Comparison of sublingual isosorbide dinitrate and Valsalva maneuver for detection of obstruction in hypertrophic cardiomyopathy

Introduction

A left ventricular outflow tract (LVOT) obstruction assessment with a provoking test should be a routine part of the evaluation of patients with hypertrophic cardiomyopathy (HCM). The aim of this study was to compare the utility of the Valsalva maneuver (VM) and sublingual spray application of isosorbide dinitrate (ISDN) for detection of an obstruction.

Material and methods

We prospectively evaluated 81 consecutive HCM patients without severe rest LVOT obstruction (defined as peak rest pressure gradient (PG) ≥ 50 mm Hg). We measured PG at rest, during the VM, after sublingual ISDN spray, and during the VM after ISDN. An obstruction was defined as a PG ≥ 30 mm Hg.

Results

An obstruction was present in 15 patients (19%) at rest (median and interquartile range of PG 16 (7–26) mm Hg), in 38 patients (47%) during the VM (PG 28 (12–49) mm Hg), in 50 (62%) patients after ISDN (PG 50 (12–79) mm Hg), and in 55 patients (68%) during the VM after ISDN (PG 59 (20–87) mm Hg). The difference in occurrence of obstruction among different provoking tests was statistically significant for all comparisons (p < 0.001, except for the comparison of the ISDN test with the VM during ISDN, p = 0.025).

Conclusions

The ISDN test and the VM are useful screening methods for the detection of an HCM obstruction. Although ISDN appears to be more precise than the VM, the best option is a combination of both methods, which maximizes inducement of LVOT obstruction in patients with HCM.     

