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The aim of this study was to assess the impact of adding long-term micronized purified flavonoid fraction (MPFF) to standard treatment of femoropopliteal deep vein thrombosis (DVT).
This pilot, comparative, open-label study with blinded outcome assessor enrolled patients with a first episode of femoropopliteal DVT confirmed by duplex ultrasound scanning (DUS). All participants were randomly allocated to one of two treatment groups: (1) control that received a standard treatment with oral rivaroxaban, and (2) experimental that involved additional treatment with MPFF 1000 mg/day. Both drugs were used for 6 months. Patients were followed for the whole treatment period and underwent DUS every 2 months to determine the degree of recanalization by popliteal (PV), femoral vein (FV), and common femoral vein (CFV) compressibility. Thrombi extension were assessed by the modified Marder score. At the end of the follow-up period, patients were assessed with Villalta and venous clinical severity scales (VCSS). Patients with a Villalta score ≥ 5 were diagnosed with post-thrombotic syndrome (PTS).
Sixty patients were randomized to the control or MPFF groups (n = 30 in each group). There were 40 men and 20 women with a mean age ± SD of 56.3 ± 13.4 years. Clinically unprovoked DVT was recognized in 65% of cases and left side localization in 45%. The mean baseline Marder score was 15.0 ± 4.8 and 11.1 ± 4.3 in the experimental and control groups, respectively (p = 0.002). At 6 months, the mean Villalta score in the MPFF group was significantly lower compared with control (2.9 ± 2.7 versus 5.8 ± 3.0; p < 0.0001). PTS was diagnosed in six patients (20%) and 17 patients (57%) in the experimental and control groups respectively (p = 0.007). A significant difference between the groups was also observed for the VCSS value (2.3 ± 1.9 versus 4.9 ± 1.9; p < 0001). After 6 months of treatment the Marder score decreased to 0.8 ± 1.6 and 2.8 ± 3.5 in the experimental and control groups, respectively (p = 0.006). In the MPFF group, there was a greater reduction in the Marder score (p < 0.0001) and more rapid rate of recanalization for the FV (p < 0.0001), with a non-significant trend for the CFV (p = 0.130) and PV (p = 0.204) compared with the control group. Full recanalization of the PV at 6 months was observed in 24 patients (80%) who had received MPFF, and only 17 patients (57%) in the control group (p = 0.095).
The addition of MPFF to standard therapy for DVT in the form of oral rivaroxaban can reduce the incidence of PTS at 6 months in patients with proximal DVT and increase the speed of deep vein recanalization.
Les Laboratoires Servier funded the article processing fees, editorial assistance, and open access fee for this manuscript.
Deep vein thrombosis (DVT) is a significant medical and social problem. According to official statistics, the incidence of DVT in the Russian Federation remained stable throughout the period 2012–2016 accounting for 1.5–1.6 cases per 1000 population per year [1,2,3], which is slightly higher than figures obtained in published epidemiological studies [4,5,6,7,8]. The main long-term issue after an episode of DVT is the occurrence of post-thrombotic syndrome (PTS), which significantly affects the patients’ quality of life. The incidence of PTS in the 10–15 years after the primary thrombotic episode reaches 19–42%, and severe forms of the disease with the presence of trophic disorders can be detected in 3–4% of patients [9,10,11,12]. The symptoms of PTS usually develop within the first 6 months following the primary DVT, but can occur years after the initial event .
The pathogenetic mechanisms leading to the development of PTS may involve lesions of the deep vein valves with the formation of blood reflux, incomplete recanalization of venous segments with the persistence of residual venous obstruction, or a combination of both mechanisms . The most important component is the presence of residual venous obstruction, which increases the risk of developing PTS by 1.6–2.0-fold [14,15,16,17,18]. The recanalization of veins is a complex biological process. One of its integral components is the immune inflammatory reaction, which is responsible for clearance of thrombotic masses from the lumen of the vessel and venous wall lesion [19, 20]. Previous studies have shown that increased levels of inflammatory markers, in particular C-reactive protein, interleukins-1 and -6, intercellular adhesion molecule-1 (ICAM-1), and a reduced level of anti-inflammatory cytokines (interleukin-10) are associated with a higher risk of PTS development [21,22,23,24,25]. This raises the possibility that pharmacological modulation of the inflammatory reaction may protect the venous wall from excessive leukocyte aggression, while retaining the natural role of immune cells in the process of vessel recanalization.
Among the potential pharmacological agents with the ability to target the inflammatory reaction directly in the venous wall, micronized purified flavonoid fraction (MPFF), an oral agent, is of particular interest. Previous experimental studies have demonstrated its prominent endothelial protective properties in the form of reduced rolling, adhesion, and migration of leukocytes in the settings of reperfusion injury and secondary venous hypertension [26,27,28,29]. It has also been shown to suppress the inflammatory reaction in patients with chronic venous disease (CVD) , including those who have undergone sclerotherapy . To test the hypothesis that long-term treatment with MPFF may affect the natural course of DVT, this study evaluated the impact of MPFF use in the treatment of patients with femoropopliteal DVT.
This pilot, single-center, open-label comparative clinical trial with blinded outcome assessment recruited patients over 18 years of age with a first episode of clinically provoked or unprovoked DVT in the femoropopliteal vascular segment with possible involvement of the calf veins and the common femoral vein. DVT location was confirmed by duplex ultrasound scan (DUS). All procedures performed in studies involving human participants were in accordance with local ethics committee of the Clinical Hospital No. 1 of the Presidents Administration of Russian Federation and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. At the authors’ institution it is not obligatory to register pilot and unfunded studies; therefore this trial is not registered.
Exclusion criteria were suspected or confirmed pulmonary embolism; bilateral DVT location; extension of the thrombosis into the iliac veins above the inguinal fold; contraindications to therapy with anticoagulants or MPFF; verified malignant tumor at the time of DVT manifestation; known severe thrombophilia (deficiency of protein C, protein S, antithrombin III, antiphospholipid syndrome); use of parenteral anticoagulants for 7 days or more from the time of DVT verification; inability to use compression stockings; any intervention for DVT (inferior vena cava filter implantation, thrombectomy, or catheter-guided thrombolysis); continued use of other drugs affecting the hemostatic system (except acetylsalicylic acid at a dose of up to 100 mg per day); and poor compliance.
The study was carried out at the facilities of the Clinical Hospital No. 1 of the Presidents Administration of the Russian Federation in 2017–2018. In accordance with the internal protocol of the institution, all patients with suspected DVT entering the emergency department were assessed using a two-level Wells score and a D-dimer evaluation . In patients with a high clinical probability of DVT or a combination of low clinical probability for DVT with an increased level of D-dimer, anticoagulant therapy was initiated with low molecular weight heparin (LMWH), followed by DUS. Patients with diagnosed femoropopliteal venous thrombosis were assessed for fulfillment of the inclusion and exclusion criteria. After signing informed consent, patients were randomly allocated to one of two groups based on the number on the patient’s medical record form: those whose last digit was even were assigned to the MPFF group, and those whose last digit was odd were assigned to the control group; if the last digit was zero, the penultimate digit was used. In the case of premature completion of recruitment to either group, all eligible patients were intentionally allocated to the second group.
During the period from hospital admission to treatment allocation, all patients received therapeutic doses of LMWH (enoxaparin 1 mg/kg twice daily). After randomization, patients in both groups were switched to the oral anticoagulant rivaroxaban at a dosage of 15 mg twice daily for up to 3 weeks from the administration of the first dose of LMWH. Thereafter they received a dosage of 20 mg once daily for up to 6 months. The first dose of rivaroxaban was administered instead of LMWH at the time of the next scheduled injection. In addition, during the first 3 days following the DVT diagnosis, patients in both groups applied individualized medical compression in the form of thigh-high stockings with a pressure of 23–32 mmHg (class 2 compression according to RAL-GZ 387 standard). Matching the size of the stocking to the diameter of the limb was controlled 3 weeks and 3 months after the start of treatment. Patients were advised to wear the stockings 24 h a day for the first week and then during the day for the next 6 months. In the MPFF group, patients received MPFF 500 mg twice daily for 6 months in addition to standard treatment. The first dose of MPFF was administered immediately after treatment allocation and in parallel with the switch to the oral form of the anticoagulant.
Patients were followed for 6 months with clinical and ultrasound evaluation every 2 months. At baseline, in addition to standard clinical data, the affected lower limb was evaluated for the presence of pre-existing CVD, and if confirmed, the clinical class according to the CEAP (Clinical, Etiological, Anatomical, and Pathological) classification was determined. CEAP clinical classes C1 (telangiectases), C2 (varicose veins), C4 (skin pigmentation, eczema, lipodermatosclerosis or athrophie blanche), C5 (healed venous ulcer), and C6 (active venous ulcer) were confirmed objectively on the basis of the presence of corresponding signs of the disease. CEAP clinical class C3 (presence of leg edema) was confirmed on the basis of the patient’s medical history (complaints of edema of the lower limb or need for compression therapy prior to the manifestation of thrombosis), as at the time of physical examination all patients had swelling due to acute deep vein occlusion. CEAP class was also determined after 6 months of treatment. CVD severity was assessed using the Venous Clinical Severity Score (VCSS) . The VCSS includes 10 clinical descriptors (pain, varicose veins, venous edema, skin pigmentation, inflammation, induration, number of active ulcers, duration of active ulceration, size of ulcer, and compressive therapy use), scored from 0 to 3 (total possible score, 30). Quality of life was assessed using the Chronic Venous Disease quality of life Questionnaire (CIVIQ-20), a validated, 20-item, self-reported scale that captures the key dimensions of quality of life specifically impaired by CVD in the following four domains: physical, psychological, social, and pain . The presence and severity of PTS was assessed using the Villalta score, which is based on the sum of severity ratings of five venous symptoms and six clinical signs (Table 1) . The final judgement about the presence of PTS and the severity of CVD was made by an independent expert who was blinded to the patient’s allocation to MPFF or control group.
DUS was performed using the MyLab30 device (Esaote, Italy) with a linear ultrasound transducer LA532 in the frequency range 5–13 MHz. The common femoral vein (CFV) and femoral vein (FV) were assessed in the supine position, popliteal vein (PV) in the prone position, and calf veins in a sitting position. At each examination, all accessible venous segments were subject to evaluation.
The criteria for DVT were incompressibility of the vein during compression by the transducer and absence of blood flow in the vein on the color mapping mode. To assess the prevalence of thrombotic occlusion, a modified Marder score was used. This allocates points to each of the deep and superficial venous segments of the lower limb that are occluded. If all the veins of one leg are occluded the total score is 34 (Table 2) . When performing the dynamic DUS, the degree of recanalization of the CFV, FV, and PV was calculated on the basis of their compressibility. This was achieved by measuring the veins’ diameters without compression and at maximum compression with the transducer at the narrowest point of each venous segment. The degree of recanalization was calculated with the following formula: [d (no compression) − d (maximal compression)]/d (no compression) × 100%. All measurements were repeated three times, and an average value was used for calculations. All ultrasound studies were performed by a specialist blinded to the patient’s allocation to the MPFF or control group.
The primary study endpoint was the presence of PTS signs at 6 months, determined by a blinded expert. For the diagnosis of PTS, the Villalta score was used. The criteria for a PTS diagnosis were a Villalta score of ≥ 5; severe PTS was defined as a score of ≥ 15 or the presence of an active venous ulcer.
