Adherence to treatment guidelines for cancer-associated thrombosis: a French hospital-based cohort study.

PURPOSE: French 2008 treatment guidelines recommend low-molecular-weight heparins (LMWH) for the treatment of cancer-associated thrombosis (CAT) with treatment duration of at least 3 months and up to 6 months and beyond if cancer remains active. Our aim was to assess adherence to guidelines in hospital clinical practice. METHODS: The French hospital database (PMSI) was used to identify patients with CAT admitted to three hospitals of the Paris region to be included in a retrospective cohort study. Adherence to guidelines was assessed in patients included from different treatment periods following the venous thromboembolism (VTE) episode i.e. first 10 days (T1), day 10 to 3 months (T2), months 3 to 6 (T3) and beyond 6 months (T4) when applicable. RESULTS: A total of 240 patients with CAT were included from January 2012 to December 2012 of whom 204 were analyzable. Treatment was adherent to guidelines in 55, 31 and 34 % of patients in T1, T2 and T3 treatment periods, respectively, while overall treatment adherence was found in 52 % of patients. Adherence rates were the highest among patients with pulmonary embolism (PE, 60.5 %), catheter-related thrombosis (62.5 %), class III/IV extended cancer (58.0 %) and metastatic malignancy (60.3 %) while only 40 % with deep vein thrombosis (DVT) received a treatment consistent with guidelines. CONCLUSION: Adherence to guidelines appears insufficient since only half of patients received an appropriate treatment. Adherence dropped significantly across treatment periods T2 and T3. VTE diagnosis and cancer characteristics influenced the anticoagulant prescription. Management of patients with CAT requires further education and information of health care professionals.

[Effect of alpha-conotoxin MII and its N-terminal derivatives on Ca2+ and Na+ signals induced by nicotine in neuroblastoma cell line SH-SY5Y].

Nicotinic acetylcholine receptors (nAChRs) are implicated in the regulation ofintracellular Ca2+-dependent processes in cells both in normal and pathological states, alpha-Conotoxins isolated from Conus snails venom are a valuable tool for the study of pharmacological properties and functional role of nAChRs. In the present study the alpha-conotoxin MII analogue with the additional tyrosine attached to the N terminus (Y0-MII) was prepared. Also we synthesized analogs with the N-terminal glycine residue labeled with the Bolton- Hunter reagent (BH-MII) or fluorestsein isothiocyanate (FITC-MII). Fluorescence microscopy studies of the neuroblastoma SH-SY5Y cells loaded with Ca2+ indicator Fura-2 or with Ca2+ and Na+ indicators Fluo-4 and SBFI were performed to examine effect of MII modification on its ability to inhibit nicotin-induced increases in intracellular free Ca2+ and Na+ concentrations ([Ca2+] and [Na+]i respectively). Monitoring of individual cell [Ca2+]i and [Na+]i signals revealed different kinetics of [Ca2+]i and [Na+]i rise and decay in responses to brief nicotine (Nic) applications (10-30 microM, 3-5 min), which indicates to different mechanisms of Ca2+ and Na+ homeostasis control in SH-SY5Y cells. MII inhibited in concentration-dependent manner the both [Ca2+]i and [Na+]i increase induced by Nic. Additional tyrosine in the Y0-MII or, especially, more sizeable label in FITC-MII significantly reduced the inhibitory effect of MII. Whereas the efficiency of the Ca2+ response inhibition by BH-MII was found to be close to the efficiency of its inhibition by natural alpha-conotoxin MII, radioiodinated derivatives BH-MII can be used in radioligand assay.

Contribution of brain imaging to the diagnosis of intracranial tuberculoma and other brain lesions in patients presenting with miliary tuberculosis.

BACKGROUND: Miliary tuberculosis (miliary TB) is characterized by a hematogenous spread of Mycobacterium tuberculosis. Cerebral lesions associated with miliary TB have been reported with diverse frequencies. METHODS: We retrospectively analyzed brain imaging in 34 patients presenting with proven miliary TB hospitalized in our teaching hospital between 2008 and 2014. RESULTS: Neurological symptoms were present at admission in 15 patients, emerged during treatment in six, and were never reported in 13. Twenty-one of 34 patients had cerebral involvement, of which five patients did not present with any neurological symptoms. The most common brain lesions on MRI were tuberculomas. Cerebrospinal fluid (CSF) analysis showed elevated cell count in eight patients who all had abnormal MRI results. Nine patients with normal CSF had abnormal MRI results. CSF cultures were positive in only eight patients. Paradoxical clinical worsening during TB and corticosteroid treatment was observed in six patients. CONCLUSION: Among patients presenting with miliary TB who underwent brain imaging, more than 60% demonstrated cerebral involvement. Abnormal imaging could occur without any clinical nor CSF impairment. Systematically performing brain imaging in miliary TB patients could therefore be informative.

