Left atrial deformation imaging with ultrasound based two-dimensional speckle-tracking predicts the rate of recurrence of paroxysmal and persistent atrial fibrillation after successful ablation procedures

Predict AF. Objective: Since predictors of recurrence of atrial fibrillation (AF) after ablation procedures are poorly defined, this prospective study was conducted to assess the value of left atrial (LA) deformation imaging with two‐dimensional speckle‐tracking (2D‐ST) to predict AF recurrences after successful ablation procedures. Methods and results: One hundred and three consecutive patients (age 58.1 ± 16.6 years, 72.8% male) with AF (76 paroxysmal, 27 persistent) and 30 matched controls underwent transthoracic echocardiography and 2D‐ST‐LA‐deformation analysis with assessment of LA‐radial and LA‐longitudinal strain (Sr, Sl), and velocities derived from the apical 4‐ and 2‐chamber views (4CV, 2CV). AF recurrence was assessed during 6 months of follow‐up. For determination of AF‐related LA changes, AF patients were compared to controls and patients with AF recurrences after ablation procedures (n = 30, 29.1%) were compared with patients who maintained sinus rhythm (n = 73, 70.9%). Atrial deformation capabilities were significantly reduced (P < 0.0005) in patients with AF (4CVSl 17.8 ± 13.5%; 4CVSr 22.3 ± 14.9%; 4CV‐velocities 2.53 ± 0.97 seconds) when compared with controls (4CVSl 31.3 ± 12.4%; 4CVSr 30.3 ± 9.1%; 4CV‐velocities 3.48 ± 1.01 cm/s). Independent predictors for AF recurrence after ablation procedures were 2CV‐LA‐global‐strain (Sr, P = 0.03; Sl, P = 0.003), 4CV‐LA‐gobal‐strain (Sr, P = 0.03; Sl, P = 0.02), and regional LA‐septal wall‐Sl (P = 0.008). LA‐global‐strain parameters were superior to regional LA function analysis for the prediction of AF recurrences, with cutoff values (cov), hazard ratios (HR), positive and negative predictive values (PPV, NPV) were: 4CVSl cov, 10.79% (HR 27.8, P < 0.0005; PPV 78.8%, NPV 93.9%), 4CVSr cov, ?16.65% (HR 24.8, P < 0.0005; PPV 69.4%, NPV 96.6%), 2CVSl cov, 12.31% (HR 22.7, P < 0.0005; PPV 75.8%, NPV 95.3%), and 2CVSr cov, ?14.9% (HR 12.9, P < 0.0005; PPV 64.3%, NPV 93.2%). Conclusion: Compared with controls, AF itself seems to decrease LA deformation capabilities. The assessment of global LA strain with 2D‐ST identifies patients with high risk for AF recurrence after ablation procedures. This imaging technique may help to improve therapeutic guiding for patients with AF. (J Cardiovasc Electrophysiol, Vol. 23 p. 247‐255, March 2012.)     

Do lower-extremity joint dynamics change when stair negotiation is initiated with a self-selected comfortable gait speed?

Previous research on the biomechanics of stair negotiation has ignored the effect of the approaching speed. We examined if initiating stair ascent with a comfortable self-selected speed can affect the lower-extremity joint moments and powers as compared to initiating stair ascent directly in front of the stairs. Healthy young adults ascended a custom-built staircase instrumented with force platforms. Kinematics and kinetics data were collected simultaneously for two conditions: starting from farther away and starting in front of the stairs and analyzed at the first and second ipsilateral steps. Results showed that for the first step, participants produced greater peak knee extensor moment, peak hip extensor and flexor moments and peak hip positive power while starting from farther away. Also, for both the conditions combined, participants generated lesser peak ankle plantiflexor, greater peak knee flexor moment, lesser peak ankle negative power and greater peak hip negative power while encountering the first step. These results identify the importance of the starting position in experiments dealing with biomechanics of stair negotiation. Further, these findings have important implications for studying stair ascent characteristics of other populations such as older adults.     

Risk and fate of residual interatrial shunting after transcatheter closure of patent foramen ovale: a long term follow up study

Background

Percutaneous transcatheter closure of patent foramen ovale (PFO) in cryptogenic stroke is an alternative to medical therapy. There is still debate on different outcome for each currently available device. The impact of residual shunting after PFO-clo- sure on recurrent arterial embolism is unknown.

Aims

(i) To evaluate the prevalence of residual interatrial shunting after device- closure of PFO, (ii) to identify risk factors predicting residual interatrial shunting after device implantation, and (iii) to investigate the outcome of patients after PFO-closure during long- term follow- up (FU).

