Cardiovascular reflex tests detect autonomic dysfunction in symptomatic and pre-symptomatic subjects with hereditary transthyretin amyloidosis.

PURPOSE: Autonomic dysfunction is a distinctive but undervalued feature of hereditary transthyretin amyloidosis (ATTRv). It may predate the onset of polyneuropathy and cardiomyopathy, thereby providing crucial prognostic and therapeutic information. The objective of this study was to assess autonomic function by means of the standardized cardiovascular autonomic reflex tests (CRTs) in a cohort of subjects with genetically proven ATTRv from non-endemic areas who were in the symptomatic and pre-symptomatic stages. METHODS: All subjects enrolled in this cross-sectional study had genetically proven ATTRv. They underwent the head-up tilt test, Valsalva manoeuvre, deep breathing test, cold face test and handgrip test while under continuous blood pressure and heart rate monitoring. Based on the results of the nerve conduction study, the subjects were divided into two groups: those with polyneuropathy (ATTRv-wPN) and those without polyneuropathy (ATTRv-woPN). Age- and sex-matched healthy controls (HC) were used for comparison. RESULTS: Thirty-seven ATTRv subjects (19 with ATTRv-wPN, 18 with ATTRv-woPN) and 41 HC performed the CRTs. Of these 37 subjects with ATTRv, four (11%) presented neurogenic orthostatic hypotension the during head-up tilt test. Based on the results of the CRTs, autonomic dysfunction characterized by either sympathetic or parasympathetic impairment was detected in 37% and 63% of ATTRv-wPN subjects, respectively. Subjects with ATTRv-woPN presented a significant impairment of autonomic responses to the Valsalva manoeuvre compared to the HC (overshoot p = 0.004; Valsalva ratio p = 0.001). CONCLUSION: Autonomic dysfunctions are frequent in subjects with ATTRv when investigated by means of standardized CRTs, and are also relevant in the pre-symptomatic stage. Cardiovagal functions are the primary functions affected, among others. This may be crucial in defining the proper diagnostic workout for early diagnosis and improving the likelihood of providing the patient with prompt administration of disease-modifying treatments.

A non-classical presentation of APECED in a family with heterozygous R203X AIRE gene mutation.

PURPOSE: Biallelic loss-of-function mutations of AIRE cause the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome. However, single nucleotide mutations may cause a milder phenotype. In this paper, we describe an unusual and mild phenotype in a mother and her two children (son and daughter) who carry a rare heterozygous mutation of AIRE. METHODS AND RESULTS: The son presented with alopecia and subclinical hypothyroidism due to Hashimoto's Thyroiditis (HT); the daughter had alopecia, vaginal mycosis, stomach pains and subclinical hypothyroidism due to HT; and the mother had alopecia, vaginal mycosis and stomach pains. Organ- and non-organ-specific autoantibodies were evaluated as well as antibodies against interleukin-17A, -17F, -22 (IL-Abs) and interferon -α and -ω (IFN-Abs). The organ- and non-organ-specific autoantibodies screening was negative in the son, while the daughter was positive for liver-kidney microsomal antibodies (LKMAbs) and the mother was positive for glutamic acid decarboxylase antibodies (GADAbs). Daughter and mother were also positive for IFN-Abs. Analysis of the AIRE gene identified a rare heterozygous R203X mutation in all three family members. CONCLUSIONS: We describe for a first time a family with heterozygous R203X AIRE mutation causing an APECED-like condition, as confirmed by presence of IFN-Abs. The unusual mild phenotype should be reassuring for the patients and assist in their clinical management.

Non-Bloch-Band Collapse and Chiral Zener Tunneling.

Non-Bloch-band theory describes bulk energy spectra and topological invariants in non-Hermitian crystals with open boundaries, where the bulk eigenstates are squeezed toward the edges (skin effect). However, the interplay of non-Bloch-band theory, skin effect, and coherent Bloch dynamics is so far unexplored. In two-band non-Hermitian lattices, it is shown here that collapse of non-Bloch bands and skin modes deeply changes the Bloch dynamics under an external force. In particular, for resonance forcing non-Bloch-band collapse results in Wannier-Stark ladder coalescence and chiral Zener tunneling between the two dispersive Bloch bands.

Probing the dynamic properties of two sites simultaneously in a protein-protein interaction process: a SDSL-EPR study.

During molecular processes, protein flexibility is a fundamental property allowing protein-protein interaction. Following structural changes during these interactions is then of crucial interest. Site-Directed Spin Labeling (SDSL) combined to EPR spectroscopy is a powerful technique to follow structural modifications within proteins and during protein-protein interactions. Usual nitroxide labels target cysteine residues and afford a 3-line spectrum, whose shape is informative of the structural environment of the label. However, it is not possible to probe two regions of a protein or two partner proteins at the same time because of the overlapping of EPR signatures. Previously, we reported the design and the characterization of a spin label based on a ß-phosphorylated (PP) nitroxide yielding a 6-line spectrum. Here, we report the use of two labels with different EPR signatures, namely maleimido-proxyl (P) and PP, to follow structural changes during a protein-protein interaction process in one single experiment. As a model system, we chose a disordered protein that undergoes an induced α-helical folding upon binding to its partner. We show that the EPR spectrum of a mixture of labeled interacting proteins can be analyzed in terms of structural changes during the interaction. This study represents an important step forward in the extension of the panoply of SDSL-EPR approaches.

