Haemodynamic and neuroendocrine effects of tezosentan in chronic experimental pulmonary hypertension

Purpose

Chronic pulmonary hypertension (PH) therapy is poorly investigated in intensive care. Our aim was to evaluate haemodynamic and neuroendocrine effects of the dual endothelin-1 (ET-1) blocker tezosentan in monocrotaline (MCT)-induced PH.

Methods

Male Wistar rats (180–200?g, n?=?194) randomly received 60?mg?kg^?1 MCT or vehicle, subcutaneously, and 2?days later, a subgroup of MCT-injected rats was gavaged with 300?mg?kg^?1?day^?1 bosentan (MCT BOS, n?=?46), while another (MCT, n?=?125) and control rats (Ctrl, n?=?23) received vehicle. At 25–30?days, 48?h after interrupting bosentan, rats randomly underwent either a dose–response evaluation (0.5–20?mg?kg^?1, n?=?7 each group) or a 4?h perfusion of tezosentan (20?mg?kg^?1 in 10?min?+?10?mg?g^?1?h^?1) or vehicle (n?=?8 per group, each). Haemodynamics, including blood gas analysis, were evaluated after thoracotomy under anaesthesia. After plasma, right ventricle (RV) and lung collection, plasma ET-1, cytokines, nitrate and 6-keto-PGF1α, and lung and right ventricular gene expression and cyclooxygenase (COX) and nitric oxide synthase (NOS) activities were quantified.

Results

Monocrotaline resulted in PH, RV dilation and decreased cardiac output (CO) that were attenuated in MCT BOS. Pulmonary hypertension was attenuated by tezosentan without systemic hypotension. Tezosentan increased CO without changing ventilation-perfusion matching. Both bosentan and tezosentan reduced ET-1 and cytokine plasma levels and tissue expression, and inducible NOS and COX-2 RV activities. Bosentan increased nitrate plasma levels and non inducible NOS activities whereas tezosentan decreased circulating 6-keto-PGF1α but increased lung COX-1 activity.

Conclusions

Tezosentan may be useful for haemodynamic handling and bosentan replacement in critically ill PH patients exerting important beneficial neuroendocrine and anti-inflammatory actions.     

Anorexia nervosa: Essstörung mit Folgen

Introduction

Anorexia nervosa (AN) is a psychiatric disorder and often associated with osteopenia or osteoporosis. The reason for bone loss in AN is still unknown but a multifactorial genesis is suspected. The purpose of this study was to understand the mechanisms involved in bone loss in AN.

Methods

We prospectively measured bone mineral density by dual x-ray absorptiometry in 20 women with AN (mean? age ±? SD, 22.9?±?4.3 years) and 20 healthy age-matched controls.

Results

Bone mineral density was significantly reduced in the spine (AN, 0.99?±?0.14 g/cm² vs. controls, 1.20?±?0.12 g/cm², p?<?0.0001) and hips (AN, 0.86?±?0.13 g/cm² vs. controls, 1.06?±?0.11 g/cm²; p?<?0.0001) in all patients with AN compared with controls.

Conclusions

Bone mineral density is significantly reduced in patients with AN. Long-term influences on bone mineral density as well as on peak bone mass are expected in these patients.     

Epoprostenol treatment of acute pulmonary hypertension is associated with a paradoxical decrease in right ventricular contractility

Objective

Prostacyclins have been suggested to exert positive inotropic effects which would render them particularly suitable for the treatment of right ventricular (RV) dysfunction due to acute pulmonary hypertension (PHT). Data on this subject are controversial, however, and vary with the experimental conditions. We studied the inotropic effects of epoprostenol at clinically recommended doses in an experimental model of acute PHT.

Design and setting

Prospective laboratory investigation in a university hospital laboratory.

Subjects

Six pigs (36?±?7?kg).

Interventions

Pigs were instrumented with biventricular conductance catheters, a pulmonary artery (PA) flow probe, and a high-fidelity pulmonary pressure catheter. Incremental doses of epoprostenol (10, 15, 20, 30, 40?ng?kg^–1?min^–1) were administered in undiseased animals and after induction of acute hypoxia-induced PHT.

