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PubMed1992

Antiretroviral chemotherapy of human immunodeficiency virus infections other than with azidothymidine.

The intense research effort to develop molecules with the ability to inhibit the replication of human immunodeficiency virus type 1 was greatly facilitated by the elucidation of the viral life cycle. This information engendered the production of novel antiretroviral agents that inhibit human immunodeficiency virus type 1 at different points in its replicative cycle. The nucleoside analogue 3'-azido-2',3'-dideoxythymidine (azidothymidine) inhibits reverse transcriptase, and it was the first compound tested in patients with the acquired immunodeficiency syndrome. Considerable knowledge of the activity and toxicity of this class of drugs has accumulated. Less well-characterized compounds inhibit human immunodeficiency virus type 1 binding and absorption to target cells, prevent the expression of viral genetic material critical for the construction of new infectious viral progeny, and inhibit the posttranslational modification of viral polypeptides. In additional, biologic response, modifiers act to restore immune function by a number of diverse mechanisms. The ultimate goal is the discovery of compounds capable of inducing a complete and permanent remission of infection.

Acquired Immunodeficiency Syndrome↗
PubMed1977

[Endocrinology of the chiasma syndromes (author's transl)].

A wealth of new knowledge about the function of the hypothalamo-hypophyseal system has been accumulated over the past ten years and progress keeps going at a fast pace. Several factors have contributed to this explosive growth: Pituitary hormones can now be measured by radio-immunoassay in body fluids, hypothalamic stimulating and inhibiting factors have been identified and are available for clinical studies and dynamic tests have been developed for detailed investigations of minor disturbances in the pituitary control system. A tremendous gain in accuracy of clinical diagnosis and endocrine follow-up is one of the consequences. Furthermore, new clinical pictures have emerged such as several variants of the hyperprolactinemia-hypogonadism syndrome or the concept of pituitary microadenoma. At the same time, neuropharmacology is also developing at a tremendous pace and exceedingly interesting perspectives linking neurotransmission with endocrinology and with various diseases of the brain are emerging. One highlight is the discovery of bromoergocryptine as a dopaminergic agonist, active in suppressing prolactin secretion as well as in treating Parkinsonism. In a second part of this presentation 5 cases with pituitary disease are presented. They were selected to cover part of the wide range of clinical signs and symptoms produced by tumours of the pituitary region. There is indeed no good relationship between ophthalmo-neurologic symptoms, destruction of the bony sella and endocrine disturbances.

Adenoma, Acidophil↗
PubMed1990

Experimental hypersensitivity pneumonitis: influence of donor sensitization.

Experimental hypersensitivity pneumonitis (EHP) can be transferred to strain 2 guinea pigs by lymphoblasts from lymph node cells from sensitized guinea pigs cultured in vitro with antigen. We sought to examine the relationship between characteristics of the donor animal and development of competence to transfer EHP. We also compared cell populations that were capable and incapable of transfer using flow cytometry and fluorescein conjugated anti-Ig to determine cell size and surface IgG + (SIg +: surface immunoglobulin-positive) cells. Lymph node cells from donor animals were cultured with a soluble extract of Micropolyspora faeni (10 micrograms/ml) for 72 hours; blasts were then isolated and transferred intravenously to syngeneic recipients. Control recipients received an equal volume of medium. Four groups of donors were used: animals systemically sensitized with Freund's adjuvant and M. faeni and challenged with two, four, or eight weekly intratracheal injections of M. faeni (2-, 4-, and 8-week group); and animals sensitized with Freund's adjuvant and normal saline and challenged with two weekly intratracheal injections of normal saline (NS group). Recipients were challenged intratracheally with M. faeni 48 hours after the cell transfer and killed 4 days thereafter. Randomly selected microscopic fields of the lung (250/animal) were judged to be normal or abnormal without knowledge of treatment. All animals were maintained in high efficiency particulate accumulator-filtered air. There was a low level of pulmonary response to an intratracheal challenge of M. faeni in animals that received media.(ABSTRACT TRUNCATED AT 250 WORDS)

Actinomycetales Infections↗
PubMed1989

Niemann-Pick disease types C and D.

