Discovery, synthesis and exploration of N-benzylsulfonyl-2-phenylazepanes as inhibitors of Bim expression in a mouse embryonic fibroblast model.

Chronic activation of beta-adrenergic receptors by the sympathetic nervous system results in the apoptosis of cardiomyocytes. Due to the inability of cardiomyocytes to regenerate, this can result in heart failure. Upregulation of the pro-apoptotic protein Bim has been implicated as the cause of cardiomyocyte apoptosis. Beta blockers are the frontline drug used to negate this apoptotic pathway, as no direct inhibitors of Bim expression currently exist. Unfortunately, treatment of heart failure using beta blockers is not optimal. Therefore, direct inhibition of Bim expression is an attractive strategy to provide protection against stress-induced apoptosis of cardiomyocytes. Herein we explore a class of N-benzylsulfonyl-2-phenylazepanes to obtain anti-apoptotic compounds capable of reducing Bim expression levels to 7% of the control at 10 µM in cardiomyocytes under conditions of chronic beta-adrenergic receptor activation with little inhibitory effect upon protein kinase A activity and minimal toxicity.

The Ponseti Method for the Treatment of Clubfeet Associated With Amniotic Band Syndrome: A Single Institution 20-Year Experience.

BACKGROUND: Amniotic band syndrome (ABS) is a congenital disorder resulting in fibrous bands that can cause limb anomalies, amputations, and deformities. Clubfoot has been reported in up to 50% of patients with ABS. The purpose of this study is to compare treatment characteristics and outcomes of clubfoot patients with ABS to those with idiopathic clubfoot treated with the Ponseti method. METHODS: An Institution Review Board (IRB) approved retrospective review of prospectively gathered data was performed at a single pediatric hospital over a 20-year period. Patients with either idiopathic clubfeet or clubfeet associated with concomitant ABS who were <1 year of age and treated by the Ponseti method were included. Initial Dimeglio score, number of casts, need for heel cord tenotomy, recurrence, and need for further surgery were recorded. Outcomes were classified as "good" (plantigrade foot±heel cord tenotomy), "fair" (need for a limited procedure), or "poor" (need for a full posteromedial release). RESULTS: Forty-three clubfeet in 32 patients with ABS, and 320 idiopathic clubfeet in 215 patients were identified. Average age at last follow up was not different between ABS and idiopathic cohorts (7.4 vs. 5.2 y, P=0.233). Average Dimeglio score was lower in the ABS cohort (12.3 vs. 13.7, P=0.006). Recurrence rate was significantly higher in the ABS (62.8%) compared with idiopathic cohort (37.2%) (P=0.001). Clinical outcomes were significantly better in the idiopathic cohort (69.4% "good", 26.9% "fair", 3.8% "poor") compared with the ABS cohort (41.9% "good", 34.9% "fair", and 23.3% "poor") (P<0.001). Within the ABS cohort, no significant differences in clinical outcomes were found based upon location, severity, or presence of an ipsilateral lower extremity band. CONCLUSION: Clubfeet associated with ABS have higher rates of recurrence, a greater need for later surgery, and worse clinical outcomes than idiopathic clubfeet. This information may prove helpful in counseling parents of infants with ABS associated clubfeet. LEVEL OF EVIDENCE: Level III.

Bioresorbable Microdroplet Lasers as Injectable Systems for Transient Thermal Sensing and Modulation.

