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.     

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.     

CAT correlates positively with respiratory rate and is a significant predictor of the impact of COPD on daily life of patients: a cross sectional study

Background

The pathophysiological changes of COPD tend to worsen with progression, triggering limiting symptoms and implying the decrease in the activities of daily living and quality of life. The COPD Assessment Test (CAT) is a questionnaire designed to measure the impact of COPD on the health status. The aim of this study was to evaluate the impact of the disease through the CAT in a Brazilian sample of COPD patients and to correlate symptoms at rest with the CAT score in these patients.

Methods

Study of cases with COPD patients was conducted by pulmonary rehabilitation program (RP). Respiratory rate (RR) and symptoms (dyspnea by Modified Borg Scale Dyspnea Index; symptoms by CAT) were analyzed at the beginning of the RP.

Results

The study analyzed 28 COPD patients, both genders, age 65.93?±?7.84 years and many patients ranging from severe and very severe disease. The majority of patients were rated by CAT with low impact-disease (n?=?13/46, 4%);medium (n?=?11/39, 3%) and the high impact-diseases were observed in a few subjects (n?=?4/14.3%). The difference between all CAT scores was significant, p?=?0.000. There was a positive correlation between respiratory rate and CAT scores impact-level (r?=?0.585, p?=?0.001). The results obtained by the Borg Scale revealed a high presence of symptoms in these COPD patients but no association with CAT.

Conclusion

The CAT is a sensitive tool to assess the current health status of COPD patients, and in Southern Brazil it is positively correlated with respiratory rate.

     

A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration and considered as an endoplasmic reticulum (ER) disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome and the identification of two causative genes, Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2), a molecular mechanism linking the ER to death of neurons and β cells has not been elucidated. Here we implicate calpain 2 in the mechanism of cell death in Wolfram syndrome. Calpain 2 is negatively regulated by WFS2, and elevated activation of calpain 2 by WFS2-knockdown correlates with cell death. Calpain activation is also induced by high cytosolic calcium mediated by the loss of function of WFS1. Calpain hyperactivation is observed in the WFS1 knockout mouse as well as in neural progenitor cells derived from induced pluripotent stem (iPS) cells of Wolfram syndrome patients. A small-scale small-molecule screen targeting ER calcium homeostasis reveals that dantrolene can prevent cell death in neural progenitor cells derived from Wolfram syndrome iPS cells. Our results demonstrate that calpain and the pathway leading its activation provides potential therapeutic targets for Wolfram syndrome and other ER diseases.The endoplasmic reticulum (ER) takes center stage for protein production, redox regulation, calcium homeostasis, and cell death (1, 2). It follows that genetic or acquired ER dysfunction can trigger a variety of common diseases, including neurodegenerative diseases, metabolic disorders, and inflammatory bowel disease (3, 4). Breakdown in ER function is also associated with genetic disorders such as Wolfram syndrome (5–8). It is challenging to determine the exact effects of ER dysfunction on the fate of affected cells in common diseases with polygenic and multifactorial etiologies. In contrast, we reasoned that it should be possible to define the role of ER dysfunction in mechanistically homogenous patient populations, especially in rare diseases with a monogenic basis, such as Wolfram syndrome (9).Wolfram syndrome (OMIM 222300) is a rare autosomal recessive disorder characterized by juvenile-onset diabetes mellitus and bilateral optic atrophy (7). Insulin-dependent diabetes usually occurs as the initial manifestation during the first decade of life, whereas the diagnosis of Wolfram syndrome is invariably later, with onset of symptoms in the second and ensuing decades (7, 10, 11). Two causative genes for this genetic disorder have been identified and named Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2) (12, 13). It has been shown that multiple mutations in the WFS1 gene, as well as a specific mutation in the WFS2 gene, lead to β cell death and neurodegeneration through ER and mitochondrial dysfunction (5, 6, 14–16). WFS1 gene variants are also associated with a risk of type 2 diabetes (17). Moreover, a specific WFS1 variant can cause autosomal dominant diabetes (18), raising the possibility that this rare disorder is relevant to common molecular mechanisms altered in diabetes and other human chronic diseases in which ER dysfunction is involved.Despite the underlying importance of ER malfunction in Wolfram syndrome, and the identification of WFS1 and WFS2 genes, a molecular mechanism linking the ER to death of neurons and β cells has not been elucidated. Here we show that the calpain protease provides a mechanistic link between the ER and death of neurons and β cells in Wolfram syndrome.