent an effective strategy for preventing AHXR.

Introduction: The imbalance in clotting homeostasis, tending towards hypercoagulation, is recognized as the real barrier to the long-term survival of porcine xenografts in pig-to-primate xenotransplatation. The present study aimed to validate in primate blood the applicability of whole blood rotation thromboelastometry, performed by ROTEM®, which evaluates the characteristics of clot formation by dynamic monitoring., Materials and Methods: ROTEM® (Pentapharm GmbH, Munich, Germany) was used to investigate native coagulation (NATEM®), the intrinsic (INTEM®) and extrinsic (EXTEM®) pathways, the function of fibrinogen (FIBTEM®), and the presence of fibrinolysis in 40 naïve cynomolgus monkeys. Using classic validation approaches, the normal thromboelastographic profile was defined and the influence of haematocrit (Hct,%), platelet count (x10(9)/L), fibrinogen (mg/dl), and factor VIII (FVIII,%) was evaluated., Results: In all four (NATEM®, INTEM®, EXTEM®, FIBTEM®) assays considered, Clotting Time (CT, sec) and Clot Formation Time (CFT, sec) were shorter in primates than humans. Moreover, α-angle (°), Maximum Clot Firmness (MCF, mm), and MaxVel (mm/min) were also higher in primates than humans. No substantial difference was observed for Hct and platelet count between the two species. On the contrary, FVIII was higher in primates than in humans whereas, interestingly enough, fibrinogen levels were lower in monkeys than in humans., Conclusion: ROTEM® depicts a hypercoagulable profile in primates as compared to humans. Taken together these data suggest that, with regard to coagulation, xenotransplantation in cynos may represent a much more difficult situation than xenotransplantation in humans., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The ROtation ThromboElastoMetry analyser (ROTEM, Pentapharm, Munich, Germany) is useful for studying whole blood (WB) clot formation and lysis. Reduction of haematocrit (HCT) has been reported to influence traditional thromboelastography parameters without compromising "in vitro" blood coagulation. We performed this case-control study to evaluate ROTEM profiles in sideropenic anaemia patients with different degrees of reduction of HCT levels. Forty consecutively referred patients with sideropenic anaemia were enrolled. A group of 40 healthy age and gender matched subjects acted as a control. The influence of HCT on ROTEM was assessed in the study population and in a model of artificially reconstituted blood with modified HCT values. Cases presented significantly increased levels of maximum clot firmness (MCF) as compared to controls (p < 0.001) mimicking a sort of "hypercoagulable profile". However, thrombin generation tests failed to detect an increase in thrombin generation in cases as compared to controls. A statistically significant inverse linear correlation between HCT and MCF (p < 0.0001) was found. In addition, ROTEM profiles following "in vitro" manipulation of HCT confirmed the inverse linear correlation between HCT and MCF found in the study population. In conclusion, the increased clot firmness found by ROTEM in anaemic patients is likely to be related to the method in itself rather than representing a marker of hypercoagulability "in vivo". Since ROTEM is widely used by anaesthesiologists when deciding the optimisation of products supplementation during surgery, attention should be paid in the case of anaemic patients taking depending on the peculiar thrombo-elastography profile found.

The invariant-mass spectrum of e+e- pairs produced in 12C+12C collisions at an incident energy of 2 GeV per nucleon has been measured for the first time. The measured pair production probabilities span over 5 orders of magnitude from the pi(0)-Dalitz to the rho/omega invariant-mass region. Dalitz decays of pi(0) and eta account for all the yield up to 0.15 GeV/c(2), but for only about 50% above this mass. A comparison with model calculations shows that the excess pair yield is likely due to baryon-resonance and vector-meson decays. Transport calculations based on vacuum spectral functions fail, however, to describe the entire mass region.

