Monoclonal gammopathy of undetermined significance : natural course and comorbidities

Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder characterized by an overproduction of monoclonal immunoglobulins. MGUS is asymptomatic but clinically relevant since annually 0.5-1.5% of individuals with MGUS will develop multiple myeloma (MM) or another malignant lymphoproliferative disease. Individuals with MGUS are followed for signs of progression, however, so far this management strategy has never been evaluated. Results from previous studies have shown that individuals with MGUS have inferior survival and increased risk of thrombosis compared to individuals without MGUS, yet all studies to date have been performed on clinically established cohorts of MGUS patients, introducing a high risk of selection bias. Recently, a new entity called light-chain MGUS (LC-MGUS) has been identified. Very little is known about the epidemiology and clinical course of LC-MGUS. In order to establish a clinically informative, correct, and easily applicable definition of LC-MGUS, and describe the prevalence of MGUS and LC-MGUS in the population, we performed a large population-based screening study. We screened more than 11,000 individuals from the Icelandic AGES-Reykjavik Study cohort and the American PLCO Study cohort. The prevalence of MGUS was 4.8-5.2%. Based on findings from the two cohorts and on statistical analysis of normal distributions, we propose a revised definition of LC-MGUS; (1) an abnormal free light-chain ratio (1.65), (2) an elevated involved light chain concentration (40 mg/L or higher), (3) no M-protein on serum protein electrophoresis or immunofixation, and (4) no evidence of end-organ damage that can be attributed to a lymphoproliferative disorder. The prevalence of LC-MGUS in our study using this definition was 0.9-1.0%. The prevalence of LC-MGUS increased with age (p<0.001), was higher in men (p<0.001), and more common among blacks (2.9%) than whites (0.7%) or Asian/Pacific Islanders (0.2%). The revised definition of LC-MGUS captures the condition in fewer but clinically relevant individuals. We conducted three population-based studies with the purpose of studying the natural course and survival of individuals with MGUS and LC-MGUS. We used the Icelandic AGES-Reykjavik Study cohort of 5,764 individuals, including 300 individuals with MGUS and 52 individuals with LC-MGUS, as well as a Swedish cohort of 18,768 MGUS patients. Through the Swedish Cancer Register we identified all patients with MM diagnosed from 1976 to 2013, as well as randomly sampled population-based controls. Individuals with MGUS had a 1.2-fold (95% confidence interval (CI) 1.04-1.4) and individuals with LC-MGUS had a 1.6-fold (1.2-2.3) increased risk of death compared to individuals without MGUS, during a median follow-up time of almost ten years. The risk remained increased after progression to lymphoproliferative disease was taken into account. We found a personal history of autoimmune disease to increase the risk of death significantly in both individuals with MM (hazard ratio (HR) = 1.2, 1.2-1.3) and individuals with MGUS (HR = 1.4, 1.3-1.4). These findings could be due to an underlying genetic susceptibility for both plasma cell disorders and other conditions, such as autoimmune disease, or to the overproduction of light chains causing organ damage. We found that MM patients with prior knowledge of MGUS had a better overall survival (median survival 2.8 years) than MM patients without prior knowledge of MGUS (median survival 2.1 years). Among MM patients with a prior knowledge of MGUS, a low M-protein concentration at MGUS diagnosis was predictive of worse survival in MM (HR = 1.9, 1.1-3.0), possibly due to patients with low M-protein concentration being followed less frequently. Our findings support the recommendations of regular clinical follow-up of individuals with MGUS, regardless of M-protein concentration. In further analysis of the AGES-Reykjavik Study cohort, we assessed the causes of death and risk of thrombosis among individuals with MGUS and LC-MGUS and found an increased risk of death from cancer (HR = 1.8, 1.6-2.3) and from heart disease (HR = 1.4, 1.1-1.8), adjusted for age and sex. We found that a history of thrombosis was more common in individuals with LC-MGUS (25%) than individuals with MGUS (10%) or without MGUS (12%), and that individuals with LC-MGUS had an increased risk of a history of arterial thrombosis especially (crude odds ratio (OR) = 2.5, 95% CI 1.3-4.9), compared to individuals without MGUS. During a median follow-up time of almost nine years, we detected an almost two-fold risk of arterial thrombosis in individuals with LC-MGUS compared to individuals without MGUS (crude HR = 1.9, 1.1-3.2). No increased risk of venous thrombosis was detected in individuals with MGUS or LC-MGUS. Our results suggest that previously detected increased risks of thrombosis in MGUS have been due to confounding factors. Our findings on LC-MGUS point towards an elevated risk of arterial, but not venous, thrombosis. In future investigations, we suggest attention is focused on characterizing the clinical, genetic, and biochemical profiles of LC-MGUS, with the purpose of understanding the connection to cancer, to heart disease, and to thrombosis

