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The temperature and enthalpy of melting of organic alloys from the binary system 2-amino-2-methyl-1,3-propanediol (AMPD) and neopentylglycol (NPG) were measured by means of differential scanning calorimetry (DSC) within the entire composition range. The analytical description of the Gibbs energies of pure AMPD and pure NPG was derived utilizing the data on temperature and enthalpy of transformations, and temperature dependencies of the heat capacity available in the literature. The phase diagram for the binary AMPD–NPG system was assessed via the CALPHAD approach using Thermo-Calc by simultaneously optimizing the thermodynamic and phase equilibrium data available in the literature and measured in the present work. An excellent agreement between the experimental and calculated data for the phase diagram as well as for the enthalpy of melting of the organic alloys was achieved. Experiments and calculations show that the binary AMPD–NPG system exhibits an eutectic reaction with the eutectic point at 378.3 K and 42.2 mol% NPG. The enthalpy of formation of the liquid, BCC and FCC phases derived from the optimisation proves an attractive interaction between dissimilar molecules in these phases. Unidirectional solidification of the eutectic alloy was performed in order to check the nature of the eutectic growth: We find that both solid phases grow with a non-facetted solid/liquid interface, but growth of a regular lamellar eutectic structure could not be observed.

The temperature and enthalpy of transformations of organic alloys from the binary system succinonitrile-( d )camphor were measured by means of differential scanning calorimetry (DSC) within the entire composition range. The analytical description of the Gibbs energies of pure succinonitrile (SCN) and pure ( d )camphor (DC) were derived utilizing the data on temperature and enthalpy of transformations, and temperature dependencies of heat capacity available in the literature. The phase diagram for the binary SCN-DC system was assessed via the CALPHAD approach using Thermo-Calc by simultaneously optimizing the thermodynamic and phase equilibrium data available in the literature and measured in the present work. A good agreement between the experimental and calculated data for the phase diagram as well as for the thermochemical properties was achieved. Experiments and calculations show that the binary system SCN-DC has an eutectic reaction with the eutectic point at 311.5 K and 13.9 mol% DC. The enthalpy of mixing derived in the optimisation proves weak attractive interaction between dissimilar molecules. Unidirectional solidification of the eutectic alloy was performed in order to verify the nature of the eutectic: we find that eutectic growth occurs with both solid phases being nonfacetted and with a rod-like eutectic structure consisting of 23 vol% (DC) and 77 vol% (SCN). Due to the optical activity of DC its distribution in the solid sample is well detectible in polarised light.

Transparent organic alloys showing a plastic crystal phase were investigated experimentally using differential scanning calorimetry and directional solidification with respect to find a suitable model system for regular ternary eutectic growth. The temperature, enthalpy and entropy of phase transitions have been determined for a number of pure substances. A distinction of substances with and without plastic crystal phases was made from their entropy of melting. Binary phase diagrams were determined for selected plastic crystal alloys with the aim to identify eutectic reactions. Examples for lamellar and rod-like eutectic solidification microstructures in binary systems are given. The system ( d )Camphor–Neopentylglycol–Succinonitrile is identified as a system that exhibits, among others, univariant and a nonvariant eutectic reaction. The ternary eutectic alloy close to the nonvariant eutectic composition solidifies with a partially faceted solid–liquid interface. However, by adding a small amount of Amino-Methyl-Propanediol (AMPD), the temperature of the nonvariant eutectic reaction and of the solid state transformation from plastic to crystalline state are shifted such, that regular eutectic growth with three distinct nonfaceted phases is observed in univariant eutectic reaction for the first time. The ternary phase diagram and examples for eutectic microstructures in the ternary and the quaternary eutectic alloy are given.

Coupled two-phase planar univariant eutectic growth occurs in Al–Cu–Ag alloys for different compositions and over a range of solidification velocities along the univariant eutectic reaction L → α(Al) + θ(Al2Cu). The classical relationship λ2v=constant is obeyed. Two limits of stability are present: morphological stability and stability of the coupling.

Sharp waves (SPWs) occur in the hippocampal EEG during behaviours such as alert immobility and slow-wave sleep. Despite their widespread occurrence across brain regions and mammalian species, the functional importance of SPWs remains unknown. Experiments in the present study indicate that long-term potentiation (LTP) is significantly impaired in slices, prepared from the temporal aspect of rat hippocampus, that spontaneously generate SPW activity. This was probably not due to anatomical and/or biochemical abnormalities in temporal slices because stable LTP was uncovered in field CA1 when SPWs were eliminated by severing the projection from CA3. The same procedure did not alter LTP in slices lacking SPWs. Robust and stable LTP was obtained in the presence of SPWs in slices treated with an adenosine A1 receptor antagonist, a finding that links the present results to mechanisms related to the LTP reversal effect. In accord with this, single stimulation pulses delivered intermittently in a manner similar to the SPW pattern interfered with LTP to a similar degree as spontaneous SPWs. Taken together, these results suggest the possibility that SPWs in the hippocampus constitute a neural mechanism for forgetting.

The onset and evolution of cellular patterns at the solid-liquid interface were investigated in directional solidification. A bulk sample of the diluted transparent alloy succinonitrile-acetone was used and the experiments were carried out under diffusive conditions onboard a Space Shuttle mission. The experimental parameters and material properties were selected to cause a supercritical planar-to-cellular transition to small-amplitude cells. Distributions of cell spacings and cell neighbors were determined from CCD images as a function of time. In the steady-state regime, a hexagonal arrangement on the interface with approximately 50 pct defects was found. The average cell spacing of 210 µm was compared to different models, of which the Lu/Hunt model concurred best. A minimal-spanning-tree analysis was carried out to examine the disorder of the cellular patterns as a function of time. The resulting order parameters were compared to those of reference patterns generated from Monte-Carlo simulations. In these simulations cellular organization is often modeled by planar lattices disturbed with Gaussian noise. We have extended this model by the constraint of a minimum distance between the lattice points in analogue to the experimentally found distinct minimum spacings. With this new inhibition model, enhanced quantitative agreement with the experimental cellular patterns was found.

