The role of the endovascular surgeon for lower extremity ischemia.

UNLABELLED: Since the data investigating endovascular therapy performed by surgeons is scarce, we retrospectively reviewed our experience of endovascular procedures performed by vascular surgeons in the operating room for lower extremity ischemia due to stenotic lesions. METHODS: A total of 14,424 procedures were performed by our division between January 1990--October 2003. Of these, 500 involved a balloon angioplasty. These made up 3.5% of the total caseload. The median age of the patients who underwent these 500 balloon angioplasty was 72+/-0.5 years old; 65% were male; 50% had a history of diabetes mellitus, and 6% had ESRD. Indications for the procedures included acute ischemia (47 cases), critical ischemia (rest pain, gangrene, or ischemic ulcers in 254 cases), failing bypass (64 cases), severe claudication (134 cases), and preoperative for a popliteal artery aneurysm repair. RESULTS: 244 of the procedures were percutaneous, and the remaining 256 were combined with some type of open procedure. Those performed as an open technique were in combination with a bypass (135 cases) and in combination with a patch angioplasty (31cases). Balloon angioplasties were performed of the aorta (5 cases), iliac arteries (281 cases), the superficial femoral artery (SFA) (101 cases), the popliteal artery (44 cases), the tibial vessels (77 cases), the subclavian/axillary artery (5 cases) and failing grafts (26 cases). Balloon angioplasty was attempted in eight cases and failed due to inability to cross the lesion with a guidewire. Intraoperative complications included 4 dissections, inability to dilate the lesion adequately (2 cases), and rupture of two iliac lesions that underwent open repair (1 case) or repair with a stent graft (1 case). Stents were initially used highly selectively but recently are now being deployed more liberally in the iliac arteries (total 251 cases with stents). CONCLUSIONS: Based on these data, we suggest that balloon angioplasty is a useful tool that can be performed by vascular surgeons safely. The advantages to the patients include one combined procedure to treat lower extremity ischemia.

Signal processing at the Ras circuit: what shapes Ras activation patterns?

A systems biology approach is applied to gain a quantitative understanding of the integration of signalling by the small GTPase Ras. The Ras protein acts as a critical switch in response to signals that determine the cell's fate. In unstimulated cells, Ras switching between an inactive GDP-binding and active GTP-binding state is controlled by the intrinsic catalytic activities of Ras. The calculated high sensitivity of the basal Ras-GTP fraction to changes in the rate constant of GTP-hydrolysis by Ras can account for the carcinogenic potential of Ras mutants with decreased GTPase activities. Extracelluar stimuli initiate Ras interactions with GDP/GTP exchange factors such as SOS, and GTP-hydrolysis activating proteins such as RasGAP. Our data on freshly isolated hepatocytes stimulated with epidermal growth factor (EGF) show transient SOS activation and sustained Ras-GTP patterns. We demonstrate that these dose-response data can only be explained by transient RasGAP activitation, and not by merely switching off the SOS signal, e.g. by inhibitory phosphorylation of SOS. A transient RasGAP activity can be brought about by a number of mechanisms. A comprehensive kinetic model of the EGF receptor (EGFR) network was developed to explore feasible molecular scenarios, including the receptor-mediated recruitment of SOS and RasGAP to the plasma membrane, phosphorylation of RasGAP and p190 RhoGAP by soluble tyrosine kinases, and RasGAP interactions with phosphoinositides and p190 RhoGAP. We show that a transient RasGAP association with EGFR followed by the capture of RasGAP through the formation of complexes with p190 RhoGAP can account for data on hepatocytes. In summary, our results demonstrate that a combination of experimental monitoring and integrated dynamic analysis is capable of dissecting regulatory mechanisms that govern cellular signal transduction.

Carotid surgery without external carotid endarterectomy: a 6-year clinical experience with 1027 cases.

