DHPS-dependent hypusination of eIF5A1/2 is necessary for TGFß/fibronectin-induced breast cancer metastasis and associates with prognostically unfavorable genomic alterations in TP53.

Metastasis is the leading cause of mortality in patients with solid tumors. In this regard, we previously reported that Pseudopodium-Enriched Atypical Kinase One (PEAK1) is necessary for non-canonical Transforming Growth Factor ß (TGFß) signaling and TGFß/fibronectin-induced metastasis. Here, we demonstrate that inhibition of DHPS-dependent eIF5A1/2 hypusination blocks PEAK1 and E-Cadherin expression, breast cancer cell viability and TGFß/fibronectin-induced PEAK1-dependent breast cancer metastasis. Interestingly, TGFß stimulation of high-grade metastatic breast cancer cells increases and sustains eIF5A1/2 hypusination. We used a suite of bioinformatics platforms to search biochemical/functional interactions and clinical databases for additional control points in eIF5A1/2 and PEAK1-Epithelial to Mesenchymal Transition (EPE) pathways. This effort revealed that interacting EPE genes were enriched for TP53 transcriptional targets and were commonly co-amplified in breast cancer patients harboring inactivating TP53 mutations. Taken together, these results suggest that combinatorial therapies targeting DHPS and protein activities elevated in TP53-mutant breast cancers may reduce systemic tumor burden and improve patient outcomes.

Antiseptic properties of two calix[4]arenes derivatives on the human coronavirus 229E.

Facing the lack in specific antiviral treatment, it is necessary to develop new means of prevention. In the case of the Coronaviridae this family is now recognized as including potent human pathogens causing upper and lower respiratory tract infections as well as nosocomial ones. Within the purpose of developing new antiseptics molecules, the antiseptic virucidal activity of two calix[4]arene derivatives, the tetra-para-sulfonato-calix[4]arene (C[4]S) and the 1,3-bis(bithiazolyl)-tetra-para-sulfonato-calix[4]arene (C[4]S-BTZ) were evaluated toward the human coronavirus 229E (HCoV 229E). Comparing these results with some obtained previously with chlorhexidine and hexamidine, (i) these two calixarenes did not show any cytotoxicity contrary to chlorhexidine and hexamidine, (ii) C[4]S showed as did hexamidine, a very weak activity against HCoV 229E, and (iii) the C[4]S-BTZ showed a stronger activity than chlorhexidine, i.e. 2.7 and 1.4log10 reduction in viral titer after 5min of contact with 10⁻³mol L⁻¹ solutions of C[4]S-BTZ and chlorhexidine, respectively. Thus, the C[4]S-BTZ appeared as a promising virucidal (antiseptic) molecule.

Accurate first-principles detailed-balance determination of auger recombination and impact ionization rates in semiconductors.

The technologically important prediction of Auger recombination lifetimes in semiconductors is addressed by means of a fully first-principles formalism, based on precise energy bands and wave functions provided by the full-potential linearized augmented plane wave code. The minority carrier Auger lifetime is determined by two related approaches: (i) a direct evaluation within Fermi's golden rule, and (ii) an indirect evaluation, based on a detailed balance formulation combining Auger recombination and its inverse process, impact ionization, in a unified framework. Lifetimes determined with the direct and indirect methods show excellent consistency between them (i) for n-doped GaAs and (ii) with measured values for GaAs and InGaAs. This indicates the computational formalism as a new sensitive tool for use in materials performance optimization.

New primary prevention trials of sudden cardiac death in patients with left ventricular dysfunction: SCD-HEFT and MADIT-II.