The development of fetal ocular gene transfer may be useful as a therapeutic tool for the prevention of retinal genetic disorders with congenital or early clinical manifestations. In this study we explored the neural progenitor transduction patterns of adeno-associated virus (AAV) vectors following delivery to the developing retina. Recombinant vectors with the same genome carrying the enhanced green fluorescent protein (EGFP) transgene packaged in capsids of differing serotypes (serotypes 1, 2, and 5, termed AAV2/1, AAV2/2, and AAV2/5, respectively) were created. Delivery of the AAV vectors during early retinal development resulted in efficient and stable transduction of retinal progenitors. Vector surface proteins and the developmental status of the retina profoundly affected viral tropism and transgene distribution. The procedure is not detrimental to retinal development and function and therefore provides a safe delivery vehicle for potential therapeutic applications and a means of assessing the mechanisms of retina development and disease.

Objectives The main objective of this study was to assess if the benefits of biventricular (BiV) pacing observed during the crossover phase were sustained over 12 months. Background MUltisite STimulation In Cardiomyopathies (MUSTIC) is a randomized controlled study intended to evaluate the effects of BiV pacing in patients with New York Heart Association (NYHA) class III heart failure and intraventricular conduction delay. Methods Of 131 patients included, 42/67 in sinus rhythm (SR) and 33/64 in atrial fibrillation (AF) were followed up longitudinally at 9 and 12 months by 6-min walked distance, peak oxygen uptake (peak VO2), quality of life by the Minnesota score, NYHA class, echocardiography, and left ventricular ejection fraction by radionuclide technique. Results At 12 months, all SR and 88% of AF patients were programmed to BiV pacing. Compared with baseline, the 6-min walked distance increased by 20% (SR) (p = 0.0001) and 17% (AF) (p = 0.004); the peak VO2by 11% (SR) and 9% (AF); quality of life improved by 36% (SR) (p = 0.0001) and 32% (AF) (p = 0.002); NYHA class improved by 25% (SR) (p = 0.0001) and 27% (AF) (p = 0.0001). The ejection fraction improved by 5% (SR) and 4% (AF). Mitral regurgitation decreased by 45% (SR) and 50% (AF). Conclusions The clinical benefits of BiV pacing appeared to be significantly maintained over a 12-month follow-up period.

The partial enthalpies of mixing of the components of liquid ternary Ag–Al–Cu ( T =1252±5 K) and Ag–Cu–Zn ( T =1068–1113 K) alloys have been determined using a high-temperature isoperibolic calorimeter. Measurements were performed starting from both pure Al and Zn and from binary liquid Ag–Cu alloys along sections with constant Ag:Cu ratios 1:3, 1:1, 3:1 (Ag–Al–Cu system) and 2:3, 3:2 (Ag–Cu–Zn system). The integral enthalpies of mixing of these ternary alloys are calculated from the partial enthalpies of mixing using different methods. The composition dependences of the partial and integral enthalpies were simultaneously analytically described according to a Redlich–Kister–Mugianu equation using a least-squares fit by Gauss–Newton method. In case of Ag–Al–Cu alloys square- and higher order terms in excess ternary part are needed to adequately describe the surfaces of enthalpies of mixing. Enthalpy data for the constituent binaries were adopted from latest calorimetric measurements and thermodynamic assessments of the phase diagrams. The evaluated integral enthalpy of mixing demonstrates that the minima for the Ag–Al–Cu (−17.1 kJ mol −1 ) and Ag–Cu–Zn (−10.0 kJ mol −1 ) correspond to binary compositions Al 0.40 Cu 0.60 and Cu 0.50 Zn 0.50 , respectively.

Background Visual prognosis after an open globe injury is typically worse than after a closed globe injury due, in part, to the immune response that ensues following open globe trauma. There is a need for an animal model of open globe injury in order to investigate mechanisms of vision loss and test potential therapeutics. Methods The left eyes of DBA/2 J mice were exposed to an overpressure airwave blast. This strain lacks a fully functional ocular immune privilege, so even though the blast wave does not rupture the globe, immune infiltrate and neuroinflammation occurs as it would in an open globe injury. For the first month after blast wave exposure, the gross pathology, intraocular pressure, visual function, and retinal integrity of the blast-exposed eyes were monitored. Eyes were collected at three, seven, and 28 days to study the histology of the cornea, retina, and optic nerve, and perform immunohistochemical labeling with markers of cell death, oxidative stress, and inflammation. Results The overpressure airwave caused anterior injuries including corneal edema, neovascularization, and hyphema. Immune infiltrate was detected throughout the eyes after blast wave exposure. Posterior injuries included occasional retinal detachments and epiretinal membranes, large retinal pigment epithelium vacuoles, regional photoreceptor cell death, and glial reactivity. Optic nerve degeneration was evident at 28 days post-blast wave exposure. The electroretinogram (ERG) showed an early deficit in the a wave that recovered over time. Both visual acuity and the ERG b wave showed an early decrease, then a transient improvement that was followed by further decline at 28 days post-blast wave exposure. Conclusions Ocular blast injury in the DBA/2 J mouse recapitulates damage that is characteristic of open globe injuries with the advantage of a physically intact globe that prevents complications from infection. The injury was more severe in DBA/2 J mice than in C57Bl/6 J mice, which have an intact ocular immune privilege. Early injury to the outer retina mostly recovers over time. In contrast, inner retinal dysfunction seems to drive later vision loss. Electronic supplementary material The online version of this article (doi:10.1186/s12974-014-0192-5) contains supplementary material, which is available to authorized users.

