Comorbidities and concomitant medications in patients with chronic hepatitis C virus infection receiving second-generation direct-acting antiviral regimens in Belgium: an observational study.

Objective: To describe comorbidities and concomitant medications in patients initiating treatment for hepatitis C virus (HCV) infection with direct-acting antiviral (DAA) regimens in Belgium. Methods: This was a noninterventional, observational, multicenter study of data from patient charts. Adult patients with HCV infection receiving second-generation DAA therapy were included. Comorbidities were assessed at the time of HCV treatment initiation. Concomitant medications were recorded at the time of diagnosis and at treatment initiation. Potential clinically relevant drug-drug interactions (DDIs) were assessed based on information available at www.hep-druginteractions.org. The primary objective was to describe concomitant medication use ; secondary objectives were to describe modifications in concomitant therapies and comorbidities. Results: 405 patients were included. A total of 956 comorbidities were reported by 362 patients (median, 2 ; range, 0-15). The most common comorbidities were hypertension (27.2%) ; HIV coinfection (22.5%), and type 2 diabetes mellitus (14.3%). Overall, 1455 concomitant medications were being taken by 365 patients (90.1% ; median, 3 ; range 0-16). The most common concomitant medications were psycholeptics (28.6%), antiviral agents (24.2%), and medications for acid-related disorders (21.0%) Overall, 74/365 (20.3%) patients receiving a concomitant medication required an adaptation to their concomitant medication. The medications that most frequently required change were drugs for acid-related disorders (n = 14) and antiviral drugs (n = 5) ; those that were most frequently stopped were lipid-modifying drugs (n = 25) and drugs for acid-related disorders (n = 13). Conclusion: Physicians are aware of the potential for DDIs with DAAs, but improved alignment between clinical practice and theoretical recommendations is required.

Social support buffering of the relation between low income and elevated blood pressure in at-risk African-American adults.

Socioeconomic disadvantage has been linked to elevated blood pressure (BP), and the purpose of this study was to assess whether interpersonal social supports buffer these adverse relations in African-American adults. In three communities matched demographically, a subsample of participants (N = 204) of the Positive Action for Today's Health trial provided measures of perceived social support, annual household income, and BP. Multiple regression analyses with cross-product interactions were conducted using follow-up data. The sample had a mean age of 52.8 years (SD = 15.1), and was predominantly female (66 %) with a high body mass index (M = 33.5, SD = 14.7). Results indicated an inverse relation between social support and diastolic BP (B = -.178, p = .005), and also an interaction with income (p = .046), such that higher social support related to lower diastolic BP in the lowest-income individuals (B = -1.05). The same direct (B = -.141, p = .025) and interacting (B = -1.42, p = .040) social support effects were present for systolic BP, however the omnibus model for systolic BP was not significant, F(6, 196) = 1.80, p = .09. The hypothesized buffering effect of social support on the adverse relation of income to BP was partially supported in at-risk African-American adults. Future prevention efforts for reducing the impact of socioeconomic stress on BP may aim to increase perceptions of social support.

[COPD and erythropoiesis: interactions and consequences]. / BPCO et érythropoïèse : interactions et conséquences.

Erythropoiesis is modified in chronic obstructive pulmonary disease (COPD). Tobacco smoke, hypoxaemia, systemic inflammation, and infectious exacerbations are the main factors involved. Polymorphisms in genes involved in the regulation of erythropoiesis probably explain the individual susceptibility and variability in the response. The roles of comorbidities related to COPD and the impact of treatment on erythropoiesis are important confounding factors. While polycythaemia is often related to tobacco smoke and hypoxaemia, it has become less common due to the improvement of COPD follow-up and especially the initiation of long-term oxygen therapy. The control of the main causes is often sufficient, but in cases of severe polycythaemia an erythrapheresis is indicated. Anaemia has recently been reported as a more common and serious complication. It increases dyspnoea and reduces physical activity and quality of life. Its impact on survival and the requirements for healthcare has recently been confirmed. The main approach to the management of anaemia remains exclusion of any curable causes, reducing exacerbations and systemic inflammation, and controlling the comorbidities. Though erythropoietin has some benefits in the so-called "anaemia of chronic disease", this still remains to be confirmed in patients with COPD.