Minimally invasive methods for temperature sensing and thermal modulation in living tissues have extensive applications in biological research and clinical care. As alternatives to bioelectronic devices for this purpose, functional nanomaterials that self-assemble into optically active microstructures offer important features in remote sensing, injectability, and compact size. This paper introduces a transient, or bioresorbable, system based on injectable slurries of well-defined microparticles that serve as photopumped lasers with temperature-sensitive emission wavelengths (>4-300 nm °C-1). The resulting platforms can act as tissue-embedded thermal sensors and, simultaneously, as distributed vehicles for thermal modulation. Each particle consists of a spherical resonator formed by self-organized cholesteric liquid crystal molecules doped with fluorophores as gain media, encapsulated in thin shells of soft hydrogels that offer adjustable rates of bioresorption through chemical modification. Detailed studies highlight fundamental aspects of these systems including particle sensitivity, lasing threshold, and size. Additional experiments explore functionality as photothermal agents with active temperature feedback (ΔT = 1 °C) and potential routes in remote evaluation of thermal transport properties. Cytotoxicity evaluations support their biocompatibility, and ex vivo demonstrations in Casper fish illustrate their ability to measure temperature within biological tissues with resolution of 0.01 °C. This collective set of results demonstrates a range of multifunctional capabilities in thermal sensing and modulation.

What Factors Influence Union and Refracture of Congenital Pseudarthrosis of the Tibia? A Multicenter Long-term Study.

OBJECTIVE: To identify factors influencing union of congenital pseudarthrosis of the tibia (CPT), refractures, and integrity of the tibia at maturity. METHODS: Data of 119 children operated for Crawford-type IV CPT and followed-up till skeletal maturity were analyzed. Logistic regression and recursive partitioning analyses were used to test associations between several variables and the outcome. RESULTS: Primary union occurred in 86% of children. At maturity, 69% remained soundly united. The odds ratio for failure of primary union was 3.89 (95% confidence interval, 1.05-14.40; P=0.042) when bone morphogenetic protein was used, and children who had a combination of the Ilizarov technique and intramedullary nailing were at risk for unsound union at maturity (odds ratio, 6.19; 95% confidence interval, 1.24-30.83; P=0.026). No other association reached statistical significance. On recursive partitioning, use of the Ilizarov technique, transfixing the ankle and subtalar joints, use of cortical graft and not operating on the fibula were associated with a better outcome; use of bone morphogenetic protein and combining intramedullary nailing with the Ilizarov technique were associated with poor results. CONCLUSIONS: A larger sample is needed to confirm which factors truly influence the outcome of CPT. This may be feasible if data are collected prospectively through a multicenter registry.

The Modular Optical Underwater Survey System.

The Pacific Islands Fisheries Science Center deploys the Modular Optical Underwater Survey System (MOUSS) to estimate the species-specific, size-structured abundance of commercially-important fish species in Hawaii and the Pacific Islands. The MOUSS is an autonomous stereo-video camera system designed for the in situ visual sampling of fish assemblages. This system is rated to 500 m and its low-light, stereo-video cameras enable identification, counting, and sizing of individuals at a range of 0.5-10 m. The modular nature of MOUSS allows for the efficient and cost-effective use of various imaging sensors, power systems, and deployment platforms. The MOUSS is in use for surveys in Hawaii, the Gulf of Mexico, and Southern California. In Hawaiian waters, the system can effectively identify individuals to a depth of 250 m using only ambient light. In this paper, we describe the MOUSS's application in fisheries research, including the design, calibration, analysis techniques, and deployment mechanism.

Solid-state source of intense yellow light based on a Ce:YAG luminescent concentrator.

A luminescent concentrator functioning as a bright source of yellow light is reported. It comprises a waveguide made of cerium-doped YAG crystal, in the form of a long-thin rectangular strip, surrounded by flowing air and optically pumped from both sides with blue light from arrays of high-efficiency InGaN LEDs. Phosphor-converted yellow light, generated within the strip, is guided to a glass taper that is butt-coupled to one of the strip's end faces. Up to 20 W of optical power, centered on 575 nm with a linewidth of 76 nm, can be continuously radiated into air from the taper's 1.67 mm × 1.67 mm square output aperture. The intensity of the outputted light is significantly greater than what any yellow (AlGaInP) LED can directly produce (either singly or arrayed), with only a modest increase in linewidth. Furthermore, the wall-plug efficiency of the source exceeds that of any yellow laser. The concept allows for further substantial increases in intensity, total output power and wall-plug efficiency through scaling-up and engineering refinements.

