Ultrasound tissue characterization detects preclinical myocardial structural changes in children affected by Duchenne muscular dystrophy

Our goal was to identify early changes in myocardial physical properties in children with Duchenne muscular dystrophy (DMDch).Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin, which triggers complex molecular and biological events in skeletal and cardiac muscle tissues. Although about 30% of patients display overt signs of cardiomyopathy in the late stage of the disease, it is unknown whether changes in myocardial physical properties can be detected in the early (preclinical) stages of the disease.We performed an ultrasonic tissue characterization (UTC) analysis of myocardium in DMDch with normal systolic myocardial function and no signs of cardiomyopathy. Both the cyclic variation of integrated backscatter (cvIBS) and the calibrated integrated backscatter (cIBS) were assessed in 8 myocardial regions of 20 DMDch, age 7 +/- 2 years (range 4 to 10 years), and in 20 age-matched healthy controls.We found large differences in the UTC data between DMDch and controls; the mean value of cvIBS was 4.4 +/- 1.5 dB versus 8.8 +/- 0.8 dB, whereas the mean value of cIBS was 36.4 +/- 7.1 dB versus 26.9 +/- 2.0 dB (p < 10(-6) for both). In DMDch, all eight sampled segments showed cIBS mean values to be significantly higher and cvIBS mean values to be significantly lower than those in the controls. Finally, interindividual differences were greater in DMDch than in controls for both parameters.The myocardium in DMDch displays UTC features different from those in healthy controls. These results show that lack of dystrophin is commonly associated with changes in myocardial features well before the onset of changes of systolic function and overt cardiomyopathy.     

A paraoxonase gene polymorphism,PON 1 (55), as an independent risk factor for increased carotid intima-media thickness in middle-aged women

Paraoxonase (PON) gene polymorphisms have been proposed as genetic markers of risk for cardiovascular disease (CVD). Sporadic results suggest they are correlated with intima-media thickness (IMT), an indicator of preclinical atherosclerotic disease. We have investigated whether polymorphisms PON 1 (M/L) 55, (Q/R) 192, PON 2 (S/C) 311 are related to site-specific carotid plaques in 310 middle-aged women. Subjects were also investigated for physical and biochemical parameters including oxidative markers to evaluate their effect on development of atherosclerotic plaques (IMT>1.2 mm) identified by high resolution B-mode ultrasound. We demonstrate that PON 1 (LL+ML) 55 is associated with plaques both at the bifurcation (OR=2.40; 95% CI 1.00-5.90) and at the common carotid artery (OR=2.75; 95% CI 1.01-7.50), and to the total number of plaques at any site (P<0.05). This polymorphism is an independent parameter with respect to other variables that are significantly associated with plaques, i.e. systolic blood pressure (OR=2.06; 95% CI 1.11-3.81) and oxidized low-density lipoprotein (LDL) antibodies (OR=1.96; 95% CI 1.05-3.69) in cases of common carotid plaques, and lipid peroxides (OR=1.86; 95% CI 1.00-3.50) in cases of bifurcation plaques. In conclusion, PON 1 (LL+ML) 55 but not PON 1 (Q/R) 192 or PON 2 (S/C) 311, appears to be an independent risk factor for increased carotid IMT in middle-aged women.     

The role of the iron responsive element in the control of ferroportin1/IREG1/MTP1 gene expression

BACKGROUND/AIMS: MTP1/Ferroportin1/IREG1, the product of the SLC40A1 gene, is a main iron export protein in mammals. However, the way this gene is regulated by iron is still unclear. The aim of this study was to investigate the functional role of genomic SLC40A1 elements in response to iron. METHODS: Vectors containing either reverse similar 2.6 kb 5' flanking region or deletion constructs, including one devoid of an iron responsive element (SLC40A1-DeltaIRE-Luc), were analyzed by luciferase reporter gene in transfected HepG2, CaCO2 and U937 cells. Expression of iron genes and activity of the iron regulatory protein were also studied. RESULTS: Iron increased and desferrioxamine decreased luciferase activity in all the cell types using both the full-length construct and the promoter deletion constructs, in the absence of changes in SLC40A1 or luciferase mRNA levels. To test the role of the SLC40A1 5' untranslated region, we first demonstrated that wild type and not SLC40A1-DeltaIRE-Luc could bind iron regulatory protein. Then, in cells transfected with SLC40A1-DeltaIRE-Luc, we found that, in spite of iron regulatory protein activation, the response to iron manipulation was lost. CONCLUSIONS: We demonstrate that the iron responsive element in the SLC40A1 gene is functional and that it controls gene expression through the cytoplasmic iron regulatory protein system.     

Urokinase expression in course of benign and malignant mammary lesions: comparison between nodular and healthy tissues

Purpose  

Increased expression of urokinase (uPA), a member of the serine protease family, is an effector of metastatic cascade and has been reported in various malignancies, including breast cancer. uPA overexpression in cancer tissues was correlated with a more aggressive phenotype and it is considered a strong and independent unfavorable prognostic factor in breast cancer.     