Measurements and results

In acute PHT epoprostenol markedly reduced RV afterload (slopes of pressure-flow relationship in the PA from 7.0?±?0.6 to 4.2?±?0.7?mmHg?min?l^–1). This was associated with a paradoxical and dose-dependent decrease in RV contractility (slope of preload-recruitable stroke-work relationship from 3.0?±?0.4 to 1.6?±?0.2?mW?s?ml^–1; slope of endsystolic pressure-volume relationship from 1.5?±?0.3 to 0.7?±?0.3?mmHg?ml^–1). Left ventricular contractility was reduced only at the highest dose. In undiseased animals epoprostenol did not affect vascular tone and produced a mild biventricular decrease in contractility.

Conclusions

Epoprostenol has no positive inotropic effects in vivo. In contrast, epoprostenol-induced pulmonary vasodilation in animals with acute PHT was associated with a paradoxical decrease in RV contractility. This effect is probably caused indirectly by the close coupling of RV contractility to RV afterload. However, data from normal animals suggest that mechanisms unrelated to vasodilation are also involved in the observed negative inotropic response to epoprostenol.     

Lung deposition of continuous and intermittent intravenous ceftazidime in experimental Pseudomonas aeruginosa bronchopneumonia

Objective

Lung tissue deposition of intravenous ceftazidime administered either continuously or intermittently was compared in ventilated piglets with experimental bronchopneumonia.

Design

Prospective experimental study

Animals

Eighteen anesthetized and ventilated piglets

Interventions

Bronchopneumonia was produced by the intrabronchial inoculation of Pseudomonas aeruginosa characterized by an impaired sensitivity to ceftazidime (MIC 16?mg/l). Ceftazidime was administered either through a continuous infusion of 90?mg/kg per 24?h after a bolus of 30?mg/kg or by an intermittent infusion of 30?mg/kg per 8?h.

Measurements and results

Piglets were killed 24?h after the initiation of continuous ceftazidime (n?=?6), and 1?h (peak, n?=?6) and 8?h (trough, n?=?6) after the third dose following intermittent administration. Lung tissue concentrations of ceftazidime, measured by HPLC, and lung bacterial burden were assessed on multiple postmortem lung specimens. During continuous administration ceftazidime lung tissue concentrations were 9.7?±?3.8?μg/g. Following intermittent administration peak and trough lung tissue concentrations were, respectively, 7.1?±?2.4?μg/g and 0.6?±?1?μg/g. Lung bacterial burden was different after continuous and intermittent administration (median 7.10³ vs. 4.10²?cfu/g).

Conclusions

Continuous infusion of ceftazidime maintained higher tissue concentrations than intermittent administration.     

Phase 1, single‐dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant,in patients with severe hemophilia

Essentials

• Marzeptacog alfa (activated) [MarzAA] is a novel variant of activated human factor VII.
• A phase 1 dose escalation trial of MarzAA was conducted in subjects with severe hemophilia.
• MarzAA was safe and tolerated at intravenous doses up to 30 μg kg^?1
• Data observed support further trials for hemophilia patients with inhibitors to factors VIII/IX.

Summary

Background

Marzeptacog alfa (activated) (MarzAA), a new recombinant activated human factor VII (rFVIIa) variant with four amino acid substitutions, was developed to provide increased procoagulant activity and a longer duration of action in people with hemophilia.

Objectives

To investigate the safety, tolerability, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending intravenous bolus doses of MarzAA in non‐bleeding patients with congenital hemophilia A or B with or without inhibitors.

Methods

This international, phase 1, open‐label study (NCT01439971) enrolled males aged 18–64 years with severe hemophilia A or B, with or without FVIII or FIX inhibitors. Subjects were assigned to single‐dose MarzAA cohorts (0.5, 4.5, 9, 18 or 30 μg kg^?1). Blood sampling was performed predose and postdose, and subjects were monitored for 60 days postdose. Safety endpoints included adverse events, vital sign changes, electrocardiograms, laboratory abnormalities, and immunogenicity; secondary endpoints included evaluation of PK and PD.

Results

Overall, in 25 patients, MarzAA was well tolerated at all dose levels tested, and was not associated with dose‐limiting toxicity. No treatment‐emergent severe or serious adverse events occurred. MarzAA showed linear dose–response PK across the 4.5–30 μg kg^?1 dose range, with a terminal half‐life of ? 3.5 h. Dose‐dependent shortening of the activated partial thromboplastin time and prothrombin time, and evidence of an increase in peak thrombin as determined with a thrombin generation assay, were observed at all doses.

Conclusions

MarzAA was tolerated at doses up to 30 μg kg^?1. The safety profile and pharmacological effects observed support further clinical trials for the treatment of hemophilic patients with inhibitors.

