Chronic lymphocytic leukemia (CLL) is the most common leukemia in the world. The TCL1 gene, responsible for prolymphocytic T cell leukemia, is also overexpressed in human B cell malignancies and ...overexpression of the Tcl1 protein occurs frequently in CLL. Aging transgenic mice that overexpress TCL1 under control of the mu immunoglobulin gene enhancer, develop a CD5+ B cell lymphoproliferative disorder mimicking human CLL and implicating TCL1 in the pathogenesis of CLL. In the current study, we exploited this transgenic mouse to investigate two different CLL-related issues: potential treatment of CLL and characterization of neoplasms that accompany CLL. We successfully transplanted CLL cells into syngeneic mice that led to CLL development in the recipient mice. This approach allowed us to verify the involvement of the Tcl1/Akt/mTOR biochemical pathway in the disease by testing the ability of a specific pharmacologic agent, rapamycin, to slow CLL. We also showed that 36% of these transgenic mice were affected by solid malignancies, in which the expression of the Tcl1 protein was absent. These findings indicate that other oncogenic mechanism(s) may be involved in the development of solid tumors in Emu-TCL1 transgenic mice.
The gene Nm23, which encodes for a nucleoside diphosphate kinase, has been defined as a metastasis-suppressor gene because of the inverse correlation between its expression and the metastatic ...capacity of the tumor cells. For colorectal cancer, however, the findings are equivocal. The aim of our study was to assess, in 160 patients undergoing surgery for colorectal cancer (CRC), the expression of the Nm23-H1 protein and to evaluate its possible associations with traditional clinicopathologic variables, with DNA-ploidy and proliferative activity (S-phase fraction, SPF), and with disease-free and overall survival of patients. Nm23-H1 expressions were evaluated on paraffin-embedded tissue by immunohistochemistry; DNA-ploidy and SPF on frozen tissue by flow-cytometric analysis. The median follow-up time in our study group was 71 months (range 34-115 months). No association was observed between Nm23-H1 protein expression and clinicopathological variables, S-phase fraction and DNA-ploidy. Furthermore, no significant differences were observed in the survival of patients with either moderate or strong Nm23-H1 expression. The major significant predictors for both disease relapse and death were advanced Dukes' stage, DNA aneuploid tumors and high SPF, while lymphohematic invasion was the only independent factor for relapse and non-curative resection for death. Our results indicate that Nm23-H1 activity is tissue-specific and that in CRCs the expression of the protein is not associated with tumor progression and patient prognosis, although further studies are required in order to throw more light on the possible clinical significance of the overexpression of the protein Nm23-H1 in such tumors.
Abstract Background The aim of the study was to verify the effects of hypertonic saline solution (HSS) plus a high furosemide dose and light restriction of sodium intake compared with a high-dose ...infusion of furosemide alone on pulmonary capillary wedge pressure (PCWP), as determined by Doppler echocardiography and tissue Doppler imaging in patients suffering from decompensated heart failure. Methods and Results Consecutive patients in New York Heart Association functional class IV, unresponsive to oral high doses of furosemide up to 250–500 mg/d and/or combinations of diuretics, with ejection fraction <40%, serum creatinine <2 mg/dL, blood urea nitrogen ≤60 mg/dL, reduced urinary volume (<500 mL/24 h), and low natriuresis (<60 mEq/24 h) were randomized into 2 groups (double blind). The first group received a furosemide infusion (250 mg) plus HSS (150 mL 3.0% Na) bid and light Na restriction (120 mmol), and the second group received furosemide infusion (250 mg) twice daily, and low Na diet (80 mmol). The fluid intake of both groups was restricted (1 L/d). Body weight, whole-body bioelectrical impedance analysis (BIA), 24-hour urinary volume, and serum and urinary laboratory parameters were measured daily. Estimations of echocardiographic PCWP (Echo-PCWP) were detected on entry, 1 hour after concluding the initial treatment, and 6 days thereafter. A total of 133 patients (47 women and 86 men), aged 65–82 years, met the entry criteria.The HSS group revealed a significant increase in daily diuresis, natriuresis, and serum sodium compared with the furosemide group. Six days after treatment, renal function was significantly improved in the HSS group. Both groups showed a significant reduction in Echo-PCWP, but the HHS group revealed a faster reduction and significant lower values at 6 days compared with the group taking furosemide alone. We observed a positive correlation between values of Echo-PCWP and BNP and an inverse correlation between BIA parameters and Echo-PCWP. Conclusions Our data show that the combination of high diuretic dose and HSS infusion plus light restriction in dietary sodium intake determine a more rapid and significant hemodynamic stabilization through the improvement of echo-PCWP, BNP levels, and BIA parameters than the group treated without HSS.