The gut connectome: making sense of what you eat

The enteric nervous system has been studied thus far as an isolated unit. As researchers probe deeper into the function of this system, it is evident that the neural network stretches beyond enteric neurons. It is formed by both intrinsic and extrinsic neurons innervating the gut, enteric glia, and innervated sensory epithelial cells, such as enteroendocrine cells. This Review series summarizes recent knowledge on function and disease of nerves, glia, and sensory epithelial cells of the gut in eight distinctive articles. The timing and growing knowledge for each individual field calls for an appropriate term encompassing the entire system. We call this neuronal ensemble the “gut connectome” and summarize the work from a food sensory perspective.“Tell me what you eat, and I will tell you what you are,” wrote the French gastronome Jean Brillat-Savarin in 1826 (1).Although at the time of Brillat-Savarin the connection between well-being and ingested food was clear, only in recent years have we discovered the mechanisms by which the gut senses food. With all its folds, villi, and microvilli, the gut is arguably the largest surface in the body. It is here where food is deconstructed into nutrients, ultimately giving rise to signals that control a range of bodily functions, including the desire to eat.Because of the need to be aware of ingested food, the body has an intricate network of electrically excitable cells, carefully arranged into circuits and strategically distributed throughout the gut. These circuits convert food into electrical signals coordinating motility, secretion, food intake, and even mood and other behaviors. In the past, study of this network was limited to neurons of the enteric nervous system, but in recent years it has become clear that the neural network extends beyond enteric neurons. It is comprised of enteric glia, neurons of peripheral ganglia innervating the gut, intrinsic neurons, and specialized innervated epithelial sensors such as enteroendocrine cells. We believe it appropriate to call this network the “gut connectome.”Two characters of the gut connectome, the glia and enteric neurons, arise from neural crest cells. They are immigrants to the bowel, traveling from the neural tube. Avetisyan et al. describe the molecular instruments orchestrating the migration of neural crest–derived cells to the intestine (2). Receptors, cofactors, and ligands meticulously coordinate the migration and transformation of progenitors into enteric ganglia. Ultimately, over 20 distinct types of neurons and accompanying glia are formed (3). These neurons are then guided by chemical cues to develop axons and establish synaptic connections with sensory and motor targets (4).The gut connectome is a neural network built around food sensing. From the moment the fetus swallows amniotic fluid, the luminal contents of the digestive tract become a major factor in axonal pathfinding; after all, the network has to find the correct location to sense and utilize nutrients. Although there are reports of bacteria colonizing internal organs, including the gut, before birth (5), the gut microbiome, primarily after birth, serves as a beacon in the development of the network by priming the immune system and producing chemoattractants (6).Kabouridis and Pachnis discuss how the gut microbiota increases the density of enteric nerves (7). The mechanisms appear to involve epithelial receptors, like those of the large family of toll-like receptors. In normal conditions, microbes in the gut do not have physical access to enteric nerves; therefore, their ability to alter the development and function of the enteric neural network is probably mediated by bacterial byproducts that sieve through the epithelium into the lamina propria or, more likely, through direct activation of epithelial sensory cells such as enteroendocrine cells. Enteroendocrine cells are in direct contact with the gut lumen and express molecular receptors specifically activated by bacterial ligands (8). If the integrity of the epithelial barrier is compromised by infection, the function of the neural circuitry is affected, as discussed by Mawe (9).Enteroendocrine cells are essential for normal life. In their absence, severe diarrhea and early death occur (10). Like taste cells in the tongue or olfactory receptor cells in the nose, enteroendocrine cells are sensory epithelial cells. Recently their molecular sensing mechanisms have been uncovered, as reported by Psichas et al. (11). Enteroendocrine cells even express some of the same olfactory and taste receptors known to mediate the sense of smell and taste (12, 13). But unlike other epithelial sensors, they were thought to lack synaptic connections with nerves. Historically, enteroendocrine cells have been studied exclusively as a source of hormones. However, they have typical neural circuit features of sensory cells, including electrical excitability; functional voltage-gated channels; small, clear synaptic vesicles; nourishment from glial-derived neurotrophic factors; and a neuropod (14). It is through neuropods that enteroendocrine cells connect to nerves (15). This discovery opens up the possibility of the gut processing sensory signals in the lumen in a temporally