A case of nontraumatic simultaneous bilateral Achilles tendon rupture.

ABSTRACT: Patients with corticosteroid-managed chronic obstructive pulmonary disease (COPD) are at increased risk of Achilles tendon rupture. This risk is further augmented in the setting of an acute COPD exacerbation in which antibiotics may be indicated, namely fluoroquinolones. This case concerns a 76-year-old man who experienced simultaneous nontraumatic bilateral Achilles tendon rupture during an acute COPD exacerbation. Treatment was conservative with analgesics, activity modification, and bilateral controlled ankle movement boots. Surgery was not advised because of his multiple medical comorbidities predisposing him to impaired wound healing and potential amputation. Included is a discussion on the pathophysiology, diagnosis, and treatment of Achilles tendon rupture. There is a need for greater awareness of the risk of Achilles tendon rupture from combined use of corticosteroids and fluoroquinolones. After this report, we hope to raise awareness of this complication and prevent patient suffering.

Homozygosity mapping identified loci and candidate genes responsible for freezing tolerance in Camelina sativa.

Homozygosity mapping is an effective tool for detecting genomic regions responsible for a given trait when the phenotype is controlled by a limited number of dominant or co-dominant loci. Freezing tolerance is a major attribute in agricultural crops such as camelina. Previous studies indicated that freezing tolerance differences between a tolerant (Joelle) and susceptible (CO46) variety of camelina were controlled by a small number of dominant or co-dominant genes. We performed whole genome homozygosity mapping to identify markers and candidate genes responsible for freezing tolerance difference between these two genotypes. A total of 28 F3 RILs were sequenced to ∼30× coverage, and parental lines were sequenced to >30-40× coverage with Pacific Biosciences high fidelity technology and 60× coverage using Illumina whole genome sequencing. Overall, about 126k homozygous single nucleotide polymorphism markers were identified that differentiate both parents. Moreover, 617 markers were also homozygous in F3 families fixed for freezing tolerance/susceptibility. All these markers mapped to two contigs forming a contiguous stretch of chromosome 11. The homozygosity mapping detected 9 homozygous blocks among the selected markers and 22 candidate genes with strong similarity to regions in or near the homozygous blocks. Two such genes were differentially expressed during cold acclimation in camelina. The largest block contained a cold-regulated plant thionin and a putative rotamase cyclophilin 2 gene previously associated with freezing resistance in arabidopsis (Arabidopsis thaliana). The second largest block contains several cysteine-rich RLK genes and a cold-regulated receptor serine/threonine kinase gene. We hypothesize that one or more of these genes may be primarily responsible for freezing tolerance differences in camelina varieties.

Boosting Bismuth(III) Complexation for Targeted α-Therapy (TAT) Applications with the Mesocyclic Chelating Agent AAZTA.

Targeted α therapy (TAT) is a promising tool in the therapy of cancer. The radionuclide 213 BiIII shows favourable physical properties for this application, but the fast and stable chelation of this metal ion remains challenging. Herein, we demonstrate that the mesocyclic chelator AAZTA quickly coordinates BiIII at room temperature, leading to a robust complex. A comprehensive study of the structural, thermodynamic and kinetic properties of [Bi(AAZTA)]- is reported, along with bifunctional [Bi(AAZTA-C4-COO- )]2- and the targeted agent [Bi(AAZTA-C4-TATE)]- , which incorporates the SSR agonist Tyr3 -octreotate. An unexpected increase in the stability and kinetic inertness of the metal chelate was observed for the bifunctional derivative and was maintained for the peptide conjugate. A cyclotron-produced 205/206 Bi mixture was used as a model of 213 Bi in labelling, stability, and biodistribution experiments, allowing the efficiency of [213 Bi(AAZTA-C4-TATE)]- to be estimated. High accumulation in AR42J tumours and reduced kidney uptake were observed with respect to the macrocyclic chelate [213 Bi(DOTA-TATE)]- .