Nanosecond time-resolved characterization of a pentacene-based room-temperature MASER.

The performance of a room temperature, zero-field MASER operating at 1.45 GHz has been examined. Nanosecond laser pulses, which are essentially instantaneous on the timescale of the spin dynamics, allow the visible-to-microwave conversion efficiency and temporal response of the MASER to be measured as a function of excitation energy. It is observed that the timing and amplitude of the MASER output pulse are correlated with the laser excitation energy: at higher laser energy, the microwave pulses have larger amplitude and appear after shorter delay than those recorded at lower laser energy. Seeding experiments demonstrate that the output variation may be stabilized by an external source and establish the minimum seeding power required. The dynamics of the MASER emission may be modeled by a pair of first order, non-linear differential equations, derived from the Lotka-Volterra model (Predator-Prey), where by the microwave mode of the resonator is the predator and the spin polarization in the triplet state of pentacene is the prey. Simulations allowed the Einstein coefficient of stimulated emission, the spin-lattice relaxation and the number of triplets contributing to the MASER emission to be estimated. These are essential parameters for the rational improvement of a MASER based on a spin-polarized triplet molecule.

Antimalarial activity of novel 4-cyano-3-methylisoquinoline inhibitors against Plasmodium falciparum: design, synthesis and biological evaluation.

Central to malaria pathogenesis is the invasion of human red blood cells by Plasmodium falciparum parasites. Following each cycle of intracellular development and replication, parasites activate a cellular program to egress from their current host cell and invade a new one. The orchestration of this process critically relies upon numerous organised phospho-signaling cascades, which are mediated by a number of central kinases. Parasite kinases are emerging as novel antimalarial targets as they have diverged sufficiently from their mammalian counterparts to allow selectable therapeutic action. Parasite protein kinase A (PfPKA) is highly expressed late in the cell cycle of the parasite blood stage and has been shown to phosphorylate a critical invasion protein, Apical Membrane Antigen 1. This enzyme could therefore be a valuable drug target so we have repurposed a substituted 4-cyano-3-methylisoquinoline that has been shown to inhibit rat PKA with the goal of targeting PfPKA. We synthesised a novel series of compounds and, although many potently inhibit the growth of chloroquine sensitive and resistant strains of P. falciparum, they were found to have minimal activity against PfPKA, indicating that they likely have another target important to parasite cytokinesis and invasion.

Enhanced magnetic Purcell effect in room-temperature masers.

Recently, the world's first room-temperature maser was demonstrated. The maser consisted of a sapphire ring housing a crystal of pentacene-doped p-terphenyl, pumped by a pulsed rhodamine-dye laser. Stimulated emission of microwaves was aided by the high quality factor and small magnetic mode volume of the maser cavity yet the peak optical pumping power was 1.4 kW. Here we report dramatic miniaturization and 2 orders of magnitude reduction in optical pumping power for a room-temperature maser by coupling a strontium titanate resonator with the spin-polarized population inversion provided by triplet states in an optically excited pentacene-doped p-terphenyl crystal. We observe maser emission in a thimble-sized resonator using a xenon flash lamp as an optical pump source with peak optical power of 70 W. This is a significant step towards the goal of continuous maser operation.

Operando X-ray scattering and spectroscopic analysis of germanium nanowire anodes in lithium ion batteries.

X-ray diffraction (XRD) and Fourier transform extended X-ray absorption fine structure (EXAFS) analysis of X-ray absorption spectroscopy (XAS) measurements have been employed to determine structural and bonding changes, as a function of the lithium content/state of charge, of germanium nanowires used as the active anode material within lithium ion batteries (LIBs). Our data, collected throughout the course of battery cycling (operando), indicate that lithium incorporation within the nanostructured germanium occurs heterogeneously, preferentially into amorphous regions over crystalline domains. Maintenance of the molecular structural integrity within the germanium nanowire is dependent on the depth of discharge. Discharging to a shallower cutoff voltage preserves partial crystallinity for several cycles.

