Augmentation index predicts mortality in patients with aortic stenosis: an echo-tracking study

The International Journal of Cardiovascular Imaging - Aortic valve stenosis (AS) shares similarities with the atherosclerotic process but little is known about the effect of the mechanical...     

Atrial function in the Fontan circulation: comparison with invasively assessed systemic ventricular filling pressure

The International Journal of Cardiovascular Imaging - Abnormal atrial mechanics in biventricular circulations have been associated with elevated left heart filling pressures. Similar associations...     

Removal of free light chains in hemodialysis patients without multiple myeloma: a crossover comparison of three different dialyzers

Background

Immunoglobulin light chains are classified as middle molecule uremic toxins able to interact with B lymphocyte membranes leading to the activation of transmembrane signaling. The ensuing impairment of neutrophil function can contribute to the chronic inflammation state of uremic patients, and the increased risk of bacterial infections or vascular calcifications. The aim of this crossover observational study was to assess the difference in free light chain removal by three different hemodialysis filters in patients not affected by multiple myeloma.

Methods

Free light chain removal was compared in the polymethylmethacrylate (PMMA) membrane Filtryzer BK-F, the polyphenylene HFR17 filter and the conventional polysulfone filter F7HPS. Twenty chronic hemodialysis patients were enrolled: mean age was 67.7?±?17.0 years, M/F?=?14/6, dialysis vintage (months) 25.5?±?32.0. The patients were randomized into two groups of treatment lasting 6 weeks each. The dialysis sessions checked were the midweek sessions and the blood was drawn at times 0, 120’ and 240’. Kappa (k) and lambda (λ) light chain levels, β2microglobulin (β2M), C reactive protein (CRP) and albumin were checked.

Results

K light chain levels were 345.0?±?100.0 mg/L, λ light chains were 121.4?±?27.0 mg/L. The values of k light chains at times 120’ and 240’ were significantly lower with PMMA and HFR17 than those obtained with F7. The reduction ratio per session (RRs) for k light chains was 44.1?±?4.3% with HFR17, 55.3?±?3.4% with PMMA, 25.7?±?8.3% with F7 (p?=?0.018). The RRs for λ light chains was 30.3?±?2.9% with HFR17, 37.8?±?17.3% with PMMA, 14.0?±?3.9% with F7 (p?=?0.032). As to β2M, RRs was 42.4?±?3.2% with HFR17 vs. 33.9?±?2.8% with PMMA vs. 6.3?±?1.9% with F7 (p?=?0.022). The three filters tested showed no differences in CRP or albumin levels.

Conclusion

In terms of light chain and β2M removal, the PMMA and on-line HFR filters are similar and both are significantly more effective than the F7 filter in chronic dialysis patients.

Trial registration

The present trial was registered retrospectively (NCT02950389, 31/10/2016).

     

The Cyclic Peptide Ecumicin Targeting ClpC1 Is Active against Mycobacterium tuberculosis In Vivo

Drug-resistant tuberculosis (TB) has lent urgency to finding new drug leads with novel modes of action. A high-throughput screening campaign of >65,000 actinomycete extracts for inhibition of Mycobacterium tuberculosis viability identified ecumicin, a macrocyclic tridecapeptide that exerts potent, selective bactericidal activity against M. tuberculosis in vitro, including nonreplicating cells. Ecumicin retains activity against isolated multiple-drug-resistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis. The subcutaneous administration to mice of ecumicin in a micellar formulation at 20 mg/kg body weight resulted in plasma and lung exposures exceeding the MIC. Complete inhibition of M. tuberculosis growth in the lungs of mice was achieved following 12 doses at 20 or 32 mg/kg. Genome mining of lab-generated, spontaneous ecumicin-resistant M. tuberculosis strains identified the ClpC1 ATPase complex as the putative target, and this was confirmed by a drug affinity response test. ClpC1 functions in protein breakdown with the ClpP1P2 protease complex. Ecumicin markedly enhanced the ATPase activity of wild-type (WT) ClpC1 but prevented activation of proteolysis by ClpC1. Less stimulation was observed with ClpC1 from ecumicin-resistant mutants. Thus, ClpC1 is a valid drug target against M. tuberculosis, and ecumicin may serve as a lead compound for anti-TB drug development.     