The abundance of HCN in circumstellar envelopes of AGB stars of different chemical types

A multi-transition survey of HCN (sub-) millimeter line emission from a large sample of AGB stars of different chemical type is presented. The data are analysed and circumstellar HCN abundances are estimated. The sample stars span a large range of properties such as mass-loss rate and photospheric C/O-ratio. The analysis of the new data allows for more accurate estimates of the circumstellar HCN abundances and puts new constraints on chemical models. In order to constrain the circumstellar HCN abundance distribution a detailed non-LTE excitation analysis, based on the Monte Carlo method, is performed. Effects of line overlaps and radiative excitation from dust grains are included. The median values for the derived abundances of HCN (with respect to H2) are 3x10-5, 7x10-7 and 10-7 for carbon stars (25 stars), S-type AGB stars (19 stars) and M-type AGB stars (25 stars), respectively. The estimated sizes of the HCN envelopes are similar to those obtained in the case of SiO for the same sample of sources and agree well with previous results from interferometric observations, when these are available. We find that there is a clear dependence of the derived circumstellar HCN abundance on the C/O-ratio of the star, in that carbon stars have about two orders of magnitude higher abundances than M-type AGB stars, on average. The derived HCN abundances of the S-type AGB stars have a larger spread and typically fall in between those of the two other types, however, slightly closer to the values for the M-type AGB stars. For the M-type stars, the estimated abundances are much higher than what would be expected if HCN is formed in thermal equilibrium. However, the results are also in contrast to predictions from recent non-LTE chemical models, where very little difference is expected in the HCN abundances between the various types of AGB stars.Comment: Accepted for publication in A&

The Infinity-Laplacian in Smooth Convex Domains and in a Square

We extend some theorems for the Infinity-Ground State and for the Infinity-Potential, known for convex polygons, to other domains in the plane, by applying Alexandroff's method to the curved boundary. A recent explicit solution disproves a conjecture

Modelling mineral dust using stereophotogrammetry

Real, three-dimensional shape of a dust particle is derived from a pair of scanning-electron microscope images by means of stereophotogrammetry. The resulting shape is discretized, and preliminary discrete-dipole-approximation computations for the single dust particle reveal that scattering by such an irregular shape differs notably from scattering by a sphere or a Gaussian random sphere which both are frequently used shape models for dust particles

Chiral Molecular Tweezers: Synthesis and Reactivity in Asymmetric Hydrogenation

We report the synthesis and reactivity of a chiral aminoborane displaying both rapid and reversible H-2 activation. The catalyst shows exceptional reactivity in asymmetric hydrogenation of enamines and unhindered imines with stereoselectivities of up to 99% ee. DFT analysis of the reaction mechanism pointed to the importance of both repulsive steric and stabilizing intermolecular non-covalent forces in the stereodetermining hydride transfer step of the catalytic cycle

Current questions and possible controversies in autophagy

Interest in autophagy has exploded over the last decade, with publications highlighting crosstalk with several other cellular processes including secretion, endocytosis, and cell suicide pathways including apoptosis. Autophagy proteins have also been implicated in other cellular processes independently of their roles in autophagy, creating complexities in the interpretation of autophagy (Atg) mutant gene data. Interestingly, this self-eating process is a survival mechanism that can also promote cell death, but when and how autophagy may \u27switch\u27 its function is still under debate. Indeed, there are currently many models of how autophagy actually influences cell death. In this review, we highlight some outstanding questions and possible controversies in the autophagy field

The GOAL study: a prospective examination of the impact of factor V Leiden and ABO(H) blood groups on haemorrhagic and thrombotic pregnancy outcomes

Factor V Leiden (FVL) and ABO(H) blood groups are the common influences on haemostasis and retrospective studies have linked FVL with pregnancy complications. However, only one sizeable prospective examination has taken place. As a result, neither the impact of FVL in unselected subjects, any interaction with ABO(H) in pregnancy, nor the utility of screening for FVL is defined. A prospective study of 4250 unselected pregnancies was carried out. A venous thromboembolism (VTE) rate of 1·23/1000 was observed, but no significant association between FVL and pre-eclampsia, intra-uterine growth restriction or pregnancy loss was seen. No influence of FVL and/or ABO(H) on ante-natal bleeding or intra-partum or postpartum haemorrhage was observed. However, FVL was associated with birth-weights &gt;90th centile [odds ratio (OR) 1·81; 95% confidence interval (CI&lt;sub&gt;95&lt;/sub&gt;) 1·04–3·31] and neonatal death (OR 14·79; CI&lt;sub&gt;95&lt;/sub&gt; 2·71–80·74). No association with ABO(H) alone, or any interaction between ABO(H) and FVL was observed. We neither confirmed the protective effect of FVL on pregnancy-related blood loss reported in previous smaller studies, nor did we find the increased risk of some vascular complications reported in retrospective studies