     

Levosimendan infusion in newborns after corrective surgery for congenital heart disease: randomized controlled trial

Purpose

To evaluate the safety and efficacy of levosimendan in neonates with congenital heart disease undergoing cardiac surgery with cardiopulmonary bypass (CPB).

Methods

Neonates undergoing risk-adjusted classification for congenital heart surgery (RACHS) 3 and 4 procedures were randomized to receive either a 72?h continuous infusion of 0.1?μg/kg/min levosimendan or standard post-CPB inotrope infusion.

Results

Sixty-three patients (32 cases and 31 controls) were recruited. There were no differences between groups regarding demographic and baseline clinical data. No side effects were observed. There were no significant differences in mortality (1 vs. 3 patients, p?=?0.35), length of mechanical ventilation (5.9?±?5 vs. 6.9?±?8?days, p?=?0.54), and pediatric cardiac intensive care unit (PCICU) stay (11?±?8 vs. 14?±?14?days, p?=?0.26). Low cardiac output syndrome occurred in 37?% of levosimendan patients and in 61?% of controls (p?=?0.059, OR 0.38, 95?% CI 0.14–1.0). Postoperative heart rate, with a significant difference at 6 (p?=?0.008), 12 (p?=?0.037), and 24?h (p?=?0.046), and lactate levels, with a significant difference at PCICU admission (p?=?0.015) and after 6?h (p?=?0.048), were lower in the levosimendan group. Inotropic score was significantly lower in the levosimendan group at PCICU admission, after 6?h and after 12?h, (p?Conclusions Levosimendan infused in neonates undergoing cardiac surgery was well tolerated with a potential benefit of levosimendan on postoperative hemodynamic and metabolic parameters of RACHS 3–4 neonates.     

Interventional closure of atrial septal defects without fluoroscopy in adult and pediatric patients

Background

Interventional closure of atrial septal defects (ASDs) with a transcatheter device is the preferred strategy in children and adults. This procedure has been proven in numerous studies, but X-ray and contrast agent exposure is still a major side effect. The aim of this study was to clarify whether the interventional closure of ASDs is possible and safe if it is guided by transesophageal echocardiography (TEE) alone.

Methods and results

We retrospectively selected and studied pediatric and adult patients with interventional closure of ASDs at the Deutsches Herzzentrum Berlin (DHZB) without fluoroscopy between 1999 and 2010. We included 330 out of 1,605 patients; 254 had an ASD II, 30 a PFO and 46 multiperforated atrial septum. Median age was 8.92 (0.96–76.3)?years and median body weight 32.6 (8.3–156)?kg. Median stretched defect size was 13 (5–29)?mm. Median procedure time was 50 (20–170)?min. Closure was performed in the majority of patients with the Amplatzer^? septal occluder or Amplatzer^? PFO occluder. The procedure succeeded in 98.2?% of cases and closure rate was 94.9?% after 48?h. Complication rate was low and procedure time was similar to that necessary with studies using fluoroscopy.

Conclusion

Interventional closure of ASDs is safe and effective if guided with TEE alone. The results can compete with those with the use of fluoroscopy. TEE-guided closure of ASD should be considered in more catheter laboratories to avoid unnecessary radiation exposure for the patient and the examiner.     

Primary echocardiographic results of the Carpentier–Edwards Perimount Magna

Purpose

The aim of this study was to investigate the primary echocardiographic results of aortic valve replacement using 21- and 19-mm Carpentier–Edwards Perimount Magna bioprosthesis aortic xenografts in patients with small aortic annulus.

Methods

Twenty patients (mean body surface area 1.63?±?0.16?m²) underwent aortic valve replacement between June 2008 and December 2009. Eight and 12 patients received 21- and 19-mm Magna bioprostheses, respectively. After 12?months, hemodynamic data were obtained by echocardiography to estimate the prosthesis–patient mismatch.

Results

At follow-up, significant decreases in peak and mean left ventricular aortic pressure gradients were observed in the 12 patients with aortic stenosis (P?<?0.05). Regression of the left ventricular mass was observed in all the patients (P?<?0.05). The mean measured effective orifice area (EOA) and EOA index (EOAI) were 1.61?±?0.28?cm² and 0.99?±?0.16?cm²/m², respectively. Prosthesis–patient mismatch (EOAI ≤0.85) was documented in three patients.

