Chordal force distribution determines systolic mitral leaflet configuration and severity of functional mitral regurgitation

AbstractOBJECTIVESThe purpose of this study was to investigate the impact of the chordae tendineae force distribution on systolic mitral leaflet geometry and mitral valve competence invitro.BACKGROUNDFunctional mitral regurgitation is caused by changes in several elements of the valve apparatus. Interaction among these have to comply with the chordal forcedistribution defined by the chordal coapting forces (FC) created by the transmitral pressure difference, which close the leaflets and the chordal tethering forces(FT) pulling the leaflets apart.METHODSPorcine mitral valves (n = 5) were mounted in a left ventricular model where leading edge chordal forces measured by dedicated miniature force transducers werecontrolled by changing left ventricular pressure and papillary muscle position. Chordae geometry and occlusional leaflet area (OLA) needed to cover the leaflet orifice for a givenleaflet configuration were determined by two-dimensional echo and reconstructed three-dimensionally. Occlusional leaflet area was used as expression for incomplete leafletcoaptation. Regurgitant fraction (RF) was measured with an electromagnetic flowmeter.RESULTSMixed procedure statistics revealed a linear correlation between the sum of the chordal net forces, ∑[FC−FT]s, and OLA with regression coefficient (minimum − maximum) beta = −115 to −65 [mm2/N]; p< 0.001 and RF (beta = −0.06 to −0.01 [%/N]; p < 0.001). Increasing FTby papillary muscle malalignment restrictedleaflet mobility, resulting in a tented leaflet configuration due to an apical and posterior shift of the coaptation line. Anterior leaflet coapting forces increased due to mitralleaflet remodeling, which generated a nonuniform regurgitant orifice area.CONCLUSIONSAltered chordal force distribution caused functional mitral regurgitation based on tented leaflet configuration as observed clinically

Model for the low-temperature magnetic phases observed in doped YBa_2Cu_3O_{6+x}

A classical statistical model for the antiferromagnetic (AFM) ordering of the Cu-spins in the CuO_2 planes of reduced YBa_2Cu_3O_{6+x} type materials is presented. The magnetic phases considered are the experimentally observed high-temperature AFI phase with ordering vector Q_I=(1/2,1/2,0), and the low-temperature phases: AFII with Q_II=(1/2,1/2,1/2) and intermediate TA (Turn Angle) phases TAI, TAII and TAIII with components of both ordering vectors. It is shown that the AFII and TA phases result from an effective ferromagnetic (FM) type coupling mediated by free spins in the CuO_x basal plane. Good agreement with experimental data is obtained for realistic model parameters.Comment: 11 pages, 2 Postscript figures, Submitted to Phys.Rev.Let

Glassy low-energy spin fluctuations and anisotropy gap in La_1.88Sr_0.12CuO₄

We present high-resolution triple-axis neutron scattering studies of the high-temperature superconductor La1.88Sr0.12CuO4 (Tc=27 K). The temperature dependence of the low-energy incommensurate magnetic fluctuations reveals distinctly glassy features. The glassiness is confirmed by the difference between the ordering temperature TN ~ Tc inferred from elastic neutron scattering and the freezing temperature Tf ~ 11 K obtained from muon spin rotation studies. The magnetic field independence of the observed excitation spectrum as well as the observation of a partial suppression of magnetic spectral weight below 0.75 meV for temperatures smaller than Tf, indicate that the stripe frozen state is capable of supporting a spin anisotropy gap, of a magnitude similar to that observed in the spin and charge stripe ordered ground state of La1.875Ba0.125CuO4. The difference between TN and Tf implies that the significant enhancement in a magnetic field of nominally elastic incommensurate scattering is caused by strictly in-elastic scattering -- at least in the temperature range between Tf and Tc -- which is not resolved in the present experiment. Combining the results obtained from our study of La1.88Sr0.12CuO4 with a critical reappraisal of published neutron scattering work on samples with chemical composition close to p=0.12, where local probes indicate a sharp maximum in Tf(p), we arrive at the view that the low-energy fluctuations are strongly dependent on composition in this regime, with anisotropy gaps dominating only sufficiently close to p=0.12 and superconducting spin gaps dominating elsewhere.Comment: 8 pages, 4 figure

