Adaptive cardiac binding: a new method for treatment of dilated cardiomyopathy

Adaptive cardiac binding, a new surgical procedure for advanced heart failure, allows a gradual increase in compression on the dilated heart, with separate loads on the left and right ventricles. A canine model of biventricular heart failure (anastomosis between the carotid artery and jugular vein and doxorubicin administration) was created. Twenty-four dogs were divided into 4 groups: control, adynamic cardiomyoplasty, plastic cardiac binding, and adaptive cardiac binding. In the adaptive cardiac binding group, fluid was added (35, 15, and 10 mL) to each side of the pouch at weeks 1, 2, and 3. Left ventricular ejection fraction was 59%+/-4% before induction of heart failure and 27%+/-2% 6 weeks later. Immediately after the main operation, left ventricular ejection fractions were 35+/-3% (cardiomyoplasty), 34%+/-4% (plastic cardiac binding), and 35%+/-4% (adaptive cardiac binding). Four weeks later, left ventricular ejection fraction had not changed in the cardiomyoplasty (37%+/-3%) and plastic cardiac binding (32%+/-2%) groups, but significantly increased in the adaptive cardiac binding group (48%+/-5%); it had decreased to 23%+/-4% in controls. Adaptive cardiac binding is a promising new surgical approach for patients with end-stage heart failure.     

Multiple quantitative trait loci for blood pressure interacting epistatically and additively on Dahl rat chromosome 2

Our previous work demonstrated 2 quantitative trait loci (QTLs), C2QTL1 and C2QTL2, for blood pressure (BP) located on chromosome (Chr) 2 of Dahl salt-sensitive (DSS) rats. However, for a lack of markers, the 2 congenic strains delineating C2QTL1 and C2QTL2 could not be separated. The position of the C2QTL1 was only inferred by comparing 2 congenic strains, one having and another lacking a BP effect. Furthermore, it was not known how adjacent QTLs would interact with one another on Chr 2. In the current investigation, first, a critical chromosome marker was developed to separate 2 C2QTLs. Second, a congenic substrain was created to cover a chromosome fragment thought to harbor C2QTL1. Finally, a series of congenic strains was produced to systematically and comprehensively cover the entire Chr 2 segment containing C2QTL2 and other regions previously untested. Consequently, a total of 3 QTLs were discovered, with C2QTL3 located between C2QTL1 and C2QTL2. C2QTL1, C2QTL2, and C2QTL3 reside in chromosome segments of 5.7 centiMorgan (cM), 3.5 cM, and 1.5 cM, respectively. C2QTL1 interacted epistatically with either C2QTL2 or C2QTL3, whereas C2QTL2 and C2QTL3 showed additive effects to each other. These results suggest that BP QTLs closely linked in a segment interact epistatically and additively to one another on Chr 2.     

Dissolution Curve Comparisons Through the F2 Parameter,a Bayesian Extension of the f2 Statistic

Dissolution (or in vitro release) studies constitute an important aspect of pharmaceutical drug development. One important use of such studies is for justifying a biowaiver for post-approval changes which requires establishing equivalence between the new and old product. We propose a statistically rigorous modeling approach for this purpose based on the estimation of what we refer to as the F₂ parameter, an extension of the commonly used f₂ statistic. A Bayesian test procedure is proposed in relation to a set of composite hypotheses that capture the similarity requirement on the absolute mean differences between test and reference dissolution profiles. Several examples are provided to illustrate the application. Results of our simulation study comparing the performance of f₂ and the proposed method show that our Bayesian approach is comparable to or in many cases superior to the f₂ statistic as a decision rule. Further useful extensions of the method, such as the use of continuous-time dissolution modeling, are considered.     

Prefrontal Cortical GABA Modulation of Spatial Reference and Working Memory

Background:

Dysfunction in prefrontal cortex (PFC) GABA transmission has been proposed to contribute to cognitive dysfunction in schizophrenia, yet how this system regulates different cognitive and mnemonic functions remains unclear.