Conclusion

The primary echocardiographic findings suggested that the hemodynamic performance of the 19- and 21-mm Carpentier–Edwards Perimount Magna bioprostheses was satisfactory in the patients with a small aortic annulus.     

Effectiveness of palonosetron for preventing delayed chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy in patients with gastrointestinal cancer

Purpose

Patients with gastrointestinal cancer who were receiving moderately emetogenic chemotherapy (MEC) were switched from granisetron, a first-generation 5-hydroxytryptamine-3 receptor antagonist, to palonosetron at our hospital. In the present study, we compared effectiveness before and after switching antiemetic treatment.

Methods

Among patients who were receiving MEC for gastrointestinal cancer, we prospectively observed 46 patients given granisetron and 46 given palonosetron. To allow adverse reactions to be graded in accordance with the Common Terminology Criteria for Adverse Events, version 4.0, a questionnaire designed at our hospital was used to compare the occurrence of delayed nausea and vomiting between patients who received granisetron (GRA group) and those who received palonosetron (PAL group).

Results

The incidence of delayed nausea was significantly lower in the PAL group (8.7 %, 4/46; p?<?0.01) than in the GRA group (37 %, 17/46). Delayed vomiting developed in five patients (10.9 %) in the GRA group, but did not occur in the PAL group. On the basis of the results of multivariate analysis, young age, female gender, and the use of granisetron were significant risk factors for delayed nausea.

Conclusion

Our survey showed that palonosetron effectively controls delayed nausea caused by MEC for gastrointestinal cancer.     

Initial Experience with the Radiotracer Anti-1-amino-3-[18F]Fluorocyclobutane-1-Carboxylic Acid (Anti-[18F]FACBC) with PET in Renal Carcinoma

Purpose

Assessment of renal masses with conventional imaging may be challenging. Anti-1-amino-3-[¹⁸F]fluorocyclobutane-1-carboxylic acid (anti-[18F]FACBC) is a synthetic l-leucine analog with relatively little renal excretion. The present study examines anti-[¹⁸F]FACBC positron emission tomography uptake in patients with renal masses.

Procedures

Six patients with seven renal lesions were imaged dynamically for 2 h after injection of 10–10.9 mCi (370–403 MBq) anti-[¹⁸F]FACBC. Lesions were evaluated qualitatively and quantitatively and correlated with histology.

Results

Four clear cell and one Rosai–Dorfman lesion were hypo/isointense to normal cortex; two papillary lesions in the same patient were hyperintense. Mean SUV_max?±?SD at 30 min was 2.8?±?0.24 for clear cell carcinomas and 4.5?±?1.7 for papillary cell lesions. Mean SUV_max/SUV_mean ratios?±?SD of lesion to normal cortex at 30 min was 1.15?±?0.19 for the clear cell carcinomas and 2.3?±?0.84 for papillary cell.

Conclusions

In this small patient sample, relative amino acid transport compared with renal cortex is elevated in renal papillary cell carcinoma but not in clear cell carcinoma.     

Treatment of postoperative emetic symptoms with granisetron in women undergoing abdominal hysterectomy: a randomized, double-blind, placebo-controlled, dose-ranging study

Background

Postoperative emetic symptoms (nausea, retching, and vomiting) frequently occur in women undergoing general anesthesia for abdominal hysterectomy. In a previous report by us, granisetron, a selective serotonin receptor antagonist, was more effective than the traditional antiemetics, droperidol and metoclopramide, for the treatment of postoperative emetic symptoms in this population.

Objective

The aim of this study was to determine the optimal dose of granisetron for the treatment of emetic symptoms following abdominal hysterectomy.

Methods

This randomized, double-blind, placebo-controlled, dose-ranging study was conducted at Toride Kyodo General Hospital (Toride, Japan). Female patients aged 33 to 66 years experiencing postoperative emetic symptoms after abdominal hysterectomy were eligible for the study. Patients received IV granisetron at 1 of 4 doses (10, 20, 40, or 100 μg/kg) or placebo; they were then observed for 24 hours. Emetic symptoms and the need for a rescue antiemetic were recorded by nursing staff, who were blinded to treatment assignment.