Patients grouped into categories termed type C Niemann-Pick disease and the Nova Scotia isolate called type D Niemann-Pick disease are characterized by mild to moderate hepatosplenomegaly, sea-blue histiocytes in the bone marrow, supranuclear gaze paresis in the vertical plane, slowly progressing ataxia, and mental deterioration. These signs are caused by abnormal intracellular cholesterol homeostasis. Cholesterol that enters cells from the circulation through the LDL receptor is not processed in a timely, normal manner by cells in parenchymal organs and the CNS. It therefore accumulates in toxic quantities as unesterified cholesterol causing cellular and tissue damage. Knowledge of the primary, consistent disturbance in cholesterol disposition has led to the development of tests to diagnose patients, identify heterozygotes, and assure the prenatal detection of these disorders. Therapeutic strategies include reduction of dietary cholesterol, apheresis techniques designed to reduce LDL cholesterol available to cells, and reduction of formation of LDL and increase of synthesis of HDL to lower cellular uptake of cholesterol and enhance egress of this lipid from intracellular storage sites. The development of procedures that block cholesterol formation but do not up-regulate LDL receptors on plasma cell membranes is considered to be highly important for the therapy of types C and D Niemann-Pick disease.

Adult↗
PubMedDate not supplied

Application of flow cytometry in chronobiology.

A survey is given on flow cytometric techniques and their applications in chronobiology. Rapid automatic single cell measurements with a high rate (1,000-5,000 single cells/sec) enable the accumulation of large numbers of data at short intervals, thus obtaining important knowledge on circadian variations of cell proliferation in epidermis and other types of surface epithelium as well as hemopoiesis. In addition, the method has to some extent been used for monitoring cancer chemotherapy, and is thus available for the application in chronotherapy of malignancy. The introduction of rapid automatic techniques such as flow cytometry is a great advantage for any study on single cells and tissues where rhythmic variations in different functions have to be taken into consideration.

Animals↗
PubMed1980

[Radiological anatomy appearances of the colon after double contrast examination (author's transl)].

In this article, concerned with the normal radiological anatomy appearances of the colon after double contrast (mucography) examination, the authors develop the notion of an anteroposterior spatial disposition of the colon. Knowledge of the inclined zones, variable with incidence, in which the barium accumulates, is derived from this notion which appears, therefore, to be of practical value when performing or interpreting double contrast images. The second part of the article concerns a radiological study of the haustrations (blind sacs) and valves of the colon. This precise description of the three rows of haustral sacs could have topographical value in pathological conditions.

Barium Sulfate↗
PubMed1996

[Optic nerve regeneration by nerve transplantation].

The optic nerve fibers of adult mammals, once injured, can not regenerate spontaneously. However, from recent studies it has become clear that when their extracellular environment is replaced with that of the peripheral nervous system, namely surrounded with Schwann cells, they can regenerate their axons through the grafted nerve. Previous studies on the optic nerve regeneration by peripheral nerve transplantation have been done mostly in rats or hamsters. With an expectation of clinical application in future, we studied the optic nerve regeneration of adult cats because a great deal of knowledge on the optic nerve fibers and retinal ganglion cells had been accumulated. From recent series of studies we have obtained following results. 1. Retinal ganglion cells that regenerated axons constitute 2--4% of the total population, and among several types of ganglion cells, alpha cells have the greatest capacity for axonal regeneration. The ability of alpha cells for axonal regeneration is related to their relative resistance to axotomy. 2. Retinal ganglion cells with regenerated axons preserve their original dendritic fields, but their axons are thinner than normal, and mostly unmyelinated. 3. Single unit activities recorded from teased fibers of regenerated axons revealed that the units have mostly normal receptive field properties, enabling us to classify them into Y, X or W cells. 4. Amplitude reduction of pattern reversed electroretinogram (ERG) after the optic nerve section was slowed, to some extent, by the peripheral nerve transplantation. How we can reconnect these regenerated optic nerve fibers to the target neurons in the central visual system is a matter for future study.

Animals↗
PubMedDate not supplied

[Evaluation of iron overload in thalassemia].