Methods:

We assessed the effects of pharmacological reduction of GABA_A signaling in the medial PFC of rats on spatial reference/working memory using different versions of the radial-arm maze task. We used a massed-trials procedure to probe how PFC GABA regulates susceptibility to proactive interference. Male rats were well-trained to retrieve food from the same 4 arms of an 8-arm maze, receiving 5 trials/day (1–2min intervals).

Results:

Infusions of the GABA_A receptor antagonist bicuculline (12.5–50ng) markedly increased working and reference memory errors and response latencies. Similar treatments also impaired short-term memory on an 8-baited arm task. These effects did not appear to be due to increased susceptibility to proactive interference. In contrast, PFC inactivation via infusion of GABA agonists baclofen/muscimol did not affect reference/working memory. In comparison to the pronounced effects on the 8-arm maze tasks, PFC GABA_A antagonism only causes a slight and transient decrease in accuracy on a 2-arm spatial discrimination.

Conclusions:

These findings demonstrate that prefrontal GABA hypofunction severely disrupts spatial reference and short-term memory and that disinhibition of the PFC can, in some instances, perturb memory processes not normally dependent on the frontal lobes. Moreover, these impairments closely resemble those observed in schizophrenic patients, suggesting that perturbation in PFC GABA signaling may contribute to these types of cognitive deficits associated with the disorder.     

Perylene bisbenzimidazole nonlinear dielectric material for energy storage

A novel perylene bisbenzimidazole comprising both donor and acceptor functional groups was designed, synthesized, and characterized. This structure exhibits potentially useful physical properties, including a nonlinear dielectric response to an increasing electric field. This material can be used in energy storage devices as the dielectric part of a capacitor. Energy storage devices based on film capacitors are targeting applications in a wide range of industrial, residential and transportation systems.

We synthesized and characterized an organic molecule which can serve as a unit for high-density energy storage.