Results

A total of 100 patients (mean [SD] age, 45 [7] years [range, 33-66 years]) were enrolled (n = 20 in each group). No significant differences in patient demographic characteristics were observed between the groups. The number of patients in whom complete control of postoperative emetic symptoms, defined as being free of emetic symptoms and not needing rescue antiemetic medication for 24 hours after study drug administration, was established was significantly greater in 3 of the granisetron groups than in the placebo group (6 patients [30%]): granisetron 10 μg/kg, 7 patients (35%; P= NS); granisetron 20 μg/kg, 17 patients (85%; P = 0.001); granisetron 40 μg/kg, 17 patients (85%; P = 0.001); and granisetron 100 μg/kg, 16 patients (80%; P = 0.002). No clinically significant adverse events attributable to the study drug were observed in any group.

Conclusion

In this study of patients who experienced emetic symptoms after undergoing general anesthesia for abdominal hysterectomy, granisetron at doses ≥20 μg/kg was effective in the treatment of established postoperative emetic symptoms.     

Pilot Study of a Novel 18F-labeled FSHR Probe for Tumor Imaging

Purpose

Follicle-stimulating hormone receptor (FSHR) is overexpressed in primary and metastatic tumor. Molecular imaging of FSHR is beneficial for prognosis and therapy of cancer. FSHβ(33–53) (YTRDLVYKDPARPKIQKTCTF), denoted as FSH1, is a FSHR antagonist. In the present study, maleimide-NOTA conjugate of FSH1 (NOTA-MAL-FSH1) was designed and labeled with [¹⁸F] aluminum fluoride. The resulting tracer, ¹⁸F-Al-NOTA-MAL-FSH1, was preliminarily evaluated in PET imaging of FSHR-positive tumor.

Procedures

NOTA-MAL-FSH1 was synthesized and radiolabeled with Al¹⁸F complex. The tumor-targeting potential and pharmacokinetic profile of the ¹⁸F-labeled compound were evaluated in vitro and in vivo using a PC3 human prostate tumor model.

Results

¹⁸F-Al-NOTA-MAL-FSH1 can be efficiently produced within 30 min with a non-decay-corrected yield of 48.6?±?2.1 % and a radiochemical purity of more than 95 %. The specific activity was at least 30 GBq/μmol. The radiotracer was stable in phosphate-buffered saline and human serum for at least 2 h. The IC₅₀ values of displacement ¹⁸F-Al-NOTA-MAL-FSH1 with FSH1 were 252?±?1.12 nM. The PC3 human prostate tumor xenografts were clearly visible with high contrast after injection of ¹⁸F-Al-NOTA-MAL-FSH1 via microPET. At 30, 60 and 120 min postinjection, the tumor uptakes were 2.98?±?0.29 % injected dose (ID)/g, 2.53?±?0.20 %ID/g and 1.36?±?0.12 %ID/g, respectively. Dynamic PET scanning showed that tumor uptake reached a plateau by about 6 min. Heart peaked earlier and then cleared quickly. Biodistribution studies confirmed that the normal organs except kidney uptakes were all below 1 %ID/g at 1 h p.i. The tumor-to-blood and tumor-to-muscle ratio at 10 min, 0.5, 1, and 2 h after injection were 1.64?±?0.36, 2.97?±?0.40, 9.31?±?1.06, and 13.59?±?2.33 and 7.05?±?1.10, 10.10?±?1.48, 16.17?±?3.29, and 30.88?±?4.67, respectively. The tracer was excreted mainly through the renal system, as evidenced by high levels of radioactivity in the kidneys. FSHR-binding specificity was also demonstrated by reduced tumor uptake of ¹⁸F-Al-NOTA-MAL-FSH1 after coinjection with an excess of unlabeled FSH1 peptide.

Conclusion

NOTA-MAL-FSH1 could be labeled rapidly and efficiently with ¹⁸F using one step method. Favorable preclinical data suggest that ¹⁸F-Al-NOTA-MAL-FSH1 may be a suitable radiotracer for the non-invasive visualization of FSHR positive tumor in vivo.     

Single-Chain VEGF/Cy5.5 Targeting VEGF Receptors to Indicate Atherosclerotic Plaque Instability

Purpose

Unstable plaques may cause clinical events. Plaque destabilization results from the synergy between intraplaque angiogenesis and inflammation. Vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) are considered to be involved in these processes. We investigated the efficacy of the anti-VEGFR mimic single-chain VEGF (scVEGF) to map intra-plaque VEGFR expression and atherosclerotic plaque instability using near-infrared fluorescence (NIRF).

