Realignment of the ventricular septum using partial direct closure of the ventricular septal defect in Tetralogy of Fallot

Objective: The aim is to describe our technique of partial direct closure of the ventricular septal defect (VSD) in Tetralogy of Fallot (TOF), and assess its influence on the realignment and remodeling of the left ventricular outflow tract. Methods: Between 2004 and 2010, 32 non-consecutive patients with TOF underwent a direct or partial direct closure of VSD. Median age and weight were 5.2 months and 6.7kg, respectively. An approach through the right atrium was used in 30 patients and through the infundibulum in two patients. The conal septum was mobilized by transecting the hypertrophic trabeculae to facilitate the approximation of the VSD. The membranous part of the VSD was closed (in the later part of the series) with a small xenopericardial patch to avoid tension on the suture line traversing the area of risk to the bundle of His. Follow-up was complete, with a median duration of 46.9 (range 12-75.3) months. Results: The VSD could be closed successfully in all patients. A residual VSD was partly responsible for one early postoperative re-operation. There were no early or late deaths. At follow-up, all patients were in sinus rhythm. Three patients showed a small residual VSD. Thirty patients had none, one showed trivial, and one had mild aortic regurgitation. The left ventricular outflow showed a good realignment of the ventricular septum in all the patients. Conclusions: Partial direct closure of the VSD corrects the primary defect in TOF, that is, the malalignment of the septum. It results in a straight, wide open left ventricular outflow tract and brings better support to the aortic roo

Loss of the Coffin-Lowry syndrome-associated gene RSK2 alters ERK activity, synaptic function and axonal transport in Drosophila motoneurons

Plastic changes in synaptic properties are considered as fundamental for adaptive behaviors. Extracellular-signal-regulated kinase (ERK)-mediated signaling has been implicated in regulation of synaptic plasticity. Ribosomal S6 kinase 2 (RSK2) acts as a regulator and downstream effector of ERK. In the brain, RSK2 is predominantly expressed in regions required for learning and memory. Loss-of-function mutations in human RSK2 cause Coffin-Lowry syndrome, which is characterized by severe mental retardation and low IQ scores in affected males. Knockout of RSK2 in mice or the RSK ortholog in Drosophila results in a variety of learning and memory defects. However, overall brain structure in these animals is not affected, leaving open the question of the pathophysiological consequences. Using the fly neuromuscular system as a model for excitatory glutamatergic synapses, we show that removal of RSK function causes distinct defects in motoneurons and at the neuromuscular junction. Based on histochemical and electrophysiological analyses, we conclude that RSK is required for normal synaptic morphology and function. Furthermore, loss of RSK function interferes with ERK signaling at different levels. Elevated ERK activity was evident in the somata of motoneurons, whereas decreased ERK activity was observed in axons and the presynapse. In addition, we uncovered a novel function of RSK in anterograde axonal transport. Our results emphasize the importance of fine-tuning ERK activity in neuronal processes underlying higher brain functions. In this context, RSK acts as a modulator of ERK signaling

Realignment of the ventricular septum using partial direct closure of the ventricular septal defect in Tetralogy of Fallot

OBJECTIVE: The aim is to describe our technique of partial direct closure of the ventricular septal defect (VSD) in Tetralogy of Fallot (TOF), and assess its influence on the realignment and remodeling of the left ventricular outflow tract. METHODS: Between 2004 and 2010, 32 non-consecutive patients with TOF underwent a direct or partial direct closure of VSD. Median age and weight were 5.2 months and 6.7 kg, respectively. An approach through the right atrium was used in 30 patients and through the infundibulum in two patients. The conal septum was mobilized by transecting the hypertrophic trabeculae to facilitate the approximation of the VSD. The membranous part of the VSD was closed (in the later part of the series) with a small xenopericardial patch to avoid tension on the suture line traversing the area of risk to the bundle of His. Follow-up was complete, with a median duration of 46.9 (range 12-75.3) months. RESULTS: The VSD could be closed successfully in all patients. A residual VSD was partly responsible for one early postoperative re-operation. There were no early or late deaths. At follow-up, all patients were in sinus rhythm. Three patients showed a small residual VSD. Thirty patients had none, one showed trivial, and one had mild aortic regurgitation. The left ventricular outflow showed a good realignment of the ventricular septum in all the patients. CONCLUSIONS: Partial direct closure of the VSD corrects the primary defect in TOF, that is, the malalignment of the septum. It results in a straight, wide open left ventricular outflow tract and brings better support to the aortic root

A study of Schumpterian (radical) vs. Kirznerian (incremental) innovations in knowledge intensive industries

The peripheral airway innervation of the lower respiratory tract of mammals is not completely functionally characterized. Recently, we have shown in rats that precision-cut lung slices (PCLS) respond to electric field stimulation (EFS) and provide a useful model to study neural airway responses in distal airways. Since airway responses are known to exhibit considerable species differences, here we examined the neural responses of PCLS prepared from mice, rats, guinea pigs, sheep, marmosets and humans. Peripheral neurons were activated either by EFS or by capsaicin. Bronchoconstriction in response to identical EFS conditions varied between species in magnitude. Frequency response curves did reveal further species-dependent differences of nerve activation in PCLS. Atropine antagonized the EFS-induced bronchoconstriction in human, guinea pig, sheep, rat and marmoset PCLS, showing cholinergic responses. Capsaicin (10 µM) caused bronchoconstriction in human (4 from 7) and guinea pig lungs only, indicating excitatory non-adrenergic non-cholinergic responses (eNANC). However, this effect was notably smaller in human responder (30 ± 7.1%) than in guinea pig (79 ± 5.1%) PCLS. The transient receptor potential (TRP) channel blockers SKF96365 and ruthenium red antagonized airway contractions after exposure to EFS or capsaicin in guinea pigs. In conclusion, the different species show distinct patterns of nerve-mediated bronchoconstriction. In the most common experimental animals, i.e. in mice and rats, these responses differ considerably from those in humans. On the other hand, guinea pig and marmoset monkey mimic human responses well and may thus serve as clinically relevant models to study neural airway responses

Cholinergic responses in EFS-triggered airway contraction.