FGF21, a liver hormone that inhibits alcohol intake in mice, increases in human circulation after acute alcohol ingestion and sustained binge drinking at Oktoberfest

Objective: Excessive alcohol consumption is a leading cause of global morbidity and mortality. However, knowledge of the biological factors that influence ad libitum alcohol intake may be incomplete. Two large studies recently linked variants in the KLB locus with levels of alcohol intake in humans. KLB encodes β-klotho, co-receptor for the liver-derived hormone fibroblast growth factor 21 (FGF21). In mice, FGF21 reduces alcohol intake, and human Fgf21 variants are enriched among heavy drinkers. Thus, the liver may limit alcohol consumption by secreting FGF21. However, whether full-length, active plasma FGF21 (FGF21 (1–181)) levels in humans increase acutely or sub-chronically in response to alcohol ingestion is uncertain. Methods: We recruited 10 healthy, fasted male subjects to receive an oral water or alcohol bolus with concurrent blood sampling for FGF21 (1–181) measurement in plasma. In addition, we measured circulating FGF21 (1–181) levels, liver stiffness, triglyceride, and other metabolic parameters in three healthy Danish men before and after consuming an average of 22.6 beers/person/day (4.4 g/kg/day of ethanol) for three days during Oktoberfest 2017 in Munich, Germany. We further correlated fasting FGF21 (1–181) levels in 49 healthy, non-alcoholic subjects of mixed sex with self-reports of alcohol-related behaviors, emotional responses, and problems. Finally, we characterized the effect of recombinant human FGF21 injection on ad libitum alcohol intake in mice. Results: We show that alcohol ingestion (25.3 g or ∼2.5 standard drinks) acutely increases plasma levels of FGF21 (1–181) 3.4-fold in fasting humans. We also find that binge drinking for three days at Oktoberfest is associated with a 2.1-fold increase in baseline FGF21 (1–181) levels, in contrast to minor deteriorations in metabolic and hepatic biomarkers. However, basal FGF21 (1–181) levels were not correlated with differences in alcohol-related behaviors, emotional responses, or problems in our non-alcoholic subjects. Finally, we show that once-daily injection of recombinant human FGF21 reduces ad libitum alcohol intake by 21% in mice. Conclusions: FGF21 (1–181) is markedly increased in circulation by both acute and sub-chronic alcohol intake in humans, and reduces alcohol intake in mice. These observations are consistent with a role for FGF21 as an endocrine inhibitor of alcohol appetite in humans. Keywords: Fibroblast growth factor 21, FGF21, Alcohol, Alcohol appetit

Comparison of Short-Term Estrogenicity Tests for Identification of Hormone-Disrupting Chemicals

The aim of this study was to compare results obtained by eight different short-term assays of estrogenlike actions of chemicals conducted in 10 different laboratories in five countries. Twenty chemicals were selected to represent direct-acting estrogens, compounds with estrogenic metabolites, estrogenic antagonists, and a known cytotoxic agent. Also included in the test panel were 17β-estradiol as a positive control and ethanol as solvent control. The test compounds were coded before distribution. Test methods included direct binding to the estrogen receptor (ER), proliferation of MCF-7 cells, transient reporter gene expression in MCF-7 cells, reporter gene expression in yeast strains stably transfected with the human ER and an estrogen-responsive reporter gene, and vitellogenin production in juvenile rainbow trout. 17β-Estradiol, 17α-ethynyl estradiol, and diethylstilbestrol induced a strong estrogenic response in all test systems. Colchicine caused cytotoxicity only. Bisphenol A induced an estrogenic response in all assays. The results obtained for the remaining test compounds—tamoxifen, ICI 182.780, testosterone, bisphenol A dimethacrylate, 4-n-octylphenol, 4-n-nonylphenol, nonylphenol dodecylethoxylate, butylbenzylphthalate, dibutylphthalate, methoxychlor, o,p′-DDT, p,p′-DDE, endosulfan, chlomequat chloride, and ethanol—varied among the assays. The results demonstrate that careful standardization is necessary to obtain a reasonable degree of reproducibility. Also, similar methods vary in their sensitivity to estrogenic compounds. Thus, short-term tests are useful for screening purposes, but the methods must be further validated by additional interlaboratory and interassay comparisons to document the reliability of the methods