Effects of IL-6 variants in multiple myeloma: growth inhibition and induction of apoptosis in primary cells

Interleukin-6 (IL-6) plays a pathogenetic role in B-cell malignancies and is a growth factor for multiple myeloma (MM) cells. Elevated serum IL-6 levels and a higher proliferative activity of bone marrow plasma cells are poor prognostic factors in MM patients. In addition to clinical trials with anti-IL-6 monoclonal antibodies, an alternative therapeutic approach based on the use of IL-6 receptor (R) super-antagonists (Sants) has been proposed. Sants are variants of the native cytokine characterized by a wild type affinity for the ligand-specific receptor chain IL-6R alpha and by a reduced ability to bind and/or dimerize the signaling chain gp-130. We report the in vitro effects of four different Sants on cell kinetic modulation and induction of apoptosis of primary cells from MM patients. Ten MM samples were cultured in the presence of four different Sants and heterogeneous effects in terms of reduction of proliferation and induction of apoptosis could be observed. A decrease of the S phase cells (> or = 25%) coupled with the induction of apoptosis was obtained in 4/10 samples: three of these samples had a diploid DNA stem line and an inferior initial percentage of S phase cells. Serum IL-6 concentrations did not correlate with the anti-proliferative activities of the Sants. Cell growth inhibition was observed especially in samples with soluble IL-6R serum concentrations > 200 ng/ml. We conclude that Sants can exert antiproliferative effects on selected MM samples. Such effects may depend on the availability of large amounts of soluble IL-6R. Further studies should aim at defining the conditions necessary for optimal antiproliferative activity.     

Color Doppler imaging of the ocular ischemic syndrome.

PURPOSE: This study describes hemodynamic characteristics of the ophthalmic, central retinal, and posterior ciliary arteries in 16 eyes of 11 patients with the ocular ischemic syndrome. Understanding the hemodynamic characteristics of the retrobulbar circulation may elucidate the natural history and pathophysiology of the ocular ischemic syndrome and perhaps form the basis for rational treatment of this condition. METHODS: Color Doppler imaging, a procedure that permits rapid noninvasive imaging of the ophthalmic, central retinal, and posterior ciliary arteries, was used to quantitate peak systolic blood flow velocities and vascular resistance (pulsatility index) within these vessels in study group eyes and in an age-matched control population. RESULTS: We demonstrated markedly reduced ocular ischemic syndrome central retinal and posterior ciliary artery peak systolic velocities compared with control group eyes. Central retinal and posterior ciliary artery vascular resistance (pulsatility index) was greater in ocular ischemic eyes versus control group eyes. Reversal of ophthalmic artery blood flow was detected in 12 of 16 ocular ischemic syndrome eyes. Study group eyes with poor vision had no detectable posterior ciliary arterial blood flow. CONCLUSION: Color Doppler imaging quantitates hemodynamic characteristics of the retrobulbar circulation in the ocular ischemic syndrome. There is markedly reduced peak systolic velocity and increased vascular resistance in ocular end arteries such as the central retinal and posterior ciliary arteries. Ophthalmic artery reversal of flow seems to represent collateral blood flow to lower resistance vascular beds. Posterior ciliary artery hypoperfusion may correlate with poor vision in the ocular ischemic syndrome.     

Regulatory pathways in inflammation

Tuning is a key aspect of inflammatory reaction essential in homeostasis and pathology. An emerging mechanism for negative regulation of proinflammatory cytokines is based on non-signaling IL-1/TLR receptors and chemokine receptors competing with signaling receptors for ligand binding and sustaining ligand internalization and degradation. Biological activities of IL-1R/TLR receptors are under control of membrane-bound binding molecules lacking the signaling domain, soluble receptor antagonists, and intracellular signaling inhibitors. The chemokine system includes at least three 'silent' receptors with distinct specificity and tissue distribution. D6 is the best characterized representative member of this class of negative regulators, binds most inflammatory, but not homeostatic, CC chemokines and shuttles in a ligand-independent way from the plasma membrane to endocytic compartments where chemokines are targeted to degradation. In vitro and in vivo evidence, including results with gene targeted mice, is consistent with the view that these non-signaling receptors for proinflammatory cytokines possess unique functional and structural features which make them ideally adapted to act as a decoy and scavenger receptors, with a non redundant role in dampening tissue inflammation and tuning draining lymph nodes reactivity.     

Advanced head and neck cancer in older adults: Results of a short course accelerated radiotherapy trial

ObjectivesTo assess the feasibility and safety of a repeated SHort course Accelerated RadiatiON therapy (SHARON) regimen in the palliative setting of Head and Neck (H&N) cancer in older adults.Material and MethodsPatients with histological confirmed H&N cancers, age ≥ 80 years, expected survival >3 months, and Eastern Cooperative Oncology Group (ECOG) performance status of ≤3 were enrolled. Patients were treated in cohorts of six patients: a total dose of 20 Gy was delivered in 2 consecutive days with a twice-daily fractionation (5 Gy per fraction) and at least 8-h interval. If no Grade 3 toxicity was registered, a second enrollment started with another cohort of six patients to whom were administered two cycles (total dose of 40 Gy). The primary endpoint was to evaluate the feasibility of the two cycles of treatment. Secondary endpoints were evaluation of symptoms control rate, symptoms-free survival (SFS), and Quality of Life (QoL) scores.ResultsSeventeen consecutive patients (median age: 85 years) were treated. Nine patients were treated with one cycle and 8 patients with two cycles. No G3 toxicity was reported in either cohort. With a median follow-up time of 4 months, 3-month SFS in the first and second cohorts was 83.3%, and 87.5%, respectively. The overall palliative response rate was 88%. Among 13 patients reporting pain, 8 (61.5%) showed an improvement or resolution of their pain.ConclusionRepeated short course accelerated radiotherapy in a palliative setting of H&N cancers is safe and well-tolerated in older adults.     