The aim of the paper is to assess the value of a series of clinical and laboratory indices used in determining the degree of iron overload in homozygous beta-thalassaemic patients. 155 thalassaemic patients of different age in chelation with subcutaneous infusions of desferrioxamine for a period of 2-7 years have been studied. Calculation of the total iron accumulated and the iron load per kg of body weight in patients undergoing chelation requires an exact knowledge of their compliance and faecal and urinary iron elimination, and is clearly open to many errors. Despite this, usefull information can be derived from its determination. We have found, for example, that serious organ damage tends to appear when iron accumulation exceeds 1 g/kg. In addition, the serum ferritin and the evaluation of the growth have been proved to be the most important and helpful indices for checking the effectiveness of the chelation therapy and forecasting the appearance of the serious complications as diabetes or hypothyroidism.

Adolescent↗
PubMed2007

The grapevine transcription factor VvMYBPA1 regulates proanthocyanidin synthesis during fruit development.

Proanthocyanidins (PAs; or condensed tannins) can protect plants against herbivores, contribute to the taste of many fruits, and act as dietary antioxidants beneficial for human health. We have previously shown that in grapevine (Vitis vinifera) PA synthesis involves both leucoanthocyanidin reductase (LAR) and anthocyanidin reductase (ANR). Here we report the characterization of a grapevine MYB transcription factor VvMYBPA1, which controls expression of PA pathway genes including both LAR and ANR. Expression of VvMYBPA1 in grape berries correlated with PA accumulation during early berry development and in seeds. In a transient assay, VvMYBPA1 activated the promoters of LAR and ANR, as well as the promoters of several of the general flavonoid pathway genes. VvMYBPA1 did not activate the promoter of VvUFGT, which encodes the anthocyanin-specific enzyme UDP-glucose:flavonoid-3-O-glucosyltransferase, suggesting VvMYBPA1 is specific to regulation of PA biosynthesis in grapes. The Arabidopsis (Arabidopsis thaliana) MYB transcription factor TRANSPARENT TESTA2 (TT2) regulates PA synthesis in the seed coat of Arabidopsis. By complementing the PA-deficient seed phenotype of the Arabidopsis tt2 mutant with VvMYBPA1, we confirmed the function of VvMYBPA1 as a transcriptional regulator of PA synthesis. In contrast to ectopic expression of TT2 in Arabidopsis, constitutive expression of VvMYBPA1 resulted in accumulation of PAs in cotyledons, vegetative meristems, leaf hairs, and roots in some of the transgenic seedlings. To our knowledge, this is the first report of a MYB factor that controls genes of the PA pathway in fruit, including both LAR and ANR, and this single MYB factor can induce ectopic PA accumulation in Arabidopsis.

Amino Acid Sequence↗
PubMed1977

[Heredopathia atactica polyneuritiformis. Hexadecanoic acid storage disease (Refsum's disease). Definition, treatment and pathogenesis. A short review].

Heredopathia atactica polyneuritiformis is a clinical-genetic-biochemical entity. It is therefore not a syndrome, but a nosological entity, a morbus sui generis and it is caused by a single autosomal gene. The importance of phytanic acid accumulation in this disease was first demonstrated by Klenk and Kahlke. To the author's knowledge no case with all the typical symptoms and signs of heredopathia atactica polyneuritiformis and without any atypical clinical features, has yet been reported without a concomitant disturbance of phytanic acid metabolism. The dietary treatment--(a low phytol, low phytanic acid diet)--was first proposed by Eldjarn, when the preliminary experimental results indicated that the phytanic acid was of exogenous origin. Whatever the biochemical mechanism is between accumulation of phytanic acid and clinical manifestations in heredopathia atactica polyneuritiformis, it appears that the observations made on patients following successful dietary treatment are convincing and leave little doubt that most, if not all, the manifestations in this disease are caused in some way by the accumulation of phytanic acid.

Blood-Brain Barrier↗
PubMed2006

Knowledge discovery in traditional Chinese medicine: state of the art and perspectives.

