Effect of glutaraldehyde fixation and valve constraint conditions on porcine aortic valve leaflet coaptation

In an investigation of the influence of glutaraldehyde fixation pressure and subsequent valve constraint on the coaptive characteristics of porcine aortic valves, 14 valves were examined, eight having been fixed at low pressure (congruent to 1 mm Hg) and six at high pressure (80 mm Hg). The coaptive ratios of the left and right coronary leaflets in the low-pressure-fixed valves showed a significant improvement over those of the same leaflets in the high-pressure-fixed valves. Inflation to 80 mm Hg results in a variable "peeling back" of the coaptive margins of the low-pressure-fixed valves but not of the high-pressure-fixed valves. Comparable coaptive ratios are therefore expected during full inflation of the unconstrained valves fixed both at low pressure and at high pressure. Constraining the low-pressure-fixed valves during inflation to simulate the effect of mounting on a rigid stent produced either a reduction or virtual elimination of this "peeling back" motion or in some instances a slight reversal of the effect, thus increasing the width of the coaptive margin. Hence it is expected that the stented low-pressure-fixed valve will manifest better coaptation than the high-pressure-fixed valve. Finally, the experimental findings of this study, combined with the improved mechanical function of the leaflet tissue already known to occur in the low-pressure-treated valves, provide a convincing case for valve fixation to be carried out under lower pressures.     

Predictors of cognitive decline in the early stage of probable Alzheimer's disease

Several papers have attempted to find neurological and neuropsychological predictors of progression in Alzheimer's disease (AD) till now. Despite this quite large amount of works, different and not univocal conclusions have been reported in this field. Different study samples, different end-points and differences in statistical methods can explain much of the inconsistency in the results obtained. In our study, AD patients were examined in a very early stage of the disease to avoid any possible risk to examine subjects at different times of evolution. All the patients underwent an extensive neuropsychological test battery twice (baseline and follow-up) spaced out over about 1 year and were divided into two groups of fast decliners (FD) and slow decliners (SD) on the basis of their rate of decay at the MMSE score. Verbal memory tests, mental control abilities and attention-demanding tasks seem to play a pivotal role in distinguishing the two groups of subjects in the early stage of the disease. Moreover, FD patients show a worse performance than SD at the baseline in most of the cognitive domains explored. In conclusion, different subtypes of AD do exist and an important predictor of progression is represented by the severity of the cognitive impairment at the onset.     

Evaluation of the Maruyama Computer Program Accuracy for Preoperative Estimation of Lymph Node Metastases from Gastric Cancer

Controversy still exists about the optimal lymph node (LN) dissection for potentially curable gastric cancer. For rational LN dissection it is important to know the incidence of metastasis at each LN station. For this purpose a computer program was developed using data from 4302 primary gastric cancers treated at the National Cancer Center Hospital in Tokyo between 1969 and 1989. To evaluate the accuracy of the computer program, the differences between the individual reports generated by the computer and the stored data were investigated in 282 Italian patients submitted to curative gastrectomy and D₂ or more extended LN dissections for gastric cancer. Receiver operating characteristic (ROC) analysis was used to assess the sensitivity and specificity of the program for predicting LN metastases in each of the 16 regional LN stations. The computer program showed good predictive ability for LN metastases in most of the 16 LN stations, as the areas under the curve ranged from 0.741 (station 15) to 0.944 (station 8), with a mean of 0.856. A critical cutoff point of 18% of the program's expected percentage was the value maximizing the validity of the prediction. Using an “absolute” cutoff point of 0%, the overall rate of false-negative (FN) predictions in 176 N+ patients was 11.9%; of these, 11 (6.2%) were absolute FNs, in which the program totally failed to estimate LN metastases; the remaining 10 cases (5.7%) were relative FNs because the specific prediction was positive for a different depth of stomach invasion. The low number of D₃/D₄ lymphadenectomies in the historical database may affect the low estimate of metastases to N₃/N₄ nodes generated by the program. Based on these data, the program predicts with good accuracy the extent of LN metastases from gastric cancer, but it is not recommended for directing the surgeon to perform more extensive lymphadenectomy.     

Effects of Hypericum extract on the acetylcholine release: a loose patch clamp approach.