Procedures

Human carotid plaques were retrieved from 15 symptomatic and five asymptomatic patients. NIRF plaque imaging was performed pre-/post-incubation with scVEGF/Cy5.5. Biopsies taken from regions with high (hot spot) and low (cold spot) NIRF signals were examined for VEGF-A, VEGFR-1 and VEGFR-2 mRNA expression levels using real-time RT-PCR analysis. Immunohistochemistry for CD31 (endothelium), CD68 (macrophages) and αSMA (smooth muscle cells) was performed to evaluate plaque composition.

Results

NIRF imaging of 20 plaques revealed a heterogeneous distribution of scVEGF/Cy5.5 binding. After incubation NIRF activity increased from 3.9×10^?5?±?5.2×10^?6 to 3.0×10^?4?±?2.2×10^?5 and 5.8×10^?5?±?1.9×10^?5 to 3.1×10^?4?±?1.9×10^?5 photons/s/cm²/sr/illumination intensity on the intraluminal and extraluminal side, respectively (both p?<?0.001). Real-time RT-PCR analysis showed a ~1.2- and ~16.4-fold increased mRNA expression of VEGFR-1 and VEGFR-2, respectively, in hot spots (vs. cold spots). Immunohistochemistry exhibited higher intraplaque capillary density in hot spots (vs. cold spots) (17.2?±?3.7 vs. 5.4?±?2.2 capillary/mm²; p?=?0.037). Hot spots contained significantly reduced numbers of α-SMA-positive cells (vs. cold spots) (2.2?±?0.7 % vs. 6.9?±?1.5 %; p?=?0.038). Finally, a ~2-fold increase of CD68⁺ infiltrating macrophages within hot spots (vs. cold spots) was observed (not significant, p?=?0.17). Significant higher capillary density in hot spots (vs. cold spots) was observed in plaques from symptomatic patients but not in plaques from asymptomatic patients.

Conclusion

Our data support that scVEGF/Cy5.5 is a suitable indicator for plaque instability and a promising diagnostic tool for risk assessment in cardiovascular diseases.     

Effect of transcatheter aortic valve implantation on the ascending aorta’s elasticity

Background

The elastic properties of the ascending aorta were studied before and 1?week after transcatheter aortic valve implantation (TAVI). Previous studies have shown that the distensibility of the ascending aorta was decreased in the early post-operative period after aortic valve replacement. Aortic stiffness is a major moderator of arterio-ventricular coupling and an independent predictor of cardiovascular risk and mortality. We evaluated the effect of TAVI on the elastic properties of the ascending aorta in the early post-operative period.

Methods

Aortic distensibility (AD) and Aortic Stiffness Index (ASI) were evaluated using echocardiographic techniques and brachial artery pressure obtained by sphygmomanometry 2–3?days before and 7–8?days after TAVI.

Results

A total of 30 patients (14 males) were studied with a mean age of 79.9?±?4.7?years and aortic valve area before TAVI of 0.61?±?0.16?cm². Mean arterial pressure decreased significantly after TAVI (from 89.6?±?8.9?mmHg to 83.3?±?10.9?mmHg, p?=?0.004). AD did not change significantly after TAVI (pre: 1.89?±?1.11?cm²/(dynes?×?10⁶), post: 2.05?±?1.50?cm²/(dynes?×?10⁶); p?=?0.813). ASI also remained unchanged (pre: 11.4?±?6.5, post: 15.6?±?14.9; p?=?0.349).

Conclusions

The elastic properties of the ascending aorta did not change significantly in the early post-procedural period after TAVI. This may in part be attributable to the less invasive procedure (compared to aortic valve replacement) which has no effect on vasa vasorum flow.     

TEG® and RapidTEG® are unreliable for detecting warfarin-coagulopathy: a prospective cohort study

Background

Thromboelastography^® (TEG) utilizes kaolin, an intrinsic pathway activator, to assess clotting function. Recent published studies suggest that TEG results are commonly normal in patients receiving warfarin, despite an increased International Normalized Ratio (INR). Because RapidTEG? includes tissue factor, an extrinsic pathway activator, as well as kaolin, we hypothesized that RapidTEG would be more sensitive in detecting a warfarin-effect.

Methods

Included in this prospective study were 22 consecutive patients undergoing elective cardioversion and receiving warfarin. Prior to cardioversion, blood was collected to assess INR, Prothrombin Time, TEG, and RapidTEG.

