Right Approach, Wrong Implications: A Critique of McKean on Products Liability

I have very little argument with the basic framework which Professor McKean presents. Indeed, if one allows for the limitations on the detail possible in a paper, the framework in many respects closely parallels parts of the framework which I have been using independently and which is partially set out in an article in the Journal of Law and Contemporary Problems and more fully in a recent book. The problems I have are more with the conclusions toward which Professor McKean tends. I say tends because at many points he makes clear that different goals would justify different results, and that, even accepting the goal of economic efficiency, one can logically defend systems of liability different from those which he seems to prefer. Yet once he has said this it seems quite clear that he believes that, to the extent economic efficiency is the goal, a system of consumer liability is likely to be best, except where producer fault or something which he feels is close to it can be shown

Phenotypic effects of expanded ataxin-1 polyglutamines with interruptions in vitro

Spinocerebellar ataxia type 1 is a neurodegenerative disease caused by expansion of an uninterrupted glutamine repeat in ataxin-1 protein. Protein aggregation and immunoreactivity to 1C2 monoclonal antibody are two distinct pathognomonic features of expanded ataxin-1, as well as of other polyglutamine disorders. Rare cases of non-affected elderly subjects carrying expanded ataxin-1 alleles were found in random population. However, in these alleles the glutamine stretch was interrupted by histidines. Due to lack of phenotype, these alleles should be considered "normal". Most importantly, occurrence of these unusual alleles provides a unique opportunity to investigate which molecular properties of expanded ataxin-1 are not coupled to polyglutamine pathogenesis. Towards this goal, we compared in vitro the immunoreactivity to 1C2 antibody and the ability to form aggregates of interrupted and uninterrupted alleles. Immunoblotting showed that expanded-interrupted ataxin-1 had an affinity to 1C2 resembling that of normal ataxin-1. On the contrary, filter assay showed that aggregation rate of expanded-interrupted ataxin-1 resembles that of expanded-uninterrupted ataxin-1. These observations indicate that affinity for 1C2 does not directly correlate with self-aggregation of ataxin-1. Moreover, self-aggregation is not directly affected by histidine interruptions. In conclusion, these results support the hypothesis that mechanisms underlying neuronal degeneration are triggered by protein misfolding rather than by protein aggregation

GR 290 (Romano's Star): 2. Light history and evolutionary state

We have built the historical light curve of the luminous variable GR 290 back to 1901, from old observations of the star found in several archival plates of M 33. These old recordings together with published and new data show that for at least half a century the star was in a low luminosity state, with B ~18. After 1960, five large variability cycles of visual luminosity were recorded. The amplitude of the oscillations was seen increasing towards the 1992-1994 maximum, then decreasing during the last maxima. The recent light curve indicates that the photometric variations have been quite similar in all the bands, and that the B-V color index has been constant within +/-0.1 m despite the 1.5m change of the visual luminosity. The spectrum of GR 290 at the large maximum of 1992-94, was equivalent to late-B type, while, during 2002-2014, it has varied between WN10h-11h near the visual maxima to WN8h-9h at the luminosity minima. We have detected, during this same period, a clear anti-correlation between the visual luminosity, the strength of the HeII 4686 A emission line, the strength of the 4600-4700 A lines blend and the spectral type. From a model analysis of the spectra collected during the whole 2002-2014 period we find that the Rosseland radius R_{2/3}, changed between the minimum and maximum luminosity phases by a factor of 3, while T_eff varied between about 33,000 K and 23,000 K. The bolometric luminosity of the star was not constant, but increased by a factor of ~1.5 between minimum and maximum luminosity, in phase with the apparent luminosity variations. In the light of current evolutionary models of very massive stars, we find that GR 290 has evolved from a ~60 M_Sun progenitor star and should have an age of about 4 million years. We argue that it has left the LBV stage and is moving to a Wolf-Rayet stage of late nitrogen spectral type.Comment: Accepted on The Astronomical Journal, 10 figures. Replaced because the previous uploaded file was that without the final small corrections requested by the refere

Lupin protein exerts cholesterol-lowering effects targeting PCSK9: from clinical evidences to elucidation of the in vitro molecular mechanism using HepG2 cells

PCSK9 inhibition is a novel approach for cholesterol reduction because of its crucial pathophysiological role in cholesterol metabolism. This work aimed at evaluating whether lupin protein/peptides may modulate PCSK9 production. Mild hypercholesterolaemic subjects consumed lupin protein or casein (30 g/day) for 4 weeks. The final level of circulating PCSK9, measured by ELISA, was reduced by 8.5% (p = 0.0454) versus baseline value, whereas it remained unchanged in the control group (casein). For investigating the mechanism of action, HepG2 cells were treated with peptic and tryptic peptides from lupin protein: reductions of PCSK9 production and secretion were observed as well as a decrease of hepatic nuclear factor 1-alpha (HNF1-alpha). For the first time, this work provides evidences that lupin protein/peptides may modulate the PCSK9 protein level production and secretion, contributing to explain the beneficial effects observed in animal and human studies and opening a completely new area of investigation on plant proteins