Capacitors are among the simplest devices that store electrical energy and feature high charge–discharge rates, high power density, and a wide range of operating temperatures.¹ As a result, they have found use in many electronic devices and in numerous industrial applications. However, while capacitors feature high power density, they do not compete with the high gravimetric energy density of batteries, precluding their use as long-term energy storage devices. This disadvantage originates from the low polarizability of conventional dielectric materials found in modern industrial capacitors. We are developing new dielectric materials with high polarizability, high resistivity, and high breakdown voltage. These materials will widen the scope of capacitor applications to a variety of energy storage devices including transportation, industry, and residential applications.For traditional materials, dielectric polarizability is a constant value with stored energy sharing a linear relationship to the dielectric permittivity of the material. At high electric fields, however, many materials exhibit a nonlinear dielectric constant.² Commonly, these materials consist of highly polarizable molecules with electron-donating and/or electron-withdrawing groups on opposite sides of a large conjugated core. These groups can increase polarizability and further impart directionality to the delocalized electrons when an electric field is applied.Here we present the general structure for a non-linear dielectric chromophore, that we named dielectrophore, that would bring the combination of required properties into capacitors: high permittivity, resistivity, and breakdown strength, as well as good processability and mechanical flexibility.³ The main three components that build these properties are: the polyaromatic core, allowing π–π stacking within the material as well as high polarizability, donor and acceptor groups at each end of the conjugated core increasing the first hyperpolarizability, and insulating subunits that prevent current leakage within the capacitor (Fig. 1). In such structures, the cores are predominantly planar polycyclic molecular system which forms column-like supramolecular stacks by π–π interactions.Open in a separate windowFig. 1General representation of an ideal dielectrophore, such as 15.Perylene-3,4,9,10-tetracarboxylic acid diimides (PDIs) are among the most extensively used cores for studies of π–π stacking and columnar liquid crystalline structures. It is noteworthy that PDI-based molecules have been widely used as colorants and dyes, as well as chromophores for optoelectronic applications such as photovoltaics and organic field effect transistors. This is due to the combination of their optoelectronic properties, such as large extinction coefficients, high fluorescent quantum yields, strong electron-accepting ability (N-type semiconductors), and high thermal and chemical stability.⁴ Most of these properties originate from the delocalization of the π electrons of the PDI''s. In addition, the modular structure and straightforward synthesis of PDI-based molecules streamline the modification of their structures, which helps to bring all the required properties of our dielectrophores.Our theoretical studies demonstrated that linear polarizability of the PDIs can be strongly increased by transforming the diimide functions into the more conjugated benzimidazole derivatives and adding donor (NEt₂) and acceptor groups (NO₂) at the opposite sides of a molecule.⁵ Considering the predicted design, we propose molecule 15 as our target molecule (Fig. 1). Long alkyl chains are added via phenyl linkers at both sides of the molecule and bring significant impact into the resistivity of the potential capacitor and help with processability during the synthetic manipulations and film coating.One of the main advantages of 15 is the modularity of its synthesis, which can be performed as a step-wise addition of two substituted o-phenylenediamines to 13 (Scheme 1). 13 was synthesized according to a modified procedure reported by Xiao and co-workers (outlined in Scheme 1).⁶ In our synthesis, 3 is accessed through a 2-step derivatization of catechol (1) through an alkylation followed by a C–H activated borylation.⁷ The electron-acceptor diamine (7) was synthesized from 2,5-dinitroaniline (4) via bromination with NBS, followed by Suzuki coupling with 6, and further reduction of one of the nitro groups with ammonium sulfide. The electron donating diamine (12) was synthesized from 3-bromo-2,5-difluoronitrobenzene (8) via nucleophilic aromatic substitution at room temperature, followed by Suzuki coupling with 3 to isolate 10. A nucleophilic aromatic substitution with benzylamine at elevated temperature yields 11 and a deprotection/reduction using Pd(OH)₂/C and H₂ at 55 psi afforded 12. 14 was obtained in two steps by stirring diamine 7 with 13 in molten imidazole at 140 °C for 12 hours then further treating the product with an excess of para-toluenesulfonic acid in toluene at 100 °C to afford 14 in 37% overall yield (Scheme 1).Open in a separate windowScheme 1Synthesis of 15.15 was made through the condensation of mono-anhydride 14 with diamine 12 with the presence of zinc acetate in quinoline at 140 °C for 12 hours. Upon precipitation into methanol, 15 was isolated as a dark purple solid. It is important to mention that reactions of 13 with 7 and then 14 with 12 are likely not regioselective, even though steric factors favour the formation of the isomers 15a and 15b (Scheme 2) with donor/acceptor groups located farther from carboxamide group, especially in the case of the bulkier diethylamino group. Indeed, six additional isomers may be present, in addition to 15a and 15b (15c–h, see ESI^†). Column chromatography to separate these regioisomeric mixtures is shown to be quite challenging.⁸ Considering our theoretical studies, that demonstrated both syn- and anti-isomers to have similar predicted polarization values, separation of individual isomers is unnecessary.⁵Open in a separate windowScheme 2Main isomers of 15.15 was characterized with UV-vis and FTIR spectroscopic techniques and molecular weight was confirmed through mass spectrometry (see ESI^†). FTIR of 15 shows the absence of the anhydride carbonyl stretches of 14 at 1769 and 1732 cm⁻¹ respectively and the emergence of benzimidazole stretches at 1691, 1592, and 1573 cm⁻¹.⁹¹H NMR of 15 in 100% CDCl₃ initially exhibit very broad signals, but when 10% dTFA is added this aggregation is broken up (see ESI^†). The formation of the benzimidazole extends the length of conjugation considerably, this transformation can be clearly observed in the UV-vis spectra where the λ_max shifts from 523 nm for 13 to 555 nm for 14 (ESI^†). The λ_max shifts even further towards the near infrared region (752 nm) upon addition of the donor block (12) and making 15 (Fig. 2A). The drastic broadening of the band from 500 to 900 nm for 15 is caused by the extended conjugation, the formation of π–π-aggregates in the solution and the presence of a mixture of isomers,^8a as well as intramolecular charge transfer (ICT) in this push–pull system.¹⁰ The UV-vis spectrum in chloroform was predicted using a B3LYP/6-31H level of theory and compared with the experimental data (see ESI^†). The computed spectrum identifies three major bands at 409, 552, and 850 nm, respectively, in some agreement with the observed λ_max at 395, 525, and 752 nm (ESI^†). 15 was then cast into films on the Indium–Tin–Oxide (ITO)/glass substrate (see ESI^†) and charged through corona poling to test its nonlinear behaviour in the presence of an electric field.Open in a separate windowFig. 2(A) UV-vis absorption spectra of intermediates 13 (solid red), and 14 (dashed green), and final perylene-bisbenzimidazole 15 (dash-dot blue) (0.05 mg mL⁻¹ in CHCl₃). (B) Corona charging capacitor experiment of films cast from polypropylene (PP, dash black) and 15 (dash-dot blue).In corona poling, a sharp corona tip is charged up to several kilovolts until the electric breakdown of surrounding atmosphere occurs and the positive or negative ions are deposited on the film surface.¹¹ With this approach, a large electric field necessary to study the nonlinear response of the material is achieved. Once charge is deposited we used a Kelvin probe to measure the surface potential and its dependence on the amount of deposited charges, which can be determined by measuring the current from the bottom ITO electrode to the ground. This current is directly proportional to the voltage of the corona electrode, as expected, and is controlled by the corona current setting. It is then a simple calculation to convert the time under the corona charge deposition into the charge density on the top of the film. In our experiment, we use the current of 10⁻⁵ A and the area of the film is 11.5 × 6 cm².The results of the corona experiment are shown in Fig. 2B for the 2.165 μm thickness film of 15 and 6 μm polypropylene (PP) thin film for the comparison. PP is a common material used as a dielectric in many high voltage capacitors and shows a usual linear relationship between increasing charge density and a growing electric field (Fig. 2B). The dielectric constant of PP is estimated through this approach to be 2.9, close to the tabulated value.¹² When 15 is exposed to the same conditions, we observe a nonlinear voltage saturation at an electric field of 40 V μm⁻¹. We can conclude that in such nonlinear regime the deposition of additional charge leads to the increase of the polarization, not to the increase of the electric field. It should be emphasized that in PP films the electric breakdown occurs after about 10 seconds of the charge deposition, while 15 can sustain up to 5 hours at the same conditions. Correspondingly, the energy stored in the capacitor based on our molecule would be larger than that of the polypropylene-based capacitor by several orders of the magnitude.     