Primary prevention of sudden arrhythmic death in patients with organic heart disease with poor left ventricular function and/or heart failure is currently a major challenge in cardiology. Amiodarone (with or without beta blockers) and the implantable cardioverter defibrillator (ICD) are considered the 2 major therapeutic tools to prevent sudden arrhythmic death in these patients. Two large trials have been launched to define the prophylactic benefit of the ICD or amiodarone on total mortality in patients that receive optimal heart failure and anti-ischemic treatment but remain at high risk of dying suddenly. The Sudden Cardiac Death in Heart Failure Trial (SCD-Heft) is designed to determine whether amiodarone or the ICD will decrease overall mortality in patients with coronary artery disease or nonischemic cardiomyopathy who are in heart failure New York Heart Association (NYHA) class II or III and have a left ventricular ejection fraction < 35%. The primary endpoint is total mortality; secondary objectives are comparison of arrhythmic and nonarrhythmic mortality and morbidity in the 3 arms as well as quality of life, cost-effectiveness, and incidence of episodes of ventricular tachyarrhythmias. The Multicenter Automatic Defibrillator Implantation Trial (MADIT) II is a follow-up study to the MADIT trial. It examines the prophylactic benefit in coronary artery disease patients with a left ventricular ejection fraction of < 30%, who have had at least 1 myocardial infarction but require no further risk stratification. MADIT II is a sequential design trial that compares ICD versus no ICD therapy. Programmed electrical stimulation to test inducibility of ventricular tachycardia is performed during ICD implantation, and various noninvasive risk markers are tested after randomization. Primary endpoint is total mortality, and secondary objectives are quality-of-life issues as well as cost-effectiveness ratio.

Clinical efficacy of the wearable cardioverter-defibrillator in acutely terminating episodes of ventricular fibrillation.

The findings of our initial study demonstrate for the first time the ability to terminate induced VT/VF reliably (100% of all episodes) by a single, monophasic 230-J shock delivered by the Wearable Cardioverter-Defibrillator (WCD). Although limited by sample size, our data suggest the WCD could be used as a feasible bridge to definitive implantation of an implantable cardioverter-defibrillator in patients in whom risk stratification for sudden death is not completed.

An increase in sinus rate following radiofrequency energy application in the posteroseptal space.

An increase in sinus rate has been previously described in patients with AV node reentry (AVNRT) following successful AV node modification. This increase could either be a specific sign of elimination of slow pathway conduction or it could be a consequence of energy application in the posteroseptal area. Thus, we compared the changes in sinus cycle length following successful slow pathway ablation (defined as complete elimination of dual AV node physiology) in patients having AVNRT with those in patients undergoing successful ablation of a posteroseptal atrioventricular accessory connection. Twenty five patients (16 women and 9 men, mean age 41 +/- 4 years) with typical AVNRT (cycle length 378 +/- 12 ms) and 29 patients (16 women and 13 men, age 34 +/- 5 years) with an accessory connection (17 manifest and 12 concealed) were studied. The electrophysiology study was performed during sedation with Fentanyl and Midazolam. The mean number of energy applications was 3 +/- 1 for successful slow pathway ablation and 4 +/- 1 for successful ablation of the accessory connection (p:NS). Following the successful energy application, the sinus cycle length decreased significantly 776 ms at baseline to 691 ms in patients with AVNRT. Following successful ablation of the posteroseptal AC, sinus cycle length decreased from 755 ms at baseline to 664 ms (p < 0.05 in both groups [difference between groups not significant]). The decrease in sinus cycle length did not correlate with the number of RF energy applications required for successful ablation or the total energy delivered. In conclusion, ablation of the AV node slow pathway and a posteroseptal accessory connection results in similar increases in the sinus rate. Thus, the increase in sinus rate is probably due to energy application in the posteroseptal space, possibly due to concomitant destruction of vagal inputs, and it is not specific for elimination of slow pathway conduction.

Minimally invasive direct coronary artery bypass grafting: two-year clinical experience.