Quadricuspid Aortic Valve: A Case Report and Review of the Literature

The quadricuspid aortic valve (QAV) is a rare malformation; often isolated, sometimes associated with other heart diseases. Before the era of echocardiography, the diagnosis was made incidentally at autopsy or during surgery of valve replacement. The extensive use of echocardiography has allowed an early and accurate diagnosis of this malformation. In many cases, the transthoracic approach is suitable for the diagnosis but, transesophageal echocardiography is a tool for the accurate definition of the valve anatomy. This review analyzes, after the presentation of a clinical case, the current knowledge on embryogenesis, classification, diagnosis and clinical course of QAV.     

Prediction of functional capacity by low-dose dobutamine stress echocardiography in chronic heart failure

AIM: The aim of this study was to determine if low-dose dobutamine stress echocardiography (LD-DSE) is associated with functional capacity in unselected elderly patients with chronic heart failure. METHODS: This was a prospective trial.Thirty five consecutive patients were included, with age >65 years and left ventricular dysfunction (12 ischemic), by blindly assessed LD-DSE and cardiopulmonary exercise testing (CPT). Contractile reserve was defined as a change (D) in wall motion score index (WMSI) = or <0.2 at peak dose dobutamine. At CPT treadmill exercise time, peak VO2, %Vo2 and VE/VCO2 slope were determined. Preserved functional capacity was defined as percent of maximal predicted O2 consumption (%VO2) >80%. Baseline NT-proBNP plasma levels were assessed. RESULTS: CPT variables were not related to clinical and baseline echocardiography characteristics but were related to DWMSI (exercise time, P=0.004; peak VO2, P=0.008; %VO2, P<0.001; VE/Vco2, P<0.001). Contractile reserve was present in 16 of 17 patients with preserved functional capacity (sensitivity=94%) and in 2 of 13 patients without (specificity=85%). Baseline NT-proBNP levels were lower in patients with contractile reserve (476+/-365 pg/mL) than in those without (1 345+/-1 219 pg/mL) (P=0.019), but were mildly related to CPT variables (P=0.049 and 0.027 with exercise time and %VO2, respectively). CONCLUSION: Contractile reserve elicited at LD-DSE is associated with functional capacity in unselected elderly patients with chronic heart failure.     

The Biagram vector: a graphical relation between reactance and phase angle measured by bioelectrical analysis in infants

BACKGROUND: Biagram vector is derived by plotting direct measurements of reactance and phase angle from the analyzer, which are not dependent on anthropometric characteristics of the subject and it can be considered an emerging method for evaluating the nutritional status in clinical practice. AIM: To calculate and plot the Biagram vector in a sample of healthy infants in their first year of life. METHODS: 174 healthy infants (99 male, 75 female) aged under 1 year, born at full term and adequate for gestational age, were enrolled in a cross-sectional study. The sample was divided into three age groups: 0-3.99 months (group A), 4-7.99 months (group B), and 8-11.99 months (group C). Bioelectric impedance analysis (BIA) was performed by a tetrapolar single frequence phase-sensitive impedance analyzer (STA/BIA; Akern Srl, Firenze, Italy). RESULTS: Biagram vector showed an increasing trend (p < 0.05) in the first year of life (group A: 27.9 +/- 12.6; group B: 32.1 +/- 9.7; group C: 37.2 +/- 9.5). Females showed Biagram vector values significantly higher than males in group A (34.7 +/- 15.0 vs. 24.0 +/- 9.1; p < 0.05). 95% confidence ellipses of Biagram vector for each age group were calculated and plotted and a comparison of our results with published data calculated in older children was conducted. CONCLUSION: The bivariate analysis of BIA measurements, plotted as a vector in relation to the age, showed an increasing trend with a higher gain rate under 1 year with respect to the following age periods. These data could reflect the variation of body composition in the first years of life and could be of interest to assess the nutritional status for clinical practice.     

Thromboembolic risk in atrial flutter. The FLASIEC (FLutter Atriale Società Italiana di Ecografia Cardiovascolare) multicentre study.

AIMS: Patients with atrial flutter are believed to be at lower risk of thromboembolism than patients with atrial fibrillation. However, the incidence of atrial thrombi and the need for anticoagulation in patients with atrial flutter is not well established. METHODS AND RESULTS: A prospective observational multicentre study was undertaken to assess the frequency of atrial thrombi and spontaneous echocontrast and the prevalence for aortic complex atherosclerotic lesions in a cohort of unselected patients with atrial flutter. We evaluated 134 patients (102 male, aged 70+/-9 years); exclusion criteria were history of atrial fibrillation, rheumatic mitral valve disease and mitral mechanical prosthesis. The median of atrial flutter duration was 33 days. Twelve patients had been taking warfarin for more than 7 days. One hundred and twenty-four patients (94%) underwent a transoesophageal echocardiogram, which revealed left atrial appendage thrombi in two patients (1.6%) and right atrial thrombi in one patient (1%). At least moderate left atrial echocontrast was found in 16/124 patients (13%). Complex atherosclerotic aortic plaques were detected in 10 patients (8%). Atrial flutter conversion was attempted in 93/134 patients (69%). At the 1-month follow-up, two patients experienced a thromboembolic event following restoration of sinus rhythm. CONCLUSIONS: Atrial thrombi and echocontrast, and complex aortic atherosclerotic plaques are relatively uncommon in patients with atrial flutter. Post-cardioversion embolism was observed in two patients in our study population.