Block Copolymers of Methyl Vinyl Ether and Isobutyl Vinyl Ether With Thermo‐Adjustable Amphiphilic Properties

The thermo‐adjustable hydrophilic/hydrophobic properties of AB, ABA and BAB block copolymers in which A is poly(methyl vinyl ether) (PMVE) and B is poly(isobutyl vinyl ether) (PIBVE) have been investigated. The block copolymers were prepared by “living” cationic polymerization using sequential addition of monomers. The polymerizations were carried out with the system acetal/trimethylsilyl iodide as initiator and ZnI₂ as activator. The initiating system based on diethoxyethane leads to AB block copolymers whereas the initiating system based on tetramethoxypropane leads to ABA or BAB triblock copolymers. Well‐defined block copolymers of different composition with controlled molecular weights up to approx. 10 000 have been prepared. When IBVE is added to living PMVE, PIBVE‐blocks form only in the presence of an additional amount of ZnI₂, which is attributed to the fact that part of the ZnI₂ is inactive because of complex formation with PMVE. At room temperature, the combination of hydrophilic (PMVE) and hydrophobic (PIBVE) segments provides the copolymers with surfactant properties. Above the lower critical solution temperature (LCST) of PMVE, situated around 36 °C, the PMVE‐blocks become hydrophobic and the amphiphilic nature of the block copolymers is lost. The corresponding changes in hydrophilic/hydrophobic balance have been evaluated by investigation of the emulsifying properties of the block copolymers for water/decane mixtures as a function of the temperature. Below the LCST, the block copolymers have emulsifying properties similar to or better than those of the commercial PEO‐PPO block copolymers (Pluronic®). Either oil‐in‐water or water‐in‐oil emulsions can be obtained, depending on the polymer architecture and the water/decane volume ratio. The emulsifying properties are strongly reduced or completely lost above 40 °C. Emulsions obtained with a PMVE₃₆‐b‐PIBVE₅₄ block copolymer for a water/decane (v/v) ratio of 85/15 remained stable for more than six months.

50/50 and a 85/15 water/decane w/o emulsion (15 g/l) with the PMVE₃₆‐b‐PIBVE₅₄ block copolymer at 20 °C.     

Hemodynamic modes of ventricular assist with a rotary blood pump: continuous, pulsatile, and failure

Pulsatile operation of rotary blood pumps (RBPs) has received interest due to potential concern with nonphysiological hemodynamics. This study aimed to gain insight to the effects of various RBP modes on the heart-device interaction. A Deltastream diagonal pump (Medos Medizintechnik GmbH) was inserted in a cardiovascular simulator with apical-to-ascending aorta cannulation. The pump was run in continuous mode with incrementally increasing rotating speed (0-5000 rpm). This was repeated for three heart rates (50-100-150 bpm) and three levels of left ventricular (LV) contractility. Subsequently, the Deltastream was run in pulsatile mode to elucidate the effect of (de)synchronization between heart and pump. LV volume and pressure, arterial pressure, flows, and energetic parameters were used to evaluate the interaction. Pump failure (0 rpm) resulted in aortic pressure drops (17-46 mm Hg) from baseline. In continuous mode, pump flow compensated by diminished aortic flow, thus yielding constant total flow. High continuous rotating speed resulted in acute hypertension (mean aortic pressure up to 178 mm Hg). In pulsatile mode, unmatched heart and pulsatile pump rates yielded unphysiologic pressure and flow patterns and LV unloading was found to be highly dependent on synchronization phase. Optimal unloading was achieved when the minimum rotating speed occurred at end-systole. We conclude that, in continuous mode, a perfusion benefit can only be achieved if the continuous pump flow exceeds the preimplant (baseline) cardiac output. Pulsatile mode of support results in complex pressure and volume variations and requires accurate triggering to achieve optimal unloading.     

Left-ventricular pressure gradients: a computer-model simulation

Both invasive left-ventricular pressure measurements and non-invasive colour M-mode echographic measurements have shown the existence of intraventricular pressure gradients (IVPGs) during early filling. The mechanisms responsible for these IVPG cannot be completely explained by the experiments. Therefore a one-dimensional numerical model is developed and validated. The model describes filling (both velocities and pressures) along a left ventricular (LV) base-apex axis. Blood-wall interaction in the left ventricle with moving boundaries is taken into account. The computational results for a canine heart indicate that the observed IVPGs during filling are the consequence of a complex interaction between, on the one hand, pressure waves travelling in the LV and, on the other hand, LV geometry, relaxation and compliance. The computational results indicate the pressure dependency of wavespeed (0.77-1.90 m-1 s) for different mean intraventricular pressures (0.88-5.00 mmHg) and IVPGs up to 2 mmHg, independent of the ratio of end systolic volume and equilibrium volume. Increasing relaxation rate not only decreases minimum basal pressure (2.8 instead of 3.6 mmHg) but also has a strong influence on the time delay between the minimum basal and apical pressures (14 ms instead of 49 ms). The results sustain the hypothesis that pressure-wave propagation determines IVPGs and that IVPGs are no proof of elastic recoil.     