Reliability of a common solution-based taste perception test: implications for validity and a briefer test.

The aim of this study was to assess test-retest reliability of a common method for quantifying taste perception and its association with gustatory responses and individual risk for obesity and related health conditions. Forty-six healthy adults rated 20 mixtures comprised of 5 dairy beverages varied in fat content and mixed with sugar concentrations of 0%, 5%, 10%, and 20%, following existing procedures. Individuals rated the sweetness, creaminess, and pleasantness of each mixture during two taste testing sessions occurring 7±2 days apart. Test-retest correlations were of the expected magnitudes (r≥.50) only for the pleasantness ratings of mixtures with higher sugar concentrations. Correlations for sweetness and creaminess taste perception ratings were low, indicating that such ratings may not be reliable over approximately one week, and challenging the validity of such ratings for measuring trait taste perception. A shortened version of the test may be warranted.

Caspase-activated ROCK-1 allows erythroblast terminal maturation independently of cytokine-induced Rho signaling.

Stem cell factor (SCF) and erythropoietin are strictly required for preventing apoptosis and stimulating proliferation, allowing the differentiation of erythroid precursors from colony-forming unit-E to the polychromatophilic stage. In contrast, terminal maturation to generate reticulocytes occurs independently of cytokine signaling by a mechanism not fully understood. Terminal differentiation is characterized by a sequence of morphological changes including a progressive decrease in cell size, chromatin condensation in the nucleus and disappearance of organelles, which requires transient caspase activation. These events are followed by nucleus extrusion as a consequence of plasma membrane and cytoskeleton reorganization. Here, we show that in early step, SCF stimulates the Rho/ROCK pathway until the basophilic stage. Thereafter, ROCK-1 is activated independently of Rho signaling by caspase-3-mediated cleavage, allowing terminal maturation at least in part through phosphorylation of the light chain of myosin II. Therefore, in this differentiation system, final maturation occurs independently of SCF signaling through caspase-induced ROCK-1 kinase activation.

Recent advances in adult T-cell leukemia therapy: focus on a new anti-transferrin receptor monoclonal antibody.

HTLV-I is an endemic retrovirus responsible for the adult T-cell leukemia/lymphoma (ATLL). This aggressive lymphoid proliferation is associated with a bad prognosis due to the resistance of HTLV-I-infected cells to most classical chemotherapeutic agents. Here we review recent advances in ATLL immunotherapy. We particularly focus on promising data from our group, characterizing a new mouse monoclonal antibody (mAb A24) against the human transferrin receptor (TfR-1). Monoclonal antibodies to target cell differentiation markers on ATLL cells have already been proposed as therapeutic agents. However, in clinical trials acute forms of ATLL were resistant to these immunotherapies. A24 binds TfR-1 (K(d) 2.7 nM) and competes with transferrin for receptor binding. It blocks the proliferation of malignant cells (TfR-1(high)), such as HTLV-I-infected T cells but not of resting cells. A24 induces TfR-1 endocytosis in lysosomal compartments where the receptor is degraded leading to intracellular iron deprivation. In HTLV-I-infected cells, A24 targets and induces apoptosis of both chronic and acute ATLL forms, independent of antibody aggregation, antibody-dependent cellular cytotoxicity and/or complement addition. The antibody efficacy was confirmed in animal models. We are currently developing strategies to use A24 in clinical trials.

Biofilms of As(III)-oxidising bacteria: formation and activity studies for bioremediation process development.