precise, circuit-specific, and finely tuned manner.Although enteroendocrine cells have a wide array of molecular receptors for chemicals in the lumen of the gut, the sensing of dietary fats has received much attention because of the obesity epidemic. The perception of fats differs between the mouth and small intestine. In the mouth, the taste of unsaturated fatty acids triggers signals to increase hunger, whereas in the small intestine, fatty acids trigger signals of satiety (16). The difference is in the epithelial sensory cells that transduce the chemical signal from a digested lipid into an electrical impulse in nerves. Some dietary fatty acids in the small intestine exert potent anorectic actions via a mechanism in which lipids bind and activate cell surface receptors such as GPR40, GPR41, or ILDR1 (17, 18). DiPatrizio and Piomelli discuss how endogenous lipids produced in the gut modulate appetitive behaviors (19). Sensory signals from fats and other nutrients are ultimately relayed via the vagus nerve to the brain, where fat ingestion is perceived.An important character of the gut connectome is the enteric glia. Discovered by Russian physiologist Dogiel in the late 1800s (20), enteric glia were first recognized as essential for normal gut function in 1998 (21). They are distributed throughout the mucosa and neuronal plexus of the gut and form a syncytium that is functionally coupled through gap junctions made of hemichannels such as connexin 43 (22). In this issue, Sharkey describes the role of enteric glia in barrier and defense functions of the gut and gastrointestinal motility disorders (23). Enteric glial cells also form neuro-glial junctions with neurons and, at least in the myenteric plexus, are known to receive cholinergic innervation (24). We have documented a physical association of enteric glia with enteroendocrine cells, highlighting how the enteric glial cell is a critical character in the gut connectome (Figure 1 and ref. 14).Open in a separate windowFigure 1The gut connectome: built for sensing food.Top left: A sensory enteroendocrine cell (EEC) in the gut epithelium can be seen extending a neuropod to connect with an underlying nerve. Bottom left: Enteric glia underneath the epithelium extend processes to contact the neuropod of an enteroendocrine cell. Right: The innervation of enteroendocrine cells brings the possibility of afferent (gut-to-brain) signaling and possible efferent (brain-to-gut; not shown) signaling, which would allow the gut to compute sensory information from food to modulate whole-body metabolism and behaviors such as hunger and satiety. Figures adapted from PLoS One (14) and J Clin Invest (15).Besides modulating the transmission of sensory information, enteric glia appear to be an important defense against pathogenic invasion. Pathogens like the JC virus and misfolded prion proteins are harbored by enteric glia. Both JC virus and prion proteins gain entry through the gut but affect the brain (25). This is an important observation because enteroendocrine cells are exposed to the gut lumen, where external viruses and prions first arrive. In an effort to unveil a gut-brain neural circuit, we recently used a modified rabies virus. This neurotropic virus infects enteroendocrine cells, and given the right conditions, the rabies virus spreads into the nervous system (15). This uncovered a conduit through which pathogens that are able to infect enteroendocrine cells could access first the peripheral then the central nervous systems. And, like astrocytes in the brain, enteric glia may also clear infections of the gut connectome.The neuronal ensemble of sensory cells, neurons, and glia is modulated and shaped by the gut microbiome. Gut microbes can have mind-altering effects as discussed by Mayer et al. and, although the mechanisms remain unknown, it is clear that the ability of the gut connectome to process sensory information is involved (26).Alterations in the gut connectome have also been observed in patients undergoing gastric bypass surgery. The procedure dates back to 1966, when Dr. Edward Mason first implemented it to treat obese patients (27). The procedure has since been refined, and there are several variations of it, the most popular being Roux-en-y (RY) gastric bypass. Manning et al. explain that RY gastric bypass forces food to bypass the stomach and enter directly into the distal small intestine (28). The effects on diabetes and body weight are remarkable. Three years after surgery almost seven of ten patients experience diabetes remission, and remarkably only six months after the surgery, an average patient loses over one-quarter of his initial body weight (29). The effects were thought to be due to the altered anatomy, but more recently it has become clear that neuroendocrine mechanisms are involved: in simple terms, the bodyweight set-point is reset.Perhaps the most remarkable observation learned from RY gastric bypass surgery is the alteration of food perception. RY gastric bypass reduces the preference for sugars and even the cravings for sweets and fatty foods (30). Rewiring of the gut connectome indeed alters where nutrients are sensed, how nutrients are sensed, and our perception of food. Jean Brillat-Savarin was right after all; we truly are what we eat.     