<p>The PCLS from either rats (n = 5) (<b>A</b>), sheep (n = 4) (<b>B</b>), marmosets (n = 5) (<b>C</b>) or human (n = 4) (<b>D</b>) were stimulated repeatedly at F = 50 Hz, B = 1 ms, A = 200 mA, TW = 2.5 s, TR = 60 s for 3.3 min, i.e. 4×EFS. As control, the first stimulation (1^st EFS) was always carried out without any cholinergic interference. In subsequent EFS separated by at least 15 min to the preceding stimulation, neostigmine and/or atropine were added to augment or inhibit cholinergic airway contraction. The response in each single PCLS before and after treatment is plotted and matched to each other by a line *, p<0.05 and **, p<0.01 for atropine <i>vs.</i> no atropine (paired t-test). <b>E.</b> To prove cholinergic responses in guinea pig (n = 6), PCLS were electrically stimulated once (F = 50 Hz, B = 1 ms, A = 200 mA, TW = 2.5 s) either after pre-incubation with atropine or without interference. The mean with SEM is indicated by the horizontal line and the error bars, respectively. ***, p<0.001 in unpaired t-test.</p

EFS-induced airway contractions are neurally mediated.

<p>Magnesium competes with calcium at the terminal synapse and prevents the release of neurotransmitters resulting in a neuromuscular block <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047344#pone.0047344-delCastillo1" target="_blank">[27]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047344#pone.0047344-Feldman1" target="_blank">[28]</a>. The muscarinic receptor agonist methacholine was used to confirm that Mg²⁺ did not affect airway smooth muscle directly. Con., contraction in marmoset PCLS, i.e. deviation below baseline airway area before EFS; EFS; electric field stimulation; IAA, initial airway area; Mg²⁺, magnesium; Rel., relaxation in marmoset, i.e. deviation above baseline airway area before EFS; w/o, without; data are shown as mean±SEM (species/number of PCLS/number of subjects: rat/5/5, guinea pig/4/4, sheep/4/4, marmoset/6/5, human/6 EFS, 5 methacholine/6 EFS, 5 methacholine); *, p<0.05; **, p<0.01 in Mann-Whitney test; ^††, p<0.01 in t-test; ^§§, p<0.01 in paired t-test.</p

Effect of capsaicin on airway tone in precision-cut lung slices (PCLS).

<p>Capsaicin was applied to PCLS from the indicated species at a concentration of 10 µM and airway contraction was monitored. Data are shown as mean – SEM (species/number of PCLS/number of subjects: mouse/6/6, rat/10/4, guinea pig/9/9, sheep/4/4, marmoset/3/3, human responder/6/4 and human non-responder/5/3.</p

Electrically activated airway contractions in mouse PCLS require higher electric fields and are neurally mediated.

<p>A. Frequency response curve: The frequency (F) was increased from 1 Hz to 200 Hz, while the other EFS settings were kept constant at B = 1 ms/2 ms, A = 200 mA≙40 V and TW = 2.5 s; data are shown as mean±SEM (1 ms: n = 5 PCLS from 5 mice; 2 ms: n = 6 PCLS from 6 mice). Frequency response curves were calculated by four parameter logistic regression and compared by the F-test; ***, p<0.001. B. Pulse duration was increased in EFS of murine PCLS from 0.5 ms to 4 ms, while the other parameters were kept constant at F = 50 Hz, A = 200 mA≙40 V and TW = 2.5 s; data are shown as mean±SEM (n = 6 PCLS from 6 mice). C. PCLS from mice were stimulated repeatedly at F = 50 Hz, B = 2 ms A = 200 mA and TW = 2.5 s each minute for 3.3 min. Upper panel: Control stimulations, each EFS train was conducted without pharmacological interference. Lower panel: 10 mM MgSO₄ was added 30 min prior to the second EFS train. Magnesium was able to block airway responses indicating specific neurally-induced bronchoconstriction. Data are shown as mean±SEM (n = 5 PCLS from 5 mice); ***, p<0.001 in the t-test on the minimal airway area before and after the application of magnesium.</p

Frequency dependence across species.

<p>Frequency response curves were performed on PCLS from the species indicated. Except for the frequency (F), which was increased from 0.4 Hz to 100 Hz after a single train at the distinct frequency each minute (TR = 60 s), EFS settings were kept constant at B = 1 ms, A = 200 mA and TW = 2.5 s. Sigmoidal curves, in which the top was constrained to 100% of the initial airway area [IAA], were plotted and the half-maximal response frequencies (EF₅₀±SEM) were determined: rat 16.5±0.3 Hz, guinea pig 7.0±0.5 Hz, sheep 0.4±0.1 Hz, marmoset 22.8±3.6 Hz, human 10.2±0.4 Hz. The four parameters in logistic regression were compared by the F-test and except for the guinea pig (p = 0.23), EF₅₀ values from all species (rats: p<0.001; sheep: p<0.01; marmoset (p<0.05) were significantly different from the human EF₅₀. Data are shown as mean±SEM (species/number of PCLS/number of subjects: rat/7/6, guinea pig/5/5, sheep/9/9, marmoset/4/3 and human/5/5).</p