PURPOSE: previously we routinely performed endarterectomy of the external carotid artery (ECA) during carotid surgery. However, discouraging experience and lack of supportive data in the literature made us question its necessity. The present report describes our experience with a modified carotid endarterectomy (CEA) technique where the ECA is left undisturbed regardless of its degree of stenosis. METHODS: from January 1996 to June 2001, 1027 CEAs were performed in 905 patients with this technique at our institution. All operations were performed for at least 60% internal carotid artery (ICA) stenosis. A preoperative carotid duplex scan was available for review in 990 cases (96%). Follow-up duplex scans were recovered from 0 to 1 months in 851 cases (83%) and from >1 month in 655 cases (64%). Seventy percent of these cases were performed for asymptomatic lesions. RESULTS: the perioperative (30-day) mortality rate for the entire group of patients was 0.5% and the stroke rate was 0.7%. Mean follow-up was 18 months (range: 2-66 months). Only two ECAs occluded in the first postoperative month. During the follow-up period, 37 additional ECAs (5.6%) were found to progress from mild to severe (>75%) stenosis postoperatively. In addition, 7% of the cases were found to have worsened the degree of stenosis, 8% improved and 85% remained unchanged. CONCLUSION: these data support sparing of the ECA during CEA.

Comparison of Magnetic Resonance Angiography (MRA) and Duplex Ultrasound Arterial Mapping (DUAM) prior to infrainguinal arterial reconstruction.

OBJECTIVE: the purpose of this study is to compare Magnetic Resonance Angiography (MRA) to Duplex Ultrasound Arterial Mapping (DUAM) and intraoperative findings to determine the clinical, accuracy of MRA for planning lower extremity revascularization procedures. METHODS: forty-two patients who underwent lower extremity revascularization procedures had both MRA and DUAM evaluations. These data were analyzed retrospectively and two distinct endpoints were considered. First, we compared the MRA and DUAM findings for aorto-iliac, femoral-popliteal and infra-popliteal segments to intraoperative findings and evaluated the degree to which they agreed. Second, if there was a disagreement between imaging modalities, it was established whether a change in operative procedure would have resulted. RESULTS: MRA and DUAM findings agreed in 26 of 31 cases (83%) of aorto-iliac segments, in 25 of 31 cases (81%) of femoral-popliteal segments, and in 16 of 21 cases (76%) of infra-popliteal segments. In total, DUAM agreed with intraoperative findings in 98% of cases while MRA agreed in 82% (p<.001). Disagreement between intraoperative findings and DUAM lead to an alternate surgical procedure in only one case (2%) while disagreement with MRA lead to a different procedure in 38% of cases (p<.001). CONCLUSIONS: these data show that MRA is not yet adequate to replace conventional angiography and is less accurate that DUAM. Further improvements are necessary before MRA can be used as the sole modality for formulation of a pre-operative plan for lower extremity revascularization.

Causes of early post carotid endartectomy stroke in a recent series: the increasing importance of hyperperfusion syndrome.

OBJECTIVE: Early stroke occurs in 0.9% to 7% of patients undergoing carotid endarterectomy (CEA). These have been thought to be mostly due to embolization. However, in our recent clinical experience, we noted hyperperfusion syndrome to be a significant cause of postoperative strokes. Therefore, we reviewed our experience and investigated the distribution of causes of early postoperative strokes. MATERIALS AND METHODS: A retrospective chart review of 444 consecutive patients who underwent CEA at our institution between June 1997 and October 1999 (500 operations) was performed to evaluate the incidence and etiology of early postoperative strokes. Indications for operation included history of stroke correlating with the side of ICA stenosis (50 patients or 10%), symptoms of transient ischemic attacks (84 patients or 16.8%), amaurosis fugax (18 patients or 3.6%), or asymptomatic stenosis (348 patients or 69.6%). All patients were evaluated with duplex scan preoperatively and postoperatively. Diagnosis of early postoperative strokes within one month after CEA was made based on clinical examination. Postoperative CT scan of the brain was available in 100% of patients with suspected diagnosis of CVA. RESULTS: Five patients (3 male and 2 female) were diagnosed with strokes postoperatively (1%). These five were symptomatic patients with ICA stenosis > or = 80% and moderate contralateral ICA stenosis. In two of those patients (40%), the reason for the stroke was considered embolization to the cerebral arteries; one patient suffered a shunt injury as a cause of stroke; two patients (40%) were diagnosed with hyperperfusion syndrome. In both patients diagnosis was made clinically, and in only one of those patients the clinical picture correlated with CT scan. Two patients (0.4%) had asymptomatic ICA occlusion at 2 weeks and 18 days postoperatively. CONCLUSION: Embolization to the cerebral arteries remains the leading cause of early postoperative strokes. However, hyperperfusion syndrome also accounts for a significant portion of these postoperative strokes. The percentage of patients with this syndrome might be even higher, once clinical picture is clearly defined. These data warrant further investigation of hyperperfusion syndrome.

The regulation of L-type Ca2+ currents in cardiac myocytes of hibernating animals.