Results

INR Results: 2.8?±?0.5 (1.6 to 4.2). Prothrombin Time Results: 19.1?±?2.2 (13.9. to 24.3). TEG Results (Reference Range): R-Time: 8.3?±?2.7 (2–8); K-Time: 2.1?±?1.4 (1–3); Angle: 62.5?±?10.3 (55–78); MA: 63.2?±?10.3 (51–69); G: 9.4?±?3.5 (4.6-10.9); R-Time within normal range: 10 (45.5%) with INR 2.9?±?0.3; Correlation coefficients for INR and each of the 5 TEG variables were insignificant (P?>?0.05). RapidTEG Results (Reference Range): ACT: 132?±?58 (86–118); K-Time: 1.2?±?0.5 (1–2); Angle: 75.4?±?5.2 (64–80); MA: 63.4?±?5.1 (52–71); G: 8.9?±?2.0 (5.0-11.6); ACT within normal range: 9 (40.9%) with INR 2.7?±?0.5; Correlation coefficients for INR and each of the 5 RapidTEG variables were insignificant (P?>?0.05).

Conclusions

TEG, using kaolin activation, and RapidTEG, with kaolin and tissue factor activation, were normal in a substantial percent of warfarin patients, despite an increased INR. The false-negative rate for detecting warfarin coagulopathy with either test is unacceptable. The lack of correlation between INR and all TEG and RapidTEG components further indicates that these methodologies are insensitive to warfarin effects. Findings suggest that intrinsic pathway activation may mitigate detection of an extrinsic pathway coagulopathy.     

Effects of exercise training on exercise capacity in patients with non-small cell lung cancer receiving targeted therapy

Purpose

Peak oxygen consumption (VO_2peak) is an important predictive factor for long-term prognosis in patients with non-small cell lung cancer (NSCLC). The purpose of this study was to investigate whether 8 weeks of exercise training improves exercise capacity, as assessed by VO_2peak, and other related factors in patients with NSCLC receiving targeted therapy.

Methods

A total of 24 participants with adenocarcinoma were randomly assigned to either the control group (n?=?11) or the exercise group (n?=?13). Subjects in the exercise group participated in individualized, high-intensity aerobic interval training of exercise. The outcome measures assessed at baseline and after 8?weeks were as follows: VO_2peak and the percentage of predicted VO_2peak (%predVO_2peak), muscle strength and endurance of the right quadriceps, muscle oxygenation during exercise, insulin resistance as calculated by the homeostasis model, high-sensitivity C-reactive protein, and quality of life (QoL) questionnaire inventory.

Results

No exercise-related adverse events were reported. After exercise training, VO_2peak and %predVO_2peak increased by 1.6?mL?kg^?1?min^?1 and 5.3% (p?<?0.005), respectively; these changes were associated with improvements in circulatory, respiratory, and muscular functions at peak exercise (all p?=?0.001). The exercise group also had less dyspnea (p?=?0.01) and favorably lower fatigue (p?=?0.05) than baseline.

Conclusions

Patients with NSCLC receiving targeted therapy have quite a low exercise capacity, even with a relatively high QoL. Exercise training appears to improve exercise capacity and alleviate some cancer-related symptoms.     

Longitudinal PET Imaging of Doxorubicin-Induced Cell Death with 18F-Annexin V

Purpose

This study aims to apply longitudinal positron emission tomography (PET) imaging with ¹⁸?F-Annexin V to visualize and evaluate cell death induced by doxorubicin in a human head and neck squamous cell cancer UM-SCC-22B tumor xenograft model.

Procedures

In vitro toxicity of doxorubicin to UM-SCC-22B cells was determined by a colorimetric assay. Recombinant human Annexin V protein was expressed and purified. The protein was labeled with fluorescein isothiocyanate for fluorescence staining and ¹⁸?F for PET imaging. Established UM-SCC-22B tumors in nude mice were treated with two doses of doxorubicin (10?mg/kg each dose) with 1?day interval. Longitudinal ¹⁸?F-Annexin V PET was performed at 6?h, 24?h, 3?days, and 7?days after the treatment started. Following PET imaging, direct tissue biodistribution study was performed to confirm the accuracy of PET quantification.

Results

Two doses of doxorubicin effectively inhibited the growth of UM-SCC-22B tumors by inducing cell death including apoptosis. The cell death was clearly visualized by ¹⁸?F-Annexin V PET. The peak tumor uptake, which was observed at day 3 after treatment started, was significantly higher than that in the untreated tumors (1.56?±?0.23 vs. 0.89?±?0.31%ID/g, p?<?0.05). Moreover, the tumor uptake could be blocked by co-injection of excess amount of unlabeled Annexin V protein. At day 7 after treatment, the tumor uptake of ¹⁸?F-Annexin had returned to baseline level.