Normal endothelial function in carriers of the apolipoprotein A-IMilano mutant despite low HDL-cholesterol levels

Carriers of the apolipoprotein A-IMilano (apoA-IM) mutant show severe reductions in the plasma concentration of antiatherogenic HDL but do not present with preclinical atherosclerosis and premature CHD. Aim of the present study was to investigate endothelial function in A-IM carriers, since low HDL-C levels have been associated with features of endothelial dysfunction. Plasma concentrations of soluble cell adhesion molecules (sCAMs) and forearm arterial compliance (FAC) during reactive hyperemia were evaluated in 21 A-IM carriers, 21 healthy subjects with low HDL-C, and 42 controls. Low HDL-C subjects had significantly higher plasma sCAM levels than controls (sVCAM-1: 656.3\ub149.3 vs 502.6\ub125.5 ng/ml; sICAM-1: 335.6\ub121.5 vs 267.0\ub18.9 ng/ml; sE-selectin: 62.9\ub14.1 vs 47.9\ub13.0 ng/ml); on the contrary, no differences were detected between A-IM carriers (sVCAM-1: 550.6\ub132.1 ng/ml; sICAM-1: 309.8\ub126.9 ng/ml; sE-selectin: 52.3\ub14.3 ng/ml) and controls. Low HDL-C subjects had lower FAC than controls, while no differences were detected between A-IM carriers and controls. These results suggest that HDL from A-IM carriers may be more efficient than control HDL in modulating endothelial function. To test this hypothesis, plasma HDL were isolated from 6 A-IM carriers and 6 controls, and their ability to inhibit VCAM-1 expression and to induce eNOS was tested in cultured endothelial cells. A-IM HDL were two times more effective than control HDL in reducing TNFalpha-induced VCAM-1 expression; the inhibition occurred at a transcriptional level, as demonstrated by RT-PCR. In addition, cells exposed to A-IM HDL showed higher expression of eNOS than cells treated with control HDL. In conclusion, despite the very low HDL-C levels, A-IM carriers do not display features of endothelial dysfunction, such as the increase of circulating sCAM levels and the impairment of arterial compliance, probably because of a superior ability of A-IM HDL to protect the endothelium

Peginterferon beta-1a improves MRI measures and increases the proportion of patients with no evidence of disease activity in relapsing-remitting multiple sclerosis: 2-year results from the ADVANCE randomized controlled trial

Summary of MRI endpoints over 2 years by original randomisation group [6]. (DOC 53kb

The variable carbon star CGCS 6107

The spectroscopic and photometric variability of CGCS 6107 has been studied with four telescopes from 2015 to 2018. The star varied between R=11.4 and 14.2 mag with a time scale of 500 days. An appreciable color variation was observed, the star being bluer when brighter. H emission was present around maxima. The spectrum is that of an N type giant veiled by a variable dusty envelope

Treatment with fibrates is associated with higher LAL activity in dyslipidemic patients

Lysosomal acid lipase (LAL) is responsible for the hydrolysis of cholesteryl esters (CE) and triglycerides (TG) within the lysosomes; generated cholesterol and free fatty acids (FFA) are released in the cytosol where they can regulate their own synthesis and metabolism. When LAL is not active, as in case of genetic mutations, CE and TG accumulate in the lysosomal compartment, while the lack of release of cholesterol and FFA in the cytosol leads to an upregulation of their synthesis. Thus, LAL plays a central role in the intracellular homeostasis of lipids. Since there are no indications about the effect of different lipid-lowering agents on LAL activity, aim of the study was to address the relationship between LAL activity and the type of lipid-lowering therapy in a cohort of dyslipidemic patients. LAL activity was measured on dried blood spot from 120 patients with hypercholesterolemia or mixed dyslipidemia and was negatively correlated to LDL-cholesterol levels. Among enrolled patients, ninety-one were taking one or more lipid-lowering drugs, as statins, fibrates, ezetimibe and omega-3 polyunsaturated fatty acids. When patients were stratified according to the type of lipid-lowering treatment, i.e. untreated, taking statins or taking fibrates, LAL activity was significantly higher in those with fibrates, even after adjustment for sex, age, BMI, lipid parameters, liver function, metabolic syndrome, diabetes and statin use. In a subset of patients tested after 3 months of treatment with micronized fenofibrate, LAL activity raised by 21%; the increase was negatively correlated with baseline LAL activity. Thus, the use of fibrates is independently associated with higher LAL activity in dyslipidemic patients, suggesting that the positive effects of PPAR-\u3b1 activation on cellular and systemic lipid homeostasis can also include an improved LAL activity