[New aspects of the theory inflammation (immune inflammation)]. / Novye aspekty ucheniia o vospalenii (immunoe vospalenie).

Immune inflammation (II) arises on the basis of immunopathological mechanisms and acquires certain qualitative and quantitative features. It develops in a sensitized host following a specific immune response. Several kinds of II are to be distinguished differing from each other by the prevalence of disorders in cellular or humoral immunity, the pattern of the antigen, involvement in the response of immunoglobulins of different classes, complement components and a set of mediators. According to Sell's scheme, six immunopathological mechanisms are distinguished which underlie the development of early (like immediate type hypersensitivity) or late (like delayed type hypersensitivity) immune inflammation. Sometimes humoral and cellular mechanisms alternate in II which is reflected in the morphological picture of inflammation. This is illustrated by an example of the study of tissue inflammatory reactions in the synovial membrane in rheumatoid arthritis. Immune inflammation shows a trend to self-reproduction and continuous course with periods of remission and exacerbation of different durations. Timely recognition of immune inflammation is important both theoretically and practically.

[60 years in pathologic anatomy]. / 60 let v patologicheskoi anatomii.

A. I. Strukov--Hero of Socialist Labour, Lenin prize winner, Honoured Scientist, Academician of the USSR Academy of Medical Sciences has been involved in a pathological anatomy for 60 years. He started studying this discipline when a student, and his first teacher was Professor V. A. Afanasyev. After a short period of work as an assistant of a Chair of Pathological Anatomy in Voronezh A. I. Strukov became a chief of a department of pathology in N. A. Semashko City Hospital in Tula. Simultaneously he attended, by correspondence, a postgraduate course in a Chair of Pathological Anatomy headed by Prof. A. I. Abrikosov at the First Moscow University. Later A. I. Strukov moved to Moscow where he started working in a laboratory of pathology of the Central Institute of Tuberculosis of the USSR Ministry of Health, headed by Prof. V. G. Stefko. He inherited from his chiefs the interest to the problem of tuberculosis and, for many years, he has been studying, together with his students, the details of morpho- and pathogenesis and pathomorphosis of this disease. The results of these studies were published in a number of monographs and journals and were included into candidate and doctor theses. A. I. Strukov developed a clinico-morphological classification of tuberculosis recognised by pathologists and clinicians of the USSR. Since 1933 A. I. Strukov worked as an assistant of A. I. Abrikosov's chair and was elected a chief of the Pathological Anatomy Chair of the First Kharkov Medical Institute. He spent the Great Patriotic War (1941-1945) in Orenburg where the Kharkov Medical Institute was evacuated. Here on the basis of local civil and military hospitals, teaching, clinical and scientific work of the institute chairs, including that of pathological anatomy, was developed. A. I. Strukov returned to Moscow in 1944, worked in Prof. V. G. Shtefko's laboratory, then was elected a Professor of a Chair of Pathological Anatomy in the First Moscow Medical Institute. In 1953, after A. I. Abrikosov has retired, A. I. Strukov became the chief of this most prominent chair of pathological anatomy in the country. Continuing the traditions of A. I. Abrikosov's school, A. I. Strukov investigates with his students various problems of pathology (tuberculosis, rheumatic diseases), develops a concept of systemic and progressing disorganisation of connective tissue in rheumatic diseases, continues studying the pathology of broncho-pulmonary lesions, cardio-vascular diseases.(ABSTRACT TRUNCATED AT 400 WORDS)

[Microcirculation and inflammation]. / Mikrotsirkuliatsiia i vospalenie.