Left atrial assist device to treat patients with heart failure with preserved ejection fraction: Initial in vitro study.

OBJECTIVES: Many patients with heart failure have preserved ejection fraction but also diastolic dysfunction, with no effective therapy. We are developing a new pump (left atrial assist device, LAAD) for implantation at the mitral position to pump blood from the left atrium to sufficiently fill the left ventricle. The purpose of the initial in vitro study was to demonstrate that the LAAD can reduce left atrial pressure (LAP) and increase cardiac output (CO) while maintaining arterial pulsatility and normal aortic valve function using a proof-of-concept device. METHODS: The LAAD concept was tested at 3 pump speeds on a pulsatile mock loop with a pneumatic pump that simulated the normal function of the native ventricle as well as 3 levels of diastolic heart failure (DHF 1, 2, and 3) by adjusting the diastolic drive pressure to limit diastolic filling of the ventricle. RESULTS: Without the LAAD, CO and aortic pressure (AoP) decreased dramatically from 3.8 L/min and 100 mm Hg at normal heart condition to 1.2 L/min and 35 mm Hg at DHF 3, respectively. With LAAD support, both CO and AoP recovered to normal heart values at 3200 rpm and surpassed normal heart values at 3800 rpm. Furthermore, with LAAD support, LAP recovered to almost that of the normal heart condition at 3800 rpm. CONCLUSIONS: These initial in vitro results support our hypothesis that use of the LAAD increases CO and AoP and decreases LAP under DHF conditions while maintaining arterial pulsatility and full function of the aortic valve.

Development and Evaluation of Motion-activated System for Improved Chest Drainage: Bench, In Vivo Results, and Pilot Clinical Use of Technology.

Objective. The aim of this study was to evaluate a motion-activated system (MAS) that applies motion-activated energy (vibration) to prevent chest tube clogging and maintain tube patency. We performed chest tube blood flow analysis in vitro, studied MAS effects on intraluminal clot deposition in vivo, and conducted a pilot clinical test. Background. Chest tube clogging is known to adversely contribute to postoperative cardiac surgery outcomes. Methods. The MAS was tested in vitro with a blood-filled chest tube model for device acceleration and performance. In vivo acute hemothorax studies (n = 5) were performed in healthy pigs (48.0 ± 2 kg) to evaluate the drainage in MAS versus control (no device) groups. Using a high-speed camera (FASTCAM Mini AX200, 100 mm Zeiss lens) in an additional animal study (n = 1), intraluminal whole-blood activation imaging of the chest tube (32 Fr) was made. The pilot clinical study (n = 12) consisted of up to a 30 minutes device tolerance test. Results. In vitro MAS testing suggested optimal device performance. The 2-hour in vivo evaluation showed a longer incremental drainage in the MAS group versus control. The total drainage in the MAS group was significantly higher than that in the control group (379 ± 144 mL vs 143 ± 40 mL; P = .0097), indicating tube patency. The high-speed camera images showed a characteristic intraluminal blood "swirling" pattern. Clinical data showed no discomfort with the MAS use (pleural = 4; mediastinal = 8). Conclusions. The MAS showed optimal performance at bench and better drainage profile in vivo. The clinical trial showed patients' tolerance to the MAS and device safety.

First In Vivo Experience With Biventricular Circulatory Assistance Using a Single Continuous Flow Pump.

