The histone deacetylase inhibitor ITF2357 has anti-leukemic activity in vitro and in vivo and inhibits IL-6 and VEGF production by stromal cells.

We have investigated the activity of ITF2357, a novel hydroxamate histone deacetylase inhibitor, on multiple myeloma (MM) and acute myelogenous leukemia (AML) cells in vitro and in vivo. ITF2357 induced apoptosis in 8/9 MM and 6/7 AML cell lines, as well as 4/4 MM and 18/20 AML freshly isolated cases, with a mean IC(50) of 0.2 microM. ITF2357 activated the intrinsic apoptotic pathway, upregulated p21 and downmodulated Bcl-2 and Mcl-1. The drug induced hyperacetylation of histone H3, H4 and tubulin. When studied in more physiological conditions, ITF2357 was still strongly cytotoxic for the interleukin-6 (IL-6)-dependent MM cell line CMA-03, or for AML samples maximally stimulated by co-culture on mesenchymal stromal cells (MSCs), but not for the MSCs themselves. Interestingly, ITF2357 inhibited the production of IL-6, vascular endothelial growth factor (VEGF) and interferon-gamma by MSCs by 80-95%. Finally, the drug significantly prolonged survival of severe combined immunodeficient mice inoculated with the AML-PS in vivo passaged cell line already at the 10 mg/kg oral dose. These data demonstrate that ITF2357 has potent anti-neoplastic activity in vitro and in vivo through direct induction of leukemic cell apoptosis. Furthermore, the drug inhibits production of growth and angiogenic factors by bone marrow stromal cells, in particular IL-6 and VEGF.     

Variability analysis of fetal heart rate signals as obtained from abdominal electrocardiographic recordings

The present paper introduces an original method of digital signal processing for an automatic analysis of non-invasive abdominal ECG recordings on pregnant women starting from the 25th week of gestation. The procedure has been implemented on a DEC-VAX 750 digital computer at the Department of Electrical Engineering, Polytechnic of Milano and the signals are recorded at the Department of Obstetrics and Gynecology "L. Mangiagalli", University of Milano, Italy. The experimental results presented in here are still preliminary as only few cases have been considered up to now (about 20) and the goal of the paper is mainly focused on the algorithmic aspects of the whole procedure implemented in the computer and on the approach of heart rate variability (HRV) signal analysis both in the mother and in the fetus. Abdominal ECG lead processing is illustrated starting from the step of maternal (M) and fetal (F) QRS recognitions through linear digital filtering (derivative and low-pass FIR filter, Weber-Cappellini window) and weighted averaging techniques synchronized with maternal QRS's. Figure 1 a shows the original abdominal lead; figure 1 b the filtered signal for MQRS recognitions; figure 2 a the template of maternal cardiac cycle as obtained after the averaging operation synchronized with the instants of MQRS occurrence. The subtraction of the template results in the abdominal lead shown in figure 1 c in which the contribution of MECG is practically entirely reduced even in the case of MQRS and FQRS overlapping.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of age on outcomes in patients undergoing mitral valve replacement

BACKGROUND: Although increasing age has been associated with greater risk of mortality for patients undergoing mitral valve replacement, it is less clear whether this elevated risk is related to age-related differences in comorbidity or other clinical characteristics. METHODS: A population of 31,688 patients from The Society of Thoracic Surgeons National Cardiac Database undergoing mitral valve replacement either alone or in combination with coronary artery bypass grafting or tricuspid surgical procedures from 1997 to 2000 was examined to assess age-related variation in clinical features, morbidity, and mortality. Multivariable logistic regression was used to determine the effect of age after adjusting for other known risk factors. A classification tree was used to identify low-risk elderly (> or = 75 years) patients. RESULTS: Operative mortality increased four-fold from 4.1% in patients aged less than 50 years up to 17.0% in patients aged 80 years or more. Similarly, major operative complications (stroke, prolonged ventilation, reoperation for bleeding, renal failure, and sternal infection) also increased with age, rising from 13.5% (age < 50 years) to 35.5% (age > or = 80 years). Multivariable adjustment attenuated the odds of operative mortality, but age remained a significant risk factor. After adjusting for other patient risk factors, age accounted for 13% and 10% of the explainable risk for mortality and morbidity, respectively. Among the elderly, four variables (hemodynamic instability, New York Heart Association class IV, renal failure, and concomitant coronary artery bypass grafting) were identified to distinguish levels of risk, from operative mortality rates exceeding 31% to those with 7.7% mortality. CONCLUSIONS: Operative mortality and morbidity rise with increasing age of patients undergoing mitral valve replacement. Although this excess risk is partially a result of increased comorbid burden and other operative factors, age remains an independent powerful risk factor for operative risk for mitral valve replacement. Understanding the relationship of age with other risk factors for mitral valve replacement can help stratify risk, enabling physicians to identify lower risk patients.     