BACKGROUND: Interest in minimally invasive coronary artery bypass grafting has been increasing. METHODS: From April 1994 through December 1996, 199 patients (age, 36 to 93 years) underwent minimally invasive coronary artery bypass grafting through minithoracotomy, subxiphoid, and lateral thoracotomy incisions, with internal mammary artery, gastroepiploic artery, and composite grafts placed using local coronary artery occlusion. RESULTS: The conversion rate to sternotomy was 7% (14/199). Preoperative risk factors included unstable angina (n = 83), reoperative coronary artery bypass grafting (n = 54), low ejection fraction (n = 53), congestive heart failure (n = 44), renal insufficiency (n = 25), chronic obstructive pulmonary disease (n = 36), cerebrovascular accident (n = 22), and diffuse vascular disease (n = 47). Morbidity included wound infections (n = 5), reoperation for management of bleeding (n = 6) and acute graft occlusion (n = 2), perioperative stroke (n = 1), atrial fibrillation (n = 14), and perioperative myocardial infarction (n = 7). The operative mortality was 3.8% (7/185). The number of grafts placed in 185 patients was as follows: single, 156; double, 28; and triple, 1. Early (less than 36 hours) angiography and Doppler flow assessment of the coronary anastomoses in 85% of the patients showed that 92% were patent. Routine use of mechanical stabilization of the coronary artery since April 1996 was found to be associated with an increase in the patency rate of the left internal mammary artery-left anterior descending coronary artery anastomosis to 97%, versus 89% (p = 0.055) associated with conventional immobilization techniques. Of the 148 patients followed up beyond 1 month (range, 1 to 32 months; mean, 9.2 +/- 7.4 months) postoperatively, 3 have died (3 to 7 months), and of the 145 survivors the cardiac-related event (percutaneous transluminal coronary angioplasty, reoperation, readmission for recurrent angina, and congestive heart failure)-free interval was 93%. CONCLUSIONS: The minimally invasive coronary artery bypass grafting operation is safe and effective. Regional cardiac wall mechanical immobilization enhances the early graft patency and must be considered an essential part of this operation.

Clinical relevance of stored electrograms for implantable cardioverter-defibrillator (ICD) troubleshooting and understanding of mechanisms for ventricular tachyarrhythmias.

A major problem in patients with cardioverter-defibrillators is to determine reliably the mechanism for spontaneous implantable cardioverter-defibrillator (ICD) discharges. Electrogram storage in ICD devices is comparable to that in permanent Holter monitors. Stored bipolar electrograms obtained from the sensing or shocking lead system contain a wide variety of different information. Intracardiac electrograms (EGMs) recorded from pace/sense electrodes (or "near-field" EGMs) show bipolar signals that have a distinct absence of any atrial activity during ventricular tachycardia or sinus rhythm. In contrast, the EGMs recording from the shocking electrodes, integrating a much larger area of myocardium, provide a more global visualization of electrical activity, which includes both atrial and ventricular deflections. Improved diagnostic capabilities available in the new generation ICD devices, in particular the stored intracardiac EGMs, facilitate sensing error diagnosis, permit a better evaluation of device function and ICD detection algorithms, and are helpful for reprogramming in order to overcome or prevent errors. In addition, EGMs give us a unique opportunity to gather information about the arrhythmic mechanism of the sudden cardiac death syndrome. Information such as the day and time of the episode, the preceding heart rate, the influence of the coupling interval of preceding premature beats, and their morphology can be gained from the analysis of stored EGM recordings. Although the availability of stored intracardiac EGMs are of enormous value in troubleshooting of ICD problems, they are occasionally not conclusive and must be complemented by additional techniques in order to complete the diagnosis. The information obtained by the analysis of stored intracardiac EGMs together with a database of EGMs can be of great importance for further improvements in future devices and may provide insights as to which patients are likely to benefit most from ICD therapy.

Pseudohypertension in hypertensive patients on multiple drug therapy.