Optical properties of PbS nanocrystal quantum dots at ambient and elevated pressure.

We investigated pressure-dependent changes in the optical properties of PbS nanocrystal quantum dots (NQD) by combining X-ray scattering and optical absorption spectroscopy in a diamond anvil cell. We discovered that the excitonic absorption peak vanishes as the NQD crystal structure reversibly undergoes the pressure-induced phase transition from rock-salt to orthorhombic structure. In the rock-salt phase, the pressure coefficient ∂E(g)/∂P of PbS NQD is negative and decreases in magnitude with decreasing NQD size. The basic theoretical model based on literature values of the PbS bulk modulus significantly overestimated the change in pressure coefficient with NQD size. We present a model that includes the size-dependence of both the pressure coefficient and bulk modulus to describe the experimentally observed optical and structural trends.

Re-creating missing population baselines for Pacific reef sharks.

Sharks and other large predators are scarce on most coral reefs, but studies of their historical ecology provide qualitative evidence that predators were once numerous in these ecosystems. Quantifying density of sharks in the absence of humans (baseline) is, however, hindered by a paucity of pertinent time-series data. Recently researchers have used underwater visual surveys, primarily of limited spatial extent or nonstandard design, to infer negative associations between reef shark abundance and human populations. We analyzed data from 1607 towed-diver surveys (>1 ha transects surveyed by observers towed behind a boat) conducted at 46 reefs in the central-western Pacific Ocean, reefs that included some of the world's most pristine coral reefs. Estimates of shark density from towed-diver surveys were substantially lower (<10%) than published estimates from surveys along small transects (<0.02 ha), which is not consistent with inverted biomass pyramids (predator biomass greater than prey biomass) reported by other researchers for pristine reefs. We examined the relation between the density of reef sharks observed in towed-diver surveys and human population in models that accounted for the influence of oceanic primary productivity, sea surface temperature, reef area, and reef physical complexity. We used these models to estimate the density of sharks in the absence of humans. Densities of gray reef sharks (Carcharhinus amblyrhynchos), whitetip reef sharks (Triaenodon obesus), and the group "all reef sharks" increased substantially as human population decreased and as primary productivity and minimum sea surface temperature (or reef area, which was highly correlated with temperature) increased. Simulated baseline densities of reef sharks under the absence of humans were 1.1-2.4/ha for the main Hawaiian Islands, 1.2-2.4/ha for inhabited islands of American Samoa, and 0.9-2.1/ha for inhabited islands in the Mariana Archipelago, which suggests that density of reef sharks has declined to 3-10% of baseline levels in these areas.

Environmental factors affecting large-bodied coral reef fish assemblages in the Mariana Archipelago.

Large-bodied reef fishes represent an economically and ecologically important segment of the coral reef fish assemblage. Many of these individuals supply the bulk of the reproductive output for their population and have a disproportionate effect on their environment (e.g. as apex predators or bioeroding herbivores). Large-bodied reef fishes also tend to be at greatest risk of overfishing, and their loss can result in a myriad of either cascading (direct) or indirect trophic and other effects. While many studies have investigated habitat characteristics affecting populations of small-bodied reef fishes, few have explored the relationship between large-bodied species and their environment. Here, we describe the distribution of the large-bodied reef fishes in the Mariana Archipelago with an emphasis on the environmental factors associated with their distribution. Of the factors considered in this study, a negative association with human population density showed the highest relative influence on the distribution of large-bodied reef fishes; however, depth, water temperature, and distance to deep water also were important. These findings provide new information on the ecology of large-bodied reef fishes can inform discussions concerning essential fish habitat and ecosystem-based management for these species and highlight important knowledge gaps worthy of additional research.

Initial severity rating of idiopathic clubfeet is an outcome predictor at age two years.