Interaction between inflammation and thrombosis in acute coronary syndrome

BACKGROUND: Inflammation and thrombosis are important in the pathogenesis of acute coronary syndrome (ACS). Cytokines [interleukin-1beta (IL-1beta) and interleukin-6 (IL-6)] are inflammation markers which play a major role in the development of coronary heart disease. Experimental data documented that an increase of cytokine and von Willebrand factor (vWF) levels in unstable angina (UA) and non-Q wave myocardial infarction (MI) predicts an adverse outcome. AIM: To examine the correlation between the IL-1beta, IL-6 and vWF levels in patients with ACS. METHODS: We examined 92 patients (74 men, 18 women, aged from 43 to 76) divided into 3 groups. The first group included 43 patients with a Q-wave MI, the second group - 33 with a non-Q-wave MI, and the third group - 18 with UA. All patients were given 125-250 mg of aspirin and bolus of 5.000 units of unfractionated heparin, followed by heparin infusion titrated to maintain an activated partial thromboplastin time of 50-75 s. Patients with a Q-wave MI received thrombolytic therapy 1.5 million units of streptokinase. The IL-1b, IL-6 and vWF levels was measured on admission and 7 as well as 21 days later. Fifteen patients with stable angina served as the control group. RESULTS: The levels of cytokines and vWF were significantly higher in patients with ACS than in control subjects. A significant correlation between vWF and IL-6 levels, measured on admission and 7 days later, was found in patients with UA (r=+0.74 and r=+0.55, respectively). Also, a significant correlation was found between vWF and IL-1beta levels measured on admission in patients with either Q-wave or non-Q wave MI (r=+0.7 and r=+0.61, respectively). CONCLUSIONS: Our data suggest that there is a positive correlation between inflammation and thrombosis markers in patients with ACS.     

Prevalence of Hypertension in Patients with Type II Diabetes in Referral versus Primary Care Clinics

We compared the prevalence of hypertension in patients with non–insulin-dependent diabetes mellitus (NIDDM) in referral and primary care practices using definitions of The Fifth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC-V), while controlling for other risk factors such as hypertension, obesity, smoking, and age. Patients (n = 1443) were enrolled consecutively from a large referral practice at the Jackson Diabetes Center and four primary care clinics in the vicinity. Blood pressures were measured at three clinic visits after a 5-min rest in a sitting position using a standard clinical sphygmomanometer. Charts were reviewed to determine diabetes duration, insulin usage, height, weight, smoking history, use of antihypertensive and oral hypoglycemic medications, socioeconomic status, and race. Patients were classified as hypertensive based on JNC-V definitions or if they were on antihypertensive medication. Hypertension was termed uncontrolled if blood pressure was JNC-V Stage 2 or higher while on antihypertensive medication.

Seventy-eight percent of referral clinic and 55% of primary care clinic patients had either JNC-V State 1 or higher hypertension or were on antihypertensive medication. Actual blood pressures indicated that more patients had JNC-V Stage 1 (mild) or higher hypertension in referral compared to primary care clinics (62% versus 48% p = 0.01) but fewer had JNC-V Stage 2 or higher (moderate-severe) hypertension (12% versus 19% p = 0.002). Patients seen in the referral clinic were significantly more likely to have greater age, greater duration of diabetes, higher insulin dosage, longer smoking history, antihypertensive medication, and live outside the metropolitan area. By logistic regression, the odds of hypertension were significantly increased with age (OR 1.51/decade), BMI greater than 27 (OR 2.17), diabetes duration (OR 1.04/year), and insulin dosage (OR 1.74/U/kg). Current smoking and attending a referral clinic were not significantly related. The odds of moderate-severe hypertension were significantly increased with age (OR 1.23/decade), decreased by attending a referral clinic (OR 0.45), and not significantly related to other confounders in the model.

The prevalence of hypertension among patients with NIDDM was higher in referral than primary care clinics. The higher prevalence in the referral practice can be accounted for by the greater severity of associated risk factors in the referral practice patients; however, most patients will be diagnosed and treated for hypertension prior to referral. More patients in the referral practice were on hypertensive medication, which lowered the stage or severity of hypertension but still not to the normal range. The results suggest that the primary detection of hypertension in patients with type II diabetes resides with the primary care physician. Management of hypertension will require both a delineation and acceptance of responsibilities between the primary care physician and diabetes specialists.     

Distinct Haplotype in Non-Ashkenazi Gaucher Patients with N370S Mutation

ABSTRACT: A new polymorphism, in intron 7 of glucocerebrosidase gene, has been identified in Gaucher Disease patients. It seems to appear only in Pv1.1^-alleles bearing the N370S mutation. This new sub-haplotype was only identified in Portuguese patients, of origins spanning all of the Portuguese continental territory. This finding indicates that, in the Portuguese, mutation N370S has existed in the context of two slightly different haplotypes and thus must be relatively ancient.