Determination of the minor component bromhexine in cotrimoxazole-containing tablets by absorption spectrophotometry and partial least-squares (PLS-1) multivariate calibration

The mucolitic bromhexine [N-(2-amino-3,5-dibromobenzyl)-N-methylcyclohexylamine] has been determined in cotrimoxazole-containing tablets by partial least-squares (PLS-1) multivariate of spectrophotometric calibration data in the spectral range 310-350 nm. In the studied commercial tablets, cotrimoxazole is present in large excess (ca. 100:1 in weight) with respect to bromhexine, and a high degree of spectral overlapping exists among bromhexine and cotrimoxazole components. However, the obtained recoveries are reasonably good with the presently discussed technique.     

Interventional radiologic procedures in the renal transplant

Percutaneous interventional procedures can be valuable in the evaluation and treatment of urologic complications of renal transplantation. Thirty-three patients underwent percutaneous procedures, including relief of obstruction by catheter nephrostomy, diagnostic antegrade pyelography with Whitaker testing, aspiration of various fluid collections (lymphocele, hematoma, urinoma, and abscess), and renal artery angioplasty, during a three year period at three institutions, to provide temporizing treatment and anatomic data. Surgical intervention was sometimes avoided, but more often it could be deferred to allow the patient to stabilize prior to surgery. Complications that required surgery occurred in two patients.     

Impermeability of the blood-brain barrier to intravenous high-iodine-dose meglumine diatrizoate in the normal dog

The effect of an intravenous bolus of 4.3 ml/kg of 60% meglumine diatrizoate on the blood-brain barrier (BBB) was studied in five adult unanesthetized dogs. Intravenous 3% Evans blue dye (4 ml/kg) was used as an indicator of BBB disruption. The animals were observed for signs of neurotoxicity for 1 hr after contrast-medium injection and then sacrificed. Their brains were removed and sectioned. None of the dogs displayed clinical evidence of neurotoxicity, and none of the brain specimens showed evidence of BBB disruption. The authors concluded that there is a statistically significant lack of correlation between the intravenous administration of 4.3 ml/kg of 60% meglumine diatrizoate and BBB disruption (p less than 0.05 with a probability of 90%). A previous publication reported focal BBB disruption in anesthetized dogs with dosages of 4 ml/kg and 6 ml/kg of 60% intravenous contrast agent given as an initial bolus followed by a drip infusion. The present study duplicated this prior experiment using the 6 ml/kg dose followed by infusion in three additional unanesthetized dogs and failed to substantiate the previous findings. This discrepancy leads to the assumption that the BBB damage noted in the previous experiment was somehow related to a factor(s) other than the intravenous contrast-medium injection. The BBB cannot be disrupted in the unanesthetized dog with intravenous doses of 60% contrast media of even 6 ml/kg.     

Pharmacological profile of mifentidine: a novel H2-receptor antagonist

Mifentidine, a representative compound of a novel class of H2-antagonists, has been investigated for its ability to interact with H2-receptors and to inhibit gastric acid secretion. Affinity estimates (KB) of mifentidine obtained from in vitro studies on cardiac and gastric mucosal histamine (H2) receptors were in the 20-50 nM range. Mifentidine appeared to be endowed with strong anti-secretory properties against histamine-stimulated secretion in the anaesthetized rat and in the conscious dog. Distinct features of mifentidine were considerable bioavailability and duration of anti-secretory effect.