On the basis of the literature analysis and own observations the author concludes that the process of inflammation involves all the components of the microcirculatory bed and the endothelial lining: arterioles, blood precapillaries, capillaries, postcapillaries, venules, lymph capillaries, systems of the interstitial tissue channels as well as the connective tissue rich in hyaluronic acid and proteoglycans. The emergence of all cardinal signs of inflammation is associated with damage of different components of the microcirculatory bed. Intensive peroxidation of lipids ("oxidative stress") was observed in the focus of inflammation. Microcirculatory disorders in the inflammation focus are always synchronously accompanied by activation of blood plasma protein systems: coagulation, anticoagulation, kinin, complementary.

[Dialectic of the interrelationship between structure and function in biology and medicine]. / Dialektika vzaimootnoshenii struktury i funktsii v biologii i meditsine.

The paper deals with some aspects of the dialectics of structure and function relationships in biological objects normally and pathologically. Idealistic and metaphysical concepts of the structure-function relationships (morphological idealism, holism, physiological idealism, functionalism) are critisized, and historical premises of these concepts are characterized. The principle of indissoluble unity and interconnection of changes in structure and function is emphasized, while the thesis of the primacy of function in the shaping of the form and the concept of functional diseases are rejected. Much attention is paid to the methodological principles of the study of structure and function based on the systemic approach to the investigation of biological objects from the point of view of structural levels and integratism. The groundlessness of the principles of reductionism and organicism in the solution of this problem is indicated. The connection of the concepts of structure and function with categories and laws of materialistic dialectics is dwelt on.

[Use of morphometry in pathological anatomy]. / O primenenii morfometrii v patologicheskoi anatomii.

The paper describes the main principles of morphometry and its concepts and characterizes the potentials of the morphometric methods. Statistical sampling and conditions of preserving its representative character are dealt with. The implications of some concepts of variation statistics are analysed: mean values, variability indices, confidence intervals, thresholds of confidence probability, criteria of significance, regularities of the distribution of frequencies of sampling elements. The main rules of the factor, correlation, regression, dispersion, and information analysis are described. Attention is drawn to the insufficient use of morphometry potentials. It is stated that morphometric description should not overshadow the specific features of the structures under study.

[Structural and functional bases of hemostasis and its pathology]. / Strukturno-funktsional'nye osnovy gemostaza i ego patologiia.

The multiphase process of blood coagulation occurs owing to the interaction of three links of hemostasis--thrombocyte apparatus, plasma factors, and vascular wall components--and is regulated by the neuro-reflectory mechanisms of the coagulating and anticoagulating systems. At the early stage of hemostasis, a set of reactions begins in the thrombocyte apparatus leading to cell aggregation, secretion of the content of granules, synthesis of prostaglandines and eventually to the formation of thrombocyte thrombus. Disorders in ultrastructures and membranes of thrombocytes, particularly in receptor glycoproteins lead to the development of molecular disease of thrombocyte and to the disturbance of hemostasis. Plasma factors are activated by some proteolysis reactions in the realization of which a great role is played by phospholipids; Ca ions and regulatory proteins. The key reaction of hemostasis is activation of prothrombin into thrombin. Hemostasis disorders at this stage are of congenital (factor deficiency) or acquired (vitamin K deficiency) nature and occur at the molecular level. Hemostasis is terminated by a step-wise formation of fibrin. Disorders of one of the stages of this process due to congenital abnormality of fibrinogen results in coagulation defect due to the molecular disease of fibrinogen. The problem of hemostasis is inseparable from that of the mechanism causing the living host resistance to thrombus formation. The regulation of the liquid state of the blood and its coagulated is performed by the combined functioning of the coagulating and anticoagulating systems.

[Acquired immunodeficiency syndrome]. / Sindrom priobretennogo immunnogo defitsita.

Literature data on etiology, immune disorders, pathological anatomy of the acquired immunodeficiency syndrome (AIDS) was analysed. AIDS is a low-contagious disease, is most likely caused by retrovirus HTLV-III affecting a subpopulation of T-lymphocytes helpers. The disease develops in a small number of persons with antibodies to the mentioned virus, first of all, in homosexuals, drug addicts using parenteral administration of drugs; in patients with hemophilia. The progress of the disease is relatively slow, but at present the outcome of most AIDS cases is fatal. The main cause of mortality is association of intercurrent infectious diseases (viral, parasitic, fungal, bacterial) on the background of the impaired immunity. The autopsy picture is non-specific. The authors pay attention to the high frequency of Kaposi sarcoma among the patients with AIDS. Besides such diagnostic features as presence of antibodies to HTLV-III retrovirus and the clinical picture one should take into account changes in the lymph nodes, presence of viral particles in their bioptates, a high level of alpha-thymosin, a drastic reduction of T-lymphocytes in blood and especially of T-lymphocytes helpers.