Biventricular assist device (BVAD) implantation is the treatment of choice in patients with severe biventricular heart failure and cardiogenic shock. Our team has developed a miniaturized continuous flow, double-ended centrifugal pump intended for total artificial heart implant (CFTAH). The purpose of this initial in vivo study was to demonstrate that the scaled-down CFTAH (P-CFTAH) can be appropriate for BVAD support. The P-CFTAH was implanted in 4 acute lambs (average weight, 41.5 ± 2.8 kg) through a median sternotomy. The cannulation was performed through the left and right atria, and cannulae length adjustment was performed for atrial and ventricular cannulation. The BVAD system was tested at 3 pump speeds (3000, 4500, and 6000 rpm). The BVAD performed very well for both atrial and ventricular cannulation within the 3000-6000 rpm range. Stable hemodynamics were maintained after implantation of the P-CFTAH. The self-regulating performance of the system in vivo was demonstrated by the left (LAP) and right (RAP) pressure difference (LAP-RAP) falling predominantly within the range of -5 to 10 mm Hg with variation, in addition to in vitro assessment of left and right heart failure conditions. Left and right pump flows and total flow increased as the BVAD speed was increased. This initial in vivo testing of the BVAD system demonstrated satisfactory device performance and self-regulation for biventricular heart failure support over a wide range of conditions. The BVAD system keeps the atrial pressure difference within bounds and maintains acceptable cardiac output over a wide range of hemodynamic conditions.

Surgery of acute occlusion of the extracranial internal carotid artery - a meta-analysis.

Acute occlusion of the extracranial internal carotid artery (eICA) is associated with poor prognosis. Surgical desobliteration has not received adequate attention in recent years. We therefore conducted a literature review and meta-analysis of surgical studies published after 2000 that treated eICA occlusion surgically in an emergency setting. The search identified 10 relevant articles that included a total of 175 patients. The outcomes analysed included rates of recanalization (93 %), early neurological improvement (66 %), modified Rankin Scale 0-2 (62 %), mortality (5 %), early reocclusion (4 %), in-hospital stroke (4 %) and symptomatic intracerebral haemorrhage (4 %). In conclusion, acute surgical desobliteration of eICA occlusion leads to high rates of recanalization and a majority of patients experience early neurological improvement and achieve favourable outcome. Rates of mortality, early reocclusion, in-hospital stroke and sICH are acceptable in the view of unfavourable natural history.

Synthesis of Symmetrical Tetrameric Conjugates of the Radiolanthanide Chelator DOTPI for Application in Endoradiotherapy by Means of Click Chemistry.

Due to its 4 carbonic acid groups being available for bioconjugation, the cyclen tetraphosphinate chelator DOTPI, 1,4,7,10-tetraazacyclododecane-1,4,7, 10-tetrakis[methylene(2-carboxyethylphosphinic acid)], represents an ideal scaffold for synthesis of tetrameric bioconjugates for labeling with radiolanthanides, to be applied as endoradiotherapeuticals. We optimized a protocol for bio-orthogonal DOTPI conjugation via Cu(I)-catalyzed Huisgen-cycloaddition of terminal azides and alkynes (CuAAC), based on the building block DOTPI(azide)4. A detailed investigation of kinetic properties of Cu(II)-DOTPI complexes aimed at optimization of removal of DOTPI-bound copper by transchelation. Protonation and equilibrium properties of Ca(II)-, Zn(II), and Cu(II)-complexes of DOTPI and its tetra-cyclohexylamide DOTPI(Chx)4 (a model for DOTPI conjugates) as well as kinetic inertness (transchelation challenge in the presence of 20 to 40-fold excess of EDTA) were investigated by pH-potentiometry and spectrophotometry. Similar stability constants of CaII-, ZnII, and CuII-complexes of DOTPI (logK(CaL) = 8.65, logK(ZnL = 15.40, logK(CuL) = 20.30) and DOTPI(Chx)4 (logK(CaL) = 8.99, logK(ZnL) = 15.13, logK(CuL) = 20.42) were found. Transchelation of Cu(II)-complexes occurs via proton-assisted dissociation, whereafter released Cu(II) is scavenged by EDTA. The corresponding dissociation rates [kd = 25 × 10-7 and 5 × 10-7 s-1 for Cu(DOTPI) and Cu(DOTPI(Chx)4), respectively, at pH 4 and 298 K] indicate that conjugation increases the kinetic inertness by a factor of 5. However, demetallation is completed within 4.5 and 7.2 h at pH 2 and 25°C, respectively, indicating that Cu(II) removal after formation of CuAAC can be achieved in an uncomplicated manner by addition of excess H4EDTA. For proof-of-principle, tetrameric DOTPI conjugates of the prostate-specific membrane antigen (PSMA) targeting motif Lys-urea-Glu (KuE) were synthesized via CuAAC as well as dibenzo-azacyclooctine (DBCO) based, strain-promoted click chemistry (SPAAC), which were labeled with Lu-177 and subsequently evaluated in vitro and in SCID mice bearing subcutaneous LNCaP tumor (PSMA+ human prostate carcinoma) xenografts. High affinities (3.4 and 1.4 nM, respectively) and persistent tumor uptakes (approx. 3.5% 24 h after injection) confirm suitability of DOTPI-based tetramers for application in targeted radionuclide therapy.

