Initiation of the tissue factor pathway of coagulation in the presence of heparin: control by antithrombin III and tissue factor pathway inhibitor

Activation of factor X by both the unactivated tissue factor:factor VII complex (TF:VII) and the activated tissue factor:factor VIIa complex (TF:VIIa) has been studied in the presence of tissue factor pathway inhibitor (TFPI), antithrombin III (ATIII), and heparin. At near-plasma concentrations of TFPI, ATIII, and factor X, factor X activation that occurs in response to TF:VII is essentially abolished in the presence of heparin (0.5 micromol/L). This effect requires both inhibitors, acting on different targets: (1) ATIII, which in the presence of heparin blocks the activation of TF:VII, and (2) TFPI, which inhibits the TF:VIIa that is generated. In the absence of ATIII, TFPI alone with heparin reduces but does not abolish factor X activation. Conversely, in the absence of TFPI, ATIII + heparin reduces but does not abolish TF:VIIa generation and allows continuing activation of factor X. These results indicated that when the unactivated TF:VII complex is the initiating stimulus, heparin-dependent reduction in the rate and extent of factor X activation requires both ATIII and TFPI. In contrast, if TF:VIIa is used to initiate activation, only TFPI is involved in its regulation.     

Hepatosplenic T-cell lymphoma: a distinct clinicopathologic entity of cytotoxic gamma delta T-cell origin

We identified eight cases of T-cell lymphoma with evidence of a gamma delta phenotype over a 13-year period. Seven of these cases conformed to a distinct clinicopathologic entity of hepatosplenic gamma delta T- cell lymphoma. Nearly all of these patients were young adult males (five of seven), with a median age at presentation of 20 years. They presented with marked hepatosplenomegaly, without lymphadenopathy or significant peripheral blood lymphocytosis. Thrombocytopenia was seen in all patients, and five of seven were mildly anemic. The clinical course was aggressive, and despite multiagent chemotherapy, the median survival duration was less than 1 year. The morphologic findings were uniform; a monomorphic population of medium-sized lymphoid cells with moderately clumped chromatin and a rim of pale cytoplasm infiltrated the sinusoids of the spleen, liver, and bone marrow. The cells had a characteristic immunophenotype: CD2+, CD3+, CD4-, CD5-, CD7+, CD16+, CD57-, CD25-, T-cell receptor (TCR)delta +, beta F1-. CD8 was positive in four of seven cases tested, and CD56 was positive in five of six. All cases expressed the cytotoxic granule-associated protein, TIA1, but perforin was detected in only one case. All cases with assessable DNA had a TCR gamma gene rearrangement, and lacked Epstein-Barr virus sequences. Isochromosome 7q was identified in two cases with cytogenetic information. The one case of cutaneous gamma delta T-cell lymphoma differed in its clinical manifestations, histologic appearance, and immunophenotype. We conclude that hepatosplenic gamma delta T-cell lymphoma is a distinct clinicopathologic entity derived from cytotoxic gamma delta T cells, and should be distinguished from other lymphomas of T-cell and natural-killer cell (NK)-like T-cell derivation.     

Interventional closure with Amplatzer PFO occluder of patent foramen ovale in patients with paradoxical cerebral embolism