The formation and activity of an As(III)-oxidising biofilm in a bioreactor, using pozzolana as bacterial growth support, was studied for the purpose of optimising fixed-bed bioreactors for bioremediation. After 60 days of continuous functioning with an As(III)-contaminated effluent, the active biofilm was found to be located mainly near the inflow rather than homogeneously distributed. Biofilm development by the CAsO1 bacterial consortium and by Thiomonas arsenivorans was then studied both on polystyrene microplates and on pozzolana. Extra-cellular polymeric substances (EPS) and yeast extract were found to enhance bacteria attachment, and yeast extract also appears to increase the kinetics of biofilm formation. Analysis of proteins, sugars, lipids and uronic acids indicate that sugars were the main EPS components. The specific As(III)-oxidase activity of T. arsenivorans was higher (by ninefold) for planktonic cells than for sessile ones and was induced by As(III). All the results suggest that the biofilm structure is a physical barrier decreasing As(III) access to sessile cells and thus to As(III)-oxidase activity induction. The efficiency of fixed-bed reactors for the bioremediation of arsenic-contaminated waters can be thus optimised by controlling different factors such as temperature and EPS addition and/or synthesis to increase biofilm density and activity.

Specific photoaffinity-labeling of Tyr-50 on the heavy chain and of Tyr-32 on the light chain in the steroid combining site of a mouse monoclonal anti-estradiol antibody using C3-, C6-, and C7-linked 5-azido-2-nitrobenzoylamidoestradiol photoreagents.

A mouse monoclonal anti-7-(O-carboxymethyl)oximinoestradiol antibody 9D3, raised against the same immunogen as that employed for generating the reported anti-estradiol antibody 15H11 [Rousselot, P., et al. (1997) Biochemistry 36, 7860-7868], was found to exhibit an opposite specificity profile with a much stronger recognition of the D-ring than of the A-ring extremity of the steroid, but a similar lack of specificity for both 6- and 7-positions of the B-ring. This antibody was photoaffinity-labeled with five (5-azido-2-nitrobenzoyl)amido (ANBA) derivatives of [17alpha-(3)H]estradiol, synthesized from 3-aminoethyloxy, 3-(aminoethylamido)carboxymethyloxy, 6alpha- and 6beta-amino, and 7-[O-(aminoethylamido)carboxymethyl]oximino precursors. After tryptic digestion, the radioactive peptides on L and H chains were immunopurified with the immobilized antibody 9D3, separated by reversed-phase liquid chromatography, sequenced, and characterized by mass spectrometry, including post-source decay-matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The long 3-(ANBA-ethylamido)carboxymethyl ether photoreagent was found to label TyrL-32 (on CDR L1), whereas no labeling was observed with the shorter 3-derivative, a result in agreement with a binding pocket large enough to explain the high cross-reactivity with estradiol 3-conjugates. The two 6alpha- and 6beta-ANBA-estradiol isomers, as well as the 7-[O-(ANBA-ethylamido)carboxymethyl]oximinoestradiol photoreagent derived from the steroid hapten, labeled the same TyrL-32 residue. The 6beta-ANBA epimer also labeled TyrH-50 (at the basis of CDR H2). These experiments indicate that TyrL-32 is freely accessible from the three C3, C6, and C7 positions, all presumed to be exposed to solvent, while TyrH-50 is probably located on the beta-face of estradiol. These results, obtained in solution, provide experimental data useful for molecular modeling of the steroid-antibody complex.

[Effect of a standardized acupuncture treatment on complains, blood pressure and serum lipids of hypertensive, postmenopausal women. A randomized, controlled clinical study]. / Der einfluss einer standardisierten akupunkturbehandlung auf beschwerden, blutdruck und serumlipide hypertensiver, postmenopausaler frauen. Randomisierte, kontrollierte klinische studie.