The action of isoproterenol and BAY K 8644 on voltage-dependent Ca2+ currents in isolated ground squirrel cardiac myocytes was studied in two (active and hibernating) states of the animal. In cardiac myocytes of active animals the effect of both drugs was shown to depend on the holding potential. At Vh of about -50 mV both isoproterenol and BAY K 8644 increased the Ca2+ current and their action was additive. At Vh of about -20 mV, both drugs inhibited the Ca2+ current. In cardiac myocytes from hibernating animals, isoproterenol increased the Ca2+ current at any holding potentials, while the effect of BAY K 8644 did not differ significantly from its effect on active animals. The combined action of the two drugs caused the inhibition of the Ca2+ current at high holding potentials. In terms of the two-site Ca2+ channel model, this means that one of the two pathways of channel phosphorylation is blocked in hibernating animal cardiac cells, and BAY K 8644 restores this pathway.

The regulation of L-type Ca2+ currents in rat cardiac myocytes.

The regulation of L-type Ca2+ current in isolated rat cardiac cells was studied using the perforated patch-clamp technique. A dual effect of the cAMP-dependent phosphorylation activator, isoproterenol, at different holding potentials (V(h)) was shown. The currents increased at V(h) = -50 mV and decreased at V(h) = -30 mV. A dihydropyridine agonist, BAY K 8644, and isoproterenol had an additive effect on the activation of Ca2+ channels at holding potentials close to the resting potential. The additivity was disturbed at more positive V(h). The activating effect of BAY K 8644 did not virtually change in the presence of a protein kinase blocker, H8, and a phosphatase activator, acetylcholine. The results were interpreted within the framework of a two-site phosphorylation model with two independent pathways of Ca2+ current regulation.

Effect of isoproterenol on the L-type Ca2+ current in cardiac cells from rats and hybernating ground squirrels.

The perforated patch clamp method was used to study the effect of the agonist of beta-adrenoreceptors isoproterenol on L-type Ca2+ current in cardiocytes of rats and ground squirrels in two states: active and hibernating. It is shown that isoproterenol exerts a dual effect on Ca2+ currents of rats and ground squirrels in the active state: at Vh = -50 mV, the current increases, whereas at Vh = -30 mV, it decreases. In hibernating ground squirrels, the dual effect of isoproterenol is not observed: isoproterenol increases Ca2+ current at any Vh values. The hypothesis is put forward that, during the entrance of ground squirrels into hibernation, the phosphorylation of one of the sites (not cAMP-dependent) of L-type Ca2+ channels is blocked.

The kinetic characteristics of L-type calcium channels in cardiac cells of hibernators. 2. Analysis of the kinetic model.

The present paper describes the experimental and theoretical investigations of the kinetic characteristics of the L-type Ca2+ channels in ground squirrels Citellus undulatus in two different physiological states (hibernation and spontaneous arousal). The perforated patch-clamp method was used in the experiments. We have shown in the previous study [1] that Ca2+ currents in hibernating and active animals may be described by the d2f1(2)f2 model. Based on that model, in this paper we studied in detail the main steps of the conductance regulation of Ca2+ channels: activation (d), slow (f1-type) and fast (f2-type) inactivations of the channel. Activation is related to the movement of the gating charge. Slow inactivation is associated with the movement of the gating charge and is current-dependent. Fast inactivation is a more complex process and cannot be represented as a single-stage conformational transition induced by the gating charge movement. It is regulated by cAMP phosphorylation. The differences in the Ca2+ current kinetics are observed virtually for all the components. In hibernating animals, the most pronounced shift (15-20 mV) towards depolarization is experienced by the normalized conductances of both inactivation components, whereas the conductance of the activation component is shifted to a lesser extent. The characteristic times of Ca2+ currents of hibernating ground squirrels are 1.5-2 times greater than those of aroused animals. The current activation gating charge of Ca2+ channels in ground squirrel cardiocytes was found to change. The gating charge was about 2 in hibernating animals and 1.5 in active squirrels. The effect of isoproterenol-induced cAMP-dependent phosphorylation on Ca2+ currents in cardiocytes from hibernating ground squirrels was studied. Isoproterenol restored the kinetic parameters of Ca2+ currents to the values close to the parameters of active animals. However, we failed to explain the suppression of the Ca2+ current in hibernating animals in terms of cAMP-dependent regulation only.

The kinetic characteristics of the L-type calcium channels in cardiocytes of hibernators. 1. Development of a kinetic model.

