The activation of the contact phase of coagulation by physiologic surfaces in plasma: the effect of large negatively charged liposomal vesicles

The endogenous, negatively charged surface that induces activation of the contact coagulation factors was investigated in plasmas taken from women in late pregnancy and control subjects of child-bearing age. The plasmas from the two groups of subjects were incubated at 4 degrees C for 24 hours either in plastic or in glass tubes and the factor VII coagulant activity (VIIc) was assayed in the treated plasmas. The activation of factor VII under these conditions involves the generation of enzymes derived from factor XII (XIIa). The contact surface is rate- limiting for the activation of factor VII in the plasmas in both groups of subjects and can be supplemented by large multilamellar liposomal vesicles carrying the appropriate density of negative charge. The size of these vesicles is within the range of sizes of the large lipoprotein particles (chylomicrons, very low and intermediate-density lipoproteins). The relationship between the density of negative charge on the liposomal vesicles and VIIc was similar in the late pregnancy and the control plasmas incubated in plastic tubes. At a saturating density of negative charge the observed relative VIIc was similar in both sets of plasmas. The incubation of late pregnancy or control plasma in plastic tubes in the presence of sodium stearate caused VIIc to increase with increasing concentration of the added fatty acid. These results suggest that large lipoprotein particles carrying the appropriate free fatty acid at a sufficient density of negative charge could provide the contact surface that induces the generation of factor XIIa and the subsequent activation of factor VII. Moreover, plasmas from women in late pregnancy have a higher concentration of potential surface and a higher density of negative charge than the plasmas from nonpregnant women.     

Does digoxin sensitize left ventricular mechanoreceptors?

Summary Afferent nerve fibre activity from left ventricular mechanoreceptors was recorded in 10 anaesthetized cats before and after two intravenous injections of 15 g/kg digoxin at 1 hour interval. These receptors are activated by coronary artery occlusion and induce a depressor cardiovascular reflex resulting in bradycardia and hypotension.Neither the spontaneous activity of the receptor's afferent nerve fibres nor their maximum activity during temporary coronary artery occlusion was affected by digoxin. The results show that digoxin in therapeutic doses has no sensitizing effect on left ventricular mechanoreceptors with vagal afferent fibres. The sensitization of cardiopulmonary baroreflexes by digitalis glycosides shown in previous investigations is thus more likely to be mediated by a central nervous effect of the drug.     

Homografts in patients with combined disease of the aortic valve and the ascending aorta: an alternative to the classical Bentall procedure

BACKGROUND AND AIM OF THE STUDY: In patients with aneurysms or dissections of the ascending aorta and additional aortic valve disease, valve-containing composite grafts are used in clinical routine. The study aim was to present our experience with homografts for aortic valve replacement extended by a vascular prosthesis as an alternative to the classical Bentall procedure. METHODS: Thirty consecutive patients (mean age 46+/-14 years) were included in this study. Indications for valve replacement were aortic stenosis (n = 15), aortic insufficiency (n = 6), combined aortic valve disease (n = 6), endocarditis of the native valve (n = 1), and endocarditis of a previously placed bioprosthesis (n = 2). The mean diameter of the ascending aorta was 5.6+/-0.5 cm; one patient had an acute dissection (diameter 4.4 cm). For valve replacement, cryopreserved homografts (mean size 24+/-2 mm) were used in a mini-root technique, and the ascending aorta was replaced by collagen-coated vascular prostheses (mean diameter 28+/-3 mm). The size of the vascular prosthesis was adjusted to the diameter of the sinutubular junction of the implanted homograft. Follow up included annual clinical examinations, transthoracic echocardiography and ultrafast computed tomography (CT) scans. RESULTS: All patients survived surgery, and no deaths occurred during follow up. None of the patients had postoperative anticoagulation, and no thromboembolic events were noted. Follow up was complete, with an average 48 months (range: 6 to 84 months). Doppler echocardiography revealed trivial to mild aortic regurgitation in nine patients postoperatively, with no deterioration during follow up. No pathologic pressure gradients over the aortic valves were measured at Doppler echocardiography; the mean valvular orifice area was 2.5+/-0.3 cm2. At ultrafast CT, normal homograft anatomy including the sinotubular junction, no calcifications, and no signs of annular dilatation were seen. In the patient who had surgery for acute endocarditis of the native valve, ultrafast CT revealed a small pseudoaneurysm below the left coronary artery, without need for reoperation. CONCLUSION: Short- and mid-term results show that cryopreserved homografts extended by small-sized vascular prostheses can be used safely for Bentall procedures in selected cases where the diameter of the aortic valve annulus is moderately dilated.     

