Arterial wave reflection during antihypertensive therapy with barnidipine: A 6-month,open-label study using an integrated cardiovascular ultrasound approach in patients with newly diagnosed hypertension

Background: Increased central aortic pressure resulting from large artery stiffening and increased wave reflection is associated with higher hypertension-related morbidity.Objective: The goal of this study was to evaluate the effects of a vasodilator-based therapy with the calcium channel blocker barnidipine on arterial stiffness, wave reflection, and left ventricular (LV) performance using an integrated cardiovascular ultrasound approach (including wave intensity analysis).Methods: Newly diagnosed, previously untreated patients with grade 1 or 2 essential hypertension (systolic blood pressure [BP] ≥140 and <180 mm Hg, and/or diastolic BP ≥90 and <110 mm Hg), and with no signs of clinical cardiovascular disease, were eligible for study. Carotid artery mechanics were investigated at baseline and after 3 and 6 months of barnidipine therapy (10–20 mg once daily, according to an open-label design) using a double-beam carotid ultrasound technique. This provided a simultaneous recording of diameter-derived pressure and flow velocity signals and allowed analysis of wave intensity. Indices of local arterial stiffness and wave reflection, as well as separated forward and backward pressure waves, were estimated. LV geometry, mass, and systolic and diastolic performance were also assessed using Doppler echocardiography. All ultrasound examinations and readings were performed by investigators blinded to patient demographics and treatment phase. Normotensive control subjects (office BP <140/90 mm Hg) were included as a reference group.Results: Twenty-one white, treatment-naive patients with hypertension (mean [SD] age, 58 [8] years; 14 males; mean body mass index, 27 [5] kg/m²; mean BP, 159 [14]/96 [5] mm Hg) were enrolled. Twenty normotensive subjects comprised the control group. Compared with the control subjects, patients with hypertension had a higher mean augmentation index ([AIx] 22.0% [7.0%] vs 13.1% [5.2%]; P < 0.01), Peterson's pressure-strain elastic modulus (175 [49] vs 126 [41] kPa; P < 0.01), and forward and backward pressure waves (137 [17] vs 108 [7] mm Hg [P < 0.001] and 21 [6] vs 17 [5] mm Hg [P < 0.05], respectively) at baseline. After 6 months of barnidipine treatment, mean office BP in the patients with hypertension decreased from 159 (14)/96 (5) mm Hg at baseline to 138 (16)/81 (9) mm Hg (P < 0.001) due to a significant reduction in forward and backward pressure waves, and AIx decreased to 17.0% (8.0%) (P < 0.01); there were no significant changes in indices of intrinsic arterial stiffness. A significant direct relationship between AIx and pulse pressure (r = 0.45 [P < 0.05]) was observed at baseline in hypertensive patients but not after therapy (r = 0.26 [P = NS]). Mean stress-adjusted LV midwall shortening increased from 110% (17%) at baseline to 118% (13%) at 6 months (P < 0.05), which was comparable to baseline values in the control subjects (119% [10%]).Conclusion: In these middle-aged patients with newly diagnosed mild to moderate hypertension, vasodilator therapy with barnidipine reduced central BP by a parallel reduction of forward and backward pressure waves, together with a later arrival of the reflected waves, with no significant changes in intrinsic arterial stiffness.     

Towards a new age in the treatment of multiple myeloma

Multiple myeloma (MM) is an incurable disease characterized by the proliferation of end-stage B lymphocytes (plasma cells, PCs). As a consequence of myeloma growth in the bone marrow, a number of signaling pathways are activated that trigger malignant PC proliferation, escape from apoptosis, migration, and invasion. Thanks to new insights into the molecular pathogenesis of MM, novel approaches aimed at targeting these abnormally activated cascades have recently been developed and others are under study. These strategies include the inhibition of membrane receptor tyrosine kinases, inhibition of the proteasome/aggresome machinery, inhibition of histone deacetylases, inhibition of farnesyltransferases, targeting of molecular chaperones, and others. We will herein review and discuss these novel biological approaches with particular emphasis on those based on biochemical pathways which drive cell signaling. By providing the rationale for innovative therapeutic strategies, the above mechanisms represent targets for new compounds being tested in the management of this disease.     