Purpose Noncoding microRNAs (miRNAs) have been implicated in the pathogenesis of glaucoma. We aimed to identify common variants in miRNA coding genes (MIR) associated with primary open-angle glaucoma (POAG). Methods Using the NEIGHBORHOOD data set (3853 cases/33,480 controls with European ancestry), we first assessed the relation between 85 variants in 76 MIR genes and overall POAG. Subtype-specific analyses were performed in high-tension glaucoma (HTG) and normal-tension glaucoma subsets. Second, we examined the expression of miR-182, which was associated with POAG, in postmortem human ocular tissues (ciliary body, cornea, retina, and trabecular meshwork [TM]), using miRNA sequencing (miRNA-Seq) and droplet digital PCR (ddPCR). Third, miR-182 expression was also examined in human aqueous humor (AH) by using miRNA-Seq. Fourth, exosomes secreted from primary human TM cells were examined for miR-182 expression by using miRNA-Seq. Fifth, using ddPCR we compared miR-182 expression in AH between five HTG cases and five controls. Results Only rs76481776 in MIR182 gene was associated with POAG after adjustment for multiple comparisons (odds ratio [OR] = 1.23, 95% confidence interval [CI]: 1.11–1.42, P = 0.0002). Subtype analysis indicated that the association was primarily in the HTG subset (OR = 1.26, 95% CI: 1.08–1.47, P = 0.004). The risk allele T has been associated with elevated miR-182 expression in vitro. Data from ddPCR and miRNA-Seq confirmed miR-182 expression in all examined ocular tissues and TM-derived exosomes. Interestingly, miR-182 expression in AH was 2-fold higher in HTG patients than nonglaucoma controls (P = 0.03) without controlling for medication treatment. Conclusions Our integrative study is the first to associate rs76481776 with POAG via elevated miR-182 expression.

Interface pattern evolution during directional solidification has been investigated in the microgravity environment of a space shuttle mission providing diffusive conditions for cellular pattern evolution. A model transparent alloy of succinonitrile–acetone was used in these studies for in situ observation of the dynamic process of pattern evolution. In addition to the microgravity environment, alloy composition and growth condition experiment parameters were selected in such a way that the planar-to-cellular transition was supercritical, and pattern evolution was examined close to the transition velocity that gave rise to very small amplitude cells. Since the supercritical transition shows continuous increase in amplitude with velocity, non-linear effects in wavelength selection are small. This means that linear theory could be used to interpret the results. The evolution of primary spacing and the order of cellular arrangements were characterized as a function of time for three different velocities. No sharp wavelength selection in primary spacing was observed in the experimental results, and the distribution of steady-state spacing was characterized for each velocity. Wavelength selection for supercritical transition near the transition point can also be explained by stability analysis.

OBJECTIVE—To determine the importance of rhythm regulation or rate control in patients with permanent atrial fibrillation (AF) and normal left ventricular function. PATIENTS AND INTERVENTIONS—Thirty six patients with a mixed fast and slow ventricular response rate to their AF were randomised to either His bundle ablation (HBA) and VVIR pacemaker (HBA group) or VVI pacemaker and atrioventricular modifying drugs (Med group). Outcomes assessed at one, three, six, and 12 months included exercise duration and quality of life. RESULTS—Exercise duration significantly improved from baseline in both groups. There was no difference in outcome between the groups (Med +40% v HBA +20%, p = NS). The heart rate profile on exercise was similarly slowed in both groups compared to baseline. Quality of life significantly improved in both treatment arms for the modified Karolinska questionnaire (KQ) (Med +50% v HBA +50%, p = NS) and the Nottingham health profile (NHP) (Med +40% v HBA +20%, p = NS). However, for the individual symptom scores of each questionnaire more were improved in the Med group (KQ-Med 6 improved v HBA 4, NHP-Med 3 v HBA 1). Left ventricular function was equally preserved by both treatments during follow up. CONCLUSION—In these patients control of ventricular response rate with either HBA + VVIR pacemaker or atrioventricular modifying drugs + VVI pacemaker will lead to a significant improvement in exercise duration and quality of life. Rhythm regulation by HBA did not confer additional benefit, suggesting rate control alone is necessary for the successful symptomatic treatment of these patients in permanent AF. Keywords: ablation; atrial fibrillation; pacemaker; atrioventricular modifying drugs

OBJECTIVE—To evaluate the incremental antifibrillatory effect of multisite atrial pacing compared with right atrial pacing in patients with drug refractory paroxysmal atrial fibrillation paced for arrhythmia prevention alone. METHODS—In 20 of these patients (mean (SD) age 64 (8) years; 14 female, six male), a single blinded randomised crossover study was performed to investigate the incremental benefit of one month of multisite atrial pacing compared with one month of right atrial pacing. Outcomes included the number of episodes of paroxysmal atrial fibrillation, their total duration obtained from pacemaker Holter memory, and quality of life using a cardiac specific questionnaire (the modified Karolinska questionnaire). RESULTS—Comparing right atrial with multisite atrial pacing, there was no significant change in either the number of paroxysmal atrial fibrillation episodes (mean (SD): right atrial pacing 77 (98) episodes v multisite pacing 52 (78) episodes, NS) or their total duration (right atrial, 4.8 (5.4) days v multisite, 6.3 (9.8) days, NS). Quality of life scores compared with baseline status were equally improved by either pacing strategy (mean percentage improvement: right atrial, 38%, p = 0.003; multisite, 44%, p = 0.003). There was no significant difference in life scores comparing the two pacing modes. CONCLUSIONS—Multisite atrial pacing has no incremental antiarrhythmic effect compared with right atrial pacing in patients paced for drug refractory paroxysmal atrial fibrillation. Quality of life is equally improved with either pacing strategy, with no differences between them. Keywords: multisite atrial pacing; atrial fibrillation; pacing