Initial in vitro testing of a paediatric continuous-flow total artificial heart.

OBJECTIVES: Mechanical circulatory support has become standard therapy for adult patients with end-stage heart failure; however, in paediatric patients with congenital heart disease, the options for chronic mechanical circulatory support are limited to paracorporeal devices or off-label use of devices intended for implantation in adults. Congenital heart disease and cardiomyopathy often involve both the left and right ventricles; in such cases, heart transplantation, a biventricular assist device or a total artificial heart is needed to adequately sustain both pulmonary and systemic circulations. We aimed to evaluate the in vitro performance of the initial prototype of our paediatric continuous-flow total artificial heart. METHODS: The paediatric continuous-flow total artificial heart pump was downsized from the adult continuous-flow total artificial heart configuration by a scale factor of 0.70 (1/3 of total volume) to enable implantation in infants. System performance of this prototype was evaluated using the continuous-flow total artificial heart mock loop set to mimic paediatric circulation. We generated maps of pump performance and atrial pressure differences over a wide range of systemic vascular resistance/pulmonary vascular resistance and pump speeds. RESULTS: Performance data indicated left pump flow range of 0.4-4.7 l/min at 100 mmHg delta pressure. The left/right atrial pressure difference was maintained within ±5 mmHg with systemic vascular resistance/pulmonary vascular resistance ratios between 1.4 and 35, with/without pump speed modulation, verifying expected passive self-regulation of atrial pressure balance. CONCLUSIONS: The paediatric continuous-flow total artificial heart prototype met design requirements for self-regulation and performance; in vivo pump performance studies are ongoing.

Limitations to Chronic Right Ventricular Assist Device Support.

Failure of the right ventricle represents a significant clinical problem and may have different causes, with rates varying between 5% and 50% in patients supported by a left ventricular assist device (LVAD). However, treatment options and device development for right ventricular failure (RVF) have significantly lagged behind those for LVADs. Newer technologies designed or adapted for RV support are needed to provide adequate long-term circulatory support. In this review, we discuss (1) the significance of RVF and its physiologic implications, (2) device constraints affecting treatment options for RVF, and (3) implantable VADs potentially available for RV support.

The Contribution to Hemodynamics Even at Very Low Pump Speeds in the HVAD.

BACKGROUND: We recently reported using bench testing that the Thoratec HeartMate II at 6,000 rpm contributed to hemodynamics when the heart had not recovered well, making weaning assessment questionable. In this bench study, we characterized hemodynamics and pump flow of the HeartWare HVAD at 1,800 rpm, the lowest speed commonly used to assess clinical recovery. METHODS: The HVAD was operated in a mock loop at 1,800, 2,400, and 3,000 rpm. We acquired pressure-flow curves in each steady state. In pulsatile mode with the pneumatic ventricle (heart simulator) activated, pump flow, total flow, and aortic pressure (AoP) data were obtained under conditions simulating normal heart function or heart failure. RESULTS: A large regurgitant flow during diastole was confirmed during normal heart function at 1,800 rpm support; however, the net flow was zero, and there was no difference in mean AoP between 1,800 rpm support and no HVAD support. In contrast, in the heart failure condition, HVAD flow at 1,800 rpm significantly contributed to mean AoP and total flow, because there was less regurgitant flow. CONCLUSIONS: Similar to the results for the HeartMate II at 6,000 rpm, we found that the net pump flow generated by the HeartWare HVAD at 1,800 rpm depends on the degree of residual left ventricular (LV) function. In the setting of improved LV function, at 1,800 rpm we noted a large regurgitant flow. Although this "marker" can serve as a useful indicator for recovery, assessing recovery at this speed is flawed unless measures are taken to prevent regurgitant flow.

