Extended-release niacin increases anti-apolipoprotein A-I antibodies that block the antioxidant effect of high-density lipoprotein-cholesterol: the EXPLORE clinical trial.

Extended-release niacin (ERN) is the most effective agent for increasing high-density lipoprotein-cholesterol (HDL-C). Having previously identified anti-HDL antibodies, we investigated whether ERN affected the antioxidant capacity of HDL and whether ERN was associated with the production of antibodies against HDL (aHDL) and apolipoprotein A-I (aApoA-I). METHODS: Twenty-one patients older than 18 years, with HDL-C ≤40 mg dl-1 (men) or ≤50 mg dl-1 (women) were randomly assigned to receive daily ERN (n = 10) or placebo (n = 11) for two sequential 12-week periods, with 4 weeks of wash-out before cross-over. Primary outcome was change of paraoxonase-1 (PON1) activity and secondary outcomes were changes in aHDL and aApoA-I antibodies. Clinical Trial Unique Identifier: EudraCT 2006-006889-42. RESULTS: The effect of ERN on PON1 activity was nonsignificant (coefficient estimate 20.83 U l-1 , 95% confidence interval [CI] -9.88 to 51.53; P = 0.184). ERN was associated with an increase in HDL-C levels (coefficient estimate 5.21 mg dl-1 , 95% CI 1.16 to 9.25; P = 0.012) and its subclasses HDL2 (coefficient estimate 2.46 mg dl-1 , 95% CI 0.57 to 4.34; P = 0.011) and HDL3 (coefficient estimate 2.73 mg dl-1 , 95% CI 0.47 to 4.98; P = 0.018). ERN was significantly associated with the production of aApoA-I antibodies (coefficient estimate 0.25 μg ml-1 , 95% CI 0.09-0.40; P = 0.001). aApoA-I titres at baseline were correlated with decreased PON activity. CONCLUSIONS: The rise in HDL-C achieved with ERN was not matched by improved antioxidant capacity, eventually hampered by the emergence of aApoA-I antibodies. These results may explain why Niacin and other lipid lowering agents fail to reduce cardiovascular risk.info:eu-repo/semantics/publishedVersio

Changes in Iron Metabolism Induced by Anti-Interleukin-6 Receptor Monoclonal Antibody are Associated with an Increased Risk of Infection

(1) Background: Treatment of patients with rheumatoid arthritis (RA) with an anti-IL-6 receptor (anti-IL-6R) monoclonal antibody (tocilizumab) has been found to influence iron metabolism. The objective of the present study was to ascertain whether changes in iron metabolism induced by anti-IL-6R biologic therapy were independently associated with an increased infection risk. (2) Methods: A prospective longitudinal study of patients with RA treated with tocilizumab was conducted. RA patients treated with an antitumor necrosis factor α monoclonal antibody were also included as a control group. The primary outcome was occurrence of infection during the first 24 months of biologic therapy. (3) Results: A total of 15 patients were included, with a mean age of 51.0 ± 4,1 and 73.3% (n = 11) female. A multivariate survival regression model, adjusted for confounding factors, was fitted for each of the iron metabolism variables. Hazard ratios for being above the median of each parameter was considered. Transferrin saturation above the median value (>32.1%) was associated with a higher infection risk (HR 4.3; 95%CI 1.0-19.69; p = 0.05). Similarly, although non-significantly, higher serum iron was strongly associated with infection occurrence. (4) Conclusions: This study identified a probable association between infection risk and higher serum iron and transferrin saturation in patients with RA on anti-IL-6R biologic therapy. We suggest that both these parameters should be considered relevant contributing factors for infection occurrence in patients on anti-IL-6R therapy.info:eu-repo/semantics/publishedVersio

Non-tumor necrosis factor-based biologic therapies for rheumatoid arthritis: present, future, and insights into pathogenesis.