The lectin peanut agglutinin (PNA) and antibodies to short (S)- and medium to long wavelength (M/L)-sensitive cones were utilized in order to define the relative distributions of the two spectral types of cone across the domestic cat’s retina. These values, in turn, were compared to those from retinas that had been experimentally detached from the retinal pigment epithelium. The pattern of cone distribution in the normal cat’s retina is established by the preponderance of M-cones that constitute between 80% and 90% of all cones. Their peak density of over 26,000 cells/mm 2 resides at the area centralis. Though M-cone density decreases smoothly to the ora serrata where they have densities as low as 2,200 cells/mm 2 , the density decrease along the nasotemporal axis is slower,creating a horizontal region of higher cone density. S-cones constitute between 10% and 20% of all cones, the number being quite variable even between individual animals of similar age. The highest S-cone densities are found in three distinct locations: at the superior far periphery near the ora serrata, immediately at the area centralis itself, and in a broad zone comprising the central and lower half of the inferior hemiretina. S-cones in the cat retina do not form a regular geometrical array at any eccentricity. As for the detached cat retina, the density of labeled S-cone outer segments (OS) decreases rapidly as early as 1 day postdetachment and continues decreasing to day 28 when the density of cones labeling with anti-S opsin has dropped to less than 10% of normal. This response points to a profound difference between rods and cones; essentially all rods, including those without OS, continue to express their opsin even in long-term detachments. The implications of these results for visual recovery after retinal reattachment are discussed. J. Comp. Neurol. 430:343‐356, 2001. © 2001 Wiley-Liss, Inc. Indexing terms: photoreceptors; blue cones; lectins; antibodies; retinal detachment

Vectors derived from adeno-associated virus (AAV) are promising for human gene therapy, including treatment for retinal blindness. One major limitation of AAVs as vectors is that AAV cargo capacity has been considered to be restricted to 4.7 kb. Here we demonstrate that vectors with an AAV5 capsid (i.e., rAAV2/5) incorporated up to 8.9 kb of genome more efficiently than 6 other serotypes tested, independent of the efficiency of the rAAV2/5 production process. Efficient packaging of the large murine Abca4 and human MYO7A and CEP290 genes, which are mutated in common blinding diseases, was obtained, suggesting that this packaging efficiency is independent of the specific sequence packaged. Expression of proteins of the appropriate size and function was observed following transduction with rAAV2/5 carrying large genes. Intraocular administration of rAAV2/5 encoding ABCA4 resulted in protein localization to rod outer segments and significant and stable morphological and functional improvement of the retina in Abca4(-/-) mice. This use of rAAV2/5 may be a promising therapeutic strategy for recessive Stargardt disease, the most common form of inherited macular degeneration. The possibility of packaging large genes in AAV greatly expands the therapeutic potential of this vector system.

The authors report on the infusion of INTASC principles into a model of teacher preparation that included a cohort of 21 students who participated in a professional development school over the course of their undergraduate program in elementary education. Specifically, the study examined how INTASC-based experiences were being integrated into the teacher education program; how the preservice teachers benefited from participating in a four year, INTASC-based PDS; and the administrators' perspectives regarding support of the PDS and its professional development opportunities for classroom teachers and university faculty.

Background —Atrial fibrillation (AF) is a common problem after CABG. Prevention with prophylactic drug therapy has had limited success, therefore alternative approaches are required. This study investigated the role of biatrial pacing compared with no pacing on AF incidence after isolated first-time CABG. Methods and Results —During surgery, temporary pacing leads were placed in the lateral wall of the right atrium and at the roof of the left atrium in Bachmann’s bundle to allow bipolar pacing and sensing at each site. After surgery, all patients were connected to an external pacemaker (Chorum ELA) that also acted as a Holter monitor. Patients were consecutively randomized to either 4 days of biatrial pacing at a base rate of 80 bpm or to no pacing (control group, base rate 30 bpm). End points included an episode of AF lasting >1 hour on pacemaker Holter, clinically detected AF, intensive care unit (ICU) and hospital stay, and postoperative complications. One hundred thirty patients were randomized. Biatrial pacing significantly reduced both monitored (13.8% versus 38.5%, P =0.001) and clinical (10.8% versus 33.8%, P =0.002) episodes of AF. Median ICU (19 versus 24 hours, P =NS) and mean hospital stay (7.7±6.9 versus 9.7±10, P =NS) did not significantly change. The number of postoperative complications was lower in the biatrial group (13 versus 35, P =0.001). Conclusions —Biatrial pacing after CABG significantly decreases the incidence of AF. This is associated with reduced postoperative complications and a trend toward reduced ICU and hospital stay.

Background : Atrio-ventricular junctional ablation with pacemaker insertion has been shown to improve quality of life in patients with drug refractory paroxysmal atrial fibrillation. It is unknown whether this improvement is secondary to the ablation procedure or to the pacemaker mode utilised. To investigate this we reviewed our experience of implanting a dual chamber rate responsive pacemaker with mode switching (DDDR/MS) alone on quality of life in this patient group. Methods and results : Over a 1-year period, 19 patients (mean age 62±9 years, 13 female) with drug refractory paroxysmal atrial fibrillation (mean duration of symptoms 8.7±7 years, failed 3.1±0.9 anti-arrhythmic drugs, amiodarone in 15) were recruited. Quality of life was assessed at baseline and after 1 month using a cardiac specific questionnaire, the modified Karolinska questionnaire. The mean score for all patients significantly improved by 39% at follow up (baseline 59±24, 1 month 36±24, P =0.001). Individually 15 patients (79%) had an improvement in their score, whilst for 13 patients (68%) their symptoms were sufficiently improved after pacing that ablation was not required. The benefit was maintained to a mean follow up of 12±5 months (score 31±20, P Conclusions : Patients with drug refractory paroxysmal atrial fibrillation, DDDR/MS pacing alone can improve quality of life without concurrent atrio-ventricular junctional ablation in a significant proportion of patients.