[Theoretical concepts of modern pathology (a critique of their medical philosophical foundations)]. / O nekotorykh teoreticheskikh kontseptsiiakh sovremennoi patologii (kritika ikh mediko-filosofskikh obosnovanii).

Separation of theoretical pathology into an independent branch of science seems to be justified and creation of the Centre of Theoretical pathology in the Heidelberg Academy of Sciences is due and useful. As W. Doerr truly states, the theoretical pathology seems to be over the pathological physiology and general pathology, exerts additional functions, studies questions of the methodology in pathology, defines more exactly and analyzes the notion of disease, other concepts and terms, clarifies early preclinical and clinical disease manifestations, determines sociological and psychological factors of disease. However, we are not in full agreement with our colleagues from the FRG in the definition of "disease" and in the interpretation of such categories as "spirit", "soul", "psychic". K. Rotschuh' suggestion to consider the disease in terms of "body-soul" appears to be interesting but to be productive, it must be linked with the problems of medical psychology. W. Doerr and his colleagues support the dualistic concepts of human nature which is unacceptable for us; they claim that the understanding of the theoretical pathology essence is possible only on the basis of theleology and spirit (theology). As the highest commencenment on the way of the theoretical pathology recognition W. Doerr's categorical declaration that theoretical pathology based on the "gestalttheorie" returns scientists, as he writes" to their great delight, to the possibility of studying "spiritual essence of the disease". In W. Doerr's opinion, studying the concept of theoretical pathology "from the spiritual point of view" will ensure its brilliant future. Of course, we, Soviet pathologists and philosophers, do not reject the significance of the integrity theory in the meaning of the disease psycophysiological integrity, yet we decidedly reject any idealistic concepts. W. Doeer and his colleagues are right that the theoretical pathology stimulates the search of the approaches to the solution of complex biomedical problems, favours the creation of more precise definitions and terminology. Likewise, W. Doerr is right that he sharply condemns the attempts of some pathologists to substitute qualitative differences in pathological processes by quantitative ones; this may result, in his view, in one-sided erroneous conclusions.(ABSTRACT TRUNCATED AT 400 WORDS)

[Rheumatoid synovitis (problems of immunomorphology and immunopathogenesis)]. / Revmatoidnyi sinovit (nekotorye voprosy immunomorfologii i immunopatogeneza).

The immunopathogenesis of rheumatoid synovitis (RS) is assumed to be as follows: antigen X interacts with the organism of subjects genetically predisposed to rheumatoid arthritis (RA) as a result of which the immune response regulation is disturbed ("immunological discomfort") leading to changes in proliferation and differentiation of immunocompetent cells immunologically manifested by disturbed ratios of lymphocyte subpopulations and morphologically by immune inflammation of synovial membranes, i.e. RS. Immune inflammation in RS is a systemic, chronic, persisting, recurrent, self-sustained process based on profound changes in qualitative and quantitative aspects of immunological homoeostasis. The results of the authors' own studies indicate that in the inflammation field (eluates of synovial membrane and synovial fluid) rearrangement of lymphocyte subpopulations is more marked than in the peripheral blood of patients with RA. The quantitative deficiency in eluates of synovial membrane and peripheral blood of T gamma-lymphocytes having the suppressive-cytotoxic function confirms the important role of immunoregulation disturbance in the pathogenesis of RA.

[Morphologic and molecular aspects of the interaction of platelets with elements of the vascular wall]. / Morfologicheskie i molekuliarnye aspekty vzaimodeistviia trombotsitov s élementami sosudistoi stenki.

