Des guidelines pour l’intelligence artificielle !

Following the emergence of open public databases and connected objects, big data and artificial intelligence are developing rapidly, especially in medicine, with many opportunities ranging from complex diagnostic assistance to real-time statistical analysis. In order to promote their development and guide their use in the field of internal medicine, guidelines and recommendations are needed. First of all, this article seeks to clarify the concepts of big data and artificial intelligence and the correlations between each other, and then to give an overview of the progress made at European level in this rapidly expanding field.     

Paper electrophoresis of abnormal hemoglobins and its clinical applications; a simple semiquantitative method for the study of the hereditary hemoglobinopathies

1. Paper electrophoresis of abnormal hemoglobins is a simple and convenienttechnic for the study of the hereditary hemoglobinopathies.

2. A semiquantitative paper electrophoretic technic is described, which allows rather accurate quantitation of the various hemoglobin components byinspection alone.

3. For exact results, the more elaborate technics of elution or photoelectric scanning may be employed. The accuracy of these quantitative technics isillustrated by artificial mixture experiments.

4. The clinical applications of the method in the study of sickle cell diseaseand hemoglobin C abnormalities are discussed. Apart from the more commonhemoglobin abnormalities (such as sickle cell trait, sickle cell anemia, C trait,sickle cell-hemoglobin C disease), a patient with 100 per cent hemoglobin C(homozygous hemoglobin C disease) and a Negro patient with sickle cell-thalassemia disease were discovered. Normal adult hemoglobin (hemoglobin A) wasfound in all other hereditary and acquired anemias studied. Slightly increasedamounts of fetal hemoglobin were detected in cases of hereditary nonspherocytichemolytic disease and aregenerative anemia.

5. This technic may be used for red cell life span determinations by seriallyfollowing the disappearance of a certain hemoglobin type transfused into apatient with a different hemoglobin variety. Further applications of the technicare suggested.

6. The combination of the technics of paper electrophoresis and alkali denaturation offer an adequate, simple, and practical tool for diagnosis and investigation of hereditary hemoglobinopathies.

7. Identical apparatus and buffer may be used for serum protein electrophoresis.

Submitted on November 10, 1953 Accepted on December 3, 1953     

Nanoparticle: a nightmare for the future

Nanotechnology is a new discipline where 1-100 nanometers long particles are used, with an extensive field of application including physics, chemistry, electronics, energy production, biology, and medicine. Just as in every innovation, the effects of this technology and its products on environment and health are wondered. Lungs are the major port of entry and target of the nanoparticles in human body. This review will discuss, in the light of the literature, the possible adverse effects of nanoparticles on living beings and especially on respiratory system.     

Modified Hemoglobin-based Blood Substitutes: Crosslinked,Recombinant and Encapsulated Hemoglobin

Native hemoglobin in the form of stroma-free hemoglobin cannot be used as blood substitute. Hemoglobin has to be modified either molecularly or encapsulated. First generation molecularly modified ultrapure hemoglobins are now in clinical trial - some in Phase III. There are a number of these. Polyhemoglo- bin is formed by crosslinking hemoglobin molecules intermolecularly and intra- molecularly. A crosslinked single hemoglobin molecule is formed by crosslinking hemoglobin intramolecularly. Recombinant hemoglobin from E.coli is formed by fusion of the subunits of each hemoglobin molecule. Conjugated hemoglobin is formed by crosslinking each hemoglobin molecule to soluble polymers. A second generation system formed by crosslinking hemoglobin- superoxide dismutase-catalase is being developed. A third generation hemoglobin-based blood substitute is based on microencapsulated hemoglobin, artificial red blood cells, that more closely resemble a complete red blood cell.     

Significant structure theory applied to liquid He

The large kinetic zero-point motion of ⁴He molecules has been properly taken into account in the significant structure theory of liquids in order to describe the liquidity of liquid ⁴He. The Debye and the Bose-Einstein partition functions are used for the solid-like molecules of the normal fluid component and for the whole gas-like molecules, respectively. The solid-like molecules of the superfluid component are considered as ground state molecules without having positional degeneracies. The Bragg-Williams approximation of an order/disorder phase transition has been applied to the λ transition of liquid ⁴He. Thermodynamic and surface properties of liquid ⁴He have been calculated up to the critical point. The results are satisfactory when compared with the observed values.     