In vitro hemodynamic characterization of HeartMate II at 6000 rpm: Implications for weaning and recovery.

OBJECTIVES: Pump-off testing to assess left ventricular recovery is not an option for continuous-flow left ventricular assist devices unless measures are taken to prevent pump regurgitation. The purpose of this bench study was to characterize the hemodynamics and pump flow of the HeartMate II (Thoratec Corp, Pleasanton, Calif) left ventricular assist device at 6000 rpm, the speed commonly used clinically to determine left ventricular recovery. METHODS: The HeartMate II device was operated in a mock loop at 3 speeds (6000, 8000, and 10,000 rpm). We acquired pressure-flow curves in each steady state. In pulsatile mode with the pneumatic ventricle (heart simulator) activated, pump flow, total flow, and aortic pressure data were obtained under conditions simulating normal heart function or heart failure. RESULTS: A large regurgitant flow during diastole was confirmed in normal heart function at 6000 rpm support; however, the net flow was zero, and there were no differences in the mean aortic pressure between 6000 rpm support and no left ventricular assist device support. In contrast, in the heart failure condition, left ventricular assist device flow at 6000 rpm significantly contributed to the mean aortic pressure and total flow because there was less regurgitant flow. CONCLUSIONS: The net pump flow generated by the HeartMate II device at 6000 rpm depends on the degree of residual left ventricular function. In the setting of improved left ventricular function, at 6000 rpm, we noted a large regurgitant flow that reloaded the left ventricle. Although this "marker" can serve as a useful indicator for left ventricular recovery, assessing left ventricular recovery at this speed is flawed unless measures are taken to prevent regurgitant flow.

First report of 90-day support of 2 calves with a continuous-flow total artificial heart.

OBJECTIVE: The Cleveland Clinic continuous-flow total artificial heart (CFTAH) is a compact, single-piece, valveless, pulsatile pump providing self-regulated hemodynamic output to left/right circulation. We evaluated chronic in vivo pump performance, physiologic and hemodynamic parameters, and biocompatibility of the CFTAH in a well-established calf model. METHODS: CFTAH pumps have been implanted in 17 calves total. Hemodynamic parameters, pump performance, and device-related adverse events were evaluated during studies and at necropsy. RESULTS: In vivo experiments demonstrated good hemodynamic performance (pump flow, 7.3 ± 0.7 L/min; left atrial pressure, 16 ± 3 mm Hg; right atrial pressure, 17 ± 3 mm Hg; right atrial pressure-left atrial pressure difference, 1 ± 2 mm Hg; mean arterial pressure, 103 ± 7 mm Hg; arterial pulse pressure, 30 ± 11 mm Hg; and pulmonary arterial pressure, 34 ± 5 mm Hg). The CFTAH has operated within design specifications and never failed. With ever-improving pump design, the implants have shown no chronic hemolysis. Three animals with recent CFTAH implantation recovered well, with no postoperative anticoagulation, during planned in vivo durations of 30, 90, and 90 days (last 2 were intended to be 90-day studies). All these longest-surviving cases showed good biocompatibility, with no thromboembolism in organs. CONCLUSIONS: The current CFTAH has demonstrated reliable self-regulation of hemodynamic output and acceptable biocompatibility without anticoagulation throughout 90 days of chronic implantation in calves. Meeting these milestones is in accord with our strategy to achieve transfer of this unique technology to human surgical practice, thus filling the urgent need for cardiac replacement devices as destination therapy.