Therapeutic options for patients suffering from the more severe forms of spondyloarthritis have been rather limited in the last decades. There is now accumulating evidence that antitumor necrosis factor therapy is highly effective in spondyloarthritis, especially in ankylosing spondylitis and psoriatic arthritis. Based on the data recently published on more than 500 patients with ankylosing spondylitis and psoriatic arthritis, this treatment seems to be even more effective than in rheumatoid arthritis. The antitumor necrosis factor-alpha agents currently available, infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira), are approved for the treatment of rheumatoid arthritis in the United States and partly in Europe. The situation in spondyloarthritis is different from that of rheumatoid arthritis because there is an unmet medical need, especially in ankylosing spondylitis: no therapies with disease-modifying antirheumatic drugs are available for severely affected patients, especially with spinal disease. Thus, tumor necrosis factor blockers may even be considered a first-line treatment in a patient with active ankylosing spondylitis and psoriatic arthritis whose condition is not sufficiently controlled with nonsteroidal antiinflammatory drugs in the case of axial disease, and sulfasalazine or methotrexate in the case of peripheral arthritis. For infliximab, a dose of 5 mg/kg was required, and intervals between 6 and 12 weeks were necessary to suppress disease activity constantly-also a major aim for long-term treatment. The standard dosage of etanercept is 2 x 25 mg subcutaneously per week. There are no studies yet on adalimumab (standard rheumatoid arthritis dose, 20-40 mg subcutaneously every 1-2 weeks) in spondyloarthritis. Infliximab was very recently approved for AS in Europe. The efficacy of etanercept was first demonstrated in psoriatic arthritis, and it is now approved for this indication. A double-blind study has also been performed in ankylosing spondylitis, with similarly clear efficacy. There is preliminary evidence that both agents do also work in other spondyloarthritis, such as undifferentiated spondyloarthritis. Ideally, both agents will be approved soon for the short-term treatment of severe, uncontrolled spondyloarthritis. In parallel, studies should be performed to document the long-term efficacy of this treatment. There is hope that ankylosis may be preventable, but it remains to be shown whether patients benefit from long-term antitumor necrosis factor therapy and whether radiologic progression and ankylosis can be stopped. Severe adverse events have remained rare. Complicated infections including tuberculosis have been reported. These can be largely prevented by appropriate screening. At it stands now, the benefits of antitumor necrosis factor therapy in ankylosing spondylitis seem to outweigh these shortcomings

Major acute splenic sequestration crisis in an adult patient with sickle-cell disease

A crise de retenção esplénica é uma complicação, frequentemente, fatal da drepanocitose. É rara em adultos, pela elevada incidência de autoesplenectomia durante a infância. Heterozigóticos com traços de drepanocitose e de beta-talassémia têm fenótipos menos graves, podendo manter um baço funcional até à idade adulta. Descrevemos um caso de crise de retenção esplénica num homem de 19 anos, com concentração mínima de hemoglobina de 2,9g/dL, que resolveu após esplenectomia emergente. Os poucos casos descritos na literatura acarretam uma mortalidade elevada. Um diagnóstico rápido e actuação imediata são necessários para garantir a sobrevivência. É apresentada uma revisão da fisiopatologia e da abordagem terapêutica desta entidade

The contribution of diet and genotype to iron status in women:a classical twin study

This is the first published report examining the combined effect of diet and genotype on body iron content using a classical twin study design. The aim of this study was to determine the relative contribution of genetic and environmental factors in determining iron status. The population was comprised of 200 BMI- and age-matched pairs of MZ and DZ healthy twins, characterised for habitual diet and 15 iron-related candidate genetic markers. Variance components analysis demonstrated that the heritability of serum ferritin (SF) and soluble transferrin receptor was 44% and 54% respectively. Measured single nucleotide polymorphisms explained 5% and selected dietary factors 6% of the variance in iron status; there was a negative association between calcium intake and body iron (p = 0.02) and SF (p = 0.04)

Benznidazole biotransformation and multiple targets in <i>Trypanosoma</i> cruzi revealed by metabolomics

&lt;b&gt;Background&lt;/b&gt;&lt;p&gt;&lt;/p&gt; The first line treatment for Chagas disease, a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi, involves administration of benznidazole (Bzn). Bzn is a 2-nitroimidazole pro-drug which requires nitroreduction to become active, although its mode of action is not fully understood. In the present work we used a non-targeted MS-based metabolomics approach to study the metabolic response of T. cruzi to Bzn.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methodology/Principal findings&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Parasites treated with Bzn were minimally altered compared to untreated trypanosomes, although the redox active thiols trypanothione, homotrypanothione and cysteine were significantly diminished in abundance post-treatment. In addition, multiple Bzn-derived metabolites were detected after treatment. These metabolites included reduction products, fragments and covalent adducts of reduced Bzn linked to each of the major low molecular weight thiols: trypanothione, glutathione, γ-glutamylcysteine, glutathionylspermidine, cysteine and ovothiol A. Bzn products known to be generated in vitro by the unusual trypanosomal nitroreductase, TcNTRI, were found within the parasites, but low molecular weight adducts of glyoxal, a proposed toxic end-product of NTRI Bzn metabolism, were not detected.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions/significance&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Our data is indicative of a major role of the thiol binding capacity of Bzn reduction products in the mechanism of Bzn toxicity against T. cruzi

Does native Trypanosoma cruzi calreticulin mediate growth inhibition of a mammary tumor during infection?