Conclusions

¹⁸?F-Annexin V PET imaging is sensitive enough to allow visualization of doxorubicin-induced cell death in UM-SCC-22B xenograft model. The longitudinal imaging with ¹⁸?F-Annexin will be helpful to monitor early response to chemotherapeutic anti-cancer drugs.     

Improved PET Imaging of Tumors in Mice Using a Novel 18 F-Folate Conjugate with an Albumin-Binding Entity

Purpose

The folate receptor (FR) is a promising target for nuclear imaging due to its overexpression in many different cancer types. A drawback of using folate radioconjugates is the high accumulation of radioactivity in the kidneys. Therefore, the aim of this study was to develop a ¹⁸?F-labeled folate conjugate with an albumin-binding entity to enhance the blood circulation time and hence improve the tumor-to-kidney ratio.

Procedures

The novel ¹⁸?F-folate was prepared by conjugation of a ¹⁸?F-labeled glucose azide to an alkyne-functionalized folate precursor containing an albumin-binding entity via Cu(I)-catalyzed 1,3-dipolar cycloaddition. The radioconjugate was tested in vitro on FR-positive KB tumor cells and by biodistribution and positron emission tomography (PET) imaging studies using KB tumor-bearing mice.

Results

The radiosynthesis of the albumin-binding [¹⁸?F]fluorodeoxyglucose–folate ([¹⁸?F]3) resulted in a radiochemical yield of 1–2 % decay corrected (d.c.) and a radiochemical purity of ≥95 %. The specific activity of [¹⁸?F]3 ranged from 20 to 50 GBq/μmol. In vitro experiments revealed FR-specific binding of [¹⁸?F]3 to KB tumor cells. In vivo we found an increasing uptake of [¹⁸?F]3 into tumor xenografts over time reaching a value of ～?15 % injected dose (ID)/g at 4 h post-injection (p.i.). Uptake in the kidneys (～?13 % ID/g; 1 h p.i.) was approximately fourfold reduced compared to previously published ¹⁸?F-labeled folic acid derivatives. An excellent visualization of tumor xenografts with an unprecedentedly high tumor-to-kidney ratio (～?1) was obtained by PET imaging.

Conclusions

[¹⁸?F]3 showed a favorable accumulation in tumor xenografts compared to the same folate conjugate without albumin-binding properties. Moreover, the increased tumor-to-kidney ratios improved the PET imaging quality significantly, in spite of a somewhat higher background radioactivity which was a consequence of the slower blood clearance of [¹⁸?F]3.     

Estimation de la consommation pic d��oxyg��ne par la perception de l��effort chez des patients ob��ses et diab��tiques de type 2

Objectives

The main objectives of this study were: 1) to assess the validity of predicting peak oxygen uptake (.VO₂peak) from ratings of perceived exertion (RPE) during a sub-maximal graded exercise test (GXT), in obese patients with diabetes, and 2) to compare the accuracy of predictions obtained from RPE ?? 15 and RPE ?? 17. Materials and methods: Seventeen obese women with type 2 diabetes performed GXT to volitional exhaustion, in which oxygen uptake (.VO₂) and RPE were measured. Individual linear regressions between.VO₂ and RPE, that were collected during the first stages of GXT (RPE ?? 15 and RPE ?? 17), were extrapolated to RPE = 20 in order to predict.VO₂peak. Results: Actual (12.7 ± 3.6 ml.min^?1.kg^?1) and predicted.VO₂peak from RPE ?? 15 and RPE ?? 17 (13.1 ± 3.7 and 13.3 ± 3.8 ml.min^?1.kg^?1, respectively) were not significantly different. The actual.V O₂peak were significantly correlated to the predicted.VO₂peak from RPE ?? 15 and RPE ?? 17 (R = 0.89 and R = 0.92, respectively). The 95% limits of agreement analysis were ?0.4 ± 3.4 and ?0.6 ± 3.0 ml.min^?1.kg^?1 for the predictions from RPE ?? 15 and RPE ?? 17, respectively.

Conclusion

Results suggested that the RPE ?? 15 provide accurate.V O₂peak prediction in obese women with type 2 diabetes. However, the accurate of predictions was improved when the.VO₂peak was predicted from RPE ?? 17. Consequently, RPE may be used to predict.VO₂peak and to decrease the risk of cardio-vascular complications during GXT.