Effect of vaccination against Mycoplasma hyopneumoniae in pig herds with an all-in/all-out production system

A multi-site field study was conducted to evaluate an inactivated Mycoplasma hyopneumoniae (Mh) vaccine in 14 pig herds infected by Mh and practising an all-in/all-out production system. In each herd, a vaccinated and control group of 250 pigs each were compared during the growing/finishing period with respect to performance parameters (major variables) and by means of clinical, serological and pathological parameters (ancillary variables). Mh vaccination significantly (P < 0.05) improved daily weight gain (+22 g), feed conversion ratio (-0.07), medication costs (-0.476 ECU/pig) (1 ECU = US$1.0269542), prevalence of pneumonia lesions (-14%) and severity of pneumonia lesions (-3%). Mortality rate, severity of coughing and carcass quality were not significantly influenced by Mh vaccination. Serological results of Mh and other respiratory pathogens are presented and discussed. A cost-benefit analysis based on significantly improved performance parameters demonstrated that Mh vaccination was economically attractive as it resulted in an increase of the net return to labour with 1.300 ECU per finishing pig sold. The sensitivity of the economic benefit was illustrated towards fluctuations in pig finishing prices.     

Expression of fibrinogen receptors during activation and subsequent desensitization of human platelets by epinephrine

Epinephrine causes platelet aggregation and secretion by interacting with alpha 2-adrenergic receptors on the platelet surface. Platelet aggregation requires the binding of fibrinogen to a specific receptor on the membrane glycoprotein IIb-IIIa complex. Although the IIb-IIIa complex is identifiable on the surface of resting platelets, the fibrinogen receptor is expressed only after platelet activation. The current studies were designed to examine the effect of occupancy of platelet alpha 2-adrenergic receptors by epinephrine on the expression of fibrinogen receptors and on the aggregation of platelets. The ability of epinephrine to induce the expression of fibrinogen receptors was studied under two different conditions: acute stimulation (less than 1 min) and prolonged stimulation (50 to 90 min), the latter of which is associated with a reduction or "desensitization" of the platelet aggregation response. Expression of the fibrinogen receptor was monitored with 125I-fibrinogen as well as with 125I-PAC-1 (PAC-1), a monoclonal antibody that binds to the glycoprotein IIb-IIIa complex only after platelets are activated. Epinephrine caused an immediate increase in PAC-1 and fibrinogen binding that was dependent on occupancy of the alpha 2-receptor by epinephrine and on the presence of extracellular free Ca (KCa = 30 mumol/L). By itself, 1 mmol/L Mg was unable to support induction of the fibrinogen receptor by epinephrine. However, it did decrease the Ca requirement by about two orders of magnitude. Prolonged stimulation of unstirred platelets by epinephrine led to a 70% decrease in the aggregation response when the platelets were subsequently stirred. Despite their decreased aggregation response, desensitized platelets bound PAC-1 and fibrinogen normally, indicating that the loss of aggregation was not due simply to a decrease in fibrinogen receptor expression. Although desensitization was not affected by pretreatment of the platelets with aspirin, it was partially prevented when extracellular Ca was chelated by EDTA during the long incubation with epinephrine. These studies demonstrate that once platelet alpha 2-adrenergic receptors are occupied by epinephrine, extracellular Ca is involved in initiating the aggregation response by supporting the induction of the fibrinogen receptor and the binding of fibrinogen. Furthermore. Ca-dependent reactions subsequent to fibrinogen binding may be necessary for maximal platelet aggregation and are impaired when platelets become desensitized to epinephrine.     

Chlorambucil therapy in hairy cell leukemia: effects on lipid composition and lymphocyte subpopulations

Two patients with progressive hairy cell leukemia following splenectomy were treated with low-dose daily chlorambucil. Both had an objective hematologic response as determined by a return to normal hematocrit and platelet count. This was also reflected in the mononuclear cell fraction by the normalization of cholesterol content, cholesterol/phospholipid ratio, and the lymphocyte subpopulations. This article confirms previous reports on the efficacy of chlorambucil in this setting and describes some morphological, and biochemical concomitant events.     