Background and Aims: Plant lateral organs such as leaves arise from a group of initial cells within the flanks of the shoot apical meristem (SAM). Alterations in the initiation of lateral organs are often associated with changes in the dimension and arrangement of the SAM as well as with abnormal hormonal homeostasis. A mutation named stem fasciated (stf) that affects various aspects of plant development, including SAM shape and auxin level, was characterized in sunflower (Helianthus annuus)., Methods: F1, F2 and F3 generations were obtained through reciprocal crosses between stf and normal plants. For the genetic analysis, a chi2 test was used. Phenotypic observations were made in field-grown and potted plants. A histological analysis of SAM, hypocotyl, epicotyl, stem and root apical meristem was also conducted. To evaluate the level of endogenous indole-3-acetic acid (IAA), a capillary gas chromatography-mass spectrometry-selected ion monitoring analysis was performed., Key Results: stf is controlled by a single nuclear recessive gene. stf plants are characterized by a dramatically increased number of leaves and vascular bundles in the stem, as well as by a shortened plastochron and an altered phyllotaxis pattern. By histological analysis, it was demonstrated that the stf phenotype is related to an enlarged vegetative SAM. Microscopy analysis of the mutant's apex also revealed an abnormal enlargement of nuclei in both central and peripheral zones and a disorganized distribution of cells in the L2 layer of the central zone. The stf mutant showed a high endogenous free IAA level, whereas auxin perception appeared normal., Conclusions: The observed phenotype and the high level of auxin detected in stf plants suggest that the STF gene is necessary for the proper initiation of primordia and for the establishment of a phyllotactic pattern through control of both SAM arrangement and hormonal homeostasis.

Resection of carotid body tumors can be difficult to perform because of its site, vascularity, arterial adherence and local cranial nerve involvement. Advances in vascular surgical technique have reduced the risks of perioperative complications such as carotid injury, stroke and death. From January 1980 to May 1994 20 patients (22 carotid body tumors) were examined. All patients except one were evaluated with a preoperative angiography. No preoperative embolization was performed. Thirteen patients underwent ultrasonography, nine a CT scan of the neck, 5 magnetic resonance scanning and two magnetic resonance angiography. One old patient refused operation. The authors report their experience on 21 carotid body tumor resections (14 Shamblin group I and 7 group II paragangliomas). Surgical technique is based on subadventitial resection (18 excisions) and 3 resections were performed from the medial surface of the carotid bifurcation which had been partially absorbed into the mass. In the last 15 operations intraoperative Somatosensorial Evoked Potential (SEP) monitoring has been used. Only two patient required arterial repair because intimal dissection and another patient needed vagus nerve section. The ligation of external carotid artery and internal carotid resection with graft replacement were never necessary in these patients. No early or late deaths occurred and no recurrences were detected at follow-up.

Purpose: To report the immediate and long-term outcome of intraoperative balloon angioplasty for the treatment of recurrent disease in the internal carotid arteries (ICAs)., Methods: Three patients (2 males, 1 female; ages 53 to 70 years) presented with > 80% restenotic lesions (bilateral in one patient) at the distal aspect of a previous carotid endarterectomy. Two patients exhibited hemianopia, while the third was asymptomatic but had a contralateral ICA occlusion. All four lesions appeared smooth and fibrous on ultrasonography and were located high in the ICA. The location and morphology of the lesions made balloon angioplasty a more potentially successful treatment option., Results: Through open access to the common carotid artery, the lesions were approached and dilated under fluoroscopic guidance with monitoring of evoked potentials. The lesions were successfully dilated as determined by control arteriography, and no complications were encountered. Over a follow-up period extending to 18 months in one patient and 24 months in the other two, ultrasound imaging and arteriography have shown no restenosis at any treatment site., Conclusions: Although caution is prudent when dealing with lesions in the cervical arteries, balloon angioplasty may have a role in treating surgically inaccessible restenotic carotid lesions that demonstrate a low potential for embolic complications. More experience with this technique will be required before widespread application of balloon angioplasty in the cervical vessels can occur.

The possibility of increasing the resistance of a synthetic vascular graft to intraoperative or immediate postoperative bacterial contamination justifies the interest in methods such as antibiotic bonding or antibiotic soaking. On the basis of this experience and with the aim of testing the efficacy of such a graft, a multicentre experimental study on sheep to compare the susceptibility to infection of Dacron Gelseal grafts (control) versus rifampicin-bonded Dacron Gelseal grafts (treated) following the intravenous infusion of 10(7)-10(8) cells Staphylococcus aureus was conducted. The grafts were implanted in both common carotid arteries of sheep. In a group of 11 animals (group A), a treated and a control graft were implanted in the same animal. In a group of four sheep (group B), only treated or control grafts were implanted in each animal. In group A, 36% of (four of 11) the treated grafts became infected versus 54% (six of 11) of the control prostheses. In group B, none of the treated grafts was infected by the inoculated pathogen, which, by contrast, infected 75% (three of four) of the controls. These observations confirm the recent interest aroused by the possibility of pretreating gelatin-coated Dacron grafts with rifampicin in the prevention of early graft infection.