The role of atrial overdrive pacing for the suppression of paroxysmal atrial fibrillation remains unclear. To investigate this we have performed a randomised study evaluating the role of an increased atrial base rate in suppressing this arrhythmia in patients implanted with a permanent pacemaker (Chorum ELA) for sick sinus syndrome with previous documented paroxysmal atrial fibrillation. Twenty-seven patients (mean age, 69; 15 female) were randomised to two 3-month single-blinded crossover periods of DDDR pacing. The pacemaker was set with a base rate of 60 bpm (normal) during one period and at 10 bpm (overdrive) above the average heart rate during the other, mean (S.D.) 75+/-7 beats/min (range, 70-96). The fallback algorithm of the pacemaker was activated to record the number and duration of paroxysmal atrial fibrillation episodes. During the overdrive period there was a significant increase in the total duration of atrial pacing (normal 60+/-26% vs. overdrive 72+/-28%, P

Aims To describe the institution of a biventricular pacing programme with particular reference to the implantation procedure and new technological considerations. Methods and Results Analysis of outcomes of a consecutive series of 54 patients undergoing attempted biventricular pacemaker implantation between February 1998 and April 1999. Successful implantation was achieved in 49 of the 54 patients (91%). Five patients required lead repositioning after initial successful implantation. Left ventricular lead pacing thresholds were found to be satisfactory and stable in the long term, with pacing thresholds of 1·3 V, 1·9 V and 1·6 V at implantation, 1 and 3 months, respectively. Left-sided lead function was not dependent on lead position within the tributaries of the coronary sinus. The implantation procedure was found to be safe, although one patient died during long-term follow-up. Conclusion With appropriate previous experience in complex and coronary sinus pacing and with access to up-to-date pacemaker and lead technology, a biventricular pacemaker implantation service can be instituted with good medium-term results.

Aims It has been reported that biatrial pacing can prevent the recurrence of atrial fibrillation. This technique requires a stable coronary sinus (CS) lead position for left atrial pacing. We report our experience of CS pacing with a specifically designed lead [Medtronic 2188 (n= 19)] and active fixation leads [Pacesetter Tendril (n=3), Medtronic Capsurefix (n=6)] in 21 patients with paroxysmal atrial fibrillation and a normal mean left atrial size of 39 mm (range 33-54 mm). Methods and results Using the Medtronic 2188 lead, successful initial CS canulation and lead positioning was achieved in all 19 patients. One patient developed subclavian vein thrombosis 3 months after initial implant. Eight patients (42%) experienced subsequent lead displacement (12 displacements in total). Of these, seven had their lead replaced with active fixation leads. In addition, two patients underwent active fixation lead implantation at first implant. CS canulation and lead positioning was successful in all nine patients. No patient suffered displacement of an active fixation lead. There were no complications in this group. Twelve of the 19 (66%) Medtronic 2188 leads were functioning at long-term follow-up (11 +/- 4 months) with a biatrial pacing threshold of 2.4 +/- 1 V. Eight of the nine (89%) active fixation leads were functioning at long-term follow-up (6 +/- 3 months) with a biatrial pacing threshold of 2.9 +/- 1.1 V. Using a combined approach 95% of patients had a functioning CS lead at long-term follow-up. Conclusion Active fixation leads can safely be used for left atrial pacing via the CS with good long-term pacing thresholds and stability.

We report our preliminary experience with the combined use of implantable cardioverter defibrillators (ICD) and biventricular pacemakers in six patients with heart failure and malignant ventricular arrhythmia. Two patients underwent ICD implantation for malignant ventricular arrhythmia after previous biventricular pacemaker implantation. One patient underwent biventricular pacemaker insertion for NYHA Class III heart failure after previous ICD implantation. Two patients underwent single device implantation. In the sixth patient, a combined implantation failed due to an inability to obtain a satisfactory left ventricular pacemaker lead position. The potential for device interaction was explored during implantation. In two patients a potentially serious interaction was discovered. Subsequent alterations in device configuration and programming prevented these interactions with long-term use. No complication of combined device use has been demonstrated during a mean follow-up of 2 months (range 1-4 months). Satisfactory ICD and pacemaker function has also been demonstrated. We conclude that combined device implantation may be feasible with currently available pacing technology and that further prospective studies are required in this area.

The influence of convection on the formation of cellular patterns is demonstrated by comparison of purely diffusive space experiments with ground-based reference experiments. The solid-liquic interfaces of the space experiments are covered by regular cellular patterns. Patterns obtained on ground reveal strong irregularities. Despite of the differences in the regularity of the patterns only slight deviations of the quantitative parameter primary spacing between ground and space experiments are found. Linear stability analysis in combination with a stagnant film model is used to include convective effects into quantitative stability curves as well as to predictions of the primary spacing.

The morphological instability of a solid-liquid interface in directional solidification was investigated under diffusive conditions during a sounding rocket flight. The use of the transparent binary alloy Saccinonitrile-Acetone allowed an in-situ observation of the evolution of interfacial perturbations. By applying a quite high cooling rate the morphological instability occured at the beginning of the initial transient of the solidification phase. Both the accelerated movement of the planar solidification front until instability and the formation of cellular structure are compared under μg and lg conditions. The time-dependent change of cellular solidification morphology is represented by the characteristic parameters primary spacing and cell amplitude.