Methods and results

Between 2000- 2005 PFO-closure was performed in 124 patients using four different devices: Amplatzer PFO-(n = 52), CardioSeal (n = 33), Helex (n = 23) and Premere (n = 16) occluder. All patients underwent serial contrast-enhanced transesophageal echocardiography (TEE) for 24 months after PFO- closure; clinical FU was at minimum 5 years up to 9.75 years (mean 6.67 ± 1.31 years). Overall-closure rate was 87% at 2 years, device-specific closure time curves differed significantly (p-logrank = 0.003). Independent risk factors for residual-shunting were implantation of a Helex occluder (hazard ratio [HR] 12.6, 95% confidence interval [CI] 2.6- 57.4, p = 0.002), PFO- canal- lengths (HR 1.2, 95%CI 1.1- 1.3, p = 0.004) and extend of atrial-septal-aneurysm (HR 1.1, 95%CI 0.9- 1.3; p = 0.05). 4 (3.2%) arterial embolic events occurred during a FU-period of 817.2 patient-years, actuarial annual thromboembolic-risk was 0.49%. All ischemic events were not related to residual PFO-shunting or device-related thrombus- formation.

Conclusion

Success rates of PFO- closure are mainly dependent on occluder-type, extend of concomitant atrial-septum-aneurysm and PFO-canal- length. Importantly, residual shunting after PFO-closure was not associated with recurrence of arterial embolism during long-term follow-up.

     

Astrocytes stimulate interleukin-17 and interferon-gamma production in vitro

Astrocytes play important roles in the complex and as yet not very well understood net of interactions among resident and infiltrating cells during central nervous system (CNS) inflammation. In such an intricate network, cytokines represent an essential means for intercellular communication, and astrocytes are able to affect their generation and/or release. Among various cytokines produced by infiltrating cells, interferon (IFN)-gamma and interleukin (IL)-17 are the focus of this research, because they are pivotal cytokines of helper T-cell type 1 (Th1) and helper T-cell type 17 (Th17), respectively. Importantly, both Th1 and Th17 cells, as well as their cytokines, have been shown to be of importance for the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of a prototypical CNS disease with inflammatory pathogenesis, multiple sclerosis. Therefore, the influence of astrocytes on the generation of IFN-gamma and IL-17 in concanavalin A- and myelin basic protein-stimulated lymph node cells of healthy rats and rats with developing EAE, respectively, was investigated in vitro. Astrocytes up-regulated IL-17 and IFN-gamma gene expression and protein synthesis in T cells, which coincided with astrocytes' ability to express IL-23 subunit p19 and common IL-12/IL-23 subunit p40 but not IL-12 subunit p35 in the co-cultivations. These results suggest one more way in which astrocytes could contribute to the complex interactions during CNS inflammation.     

An Automated Multidose Synthesis of the Potentiometric PET Probe 4-[<Superscript>18</Superscript>F]Fluorobenzyl-Triphenylphosphonium ([<Superscript>18</Superscript>F]FBnTP)

Purpose

The aim of this study was the automated synthesis of the mitochondrial membrane potential sensor 4-[¹⁸F]fluorobenzyl-triphenylphosphonium ([¹⁸F]FBnTP) on a commercially available synthesizer in activity yields (AY) that allow for imaging of multiple patients.

Procedures

A three-pot, four-step synthesis was implemented on the ELIXYS FLEX/CHEM radiosynthesizer (Sofie Biosciences) and optimized for radiochemical yield (RCY), radiochemical purity (RCP) as well as chemical purity during several production runs (n = 24). The compound was purified by solid-phase extraction (SPE) with a Sep-Pak Plus Accell CM cartridge, thereby avoiding HPLC purification.

Results

Under optimized conditions, AY of 1.4–2.2 GBq of [¹⁸F]FBnTP were obtained from 9.4 to 12.0 GBq [¹⁸F]fluoride in 90–92 min (RCY = 28.6 ± 5.1 % with n = 3). Molar activities ranged from 80 to 99 GBq/μmol at the end of synthesis. RCP of final formulations was >?99 % at the end of synthesis and >?95 % after 8 h. With starting activities of 23.2–33.0 GBq, RCY decreased to 16.1 ± 0.4 % (n = 3). The main cause of the decline in RCY when high amounts of [¹⁸F]fluoride are used is radiolytic decomposition of [¹⁸F]FBnTP during SPE purification.

