Autoantibodies to the insulin receptor. Effect on the insulin-receptor interaction in IM-9 lymphocytes

The serum of some patients with insulin-resistant "diabetes" contains antibodies that bind to and block the cell membrane receptors for insulin. In this report, we have characterized the effects of the antireceptor antibodies on the interaction of (125)I-insulin with its receptor on the human lymphoblastoid cell line IM-9. Up to 95% of specific insulin binding can be inhibited by pretreatment of the cells with these immunoglobulins. The onset of the inhibitory effect is time- and temperature-dependent, and the effect is reversed extremely slowly if the cells are suspended in a large excess of antibody-free buffer. These features of antibody binding can be easily distinguished from those for insulin binding to its receptor. The inhibitory effect of the antibodies can be reversed by exposure of the cells to conditions known to elute surface immunoglobulins. The three antireceptor sera studied appear to alter the insulin-receptor interaction in different ways. Two antisera markedly reduce receptor affinity through combined effects on the insulin association and dissociation rates, and, additionally, have smaller effects on available receptor number. A third antiserum primarily affects available receptor number and has little effect on receptor affinity. All three antisera inhibit the capacity of insulin to promote negatively cooperative site-site interactions among insulin receptors. The data suggest that these autoantibodies to the insulin receptor bind to different determinants on the receptor and may therefore be useful as unique probes of insulin receptor structure and function.     

Structured learning with constrained conditional models

Making complex decisions in real world problems often involves assigning values to sets of interdependent variables where an expressive dependency structure among these can influence, or even dictate, what assignments are possible. Commonly used models typically ignore expressive dependencies since the traditional way of incorporating non-local dependencies is inefficient and hence leads to expensive training and inference. The contribution of this paper is two-fold. First, this paper presents Constrained Conditional Models (CCMs), a?framework that augments linear models with declarative constraints as a way to support decisions in an expressive output space while maintaining modularity and tractability of training. The paper develops, analyzes and compares novel algorithms for CCMs based on Hidden Markov Models and Structured Perceptron. The proposed CCM framework is also compared to task-tailored models, such as semi-CRFs. Second, we propose CoDL, a?constraint-driven learning algorithm, which makes use of constraints to guide semi-supervised learning. We provide theoretical justification for CoDL along with empirical results which show the advantage of using declarative constraints in the context of semi-supervised training of probabilistic models.     

Demagnetization of Ce impurities in superconducting (La,Th)Ce alloys: Specific heat results

Detailed measurements of the specific heat jump C at the superconducting transition temperatureT _c as a function ofT _c are reported for several (La, Th)Ce systems. The measurements document the continuous demagnetization of the Ce impurity ions which proceeds with increasing Th concentration, and provide a critical test of a theory recently developed by Müller-Hartmann and Zittartz for the superconducting behavior of matrix-impurity systems which simultaneously exhibit both superconductivity and the Kondo effect.Research supported by the U.S. Air Force Office of Scientific Research, Grant No. AF-AFOSR-71-2073.Research supported by the University of Chile-University of California Cooperative Program sponsored by the Ford Foundation.     

Oxidative erosion of graphite in air between 600 and 1000 K

The oxidative erosion of seven types of graphite has been investigated by heating in air at temperatures between 600 and 1000 K. The specimens include pyrolytic graphite, fine-grain graphites, carbon-fibre composites (CFC), and graphites doped with Si and Ti. The weight loss was measured using a microbalance, the surface morphology by scanning electron microscopy, and the composition of the surface layer by MeV ion beam techniques. Pyrolytic graphite is least affected by erosion, while pure and Si-doped CFCs erode particularly fast. Typical erosion rates for specimens with a surface area of ?4 cm² are below 0.2 μg/m² s at 600 K for all graphite types, and at 900 K range from 0.34 mg/m² s for pyrolytic graphite to about 9 mg/m² s for the strongest eroding types. The temperature dependence of the erosion rate of all types of graphite studied is well described by an activation energy of 1.7 eV. The erosion rates of these graphites are by far lower than the removal rates for deposited amorphous hydrocarbon layers. In contrast to all other types, the Ti-doped graphite absorbs a significant amount of oxygen reaching up to ?5% of its original mass. Once the oxygen uptake is saturated, it erodes with rates similar to those of the strongest eroding types.     

Electronic energy-density effects in ion tracks of metals

High resolution Auger-electron spectroscopy has been applied to the interaction of swift heavy ions with atomically clean metallic solids. Spectra have been taken for fast projectile electrons and for charge-state equilibrated ions at normal incidence on microcrystalline beryllium samples, Al(1 0 0) single crystals and several metallic glasses (Al₈₇La₇Ni₅Zr₁, Ni₇₈B₁₄Si₈, Co₆₆Si₁₆B₁₂Fe₄Mo₂). From the energy shift and from the Auger-line width we have extracted ion-track potentials and also electron temperatures inside ion tracks. A first determination of the angular distribution of multiple-ionization lines is presented as well.     