Congressional language in the 1998 US Senate Armed Services Committee authorization bill directed ‘... the Secretary of the (United States) Air Force to undertake a design study of a system that could catalog and track debris down to one centimeter in size out to 1000 kilometer in altitude.’ The US Air Force Research Laboratory, in conjunction with other US National Laboratories and the National Aeronautics and Space Administration (NASA) conducted a study that examined what technical systems and operations would be required to perform such a mission. This paper outlines the study process, details the findings, draws conclusions, and makes recommendations as to what would be needed to develop an optically based system capable of cataloging and tracking small debris in low Earth orbit.

By a combination of a many-body evaluation of the s–f model (Kondo-lattice model) with an `ab initio’ bandstructure calculation the temperature-dependent electronic quasiparticle structure of the `local moment’ ferromagnet Gd is derived. The s–f model incorporates the exchange interaction between itinerant (5d, 6s) conduction electrons and localized 4f electrons which form the permanent magnetic moments. The s–f model possesses an instructive special case, concerning a ferromagnetically saturated semiconductor, that can be treated rigorously revealing thereby the basic excitation processes and correlation effects induced by the s–f exchange interaction. The model evaluation is finally combined with an ASW bandstructure calculation to get the temperature-dependent quasiparticle bandstructure and the spectral density of Gd. Depending on the effective exchange coupling J / W ( J : exchange constant; W : bandwidth) strikingly different behaviour of the induced exchange splitting of the (5d, 6s) band states is observed. In the weak coupling case a `Stoner-like'spin splitting of the band states proportional to the f-magnetization occurs, while for stronger exchange an additional splitting of the quasiparticle dispersions for each spin direction happens, that even persists in the paramagnetic phase ( T > T c ). The depolarization for T → T c is then no longer due to a `Stoner shift’ but rather to a redistribution of spectral weight between two quasiparticle peaks. Extremely complicated behaviour is found for intermediate couplings J / W that requires a careful interpretation of respective photoemission data.

Directional solidification with a cellular solid–liquid interface morphology is characterized by two typical length scales – the size of the cells and the thickness of the solutal boundary layer ahead of the growing interface. The interaction of the solutal field with the morphology is investigated by using the model alloy succinonitrile–acetone which allows by its transparency the in situ observation of the interface structure. To avoid wall effects and decouple the solidification parameters temperature gradient and solidification velocity a rod-like bulk sample and a Bridgman Stockbarger-type gradient furnace are used. In the experiments the development of the interface morphology is affected by buoyancy driven melt convection which stabilizes significantly the planar morphology. At the planar to cellular transition quasi-hexagonal and elongated cells exist simultaneously, both at grain boundaries as well as inside the grains. With increasing solidification length a quasi-hexagonal pattern covers the interface which shows a random rearrangement of the cells. The size of the cells varies in a wide range and no wavelength selection is found.

Microstructural evolution in the commercial aluminum-based metal matrix composite 2014+10 vol pct Al2O3 was investigated during directional solidification with planar interface within the initial transient. Investigations were directed toward phase formation and phase distribution, with special emphasis on the critical conditions for the transition from particle pushing to engulfment. In situ nucleation of intermetallic particles, identified as being the complex silicides (Fe, Mn)3Si2Al15, their growth, pushing, and subsequent engulfment are shown to be interactively coupled to the pushing and engulfment of the inert alumina particles. The experimental conditions for engulfment of the inert particles are in good agreement with predictions according to the “critical velocity” model of Potschke and Rogge, the critical velocities ranging from 0.3 to 1.0 μm/s, due to the effect of the solutal field. This indicates that in castings with equiaxed dendritic solidification patterns, the radial growth velocities are not necessarily responsible for pushing the particles into the interdendritic spaces. For the intermetallic particles, the dependence of the critical velocity on particle size is not linear as for inert particles, but deflected upward for increasing size. This is probably due to the fact that they act as a sink for certain species of segregated solute atoms, meaning that size and solutal distortions are reactively coupled.

We propose a self-consistent approximate solution of the s - f model for describing the exchange coupling of a local moment system with a partially filled energy band. Induced electronic correlations account for the characteristic quasiparticle band effects which become manifest via striking temperature dependencies, band deformations and splittings. For weak s - f exchange interactions a `Stoner-like' spin splitting of the conduction band proportional to the f magnetization occurs. As soon as the coupling exceeds a critical value an additional spin splitting of the quasiparticle dispersion sets in, which is due to different elementary excitations. One of these appears as a repeated emission and reabsorption of a magnon by the conduction electron, resulting in an effective electron - magnon attraction. This gives rise to a polaron-like quasiparticle (a `magnetic polaron'). Other elementary processes are connected to magnon emission or absorption by the conduction electron (`scattering states'). The polarization of the conduction band due to the s - f exchange interaction J feeds back to the localized spin system leading to an indirect coupling between the spins. For weak s - f coupling the RKKY mechanism dominates , but with remarkable deviations for intermediate and strong couplings. The Curie temperature saturates with increasing J, where the saturation value is strongly dependent on the band occupation n. The oscillating behaviour of the effective exchange integral connecting the localized spins restricts ferromagnetism to special regions for n. The magnetization curve, the spin polarization of the itinerant electrons, and f - f as well as s - f spin correlation functions are worked out for a simple cubic lattice and discussed in terms of the band occupation n and the s - f exchange coupling J.