This study was performed to determine if rating the severity of clubfeet before Ponseti treatment was predictive of the outcomes at age two years. Four hundred and seventy-nine idiopathic clubfeet (323 patients) were numerically rated for severity using Dimeglio classification. Eighty-six feet rated moderate, 305 feet rated severe, and 88 feet rated very severe. Outcomes were classified as Good (plantigrade foot with or without a tendoachilles lengthening), Fair (limited surgery), or Poor (posteromedial release). Significant correlation existed between initial severity of the foot and outcomes, with moderate better than severe and very severe, and severe better than very severe. Initial numerical severity rating strongly correlated with the probability of a good outcome (P<0.0001). Evaluating the severity of clubfeet before Ponseti treatment provides prognostic information for parents.

Male-female differences in Scoliosis Research Society-30 scores in adolescent idiopathic scoliosis.

STUDY DESIGN: Longitudinal cohort study. OBJECTIVE: To compare functional outcomes between male and female patients before and after surgery for adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: There is no clear consensus in the existing literature with respect to sex differences in functional outcomes in the surgical treatment of AIS. METHODS: A prospective, consecutive, multicenter database of patients who underwent surgical correction for adolescent idiopathic scoliosis was analyzed retrospectively. All patients completed Scoliosis Research Society-30 (SRS-30) questionnaires before and 2 years after surgery. Patients with previous spine surgery were excluded. Data were collected for sex, age, Risser grade, previous bracing history, maximum preoperative Cobb angle, curve correction at 2 years, and SRS-30 domain scores. Paired sample t tests were used to compare preoperative and postoperative scores within each sex. Independent sample t tests were used to compare scores between sexes. A P value of <0.05 was considered statistically significant. RESULTS: Seven hundred forty-four patients (621 females and 123 males) were included. On average, males were 1 year older than females. There were no differences between sexes in Risser grade, bracing history, maximum curve magnitude, or correction after surgery. Both males and females had similar improvement in all SRS-30 domains after surgery. Self-image/appearance had the greatest relative improvement. Males had better self-image/appearance scores preoperatively, better pain scores at 2 years, and better mental health and total scores both preoperatively and at 2 years. Both males and females were similarly satisfied with surgery. CONCLUSIONS: Males treated with surgery for AIS report better preoperative self-image, less postoperative pain, and better mental health than females. These differences may be clinically significant. For both males and females, the most beneficial effect of surgery is improved self-image/appearance. Overall, the benefits of surgery for AIS are similar for both sexes.

Occult tight filum terminale syndrome: results of surgical untethering.

The entity of an occult tight filum terminale syndrome, characterized by clinical findings consistent with a tethered cord syndrome, but with the conus ending in a normal position, has been recognized recently. The indications for sectioning the filum terminale in this situation are not well characterized and are controversial. We report a retrospective review of a consecutive series of 60 children (ages 3-18 years) with a diagnosis of occult tight filum terminale syndrome who underwent section of the filum and were followed for more than 6 months (mean 13.9 months). The criteria for surgical intervention were (1) spina bifida occulta, (2) progressive bladder instability unresponsive to conservative measures, (3) urological/nephrological evaluation to confirm or rule out nonneurogenic etiology, and (4) two or more of the following: (a) bowel involvement (fecal incontinence or chronic constipation), (b) lower extremity weakness, (c) gait changes, (d) reflex/tone abnormalities, (e) sensory disturbances, (f) back/leg pain, (g) orthopedic abnormalities/limb length discrepancy, (h) scoliosis/lordosis, (i) recurrent urinary tract infections, (j) abnormal voiding cystourethrogram/ultrasound, (k) syringomyelia, and (l) neurocutaneous stigmata. Postoperatively, urinary incontinence/retention showed complete resolution in 52%, marked improvement (>95% resolution) in 35%, moderate improvement (>75%) in 6%, minimal improvement (> 50%) in 6%, and no improvement (<50%) in 2%. Fecal incontinence completely resolved in 56%, improved in 41%, and was unchanged in 3%. Weakness, sensory abnormalities, and pain improved or resolved in all patients.