Assay of ghrelin concentration in infant formulas and breast milk

AIM: To test if total ghrelin is present in infant formulas. METHODS: Using a radioimmunoassay, we measured total ghrelin concentrations in 19 samples of commercial infant formulas and in 20 samples of human milk. We also determined ghrelin concentration in the serum of infants and lactating mothers. RESULTS: Ghrelin concentrations were significantly higher in artificial milk (2007.1 ± 1725.36 pg/mL) than in human milk (828.17 ± 323.32 pg/mL) (P = 0.005). The mean ghrelin concentration in infant serum (n = ...     

Charlson comorbidity index and adult comorbidity evaluation-27 scores might predict treatment compliance and development of pleural effusions in elderly patients with chronic myeloid leukemia treated with second-line dasatinib

Background

Comorbidities may affect survival and choice of treatment among cancer patients. In fact, comorbidities have been identified as significant determinants of response to therapy in older patients with acute myeloid leukemia, breast cancer, head and neck cancer, and lung cancer. The Charlson comorbidity index and adult comorbidity evaluation-27 are lists of comorbidities with a weight assigned from 1 to 6 for the former and from 0 to 3 for the latter score, derived from relative risk estimates of a proportional hazard regression model using clinical data.

Design and Methods

We retrospectively evaluated the Charlson index and adult comorbidity evaluation-27 score in a cohort of 125 elderly (> 60 years) patients with chronic phase chronic myeloid leukemia who received dasatinib after showing resistance or intolerance to imatinib with the aim of establishing associations between comorbidities and the development of pleural effusions or compliance with the drug treatment.

Results

We found a significant association between the Charlson index as well as the adult comorbidity evaluation-27 score and the rate of drug reduction or suspension: with regards to the Charlson index, 49% of score 0 patients had a dose reduction compared to 63% of patients with score 1, 74% of those with score 2 and 100% of patients with score 3–5 (P=0.03); with regards to the adult comorbidity evaluation-27 score, 45% of patients had score 0–1 and 69% of patients with score 2–3 had a dose reduction. Of the 65 patients with Charlson score 0, 29% had at least one suspension of treatment (79% for hematologic and 21% for non-hematologic toxicity), compared to 46% of patients with score 1 (37% for hematologic and 69% for non-hematologic toxicity), 58% of patients with score 2 (36% for hematologic and 64% for non-hematologic toxicity) and 100% of patients with score 3 or 4 (all patients for both types of toxicity). High adult comorbidity index-27 scores identified patients at high risk of grade 3/4 hematologic toxicity. Forty-one patients (32.8%) experienced pleural effusion during treatment: the highest scores for both indices were associated with an increased risk of pleural effusions.

Conclusions

In elderly patients with chronic myeloid leukemia treated with dasatinib, the rate of drug reduction or suspension and the incidence of pleural effusions seem to be associated with the presence of comorbidities: stratification according to the Charlson index and adult comorbidity evaluation-27 score before dasatinib therapy may enable the identification of patients at risk of major toxicities.     

Prognostic relevance of cytometric quantitative assessment in patients with myelodysplastic syndromes

Objectives: Morphology and cytogenetics are currently used to define prognosis in myelodysplastic syndromes (MDS). However, these parameters have some limits. Flow cytometry has been recently included in the diagnostic panel for MDS, and its prognostic significance is under evaluation. Methods: Marrow aspirates from 424 MDS patients were analyzed by flow cytometry to evaluate the impact of bone marrow cell immunophenotype on overall survival (OS) and leukemia‐free survival (LFS). The immature compartment of myeloblasts was analyzed by the quantitative expression of CD34 (<3% vs. ≥3%), CD117, and CD11b^?/CD66b^? (<5% vs. ≥5%); myeloid maturation was analyzed by the expression of CD11b⁺/CD66b⁺⁺ (<15% vs. ≥15%) and CD11b⁺/CD66b⁺ (<25% vs. ≥25%). Results:  In univariate analysis, the expression of immaturity markers (CD34⁺, CD117⁺, and CD11b^?/CD66b^?) was associated with shorter LFS and OS (P < 0.0001); higher expression of differentiation markers (CD11b⁺/CD66b⁺⁺ and CD11b⁺/CD66b⁺) was associated with longer LFS (P < 0.0001 and P = 0.0002, respectively) and OS (P < 0.0001). In multivariate analysis, expression of CD34⁺ (P = 0.007), CD117⁺ (P = 0.013), and CD11b⁺/CD66b⁺⁺ (P = 0.023) retained independent prognostic value for OS, while only the expression of CD34⁺ was a prognostic factor for LFS (P = 0.0003). Two different risk groups were defined according to the presence of 0–1 or ≥2 of these factors with significant different LFS and OS (P < 0.0001). This score showed prognostic value in predicting survival even in subanalysis according to IPSS and WHO subgroups. Conclusions: Flow cytometric analysis in MDS may provide meaningful prognostic information. Blast percentage expressed as CD117⁺ or CD34⁺ cells and the quantitative assessment of myeloid maturation showed prognostic value for survival.     