Emotional disorders are a common outcome from mild traumatic brain injury (TBI) in humans, but their pathophysiological basis is poorly understood. We have developed a mouse model of closed-head blast injury using an air pressure wave delivered to a small area on one side of the cranium, which we have used to create mild TBI. We found that 20-psi blasts in 3-month old C57BL/6 male mice yielded no obvious behavioral or histological evidence of brain injury, while 25-40 psi blasts produced transient anxiety in an open field arena but little histological evidence of brain damage. By contrast, 50-60 psi blasts resulted in anxiety-like behavior in an open field arena that became more evident with time after blast. In additional behavioral tests conducted 2-8 weeks after blast, 50-60 psi mice also demonstrated increased acoustic startle, perseverance of learned fear, and enhanced contextual fear, as well as depression-like behavior and diminished prepulse inhibition. We found no evident cerebral pathology, however, and only scattered axonal degeneration in brain sections from 50-60 psi mice 3-8 weeks after blast. Thus, the TBI caused by single 50-60 psi blasts in mice exhibits the minimal neuronal loss coupled to diffuse axonal injury characteristic of human mild TBI. A reduction in the abundance of a subpopulation of excitatory projection neurons in basolateral amygdala enriched in Thy1 was, however, observed. The reported link of this neuronal population to fear suppression suggests their damage by mild TBI may contribute to the heightened anxiety and fearfulness observed after blast in our mice. Our overpressure air blast model of concussion in mice will enable further studies of the mechanisms underlying the diverse emotional deficits seen after mild TBI.

Erythropoietin (EPO) can protect the retina from acute damage, but long-term systemic treatment induces polycythemia. Intraocular gene delivery of EPO is not protective despite producing high levels of EPO likely due to its bellshaped dose curve. The goal of this study was to identify a therapeutic dose of continuously produced EPO in the eye. We packaged a mutated form of EPO (EPOR76E) that has equivalent neuroprotective activity as wild-type EPO and attenuated erythropoietic activity into a recombinant adeno-associated viral vector under the control of the tetracycline inducible promoter. This vector was injected into the subretinal space of homozygous postnatal 5-7 day retinal degeneration slow mice, that express the tetracycline transactivators from a retinal pigment epithelium specific promoter. At weaning, mice received a single intraperitoneal injection of doxycycline and were then maintained on water with or without doxycycline until postnatal day 60. Intraocular EPO levels and outer nuclear layer thickness were quantified and correlated. Control eyes contained 6.1 ± 0.1 (SEM) mU/ml EPO. The eyes of mice that received an intraperitoneal injection of doxycycline contained 11.8 ± 2.0 (SEM) mU/ml EPO-R76E. Treatment with doxycycline water induced production of 35.9 ± 2.4 (SEM) mU/ml EPO-R76E in the eye. The outer nuclear layer was approximately 8 μm thicker in eyes of mice that received doxycycline water as compared to the control groups. Our data indicates that drug delivery systems should be optimized to deliver at least 36 mU/ml EPO into the eye since this dose was effective for the treatment of a progressive retinal degeneration.

Erythropoietin (Epo) is neuroprotective in a number of preparations, but can lead to unacceptably high and even lethal hematocrit levels. Recent reports show that modified Epo variants confer neuroprotection in models of glaucoma and retinal degeneration without raising hematocrit. In this study, neuroprotective effects of two Epo variants (EpoR76E and EpoS71E) were assessed in a model of Parkinson’s disease. The constructs were packaged in recombinant adeno-associated viral (rAAV) vectors and injected intramuscularly. After 3 weeks, mice received five daily injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and were killed 5 weeks later. The MPTP-lesioned mice pretreated with rAAV.eGFP (negative control) exhibited a 7- to 9-Hz tremor and slower latencies to move on a grid test (akinesia). Both of these symptomatic features were absent in mice pretreated with either modified Epo construct. The rAAV.eGFP-treated mice lesioned with MPTP exhibited a 41% reduction in tyrosine hydroxylase (TH)-positive neurons in the substantia nigra. The rAAV.EpoS71E construct did not protect nigral neurons, but neuronal loss in mice pretreated with rAAV.EpoR76E was only half that of rAAV.eGFP controls. Although dopamine levels were normal in all groups, 3,4-dihydroxyphenylacetic acid (DOPAC) was significantly reduced only in MPTP-lesioned mice pre-treated with rAAV.eGFP, indicating reduced dopamine turnover. Analysis of TH-positive fibers in the striatum showed normalized density in MPTP-lesioned mice pretreated with rAAV.EpoS71E, suggesting that enhanced sprouting induced by EpoS71E may have been responsible for normal behavior and dopaminergic tone in these mice. These results show that systemically administered rAAV-generated non-erythropoietic Epo may protect against MPTP-induced parkinsonism by a combination of neuroprotection and enhanced axonal sprouting.

Estrogen, in addition to its genomic effects, triggers rapid synaptic changes in hippocampus and cortex. Here we summarize evidence that the acute actions of the steroid arise from actin signaling cascades centrally involved in long-term potentiation (LTP). A 10-min infusion of E2 reversibly increased fast EPSPs and promoted theta burst-induced LTP within adult hippocampal slices. The latter effect reflected a lowered threshold and an elevated ceiling for the potentiation effect. E2’s actions on transmission and plasticity were completely blocked by latrunculin, a toxin that prevents actin polymerization. E2 also caused a reversible increase in spine concentrations of filamentous (F-) actin and markedly enhanced polymerization caused by theta burst stimulation (TBS). Estrogen activated the small GTPase RhoA, but not the related GTPase Rac, and phosphorylated (inactivated) synaptic cofilin, an actin severing protein targeted by RhoA. An inhibitor of RhoA kinase (ROCK) thoroughly suppressed the synaptic effects of E2. Collectively, these results indicate that E2 engages a RhoA >ROCK> cofilin> actin pathway also used by brain-derived neurotrophic factor and adenosine, and therefore belongs to a family of ‘synaptic modulators’ that regulate plasticity. Finally, we describe evidence that the acute signaling cascade is critical to the depression of LTP produced by ovariectomy.