A Pantetheinase-Resistant Pantothenamide with Potent,On-Target,and Selective Antiplasmodial Activity

Pantothenamides inhibit blood-stage Plasmodium falciparum with potencies (50% inhibitory concentration [IC₅₀], ∼20 nM) similar to that of chloroquine. They target processes dependent on pantothenate, a precursor of the essential metabolic cofactor coenzyme A. However, their antiplasmodial activity is reduced due to degradation by serum pantetheinase. Minor modification of the pantothenamide structure led to the identification of α-methyl-N-phenethyl-pantothenamide, a pantothenamide resistant to degradation, with excellent antiplasmodial activity (IC₅₀, 52 ± 6 nM), target specificity, and low toxicity.     

On the Ablation Behavior of Carbon Fiber-Reinforced Plastics during Laser Surface Treatment Using Pulsed Lasers

This contribution discusses the ablation phenomena observed during laser treatment of carbon fiber-reinforced plastics (CFRPs) with pulsed lasers observed employing laser sources with wavelengths of 355 nm, 1064 nm and 10.6 µm and pulse durations from picoseconds (11 ps) to microseconds (14 µs) are analyzed and discussed. In particular, the threshold fluence of the matrix material epoxy (EP) and the damage threshold of CFRP were calculated. Moreover, two general surface pretreatment strategies are investigated, including selective matrix removal and structure generation through indentation (ablation of both, matrix material and fibers) with a cross-like morphology. The surfaces obtained after the laser treatment are characterized by means of optical and scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy is employed for the analysis of composite and constituent materials epoxy and carbon fibers. As a result, different ablation mechanisms, including evaporation and delamination are observed, depending on the employed laser wavelength and pulse duration. For both 355 nm and 1064 nm wavelength, the laser radiation produces only partial ablation of the carbon fibers due to their higher absorption coefficient compared to the epoxy matrix. Although a selective matrix removal without residues is achieved using the pulsed CO₂ laser. Differently, both constituent materials are ablated with the nanosecond pulsed UV laser, producing indentations. The sum of the investigations has shown that existing theories of laser technology, such as the ablation threshold according to Liu et al., can be applied to composite materials only to a limited extent. Furthermore, it has been found that the pronounced heterogeneity of CFRP mostly leads to an inhomogeneous ablation result, both when creating grooves and during selective matrix removal, where the carbon fibers influence the ablation result by their thermal conductivity, depending on fiber direction. Finally, despite the material inhomogeneity, a scanning strategy has been developed to compensate the heterogeneous ablation results regarding structure depth, width and heat affected zone.     

Differential presentation of endogenous and exogenous hepatitis B surface antigens influences priming of CD8+ T cells in an epitope‐specific manner

Little is known about whether presentation of endogenous and exogenous hepatitis B virus (HBV) surface antigens on APCs targeted by vaccination and/or virus‐harboring hepatocytes influences de novo priming of CD8⁺ T cells. We showed that surface antigen‐expressing transfectants exclusively display a K^b/S190 epitope, whereas cells pulsed with recombinant surface particles (rSPs) exclusively present a K^b/S208 epitope to CD8⁺ T cells. The differential presentation of these epitopes largely reflects the selective, but not exclusive, priming of K^b/S190‐ and K^b/S208‐specific T cells in C57BL/6 mice by endogenous/DNA‐ or exogenous/protein‐based vaccines, respectively. Silencing the K^b/S190 epitope (K^b/S190_V194F) in antigen‐expressing vectors rescued the presentation of the K^b/S208 epitope in stable transfectants and significantly enhanced priming of K^b/S208‐specific T cells in C57BL/6 mice. A K^b/S190‐mediated immunodominance operating in surface antigen‐expressing cells, but not in rSP‐pulsed cells, led to an efficient suppression in the presentation of the K^b/S208 epitope and a consequent decrease in the priming of K^b/S208‐specific T cells. This K^b/S190‐mediated immunodominance also operated in 1.4HBV‐S^mut transgenic (tg) hepatocytes selectively expressing endogenous surface antigens and allowed priming of K^b/S208‐ but not K^b/S190‐specific T cells in 1.4HBV‐S^mut tg mice. However, IFN‐γ⁺ K^b/S208‐specific T cells could not inhibit HBV replication in the liver of 1.4HBV‐S^mut tg mice. These results have practical implications for the design of T‐cell‐stimulating therapeutic vaccines.     