The secondary study endpoints included severe PTS; symptomatic or asymptomatic recurrence of DVT; symptomatic pulmonary embolism; change in CEAP clinical class; CVD severity assessed by VCSS, quality of life assessed by CIVIQ-20; complete recanalization of vessels; change in degree of recanalization for the CFV, FV, and PV; change in thrombus extension by the Marder score; and the occurrence of bleeding and/or other adverse events associated with therapy.
Symptomatic recurrence of DVT was defined as an increase in edema, pain, or hyperemia of the affected lower limb, or the occurrence of the same signs on the intact leg. The asymptomatic recurrence of DVT was defined as the occurrence of signs of total occlusion in a previously recanalized venous segment. A complete recanalization was the clearance of thrombotic masses by 80% or more in the venous lumen (residual vein occlusion less than 20%).
Bleeding related to anticoagulant therapy was classified as major (according to the International Society on Thrombosis and Hemostasis criteria) , clinically relevant non-major (any episode not fulfilling the criteria of major bleeding, but resulting in withdrawal of anticoagulant therapy and/or requiring a specific medical intervention and/or leading to an unscheduled visit to the doctor), or minor (any episode not fulfilling the criteria of major or clinically relevant non-major bleeding).
Patients’ general health status was assessed at each follow-up visit with an emphasis on identifying possible adverse events of therapy.
As this was a pilot study with an exploratory nature the minimum sample size was not calculated. Statistical analysis was carried out using IBM SPSS Statistics v.19 software package. All absolute values are presented as the mean value with the standard deviation (mean ± SD). The distribution was verified by a Kolmogorov–Smirnov test. If a normal distribution was confirmed, comparisons were performed using the t test for independent samples for continuous variables, or the two-sided Fisher’s exact test and a Chi-square test for categorical variables. Comparisons of mean values with time were performed by assessment of within- and between-subject effects, as well as their within-subject interaction using the general linear model for repeated measurements (GLM-RM). Differences were considered statistically significant when the p value was less than 0.05.
During the inclusion period, 132 patients with suspected DVT were admitted to the hospital and thrombosis was confirmed in 104 cases. Of these, 68 patients fulfilled the selection criteria and 8 patients refused to participate. The remaining 60 patients were allocated to one of the two treatment groups (n = 30 in each group), and all patients completed the study (Fig. 1).
The clinical characteristics of the groups are presented in Table 3. Patients in the control group receiving standard treatment had a higher rate of CVD prior to the occurrence of DVT, in particular CEAP clinical class C2–C4. Patients in the two groups were comparable in terms of the prevalence of lesions of the main vessels in the femoropopliteal venous segment, although the total extent of the pathological process as determined by the Marder score was higher in the MPFF group (Table 3). These differences were associated primarily with the greater involvement of calf veins in patients treated with MPFF.
The results for the primary and secondary endpoints are summarized in Table 4. PTS was reported in 56.7% patients after 6 months of anticoagulant therapy with rivaroxaban and compression therapy and in 20% of patients randomized to MPFF plus standard therapy (p = 0.007). No severe forms of PTS were reported in either group. The mean score on the Villalta scale and the mean VCSS value were also lower in patients in the MPFF group. The CIVIQ-20 global index score revealed an improved quality of life in the MPFF group.
Progression of pre-existing CVD was observed in one patient in the MPFF group (transition from C2 to C4 class) and six patients in the control group (transition from C2 to C4 class in one patient, and transition from C2 to C3 class in five patients). Thus, the signs of CVD progression were observed in 20% of patients receiving standard therapy for DVT and only in 3.3% of patients with additional use of MPFF.
The recurrence of a venous thromboembolic event was observed in one patient from the control group, who had a symptomatic recurrent DVT on the contralateral limb, which required a temporary switch to LMWH followed by therapy with vitamin K antagonists. No major bleedings were observed in either group. Clinically relevant, non-major bleedings were represented by one case of hemorrhoidal bleeding in the MPFF group and two cases of macrohematuria in the control group. In addition, two cases of minor bleeding were reported (one in each group): rectal bleeding in the MPFF group and epistaxis in the control group.
In terms of other adverse effects, three patients in the MPFF group experienced a mild dyspeptic disorder, which did not require treatment discontinuation.
Rates of recanalization in the main venous segments are presented in Fig. 2. In both groups, there was a significant trend towards progressive clearance of thrombotic masses from the vessel lumen (p < 0.0001 for within-subject effect “time”). There were no significant differences in the rate of recanalization in the popliteal vein between the two groups, and complete recovery of vascular patency was achieved in 80% of patients in the MPFF group and 57% of patients in the control group (p = 0.095). The recanalization of the femoral vein, in turn, occurred significantly faster in patients receiving MPFF (p < 0.0001 for within-subject interaction “time × group”); however, the rate of achieving complete recovery of vascular patency was not significantly different: 92% in the MPFF group vs. 75% in the control group (p = 0.214).
There were no significant differences between the groups in the CFV analyses, both in terms of the rate of recanalization and in the rate of achieving complete recovery: 92% in the MPFF group vs. 70% in the control group (p = 0.293). At the same time, significant differences between the groups in total extent of the thrombus were revealed using the Marder score (Fig. 3). At baseline, the extent of thrombus in the MPFF group was significantly higher than in the control group (15.0 ± 4.8 vs. 11.1 ± 4.3, respectively; p = 0.002), but after 6 months of therapy it was significantly lower (0.8 ± 1.6 vs. 2.8 ± 3.5 points, p = 0.006). This suggests that long-term use of MPFF in addition to standard DVT therapy provides a faster reduction in thrombus burden.
Recanalization of a thrombosed vein is a complex biological process, an integral component of which is the immune inflammatory reaction involving a large number of neutrophils, monocytes, and lymphocytes [19, 20]. The clearance of thrombus from the vessel lumen involves lysis of the fresh clot triggered by activation of the plasma fibrinolytic system, fragmentation of the thrombotic masses by endothelial lytic activity, contraction and retraction of the thrombus as a result of active formation of collagen on the framework of fibrin filaments, and also through the formation of new channels, lined with endothelium, directly in the thrombotic mass . At the same time, thrombus resolution is strongly correlated with preservation of valvular function of the affected vessels . However, initial attempts to treat DVT with unfractionated heparin followed by a switch to long-term intake of vitamin K antagonists led to inconsistent results in terms of recanalization of the affected venous segments. In approximately 50% of cases, there were no changes or an increase in the extent of thrombosis after 5–10 days of treatment, and after 3–6 months the number of patients with an unchanged thrombus burden reached 23% .
At the same time, the long-term use of LMWH in comparison with standard therapy with vitamin K antagonists increased the chance of complete vascular recanalization 1.5-fold and reduced the probability of PTS occurrence by 23% . Most likely, this was due to the pronounced pleiotropic effects of LMWH and the presence of anti-inflammatory, profibrinolytic, antisclerotic, and endothelioprotective properties in addition to anticoagulant activity .
The introduction of direct oral anticoagulants was a milestone in DVT therapy, simplifying the treatment regimen, improving safety while maintaining high efficiency, and also eliminating the need for routine laboratory monitoring of treatment adequacy . In addition, it has been shown that treating venous thrombosis with rivaroxaban is associated with a higher rate of recanalization of venous segments and a lower risk of PTS [44,45,46]. The exact mechanisms of action have not been fully elucidated, but it is assumed that direct oral anticoagulants, and in particular rivaroxaban, have certain anti-inflammatory properties, which can be mediated through protease-activated receptors [47, 48]. However, this hypothesis requires experimental confirmation.
When assessing the effect of anticoagulant therapy on the completeness of recanalization of thrombosed vessels, a particular difficulty is the interpretation of the clinical significance of residual venous obstruction. Thus, Piovella et al. and Siragusa et al. consider residual thrombus as “clinically significant” if it occupies more than 40% of the vessel lumen [49, 50]. At the same time, Prandoni et al. in their early studies defined residual obstruction in the femoropopliteal segment to be significant if vein thickness at maximum compression exceeded 2–3 mm [51, 52]. In more recent studies evaluating the degree of vascular recanalization in patients receiving direct oral anticoagulants, the cutoff for vein thickness was increased to 4 mm . Given this uncertainty, the rate of residual venous obstruction detection, as well as its impact on disease outcome, can vary substantially from study to study. In this study, we assumed a clinically significant residual obstruction at 20% of the vessel cross-sectional diameter, which is approximately 1–2 mm for the femoropopliteal segment and corresponds to the early criteria of Prandoni et al. [51, 52]. When this cutoff value was used, the rate of residual venous obstruction diagnosis on rivaroxaban monotherapy was 43% for the popliteal vein, 25% for the femoral vein, and 30% for the common femoral vein. These figures are significantly higher than that obtained using a 4-mm cutoff value, at which the rate of residual obstruction diagnosis was only 21.1% .
When long-term use of rivaroxaban was combined with MPFF, the rate of residual venous obstruction was reduced to 20% for the popliteal vein, and 8% for the femoral vein and common femoral vein, which indicates a significant improvement in the recanalization process with the addition of flavonoid. The benefits of MPFF were even more pronounced when analyzed by changes in the Marder score reflecting the total extent of thrombus.
The addition of MPFF resulted in a more rapid and complete clearance of thrombotic masses from the blood vessels, and as a result, by the end of the 6-month follow-up period the scores in the MPFF group were significantly lower than in the control group. The observed differences can be explained by the known anti-inflammatory activity of MPFF. Previous research in patients with CVD has shown that MPFF treatment for 60 days decreased levels of cellular adhesion molecules (ICAM-1 by 32% and VCAM by 29%) in the regional venous blood . In women with CVD class CEAP C1, significant increases in levels of C-reactive protein, histamine, interleukin-1, tumor necrosis factor-alpha, and vascular endothelial growth factor have been observed in blood samples taken from the vessel supplying the telangiectasia 10 days after microsclerotherapy . When sclerotherapy is performed with adjunctive MPFF the activity of these inflammatory markers is significantly reduced. Further studies are now warranted to confirm whether MPFF can also affect levels of inflammatory biomarkers in venous thrombosis.
A further difficulty when assessing long-term DVT outcomes is objective confirmation of the presence of PTS. In previous studies, the rate of PTS diagnosis by the Villalta scale in patients treated with rivaroxaban was 25–45% for a mean follow-up period of about 2 years [44, 45]. In our study, the rate of PTS diagnosis after 6 months of rivaroxaban monotherapy was higher at 56.7%. This may be due to the peculiarities of the Villalta scale, which has a high sensitivity to the presence of pre-existing CVD. It is known that the presence of primary venous insufficiency prior to the development of DVT raises the risk of PTS occurrence 1.5–3.2-fold . Moreover, the Villalta scale has been reported to result in a misdiagnosis of PTS in 42% of patients who do not have specific post-thrombotic changes in the deep veins . The high sensitivity of this tool to pre-existing CVD can result in a wide dispersion in the rates of registered long-term adverse DVT outcomes. In our study, about three-quarters of the patients in the control group had a primary lesion of the superficial veins before the development of thrombosis, which could have had an impact on the high prevalence of PTS. At the same time, around half the patients in the MPFF group also had pre-existing CVD. However, signs of disease progression in terms of a worsening in CEAP clinical class to more severe forms were much less common with the use of the MPFF (3.3% vs. 20%). This apparent trend may be associated with the ability of MPFF to reverse the symptoms and signs of CVD, and thus have a positive effect on the prevention and treatment of early forms of PTS .