Percutaneous transcatheter closure has been proposed as an alternative to surgical closure or long-term anticoagulation in patients with presumed paradoxical embolism and patent foramen ovale (PFO). We report our mid-term results of 55 consecutive symptomatic patients (mean age: 47 years, range: 20-79) who underwent percutaneous transcatheter closure of PFO after at least one event of cerebral ischemia; 16 (29%) patients had at least one transient ischemic attack and 39 (71%) patients at least one embolic stroke. Multiple embolic events had occurred in 6 (11%) patients. Percutaneous transcatheter closure was technically successful in all 55 patients (100%). For the majority of patients, an Amplatzer PFO occluder measuring 25 mm in diameter (n=49) or an Amplatzer PFO occluder measuring 35 mm in diameter (n=6) was used. Complete occlusion by color Doppler and transesophageal contrast echocardiography investigation was achieved in 96% at follow-up 3-6 months after implantation; only 2 patients had a trivial residual shunt at follow-up. Mean fluoroscopy time was 6.7 minutes (range: 1.7-47.1), and in-hospital follow-up was uneventful except for 1 patient who developed a cardiac tamponade requiring uneventful and successful needle pericardiocentesis. At a mean follow-up of 19 months (range: 3-32) no recurrent embolic neurological events was observed. Transcatheter closure of PFO with Amplatzer PFO occluder devices is a safe and effective therapy for patients with previous paradoxical embolism and aneurysmatic or nonaneurysmatic PFO. Percutaneous closure is associated with a high success rate, low incidence of hospital complications, and freedom of cerebral ischemia events.     

DLA-identical bone marrow grafts after low-dose total body irradiation: effects of high-dose corticosteroids and cyclosporine on engraftment

Previous studies found that marrow allografts from DLA-identical littermates resulted in survival of 60% of recipient dogs after an otherwise lethal dose of 450 cGy of total body irradiation (TBI), either because of successful allografts or autologous recovery after rejection of the allografts. Forty percent of dogs died with marrow aplasia after allograft rejection. The current study asked whether allogeneic engraftment could be enhanced and survival improved by treating allograft recipients with high doses of corticosteroids or with cyclosporine (CSP), administered either before or after transplantation. Five dogs in group 1 received corticosteroids beginning on day -5 and ending on day 32 after transplant. The starting dose was 12.5 mg of prednisone per kilogram orally twice daily. All five dogs rejected their allografts; three died early with marrow aplasia and two showed endogenous marrow recovery. Nine dogs received CSP from day -6 to day -1 before transplantation at a dose of 20 mg/kg/d intravenously administered in divided doses. All nine dogs rejected the marrow allograft; six died with marrow aplasia and three survived with endogenous marrow recovery. Seven dogs received CSP after transplantation at a dose of 30 mg/kg/d orally from day -1 to day 35. All seven had sustained allografts (two mixed chimeras and five complete donor-type chimeras) and became healthy long-term survivors without graft-versus-host disease. These results extend previous observations and confirm that grafts of marrow from DLA-identical littermates improved survival of dogs exposed to low but otherwise lethal doses of TBI. Additional therapy with high-dose corticosteroids administered peritransplantation and posttransplantation or CSP administered before transplantation neither enhanced the rate of allogeneic engraftment nor improved survival; however, CSP administered after transplantation resulted in successful allografts and event-free survival in all cases.     

Effect of recombinant canine granulocyte-macrophage colony-stimulating factor on hematopoietic recovery after otherwise lethal total body irradiation

Recombinant canine granulocyte-macrophage colony-stimulating factor (rcGM-CSF) was studied in normal dogs and in dogs receiving otherwise lethal total body irradiation (TBI) without marrow transplant. Five normal dogs receiving 25 micrograms/kg of rcGM-CSF by subcutaneous (SC) injection twice daily (BID) for 14 days showed increases in peripheral blood neutrophil counts of three to five times the baseline. Platelet counts decreased during administration of rcGM-CSF to a mean nadir of 52,800. Ten dogs received 400 cGy TBI at 10 cGy/min from two opposing 60Co sources and no marrow graft. Within 2 hours of TBI, rcGM-CSF was begun at a dose of 50 micrograms/kg SC BID for 5 doses and then continued at 25 micrograms/kg SC BID for 21 days. Only 1 of the 10 dogs receiving rcGM-CSF survived with complete and sustained recovery of hematopoiesis. One of 13 historical control dogs survived after 400 cGy with no hematopoietic growth factor or marrow infusion. Results with rcGM-CSF were compared with previous and concurrent data with G-CSF studied in the same model. Of 10 dogs receiving G-CSF, 8 survived with complete and sustained hematopoietic recovery, a significantly better survival than that seen with rcGM-CSF (P = .006). Neutrophil counts were sustained at higher levels after TBI for the first 18 days in the G-CSF group (P < .016) and the neutrophil nadirs were higher. No differences in neutrophil nadirs were noted between the rcGM-CSF and control groups. Dogs treated with rcGM-CSF experienced a more rapid decline of platelet counts than G-CSF-treated or control dogs over the first 18 days (P < .001). The nadir of the platelet count was higher in the control group than in either the G-CSF or rcGM-CSF group and no significant difference was observed between the G-CSF and rcGM-CSF groups. After otherwise lethal TBI (400 cGy) in dogs, rcGM-CSF was not effective in promoting hematopoietic recovery or improving survival.     