New insights into the phenotypic covariance structure of the anthropoid cranium

In complex organisms, suites of non-random, highly intercorrelated phenotypic traits, organized according to their developmental history and forming semi-autonomous units (i.e. modules), have the potential to impose constraints on morphological diversification or to improve evolvability. Because of its structural, developmental and functional complexity, the cranium is arguably one of the best models for studying the interplay between developmental history and the need for various parts of a structure to specialize in different functions. This study evaluated the significance of two specific types of developmental imprints in the adult anthropoid cranium, those imposed by ossification pattern (i.e. ossification with and without a pre-existing cartilaginous phase) and those imposed by tissue origin (i.e. tissues derived principally from neural-crest vs. those derived from paraxial mesoderm). Specifically, this study tests the hypothesis that the face and the basicranium form two distinct modules with higher within-unit trait integration magnitudes compared with the cranium as a whole. Data on 12 anthropoid primate species were collected in the form of 23-dimensional landmarks digitized on cranial surface models that sample the basicranium as well as regions of functional importance during feeding. The presence of a significant modularity imprint in the adult cranium was assessed using a between-region within-species comparison of multivariate correlations (RV coefficients) obtained with partial least-squares, using within-module within-species eigenvalue variance (EV), and using cluster analyses and non-metric multidimensional scaling. In addition to addressing the validity of the cranial modularity hypothesis in anthropoids, this study addressed methodological aspects of the interspecific comparison of morphological integration, namely the effect of sample size and the effect of landmark number on integration magnitudes. Two methodological findings that are of significance to research in morphological integration are that: (i) a smaller sample size increases integration magnitude, but preserves the pattern of variation of integration magnitudes from block to block within species; and that (ii) the number of landmarks per cranial block does not significantly impact block integration magnitude measured as EV. Results from the analyses testing for cranial modularity imprints in the adult anthropoid cranium show that some facial landmarks covary more strongly with basicranial landmarks than with other facial landmarks. Cluster methods, non-metric multidimensional scaling and, to an extent, RV results show that the rostral and the zygomatic landmarks covary more strongly with the basicranial landmarks than they do with the molar landmarks. However, the rostral–zygomatic–basicranial block, the molar block, the facial block, the basicranial block and the other analyzed cranial and facial blocks are not more integrated than the cranium. Thus, the morphological variation in the adult anthropoid cranium is not significantly constrained by at least two of the potential developmental sources of its covariance structure.     

Benzophenone assisted UV-activated synthesis of unique Pd-nanodendrite embedded reduced graphene oxide nanocomposite: a catalyst for C–C coupling reaction and fuel cell

In this work we report the use of benzophenone (BP) for the synthesis of a palladium (Pd) embedded on reduced graphene oxide (rGO) nanocomposite (Pd/rGO) using a simple aqueous solution and UV irradiation. The simple and facile evolution of thermodynamically unstable branched Pd(0) nanodendrites was achieved by BP photoactivation, circumventing the growth of more stable nanomorphologies. The synthesis of Pd(0)-embedded rGO nanosheets (PRGO-nd) was made possible by the simultaneous reduction of both the GO scaffold and PdCl₂ by introducing BP into the photoactivation reaction. The nanocomposites obtained in the absence of BP were common triangular and twinned Pd(0) structures which were also implanted on the rGO scaffold (PRGO-nt). The disparity in morphologies presumably occurs due to the difference in the kinetics of the reduction of Pd²⁺ to Pd⁰ in the presence and absence of the BP photoinitiator. It was observed that the PRGO-nd was composed of dense arrays of multiple Pd branches around nucleation site which exhibited (111) facet, whereas PRGO-nt showed a mixture of (100) and (111) facets. On comparing the catalytic efficiencies of the as-synthesized nanocatalysts, we observed a superiority in efficiency of the thermodynamically unstable PRGO-nd nanocomposite. This is due to the evolved active facets of the dendritic Pd(0) morphology with its higher surface area, as testified by Brunauer–Emmett–Teller (BET) analysis. Since both PRGO-nd and PRGO-nt contain particles of similar size, the dents and grooves in the structure are the cause of the increase in the effective surface area in the case of nanodendrites. The unique dendritic morphology of the PRGO-nd nanostructures makes them a promising material for superior catalysis, due to their high surface area, and the high density of surface atoms at their edges, corners, and stepped regions. We investigated the efficiency of the as-prepared PRGO-nd catalyst in the Suzuki–Miyaura coupling reaction and showed its proficiency in a 2 h reaction at 60 °C using 2 mol% catalyst containing 0.06 mol% active Pd. Moreover, the electrochemical efficiency for the catalytic hydrogen evolution reaction (HER) was demonstrated, in which PRGO-nd provided a decreased overpotential of 68 mV for a current density of 10 mA cm⁻², a small Tafel slope of 57 mV dec⁻¹ and commendable stability during chronoamperometric testing for 5 h.

Benzophenone photoinitiator aided synthesis of Pd-nanodendrite embedded rGO nanocatalyst possessing superior potential in C–C coupling reaction and fuel cell application.