The symptoms of thoracic outlet syndrome (TOS) may be improved or cured either by physiotherapy or by a surgical operation. The choice of patients to be submitted to surgery must be performed on the basis of clinical picture and of non invasive and invasive assessment. Moreover the surgeon must choose the best procedure to relieve symptoms. The Authors on the basis of their experience and of a literature review refer to the various surgical approaches used in the treatment of TOS.

To compare the effects of indobufen (INB) with those of ASA+dipyridamole (DP) on graft patency, 113 patients undergoing femoropopliteal bypass surgery were randomly and blindly assigned to treatment with INB 400 mg daily or with ASA 900 mg daily plus DP 225 mg daily. Treatment started 2 days before surgery and lasted for 12 months. All patients underwent two angiographic examinations: the first early after surgery (mean 6 days) and the second at the end of the study (mean 368 days). The 1 year cumulative patency rate for INB was 60% higher but not statistically different from the ASA-DP group (53.2%). The relative risk (INB/ASA+DP) calculated by the Mantel-Haenszel test was 0.86 (confidence limits 0.54-1.35). Only the site of operation (above-knee or below-knee) has a significant prognostic value on the fate of the graft.

A randomized clinical trial was undertaken to assess the efficacy of indobufen in inhibiting platelet adhesiveness in carotid thromboendarterectomy. The patients were treated under double-blind conditions with indobufen and with placebo, and were then assessed by means of scintigraphy with labelled platelets, ultrasonic tomography and angiography for a minimum follow-up period of 6 months. Haematological and clinical assessments were also performed. The results of the study suggest that platelet accumulation in carotid endarterectomy may be an early sign of restenosis; anti-aggregant treatment with indobufen carried out at an early stage prior to surgery inhibited platelet accumulation. The final result showed that anti-aggregant treatment had a positive influence on the short- and medium-term outcome of carotid endarterectomy.

The reaction of 1,8-naphthyridine azides with ethyl acrylate leads to the formation of 2-pyrazolines instead of 1,2,3-triazolines. Some of the compounds obtained have undergone pharmacological and microbiological (antibacterial) testing.

By treating pyrido (2,3-e)-1,4-diazepinones with alkyl halides, N4-alkylpyrido (2,3-e)-1,4-diazepines were obtained. In addition a number of N1-alkylpyrido (2,3-e)-1,4-diazepines were prepared from alkyltetrahydronaphthyridinones by the Schmidt reaction. Preliminary pharmacological screening of some of these compounds showed no appreciable activity.

The Schmidt reaction on tetrahydro-1,8-naphthyridin-4-ones gave pyrido [2,3-e]-1,4-diazepines and pyrido[2,3-b][1,4]diazepines. The preliminary pharmacological screening of some of these compounds showed no appreciable activity.

Somatosensory Evoked Potentials (SEPs), to median nerve stimulation, were continuously monitored in 58 patients undergoing carotid endarterectomy A first group of patients was shunted routinely; in a second group the shunt was selectively applied when inadequacy of collateral circulation was suspected based on stump pressure values and SEP changes. Both amplitude and latency modifications of SEPs occurred during surgery; however no post-operative neurological deficit was seen unless there was a complete flattening of cortical waves, even a transitory one. Inadequate collateral circulation and embolic ischemia affected SEPs differently. While the latter produced a disappearance of all cortical waves, the former led first to a progressive flattening of later cortical waves and then of N20 as well. For values of stump pressure ranging between 20 and 50 mmHg SEPs were unchanged in some patients and altered in others. These findings may explain the controversies existing about the usefulness of stump pressure for predicting tolerance to carotid clamping.

The synthesis of a number of 1-alkyl-7-(2-hydroxy-3-alkylaminopropoxy)-1,8-naphthyridin-2-ones is described. The compounds studied were prepared by reaction of 1-alkyl-7-hydroxy-1,8-naphthyridin-2-ones with epichlorohydrin. The substituted epoxy intermediates obtained were allowed to react with amines and gave the desired products. All the compunds prepared were devoid of beta-blocking activity.

The synthesis of N-substituted amino-1,8-naphthyridines is described. Some products were subyected to pharmacological screening and the resulting data are reported.