OBJECTIVE: As a complementary medical system to Western medicine, traditional Chinese medicine (TCM) provides a unique theoretical and practical approach to the treatment of diseases over thousands of years. Confronted with the increasing popularity of TCM and the huge volume of TCM data, historically accumulated and recently obtained, there is an urgent need to explore these resources effectively by the techniques of knowledge discovery in database (KDD). This paper aims at providing an overview of recent KDD studies in TCM field. METHODS: A literature search was conducted in both English and Chinese publications, and major studies of knowledge discovery in TCM (KDTCM) reported in these materials were identified. Based on an introduction to the state of the art of TCM data resources, a review of four subfields of KDTCM research was presented, including KDD for the research of Chinese medical formula, KDD for the research of Chinese herbal medicine, KDD for TCM syndrome research, and KDD for TCM clinical diagnosis. Furthermore, the current state and main problems in each subfield were summarized based on a discussion of existing studies, and future directions for each subfield were also proposed accordingly. RESULTS: A series of KDD methods are used in existing KDTCM researches, ranging from conventional frequent itemset mining to state of the art latent structure model. Considerable interesting discoveries are obtained by these methods, such as novel TCM paired drugs discovered by frequent itemset analysis, functional community of related genes discovered under syndrome perspective by text mining, the high proportion of toxic plants in the botanical family Ranunculaceae disclosed by statistical analysis, the association between M-cholinoceptor blocking drug and Solanaceae revealed by association rule mining, etc. It is particularly inspiring to see some studies connecting TCM with biomedicine, which provide a novel top-down view for functional genomics research. However, further developments of KDD methods are still expected to better adapt to the features of TCM. CONCLUSIONS: Existing studies demonstrate that KDTCM is effective in obtaining medical discoveries. However, much more work needs to be done in order to discover real diamonds from TCM domain. The usage and development of KDTCM in the future will substantially contribute to the TCM community, as well as modern life science.

Databases, Factual↗
PubMed1999

Storage of whole blood before separation: the effect of temperature on red cell 2,3 DPG and the accumulation of lactate.

BACKGROUND: Although whole blood intended for component preparation is commonly left to cool at ambient temperature, knowledge is insufficient as to the effects this may have on red cell quality, in particular after a prolonged hold. STUDY DESIGN AND METHODS: Whole blood collected in ACD-A (7% wt/wt) and CPD (12% wt/wt) was incubated at 4, 10, 15, 20, 25, and 30 degrees C for 24 hours. Blood gases, pH, bicarbonate, glucose, lactate, and red cell 2,3 DPG were investigated. RESULTS: When the blood was stored at 30 degrees C, the 2,3 DPG concentration decreased within 4 hours from 858 +/- 106 to 316 +/- 172 mmol per mol of hemoglobin (a 63% decrease); 99 percent was lost within 18 hours. At 25 degrees C, 46 percent was lost within 4 hours and 94 percent within 18 hours; at 20 degrees C, the decrease at 18 hours was 62 percent and that at 15 degrees C was 24 percent. No loss of 2,3 DPG was observed at 4 degrees C and 10 degrees C storage. No difference was attributable to the anticoagulant used. After 24 hours, the lactate concentration at 15 degrees C was 2.9 times the original, that at 20 degrees C was 3.8 times the original, that at 25 degrees C was 7.0 times, and that at 30 degrees C was 9.2 times. CONCLUSIONS: With current anticoagulants, storage of whole blood at temperatures of 25 to 30 degrees C before separation causes a great and rapid loss of 2,3 DPG and an accumulation of acid metabolites. In a hold of blood for >4 hours, rapid cooling is desirable to avoid initial loss of 2,3 DPG.

2,3-Diphosphoglycerate↗
PubMed2006

Metabolic engineering of strains of Ralstonia eutropha and Pseudomonas putida for biotechnological production of 2-methylcitric acid.

