Decreased turnover aspirin resistance by bidaily aspirin intake and efficient cytoreduction in myeloproliferative neoplasms

Essential thrombocythemia (ET) and polycythemia vera (PV) are myeloproliferative neoplasms (MPN) with an increased risk of arterial and venous thrombosis. Aspirin is recommended to reduce this risk, but resistance to antiplatelet therapy seems to hamper its efficacy in some patients. We have previously shown that multiple electrode aggregometry (MEA) was a valuable tool to assess aspirin resistance in MPN. In this study, MEA was used to assess the reduction in aspirin resistance after bi-daily (BID) aspirin intake or cytoreduction.

Fifty one MPN patients (31 ET and 20 PV) receiving 75 mg aspirin once daily (OD) or BID, with or without cytoreductive treatment, were analyzed. Aspirin resistance was assessed using whole blood MEA (Multiplate®, Roche Diagnostics, Meylan, France).

In all patients, global aspirin resistance consisted mainly of turnover resistance (TOR). 94% of patients with OD aspirin intake and without cytoreduction displayed biological aspirin resistance. By switching to a BID aspirin regimen, the proportion of resistant patients reduced to 47%. Cytoreduction also contributed to reduce aspirin resistance in a similar way (50% of aspirin resistant patients). Combining cytoreduction and BID aspirin regimen was the most efficient way to reduce aspirin resistance yielding to 12% resistant patients. Moreover, a nonlinear correlation was observed between TOR and naive platelet counts regardless of aspirin regimen. Last, mutational status did not seem to affect TOR.

This study confirmed that BID aspirin is biologically more effective than OD aspirin in reduction of aspirin resistance. The latter was achieved through a reduction in TOR which was also decreased by cytoreductive therapy.     

Severe cardiac involvement in children with systemic sclerosis and myositis

OBJECTIVE: To assess the outcome of children with systemic sclerosis (SSc) and features of polymyositis. METHODS: The charts of 4 children who met the American College of Rheumatology criteria for SSc and had features of polymyositis, as defined by the presence of proximal muscle weakness and elevated serum creatine phosphokinase or aldolase level, were retrospectively reviewed. RESULTS: All children had multivisceral involvement including (1) myocardial perfusion defects in all cases, with mild to severe dilated cardiomyopathy in 3; (2) lung restrictive syndrome in 3; (3) mild to severe esophageal involvement in all cases; and (4) severe intestinal dysfunction in one child. Combination therapy of corticosteroids, methotrexate (MTX), and cyclosporine resulted in improved skin thickness and muscle strength scores in all cases, as well as in lung restrictive syndrome in 2, but was not effective regarding the progression of intestinal malabsorption in one patient, esophageal dysmotility in 3 patients, and dilated cardiomyopathy in 3. Endstage cardiac failure caused 2 deaths. In one child, heart transplantation was performed for the first time in this indication. CONCLUSION: Children with diffuse cutaneous SSc and features of polymyositis are prone to develop severe cardiomyopathy. Combination therapy of corticosteroids, MTX, and cyclosporine seems to be active on muscle, skin, and lung involvement but does not impair progression of esophageal or myocardial dysfunction. Heart transplantation might be considered, as an experimental treatment, in young patients with severe cardiomyopathy and no other irreversible organ damage.     

Genomic Analysis of Reduced Susceptibility to Tigecycline in Enterococcus faecium

Tigecycline (TIG) is approved for use for the treatment of complicated intra-abdominal infections, skin and skin structure infections, as well as pneumonia. Acquired resistance or reduced susceptibility to TIG has been observed in Gram-negative rods, has seldom been reported in Gram-positive organisms, and has not yet been reported in Enterococcus faecium. Using the serial passage method, in vitro mutant AusTig and in vitro mutants HMtig1 and HMtig2 with decreased TIG susceptibility (MICs, 0.25 μg/ml) were obtained from strains E. faecium Aus0004 and HM1070 (MICs, 0.03 μg/ml), respectively. In addition, two vancomycin-resistant E. faecium clinical isolates (EF16 and EF22) with reduced susceptibility to TIG (MICs, 0.5 and 0.25 μg/ml, respectively) were studied. Compared to the wild-type strains, the in vitro mutants also showed an increase in the MICs of other tetracyclines. An efflux mechanism did not seem to be involved in the reduced TIG susceptibility, since the presence of efflux pump inhibitors (reserpine or pantoprazole) did not affect the MICs of TIG. Whole-genome sequencing of AusTig was carried out, and genomic comparison with the Aus0004 genome was performed. Four modifications leading to an amino acid substitution were found. These mutations affected the rpsJ gene (efau004_00094, coding for the S10 protein of the 30S ribosomal subunit), efau004_01228 (encoding a cation transporter), efau004_01636 (coding for a hypothetical protein), and efau004_02455 (encoding the l-lactate oxidase). The four other strains exhibiting reduced TIG susceptibility were screened for the candidate mutations. This analysis revealed that three of them showed an amino acid substitution in the same region of the RpsJ protein. In this study, we characterized for the first time genetic determinants linked to reduced TIG susceptibility in enterococci.     