Das Problem der verantworteten Therapieentscheidung in der Neonatologie

Definition of the problem: Physicians and nurses who work in neonatology—as in intensive care at all—are often forced to decide whether to stop or to continue with the treatment of a severely ill patient. The literature provides several decision making instruments, which are meant to help and to rationalize such decisions. Method and conclusion: Two of these instruments (“Schema zur ethischen Urteilsbildung nach dem Muster der aristotelischen Ethik”, Honnefelder 1994; “Nimwegener Methode für ethische Fallbesprechung”, Gordijn 1998) were tested by retrospectively examining two cases of our NICU. Results of our study show that the use of a decision making instrument is basically helpful. But the above mentioned instruments showed also shortcomings when used in the framework of neonatology. Therefore we developed the “Kölner Arbeitsbogen zur ethischen Entscheidungsfindung in der Neonatologie”, which is adapted to the specific needs of neonatology.     

Terminale Sedierung aus juristischer Sicht

Definition of the problem: Terminal sedation has recently been discussed as part of the standard of care in the end of life area. Within the palliative care context the term is commonly used as the “induction and maintainance of a sedated state with the intent of relieving otherwise intractable distress, both physical and mental in a patient close to death”. While some representatives of palliative care medicine stress that terminal sedation is only used as a “last resort”, e.g. when other standard methods of palliative care have failed, the opponents express fear of a new and uncontrolled “form of active euthanasia.” Especially when instituted together with a withdrawal of nutrition and hydration, terminal sedation is often deemed to be closer to active euthanasia and a prohibition is demanded. Arguments and conclusion: This article explores the legal meaning of terminal sedation. Along the way it will demonstrate that terminal sedation is — under certain conditions — neither equivalent to active euthanasia nor is it forbidden physician-assisted suicide. Examples for practice guidelines that meet the legal framework are suggested in the article.     

Calorimetric and thermodynamic analysis of palladium-deuterium electrochemical cells

An analysis is made of the chemical heats liberated from a palladium-deuterium electrochemical cell operating inside a calorimeter. It is important, in such an analysis, to carefully identify the chemical and electrochemical sources of heat, before any “excess heats” can be ascribed to non-chemical reactions.⁽¹⁾ The calorimeter measures the enthalpy (ΔH _r ) of the reaction; whereas, the electrochemical voltage of the cell reflects the free energy (ΔG _r ) of the reaction within the Pd-D electrolysis cell. The heat energy from the calorimeter cell therefore doesnot equal the electrical energy supplied to the cell, as might initially be expected. The magnitudes of the differing calorimetric and electrochemical energies were found to be related through the “thermoneutral potential” (ξ_H) of the electrochemical reaction. The chemical heat theoretically expected from the calorimeter is given by (1) I(ξ_L-ξ_H), the cell current (I), multiplied by the difference between the operating cell voltage (ξ_L) and the thermoneutral potential (ξ_H), rather than (2) Iξ_L, the electrical input power. This was verified empirically using a freon vaporization calorimeter, which operates on the principle of accurate measurement of the vaporization rate of liquid freon which completely surrounds the electrochemical cell. The calorimetrically-measured heats observed from a Pt/D₂O, 0.1M LiOD/Pd electrochemical cell were within 2% of the thermoneutral potential predicted value, I(ξ_L-ξ_H); but were found to be 15–30% less than the electrical work supplied to the cell, Iξ_L. Measurements of D₂O consumed by the cell reactions also verified that essentially no significant recombination of D₂ and O₂ gases occurred within the cell. No “excess heats” were observed from this Pd cell during the 36 days of its electrolytic operation. Likewise, no increase in the neutron flux around the cell was found, using three³He radiation detectors.     

Patient-Derived Multiple Myeloma 3D Models for Personalized Medicine—Are We There Yet?

Despite the wide variety of existing therapies, multiple myeloma (MM) remains a disease with dismal prognosis. Choosing the right treatment for each patient remains one of the major challenges. A new approach being explored is the use of ex vivo models for personalized medicine. Two-dimensional culture or animal models often fail to predict clinical outcomes. Three-dimensional ex vivo models using patients’ bone marrow (BM) cells may better reproduce the complexity and heterogeneity of the BM microenvironment. Here, we review the strengths and limitations of currently existing patient-derived ex vivo three-dimensional MM models. We analyze their biochemical and biophysical properties, molecular and cellular characteristics, as well as their potential for drug testing and identification of disease biomarkers. Furthermore, we discuss the remaining challenges and give some insight on how to achieve a more biomimetic and accurate MM BM model. Overall, there is still a need for standardized culture methods and refined readout techniques. Including both myeloma and other cells of the BM microenvironment in a simple and reproducible three-dimensional scaffold is the key to faithfully mapping and examining the relationship between these players in MM. This will allow a patient-personalized profile, providing a powerful tool for clinical and research applications.