The goal of the present study was to determine the minimum concentration of systemic erythropoietin-R76E required for neuroprotection in the retina. Erythropoietin (EPO) exhibits neuroprotective effects in both in vitro and in vivo models of neuronal cell death although its classical function is the regulation of red blood cell production. It can cross the blood brain barrier and therefore can be delivered systemically to affect the retina. However, long-term treatment with exogenous erythropoietin causes polycythemia. To decrease this potentially lethal effect, we generated and tested a modified form that contains a single arginine to glutamate mutation at the 76th position (EPO-R76E). In previous studies, this mutant protected retinal neurons in mouse models of retinal degeneration and glaucoma with similar efficacy as wild-type EPO. However, EPO-R76E has attenuated erythropoietic activity, therefore, neuroprotection can be achieved without causing a significant rise in hematocrit. BALB/cByJ mice received a single intramuscular injection of recombinant adeno-associated virus carrying enhanced green fluorescent protein, Epo, or Epo-R76E. To result in continuous production of four different doses of EPO-R76E, two doses of two different serotypes (2/5 and 2/8) were used. Mice were subjected to optic nerve crush and analysis was performed thirty days later. EPO-R76E showed dose-dependent protection of the retinal ganglion cell bodies, but was unable to prevent axonal degeneration. Furthermore, EPO-R76E induced a dose-dependent rise in the hematocrit that was still attenuated as compared to wild-type EPO.

Modifications of a recent model by Izumi et al.1 on diffusion controlled growth of YBa2Cu3O7−x (123) superconductors are proposed, taking into account especially the engulfment process of the Y2BaCuO5 (211) particles into the solidifying 123 interface. The proposed modifications are evidenced by experimental results and applied to explain microstructural features of the 123 superconducting material. In particular, the 1:1 correlation between 123 platelet thickness (planar defect spacing) and 211 particle size as described by Jin et al.2 is explained by an observed bridge growth resulting in a zipper-like mechanism. By this mechanism the platelets grow together in an oriented way leading to a quasi single crystalline material.

The noble gas xenon exerts favorable anesthetic properties along with remarkable hemodynamic stability in healthy patients undergoing elective surgery. It represents the nearly ideal anesthetic and provides safe and well controllable anesthesia although the exact mechanism by which xenon produces anesthesia remains to be elucidated. In addition xenon offers organ protective properties for vital organs including the brain, heart and kidneys which seem to be synergistic when used in combination with therapeutic hypothermia. As the high cost of xenon will probably preclude its wider use as a routine anesthetic, data from extensive tests in large numbers of high risk patients is needed to confirm its possible superiority in this setting.

SummaryReorganization of the actin cytoskeleton is essential for synaptic plasticity and memory formation. Presently, the mechanisms that trigger actin dynamics during these brain processes are poorly understood. In this study, we show that myosin II motor activity is downstream of LTP induction and is necessary for the emergence of specialized actin structures that stabilize an early phase of LTP. We also demonstrate that myosin II activity contributes importantly to an actin-dependent process that underlies memory consolidation. Pharmacological treatments that promote actin polymerization reversed the effects of a myosin II inhibitor on LTP and memory. We conclude that myosin II motors regulate plasticity by imparting mechanical forces onto the spine actin cytoskeleton in response to synaptic stimulation. These cytoskeletal forces trigger the emergence of actin structures that stabilize synaptic plasticity. Our studies provide a mechanical framework for understanding cytoskeletal dynamics associated with synaptic plasticity and memory formation.

Stress affects the hippocampus, a brain region crucial for memory. In rodents, acute stress may reduce density of dendritic spines, the location of postsynaptic elements of excitatory synapses, and impair long-term potentiation and memory. Steroid stress hormones and neurotransmitters have been implicated in the underlying mechanisms, but the role of corticotropin-releasing hormone (CRH), a hypothalamic hormone also released during stress within hippocampus, has not been elucidated. In addition, the causal relationship of spine loss and memory defects after acute stress is unclear. We used transgenic mice that expressed YFP in hippocampal neurons and found that a 5-h stress resulted in profound loss of learning and memory. This deficit was associated with selective disruption of long-term potentiation and of dendritic spine integrity in commissural/associational pathways of hippocampal area CA3. The degree of memory deficit in individual mice correlated significantly with the reduced density of area CA3 apical dendritic spines in the same mice. Moreover, administration of the CRH receptor type 1 (CRFR 1 ) blocker NBI 30775 directly into the brain prevented the stress-induced spine loss and restored the stress-impaired cognitive functions. We conclude that acute, hours-long stress impairs learning and memory via mechanisms that disrupt the integrity of hippocampal dendritic spines. In addition, establishing the contribution of hippocampal CRH–CRFR 1 signaling to these processes highlights the complexity of the orchestrated mechanisms by which stress impacts hippocampal structure and function.

Recent work has resolved many long-standing questions about the substrates of long-term potentiation (LTP) and thereby opened new possibilities for a neurobiological description of how memory is encoded, organized, and retrieved. The formation of LTP is typically divided into induction, expression, and consolidation (stabilization) phases that involve very different sets of cellular processes. Close analysis of induction helps explain the contiguity requirements of learning while the specifics of expression may be related to the clustering and hierarchical organization of memory. Work on consolidation has opened the way to mapping where, in the forebrain, learning-related synaptic changes occur, an essential first step in understanding retrieval.