Differences in blood pressure between direct intra-arterial and indirect cuff measurements have been reported, especially in elderly patients. We investigated the incidence of pseudohypertension among hypertensives with a poor response to drug therapy. We studied 24 patients, aged between 18 and 65 years, whose blood pressure could not be normalized with a combination of at least two antihypertensive drugs. We found no difference in systolic blood pressure but diastolic blood pressure was significantly (P less than 0.001) lower when measured intra-arterially. The mean difference between the direct and the indirect blood pressure determination was 16.2 +/- 1.5 mmHg (s.e.m.), and the range was 2.3-39.6 mmHg. Age, duration of hypertension and left ventricular hypertrophy was not correlated with the incidence and extent of pseudohypertension. We conclude that in hypertensives with a poor response to drug therapy, blood pressure measurements should be taken intra-arterially in order to avoid the hazards of overtreatment.

Atrial natriuretic peptide in patients with diabetes mellitus type I. Effects on systemic and renal hemodynamics and renal excretory function.

In the present study the effects of 1 h intravenous infusion of alpha-human atrial natriuretic peptide (24 ng/min/kg) on systemic and renal hemodynamics and on renal excretory function were studied in six insulin-treated and metabolically well-controlled patients with diabetes mellitus (DM) type I and in six healthy control subjects (C). Basal plasma atrial natriuretic peptide (ANP) concentration was 14.6 +/- 2.0 in DM patients and 14.9 +/- 1.3 pmol/L in C and rose similarly in both groups to 87.1 +/- 22.1 and to 86.9 +/- 11.1 pmol/L, respectively, during alpha-hANP infusion (P less than .05). Maximal effects of alpha-hANP occurred between 30 and 60 min after the start of the infusion. Mean arterial pressure (MAP) (83 +/- 5 v 81 +/- 3 mm Hg), heart rate (HR) (63 +/- 2 v 64 +/- 4/min) and total peripheral resistance (TPR) (11 +/- 1 v 10 +/- 1 mm Hg.min/L) remained unaltered in patients with DM. In contrast, in C MAP and TPR decreased from 83 +/- 3 to 77 +/- 2 mm Hg and from 12 +/- 1 to 10 +/- 1 1 mm Hg.min/L, respectively (P less than .05), whereas HR increased from 53 +/- 2 to 59 +/- 3 beats/min (P less than .05). Cardiac output (CO) rose initially by 11% and by 9% in DM and C, respectively. Urine flow increased from 4.1 +/- 0.9 to 11.3 +/- 1.5 mL/min in DM patients and from 3.9 +/- 1.0 to 8.4 +/- 0.8 mL/min in C (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Special education supervisors' perceptions of secondary LD programs: a comparison with LD teachers' views.

Perceptions of secondary LD program supervisors were identified and compared with views of secondary LD teachers regarding the presence of specific program features, field-related issues, and suggestions for program improvement. Responses indicated that the supervisors were more positive and, in many cases, held significantly different views than LD teachers.

Diagnosis of bronchogenic carcinoma through the cytologic examination of sputum, with special reference to tumor typing.

The results obtained in the cytologic study of sputa from 630 patients are presented. There were 251 cases of bronchogenic carcinoma; diagnosis through sputum examination was possible in 57.4 per cent of the patients. Abnormal cells were detected in an additional 24.3 per cent. Sputum examination has proven to be a valuable complement by establishing the correct diagnosis when other methods failed. Cancer cells were unequivocally identified in 45.8 per cent of the cases with normal bronchoscopic examination and in 52.4 per cent of the cases in which bronchial biopsy did not include malignant tissue. The same proportion of cases with the various tumor types was obtained by cytologic and by histologic study. However, one of the methods often showed a higher degree of cellular differentiation than the other. The number of cases with undifferentiated cancer or unclassified tumors was markedly reduced when the information concerning cell differentiation available through both methods was used. In this manner, excluding the oat cell carcinomas, only 7.6 per cent of the cases of bronchogenic carcinoma did not show any cellular differentiation. The authors recommend wider use of the information provided by simultaneous evaluation of both cytologic smears and tissue sections in order to achieve a more accurate appraisal of tumor type.