Studies on the serum haptoglobin level in hemoglobinemia and its influence on renal excretion of hemoglobin

A short survey is given of the literature on haptoglobin, the hemoglobin-binding serum protein, its properties and biologic variations. The principles of anelectrophoretic method for quantitative determination of the serum haptoglobinare described.

Electrophoretic studies showed that haptoglobin has a high affinity for hemoglobin at physiologic pH and that every haptoglobin molecule can bind at least2 hemoglobin molecules.

Observations made following the intravenous injection of hemoglobin showed:

that hemoglobin administered intravenously is bound by the haptoglobin;

that free hemoglobin is not demonstrable until more hemoglobin has beeninjected than can be bound by the haptoglobin;

that the complex hemoglobin-haptoglobin is eliminated from the plasma afterintravascular hemolysis or intravenous administration of hemoglobin withoutbeing excreted in the urine;

that the hemoglobin-haptoglobin complex is removed from the plasma at aconstant rate during the major part of the elimination period;

that the haptoglobin level will fall to nil within 24 hours, if the amount ofhemoglobin injected is sufficient to bind all the haptoglobin available. Duringthe following days the rate of formation of haptoglobin can be studied.

From the data available it can be concluded that hemoglobinuria cannotappear until the amount of hemoglobin administered intravenously or the amountliberated intravascularly exceeds the binding power of the haptoglobin and thereabsorption capacity of the tubules. The variation observed by earlier authorsin the so-called renal threshold for hemoglobin on intravenous injection of hemoglobin can be explained among other things by the variation in the haptoglobincontent in one and the same subject, i.e., if the haptoglobin level is low, thethreshold value will also be low, and vice versa.

Submitted on August 21, 1956 Accepted on November 28, 1956     

Nanotechnology in cardiovascular medicine.

Nanotechnology is a new field of science and technology that has already had significant impact in the development of novel products in industry. In medicine, application of nanotechnology has the potential to develop new imaging agents, pharmaceutical drugs and medical devices with unique physical and chemical properties. This article reviews the potential for various nanoparticles in cardiovascular imaging and therapeutics, nanoporous structures for sensing and implant based drug delivery, and self-assembled monolayers for surface modification and implant based drug delivery.     

Nonspecific serum iron in thalassemia: quantitation and chemical reactivity.

We reported earlier an abnormal iron population in the serum of patients with transfusional hemosiderosis secondary to thalassemia. The iron is not bound to transferrin, ferritin, or hemoglobin and is referred to as nonspecific iron. This publication reports studies of the chemical reactivity and nature of the nonspecific iron and the development and validation of a method for its quantitative analysis. The quantitation depends on the mobilization of this iron from nonspecific macromolecular binding sites by ethylenediamine tetraacetic acid and subsequent separation from Fe³⁺-transferrin-CO⅔⁻ and residual hemoglobin by ultrafiltration. Analyses of filtrate iron were carried out by atomic absorption and colorimetric methods. The accuracy of the test was established via an ultrafiltration titration of serum of known unsaturated iron-binding capacity. The method proved to be accurate and highly reproducible. Sera containing artificial introduced nonspecific iron were prepared. The reactivity of artificial and thalassemic nonspecific iron was examined with regard to reduction and chelation, and chelation by apotransferrin. Artificial and thalassemic nonspecific iron were found to be virtually identical in reactivity and to exhibit multiphasic kinetics consistent with nonspecific binding to several serum protein sites. The reaction of apotransferrin with nonspecific iron was complete within one minute. The reduction-chelation and apotransferrin reactivity studies offer independent analyses of nonspecific serum iron concentrations which compared closely with the chelation-ultrafiltration technique.     

Personalized medicine in women's obesity prevention and treatment: implications for research,policy and practice

The prevalence of obesity in America has reached epidemic proportions, and obesity among women is particularly concerning. Severe obesity (body mass index ≥35 kg m^?2) is more prevalent in women than men. Further, women have sex‐specific risk factors that must be considered when developing preventive and therapeutic interventions. This review presents personalized medicine as a dynamic approach to obesity prevention, management and treatment for women. First, we review obesity as a complex health issue, with contributing sex‐specific, demographic, psychosocial, behavioural, environmental, epigenetic and genetic/genomic risk factors. Second, we present personalized medicine as a rapidly advancing field of health care that seeks to quantify these complex risk factors to develop more targeted and effective strategies that can improve disease management and/or better minimize an individual's likelihood of developing obesity. Third, we discuss how personalized medicine can be applied in a clinical setting with current and emerging tools, including health risk assessments, personalized health plans, and strategies for increasing patient engagement. Finally, we discuss the need for additional research, training and policy that can enhance the practice of personalized medicine in women's obesity, including further advancements in the ‘‐omics’ sciences, physician training in personalized medicine, and additional development and standardization of innovative targeted therapies and clinical tools.     