The St. John's Wort (Hypericum perforatum) extract (Hp) represents one of the most useful natural therapeutic agents in the treatment of moderate and mild depression. The antidepressant effects of Hp are different, by a molecular mechanism point of view, when compared to those of other antidepressant drugs and, we think, a further pharmacological characterization is needed. It is suggested that the neurochemical effects of Hp could be bind either to its activity on the uptake of some mediators in the central nervous system or to the inhibition of some enzymatic activity at the receptor level. The present study carried out with the loose patch clamp (LPC) in the mouse neuromuscular junction, indicates a potentiation of the acetylcholine (ACh) action at the mouse neuromuscular junction. The spontaneous release of ACh was unaffected by Hp indicating that neither presynaptic nor postsynaptic function are modified by Hp. Indeed, both the frequency and the amplitude of the miniature end-plate currents (mepcs) were unmodified by Hp. Furthermore, the mepcs decay time (tau), i.e. the apparent cholinergic channel life time, was significantly increased after Hp treatment. The other parameter affected was the amplitude of the evoked end-plate currents (epcs) which was constantly and in a dose dependent manner increased by Hp. These findings suggest a possible action of Hp on the acetylcholinesterase (AChE) in terms of a reduction of the degradation rate of ACh.     

Pegylated arginine deiminase treatment of patients with unresectable hepatocellular carcinoma: results from phase I/II studies.

PURPOSE: Recently, we reported that a large number of human hepatocellular cancer (HCC) cell lines were auxotrophic for arginine. Here we report the results obtained with the amino acid-degrading enzyme arginine deiminase (ADI) conjugated to polyethylene glycol (ADI-SS PEG 20,000 mw) as a means of lowering plasma arginine to treat HCC. The study was a cohort dose-escalation phase I/II study. PATIENTS AND METHODS: Pharmacodynamic studies indicated an ADI-SS PEG 20,000 mw dose level of 160 U/m(2) was sufficient to lower plasma arginine from a resting level of approximately 130 micromol/L to below the level of detection (< 2 micromol/L) for more than 7 days, a dose later defined as the optimal biologic dose. All patients were to receive three cycles at the optimum biologic dose. RESULTS: This therapy was well tolerated, even in patients who had no detectable plasma arginine for 3 continuous months of therapy. Of the 19 patients enrolled, two had a complete response, seven had a partial response, seven had stable disease, and three had progressive disease. The median survival for the 19 patients enrolled on this study was 410 days, with four patients still alive at present (> 680 days). CONCLUSION: Elimination of all detectable plasma arginine in patients with HCC was well tolerated and seemed to be effective in the treatment of some patients with HCC. Further testing of ADI-SS PEG 20,000 mw in a larger population of individuals with HCC as well as other human tumors auxotrophic for arginine is warranted.     

Stroma cells: a novel target of herceptin activity.

PURPOSE: Stroma cells play a relevant role in tumor development and progression. We investigated the activity of herceptin (HER), a humanized monoclonal antibody widely used for the treatment of HER2-overexpressing epithelial cancer, toward stroma cell lines L87/4 and L88/5. EXPERIMENTAL DESIGN: We studied the antiproliferative potential of HER and role of human serum in HER activity. We also investigated the ability of HER to alter ancillary functions of L87/4 and L88/5, such as support to long-term hematopoiesis, growth factor production, breast cancer cell adhesion, and proliferation. RESULTS: Flow cytometry showed that HER2 membrane expression in L87/4 and L88/5 stroma cells was intermediate between the expression in HER2-negative/dim MCF-7 breast cancer cells and HER2-bright SK-BC3 breast cancer cells. HER2 gene amplification was not detected by fluorescence in situ hybridization in either stromal cell lines. HER significantly inhibited L87/4 and L88/5 proliferation. Mean ID(50)s were found to be 2000 and 1700 micro g/ml for L87/4 and L88/5, respectively, after 3-day exposure and 800 micro g/ml for both cell lines after 9-day exposure. The presence of 10% human serum in the culture increased HER inhibitory activity. IC(50) of stroma cells was found to be intermediate between HER2-bright breast cancer cells (SK-BC3) and HER2-negative/dim breast cancer cells (MCF-7). The drug did not significantly affect the ability of stroma cells to support long-term hematopoiesis in the cobblestone area forming cell assay. In contrast, in coculture assay, MCF7 cells demonstrated a worse adhesion and growth capability on HER-treated stroma layers when compared with untreated stroma. Moreover, HER significantly reduced vascular endothelial growth factor production by L88/5 cells. CONCLUSIONS: Our data support the novel finding that HER may have a relevant activity against stroma cells.     

Venous thromboembolism associated with long-term use of central venous catheters in cancer patients.