Topological Phase Transition in non-Hermitian Quasicrystals.

The discovery of topological phases in non-Hermitian open classical and quantum systems challenges our current understanding of topological order. Non-Hermitian systems exhibit unique features with no counterparts in topological Hermitian models, such as failure of the conventional bulk-boundary correspondence and non-Hermitian skin effect. Advances in the understanding of the topological properties of non-Hermitian lattices with translational invariance have been reported in several recent studies; however little is known about non-Hermitian quasicrystals. Here we disclose topological phases in a quasicrystal with parity-time (PT) symmetry, described by a non-Hermitian extension of the Aubry-André-Harper model. It is shown that the metal-insulating phase transition, observed at the PT symmetry breaking point, is of topological nature and can be expressed in terms of a winding number. A photonic realization of a non-Hermitian quasicrystal is also suggested.

Quantum interference and exceptional points.

Exceptional points (EPs), that is, branch point singularities of non-Hermitian Hamiltonians, are ubiquitous in optics. So far, the signatures of EPs have been mostly studied assuming classical light. In the passive parity-time (PT) optical coupler, a fingerprint of EPs resulting from the coalescence of two resonance modes is a qualitative change of the photon decay law, from damped Rabi-like oscillations to transparency, as the EP is crossed by increasing the loss rate. However, when probed by nonclassical states of light, quantum interference can hide EPs. Here it is shown that, under excitation with polarization-entangled two-photon states, the EP phase transition is smoothed until it disappears as the effective particle statistics are changed from bosonic to fermionic.

Probing one-dimensional topological phases in waveguide lattices with broken chiral symmetry.

One-dimensional lattices with chiral symmetry are known to possess quantized Zak phase and nontrivial topological phases. Here it is shown that the quantized Zak phase and nontrivial edge states, partially protected by inversion symmetry rather than chiral symmetry, can be observed and probed in the bulk exploiting continuous-time photonic quantum walk in zig-zag waveguide arrays. The averaged beam displacement measurements can detect quantized Zak phase and nontrivial topological phases in the extended Su-Schrieffer-Heeger model with broken chiral symmetry.

PT symmetry and antisymmetry by anti-Hermitian wave coupling and nonlinear optical interactions.

Light propagation in systems with anti-Hermitian coupling, described by a spinor-like wave equation, provides a general route for the observation of antiparity-time (PT) symmetry in optics. Remarkably, under a different definition of parity operator, a PT symmetry can be found as well in such systems. Such symmetries are ubiquitous in nonlinear optical interactions and are exemplified by considering modulation instability in optical fibers and optical parametric amplification.

Exceptional points and photonic catastrophe.

Exceptional points (EPs) with a global collapse of pairs of eigenfunctions are shown to arise in two locally coupled and spatially extended optical structures with balanced gain and loss. The global collapse at the EP deeply changes light propagation, which becomes very sensitive to small changes of initial conditions or system parameters, similar to what happens in models of classical or quantum catastrophes. The implications of global collapse for light behavior are illustrated by considering discrete beam diffraction and Bloch oscillation catastrophe in coupled waveguide lattices.

Coherent virtual absorption for discretized light.

Coherent virtual absorption (CVA) is a recently introduced phenomenon for which exponentially growing waves incident on a conservative optical medium are neither reflected nor transmitted, at least transiently. CVA has been associated with complex zeros of the scattering matrix and can be regarded as the time reversal of the decay process of a quasi-mode sustained by the optical medium. Here we consider CVA for discretized light transport in coupled resonator optical waveguides or waveguide arrays and show that a distinct kind of CVA, which is not related to the complex zero excitation of quasi-modes, can be observed. This result suggests that a scattering matrix analysis cannot fully capture CVA phenomena.

Equivalence principle and quantum mechanics: quantum simulation with entangled photons.

Einstein's equivalence principle (EP) states the complete physical equivalence of a gravitational field and corresponding inertial field in an accelerated reference frame. However, to what extent the EP remains valid in non-relativistic quantum mechanics is a controversial issue. To avoid violation of the EP, Bargmann's superselection rule forbids a coherent superposition of states with different masses. Here we suggest a quantum simulation of non-relativistic Schrödinger particle dynamics in non-inertial reference frames, which is based on the propagation of polarization-entangled photon pairs in curved and birefringent optical waveguides and Hong-Ou-Mandel quantum interference measurement. The photonic simulator can emulate superposition of mass states, which would lead to violation of the EP.

Thunderstorm asthma: a critical appraisal based on clinical practice

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Refractionless propagation of discretized light.

Light refraction, i.e., the bending of the path of a light wave at the interface between two different dielectric media, is ubiquitous in optics. Refraction arises from the different speeds of light and is unavoidable in continuous media, according to Snell's Law. Here we show rather counterintuitively that omnidirectional refractionless propagation can be observed for discretized light crossing a tilted interface separating two homogeneous waveguide lattices.