BACKGROUND: Acupuncture according to the Chinese syndrome is often used in patients with postmenopausal complaints. Often these patients have an increased blood pressure. As experienced therapists report that acupuncture is efficient also in hypertension, our aim was to investigate whether the acupuncture used for the treatment of postmenopausal syndrome also has an effect on blood pressure. PATIENTS AND METHODS: The efficacy of a standardized acupuncture according to the Chinese syndrome was evaluated in a randomized, single-blind, placebo-controlled cross-over study with 10 postmenopausal patients with mild hypertension. Blood pressure was measured by 24-hour ambulatory blood pressure measurement. Complaints and well-being were evaluated by validated questionnaires. In addition, serum lipids and excretion of catecholamines in the 24-hour urine were measured. RESULTS: Blood pressure was altered neither by verum nor placebo acupuncture, however, complaints were significantly reduced and well-being was improved after verum treatment. The improvement lasted less than two months. Serum lipids did not change, but the excretion of normetanephrine was reduced by verum acupuncture. CONCLUSIONS: Acupuncture with a standardized combination of acupuncture points according to the Chinese syndrome can transitorily reduce postmenopausal complaints, but does not alter blood pressure or serum lipids at the same time.

A French monitoring programme for determining ochratoxin A occurrence in pig kidneys.

Ochratoxin A is a carcinogen and nephrotoxin which can enter the food chain resulting in human exposure. As pig herds are exposed to ochratoxin A through their feed, their kidneys, livers and pork meat are considered as a possible route of exposure for humans. France, an important producer of pork and pork products, set up a national monitoring programme which included the training of six routine public laboratories in the analysis of ochratoxin A using an immunoaffinity step followed by a HPLC-fluorimetric detection. The programme randomly sampled 300 healthy and 100 nephropathic pig kidneys in 1997 and 710 healthy pig kidneys in 1998. Less than 10% of samples were significantly contaminated by ochratoxin A : in the 1997 survey, 1% of samples contained 0.40-1.40 microg kg(-1) of ochratoxin A and in the 1998 survey 7.6 % exhibited ochratoxin A levels in the range 0.5-5 microg kg(-1). In the case of nephropathic kidneys, only traces of ochratoxin A (0.16 to 0.48 microg kg(-1)) were detected in six samples out of 100. Even if not a major route of exposure for humans, pigs are clearly exposed to this mycotoxin and monitoring of pork products and of feed for swine is necessary.

Improving the affinity and the fine specificity of an anti-cortisol antibody by parsimonious mutagenesis and phage display.

Immunoassays are widely used to determine steroid concentrations. However, they are limited by the specificity of antisteroid mAbs. We used the phage display system combined with molecular modeling and site-specific randomization to improve the affinity and the fine specificity of an anti-cortisol mAb. Using parsimonious mutagenesis, we have generated a library of mutant Ab fragments (scFv) derived from this Ab by randomizing five amino acids chosen by molecular modeling and Ab-hapten contact structural analysis. Anti-cortisol Ab fragments were selected from the library in the presence of steroid analogues to block cross-reacting binders. Specific elution with free cortisol allowed the recovery of clones with up to eightfold better affinity and fivefold less cross-reactivity than the wild-type scFv. This approach can be applied to any anti-hapten Ab and represents a useful approach for obtaining highly specific Abs for use in steroid immunoassays.

Identification of streptococci to species level by sequencing the gene encoding the manganese-dependent superoxide dismutase.

We have used a PCR assay based on the use of degenerate primers in order to characterize an internal fragment (sodA(int)) representing approximately 85% of the genes encoding the manganese-dependent superoxide dismutase in various streptococcal type strains (S. acidominimus, S. agalactiae, S. alactolyticus, S. anginosus, S. bovis, S. constellatus, S. canis, S. cricetus, S. downei, S. dysgalactiae, S. equi subsp. equi, S. equi subsp. zooepidemicus, S. equinus, S. gordonii, S. iniae, S. intermedius, S. mitis, S. mutans, S. oralis, S. parasanguis, S. pneumoniae, S. porcinus, S. pyogenes, S. salivarius, S. sanguis, S. sobrinus, S. suis, S. thermophilus, and S. vestibularis). Phylogenetic analysis of these sodA(int) fragments yields an evolutionary tree having a topology similar to that of the tree constructed with the 16S rRNA sequences. We have shown that clinical isolates could be identified by determining the positions of their sodA(int) fragments on the phylogenetic tree of the sodA(int) fragments of the type species. We propose this method for the characterization of strains that cannot be assigned to a species on the basis of their conventional phenotypic reactions.