The present paper described the experimental and theoretical investigations of the kinetic characteristics of the L-type Ca2+ channels in ground squirrels Citellus undulatus in two different physiological states (hibernation and spontaneous arousal). The perforated patch-clamp method was used in the experiments. It is shown that the potential-dependent Ca2+ current in isolated cardiocytes from hibernating animals is strongly inhibited during hibernation. An attempt was made to describe the kinetics of Ca2+ currents by the modified Hodgkin-Huxley equations. The experimental current traces are compared to the nonstationary solutions of the modified model, and the model parameters were found by optimization methods. It is shown that the simple dmfn model, where d is activation, f is inactivation, can not be used to describe the experimental characteristics at any power values m and n. Analysis of other models based on the conception of independence of activation and inactivation processes showed that in both physiological states-hibernation and spontaneous arousal-Ca2+ current was described by the model d2f1(2)f2, where d is activation, f1 and f2 are slow (f1-type) and fast (f2-type) inactivations of the channel.

Comparative analysis of the kinetic characteristics of L-type calcium channels in cardiac cells of hibernators.

An undefined property of L-type Ca2+ channels is believed to underlie the unique phenotype of hibernating hearts. Therefore, L-type Ca2+ channels in single cardiomyocytes isolated from hibernating versus awake ground-squirrels (Citellus undulatus) were compared using the perforated mode of the patch-clamp technique, and interpreted by way of a kinetic model of Ca2+ channel behavior based upon the concept of independence of the activation and inactivation processes. We find that, in hibernating ground-squirrels, the cardiac L-type Ca2+ current is lower in magnitude when compared to awake animals. Both in the awake or hibernating states, kinetics of L-type Ca2+ channels could be described by a d2f1(2)f2 model with an activation and two inactivation processes. The activation (or d) process relates to the movement of the gating charge. The slow (or f1) inactivation is associated with movement of gating charge and is current-dependent. The rapid (or f2) inactivation is a complex process which cannot be represented as a single-step conformational transition induced by the gating charge movement, and is regulated by beta-adrenoceptor stimulation. When compared to awake animals, the kinetic properties of Ca2+ channels from hibernating ground-squirrels differed in the following parameters: (1) pronounced shift (15-20 mV) toward depolarization in the normalized conductance of both inactivation components, and moderate shift in the activation component; (2) 1.5-2-fold greater time constants; and (3) two-fold greater activation gating charge. Thus, L-type Ca2+ channels apparently switch their phenotype during the hibernating transition. Stimulation of beta-adrenoceptors by isoproterenol, reversed the hibernating kinetic- (but not amplitude-) phenotype toward the awake type. Therefore, an aberrance in the beta-adrenergic system can not fully explain the observed changes in the L-type Ca2+ current. This suggests that during hibernation additional mechanisms may reduce the single Ca2+ channel-conductance and/or keep a fraction of the cardiac L-type Ca2+ channel population in a non-active state.

[The mechanisms of the formation of heterologous resistance in peroral immunization with a complex anti-influenza preparation]. / Izuchenie mekhanizmov formirovaniia geterologicheskoi ustoichivosti pri peroral'noi immunizatsii kompleksnym protivogrippoznym preparatom.

The paper presents experimental findings of the combined antiinfluenza drug (inactivated influenza vaccine + an interferon inducer - an immunogenetic anstimulator - polysaccharide 1,3beta-glucan). The oral immunization with the drug induces antibody accumulation in the secretions of the upper airway and blood sera in defense titers, interferon synthesis at days 1-3 postadministration, forms murine resistance to infection with homologous and heterologous viruses, enhances the functional activity of alveolar macrophages.

[Immune replacement therapy in RS infection]. / Immunozamestitel'naia terapiia RS-infektsii.

Respiratory syncytial (RS) virus is the main cause of severe respiratory infections in newborns and infants during the first year of life. In the recent years, search is under way for chemo- and immune replacement therapy preparations for etiotropic RS-infection therapy. Procedures have been developed to prepare immunoglobulins and Chigain preparations having a target-oriented action. They were clinically tested. There was a positive dynamics in the clinical manifestations of the disease and a positive influence on immunological parameters in children.

Parametric resonance and amplification in excitable membranes. The Hodgkin-Huxley model.

