Inhibition of Ras and related G-proteins as a therapeutic strategy for blocking malignant glioma growth

OBJECTIVE: Preliminary studies have demonstrated that the Ras family and related guanosine 5'-triphosphate-dependent proteins (G-proteins) are overactivated in malignant gliomas and may function as indirect mediators of glial transformation initiated by deregulated upstream signaling elements. We postulated that inhibiting the activation of such proteins might represent a promising strategy for blocking the aberrant proliferation of these tumors. METHODS AND RESULTS: Accordingly, we examined the therapeutic efficacy against malignant glioma cells in vitro of a series of selective peptidomimetic inhibitors of farnesylation (FTI-277) and geranylgeranylation (GGTI-286 and GGTI-298), which are critical steps in the post-translational processing (prenylation) of these proteins. We first defined concentration-response relationships for each of these agents, using MTS-based cell proliferation assays in the established malignant glioma cell lines U-87 and LN-Z308 and the low-passage malignant glioma cell line SG-388. FTI-277, GGTI-286, and GGTI-298 each produced a striking concentration-dependent antiproliferative effect on the glioma cell lines, with the median effective dose ranging from 2.5 to 15.5 micromol/L. We then assessed the effect of prenylation inhibition on cell viability using clonogenic growth assays. This demonstrated a steady drop in the number of colonies with increasing drug concentrations for all three inhibitors. Third, we examined whether the cytotoxic effects of one of these inhibitors (GGTI-298) were associated with the induction of apoptosis using a terminal transferase-catalyzed in situ end-labeling technique. This approach showed a time-dependent increase in apoptotic cell numbers, which correlated with a progressive decrease in the percentage of cells that were viable as assessed by trypan blue exclusion. CONCLUSION: Our studies demonstrated that FTI-277, GGTI-286, and GGTI-298 each yielded significant antiproliferative effects in human malignant glioma cells in vitro at low micromolar concentrations, which have been achievable in vivo without major systemic toxicity. Extended periods of drug treatment produced cytotoxicity in the tumor cells, which correlated with the induction of apoptosis. We conclude that inhibition of Ras and related G-proteins offers a promising approach for blocking glioma proliferation that justifies further investigation in vivo.     

Measurement of cerebral blood flow during cardiopulmonary bypass with near-infrared spectroscopy

OBJECTIVES: We sought to assess the incidence and clinical relevance of examination data to recurrent ischemia within an international randomized trial. BACKGROUND: Ischemic symptoms commonly recur after thrombolysis for acute myocardial infarction. METHODS: Patients (n = 40,848) were prospectively evaluated for recurrent angina and transient electrocardiographic (ECG) or hemodynamic changes. Five groups were developed: Group 1, patients with no signs or symptoms of recurrent ischemia; Group 2, patients with angina only; Group 3, patients with angina and ST segment changes; Group 4, patients with angina and hemodynamic abnormalities; and Group 5, patients with angina, ST segment changes and hemodynamic abnormalities. Baseline clinical and outcome variables were compared among the five groups. RESULTS: Group 1 comprised 32,717 patients, and Groups 2 to 5 comprised 20% of patients (4,488 in Group 2; 3,021 in Group 3; 337 in Group 4; and 285 in Group 5). Patients with recurrent ischemia were more often female, had more cardiovascular risk factors and less often received intravenous heparin. Significantly more extensive and more severe coronary disease, antianginal treatment, angioplasty and coronary bypass surgery were observed as a function of ischemic severity. The 30-day reinfarction rate was 1.6% in Group 1, 6.5% in Group 2, 21.7% in Group 3, 13.1% in Group 4 and 36.5% in Group 5 (p < 0.0001); in contrast, the 30-day mortality rate was significantly lower (p < 0.0001) in Groups 1, 2 and 3 (6.6%, 5.4% and 7.7%, respectively) than in Groups 4 and 5 (21.8% and 29.1%). CONCLUSIONS: Postinfarction angina greatly increases the risk of reinfarction, especially when accompanied by transient ECG changes. However, mortality is markedly increased only in the presence of concomitant hemodynamic abnormalities.     

Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs

Factors that modify onset of Alzheimer's disease (AD) may be revealed by comparing environmental exposures in affected and unaffected members of discordant twin pairs or sibships. Among siblings at high risk of AD, sustained use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with delayed onset and reduced risk of AD. After adjustment for use of NSAIDs, there was minimal effect on onset with reported history of any of three common illnesses (arthritis, diabetes, or acid-peptic disease). However, independent of exposure to NSAIDs, onset was unexpectedly delayed in those reporting extended use of histamine H2 blocking drugs. Randomized clinical trials will be needed to affirm the utility of these drugs for prevention, but the present findings may have implications for pathogenesis: because NSAIDs block the calcium-dependent postsynaptic cascade that induces excitotoxic cell death in NMDA-reactive neurons, and because histamine potentiates such events, excitotoxicity may deserve additional investigation in AD.     