Photonic Loschmidt echo in binary waveguide lattices.

Time reversal is one of the most intriguing yet elusive wave phenomena of major interest in different areas of classical and quantum physics. Time reversal requires in principle to flip the sign of the Hamiltonian of the system, leading to a revival of the initial state (Loschmidt echo). Here it is shown that Loschmidt echo of photons can be observed in an optical setting without resorting to reversal of the Hamiltonian. We consider photonic propagation in a binary waveguide lattice and show that, by exchanging the two sublattices after some propagation distance, a Loschmidt echo can be observed. Examples of Loschmidt echoes for single photon and NOON states are given in one- and two-dimensional waveguide lattices.

Reflectionless and invisible potentials in photonic lattices.

An arbitrarily shaped optical potential on a discrete photonic lattice, which transversely drifts at a speed greater than the maximum speed allowed by the light cone of the lattice band, becomes reflectionless. Such an intriguing result, which arises from the discrete translational symmetry of the lattice, is peculiar to discretized light and does not have any counterpart for light scattering in continuous optical media. A drifting non-Hermitian optical potential of the Kramers-Kronig type also is an invisible potential, i.e., a discrete optical beam crosses the drifting potential without being distorted, delayed, nor advanced.

The relationship between hyperthyrotropinemia and metabolic and cardiovascular risk factors in a large group of overweight and obese children and adolescents.

PURPOSE: Mild TSH elevations are frequently observed in obese patients, in the absence of any detectable thyroid disease. Our objective is to evaluate the relationship between the raised TSH levels and the biochemical and clinical consequences of obesity. METHODS: This is a retrospective cross-sectional study of a large population of obese children and adolescents. We evaluated 833 subjects (340 m, 493 f), aged 14.4 ± 2.5 (range 5.2-18.5) years, height SDS 0.27 ± 1.04 (-3.49-4.35), and BMI SDS 2.94 ± 0.59 (1.60-4.68). Body composition, free T4, TSH, anti-TPO antibodies, anti-TG antibodies, inflammation markers (total WBC and the subtypes, ultrasensitive C-reactive protein), and metabolic parameters [AST, ALT, γGT, ALP, glycaemia, insulin, total cholesterol (TC), HDL-cholesterol (HDL-C), and LDL-cholesterol (LDL-C), triglycerides (TG)] were measured, and oral disposition index (ODI) and cardiovascular risk factors (TC/HDL-C and TG/HDL-C) were calculated. After exclusion of the subjects showing anti-thyroid antibodies, the remaining 779 (325 m, 454 f) were then subdivided into two subgroups according to a TSH value below (group A) or above (group B) 4.5 mU/L. RESULTS: Clinical characteristics and hematological markers of patients with and without positive anti-thyroid antibodies were similar, with the exception of higher TSH levels in the latter group. Using analysis of covariance, the subjects of group B had significantly higher values of TC (170.3 ± 28.7 vs 163.3 ± 32.9 mg/dL; p < 0.05), systolic (125.8 ± 13.5 vs 124.5 ± 13.1 mm/Hg), and diastolic blood pressure (79.2 ± 8.0 vs 77.9 ± 8.2 mm/Hg) than subjects of group A. No difference was observed in body composition, ODI, and the cardiovascular risk factors between these two groups. CONCLUSION: TSH elevation in overweight and obese children and adolescents, being associated with a higher TC and blood pressure, might negatively influence the cardiac status. Longitudinal studies are requested, however, to confirm this hypothesis and, therefore, to conclude whether a substitutive treatment with l-thyroxine is really needed in these patients.

Probing Conformational Changes and Interfacial Recognition Site of Lipases With Surfactants and Inhibitors.

Structural studies on lipases by X-ray crystallography have revealed conformational changes occurring in the presence of surfactants/inhibitors and the pivotal role played by a molecular "lid" of variable size and structure depending on the enzyme. Besides controlling the access to the enzyme active site, the lid is involved in lipase activation, formation of the interfacial recognition site (IRS), and substrate docking within the active site. The combined use of surfactants and inhibitors has been critical for a better understanding of lipase structure-function relationships. An overview of crystal structures of lipases in complex with surfactants and inhibitors reveals common structural features and shows how surfactants monomers interact with the lid in its open conformation. The location of surfactants, inhibitors, and hydrophobic residues exposed upon lid opening provides insights into the IRS of lipases. The mechanism by which surfactants promote the lid opening can be further investigated in solution by site-directed spin labeling of lipase coupled to electron paramagnetic resonance spectroscopy. These experimental approaches are illustrated here by results obtained with mammalian digestive lipases, fungal lipases, and cutinases.

PT-symmetric mode-locking.

Parity-time (PT) symmetry is one of the most important accomplishments in optics over the past decade. Here the concept of PT mode-locking (ML) of a laser is introduced, in which active phase-locking of cavity axial modes is realized by asymmetric mode coupling in a complex time crystal. PT ML shows a transition from single- to double-pulse emission as the PT symmetry breaking point is crossed. The transition can show a turbulent behavior, depending on a dimensionless modulation parameter that plays the same role as the Reynolds number in hydrodynamic flows.