Electric field effect on cholesterol-phospholipid complexes

Monolayer mixtures of dihydrocholesterol and phospholipids at the air-water interface are used to model membranes containing cholesterol and phospholipids. Specific, stoichiometric interactions between cholesterol and some but not all phospholipids have been proposed to lead to the formation of condensed complexes. It is reported here that an externally applied electric field of the appropriate sign can destabilize these complexes, resulting in their dissociation. This is demonstrated through the application of an electric field gradient that leads to phase separations in otherwise homogeneous monolayers. This is observed only when the monolayer composition is close to the stoichiometry of the complex. The electric field effect is analyzed with the same mean field thermodynamic model as that used previously to account for pairs of upper miscibility critical points in these mixtures. The concentrations of dihydrocholesterol, phospholipid, and complex vary strongly and sometimes discontinuously in the monolayer membrane in the field gradient. The model is an approximation to a two-dimensional liquid in which molecules freely exchange between free and complexed form so that the chemical potentials are constant throughout the membrane. The calculations are illustrated for a complex of about 15 molecules, composed of 5 cholesterol molecules and 10 phospholipid molecules.     

An aspartate and a water molecule mediate efficient acid-base catalysis in a tailored antibody pocket

Design of catalysts featuring multiple functional groups is a desirable, yet formidable goal. Antibody 13G5, which accelerates the cleavage of unactivated benzisoxazoles, is one of few artificial enzymes that harness an acid and a base to achieve efficient proton transfer. X-ray structures of the Fab-hapten complexes of wild-type 13G5 and active-site variants now afford detailed insights into its mechanism. The parent antibody preorganizes Asp^H35 and Glu^L34 to abstract a proton from substrate and to orient a water molecule for leaving group stabilization, respectively. Remodeling the environment of the hydrogen bond donor with a compensatory network of ordered waters, as seen in the Glu^L34 to alanine mutant, leads to an impressive 10⁹-fold rate acceleration over the nonenzymatic reaction with acetate, illustrating the utility of buried water molecules in bifunctional catalysis. Generalization of these design principles may aid in creation of catalysts for other important chemical transformations.     

Erythropoietic Activity of Steroid Metabolites in Mice

The per cent Fe⁵⁹ incorporation into circulating erythrocytes as an indicator for new hemoglobin production was used in the polycythemic exhypoxic mouse system to study the effects of certain steroid hormone metabolites on erythropiesis. Enhanced Fe⁵⁹ incorporation was observed after the administration of several metabolites with a 5β-H configuration, while those with a 5α-H configuration had no stimulatory effect. The stimulatory effect in avian systems has been shown by others to be due to an increased activity of δ-aminolevulinic acid synthetase, the limiting enzyme in heme biosynthesis. These in vivo studies thus indicate that in this mouse system, as in previously reported studies with avian and human bone marrow cells, some steroid metabolites stimulate hemoglobin synthesis. The observation that the same structure-junction relationship exists in the currently described system as in the avian suggests that these steroids probably induce δ-aminolevulinic acid synthetase in the mouse. The erythropoietic action of these nonandrogenic steroid metabolites may prove to be clinically useful.     

On the Williams-Watts function of dielectric relaxation

It has been observed over the past 15 years that experimental frequency-dependent dielectric constants of broad classes of materials including polymeric systems and glasses may be interpreted in terms of the Williams-Watts polarization decay function [Formula: see text] The exponent α and the time constant T depend on the material and fixed external conditions such as temperature and pressure. We derive this form of ϕ_α(t) from the following random-walk model. Suppose that an electric field has been applied for some time to a medium containing many polar molecules (or polar groups in complex molecules) and the direction of their dipole moments remains frozen as the field is removed. Furthermore, suppose that the medium contains mobile defects that on reaching the site of a frozen dipole relax the medium to the degree that the dipole may reorient itself. If the diffusion of defects toward dipoles is executed as a continuous-time random walk composed of an alternation of steps and pauses and the pausing-time distribution function has a long tail of the form ψ(t) ∞ t^-1-α, then the relaxation function has the above fractional exponential form.     