Changes in lung volume and volume of emphysema after unilateral lung reduction surgery: analysis with CT lung densitometry

PURPOSE: To evaluate changes in volume of the lungs and volume of emphysema after unilateral lung reduction surgery (ULRS) by using computed tomographic (CT) lung densitometry. MATERIALS AND METHODS: Twenty-eight patients underwent CT before and 3 months after ULRS. With use of a density mask software program and a three-dimensional graphics workstation, CT scans were analyzed to define the volume of the lungs and the volume of emphysema. Pre- and postoperative mean CT numbers were determined. RESULTS: After ULRS, the surgically reduced lung volume decreased 22%, and the intact opposite lung volume increased 4%. Emphysema in the surgically reduced lung decreased 14% and was unchanged in the intact opposite lung. Mean CT numbers in the surgically reduced lung increased 26 HU but were unchanged in the intact opposite lung. CONCLUSION: The effects of ULRS on each lung can be evaluated by using CT lung densitometry and a three-dimensional graphics workstation. ULRS reduces emphysema and lung volume in the surgically reduced lung without statistically significant worsening of contralateral emphysema at 3 months.     

The Yin and Yang of oxidation in the development of the fatty streak. A review based on the 1994 George Lyman Duff Memorial Lecture

Recent data support the hypothesis that the fatty streak develops in response to specific phospholipids contained in LDL that become trapped in the artery wall and become oxidized as a result of exposure to the oxidative waste of the artery wall cells. The antioxidants present within both LDL and the microenvironments in which LDL is trapped function to prevent the formation of these biologically active, oxidized lipids. Enzymes associated with LDL and HDL (eg, platelet activating factor acetylhydrolase) or with HDL alone (eg, paraoxonase) destroy these biologically active lipids. The regulation and expression of these enzymes are determined genetically and are also significantly modified by environmental influences, including the acute-phase response or an atherogenic diet. The balance of these multiple factors leads to an induction or suppression of the inflammatory response in the artery wall and determines the clinical course.     

America's first medical malpractice crisis, 1835-1865

Prior to the early 1800's, medical malpractice was almost unknown in the United States. However, a large number of malpractice law suits inundated the courts between 1835 and 1865. About 70 to 90 percent of the litigation involved fractures and dislocations with imperfect results or deformities such as shortened or crooked limbs. Lawyers alleged that the physicians did not provide due proper care, skill and diligence despite the fact that the better surgeons tried to save limbs rather than follow the common practice of amputation, especially for compound fractures. While a number of texts dealt with medical jurisprudence, it was not until 1860 that a text on the subject intensively delved into the issue of medical malpractice. Coincidentally, the attitudes and behaviors of patients, lawyers, physicians and judges during the first medical malpractice crisis were surprisingly similar to those currently held.     

Physiological correlates of 3-kilometer running performance in male children

The purpose of this study was to examine the influence of body fatness, aerobic and anaerobic ability on 3-km running performance in 19 physically active boys (mean +/- SD, age = 10.4 +/- 0.9 yrs). The sum of six skinfolds, VO2 at 8.04 and 9.65 km.hr-1, and VO2max were measured in the laboratory. Run time for 3 km was assessed twice on separate days on a 200-meter indoor track. Prior to each run, every child performed two 55-meter sprints and two vertical jumps. Mean +/- SD values for the sum of skinfolds, %VO2max at each running speed, VO2max and 3-km run time were: 33.9 +/- 14.9 mm; 70.6 +/- 6.6% and 81.0 +/- 7.9%; 54.6 +/- 5.0 ml.kg-1.min-1; 16.41 +/- 2.58 min, respectively. Significant (p < 0.05) correlations were observed between the following variables and run time: sum of skinfolds (r = 0.72); vertical jump (r = 0.67); sprint time (r = 0.59); VO2max (r = 0.61); and, %VO2max at each treadmill speed (r = 0.79 and r = 0.75, respectively). Stepwise multiple regression analysis indicated that the combination of the %VO2max at 8.04 km.hr-1 and vertical jump accounted for 83% (adjusted R2) of the variance in running time (SEE = 1.06 min, p < 0.05). This study suggests that 3-km run time in physically active boys is influenced by aerobic and anaerobic indices as well as body fatness, supporting the notion that children, compared to adults, are not metabolic specialists.