The current study has demonstrated the benefits of using MPFF together with rivaroxaban for the long-term treatment of DVT. The addition of MPFF not only allowed the rate of PTS to be reduced, but also accelerated recanalization of affected venous segments. At the same time, the proposed therapeutic approach was associated with a high safety profile; no serious events associated with long-term intake of MPFF were recorded, and all the identified adverse events were mild in nature and did not result in treatment discontinuation.
This preliminary research had a pilot study design and was subject to certain limitations. First, the small sample size did not allow adjustments to be made for differences between treatment groups, in particular the extent of thrombus and the presence of pre-existing CVD. When planning further studies, appropriate randomization methods should be used to eliminate any source of bias in treatment assignments, patient recruitment should be carefully balanced for pre-existing CVD or exclude participants with this condition. Other important limitations were the absence of a placebo control and the short follow-up period. These limitations must be overcome in subsequent studies. Larger randomized controlled trials are now required to establish the superiority of the combined regimen before routine use in clinical practice can be recommended.
Preliminary data demonstrate that long-term therapy for DVT with a combination of rivaroxaban and MPFF reduced the rate of PTS development compared with rivaroxaban monotherapy and accelerated recanalization of affected venous segments. These results now need to be confirmed in larger randomized, double-blind, placebo-controlled studies.
Oбщaя зaбoлeвaeмocть вceгo нaceлeния Poccии в 2012 гoдy. Cтaтиcтичecкиe мaтepиaлы, Чacть II 2013. [The general prevalences of diseases in the total population of Russia in 2012. Statistical Materials, Part II 2013 (In Russian)]. http://www.rosminzdrav.ru/documents/8029-statisticheskaya-informatsiya-2012. Accessed 19 Oct 2018.
Зaбoлeвaeмocть вceгo нaceлeния Poccии в 2014 гoдy. Cтaтиcтичecкиe мaтepиaлы, Чacть II 2015 [The prevalences of diseases in the total population of Russia in 2014. Statistical Materials, Part II 2015 (In Russian)]. https://www.rosminzdrav.ru/documents/9479-statisticheskaya-informatsiya-za-2014. Accessed 19 Oct 2018.
Зaбoлeвaeмocть вceгo нaceлeния Poccии в 2016 гoдy. Cтaтиcтичecкиe мaтepиaлы Чacть II 2017. [The prevalences of diseases in the total population of Russia in 2016. Statistical Materials, Part II 2017 (In Russian)]. https://www.rosminzdrav.ru/ministry/61/22/stranitsa-979/statisticheskie-i-informatsionnye-materialy/statisticheskiy-sbornik-2016-god. Accessed 19 Oct 2018.
Hippisley-Cox J, Coupland C. Development and validation of risk prediction algorithm (QThrombosis) to estimate future risk of venous thromboembolism: prospective cohort study. BMJ. 2011;343:d4656.
Oger E. Incidence of venous thromboembolism: a community-based study in Western France. EPI-GETBP Study Group. Groupe d’Etude de la Thrombose de Bretagne Occidentale. J Thromb Haemost. 2000;83(5):657–60.
Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrom J. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost. 2007;5(4):692–9.
Van Beek E, Buller H, Ten Cate J. Epidemiology of venous thromboembolism. A textbook of vascular medicine. London: Arnold; 1996. p. 471–88.
Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ 3rd. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998;158(6):585–93.
Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996;125(1):1–7.
Mohr DN, Silverstein MD, Heit JA, Petterson TM, O’fallon WM, Melton LJ. The venous stasis syndrome after deep venous thrombosis or pulmonary embolism: a population-based study. Mayo Clin Proc. 2000;75(12):1249–56.
Franzeck UK, Schalch I, Jäger KA, Schneider E, Grimm J, Bollinger A. Prospective 12-year follow-up study of clinical and hemodynamic sequelae after deep vein thrombosis in low-risk patients (Zürich study). Circulation. 1996;93(1):74–9.
Beyth RJ, Cohen AM, Landefeld CS. Long-term outcomes of deep-vein thrombosis. Arch Intern Med. 1995;155(10):1031–7.
Kahn S, Comerota A, Cushman M. Council on Clinical Cardiology, Council on Cardiovascular and Stroke Nursing. The postthrombotic syndrome: evidence-based prevention, diagnosis, and treatment strategies: a scientific statement from the American Heart Association. Circulation. 2014;130(18):1636–61.
Prandoni P, Frulla M, Sartor D, Concolato A, Girolami A. Vein abnormalities and the post-thrombotic syndrome. J Thromb Haemost. 2005;3(2):401–2.
Vedovetto V, Dalla Valle F, Milan M, Pesavento R, Prandoni P. Residual vein thrombosis and trans-popliteal reflux in patients with and without the post-thrombotic syndrome. Thromb Haemost. 2013;110(4):854–5.
Galanaud J, Holcroft C, Rodger M, et al. Predictors of post-thrombotic syndrome in a population with a first deep vein thrombosis and no primary venous insufficiency. J Thromb Haemost. 2013;11(3):474–80.
Tick L, Kramer M, Rosendaal F, Faber W, Doggen C. Risk factors for post-thrombotic syndrome in patients with a first deep venous thrombosis. J Thromb Haemost. 2008;6(12):2075–81.
Comerota AJ, Grewal N, Martinez JT, et al. Postthrombotic morbidity correlates with residual thrombus following catheter-directed thrombolysis for iliofemoral deep vein thrombosis. J Vasc Surg. 2012;55(3):768–73.
Budnik I, Brill A. Immune factors in deep vein thrombosis initiation. Trends Immunol. 2018;39:610–23.
Henke PK, Wakefield T. Thrombus resolution and vein wall injury: dependence on chemokines and leukocytes. Thromb Res. 2009;123:S72–8.
Rabinovich A, Cohen JM, Cushman M, et al. Inflammation markers and the risk of post thrombotic syndrome: results from the Bio-Sox Study. Blood. 2013;122(21):36.
Rabinovich A, Cohen JM, Cushman M, et al. Association between inflammation biomarkers, anatomic extent of deep venous thrombosis, and venous symptoms after deep venous thrombosis. J Vasc Surg Venous Lymphat Disord. 2015;3(4):347–53.
Roumen-Klappe E, Janssen M, Van Rossum J, et al. Inflammation in deep vein thrombosis and the development of post-thrombotic syndrome: a prospective study. J Thromb Haemost. 2009;7(4):582–7.
Shbaklo H, Holcroft CA, Kahn SR. Levels of inflammatory markers and the development of the post-thrombotic syndrome. J Thromb Haemost. 2009;101(03):505–12.
Bouman A, Smits J, Ten Cate H, Ten Cate-Hoek A. Markers of coagulation, fibrinolysis and inflammation in relation to post-thrombotic syndrome. J Thromb Haemost. 2012;10(8):1532–8.
Korthuis RJ, Gute DC. Adhesion molecule expression in postischemic microvascular dysfunction: activity of a micronized purified flavonoid fraction. J Vasc Res. 1999;36(Suppl 1):15–23.
Takase S, Lerond L, Bergan JJ, Schmid-Schonbein GW. The inflammatory reaction during venous hypertension in the rat. Microcirculation. 2000;7(1):41–52.
Takase S, Pascarella L, Lerond L, Bergan JJ, Schmid-Schonbein GW. Venous hypertension, inflammation and valve remodeling. Eur J Vasc Endovasc Surg. 2004;28(5):484–93.
Maria das Graças C, Cyrino FZ, de Carvalho JJ, Blanc-Guillemaud V, Bouskela E. Protective effects of micronized purified flavonoid fraction (MPFF) on a novel experimental model of chronic venous hypertension. Eur J Vasc Endovasc Surg. 2018;55(5):694–702.
Shoab SS, Porter JB, Scurr JH, Coleridge-Smith PD. Effect of oral micronized purified flavonoid fraction treatment on leukocyte adhesion molecule expression in patients with chronic venous disease: a pilot study. J Vasc Surg. 2000;31(3):456–61.
Bogachev VY, Boldin BV, Lobanov VN. Benefits of micronized purified flavonoid fraction as adjuvant therapy on inflammatory response after sclerotherapy. Int Angiol. 2018;37(1):71–8.
Wells PS, Anderson DR, Rodger M, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Eng J Med. 2003;349(13):1227–35.
Vasquez MA, Munschauer CE. Venous Clinical Severity Score and quality-of-life assessment tools: application to vein practice. Phlebology. 2008:259–75.
CIVIQ users’ guide. http://www.civiq-20.com. Accessed 19 Oct 2018.
Villalta S, Bagatella P, Piccioli A, Lensing A, Prins M, Prandoni P. Assessment of validity and reproducibility of a clinical scale for the post-thrombotic syndrome [abstract]. Haemostasis. 1994(24 suppl 1):158a.
Marder VJ, Soulen RL, Atichartakarn V, et al. Quantitative venographic assessment of deep vein thrombosis in the evaluation of streptokinase and heparin therapy. J Lab Clin Med. 1977;89(5):1018–29.
Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692–4.
Henke PK, Wakefield TW, Diaz JA. Acute and chronic venous thrombosis: pathogenesis and new insights. Handbook of venous and lymphatic disorders. Boca Raton: CRC; 2017. p. 121–36.
Meissner MH, Caps MT, Bergelin RO, Manzo RA, Strandness DE Jr. Propagation, rethrombosis and new thrombus formation after acute deep venous thrombosis. J Vasc Surg. 1995;22(5):558–67.
Egermayer P. The effects of heparin and oral anticoagulants on thrombus propagation and prevention of the postphlebitic syndrome: a critical review of the literature. Prog Cardiovasc Dis. 2001;44(1):69–80.
Hull RD, Liang J, Townshend G. Long-term low-molecular-weight heparin and the post-thrombotic syndrome: a systematic review. Am J Med. 2011;124(8):756–65.
Poredos P, Jezovnik M. Heparin promotes recanalization of venous thrombotic occlusions. Int Angiol. 2018;37(4):261–8.
Roussin A. Effective management of acute deep vein thrombosis: direct oral anticoagulants. Int Angiol. 2015;34(1):16–29.
Utne K, Dahm A, Wik H, Jelsness-Jørgensen L, Sandset P, Ghanima W. Rivaroxaban versus warfarin for the prevention of post-thrombotic syndrome. Thromb Res. 2018;163:6–11.
Jeraj L, Jezovnik M, Poredos P. Rivaroxaban versus warfarin in the prevention of post-thrombotic syndrome. Thromb Res. 2017;157:46–8.
Prandoni P, Ageno W, Mumoli N, et al. Recanalization rate in patients with proximal vein thrombosis treated with the direct oral anticoagulants. Thromb Res. 2017;153:97–100.
Rothmeier AS, Ruf W. Protease-activated receptor 2 signaling in inflammation. Semin Immunopathol. 2012;34(1):133–4.
Ramacciotti E, Volpiani GG, Davila R, Resende VA, Silveira FM, Fareed J. Early recanalization of veins in patients with DVT treated with rivaroxaban: do we need to move from bedside to bench again? Int Angiol. 2018;37(1):1–3.
Piovella F, Crippa L, Barone M, et al. Normalization rates of compression ultrasonography in patients with a first episode of deep vein thrombosis of the lower limbs: association with recurrence and new thrombosis. Haematologica. 2002;87(5):515–22.
Siragusa S, Malato A, Anastasio R, et al. Residual vein thrombosis to establish duration of anticoagulation after a first episode of deep vein thrombosis: the Duration of Anticoagulation based on Compression UltraSonography (DACUS) study. Blood. 2008;112(3):511–5.
Prandoni P, Lensing AW, Prins MH, et al. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med. 2002;137(12):955–60.
Prandoni P, Prins MH, Lensing AW, et al. Residual thrombosis on ultrasonography to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial. Ann Intern Med. 2009;150(9):577–85.
Trinh F, Paolini D, Fish J, Kasper G, Lurie F. Use of Villalta score for defining post-thrombotic disease may lead to false-positive diagnosis in 42% of patients with primary chronic venous disease. J Vasc Surg Venous Lymphat Disord. 2018;6(2):291.
Kakkos SK, Nicolaides AN. Efficacy of micronized purified flavonoid fraction (Daflon®) on improving individual symptoms, signs and quality of life in patients with chronic venous disease: a systematic review and meta-analysis of randomized double-blind placebo-controlled trials. Int Angiol. 2018;37(2):143–54.
We thank the participants of the study. The study was carried out at the facilities of the Clinical Hospital No. 1 of the Presidents Administration of the Russian Federation in 2017–2018.
The open access fee, article processing charges, and editorial assistance for the production of this article were funded by Les Laboratoires Servier. The study was conducted without any financial or technical support. All authors had full access to all of the data in this study, contributed to the concept and interpretation of the literature, were involved in the drafting and revising of the paper and approval of the final submitted version, and take complete responsibility for the integrity of the data and accuracy of the data analysis.
Editorial assistance for English language editing was provided by Jenny Grice, Bieuzy les Eaux, France and funded by Les Laboratoires Servier.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Kirill Lobastov, Ilya Schastlivtsev and Victor Barinov have nothing to disclose.
Compliance with Ethics Guidelines
All procedures performed in studies involving human participants were in accordance with local ethics committee of the Clinical Hospital No. 1 of the Presidents Administration of Russian Federation and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
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To view enhanced digital features for this article go to https://doi.org/10.6084/m9.figshare.7378130.
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Lobastov, K., Schastlivtsev, I. & Barinov, V. Use of Micronized Purified Flavonoid Fraction Together with Rivaroxaban Improves Clinical and Ultrasound Outcomes in Femoropopliteal Venous Thrombosis: Results of a Pilot Clinical Trial. Adv Ther 36, 72–85 (2019). https://doi.org/10.1007/s12325-018-0849-z