Integrating the Accreditation Council for Graduate Medical Education Core competencies into the model of the clinical practice of emergency medicine

In response to public pressure for greater accountability from the medical profession, a transformation is occurring in the approach to medical education and assessment of physician competency. Over the past 5 years, the Accreditation Council for Graduate Medical Education (ACGME) has implemented the Outcomes and General Competencies projects to better ensure that physicians are appropriately trained in the knowledge and skills of their specialties. Concurrently, the American Board of Medical Specialties, including the American Board of Emergency Medicine (ABEM), has embraced the competency concept. The core competencies have been integral in ABEM's development of Emergency Medicine Continuous Certification and the development of the Model of Clinical Practice of Emergency Medicine (Model).¹ ABEM has used the Model as a significant part of its blueprint for the written and oral certification examinations in emergency medicine and is fully supportive of the effort to more fully define and integrate the ACGME core competencies into training emergency medicine specialists.To incorporate these competencies into our specialty, an Emergency Medicine Competency Taskforce (Taskforce) was formed by the Residency Review Committee–Emergency Medicine to determine how these general competencies fit in the Model.¹ This article represents a consensus of the Taskforce with the input of multiple organizations in emergency medicine. It provides a framework for organizations such as the Council of Emergency Medicine Residency Directors (CORD) and the Society for Academic Emergency Medicine to develop a curriculum in emergency medicine and program requirement revisions by the Residency Review Committee–Emergency Medicine. In this report, we describe the approach taken by the Taskforce to integrate the ACGME core competencies into the Model. Ultimately, as competency-based assessment is implemented in emergency medicine training, program directors, governing bodies such as the ACGME, and individual patients can be assured that physicians are competent in emergency medicine.     

Switching to BCL-6 Negativity in Relapsed Diffuse Large B Cell Lymphoma Correlated with More Aggressive Disease Course

Diffuse large B-cell lymphoma (DLBCL) is the most frequent, complex and heterogeneous lymphoma of adulthood. Heterogeneity is expressed at clinical, genetic, and molecular levels. It is known that BCL-6 expression is a favorable prognostic factor in DLBCL. However, the underlying mechanisms of BCL-6 expression in DLBCL relapse are not yet elucidated. Here, we present so far undescribed clinical phenomenon of switching BCL-6⁺ protein expression into BCL-6⁻ expression in 19 of 41 relapsed DLBCL patients. The switch in relapsed DLBCL was associated with more aggressive clinical course of the disease. Bone marrow infiltration and high IPI risk were more often present in BCL-6⁻ patients. Significantly increased biochemical parameters, such as LDH, beta-2 macroglobulin, CRP, and ferritin have been found, as well as significantly decreased serum Fe, TIBC, and hemoglobin. A Ki-67 proliferation marker was considerably high in relapsed DLBCL, but without significant differences between BCL-6⁺ and BCL-6⁻ groups of patients. Thus, switching of the positive into negative BCL-6 expression during DLBCL relapse could be used as a prognostic factor and a valuable criterion for treatment decision.     

Personalized Medicine for Diabetes: Circulating Biomarkers of Glycemia in Diabetes Management and Implications for Personalized Medicine

Personalized medicine represents a new model in how the medical community approaches disease management. Rather than managing those with a particular diagnosis according to an established guideline, the personalized medicine model seeks to identify unique characteristics within each patient that can serve as a basis for disease characterization and specialized treatment. This article reviews several circulating biomarkers of glycemia that are used in the medical management of diabetes, to include hemoglobin A1c, fructosamine, and 1,5-anhydroglucitol. Within the discussion, specific attention is paid to areas in which biomarker results do not correlate with anticipated results based on actual mean glycemia. Variability between actual and anticipated results of the various biomarker tests represents opportunities to identify previously undefined subcategories of diabetes and groups of patients that fit into these subcategories. Finally, research areas are proposed for these subcategories that would further promote the field of personalized medicine in diabetes.     