Long-term central venous catheters (CVCs) have considerably improved the management of cancer patients because they facilitate chemotherapy, transfusions, parenteral nutrition, and blood sampling. However, the use of long-term CVCs, especially for chemotherapy, has been associated with the occurrence of upper-limb deep venous thrombosis (UL-DVT). The incidence of clinically overt UL-DVT related to CVCs has been reported to vary between 0.3% and 28.3%. The incidence of CVC-related UL-DVT screened by venography reportedly varies between 27% and 66%. The incidence of clinically overt pulmonary embolism (PE) in patients with CVC-related UL-DVT ranges from 15% to 25%, but an autopsy-proven PE rate of up to 50% has been reported. Vessel injury caused by the procedure of CVC insertion, venous stasis caused by the indwelling CVC, and cancer-related hypercoagulability are the main pathogenetic factors for CVC-related venous thromboembolism (VTE). Several studies have assessed the benefit of the prophylaxis of UL-DVT after CVC insertion in cancer patients. According to the results of these studies, prophylaxis with low molecular weight heparin or a low fixed dose of warfarin has been recently proposed. However, the limitations of the experimental design of the prophylactic studies do not allow definitive recommendations. The recommended therapy for UL-DVT associated with CVC is based on anticoagulant therapy with or without catheter removal. This review focuses on the epidemiology, pathogenesis, diagnosis, prevention, and treatment of VTE in cancer patients with long-term CVC.     

Suppression of maintenance of alcohol-drinking behavior by the concurrent availability of saccharin in Sardinian alcohol-preferring (sP) rats.

In the current study, we investigated the effect of the concurrent presentation of saccharin on the maintenance of alcohol-drinking behavior in selectively bred Sardinian alcohol-preferring (sP) rats. Rats were initially given access to alcohol [10% (volume/volume) in water] and water under the home cage, two-bottle, free-choice regimen, with unlimited access for 24 h/day for eight consecutive weeks. Next, a third bottle, containing saccharin [0%, 0.01%, 0.1%, 1%, or 3% (weight/volume) in water], was concomitantly offered for an additional 10 consecutive days. Intake of saccharin solution resulted as an inverted-U function of saccharin concentration, with the 0.1% saccharin solution being the highest accepted. Alcohol intake was a U function of saccharin concentration, being reduced by 65%-95% in the group of rats exposed to the 0.1% saccharin solution. These results indicate that (1) the concurrent presentation of highly palatable solutions of saccharin markedly reduced alcohol intake in alcohol-experienced sP rats and (2) the reducing effect of saccharin solutions on the alcohol intake in sP rats was positively related to their degree of acceptability. We hypothesized that saccharin solutions may have functioned as a reinforcer, partially substituting for alcohol reinforcement and rendering alcohol drinking less urgent.     

Enoxaparin for the prevention of venous thromboembolism associated with central vein catheter: a double-blind, placebo-controlled, randomized study in cancer patients.

PURPOSE: The extent of venous thromboembolism (VTE) associated with central vein catheters (CVC) in cancer patients remains unclear. The aim of this study was to evaluate the efficacy and safety of the low molecular weight heparin, enoxaparin, in the prevention of VTE. PATIENTS AND METHODS: In a multicenter, double-blind study, consecutive cancer patients scheduled for CVC insertion were randomly assigned to receive either subcutaneous enoxaparin 40 mg once a day or placebo. Treatment was started 2 hours before CVC insertion and continued for 6 weeks. The primary end points of the study were deep vein thrombosis (DVT), confirmed by venography of the CVC limb performed 6 weeks after randomization, or clinically overt pulmonary embolism, confirmed by objective testing during the study drug administration. Patients were assessed for bleeding complications. RESULTS: Three hundred eighty-five patients were randomized, of which 321 (83.4%) underwent venography. A venography was adequate for adjudication in 155 patients in each treatment group. A DVT was observed in 22 patients (14.1%) treated with enoxaparin and in 28 patients (18.0%) treated with placebo, corresponding to a relative risk of 0.78 (95% CI, 0.47 to 1.31). No major bleeding occurred. Five patients (2.6%) in the enoxaparin group and two patients (1.0%) in the placebo group died during the treatment period. CONCLUSION: In this study, no difference in the rate of CVC-related VTE was detected between patients receiving enoxaparin and patients receiving placebo. The dose of enoxaparin used in this study proved to be safe. Clinical trials evaluating higher enoxaparin doses could optimize the efficacy of this agent for this indication.     

Continuous intrathecal pump infusion of baclofen with antibiotic drugs for treatment of pump-associated meningitis. Case report

Intrathecal baclofen administered by means of an implantable pump is being increasingly used for successful treatment of spasticity. Meningitis following intrathecally administered baclofen is a rare but serious complication that is difficult to treat without removal of the pump. Because success rates with intravenously administered antibiotic drugs for the treatment of meningitis have been low, intrathecal administration of antibiotic agents is often required to eradicate the pathogen. The authors report the case of a patient in whom Staphylococcus epidermidis meningitis developed after insertion of an intrathecal baclofen pump. The patient was successfully treated by intrathecal coadministration of vancomycin and baclofen.