Release of interleukin-12 in experimental Escherichia coli septic shock in baboons: relation to plasma levels of interleukin-10 and interferon- gamma

Interleukin (IL)-12 is thought to be a key factor for the induction of interferon gamma (IFN-gamma), a cytokine essential for the lethal effects of endotoxin. We report here on the release of the nonfunctional subunit of IL-12, p40, as well as biologically active heterodimeric IL-12, p70, after administration of a lethal (n = 5) or sublethal (n = 8) dose of live Escherichia coli to baboons. Remarkably, on lethal challenge, peak levels of p40 were observed at 3 hours that were about twofold lower than those elicited after sublethal challenge (2,813 +/- 515 pg/mL v 4,972 +/- 732 pg/mL, P < .05). This disparity was also observed, although to a lesser extent, for IL-12 p70 antigen, of which maximum levels of 91 +/- 47 pg/mL and 151 +/- 41 pg/mL were measured 6 hours after a lethal or sublethal dose of E coli, respectively. Circulating p70 antigen correlated with IL-12 biologic activity (r = 0.869; P < .001). When comparing lethal to sublethal conditions, lower peak levels of IL-12 on lethal E coli sharply contrasted with higher levels of other proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, IL-1beta, IL-6, and IL-8 observed in these animals. Lower IL-12 concentrations in the lethal group may have resulted in part from the enhanced production of IL-10, a known inhibitor of IL-12 synthesis in vitro, as peak levels of this cytokine 3 hours postchallenge inversely correlated with peak levels of IL-12, in particular p40 (r = -0.802; P < .01). Contrary to what might be expected if IFN-gamma were solely induced by IL-12, lethally challenged baboons generated threefold more IFN-gamma at 6 hours than those receiving a sublethal dose (P < .05). Moreover, higher levels of IFN- gamma were associated with lower p40/p70 ratios, suggesting that, in agreement with observations in vitro, IFN-gamma may have preferentially upregulated the release of p70 over p40. These data show that IL-12 is released in experimental septic shock in nonhuman primates and suggest that IL-10 and IFN-gamma are involved in the regulation of this release. Furthermore, this study indicates that the systemic release of IL-12 might be essential, but is not likely sufficient, to promote lethal production of IFN-gamma in sepsis.     

乳酸水平监测在治疗早期重症监护患者中的指导作用

背景和目的:乳酸水平增高与患者的致病率和病死率显著相关.该研究探讨了在危重患者的早期治疗中,监测乳酸水平是否可以改善患者的预后及其效果.方法:将入住ICU时血乳酸水平≥3.0 mmol/L(3.0 mEq/L)的患者随机分为2组,乳酸组以乳酸水平指导治疗,使患者在最初8h内乳酸水平每2h 下降20%以上;对照组仅有基线乳酸水平,不进行乳酸水平监测.     