Introduction
Diuretic responsiveness in patients with chronic heart failure (CHF) is better assessed by urine production per unit diuretic dose than by the absolute urine output or diuretic dose. ...Diuretic resistance arises over time when the plateau rate of sodium and water excretion is reached prior to optimal fluid elimination and may be overcome when hypertonic saline solution (HSS) is added to high doses of furosemide.
Methods
Forty-two consecutively hospitalized patients with refractory CHF were randomized in a 1:1:1 ratio to furosemide doses (125 mg, 250 mg, 500 mg) so that all patients received intravenous furosemide diluted in 150 ml of normal saline (0.9%) in the first step (0–24 h) and the same furosemide dose diluted in 150 ml of HSS (1.4%) in the next step (24–48 h) as to obtain 3 groups as follows: Fourteen patients receiving 125 mg (group 1), fourteen patients receiving 250 mg (group 2), and fourteen patients receiving 500 mg (group 3) of furosemide. Urine samples of all patients were collected at 30, 60, and 90 min, and 3, 4, 5, 6, 8, and 24 h after infusion. Diuresis, sodium excretion, osmolality, and furosemide concentration were evaluated for each urine sample.
Results
After randomization, 40 patients completed the study. Two patients, one in group 2 and one in group 3 dropped out. Patients in group 1 (125 mg furosemide) had a mean age of 77 ± 17 years, 43% were male, 6 (43%) had heart failure with a preserved ejection fraction (HFpEF), and 64% were in New York Heart Association (NYHA) class IV; the mean age of patients in group 2 (250 mg furosemide) was 80 ± 8.1 years, 15% were male, 5 (38%) had HFpEF, and 84% were in NYHA class IV; and the mean age of patients in group 3 (500 mg furosemide) was 73 ± 12 years, 54% were male, 6 (46%) had HFpEF, and 69% were in NYHA class IV. HSS added to furosemide increased total urine output, sodium excretion, urinary osmolality, and furosemide urine delivery in all patients and at all time points. The percentage increase was 18,14, and 14% for urine output; 29, 24, and 16% for total sodium excretion; 45, 34, and 20% for urinary osmolarity; and 27, 36, and 32% for total furosemide excretion in groups 1, 2, and 3, respectively. These findings were translated in an improvement in the furosemide dose–response curves in these patients.
Conclusion
These results may serve as new pathophysiological basis for HSS use in the treatment of refractory CHF.
There are several new strategies proposed to improve the outcome of patients with ST-elevation myocardial infarction (STEMI). One approach is the resurgent use of facilitated percutaneous coronary ...interventions (PCI). Until recently, deciding whether immediate PCI after combined treatment (facilitated PCI) is more appropriate than delayed PCI (short time) has not been investigated. The aim of this study, therefore, was to investigate the outcomes in patients initially successfully treated pharmacologically and immediate PCI < 2 hr, and in patients initially successfully treated with pharmacological therapy and with delayed PCI (12-72 h).
451 reperfused STEMI patients, aged 18 to 75 years, class I-II Killip, with an acceptable echocardiographic window and admitted within 12 hs of the onset of symptoms were randomized into two groups. All patients had to have successful reperfusion, to receive the combination of a standard tirofiban infusion or abciximab plus half dose rtPA. Thereafter, patients were sub-grouped as follows:group 1 (immediate PCI) patients had PCI within 2 h; and group 2 (delayed PCI) patients in which PCI was performed after 12 hs and within 72 hs.
The 225 reperfused (immediate-PCI) and 226 reperfused (delayed-PCI) patients (time from randomization to PCI 165 +/- 37 min in immediate PCI versus 45.1 +/- 20.2 h in delayed PCI group) showed similar results in ejection fraction, CK release and patency of the IRA. In addition, the delayed PCI group showed a significant reduction in ischemic events, restenosis and bleedings (P = 0.005, 0.01, 0.01 respectively) and significant reduced angiographic evidence of thrombus formation in the infarction-related artery (IRA) (p = 0.001).