Frontline imatinib treatment of chronic myeloid leukemia: no impact of age on outcome, a survey by the GIMEMA CML Working Party

The median age of chronic myeloid leukemia (CML) patients is ~60 years, and age is still considered an important prognostic factor, included in Sokal and EURO risk scores. However, few data are available about the long-term outcome of older patients treated with imatinib (IM) frontline. We analyzed the relationship between age and outcome in 559 early chronic-phase CML patients enrolled in 3 prospective clinical trials of Gruppo Italiano Malattie Ematologiche dell'Adulto CML Working Party, treated frontline with IM, with a median follow-up of 60 months. There were 115 older patients (≥ 65 years; 21%). The complete cytogenetic and major molecular response rates were similar in the 2 age groups. In older patients, event-free survival (55% vs 67%), failure-free survival (78% vs 92%), progression-free survival (62% vs 78%), and overall survival (75% vs 89%) were significantly inferior (all P < .01) because of a higher proportion of deaths that occurred in complete hematologic response, therefore unrelated to CML progression (15% vs 3%, P < .0001). The outcome was similar once those deaths were censored. These data show that response to IM was not affected by age and that the mortality rate linked to CML is similar in both age groups. This trial was registered at www.clinicaltrials.gov as #NCT00514488 and #NCT00510926.     

Influence of Aortic Dilation on the Regional Aortic Stiffness of Bicuspid Aortic Valve Assessed by 4-Dimensional Flow Cardiac Magnetic Resonance: Comparison With Marfan Syndrome and Degenerative Aortic Aneurysm

ObjectivesThis study sought to ascertain whether patients with a bicuspid aortic valve (BAV) have an intrinsic alteration in regional aortic stiffness compared with patients with tricuspid aortic valve (TAV) and Marfan syndrome (MFS) patients with similar aortic sizes, as well as to assess the influence of ascending aorta (AAo) dilation on regional stiffness parameters in BAV patients.BackgroundImaging biomarkers as predictors of BAV, MFS, and degenerative AAo aneurysms in TAV patients (DA-TAV) are lacking. Biomechanical characterization has been proposed as a possible tool for further aneurysm stratification.MethodsA total 234 subjects (136 BAV, 44 MFS, and 18 DA-TAV patients and 36 healthy control subjects) were included. The cardiac magnetic resonance protocol comprised 4-dimensional flow to assess AAo and descending aorta (DAo) pulse wave velocities (PWVs) and double-oblique, 2-dimensional, steady-state free-precession cine cardiac magnetic resonance to compute aortic distensibility (AD).ResultsOn adjusted analysis, nondilated BAV patients had similar PWV and AD as healthy control subjects in both AAo and DAo, whereas dilated BAV did not differ from DA-TAV. In contrast, AAo and DAo stiffness in MFS patients was markedly greater than in BAV patients, increasing slightly with dilation severity. AAo PWV showed a biphasic pattern in BAV patients: it first decreased and then increased throughout AAo dilation, with a clear turning point at 50 mm, whereas distensibility did not discern mildly dilated aorta. In multivariate analysis adjusted for clinical and demographic characteristics, only PWV was related to AAo dilation in BAV patients.ConclusionsThe mechanical properties of AAo aneurysms are similar in BAV and TAV patients, whereas MFS patients have a stiffer aorta. Aortic stiffness strongly depends on dilation severity. AAo PWV resulted in a potentially clinically useful biphasic trend with respect to aneurysm diameter, whereas distensibility did not discern mildly dilated aorta. Beyond clinical risk factors, PWV but not AD was independently related to AAo dilation in BAV patients.     

Sex differences in coronary plaque changes assessed by serial computed tomography angiography

Long-term data on sex-differences in coronary plaque changes over time is lacking in a low-to-intermediate risk population of stable coronary artery disease (CAD). The aim of this study was to evaluate the role of sex on long-term plaque progression and evolution of plaque composition. Furthermore, the influence of menopause on plaque progression and composition was also evaluated. Patients that underwent a coronary computed tomography angiography (CTA) were prospectively included to undergo a follow-up coronary CTA. Total and compositional plaque volumes were normalized using the vessel volume to calculate a percentage atheroma volume (PAV). To investigate the influence of menopause on plaque progression, patients were divided into two groups, under and over 55 years of age. In total, 211 patients were included in this analysis, 146 (69%) men. The mean interscan period between baseline and follow-up coronary CTA was 6.2?±?1.4 years. Women were older, had higher HDL levels and presented more often with atypical chest pain. Men had 434 plaque sites and women 156. On a per-lesion analysis, women had less fibro-fatty PAV compared to men (β -1.3?±?0.4%; p?<?0.001), with no other significant differences. When stratifying patients by 55 years age threshold, fibro-fatty PAV remained higher in men in both age groups (p?<?0.05) whilst women younger than 55 years demonstrated more regression of fibrous (β -0.8?±?0.3% per year; p?=?0.002) and non-calcified PAV (β -0.7?±?0.3% per year; p?=?0.027). In a low-to-intermediate risk population of stable CAD patients, no significant sex differences in total PAV increase over time were observed. Fibro-fatty PAV was lower in women at any age and women under 55 years demonstrated significantly greater reduction in fibrous and non-calcified PAV over time compared to age-matched men. (ClinicalTrials.gov number, NCT04448691.)