The review presents and analyzes the data available on the structure and functions of adhesive proteins, Willebrand's factor, fibrinogen, thrombospondin, and fibronectin, their secretion and interaction with blood cells and subendothelial matrix in the focus of endothelial desquamation. A structural similarity of these modular glycoproteins, their domain structure-related functions, distinctive features of cellular reception are shown. The authors also consider structural changes in platelets in their activation, rearrangement of glycoprotein complexes IIb/IIIa on the membrane for binding adhesive proteins, role of these proteins in the organization of reversible and stabilized cellular aggregates and their location in the area of the damaged endothelium. The evidence is given for one of the most important mechanisms of limiting the platelet formation-activation system of C protein, which is mediated through thrombin binding to endothelial thrombomodulin. Hemostatic abnormalities occur with congenital defects in the structure of adhesive factors or their receptors while protein deficiency in the C protein system results in formation of thromboses.

[Fibronectin and its role in granuloma formation]. / Fibronektin i ego rol' v granulemoobrazovanii.

Fibronectin (F) is a high-molecular-weight glycoprotein widely presented on the cell surface of fibroblasts, monocytes, endothelial cells and several types of other cells. It is also available in the extracellular matrix of connective tissue and in plasma. Active biologically, F is involved in cell-to-cell and cell-to-substrate adhesion, migration and differentiation of cells, maintenance of cellular structure, wound healing, blood coagulation and opsonic function. In addition, F has a special affinity to collagen, heparin, fibrin and fibrinogen. The above properties suggest F relevance to evolution of productive inflammation and granuloma development. The studies of F presentation, distribution, localization, concentration, function and influence on cell transformation throughout different stages of granuloma evolution can be helpful in elucidation of so far obscure traits of granuloma histogenesis.

[Pathomorphosis of tuberculosis]. / Patomorfoz tuberkuleza.

Based on the analysis of changes considered from the point of view of 4 aspects (epidemiology, pathogenesis, clinico-anatomical manifestations, outcomes, of the disease), the current features of pathomorphosis of tuberculosis are described. It is noted that the present favourable epidemiological situation with regard to tuberculosis does not permit any weakening of measures for control of this disease. In economically developed countries, therapeutic pathomorphosis of tuberculosis is prevalent. In the qualitative spectrum of pathomorphosis of tuberculosis as a disease of the whole organism, particular attention should be paid to residual alterations after clinical cure of tuberculosis, late results of tuberculosis therapy, and complications of various medical interventions, particularly inadequate therapy with the development of immunodeficient condition.

[Comparative pathology of the microcirculatory bed]. / Sravnitel'naia patologiia mikrotsirkuliatornogo rusla

This paper presents an analysis of publications, mostly by Soviet authores, on clinical studies and morphological examinations of the microcirculatory bed in different pathology. It is concluded that the microcirculatory bed should be regarded as an integral system responding to the pathological effects by a local and general reaction of its structural components and by changing the rheological properties of blood. Two types of changes develop in the microcirculatory system -- sterotyped ones, typical for extreme states (various kinds of shock, hypertensive crisis, stress situations), and those specific for certain diseases (diabetes melitus, essential hypertension, athersclerosis, collagenoses, etc.). In all the above diseases the pathological process affects the functional structures of microcirculation that undergo a rearrangement in accordance with the requirements of the body. In the initial period of the disease this re-arrangement is of a compensatory nature and passes ahead of the clinical manifestations. A comparison of the pictutrs obtained by biomicroscopy of the bulbconjunctiva of the eye and of other mucosae with film preparations of the serosae demonstrates their complete similarity. Therefore, the method of biomicroscopy of the eyeball and of the mucosae as a method reflecting the state of microcirculation in the body as a whole should become an integral part of the clinical examination of patients.

[Morphology of immune inflammation in rheumatic diseases]. / Morfologiia immunnogo vospaleniia pri revmaticheskikh zabolevaniiakh.

The results of combined histochemical, immunomorphological, and immunological studies on biopsy, operation, and autopsy materials from 184 patients with rheumatoid arthritis, 41 patients with systemic lupus erythematosus, 66 patients with systemic sclerodermia. 35 patients with periarteritis nodosa are summarized. The main morphological changes in rheumatic diseases were found to be due to immunopathological reactions manifested as immune inflammation. According to the pattern of immunopathological mechanism, early and late immune inflammation manifested by humoral and cellular immunopathological reactions are distinguished. The predominant localization of lesions typical of each rheumatic disease, and the chronic self-maintaining pattern of inflammation are discussed.

[The initial stage of disease]. / O nachal'nom periode bolezni.