Our data suggest the safety and possible use of delayed facilitated PCI in patients with STEMI, and that delayed PCI in patients treated with combined lytic and IIb/IIIa inhibitors appears to be as effective and possibly superior (reduced ischemic events and repeat PCI) as immediate PCI. The patients in this study were successfully reperfused, with TIMI-3 flow and our data may not apply to patients with TIMI 0-2 flow. This strategy could allow transferring the reperfused patients and performing PCI after hours < 72 hours and not immediately, thereby reducing the number of urgent PCI and costs, obtaining similar results, but mostly causing less discomfort to the patient. Our results had to be interpreted with caution, because current guidelines do not recommend the combined therapy, but suggest further studies. The study was aimed to investigate the outcomes in patients initially successfully treated pharmacologically and immediate PCI < 2 h, and in patients initially successfully treated with pharmacological therapy and delayed PCI (12-72 h). All patients had to have successful reperfusion, to receive the combination of a standard abciximab or tirofiban infusion plus half dose rtPA. Similar results were observed in both groups. Delayed PCI group showed a significant lower incidence in restenosis (0.01), minor bleedings (0.005), ischemic events (0.01) and a reduced angiographic evidence of thrombus formation in IRA (0.001). Our data suggest the safety and possible use of delayed facilitated PCI in patients with STEMI. Our results had to be interpreted with caution, because current guidelines do not recommend the combined therapy, but suggest further studies.
Experiments of differential scanning calorimetry and dynamic mechanical spectroscopy on linear and cross-linked heterocyclic polymer networks (HPNs) have been performed over the temperature range ...between 120 and 400
K. The temperature dependences of the storage modulus
E′ and the internal friction
Q
−1 of HPNs, investigated by mechanical waves of frequencies ranging between 0.3 and 30
Hz, reveal anelastic behaviors which are mainly governed by the secondary β- and primary α-relaxations. The addition of cross-links in an apparently linear polymer network was accompanied by the shift of the glass transition to higher temperatures. Differently from the α-relaxation whose strength decreases with cross-linking, the β-relaxation strength increases. This observation implies the lack of any dynamical hierarchy between the local and cooperative segmental dynamics in these systems. The β-relaxation follows the Arrhenius law with values of the characteristic frequency
ω
0 and the activation energy
E
act
ranging between 10
15 and 10
16
s
−1 and 43.7 and 48.7
kJ/mole, respectively. In both the HPNs the β-loss peaks have been quantitatively analyzed by the symmetric double-well potential (SDWP) model.
Background and objectives:
Hypertension is a significant cause of chronic renal injury and its effective treatment is capable of reducing the rate of renal failure. β-Adrenoceptor antagonists ...(β-blockers) have been reported to induce a deterioration in renal function, while several data have indicated a renoprotective effect of treatment with the angiotensin II type 1 receptor antagonist losartan. Previous studies of the interaction between the selective β
1
-blocker bisoprolol and kidney function were performed only for short-and medium-term periods. The aim of this study was to compare the antihypertensive efficacy and renal and cardiac haemodynamic effects of bisoprolol with those of losartan over a 1-year time period in patients with essential hypertension.
Methods:
Seventy-two patients (40 males) with recently diagnosed uncomplicated (European Society of Hypertension ESH criteria stage 1–2) hypertension (mean ± SD age 52 ± 12 years) were enrolled in the study. After a run-in period of 14 days on placebo, the patients were randomized in a double-blind, prospective study to receive either bisoprolol 5 mg or losartan 50 mg, administered once daily for 1 year. At recruitment and 12 months after treatment, cardiac output and renal haemodynamics and function were evaluated by echocardiography and radionuclide studies, respectively.
Results:
There were no significant differences in baseline clinical data, including glomerular filtration rate and blood pressure, between the two treatment groups. At 1 year, blood pressure had decreased significantly (p < 0.001) with both treatments, and heart rate was reduced only in the group taking bisoprolol. The long-term effects on renal haemodynamics and cardiac function were similar with both drugs, the only change being a significant reduction in the filtration fraction for each group.
Conclusions:
These data suggest that both bisoprolol and losartan are effective agents for the treatment of patients with recently diagnosed ESH stage 1–2 hypertension. Over a 1-year period, both agents maintained good renal and cardiac performance and haemodynamics.
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