Kidney aging: from phenotype to genetics

Aging is a physiological process that causes structural and functional changes in human body systems, sometimes leading to various organ failure. As far as the kidney is concerned, both genetic factors and environmental agents may influence the tissues damage in elderly people and the related loss of function. On the other hand, functional adaptations to structural changes appear to be compromised by co-morbid conditions that are frequently found in elderly people, such as atherosclerosis and hypertension. It is not yet known whether physiological aging is inevitably accompanied by a decline in renal function or how rapidly it might happen. The discovery of molecular mechanisms responsible for tissue damage in aging could offer new perspectives on interventions. The role of nitric oxide, oxidative stress, the renin-angiotensin system, changes in length of telomeres, and klotho gene expression are important subjects for further in-depth studies about aging. A better understanding of physiological renal aging could improve the clinical approach to this process and widen the therapeutic possibilities offered by transplantation.     

Driver mutations and prognosis in primary myelofibrosis: Mayo‐Careggi MPN alliance study of 1,095 patients

The 2013 discovery of calreticulin (CALR) mutations in myeloproliferative neoplasms was attended by their association with longer survival in primary myelofibrosis (PMF). Subsequent studies have suggested prognostic distinction between type 1/like and type 2/like CALR mutations and detrimental effect from triple‐negative mutational status. Among 709 Mayo Clinic patients with PMF, 467 (66%) harbored JAK2, 112 (16%) CALR type 1/like, 24 (3.4%) CALR type 2/like, 38 (5.4%) MPL mutations and 68 (10%) were triple‐negative. Survival was longer with type 1/like CALR, compared to JAK2 (HR 2.6, 95% CI 1.9‐3.5), type 2/like CALR (HR 2.5, 95% CI 1.4‐4.5), MPL (HR 1.8, 95% CI 1.1‐2.9) and triple‐negative mutational status (HR 2.4, 95% CI 1.6‐3.6), but otherwise similar between the non‐type 1/like CALR mutational states (P = .41). In multivariable analysis, the absence of type 1/like CALR (P < .001; HR 2, 95% CI 1.4‐2.7), presence of ASXL1/SRSF2 mutations (P < .001; HR 1.9, 95% CI 1.5‐2.4) and DIPSS‐plus (P < .001) were each predictive of inferior survival. Furthermore, among 210 patients with ASXL1/SRSF2 mutations, survival was significantly longer in the presence vs. absence of type 1/like CALR mutations (median 5.8 vs. 2.9 years; P < .001). Triple‐negative status did not disclose additional prognostic information for overall or leukemia‐free survival. The observations regarding the prognostic distinction between CALR mutation variants were validated in an external cohort of 386 patients from the University of Florence Careggi hospital. We conclude that type 1/like CALR mutations in PMF not only predict superior survival, but also partially amend the detrimental effect of high molecular risk mutations.     

B-type natriuretic peptide may predict prognosis in older adults admitted with a diagnosis other than heart failure

Background and Aims

The diagnosis of heart failure (HF) in elderly patients is often difficult, due to overlap of typical signs and symptoms with those of comorbidities. B-type Natriuretic Peptide (BNP) predicts diagnosis and prognosis of HF, but little is known on its predictive role of short-term prognosis when admission diagnosis is other than HF.

Unrecognized venous injuries after cardiac implantable electronic device transvenous lead extraction

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Hepatitis E virus in South America: The current scenario

Hepatitis E virus (HEV) is one of the most frequent causes of acute viral hepatitis of enteric transmission worldwide. In South America the overall epidemiology has been little studied, and the burden of the disease remains largely unknown. A research of all scientific articles about HEV circulation in South America until November 2017 was carried out. Human seroprevalences of HEV varied according to the studied population: blood donors presented prevalence rates ranging from 1.8% to 9.8%, while reports from HIV‐infected individuals, transplant recipients and patients on hemodialysis showed higher prevalence rates. Only 2 cases of chronic hepatitis in solid‐organ transplant patients from Argentina and Brazil have been described. Detection of HEV in the swine population is widely prevalent in the region. Anti‐HEV antibodies have also been recently documented in wild boars from Uruguay. Although scarce, studies focused on environmental and food HEV detection have shown viral presence in these kind of samples, highlighting possible transmission sources of HEV in the continent. HEV genotype 3 was the most frequently detected in the region, with HEV genotype 1 detected only in Venezuela and Uruguay. HEV is widely distributed throughout South America, producing sporadic cases of acute hepatitis, but as a possible agent of chronic hepatitis. Finding the virus in humans, animals, environmental samples and food, show that it can be transmitted through many sources, alerting local governments and health systems to improve diagnosis and for the implementation of preventive measures.     