Zinc chlorins for artificial light-harvesting self-assemble into antiparallel stacks forming a microcrystalline solid-state material

We introduce a concept to solve the structure of a microcrystalline material in the solid-state at natural abundance without access to distance constraints, using magic angle spinning (MAS) NMR spectroscopy in conjunction with X-ray powder diffraction and DFT calculations. The method is applied to a novel class of materials that form (semi)conductive 1D wires for supramolecular electronics and artificial light-harvesting. The zinc chlorins 3-devinyl-3¹-hydroxymethyl-13²-demethoxycarbonylpheophorbide a (3′,5′-bis-dodecyloxy)benzyl ester zinc complex 1 and 3-devinyl-3¹-methoxymethyl-13²-demethoxycarbonylpheophorbide a (3′,5′-bis-dodecyloxy)benzyl ester zinc complex 2, self-assemble into extended excitonically coupled chromophore stacks. ¹H-¹³C heteronuclear dipolar correlation MAS NMR experiments provided the ¹H resonance assignment of the chlorin rings that allowed accurate probing of ring currents related to the stacking of macrocycles. DFT ring-current shift calculations revealed that both chlorins self-assemble in antiparallel π-stacks in planar layers in the solid-state. Concomitantly, X-ray powder diffraction measurements for chlorin 2 at 80 °C revealed a 3D lattice for the mesoscale packing that matches molecular mechanics optimized aggregate models. For chlorin 2 the stacks alternate with a periodicity of 0.68 nm and a 3D unit cell with an approximate volume of 6.28 nm³ containing 4 molecules, which is consistent with space group P2₁22₁.     

Elevated micronuclei frequency in type 2 diabetes with high glycosylated hemoglobin

Aim

The role of oxidative damage to DNA due to hyperglycemia is well known. In the current study we have evaluated the induction of micronuclei due to increased glycosylation in type 2 diabetes.

Methods

Forty-nine subjects divided into two groups of normoglycemic controls and type 2 diabetic cases were recruited in the study. Whole blood was cultured and micronuclei were scored in all the cases. This was correlated with age, sex, blood glucose levels and glycosylated hemoglobin.

Results

Age and sex matched diabetic patients had an increased micronuclei frequency in response to elevated glycosylation of hemoglobin (R² = 0.229, p = 0.037) compared to normoglycemic subjects.

Conclusion

The increased glycosylation seems to induce oxidative damage in the DNA of the diabetic patients, which manifests as an increased micronuclei frequency. This has a potential to be used as a biomarker for subsequent diabetic complications.     

Conformation of cyclo(-L-Pro-Gly-)(3) and its Ca and Mg complexes

The synthetic hexapeptide cyclo(-L-Pro-Gly-)₃ is an ionophore that shows interesting conformational changes upon binding metal ions. X-ray crystallographic studies of this peptide show that when it is crystallized from an ethanol/ethyl acetate mixture the ring takes up an asymmetric conformation containing one cis peptide bond. In crystals of a Ca²⁺ complex, the cation is sandwiched between two peptide molecules that differ markedly in conformation. However, both exhibit threefold symmetric forms, with all six peptide bonds in the molecule occurring in the usual trans conformation. The Ca²⁺ is octahedrally surrounded by six glycyl carbonyl oxygens from the two peptides at an average distance of 2.26 Å and can easily be released by the disruption of the peptide sandwich. In the magnesium complex, the peptide forms a 1:1 complex with the ion. The Mg²⁺ is octahedrally coordinated to three glycyl carbonyls and three water oxygens. The average coordination distance between magnesium and the peptide oxygens is 2.03 Å and that between magnesium and water oxygen is 2.11 Å. The two peptide molecules in the asymmetric unit have similar conformations and have approximate threefold symmetry.     

Successfully implemented artificial intelligence and machine learning applications in cardiology: State-of-the-art review

The omnipresence and deep impact of artificial intelligence (AI) in today's society are undeniable. While the technology has already established itself as a powerful tool in several industries, more recently it has also started to change the practice of medicine. The aim of this review is to provide healthcare providers working in the field of cardiovascular medicine with an overview of AI and machine learning (ML) algorithms that have passed the initial tests and made it into contemporary clinical practice. The following domains where AI/ML could revolutionize cardiology are covered: (i) signal processing, (ii) image processing, (iii) clinical risk stratification, (iv) natural language processing, and (v) fundamental clinical discoveries.