In this study strains of Ralstonia eutropha H16 and Pseudomonas putida KT2440 were engineered which are suitable for biotechnological production of 2-methylcitric acid (2MC). Analysis of a previous mutant of R. eutropha able to accumulate 2MC recommended this strain as a candidate for fermentative production of 2MC. This knowledge was used for construction of strains of R. eutropha H16 and P. putida KT2440 capable of enhanced production of 2MC. In both bacteria the chromosomal genes encoding the 2-methyl-cis-aconitate hydratase (acnM) were disrupted by directed insertion of a copy of an additional 2-methylcitrate synthase gene (prpC) yielding strains R. eutropha DeltaacnM(Re)OmegaKmprpC(Pp) and P. putida DeltaacnM(Pp)OmegaKmprpC(Re). In both strains 2-methylcitrate synthase was expressed under control of the constitutive kanamycin-resistance gene (OmegaKm) resulting in up to 20-fold higher specific 2-methylcitrate synthase activities in comparison to the wild type. The disruption of the acnM gene by insertion of prpC led to a propionate- and levulinate-negative phenotype of the engineered strains, and analysis of supernatant of these strains revealed overproduction and accumulation of 2MC in the medium. A two stage cultivation regime comprising an exponential growth phase and a 2MC production phase was developed and applied to both engineered strains for optimum production of 2MC. Whereas gluconate, fructose or succinate were provided as carbon source for the exponential growth phase, a combination of propionate or levulinate as precursor substrate for provision of propionyl-CoA and succinate or fumarate as precursor substrate for provision of oxaloacetate were used in the production phase to make sure that the 2-methylcitrate synthase was provided with their substrates. Employing the optimised feeding regime P. putida DeltaacnM(Pp)OmegaKmprpC(Re) and R. eutropha DeltaacnM(Re)OmegaKmprpC(Pp) produced 2MC up to maximal concentrations of 7.2 g/L or 26.5 mM and 19.2 g/L or 70.5 mM, respectively, during 144 h of cultivation.

Bioreactors↗
PubMed1999

Role for NF-kappa B in mediating the effects of hyperoxia on IGF-binding protein 2 promoter activity in lung alveolar epithelial cells.

The surface of the pulmonary alveolus is a major target for oxidant injury, and its proper repair following injury is dependent on the proliferative response of the stem cells of the alveolar epithelium, the type 2 cells. In previous studies on the mechanisms controlling this response, we have documented involvement of several components of the IGF system, and mainly of the IGF binding protein-2 (IGFBP-2). We have provided evidence that this binding protein was associated with inhibition of DNA synthesis of type 2 cells exposed to oxidants and that its expression was regulated mostly at the level of transcription. In the present study, we focused on the factors involved in this regulation. From examination of the IGFBP-2 gene promoter sequence which revealed the presence of four potential binding sites for transcription factors of the NF-kappa B/Rel family, we hypothesized that NF-kappa B might be involved in the transcriptional activation of IGFBP-2 in oxidant-exposed cells. Data reported herein demonstrated that NF-kappa B activated IGFBP-2 promoter in transient transfection assays, and that exposure of cells to hyperoxia was associated with accumulation of the active form of NF-kappa B. Using gel shift analysis, we documented in O2-treated cells an increased binding to the four NF-kappa B binding sites. We also showed that accumulation of NF-kappa B was associated with a decrease in the inhibitory molecule I kappa B-alpha. Based on the current knowledge on NF-kappa B regulation, it is likely that in a number of situations associated with injury of lung alveolar epithelial cells signaling events involving accumulation of NF-kappa B converge to activate IGFBP-2 and to block entry into S phase.

Animals↗
PubMed2006

Evaluation of PROforma as a language for implementing medical guidelines in a practical context.

BACKGROUND: PROforma is one of several languages that allow clinical guidelines to be expressed in a computer-interpretable manner. How these languages should be compared, and what requirements they should meet, are questions that are being actively addressed by a community of interested researchers. METHODS: We have developed a system to allow hypertensive patients to be monitored and assessed without visiting their GPs (except in the most urgent cases). Blood pressure measurements are performed at the patients' pharmacies and a web-based system, created using PROforma, makes recommendations for continued monitoring, and/or changes in medication. The recommendations and measurements are transmitted electronically to a practitioner with authority to issue and change prescriptions. We evaluated the use of PROforma during the knowledge acquisition, analysis, design and implementation of this system. The analysis focuses on the logical adequacy, heuristic power, notational convenience, and explanation support provided by the PROforma language. RESULTS: PROforma proved adequate as a language for the implementation of the clinical reasoning required by this project. However a lack of notational convenience led us to use UML activity diagrams, rather than PROforma process descriptions, to create the models that were used during the knowledge acquisition and analysis phases of the project. These UML diagrams were translated into PROforma during the implementation of the project. CONCLUSION: The experience accumulated during this study highlighted the importance of structure preserving design, that is to say that the models used in the design and implementation of a knowledge-based system should be structurally similar to those created during knowledge acquisition and analysis. Ideally the same language should be used for all of these models. This means that great importance has to be attached to the notational convenience of these languages, by which we mean the ease with which they can be read, written, and understood by human beings. The importance of notational convenience arises from the fact that a language used during knowledge acquisition and analysis must be intelligible to the potential users of a system, and to the domain experts who provide the knowledge that will be used in its construction.