Multisite rTMS for the Treatment of Chronic Tinnitus: Stimulation of the Cortical Tinnitus Network—A Pilot Study

Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the auditory cortex has been shown to significantly reduce tinnitus severity in some patients. There is growing evidence that a neural network of both auditory and non-auditory cortical areas is involved in the pathophysiology of chronic subjective tinnitus. Targeting several core regions of this network by rTMS might constitute a promising strategy to enhance treatment effects. This study intends to test the effects of a multisite rTMS protocol on tinnitus severity. 45 patients with chronic tinnitus were treated with multisite stimulation (left dorsolateral prefrontal, 2,000 stimuli, 20 Hz; left temporoparietal, 1,000 stimuli, 1 Hz; right temporoparietal, 1,000 stimuli, 1 Hz). Results were compared with a historical control group consisting of 29 patients who received left temporal stimulation (2,000 stimuli, 1 Hz). Both groups were treated on ten consecutive working days. Tinnitus severity was assessed at three time points: at baseline, after the last treatment session (day 12) and after a follow-up period of 90 days. A change of tinnitus severity over time was tested using repeated measures ANOVA with the between-subjects factor treatment group. Both groups improved similarly from baseline to day 12. However, there was a difference on day 90: the multisite stimulation group showed an overall improvement whereas patients receiving temporal stimulation returned to their baseline level of tinnitus severity. These pilot data suggest that multisite rTMS is superior to temporal rTMS and represents a promising strategy for enhancing treatment effects of rTMS in tinnitus. Future studies should explore this new protocol with respect to clinical and neurobiological effects in more detail.     

Activation of the coagulation cascade after infusion of a factor XI concentrate in congenitally deficient patients

Virally inactivated, high-purity factor XI concentrates are available for treatment of patients with factor XI deficiency. However, preliminary experience indicates that some preparations may be thrombogenic. We evaluated whether a highly purified concentrate produced signs of activation of the coagulation cascade in two patients with severe factor XI deficiency infused before and after surgery. Signs of heightened enzymatic activity of the common pathway of coagulation (elevated plasma levels of prothrombin fragment 1 + 2 and fibrinopeptide A) developed in the early post-infusion period, accompanied by more delayed signs of fibrin formation with secondary hyperfibrinolysis (elevated D-dimer and plasmin-antiplasmin complex). These changes occurred in both patients, but were more severe in the older patient with breast cancer when she underwent surgery, being accompanied by fibrinogen and platelet consumption. There were no concomitant signs of heightened activity of the factor VII-tissue factor mechanism on the factor Xase complex (plasma levels of activated factor VII and of factor IX and X activation peptides did not increase). The observed changes in biochemical markers of coagulation activation indicate that concentrate infusions increased thrombin generation and activity and that such changes were magnified by malignancy and surgery. Because some factor XI concentrates may be thrombogenic, they should be used with caution, especially in patients with other risk factors for thrombosis.     

Recombination hotspots in bacteriophage T4 are dependent on replication origins.

Bacteriophage T4 recombination "hotspots" were first detected by the rescue of genetic markers from UV-irradiated phage particles. These hotspots have since been detected following treatments that yield other forms of DNA damage, and at least one is active in the absence of damage. The previous mapping of phage replication origins near the peaks of two recombination hotspots suggested that the origins cause the localized enhancement of recombination. Here we show that deletion of one origin eliminates the corresponding recombination hotspot, as judged by rescue of markers from UV-irradiated phage. Furthermore, insertion of either origin into a recombination "coldspot" enhances rescue of nearby markers. We conclude that these origins are necessary, and very likely sufficient, for the generation of recombination hotspots. We also show that the hotspots are active in the absence of both phage-encoded UvsY and host-encoded RecA proteins, suggesting that some of the stimulated recombination occurs by a synaptase-independent mechanism.