Low income,community poverty and risk of end stage renal disease

Background

The risk of end stage renal disease (ESRD) is increased among individuals with low income and in low income communities. However, few studies have examined the relation of both individual and community socioeconomic status (SES) with incident ESRD.

Methods

Among 23,314 U.S. adults in the population-based Reasons for Geographic and Racial Differences in Stroke study, we assessed participant differences across geospatially-linked categories of county poverty [outlier poverty, extremely high poverty, very high poverty, high poverty, neither (reference), high affluence and outlier affluence]. Multivariable Cox proportional hazards models were used to examine associations of annual household income and geospatially-linked county poverty measures with incident ESRD, while accounting for death as a competing event using the Fine and Gray method.

Results

There were 158 ESRD cases during follow-up. Incident ESRD rates were 178.8 per 100,000 person-years (10⁵ py) in high poverty outlier counties and were 76.3 /10⁵ py in affluent outlier counties, p trend?=?0.06. In unadjusted competing risk models, persons residing in high poverty outlier counties had higher incidence of ESRD (which was not statistically significant) when compared to those persons residing in counties with neither high poverty nor affluence [hazard ratio (HR) 1.54, 95% Confidence Interval (CI) 0.75-3.20]. This association was markedly attenuated following adjustment for socio-demographic factors (age, sex, race, education, and income); HR 0.96, 95% CI 0.46-2.00. However, in the same adjusted model, income was independently associated with risk of ESRD [HR 3.75, 95% CI 1.62-8.64, comparing the?<?$20,000 income group to the?>?$75,000 group]. There were no statistically significant associations of county measures of poverty with incident ESRD, and no evidence of effect modification.

Conclusions

In contrast to annual family income, geospatially-linked measures of county poverty have little relation with risk of ESRD. Efforts to mitigate socioeconomic disparities in kidney disease may be best appropriated at the individual level.

     

Are the antiplatelet and profibrinolytic properties of selective serotonin-reuptake inhibitors relevant to their brain effects?

The serotonin transporter (SERT) is found in neuron and platelet membranes. Selective serotonin-reuptake inhibitors (SSRIs) are widely prescribed for severe depression. They may at least partly counteract the effects of serotonin on the vascular biology system, can lower agonists-induced platelet activation, aggregation and procoagulant activity in vitro, thus modulating platelet thrombogenicity. Other effects, such as those mediated through PAI-1 modulation, may indirectly influence neurobiology-relevant mechanisms involved in depression. Patients receiving SSRIs are at increased bleeding risk and decreased risk of arterial occlusive events, such as myocardial infarction, compared to those using non-SSRI antidepressants. The objectives of this review were to highlight antiplatelet and profibrinolytic properties of SSRIs and discuss the potential role of these activities in the context of SSRI brain effects.     

New European initiatives in colorectal cancer screening: Budapest Declaration. Official appeal during the Hungarian Presidency of the Council of the European Union under the Auspices of the United European Gastroenterology Federation, the European Association for Gastroenterology and Endoscopy and the Hungarian Society of Gastroenterology

Colorectal cancer (CRC) is the second most common newly diagnosed cancer and the second most common cause of death in the European Union (EU). CRC is an enormous health and economic burden. Early detection and prevention have the possibility of reducing this burden significantly. Many cancer-associated deaths can be avoided through early detection by high-quality colorectal screening programs followed by appropriate treatment. Under the auspices of the United European Gastroenterology Federation (UEGF), the European Association for Gastroenterology and Endoscopy, the Hungarian Society of Gastroenterology and the Hungarian College of Gastroenterology, the 'Budapest Declaration' (2011) was an accepted official scientific program during the Hungarian Presidency of the Council of the European Union. The Budapest Declaration follows the Munich Declaration (2001), the Brussels Declaration (2007), the Transatlantic Declaration (2009), the Barcelona Declaration (2010), the written declaration of CRC screening, a joint initiative with European Parliamentarians coordinated by the UEGF, and finally, the 'European Guidelines for Quality Assurance in Colorectal Cancer Screening and Diagnosis'. The 'Budapest Declaration' together with previous declarations aims to urge the national and supranational healthcare decision makers to launch new Europe-wide initiatives to establish high-quality CRC programs to achieve optimal efficiency in CRC screening. In case of implementation of the proposals, actions and conditions recommended, we can achieve that one of the basic principles of the EU - the chance of equal access - be realized in member states with respect to the prevention of CRC and reduction of cancer-related mortality. To better achieve this goal, we propose to establish an UEGF joint committee, with one participant representing each EU member state to coordinate and supervise the implementation of CRC screening.