domain: literature


text:
Projects & Events
Workshop for journalists on Post Rape Care30 August 2011
Population Council South Africa and the HIV/AIDS and the Media Project’s post rape care workshop seeks to address the ethical challenges that journalists face in reporting and writing about sexual assault issues. The workshop also aims to empower journalists with accurate and accessible HIV-prevention information, particularly post exposure prophylaxis for those affected by sexual assault.
The workshop is intended to encourage journalists to engage more frequently with sexual assault issues and to have the confidence to do so accurately and ethically. Doing so will empower news consumers with the knowledge required to deal with sexual assault appropriately and will go a long way to addressing the stigma and taboo associated with sexual assault.
Objective of the post rape care workshop
PCSA and the HIV/AIDS and the Media Project will facilitate the Post Rape Care workshop. Objectives are:
- To encourage ethical, accurate and informative reporting on sexual assault issues.
- To empower journalists with the knoweldge, understanding, insight and key contacts necessary to cover sexual assualt stories.
- To increase knowledge amongst journalists on the post rape care services that are available to survivors of sexual assault.
- To engage critically with issues of stigma and the ethical challenges associated with sexual assault.
- To discuss and analayse how sexual assault is currently covered in South Africa.
Participation in the training
PCSA and the HIV/AIDS and the Media Project have identified the following media practitioners who will benefit from this training:
- Print media journalists
- Radio presenters/journalists
- Television presenters/journalists
Key members of the civil and medical sector are involved in facilitating the programme, These include:
- Sexual assault experts (who will share technical information around sexual assault)
- The South African Police Service
- Public health facility officials (to share information about procedures and protocol around post-rape care)
- Sexual assault NGOs (to share their interventions on the community level and speak about the psycho-social support they provide)
Implementation of the training
PCSA and the HIV/AIDS and Media Project are hosting a one-day journalist training/workshop event. The workshop is outlined as follows:
- Introduction and rationale of the training
- The importance of engaging with the issue of sexual assault
- Understanding post rape care
- A discussion of the rights and responsibilities of sexual assault survivors and perpetrators and the role of the SAPS
- An assessment of how the media is currently engaging with sexual assault issues
- A discussion of the key messages central to reporting on sexual assault as well as the ethical challenges associated with covering this issue
- Engagement with NGOs who provide care for survivors of sexual assault
The workshop will take place on the 30 August 2011 from 08:00- 16:00 at the Wits Development Hub in Johannesburg
A full programme will be made available shortly.
Communications Officer, Population Council South Africa
Publications and Presentations
Presentation by Melissa Meyer (167.37 KB) Ethical implications of reporting on sexual violence in the context of HIV
Presentation by Zuki Fipaza (91.22 KB) Journalist workshop on writing and reporting about sexual assault
Presentation by William Brid (211.66 KB) Sexual assault, and the media, a tale of extremes
Presentation by Sindi Van Zyl (201.64 KB) Structure of HIV