Single scattering by realistic, inhomogeneous mineral dust particles with stereogrammetric shapes

Light scattering by single, inhomogeneous mineral dust particles was simulated based on shapes and compositions derived directly from measurements of real dust particles instead of using a mathematical shape model. We demonstrate the use of the stereogrammetric shape retrieval method in the context of single-scattering modelling of mineral dust for four different dust types – all of them inhomogeneous – ranging from compact, equidimensional shapes to very elongated and aggregate shapes. The three-dimensional particle shapes were derived from stereo pairs of scanning-electron microscope images, and inhomogeneous composition was determined by mineralogical interpretation of localized elemental information based on energy-dispersive spectroscopy. Scattering computations were performed for particles of equal-volume diameters, from 0.08 μm up to 2.8 μm at 550 nm wavelength, using the discrete-dipole approximation. Particle-to-particle variation in scattering by mineral dust was found to be quite considerable and was not well reproduced by simplified shapes of homogeneous spheres, spheroids, or Gaussian random spheres. Effective-medium approximation results revealed that particle inhomogeneity should be accounted for even for small amounts of absorbing media (here up to 2% of the volume), especially when considering scattering by inhomogeneous particles at size parameters 3<<i>x</i><8. When integrated over a log-normal size distribution, the linear depolarization ratio and single-scattering albedo were also found to be sensitive to inhomogeneity. The methodology applied is work-intensive and the light-scattering method used quite limited in terms of size parameter coverage. It would therefore be desirable to find a sufficiently accurate but simpler approach with fewer limitations for single-scattering modelling of dust. For validation of such a method, the approach presented here could be used for producing reference data when applied to a suitable set of target particles

Notocene stratigraphy of the Fletcher Creek and Inangahua Junction areas, North Westland

In the Inangahua and Fletcher Creek areas, North Westland, Greenland Group greywackes and argillites, into which the Tuhua Group granitic rocks have intruded, are unconformably overlain by lower Tertiary to lower Pleistocene transgressive and regressive sediments. Several reference sections in the Tertiary strata have been measured, of which the thickest totals over 1000 m, and is subdivided into the Brunner Formation (coal measures): Island Formation; sandstone and algal limestone and the Kaiata Formation, mudstone, interpretted as a transgressive sequence. The Cobden formation, unconformably lapping onto the Kaiata Formation is delimited at its base by a breccia, deposited during Whaingaroan basin warping and basement faulting, and at its top by a glauconitic phosphatic richly fossiliferous horizon. The regressive sequence is represented by the Inangahua Formation of graded bedded foraminiferal limestones, sandstones and silts conformably overlain by coal measures in Fletcher Creek. Overlying the coal measures is a thin sequence of fossiliferous marine strata of possibly Waitotaram age, overlain by Old Man Gravels deposited at the beginning of the Kaikoura Orogeny. Calcareous Algae and a Teredenit are described in detail

The proper motion of the Arches cluster with Keck Laser-Guide Star Adaptive Optics

We present the first measurement of the proper motion of the young, compact Arches cluster near the Galactic center from near-infrared adaptive optics (AO) data taken with the recently commissioned laser-guide star (LGS) at the Keck 10-m telescope. The excellent astrometric accuracy achieved with LGS-AO provides the basis for a detailed comparison with VLT/NAOS-CONICA data taken 4.3 years earlier. Over the 4.3 year baseline, a spatial displacement of the Arches cluster with respect to the field population is measured to be 24.0 +/- 2.2 mas, corresponding to a proper motion of 5.6 +/- 0.5 mas/yr or 212 +/- 29 km/s at a distance of 8 kpc. In combination with the known line-of-sight velocity of the cluster, we derive a 3D space motion of 232 +/- 30 km/s of the Arches relative to the field. The large proper motion of the Arches cannot be explained with any of the closed orbital families observed in gas clouds in the bar potential of the inner Galaxy, but would be consistent with the Arches being on a transitional trajectory from x1 to x2 orbits. We investigate a cloud-cloud collision as the possible origin for the Arches cluster. The integration of the cluster orbit in the potential of the inner Galaxy suggests that the cluster passes within 10 pc of the supermassive black hole only if its true GC distance is very close to its projected distance. A contribution of young stars from the Arches cluster to the young stellar population in the inner few parsecs of the GC thus appears increasingly unlikely. The measurement of the 3D velocity and orbital analysis provides the first observational evidence that Arches-like clusters do not spiral into the GC. This confirms that no progenitor clusters to the nuclear cluster are observed at the present epoch.Comment: 22 pdflatex pages including 12 figures, reviewed version accepted by Ap