Influence of antiviral therapy on the liver stiffness in chronic HBV hepatitis

Purpose

The aim of this study was to evaluate the effects of antiviral therapy on liver stiffness measurement (LSM).

Methods

Two hundred HBV patients were enrolled from four hospital centers in southern Italy; median age was 50.7 (25–75) males were 68%; 171 patients underwent to liver biopsy and 200 patients had LSM at baseline and 189 at the end of follow-up. One hundred and forty-nine patients were treated with nucleos(t)ide analogs, while 51 patients were untreated. The cutoffs of the LSM, related to the fibrosis stages, were as follows: non-advanced fibrosis ≤ 8.1 kPa and advanced fibrosis ≥ 8.2 Kpa.

Results

At baseline, the median value of LSM was 14.1 kPa for advanced fibrosis/cirrhosis and 6.9 kPa for non-advanced fibrosis. LSM was performed at 24 months from the start of therapy. The treated patients (68% received Entecavir and 32% Tenofovir) showed a decrease in liver stiffness measurement of 1.5 kPa (p < 0.001) in non-advanced fibrosis and of 6 kPa (p < 0.001) in advanced fibrosis/cirrhosis. In the patients not undergoing antiviral treatment, no statistically significant change of the LSM was observed (p = 0.26). A logistic binary regression model showed that the only independent factor associated with a significant change in the LSM was the liver stiffness value at baseline (odd ratio 2.855; 95% CI 1.456–5.788; (p = 0.007).

Conclusion

Long-term antiviral therapy induced a significant reduction of liver stiffness measurement and this result may be related to the reduction of liver fibrosis.

     

The chemokine receptor CXCR3 is expressed on malignant B cells and mediates chemotaxis

B- and T-cell recirculation is crucial for the function of the immune system, with the control of cell migration being mainly mediated by several chemokines and their receptors. In this study, we investigated the expression and function of CXCR3 on normal and malignant B cells from 65 patients with chronic lymphoproliferative disorders (CLDs). Although CXCR3 is lacking on CD5(+) and CD5(-) B cells from healthy subjects, it is expressed on leukemic B lymphocytes from all (31/31) patients with chronic lymphocytic leukemia (CLL). The presence of CXCR3 was heterogeneous in other B-cell disorders, being expressed in 2 of 7 patients with mantle cell lymphoma (MCL), 4 of 12 patients with hairy cell leukemia (HCL), and 11 of 15 patients with other subtypes of non-Hodgkin's lymphomas (NHLs). Chemotaxis assay shows that normal B cells from healthy subjects do not migrate in response to IFN-inducible protein 10 (IP-10) and IFN-gamma-induced monokine (Mig). In contrast, a definite migration in response to IP-10 and Mig has been observed in all malignant B cells from patients with CLL, but not in patients with HCL or MCL (1/7 cases tested). Neoplastic B cells from other NHLs showed a heterogenous pattern. The migration elicited by IP-10 and Mig was inhibited by blocking CXCR3. No effect of IP-10 and Mig chemokines was observed on the cytosolic calcium concentration in malignant B cells. The data reported here demonstrate that CXCR3 is expressed on malignant B cells from CLDs, particularly in patients with CLL, and represents a fully functional receptor involved in chemotaxis of malignant B lymphocytes.     

Von Hippel-Lindau-dependent polycythemia is endemic on the island of Ischia: identification of a novel cluster

Chuvash polycythemia (MIM 263400) is an autosomal recessive disorder characterized by a high hemoglobin level, relatively high serum erythropoietin, and early death. It results from a Von Hippel-Lindau (VHL) gene mutation (C598T) that causes increased HIF-1alpha activity and erythrocyte production in the face of normoxia. This polycythemia is endemic in Chuvashia, whereas its worldwide frequency is very low. We investigated the incidence of the Chuvash-type VHL mutation in Campania (South Italy) and identified 14 affected subjects (5 families). Twelve live on the island of Ischia (Bay of Naples). From analysis of the mutated allele, we found that the disease was more frequent on Ischia (0.070) than in Chuvashia (0.057). The haplotype of all patients matched that identified in the Chuvash cluster, thereby supporting the single-founder hypothesis. We also found that nonaffected heterozygotes had increased HIF-1alpha activity, which might confer a biochemical advantage for mutation maintenance. In conclusion, we have identified the first large cluster of Chuvash erythrocytosis outside Chuvashia, which suggests that this familial polycythemia might be endemic in other regions of the world.