Treatment of periodontal disease for glycaemic control in people with diabetes

Background: Glycaemic control is a key issue in the care of people with diabetes mellitus (DM). Some studies have suggested a bidirectional relationship between glycaemic control and periodontal disease. Objectives: To investigate the relationship between periodontal therapy and glycaemic control in people with diabetes and to identify the appropriate future strategy for this question. Search strategy: A comprehensive approach was adopted employing handsearching; searching of electronic databases including the Cochrane Oral Health Group’s Trials Register, CENTRAL, MEDLINE, EMBASE, CINAHL, ZETOC, ISI Web of Knowledge and LILACS; contact with appropriate non‐English language healthcare professionals; authors and organizations. The final date for searching for studies was 24 March 2010. Selection criteria: This review studied randomized controlled trials of people with Type 1 or 2 diabetes mellitus (DM) with a diagnosis of periodontitis. Suitable interventions included mechanical periodontal therapy with or without adjunctives and oral hygiene education. Data collection and analysis: The titles and abstracts of 690 papers were examined by two review authors independently. Ultimately, seven studies were included and 19 excluded after full text scrutiny. All trials were assessed for risk of bias. Main results: Three studies had results pooled into a meta‐analysis. The effect for the mean percentage difference in HbA1c for scaling/root planing and oral hygiene (+/? antibiotic therapy) versus no treatment/usual treatment after 3–4 months was ?0.40% (95% confidence interval (CI) fixed effect ?0.78% to ?0.01%), representing a statistically significant reduction in HbA1c (P = 0.04) for scaling/root planing. One study was assessed as being at low risk of bias with the other two at moderate to high risk of bias. A subgroup analysis examined studies without adjunctive antibiotics ?0.80% (one study: 95% CI ?1.73% to 0.13%; P = 0.09), with adjunctive antibiotics in the test group ?0.36% (one study: 95% CI ?0.83% to 0.11%; P = 0.14), and with antibiotics in both test and control groups after 3/4 months ?0.15% (one study: 95% CI ?1.04% to 0.74%; P = 0.74). Authors’ conclusions: There is some evidence of improvement in metabolic control in people with diabetes, after treating periodontal disease. There are few studies available and individually these lacked the power to detect a significant effect. Most of the participants in the study had poorly controlled Type 2 DM with little data from randomized trials on the effects on people with Type 1 DM.     

Behandlung des akuten ST-Hebungsinfarkts in Netzwerkstrukturen

Management of acute ST elevation myocardial infarction (STEMI) demands rapid and complete reperfusion of the infarct-related artery (IRA). With postinfarction prognosis depending on time delay from onset of symptoms to complete reperfusion (TIMI 3 flow) of the IRA, primary percutaneous coronary intervention (PPCI) performed by an experienced team has been shown to be superior to thrombolytic therapy with lower mortality, less frequent occurrence of nonfatal reinfarction and stroke, and thus represents the preferred treatment strategy according to the national and international guidelines.For regional implementation of PPCI, particularly in rural areas, information and transfer logistics within networks of care and direct transport of an infarction patient to a PCI hospital rather than to the closest hospital are a challenge. With successful implementation of network logistics and standardized therapeutic pathways, current guidelines and requested timelines versus thrombolysis could be met. The implemented logistics comprised 24 h/7 days stand-by services of an experienced PCI team, direct telephone hotline contact between rescue service/emergency physician and interventional cardiologist on call, and direct open access to a catheterization laboratory at any time.Within the Drip&Ship network Rostock, to date (July 2007) 1,022 consecutive patients with PCI for STEMI were documented and analyzed over 5 years; of these, 490 patients were transferred from a community hospital to the PCI center and 532 patients were admitted directly to the interventional center. In 95.1% of all transferred and in 94.8% of all directly admitted patients, PCI was successfully accomplished upon arrival. A normalized flow to the IRA after PCI was documented in 96% of both groups, no patient was subjected to thrombolytic therapy. At 12-month follow-up, there were no differences between both groups with respect to infarct size and mortality. Moreover, there was no evidence of differences in left ventricular ejection fraction between groups. Thus, transportation of STEMI patients within an established PCI network did not result in any prognostic disadvantage. Efficient network logistics with transportation for PPCI in acute STEMI ensure both safety and outcome profiles similar to patients treated by PCI in metropolitan areas.