Indexación: Web of Science.Background: For several decades now an antagonism between Trypanosoma cruzi infection and tumor development has been detected. The molecular basis of this phenomenon remained basically unknown until our proposal that T. cruzi Calreticulin (TcCRT), an endoplasmic reticulum-resident chaperone, translocated-externalized by the parasite, may mediate at least an important part of this effect. Thus, recombinant TcCRT (rTcCRT) has important in vivo antiangiogenic and antitumor activities. However, the relevant question whether the in vivo antitumor effect of T. cruzi infection is indeed mediated by the native chaperone (nTcCRT), remains open. Herein, by using specific modified anti-rTcCRT antibodies (Abs), we have neutralized the antitumor activity of T. cruzi infection and extracts thereof, thus identifying nTcCRT as a valid mediator of this effect. Methods: Polyclonal anti-rTcCRT F(ab')(2) Ab fragments were used to reverse the capacity of rTcCRT to inhibit EAhy926 endothelial cell (EC) proliferation, as detected by BrdU uptake. Using these F(ab')(2) fragments, we also challenged the capacity of nTcCRT, during T. cruzi infection, to inhibit the growth of an aggressive mammary adenocarcinoma cell line (TA3-MTXR) in mice. Moreover, we determined the capacity of anti-rTcCRT Abs to reverse the antitumor effect of an epimastigote extract (EE). Finally, the effects of these treatments on tumor histology were evaluated. Results: The rTcCRT capacity to inhibit ECs proliferation was reversed by anti-rTcCRT F(ab')(2) Ab fragments, thus defining them as valid probes to interfere in vivo with this important TcCRT function. Consequently, during infection, these Ab fragments also reversed the in vivo experimental mammary tumor growth. Moreover, anti-rTcCRT Abs also neutralized the antitumor effect of an EE, again identifying the chaperone protein as an important mediator of this anti mammary tumor effect. Finally, as determined by conventional histological parameters, in infected animals and in those treated with EE, less invasive tumors were observed while, as expected, treatment with F(ab')(2) Ab fragments increased malignancy. Conclusion: We have identified translocated/externalized nTcCRT as responsible for at least an important part of the anti mammary tumor effect of the chaperone observed during experimental infections with T. cruzi.http://bmccancer.biomedcentral.com/articles/10.1186/s12885-016-2764-

A Human-Health Risk Assessment for West Nile Virus and Insecticides Used in Mosquito Management

West Nile virus (WNV) has been a major public health concern in North America since 1999, when the first outbreak in the Western Hemisphere occurred in New York City. As a result of this ongoing disease outbreak, management of mosquitoes that vector WNV throughout the United States and Canada has necessitated using insecticides in areas where they traditionally have not been used or have been used less frequently. This has resulted in concerns by the public about the risks from insecticide use. The objective of this study was to use reasonable worst-case risk assessment methodologies to evaluate human-health risks for WNV and the insecticides most commonly used to control adult mosquitoes. We evaluated documented health effects from WNV infection and determined potential population risks based on reported frequencies. We determined potential acute (1-day) and subchronic (90-day) multiroute residential exposures from each insecticide for several human subgroups during a WNV disease outbreak scenario. We then compared potential insecticide exposures to toxicologic and regulatory effect levels. Risk quotients (RQs, the ratio of exposure to toxicologic effect) were < 1.0 for all subgroups. Acute RQs ranged from 0.0004 to 0.4726, and subchronic RQs ranged from 0.00014 to 0.2074. Results from our risk assessment and the current weight of scientific evidence indicate that human-health risks from residential exposure to mosquito insecticides are low and are not likely to exceed levels of concern. Further, our results indicate that, based on human-health criteria, the risks from WNV exceed the risks from exposure to mosquito insecticides