Trastuzumab-induced cardiotoxicity in elderly women with HER-2-positive breast cancer: a meta-analysis of real-world data

Background: We conducted a meta-analysis to assess the overall risk of cardiac toxicity associated with trastuzumab treatment in elderly breast cancer patients.

Methods: We searched databases from PubMed, EMBASE and Cochrane Central Registry of Controlled Trials to identify relevant studies. Statistical analyses were conducted to calculate the incidence rate, overall hazard ratio (HR) and 95% CIs using a fixed effects model.

Results: A total of 116,342 and 360 elderly patients from five cohort studies and two randomized clinical trials (RCTs) were included for analysis. The pooled incidences of symptomatic congestive heart failure (CHF) and CHF/HF/CM were 6.4% (95% CI 4.1% – 9.4) and 16.4% (95% CI 16.19% – 16.61) in patients with median age of 67.5 years from two RCTs and in patients with median age of 67.5 (60 – 75), 71 (66 – 80+), 74.5 (65 – 89), 75 (66 – 81+) and 79.5 (60 – 99) from five cohort studies, respectively. Trastuzumab was significantly correlated with an increased risk of defined cardiac toxicities in five cohort studies (HR = 1.89, 95% CI 1.72 – 2.07, p < 0.00001) and two RCTs (HR = 3.00, 95% CI 1.71, 5.26, p < 0.00001). Sub-group analysis showed that the anthracycline-based chemotherapy increased the risk of CHF/HF and CM in patients among five cohort studies (HR = 2.16, 95% CI: 1.8 – 1.87, p < 0.00001).

Conclusion: Trastuzumab is likely associated with an increased risk of cardiac toxicity in elderly patients with HER-2-positive breast cancer. Carefully monitoring cardiac function in elderly patients receiving trastuzumab, particularly with concurrent use of anthracycline, is warranted.     

Prevention of bacteremia caused by α-hemolytic streptococci by roxithromycin (RU-28 965) in granulocytopenic patients receiving ciprofloxacin

Summary We previously demonstrated that ciprofloxacin prevents infections caused by gram-negative bacilli in patients with granulocytopenia. However, in patients with intensive cytotoxic treatment leading to severe mucosal damage a high incidence of bacteremias caused by -hemolytic streptococci was seen. In the present study 45 consecutive patients undergoing intensive cytotoxic treatment received a short course of roxithromycin (10 days) in addition to ciprofloxacin for prevention of bacteremias caused by -hemolytic streptococci. The results of this study were compared with the results obtained in previous comparable patients receiving ciprofloxacin alone. During the days with addition of roxithromycin no infections caused by -hemolytic streptococci occurred, while in the control group of 80 patients 16 bacteremias (20%) were seen. Although roxithromycin was shown to antagonize bactericidal action of ciprofloxacin on gram-negative bacilliin vitro, in vivo study based on serum bactericidal titers and on results of surveillance cultures showed no antagonistic interactions.

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Roxithromycin (RU-28 965) zur Prävention der Bakteriämie durch alpha-hämolytische Streptokokken bei granulozytopenischen Patienten unter Ciprofloxacin-Prophylaxe

Zusammenfassung In früheren Studien konnte die präventive Wirksamkeit von Ciprofloxacin gegen Infektionen durch gramnegative Bakterien bei granulozytopenischen Patienten belegt werden. Jedoch traten bei Patienten, die mit intensiven Zytostatikaschemata behandelt wurden, häufig Bakteriämien durch alpha-hämolytische Streptokokken auf. In der vorliegenden Studie erhielten 45 Patienten, die nacheinander eingewiesen wurden und eine hochdosierte Zytostatikatherapie durchmachten, zehn Tage lang Roxithromycin als Zusatz zu einer Prophylaxe mit Ciprofloxacin, um das Auftreten septischer Infektionen durch alpha-hämolytische Streptokokken zu verhüten. Die Ergebnisse dieser Studie wurden denjenigen einer vorausgegangenen Studie mit vergleichbaren Patienten unter Prophylaxe mit Ciprofloxacin allein gegenübergestellt. Während in der Vergleichsgruppe bei 16 von 80 Patienten Bakteriämien durch alpha-hämolytische Streptokokken aufgetreten waren, kam es bei den Patienten, die Roxithromycin erhielten, zu keiner einzigen solchen Infektion, solange dieses Antibiotikum verabreicht wurde. Im Gegensatz zuIn vitro-Beobachtungen, die darauf schließen lassen, daß Roxithromycin die bakterizide Aktivität von Ciprofloxacin gegen gramnegative Bakterien antagonisiert, waren antagonistische Interaktionen in einerIn vivo-Studie anhand der Serumbakterizidietiter und Ergebnisse von Überwachungskulturen nicht festzustellen.