Conclusions

In initial attempts, the probe was synthesized with RCY <?0.6 % when starting activities up to 44.6 GBq were used. Rapid radiolysis of the intermediate 4-[¹⁸F]fluorobenzaldehyde and the final product [¹⁸F]FBnTP during purification was identified as the main cause for low yields in high-activity runs. Radiolytic decomposition was hindered by the addition of radical scavengers during synthesis, purification, and formulation, thereby improving AY and RCP. The formulated probe in injectable form was synthesized without the use of HPLC and passed all applicable quality control tests.

     

A potent immunomodulatory compound, (S,R)-3-Phenyl-4,5-dihydro-5-isoxazole acetic acid, prevents spontaneous and accelerated forms of autoimmune diabetes in NOD mice and inhibits the immunoinflammatory diabetes induced by multiple low doses of streptozotocin in CBA/H mice

(S,R)-3-Phenyl-4,5-dihydro-5-isoxasole acetic acid (VGX-1027) is an isoxazole compound that exhibits various immunomodulatory properties. The capacity of VGX-1027 to prevent interleukin (IL)-1beta plus interferon-gamma-induced pancreatic islet death in vitro prompted us to evaluate its effects on the development of autoimmune diabetes in preclinical models of human type 1 diabetes mellitus (T1D). Administration of VGX-1027 to NOD mice with spontaneous or accelerated forms of diabetes induced either by injection of cyclophosphamide or by transfer of spleen cells from acutely diabetic syngeneic donors markedly reduced the cumulative incidence of diabetes and insulitis. In addition, VGX-1027 given either i.p. or p.o. to CBA/H mice made diabetic with multiple low doses of streptozotocin successfully counteracted the development of destructive insulitis and hyperglycemia. The animals receiving VGX-1027 exhibited reduced production of the proinflammatory mediators tumor necrosis factor-alpha, IL-1beta, macrophage migration inhibitory factor, and inducible nitric-oxide synthase-mediated nitric oxide generation in both pancreatic islets and peripheral compartments. These results indicate that VGX-1027 probably exerts its antidiabetogenic effects by limiting cytokine-mediated immunoinflammatory events, leading to inflammation and destruction of pancreatic islets. VGX-1027 seems worthy of being considered as a candidate drug in the development of new therapeutic strategies for the prevention and early treatment of T1D.     

Strain difference in susceptibility to experimental autoimmune encephalomyelitis between Albino Oxford and Dark Agouti rats correlates with disparity in production of IL-17, but not nitric oxide

Albino Oxford (AO) rats, unlike Dark Agouti (DA) rats are resistant to the induction of experimental autoimmune encephalomyelitis (EAE). The reason for the resistance could be some restraining mechanism preventing auto-aggressive cell activation at the level of draining lymph nodes (DLN) during the induction phase of the disease. Such a mechanism could be anti-proliferative action of nitric oxide (NO), which has already been shown of importance for the resistance of several rat strains to the induction of the disease. Importantly, number of AO DLN cells (DLNC) is markedly lower and with lower proliferative response to myelin basic protein (MBP) ex vivo in comparison to DA DLNC in the inductive phase of EAE, thus implying that in AO rats DLNC do not proliferate as extensively as in DA rats. We show that AO rats do not produce larger quantities of NO than DA rats after immunization. Further, DLNC of immunized AO rats have significantly lower mRNA expression and synthesis of interferon (IFN)-gamma and interleukin (IL)-17 compared to DLNC of DA rats. Collectively, these results suggest that there is a substantial difference between EAE-resistant AO rats and EAE-prone DA rats in the initiation of autoimmune response. This difference seems to be independent of anti-proliferative actions of NO, but correlates with impaired IL-17 production in AO rats.     

Microtubule release from the centrosome

Although microtubules (MTs) are generally thought to originate at the centrosome, a number of cell types have significant populations of MTs with no apparent centrosomal connection. The origin of these noncentrosomal MTs has been unclear. We applied kinetic analysis of MT formation in vivo to establish their mode of origin. Time-lapse fluorescence microscopy demonstrated that noncentrosomal MTs in cultured epithelial cells arise primarily by constitutive nucleation at, and release from, the centrosome. After release, MTs moved away from the centrosome and tended to depolymerize. Laser-marking experiments demonstrated that released MTs moved individually with their plus ends leading, suggesting that they were transported by minus end-directed motors. Released MTs were dynamic. The laser marking experiments demonstrated that plus ends of released MTs grew, paused, or shortened while the minus ends were stable or shortened. Microtubule release may serve two kinds of cellular function. Release and transport could generate the noncentrosomal MT arrays observed in epithelial cells, neurons, and other asymmetric, differentiated cells. Release would also contribute to polymer turnover by exposing MT minus ends, thereby providing additional sites for loss of subunits. The noncentrosomal population of MTs may reflect a steady-state of centrosomal nucleation, release, and dynamics.