The many-year experience of comparing the clinical picture of human disease with its pathological picture indicates that man begins to be aware of the pathological process typical of a given disease in many cases after some, not infrequently long period after its initiation and against the background of already developed morphological changes of organs and tissues. This difference in the time between morphologically initial and clinically early manifestation of disease may be explained by the existence in the body of a strong system of compensatory-adaptive reactions directed to the preservation of homeostasis. When these reactions are disturbed, homeostasis is broken and the disease becomes clinically manifest. A disease may be diagnosed early only when it is recognized in this "latent" period. It is in this period that the damage ("break" according to Pavlov) of the regulating systems frequently far from the target organ occurs. Thus, hypertension arises when the centers regulating the constant level of arterial pressure are damaged, while the entire pathology of hypertension is the effect of this damage. Mammary cancer is the effect of dyshormonal damages occurring in endocrine glands. Many diseases of the stomach are associated with primary involvement of various parts of the central and vegetative nervous system. Damages of the immunocompetent system and disturbances of immunological homeostasis are primary in diseases of the connective tissue with immune disorders and determine their clinical pattern and morphology. The results of morphological investigations performed by modern methods indicate that there are no functional diseases and that each disease has its material substrate determined at all levels of organization beginning from molecular and subcellular and ending with systemic. The material substrate of disease is formed from alterations at the site of the initial lesion and alterations in the target organ in which this lesion is manifested externally. The task of the current medicine is to recognize the morphological and clinical essence of the initial period of disease as an entity which is very important for early diagnosis.

[Morphologic changes in the lymph microcirculation of serous membranes in rheumatism and systemic lupus erythematosus]. / Morfologicheskie izmeneniia limfomikrotsirkuliatsii seroznykh obolochek pri revmatizme i sistemnoi krasnoi volchanke

Microcirculation consists of two elements--hemomicrocirculation and lymphomicrocirculation, the both being closely interrelated with each other. Lymphomicrocirculation was studied on the serous membranes taken from dead people who had died of rheumatism and systemic lupus erythematosus (SLE). The microcirculatory bed in the serous membranes was identified by V. V. Kupriyanov's method. The results of the studies showed that in serous membranes in rheumatism there occurred gradual emptying of lymphomicrocirculation and at the same time--compensatory-adaptive and regeneratory processes, the latter being manifested in formation of blind projections of capillaries, in broadening of the lumen. In SLE the lymphatic link actively participated in elimination of metabolism products and underwent a continuous rearrangement with formation of closed and communicant cysterns. Moreover, there was noted a new formation of lymphatic capillaries, which should be considered as a compensatory-adaptive process. Hemo- and lymphomicrocirculation elements are intimately connected due to close contacts between capillaries of the two elements of microcirculation, however, without formation of connecting fistulas. Hemo- and lymphomicrocirculation is an integrate, and under conditions of pathology there developed therein compensatory-adaptive and regenerative processes aimed at the maintenance of tissue metabolic and hemodynamic homeostasis.

[Leukocyte cytoskeleton under normal and pathological conditions]. / Kletochnyi skelet leikotsitov v norme i patologii.

Like other cells, leukocytes have the cellular skeleton comprising microtubules, actine, myosine, and intermediate filaments. Elements of the cellular skeleton are connected with receptors on the plasma membrane surface and determine the distribution density of these receptors. There is functional relationship between microtubules and actine filaments, in particular, microtubules determine uniform distribution of actine filaments in the cell cytoplasm. The basic principle of functioning of the cellular skeleton consists of the process of polymerization and reversible depolymerization of proteins forming components of the cellular skeleton. These processes are regulated by Ca2+, calmoduline, as well as by the ratio of cyclic adenosine monophosphate and guanidine monophosphate in the cell. The cellular skeleton determines the most important functions of leukocytes: their mobility, binding and absorption of various substances, processes of degranulation, fusion of granules with phagocytic vacuole. Cellular skeleton defects are accompanied by recurrent bacterial infections. Several such defects are known: leukocyte actine dysfunction syndrome, Chediak-Higashi syndrome, syndrome with marked increase in the content of cGMP and microtubules in leukocytes. In these syndromes, the therapeutic effect is achieved with the substances which regulate the level of cyclic nucleotides in leukocytes, among them large doses of ascorbic acid.