Efficient synthesis of ether phosphonates using trichloroacetimidate and acetate coupling methods

A series of ether phosphonates have been prepared by trichloroacetimidate and acetate coupling methods. Trichloroacetimidates or acetates were treated with primary and secondary alcohols as O-nucleophiles in the presence of catalytic TMSOTf to afford 21 examples of diethyl alkyloxy(substitutedphenyl)methyl phosphonates via C–O bond formation in 55–90% yields and short reaction time.

An efficient method for the synthesis of various ether phosphonates by trichloroacetimidate and acetate coupling methods is described.     

Injury Prevention in Baseball: from Youth to the Pros

Purpose of Review

This review examines recent literature on injury epidemiology and prevention in the sport of baseball from youth to professional levels.

Recent Findings

Overuse is the predominant mechanism of injury in youth baseball players. Newer stretching and exercise protocols may help prevent these injuries. At the professional level, however, overuse has not been proven to correlate with increased injury incidence, but pitch counts are still monitored. There continues to be a rise in operations performed for baseball-related injuries, including ulnar collateral ligament (UCL) reconstruction, particularly in younger athletes. As the level of play increases, there is significant loss of participation due to injuries, such as the UCL in the upper extremity and the hamstrings in the lower extremity.

Summary

Baseball is a widely popular sport, which has led to a focus on injury epidemiology and prevention. While the majority of research regarding baseball injuries focuses on pitchers, fielders and catchers are also at risk. In an attempt to decrease non-contact injuries in the upper and lower extremities, stretching and strengthening exercises are vitally important. Because injury profiles demonstrate significant variability from youth to professional baseball, unique prevention strategies are likely necessary at each level. More research is needed to develop and validate appropriately targeted injury prevention programs.