Switchgrass (Panicum virgatum L) flag leaf transcriptomes reveal molecular signatures of leaf development, senescence, and mineral dynamics.

Switchgrass flag leaves can be expected to be a source of carbon to the plant, and its senescence is likely to impact the remobilization of nutrients from the shoots to the rhizomes. However, many genes have not been assigned a function in specific stages of leaf development. Here, we characterized gene expression in flag leaves over their development. By merging changes in leaf chlorophyll and the expression of genes for chlorophyll biosynthesis and degradation, a four-phase molecular roadmap for switchgrass flag leaf ontogeny was developed. Genes associated with early leaf development were up-regulated in phase 1. Phase 2 leaves had increased expression of genes for chlorophyll biosynthesis and those needed for full leaf function. Phase 3 coincided with the most active phase for leaf C and N assimilation. Phase 4 was associated with the onset of senescence, as observed by declining leaf chlorophyll content, a significant up-regulation in transcripts coding for enzymes involved with chlorophyll degradation, and in a large number of senescence-associated genes. Of considerable interest were switchgrass NAC transcription factors with significantly higher expression in senescing flag leaves. Two of these transcription factors were closely related to a wheat NAC gene that impacts mineral remobilization. The third switchgrass NAC factor was orthologous to an Arabidopsis gene with a known role in leaf senescence. Other genes coding for nitrogen and mineral utilization, including ureide, ammonium, nitrate, and molybdenum transporters, shared expression profiles that were significantly co-regulated with the expression profiles of the three NAC transcription factors. These data provide a good starting point to link shoot senescence to the onset of dormancy in field-grown switchgrass.

Preload sensitivity in cardiac assist devices.

With implantable cardiac assist devices increasingly proving their effectiveness as therapeutic options for end-stage heart failure, it is important for clinicians to understand the unique physiology of device-assisted circulation. Preload sensitivity as it relates to cardiac assist devices is derived from the Frank-Starling relationship between human ventricular filling pressures and ventricular stroke volume. In this review, we stratify the preload sensitivity of 17 implantable cardiac assist devices relative to the native heart and discuss the effect of preload sensitivity on left ventricular volume unloading, levels of cardiac support, and the future development of continuous-flow total artificial heart technology.

Implantable continuous-flow right ventricular assist device: lessons learned in the development of a cleveland clinic device.

Although the need for right ventricular assist device (RVAD) support for right ventricular failure after the implantation of a continuous-flow left ventricular assist device has decreased, right ventricular failure still occurs in as many as 44% of patients after continuous-flow left ventricular assist device insertion. Cleveland Clinic's DexAide continuous-flow RVAD was implanted in 34 calves during the course of its development. This review discusses lessons learned in the design and development of an implantable continuous-flow RVAD that are drawn from the results of these in vivo studies, our clinical experience with RVAD support, and a review of previously published reports on clinical RVAD use.

Cleveland clinic CorAide blood pump circulatory support without anticoagulation.

The Cleveland Clinic CorAide left ventricular assist system consists of a permanently implantable centrifugal pump in which the rotating assembly is completely suspended and noncontacting. A series of chronic animal in vivo studies were conducted to evaluate the biologic effects of CorAide circulatory support without the use of anticoagulation therapy. The CorAide pump was implanted in six calves (five calves for 21 to 32 days and one calf for 95 days). The first five calves received intravenous heparin during the early postoperative periods (2-7 days). Heparin administration was then discontinued and no other anticoagulant drugs were used for the duration of the experiments. The last calf did not receive any anticoagulant except for a bolus dose of heparin (200 U/kg) during surgery. Hemodynamics were stable in all six calves, with a mean pump flow of 5.6+/-1.2 L/min and mean arterial pressure of 100+/-4 mm Hg. The blood pump surfaces were clean of thrombus in all six calves. Significant findings at autopsy were limited to one case of renal infarction. There was no incidence of mechanical failure, bleeding, or device infection. The CorAide pump can be safely run with minimal or no anticoagulant therapy.