domain: sociology


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text:
KUALA LUMPUR — Relatives of passengers who were onboard a Malaysia Airlines jet that disappeared more than two years ago have pleaded with the Australian, Chinese and Malaysian governments to keep looking for the missing aircraft.
The relatives’ concerns were raised after the head of the Australian Transport Safety Bureau, which was leading the underwater search for MH370 in the southern Indian Ocean, said there was no indication that the search would be continued beyond August after the designated 120,000 sq. km of ocean had been combed through.
“We are gravely concerned about the impending completion of the search in the current targeted area,” the Voice370 group told Agence France-Presse. Voice370 is made up of the families of the 239 people onboard on the plane, which was en route from Kuala Lumpur to Beijing on March 8 2014 when it disappeared. Voice370 aims “to seek the truth about the incident and find our loved ones onboard MH370,” according to the group’s Facebook page.
ATSB Chief Executive Martin Dolan said on May 20 that there was a “diminishing level of confidence we will find the aircraft,” but added that “the remaining 13,000 sq. km is still a lot of territory and it’s still entirely possible the aircraft is there.”
The authorities’ increasing pessimism marks a change from past statements that the search would be a success. Dolan said in July 2015 that MH370 “will be found within the next year.” Malaysia’s Minister of Defence Hishammuddin Hussein was similarly confident in October 2014 when he said: “We are looking in the right place, we’re talking about 99.9%.”
The search — by three vessels — was due to be wrapped up in July, but delays were caused by bad weather that brought waves of up to 12m. The ATSB reported in its most recent update that “winter weather conditions brought rough seas and strong winds to the search area which impacted on operations.”
The ATSB website said that “in the absence of credible new information that leads to the identification of a specific location of the aircraft, governments have agreed that there will be no further expansion of the search area.” The search cost is estimated at $130 million, the highest in aviation history, and covers some of the roughest and remotest areas on earth — “as close to nowhere as it’s possible to be,” said Tony Abbott, who was prime minister of Australia when the plane disappeared.
The cause of the flight’s disappearance is unknown and ranks as one of the world’s most baffling and tragic mysteries. The initial confusion over what happened after the flight disappeared from radar and lost contact with air traffic control resulted in a welter of conspiracy theories and unconfirmed sightings of wreckage in the Indian Ocean. The last known position of the aircraft was west of peninsular Malaysia, showing that the plane had diverted from its intended route before it took an unknown course south across the vast ocean.
To date, five pieces of debris thought to have been part of the missing jet have washed up thousands of kilometers west of the search zone, first on Reunion island in July 2015, and later on Mozambique, Mauritius and South Africa. The location of the debris suggests that the search operation has been taking place in roughly the correct location, but currents had swept wreckage across the Indian Ocean.
A May 12 statement from Infrastructure and Transport Ministry described the part that washed up on South Africa as “confirmed as a segment from an engine cowling. It was identified by the Rolls Royce stencil, which was found to be consistent with that developed and used by Malaysia Airlines.” It also said that the part that washed up on Mauritius in April was an interior panel from the main cabin and “consistent with the decorative laminate of a work table used at the forward right hand door on Malaysian Boeing 777s.”
For Malaysia Airlines, the disappearance of MH370 was but the first major disaster in 2014. Four months later, an MH17 flight from Amsterdam to Kuala Lumpur was shot down over eastern Ukraine, a warzone where Russian-backed rebels were fighting the Ukrainian army. All 298 passengers and crew died as the aircraft broke up mid-air.
Relatives of those onboard MH17 are weighing legal action against Malaysia Airlines. Chief Executive Christoph Mueller announced on April 19 that he was stepping down for personal reasons, halfway through a three-year stint during which the German had hoped to revive the flagging state carrier.
MH370’s disappearance has prompted some soul-searching in the aviation sector. The International Civil Aviation Organization, a UN agency, announced on March 8 that aircraft should carry “distress tracking devices which can autonomously transmit location information at least once every minute in distress circumstances” and “to be equipped with a means to have flight recorder data recovered and made available in a timely manner.” The ICAO said that cockpit voice recordings should be extended to possibly 25 hours to cover all phases of a flight for all types of operations.
For the families of those onboard MH370, the sense of loss and confusion has not faded. Intan M Othman, the wife of steward Rain Hasnan, said on May 22: “No one wants to tell us what actually happened. We are tired of climbing up and down the stairs looking for the truth. We met ministers, police. My children until today are still asking, where is their father’s grave?”
Before the ATSB’s latest updates, Malaysia said it would organize a meeting with officials from China and Australia to discuss the future of the search operation. Malaysian Transport Minister Liow Tiong Lai said he was hopeful that the meeting would take place before the designated search area was covered. The relatives of the people onboard the flight have demanded that “a highly concerted effort must be made to find more pieces if the authorities are interested to solve the mystery.”
Whether that happens will hinge on any future discussion between the three countries. Malaysian Prime Minister Najib Razak promised in August 2015: “The government of Malaysia is committed to do everything within our means to find out the truth of what happened. MH370’s disappearance marked us as a nation. We mourn with you, as a nation.”
A flicker of hope for the relatives that the search — although perhaps on a smaller scale — may be continued came in a statement on May 19. MacArtney Group, an underwater technology company, stated in a press release that it won a tender to supply an underwater winch for a deepsea sonar device used in underwater searches. Without giving further details, the release also said that “the search for flight MH370 is going to be reinitiated in June 2016 by an Australian-based search team.”
MacArtney declined to elaborate on the statement and Australian authorities could not be reached for comment.Show

domain: news


text:
Lake Luzerne in Warren County, New York — The American Northeast (Mid-Atlantic)
First Wilderness/ Lake Luzerne
The Adirondacks was the first place Americans embraced the wilderness as a feature of civilization. The First Wilderness Corridor follows the Upper Hudson from Saratoga Springs to North Creek. This wild and scenic river rolls through rapids, past dramatic cliffs of magnificent marble before it slows to flow easily through ice meadows, kept perpetually clear of trees by the annual scouring of spring ice floes.
The land along the river served as a hunting ground for Indian people, who established trails connecting the Mohawk Valley with the Champlain Valley. American and European soldiers followed these trails during the French and Indian War. Once fighting had subsided, the vast tracts of timber spurred the logging and tanning industries. Construction of a railroad just after the Civil War gave vacationers easy access to hotels and resorts, and Americans discovered the lure of nature to restore their lives.
Today, communities along the First Wilderness Corridor celebrate their shared history along this route into the heart of the Adirondack wilderness. Drive the scenic byway, or paddle
Lake Luzerne presides on the banks of the Hudson River at one of the most picturesque spots of the river’s run from the Adirondack Mountains to the Atlantic Ocean. Here, the water from Lake Luzerne joins the Hudson at a narrow gorge of tumbling water at Rockwell Falls, which can be seen best from the north side of the Bridge of Hope. A little further south, the confluence of the Hudson and Sacandaga rivers form Phelps Bay, a stretch of water broad enough for water skiing. These historic waterways were used by Mohawk, Abenaki, and Iroquois Indians to travel between what is now known as Johnstown to Lake George.
Located at the foothills of the Adirondacks, Lake Luzerne‘s first settlements included grist mills, saw mills, a creamery and cheese factory, distillery, and even a shirt factory; but leather was Luzerne’s biggest business during the last half of the nineteenth century. The first pulp mill in the United States using American-made equipment was built at the outlet of Lake Luzerne, it still stands with some of the original machinery as a public museum, and together with an iron ore smelter, a gristmill, and sawmill, are included in Mill Park. Adirondack Folk School is a unique school providing hands-on classes teaching the arts, crafts, and culture of the Adirondack region on Main St.
Loggers ran river drives until the 1930’s, when the old logging camps found new lives as dude ranches. The first one, Northwoods Dude Ranch, succeeded in bringing the West, and all its cowboy flavor, to the East in Lake Luzerne. Today, the Painted Pony Ranch is a historic vacation spot and home of championship rodeos, and you can find stables on Route 9N that still offer horseback riding. Although the Hudson River is mapped as the demarcation between Warren and Saratoga Counties, and Lake Luzerne and Hadley, residents and visitors alike find this little valley one wonderful place to “ride, raft, and rest.”
Location. 43° 19.147′ N, 73° 50.494′ W. Marker is in Lake Luzerne, New York, in Warren County. Marker is on Main Street, on the left when traveling north. Touch for map. Marker is in this post office area: Lake Luzerne NY 12846, United States of America. Touch for directions.
Other nearby markers. At least 8 other markers are within walking distance of this marker. First Methodist (within shouting distance of this marker); Jessup's Patent (about 400 feet away, measured in a direct line); Garnar Tannery (about 600 feet away); Church Of Rockwell Falls (approx. 0.2 miles away); Jeremy Rockwell (approx. 0.2 miles away); Paper Mill (approx. 0.2 miles away); St. Mary’s Church (approx. 0.2 miles away); Site of Wayside Inn (approx. ¼ mile away). Touch for a list and map of all markers in Lake Luzerne.
Also see . . . First Wilderness. (Submitted on April 4, 2019, by Steve Stoessel of Niskayuna, New York.)
Categories. • Entertainment • Environment • Native Americans • Waterways & Vessels •
Credits. This page was last revised on April 4, 2019. This page originally submitted on April 4, 2019, by Steve Stoessel of Niskayuna, New York. This page has been viewed 62 times since then. Photos: 1, 2. submitted on April 4, 2019, by Steve Stoessel of Niskayuna, New York. • Bill Pfingsten was the editor who published this page.