Antihypertensive Agents↗
PubMed1984

Adverse drug reactions: the magnitude of the problem.

Much quantitative information on the clinical use and adverse effects of drugs has been accumulated in the past 15 years. These data provide a basis for substantial knowledge and perspective on the problem of drug toxicity, particularly for drugs that have been marketed for many years. We have also learned how to study adverse effects of newly marketed drugs in a cost-efficient and effective manner. Studies have shown that hospitalized adult patients in the United States receive on average about 10 drugs during hospitalization. Outpatient adults take on average about two drugs on a regular basis (i.e., at least once a week). Results from in-hospital studies indicate that some type of adverse reaction occurs about once in every 20 drug treatments. Most of these drug reactions are clinically minor and reversible, but about 10% of adverse reactions are regarded as life-threatening. Virtually all organ systems have been involved with adverse drug effects. Deaths in hospitalized patients that are attributable to drugs are rare and tend to occur in patients who are quite ill from their primary illness and receive potent drugs such as antitumor agents. However, some drug-induced illnesses appear to be preventable. Out-patient drug toxicity is the cause of about 3% of all hospitalizations. When considered with the enormous use of drugs in the outpatient population, however, this number of admissions secondary to drug toxicity seems to represent a small incidence.

Adrenal Cortex Hormones↗
PubMed2004

The intravenous anesthetic propofol inhibits hypoxia-inducible factor 1 activity in an oxygen tension-dependent manner.

Hypoxia elicits a wide range of responses that occur at different organizational levels in the body. Hypoxia is not only a signal for energy conservation and metabolic change, but triggers expression of a select set of genes. The transcription factor hypoxia-inducible factor 1 (HIF-1) is now appreciated to be a master factor of the gene induction. Although knowledge on molecular mechanisms of HIF-1 activation in response to hypoxia is accumulating, the molecular mechanism of maintenance of HIF-1 activity under normoxic conditions remains to be elucidated. We demonstrate that the intravenous anesthetic propofol reversibly inhibits HIF-1 activity and the gene expression mediated by HIF-1 by blocking the synthesis of the HIF-1alpha subunit under 20% or 5% O2 conditions, but not under 1% O2 conditions.

Anesthetics, Intravenous↗
PubMed1987

Assay of mitogen-induced effects on cellular incorporation of precursors for scavenger, de novo, and net DNA synthesis.

In summary we have presented data on [3H]dThd incorporation into DNA for a positive and negative growth modulator. These data clearly do not correspond to those based on net DNA synthesis (ortho[32P]phosphate incorporation into purified DNA) and previous knowledge of the effects of these hormones on cell number and cellular DNA accumulation. The paradox was resolved by directly analyzing effects of hormones on de novo pyrimidine biosynthesis. E2 stimulated both de novo and scavenger pathways in the first wave of DNA synthesis and only de novo in the second (and subsequent) waves. In contrast, tam progressively inhibited de novo pyrimidine biosynthesis. These hormonal effects on intracellulr pyrimidine pool sizes rendered [3H]dThd incorporation data by itself uninterpretable. [3H]dThd is a useful measure of DNA synthesis only if verified by independent measures of net DNA synthesis for the same time course and treatment conditions. In addition it may prove beneficial in various experimental systems to develop direct assays of de novo pyrimidine biosynthesis to assess mitogen effects. The experiments presented may also prove to be useful in evaluating the effects of mitogens and antimitogens on cells synchronized in the cell cycle by any of a variety of means.

Acetates↗