It has previously been shown by different investigators that the excitable membrane shows a resonant sensitivity to periodic external perturbations, but its Q-factor is, as a rule, low. The present paper analyses the possible ways of increasing the membrane Q, using a model of the Hodgkin-Huxley type. It is found, in particular, that it can be increased considerably by modulating periodically the membrane capacitance or the activation and inactivation rate constants of ionic channels, with a frequency of about 2 fo (fo being the fundamental frequency of damped oscillations in the membrane), the extent of modulation not exceeding the critical value 2/Q. In this case, a significant parametric amplification of the membrane current takes place. If the modulation coefficient is above 2/Q, the membrane can display a parametric resonance that causes stable self-oscillations in the potential with a frequency approximately fo. The conditions for the realization of parametric amplification and resonance in biological membranes are discussed.

[The role of Na+/Ca2+ exchange in the generation of delayed electrical activity of smooth muscle cells]. / Rol' Na+/Ca2+-obmena v generatsii medlennoi élektricheskoi aktivnosti gladkomyshechnykh kletok.

It was shown that electrogenic 3Na+/Ca2+ antiport evoked depolarization of the membranes and Ca2+ ions influx through Ca2+ activated channels which lead to the appearance of stable self-oscillation of the membrane potential (MP), as well as Na+ and Ca2+ ions intracellular concentrations.

[Parametric resonance and amplification of periodic disturbances in membranes containing ion channels with inactivation]. / Parametricheskii rezonans i usilenie periodicheskikh vozmushchenii v membranakh, soderzhashchikh ionnye kanaly s inaktivatsiei.

Parametric resonance and amplification of periodic perturbations in the membrane transport of ions through channels with inactivation was studied in computational experiments. It has been shown that a periodic change in the membrane capacitance or in the applied electric current with a frequency approximately 2 omega 0 (omega 0--the own angular frequency of the membrane) may excite stable self-oscillations in the membrane with a frequency of approximately omega 0. For this to occur, the degree of the capacitance modulation m or the amplitude of the applied current i0 must exceed some critical values mcr and i0cr. Excitation of self-oscillations by alternating electric current of the frequency approximately 2 omega 0 has the characteristics of parametric resonance. This can be explained by the fact that the equivalent membrane inductance depends on ionic current and displays periodic changes with a frequency approximately 2 omega 0, as also does the current. Small-amplitude periodic changes in the capacitance (m less than mcr) with frequencies approximately 2 omega 0 may result in significant amplification of periodic perturbations with frequencies approximately omega 0.

[Resonance phenomena in membranes containing ion channels with inactivation]. / Rezonansnye iavleniia v membranakh, soderzhashchikh ionnye kanaly s inaktivatsiei.

A mathematical model of the ion transport across a membrane containing channel with inactivation has been analysed. Under certain conditions, such a membrane has been shown to behave as a selfoscillating circuit of a very high quality, its own frequency ranging for a variety of natural channels between 10(-1)-10(3) cycles. When exposed to an alternating electric field with a frequency approximating f0, the membrane displays resonance changes in its potential and channel conductivity. The average (over a period of forced oscillations) values of the potential and conductivity also show a resonance type of dependence on the frequency of the external field.

[resonant events in membranes having ion channels with two conformational states]. / Rezonansnye iavleniia v membranakh, soderzhashchikh ionnye kanaly s dvumia konformatsionnymi sostoianiiami.

A study was carried out of a mathematical model of ion transport through biological membranes along the channels capable of conformational transitions between two states (R, T) with different conductivities. The model describes changes in time of te membrane potential and surface concentration of channels in one of the states (R). It has been shown that there may exist extinguishing oscillations with the frequency close to f0 on such a system may induce the resonance changes of the membrane potential. The resonance frequency f0 increases with an increase of the amplitude of external influence, this induces hesteresis of the membrane resonance parameters.

[Selectivity of the channels formed by flavomycoin in a lipid bilayer as a function of the concentrations of transported ions]. / Zavisimost' selektivnosti kanalov, obrazovannykh flamikoinom v lipidnom bisloe, ot kontsentratsii perenosimykh ionov.

Experiments on selective properties of the flavomycoin channels in a lipid bilayer in the solution of KCl show that the permeability ratio PCl/PK decreased with KCl concentration. A mathematical model of ion transport is developed which provides a quantitative description of the observed nonmonotonic dependence of transmembrane potential at a zero current on the concentration of KCl. An increase in PK relative to PCl is due to the difference in location of the binding sites of K+ and Cl- in a channel. The binding sites of Cl- are closer to the channel mouth as compared with those of K+.