domain: travel


text:
Why does Macbeth have second thoughts about killing Duncan?
Macbeth is having second thoughts about killing Duncan. What are the reasons he gives? He gives several reasons why he should not kill Duncan: 1) Duncan is his cousin; 2) He is a loyal subject to the King; 3) Duncan is his friend; 4) Duncan has never abused his royal power; and 5) Duncan is a guest in his home.
What is the importance of Lady Macbeth?
Lady Macbeth is the ambitious wife of Macbeth, who encourages him to murder his king, helps him to do it, and so becomes queen of Scotland. In the play, Lady Macbeth: invokes the powers of evil to help her influence her husband (I.
Is Macbeth loyal to the king?
Loyalty and Betrayal: At the start of the play, Macbeth is loyal to his King and country as he fights for Duncan and gives him his “service and loyalty”. However, this loyalty soon wanes as Macbeth lets his dark desires get in the way of his loyalty as he betrays Duncan by murdering him.
Who betrays who in Macbeth?
Banquo who is Macbeth’s friend and co-commander of the army will be betrayed and murdered by Macbeth because he fears that Banquo is a threat and knows exactly what the witches said. Therefore Macbeth decides he must be killed along with his innocent son.
What are the character traits of Lady Macbeth?
Lady Macbeth is one of Shakespeare’s most famous and frightening female characters. When we first see her, she is already plotting Duncan’s murder, and she is stronger, more ruthless, and more ambitious than her husband. She seems fully aware of this and knows that she will have to push Macbeth into committing murder.
What does Lady Macbeth mean when she says was hope drunk?
What does Lady Macbeth mean when she says, “Was hope drunk wherein you dressed yourself? Hath it slept since? And wakes it now to look so green and pale? Lady Macbeth is basically asking Macbeth if he’s a chicken and too scared to kill Duncan. She’s saying he’s not man enough.
How does Lady Macbeth convince Macbeth to kill Duncan?
How does Lady Macbeth persuade Macbeth to kill King Duncan? Lady Macbeth persuades Macbeth to kill King Duncan by preying on his sense of manhood and courage. When Macbeth reveals that he has had a change of heart and is no longer willing to kill King Duncan, Lady Macbeth becomes enraged.
How is Lady Macbeth presented as a dangerous character?
She is shown to be dangerous because she is not a mother, she is not feminine, and she is ambitious. She is dangerous because she is in control of her sexuality. She is dangerous because she does not conform to the gender roles that have been assigned to her.
Why did Duncan kill the first Thane of Cawdor?
The original Thane of Cawdor was executed for treason because he fought with the Norwegians against Scotland. His execution foreshadows Macbeth’s own death later in the play. Ironically, Macbeth’s rise in power begins when he is given the executed thane’s title and possessions as a reward for his bravery in battle.

domain: entertainment


text:
David Lister: If opera is going to reflect everyday life, it needs to get rid of the stereotypes
The Week in Arts
A founder member of The Independent David Lister joined the paper in 1986 as Assistant Home Editor. He became the paper's arts correspondent in 1988 and is now Arts Editor and writes a column each Saturday. He is a Fellow of the Royal Society of Arts.
Saturday 17 March 2012
When Kasper Holten, the Dane who is now running the Royal Opera House, gave his first press conference this week, he said he would learn from the success of TV dramas like The Killing, "not go for short-term gratification" and take ROH audiences "out of their comfort zone".
I wonder if there were belly laughs around the room. The Covent Garden comfort zone has been pretty hard to find recently. A couple of weeks ago, the new production of Rusalka was booed by the first-night audience, and a few days ago the UK premiere of Judith Weir's Miss Fortune received some of the worst reviews ever given to a Royal Opera production.
The Royal Opera House is more than capable of bearing bad reviews, though as Oscar Wilde said about something else, one is unfortunate, two is beginning to look like carelessness. But as far as Miss Fortune goes, there is something more important to chew on than the quality of playing in the pit or the staging of an aria.
In Ms Weir's piece about a lottery winner, the heroine's workplace is destroyed by a group of break-dancing vandals. The ROH was rather proud of its introduction of break-dancing into opera, and manipulated the publicity so that this novelty became quite a news story before the first performance.
What I suspect the ROH management did not anticipate for a moment was that the critics might see something beyond the commendable blending of traditional and current art forms. They might see, they did see, that most of the breakdancers who smashed up the heroine's workplace were black.
The critic of the respected website TheArtsDesk wrote that "the racism" was baffling, adding: "As Miss Fortune sings of entering the shadows and dark streets of the real world, she's set upon by six representatives of this rough shadowy place, a gang of bopping black thugs, who go on to destroy the factory she's working for and torch a kebab van she finds herself taking shelter in. Only in opera could ethnic street dancing still so shamelessly be used to connote criminality."
That's quite a charge, and what an irony that in trying so studiedly to be controversial in its story, staging and cross-fertilisation of art forms, the Royal Opera has utterly unwittingly succeeded in being controversial with its casting.
Should the ROH management have given a little more thought to this casting, or should it have said: "To hell with political correctness, we're using the six best breakdancers we can find." The ROH tells me it operates a colour-blind casting policy. That's to be applauded, but on this occasion, and in the wake of the stereotyping that followed last summer's riots, I think a little more thought about perceptions might have been useful. It's only an opera, I know, but isn't it the Royal Opera House that is trying to tell us that opera should reflect and impinge on real, everyday life?
Spacey takes up the ticket fight
This column has long championed the cause of lower threatre ticket prices for young people, so it's great to see no less a figure than Kevin Spacey waking up to the issue. The artistic director of London's Old Vic theatre and Hollywood star says he is embarrassed that theatre is not more accessible to young people. He says: "It is the single most embarrassing thing about being in the theatre, that it has become an exclusive club. I am embarrassed by the fact that there is such short-sightedness on the heads of producers and theatre directors. What happens when this generation that is currently going to the theatre passes on to the great theatre in the sky?"
Mr Spacey was launching a sponsorship deal with PricewaterhouseCoopers for £12 tickets for under-25s at the Old Vic. I have campaigned over many years for cinema-priced tickets to encourage young audiences to the theatre. So congratulations to Kevin, but more needs to be done. One small additional gesture would be Broadway-style free programmes at all theatres, including the Old Vic. A bigger gesture would be for all those short-sighted producers to follow his lead and start thinking about new audiences rather than just profit. And, of course, how's about stopping alienating all audiences with those wretched booking fees (£2.50 at the Old Vic)? But Spacey has made a bold move in the right direction.
Lily Allen could learn from Sade
The surprise music news of the week is that Eighties soul singer Sade is currently the biggest British act in America. Sade, almost forgotten over here, lives quietly in the Cotswolds with her partner and teenage daughter. She told Ebony magazine in one of her very rare interviews of recent years that her partner Ian "was a Royal Marine, then a fireman, then a Cambridge graduate in chemistry", adding: "I always said that if I could just find a guy who could chop wood and had a nice smile it didn't bother me if he was an aristocrat or a thug as long as he was a good guy. I've ended up with an educated thug."
All of which is, I think, a lesson for Lily Allen, who, wrongly in my view, decided to give up music to concentrate on family. No need to give it up. Take a leaf out of Sade's book. Live a quiet family life in the English countryside, and record, tour and make a mint in America.
Art Somebody is going around telling people he's Banksy - but it isn't the street artist
Maisie Williams single-handedly rises to the challengeTV
Academy criticised after no non-white actors nominated
tvAn expose of hooliganism masquerading as an ideological battle
artLee Hadwin can't draw when he's awake, but by night he's an artist
Arts & Ents blogs
- 1 Saudi preacher who 'raped and tortured' his five -year-old daughter to death is released after paying 'blood money'
- 2 Mystery man who gave mum heart-warming note on train 'wanted to put a smile on her face'
- 3 Michelle Obama highlights harsh restrictions faced by Saudi women after meeting King Salman without wearing a headscarf
- 4 Mafia's wall of silence broken: Victim of Cosa Nostra's extortion rackets in its Corleone heartland co-operates with authorities for the first time ever
- 5 Amal Clooney gives excellent answer to fashion question at European Court of Human Rights
Heavy metal producer's corpse to be mutilated by models as per his dying wish
Game of Thrones season 5: Grey Worm actor Jacob Anderson is all for more male nudity – as long as it’s not him
The Jump 2015 line-up: Joey Essex, Phil Tufnell, Heather Mills and co take to the slopes
Costa Book Awards 2015: H is for Hawk named book of the year
New Ghostbusters movie lands all-female cast with Kristen Wiig, Melissa McCarthy, Kate McKinnon and Leslie Jones
'We would evict Queen from Buckingham Palace and allocate her council house,' say Greens
French court convicts three over homophobic tweets, in case hailed as a 'significant victory' by LGBT rights campaigners
Greece elections: Syriza and EU on collision course after election win for left-wing party
British Muslim school children suffering a backlash of abuse following Paris attacks
British grandmother Lindsay Sandiford faces execution by firing squad in Indonesia
Liberal Democrat minister defends comments suggesting immigration causes pub closures

domain: artistic


In the wake of the Corona crisis, global networks have had to make adjustments to increase their flexibility and respond to short-term fluctuations. But what challenges do innovative supply chains bring with them? With Thomas Spiess, member of the management board of Staufen.Inova AG, we discuss where companies have opportunities to connect and what proven solution strategies already exist.
Mr. Spiess, we learned in the first part what the most important elements in supply chain network management are, and also where the greatest challenges lie. What practical experience have you had in this regard during your long consulting career?
We talked about the four elements in supply chain network management.
1. Network. How is the network structured?
2. Management system. How is the network operated?
3. Planning. How does planning take place in the network?
4. Information management. How is information prepared and exchanged?
With regards to point 1, I can say the following based on my practical experience: Very few companies are still in a position to outline their network and associated relationships as a whole. If we sketch this network on the wall using a visualized footprint, we regularly observe customers’ aha! moments.
Displaying a footprint in this manner also enables supply chain segmentation, showing which product types can be routed through which networks. As a result, you can perfectly match different supply chains, such as one with efficient but long lead times for predictable products together with another that is short, close to the sales market and allows you to react with agility to seasonal fluctuations.
If you implement comprehensive planning systems that transcend divisional boundaries and enable the organization to respond even to short cycles, then nothing can really surprise you during a crisis.
Has the pandemic caused major changes in supply chain network management?
Yes. The awareness of having to maintain closer ties with one’s network in order to know early on when things are going to get rough and where has increased significantly. Open and honest communication between network partners has also increased significantly. One client told me about his networking experience when they used to meet twice a month. He said it was “The Chamber of Lies” but has now become “The Chamber of Truth” during the crisis. Many companies have also become more flexible during the crisis. In some areas, adaptability has even led to new opportunities.
As a supply chain network expert, what is your opinion on the subject of sustainability?
That is a very important issue. In some industries, such as textiles, supply chains are still lacking transparency. There are still many production facilities that do not produce according to European standards, both socially and ecologically. But for some time now, there has been a noticeable positive tendency in production capacities. Romania, Bulgaria or Hungary offer shorter transport routes and thus also a more stable as well as more sustainable value chain. A great deal of technology also went missing by moving everything to the Far East. But a change in thinking has taken place, further confirmed by the Corona pandemic. Producing on your own doorstep and having everything under control is en vogue.
One term that comes up again and again in connection with the supply chain is resilience. What exactly do you mean by that?
In general, this refers to the stability to cope with unexpected disruptions in order to ensure that the normal state is restored quickly and without major failures. In supply chain networks in particular, the ripple effect occurs time and again, namely that a disruption causes a ripple that then ripples from procurement to production to the customer. Because what ultimately counts is the ability to deliver to the customer. If the product is not delivered on time, you may lose your customer to your competitor. Brands like Audi and Toyota will then no longer fight each other for customers, but rather the focus will be on value networks and their resilience. The world has become more vulnerable and this must be specifically addressed through supply chain network management today.
Dr. Thilo Greshake, Partner Automotive, STAUFEN.AG
With a doctorate in mechanical engineering and more than 15 years of international consulting experience in lean development, engineering excellence and quality management, Dr. Thilo Greshake has been responsible for the Automotive division at Staufen AG since 2017.
Thomas Spiess, Member of the Executive Board, STAUFEN.INOVA AG, Switzerland
He studied mechanical engineering at ETH Zurich and has been an expert for supply chain management for almost 30 years.


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During congressional testimony, a representative for the Appraisal Institute handed down a very unfavorable appraisal of industry regulation.
Alan Eugene Hummel, immediate past president of the Appraisal Institute, told members of the Senate Committee on Banking, Housing and Urban Affairs that the industry lacks regulatory direction, disclosure and discipline. The Financial Institutions Reform, Recovery and Enforcement Act of 1989 (FIRREA), which was supposed to improve the regulation of the industry, is itself in a sorry state of disrepair, Hummel reported to committee members.
In a survey conducted by the Appraisal Institute, an international membership association of professional real estate appraisers with more than 18,000 members and 99 chapters in the U.S., Canada and abroad, about half of the respondents said appraisal quality has declined since the passage of FIRREA, while 28 percent said they saw improvement since the act.
While the act was intended to guard against corruption in the industry, Hummel said, “Without effective enforcement, financiers still pressure appraisers to come up with the ‘right numbers for their deals – just as they did in the freewheeling ’80s.” He said the provisions of FIRREA discriminate against seasoned professionals in the industry while favoring newcomers, and noted that less than 40 percent of appraisers now belong to professional organizations. “Our system is floundering. Discipline and direction can help it make the grade,” he said.—Inman NewsWeather cools housing starts in FebruaryPace Still Ahead of 2003 Annual Total
Unusually cold and wet weather in the South and West helped cool the national pace of new-home construction for February. Housing starts slipped to the seasonably adjusted annual rate of 1.855 million units, as reported by the Commerce Depart-ment. Even so, the starts pace remain-ed well above the 2003 annual total of 1.848 million, which was the highest in 26 years.
Overall, the February construction pace was 4.0 percent below January’s upwardly revised rate of 1.932 million and 13.1 percent above the February 2003 pace.
“Builders continued to adjust their new production to a more sustainable level after the surge of late 2003,” said Bobby Rayburn, president of the National Association of Home Builders (NAHB) and a home and apartment builder from Jackson, Miss.
“But builders remain very confident about the market, and we expect to maintain a very healthy pace through the coming months.”
For the month, single-family housing starts were down 4.1 percent to a pace of 1.489 million. This was a 13.5 percent increase over the February 2003 pace.
The pace of multifamily housing starts decreased 3.4 percent from January to a seasonally adjusted rate of 366,000 units. This was 11.6 percent above the pace of a year ago.
Construction of new homes and apartments decreased in the South by 10.6 percent and in the West by 7.5 percent from January’s rate, while the Northeast and Midwest posted increases of 25.3 percent and 7.1 percent, respectively.CA governor to join plastic pipe fight
California Governor Arnold Schwarzenegger has placed the issue of whether builders should be allowed to use plastic pipe for plumbing as No. 5 on his list of ways to improve the state’s economy, according to the Los Angeles Times.
“Schwarzenegger is embracing plastic construction piping, sharing the view of his building-industry patrons that plastic should be permitted as a less-expensive alternative to copper,” the paper wrote.
The Plastic Pipe & Fittings Association filed a lawsuit in late 2002 on behalf of PEX pipe manufacturers against the California Building Standards Commission
for excluding PEX plastic pipe from the California Plumbing Code. In January 2003, a Los Angeles superior judge ruled in favor of the association. That ruling is now under appeal. —PMmagazine.com

domain: law


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The recent emergence of streaming services has been a boon for film fans eager to catch the latest releases, as well as dive into a curated selection of classic cinema. Having access to some of the greatest films & TV of all time is the stuff of dreams for those of us who remember the never-ending shelves at our local video store. And now there’s a new (well-known, much loved) name that is setting up their stall.
StudioCanal Presents is the latest streaming channel to arrive, this time as an exclusive on the AppleTV app. It is available via the app on Apple TV, smart TVs and streaming devices, game consoles as well as the obligatory iPhones and iPads. Though for the type of films & TV they are showing we’d recommend the biggest screen you can find.
Here’s a taster of what you’ll find there.
The channel is available for £4.99 a month, and their opening salvo contains stone cold classics such as a restored version of The Third Man, the 4K release of Apocalypse Now: Final Cut, as well as films from The Coen Brothers, Lynne Ramsay and Céline Sciamma. The channel also offers TV highlights such as Hannibal and, for the first time ever on a streaming channel, acclaimed crime drama Spiral.
To celebrate the launch of the channel we have teamed up with StudioCanal for the long awaited return of the HeyUGuys Zoom Quiz!
When will it take place?
We will be hosting the Film & TV quiz on Zoom at 8pm GMT on Wednesday, the 24th of November, 2021.
Quizmaster Scott Davis will return to test your Film & TV knowledge using the StudioCanal catalogue of film and television classics as our base.
How to sign up
Please enter your details below through the Sign up link to participate and you’ll receive a Zoom link before the quiz launch at 8pm on the 24th of November.
You can enter in a team (up to 4 teammates), or go it alone. We have limited spaces so book in early to guarantee your spot and we cant wait to see you there!


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Landscaping. It’s probably the biggest factor to pay attention to as a homeowner or house hunter. The right landscape can make any house look THAT much more desirable to the buyer and add a certain je ne sais quoi to your property. There’s only one issue that can arise from a landscape job: you’ll be the most envied house in the neighbourhood.
But on a more serious note, while all of us would die for the perfect landscape, these things cost tons of money. There’s the labour cost to hire someone, then the risk of not liking their choice options when the job is done, and the potential risk of them not following instructions. So, to avoid any of those potential risks from happening to you, here’s a simple DIY landscaping project that’s fun, quick, quirky and loads cheaper. You can even get the kids involved and make it an at-home art project. And you won’t even have to wait for “the weekend” like your husband promised you 6 months ago that never came around!
This project is pretty simple – and as for the involvement of the kids’ sake – pretty safe too. There’s no involvement of drills or saws, hammer or nails. And there’s that extra plus that there’s no grave worry about them hurting themselves if you leave them unattended for any period of time…unless of course they decide to eat the paint. Then that’ll be bad. Very, very bad! So how about you just don’t leave them unattended at all?
Worries aside; these are all the stuff you’ll need to get for this fun Garden Mushrooms project:
- Plant Pots and Plant Saucers of varying sizes (clay preferably)
- Spray or Acrylic Paints (colours of your choice for the mushroom tops) .
- White Acrylic Craft Paint.
- 1 1/2” Paint Brush.
- Small Paintbrush.
- Epoxy or Waterproof Outdoor Glue (optional).
In an open space, paint the outside of the pots in white, and the underside of each of the saucers in a different colour. Apply as many coats as you’ll need to get full coverage and then let it dry for a few hours.
For the spots of the mushroom heads, dip the small round paintbrush in the white acrylic paint – coating it generously – and then dab it firmly onto the painted plant saucers, making a few randomly placed white spots. Repeat for all the plant saucers to get your mushroom tops. Let it dry completely.
For assembly: place a saucer upside down (painted side up) on top of each of the upside down white painted plant pots. For stability, use epoxy or waterproof outdoor glue to stick and centre the saucers to the base of the pots.
Find a good place to show off your DIY Garden Mushrooms where the neighbours can see and feel jealous. They’re lightweight and easily moveable to any part of your yard, too, just in case the jealousy gets too much.
And in those five easy steps, you’ve now created a fun and quirky garden that adds beautiful character to your home, and gives you a very Winnie the Pooh/Wonderland type finish. The kids will love it and it adds a great pop of colour to your garden.


It's not all the time that you discover you need a replacement Intake Manifold Gasket for your vehicle. You purchased your CB300 because its dependability and a trusted name appealed to your senses; so why would you settle for anything but the best when it comes to great quality auto parts? Auto enthusiasts appreciate the aggressive styling built into each Dodge, and understand that only the highest quality repair CB300 parts will suffice when repairs are needed. Your Dodge dealership isn't the only place to find trusted parts to repair your CB300.
Maintaining intake vacuum and the optimal air/fuel ratio is of utmost importance for any Dodge CB300 driver. If you are experiencing difficulties generating power or noticing your gas mileage dropping, a replacement Dodge CB300 intake manifold gasket will most likely solve all the engine problems for your vehicle. The original intake manifold gasket or gaskets on your vehicle are likely made of a pulp or cork composite material, rubber, or silicone. High-performance engines may have a metal or synthetic intake manifold gasket due to high heat or compression conditions.
Get your CB300 back on the road with the highest quality repair parts from the experts at Car Parts Discount. Ordering new Dodge parts from www.carpartsdiscount.com means you are taking advantage of the most superior original and aftermarket replacement CB300 parts on the internet. Make all your future car parts purchases at carpartsdiscount.com and realize incredible savings on all your upcoming repairs. If your car or truck was built in 1980, 1979, 1978, 1977, 1976, 1975, 1974, 1973, then you will find the correct Dodge CB300 Intake Manifold Gasket parts right here.


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The article below is written by Susan E. Bernard - Author, Publisher, OCCC High School Equivalency Coordinator, and Kenneth Ludolph's tutor
"In December of 2017, Kenneth Lee Ludolph, Jr. began a prison term at the Oklahoma State Reformatory. Inspired by the book, The Purpose Driven Life by Rick Warren, Kenneth decided to take charge of his life while he was in prison and do something positive, so he began attending GED® class.
It wasn't long, though, when in February of 2018, he was transferred to the OCTC halfway house in Oklahoma City. On his first Saturday evening, he heard an announcement for the GED® students to go to class. Although he wasn't yet enrolled, he ran to join the others. Kenneth had been disappointed to leave his dream behind when he was transferred, so he was excited to learn that he could continue to pursue his goal. His plan was interrupted again, however, when he was assigned a job at a restaurant which required him to work evenings and kept him from attending his new class.
As the supervisor of the OCTC class, I soon learned about Kenneth's situation, and I offered to tutor him during the daytime before he left for work. Kenneth primarily needed help with his math, and with brief tutoring sessions and countless hours of independent study from the "I'm Not Afraid of Math Anymore!" materials, he passed his high school equivalency test and achieved his goal exactly two months after running to that first class at the halfway house.
With the high school equivalency under his belt, new doors of opportunity began to open. Kenneth attended a Career Success class where he earned a Certificate of Work Ethic Proficiency. He was also honored at the annual Oklahoma City Community College Student Awards Ceremony that recognizes the two most outstanding high school equivalency students along with other outstanding students from each college department. Kenneth was released from prison on June 1st and began college for automotive technology just three days later on June 4th. In September, Kenneth was honored again as the 2018 Adult Student of the Year at the Oklahoma Literacy Coalition Conference. Kenneth has continued to excel in his college courses -- accomplishing this while also working 35 hours per week.
Kenneth has always stood out as a leader. I witnessed him contributing to his Career Success class and sharing helpful information to other students when it would have been more self-preserving to remain quiet. He also led the way at our OCCC June graduation as the graduates marched into the ceremony, and despite limited resources, he has been “paying it forward” to others. For example, after experiencing a four-hour trip home from class one day when his bike had a flat, he had begun carrying a spare inner tube in his backpack to be prepared for any future breakdowns. He freely shared that inner tube, however, with a stranger who was experiencing the same calamity just a few weeks later. Another time, he purchased parts and freely repaired a single mom’s car because he was more concerned about her family’s safety than he was about his own financial needs. Kenneth hopes to one day have his own shop where he can continue to serve people in need of automotive repair.
In 2019, Kenneth was named as the COABE Outstanding Adult Learner of the Year. COABE (the Commission on Adult Basic Education) is a large national organization that promotes and honors adult education. Kenneth has proven over and over again that perseverance pays off and that faith and hope are available for all who choose to reach out for it."

domain: library


text:
Background - Low-dose dopamine is frequently used in patients in the intensive care setting. Dopamine may inhibit chemoreceptor afferents and hence decrease chemoreflex sensitivity to hypoxia. Methods and Results - In a double-blind, randomized, crossover study, we determined the effects of dopamine (5 μ · kg-1 · min-1) and placebo infusion on oxygen saturation, minute ventilation, and sympathetic nerve activity during normoxia and 5 minutes of hypoxia in 10 normal young subjects. We further investigated the effects of dopamine and placebo on minute ventilation during normoxic breathing in 8 patients with severe heart failure and in 8 age- matched control subjects. Dopamine did not decrease minute ventilation during normoxia in normal subjects. During hypoxia, minute ventilation was 12.9±1.3 L/min on dopamine and 15.8±1.5 L/min on placebo (P<0.0001). Oxygen saturation during hypoxia was lower with dopamine (78±3%) than placebo (84±2%; P<0.0001). Sympathetic nerve activity during hypoxia was not enhanced with dopamine despite the lower O2 saturation. Subjects were able to maintain a voluntary apnea to a lower oxygen saturation on dopamine than on placebo (P<0.05). In heart failure patients breathing room air, but not in age-matched control subjects, dopamine decreased minute ventilation despite decreased oxygen saturation and increased PETCO2 during dopamine (all P≤0.02). Conclusions - Dopamine inhibits chemoreflex responses during hypoxic breathing in normal humans, preferentially affecting the ventilatory response more than the sympathetic response. Dopamine also depresses ventilation in normoxic heart failure patients breathing room air. Ventilatory inhibition by low-dose dopamine may adversely influence outcome in hypoxic patients, especially in patients with heart failure.
- Heart failure
- Nervous system, sympathetic
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)


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Sterile Filtered colorless solution.
The STX4 solution (1mg/1ml) contains 20mM Tris-HCl buffer (pH 8.0), 100mM NaCl, 1mM DTT and 40% glycerol.
Greater than 90% as determined by SDS-PAGE.
MGSSHHHHHH SSGLVPRGSH MGSHMMRDRT HELRQGDDSS DEEDKERVAL VVHPGTARLG SPDEEFFHKV RTIRQTIVKL GNKVQELEKQ QVTILATPLP EESMKQELQN LRDEIKQLGR EIRLQLKAIE PQKEEADENY NSVNTRMRKT QHGVLSQQFV ELINKCNSMQ SEYREKNVER IRRQLKITNA GMVSDEELEQ MLDSGQSEVF VSNILKDTQV TRQALNEISA RHSEIQQLER SIRELHDIFT FLATEVEMQG EMINRIEKNI LSSADYVERG QEHVKTALEN QKKARKKKVL
Protein Name & Synonyms:
Syntaxin 4, syntaxin 4A (placental), STX4A, Renal carcinoma antigen NY-REN-31, p35-2.
STX4 Human Recombinant produced in E. coli is a single polypeptide chain containing 300 amino acids (1-275) and having a molecular mass of 34.7 kDa.STX4 is fused to a 25 amino acid His-tag at N-terminus & purified by proprietary chromatographic techniques.
Store at 4°C if entire vial will be used within 2-4 weeks. Store, frozen at -20°C for longer periods of time. For long term storage it is recommended to add a carrier protein (0.1% HSA or BSA).Avoid multiple freeze-thaw cycles.

domain: chemistry


A CRM is a customer relationship management solution that helps businesses of all types manage cross-selling, compliance, client knowledge, and task automation. CRMs enable companies to manage their data, including client profiles, past transactions, and communication history via email, telephone, social media, etc.
But how specifically can CRMs enable professional service organisations to leverage their most important asset – their clients?
CRM solutions are powerful tools that enable PSOs, such as law or accountancy firms, to build closer and better-managed relationships with their clients, inevitably leading to more referrals and repeat business.
It is important to keep in mind that PSOs operate very differently to corporate entities that have specific goods or straightforward services to sell to a mass market. A PSO sells the skills and expertise of highly skilled professionals, and each engagement is usually unique and tailored specifically to the needs of the client. Professional service organisations usually depend on their skilled professionals to network and bring in business themselves as opposed to strictly using mass-market marketing techniques.
Smaller operations allow for their member professionals to communicate with clients and prospects face-t0-face, usually through formal meetings. As firms grow, however, and as business processes grows increasingly digital and remote, the ability to facilitate such interactions grows increasingly difficult.
In order for everyone to keep up with all client contacts, leads, and ongoing projects, it becomes crucial to implement a CRM system that ensures that no opportunities are missed.
The following are some of the main benefits of employing a CRM system for a professional service firm, and how specifically to make the most of this type of technological infrastructure.
Professional service firms sell the knowledge and skills of its experts, which change and expand as the firm grows. As such, it’s important to take reconnaissance of the firm’s clientele in order to identify client needs that match the skillsets of their respective salesperson or consultant.
A CRM can be used as a strategic tool to identify future avenues of growth and areas that might be worth future investment. CRMs allow for a 360-degree view of the customer based on all the contact that the customer has had with the firm thus far. By analysing that data and using the results intelligently, you’ll know what you can offer your customers next that they are most likely to purchase.
A key characteristic of a professional service organisation is that the professionals who make up the firm build strong networks of contacts that they then leverage to win new business. This becomes precarious if they ever leave the firm, since there is a danger then that the entire network is lost.
When this happens, having a CRM can make all the difference. Details regarding client profile, contacts, past transactions, notes regarding conversations, and easy access to email threads are fundamental when picking up the mantle after a professional leaves the firm.
One of the biggest hassles facing PSOs (and almost every business for that matter!) is compliance.
Top CRM solutions such as Salesforce make keeping up with regulatory requirements relatively straightforward, with built-in functionality enabling firms to record compliance in an intuitive but completely secure way. Users are able to scan and attach important documents to AML (anti-money laundering) records, making KYC (know your customer) proof readily available on demand. This data is then stored in a secure manner with restricted access on a need-to-know basis.
GDPR (General Data Protection Regulation) imposes strict requirements on how firms can store and manage client data (the type of data stored in a CRM system). Good CRM systems have evolved to put users in full control of the data, with full transparency about how it is used. It is therefore possible to keep track of the source of the data and why it is being held. In addition, the CRM solution keeps track of when the data is first created, enabling users to make sure that it is not kept longer than necessary. The CRM also greatly facilitates erasing data if a client requests their “Right to be forgotten”.
HubSpot’s CRM service makes this process ridiculously simple. With the flip of a toggle in your account settings, you can automatically enable GDPR-compliant features throughout your entire account.
There are many tasks that are crucial to foster good client relations that are somewhat repetitive and therefore subject to human error. Examples include sending out texts or emails to remind clients about appointments, or contacting clients on an annual basis to request updated documents.
CRM solutions can be used to automate such tasks, ensuring that they are done on time and to a high level of accuracy. Not only will utilising this type of automated communication strengthen the client’s faith in the efficiency of the firm, but it will take tedious tasks of the hands of your staff so that they may focus on more important and dynamic tasks at hand.
You can see how a good CRM system would quickly become an integral part of any successful firm’s system of processes.
Without one, managing client relationships and leveraging them for growth becomes increasingly more challenging.
Do you have any questions about CRMs, or are you thinking of changing or upgrading your current system? We’d love to hear from you!