Differential regulation of discrete apoptotic pathways by Ras

The products of the ras genes are known to regulate cell proliferation and differentiation; recently, they have been found to play a role in apoptosis. The expression of oncogenic p21(ras) in a number of cell types, including Jurkat (a human T lymphoblastoid cell line) and murine fibroblasts, makes the cells susceptible to apoptosis following suppression of protein kinase C (PKC) activity (PKC/Ras-mediated apoptosis). Engagement of Fas antigen, a potent effector of apoptosis, activates cellular p21(ras), which may be required for completion of the cell death program. To further investigate the role of p21(ras) in the regulation of apoptosis, the cellular mechanisms employed in these two apoptotic processes in which Ras activity is involved (PKC/Ras-related and Fas-triggered apoptosis), was explored. Increasing p21(ras) activity by expressing v-ras or by treatment with an antisense oligonucleotide to the GTPase-activating protein was found to accelerate the Fas-mediated apoptotic process in Jurkat and mouse LF cells. PKC/Ras-related apoptosis was associated with, and required, cell cycle progression, accompanied by the expression of the G1/S cyclins. In contrast, Fas engagement, although inducing a vigorous and PKC-independent activation of endogenous p21(ras), did not alter cell cycle progression, nor did it require such progression for apoptosis. Both the protein synthesis inhibitor cycloheximide and cyclin E antisense oligonucleotides partially abolished PKC/Ras-mediated apoptosis but had only a moderate effect on Fas-induced apoptosis. In contrast, the CED-3/interleukin-1beta-converting enzyme (ICE) protease inhibitor Z-VADfmk efficiently suppressed Fas-induced apoptosis and only marginally inhibited PKC/Ras-mediated apoptosis. Induction of both pathways resulted in activation of the Jun NH2-terminal kinase/JUN signaling system. These results suggest that different cell death programs, such as PKC/Ras-mediated and Fas-mediated apoptosis, may be interconnected via p21(ras) and perhaps Jun NH2-terminal kinase/JUN. In response to various death stimuli, p21(ras) may act as a common intermediate regulator in the transduction of apoptotic signals.     

Relation between insulin-like growth factor-I concentrations, osteoarthritis, bone density, and fractures in the general population: the Chingford study

OBJECTIVE: To assess the association between serum insulin-like growth factor-I (IGF-1) concentrations and osteoarthritis, and bone mineral density, and fractures in a large group of middle aged women from the general population. METHODS: 761 women aged 44-64 years from the Chingford study had serum IGF-I concentrations measured; hand, hip, spine, and anteroposterior weight bearing knee radiographs taken; and dual energy x ray absorptiometry (DEXA) scans of the hip and spine. X rays were scored using the Kellgren and Lawrence system. In addition knee x rays were scored using a standard atlas for individual features of osteophytes and joint space narrowing (both graded 0-3). IGF-I concentrations were adjusted for the effects of age. RESULTS: In the osteoarthritis analysis results were compared to a constant group of 155 subjects with no evidence of osteoarthritis at any site. There was no significant difference in serum IGF-I between these subjects and 606 subjects with osteoarthritis at any site. When individual sites were analysed, serum IGF-I was higher in those cases with more severe bilateral knee osteoarthritis and in those with distal interphalangeal (DIP) joint disease. There was no significant association between serum IGF-I and other forms of osteoarthritis or milder forms of knee osteoarthritis. There was no correlation between IGF-I concentrations and bone mineral density at the spine or hip, nor any difference between IGF-I concentrations in subjects with and without a history of non-traumatic fracture [22.8 (SD 6.6) v 23.1 (SD 6.6) nmol litre-1, P = 0.6] CONCLUSIONS: There is a modest association between IGF-I concentrations and the development of DIP osteoarthritis and more severe or bilateral knee joint osteoarthritis in women from the normal population, but no association with other forms of osteoarthritis, bone density, or fractures.     

The asymmetric synthesis and in vitro characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of matrix metalloproteinases

A series of succinyl based mercaptoketones and diastereomeric mercaptoalcohols were prepared and evaluated in vitro as inhibitors of the matrix metalloproteinases collagenase-1 (MMP-1), stromelysin (MMP-3), and gelatinase-B (MMP-9).     

Effects of age, system experience, and navigation technique on driving with an advanced traveler information system

This paper explores the effects of age, system experience, and navigation technique on driving, navigation performance, and safety for drivers who used TravTek, an Advanced Traveler Information System. The first two studies investigated various route guidance configurations on the road in a specially equipped instrumented vehicle with an experimenter present. The third was a naturalistic quasi-experimental field study that collected data unobtrusively from more than 1200 TravTek rental car drivers with no in-vehicle experimenter. The results suggest that with increased experience, drivers become familiar with the system and develop strategies for substantially more efficient and safer use. The results also showed that drivers over age 65 had difficulty driving and navigating concurrently. They compensated by driving slowly and more cautiously. Despite this increased caution, older drivers made more safety-related errors than did younger drivers. The results also showed that older drivers benefited substantially from a well-designed ATIS driver interface.     

Virilizing ovarian tumor of low malignant potential associated with antecedent tamoxifen use for breast cancer

OBJECTIVE: To assess the value and the associated morbidity of endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic endoprosthesis insertion in the treatment of patients with Klatskin tumors. DESIGN: Retrospective study. SETTING: A tertiary referral center. PATIENTS: Fifty-five consecutive patients with Klatskin tumors diagnosed through typical cholangiographic and computed tomographic findings. INTERVENTION: Standard ERCP with endoscopic stenting technique was employed. Once the diagnosis of Klatskin tumor was confirmed on cholangiogram, endoscopic stenting was performed to bypass the stricture. Multiple stents were inserted if necessary to ensure adequate biliary drainage. MAIN OUTCOME MEASURES: The success rate of ERCP and endoscopic endoprosthesis insertion, successful drainage rate, early complications of endoscopic procedure, procedure-related mortality, and long-term outcome of endoprosthesis. RESULTS: Of the 55 patients, cholangiography was performed in 53 (96%). In the 49 patients in whom endoscopic stenting was attempted, the procedure was successful in 28 patients (57%) at the first attempt and 8 patients (16%) at the second attempt, resulting in a cumulative success rate of 73%. Only 20 of these patients had satisfactory biliary drainage, resulting in an overall successful drainage rate of 41%. Early complications, including acute cholangitis, acute pancreatitis, and postpapillotomy bleeding occurred in 14 patients (25%). Three patients (5%) died of procedure-related complications. The median patency of the first endoprosthesis inserted was 1 week (range, 0-8 wk). The 30-day mortality rate was 18%. CONCLUSIONS: In patients with Klatskin tumors, ERCP and endoscopic endoprosthesis insertion have a low successful drainage rate, are associated with high morbidity and procedure-related mortality, and have a limited effect on long-term palliation. Endoscopic retrograde cholangiopancreatography and endoscopic endoprosthesis insertion have a limited value in the management of patients with Klatskin tumors.     

Recurrent spheno-orbital meningioma

A series of 15 patients who underwent neurosurgical procedures for recurrent spheno-orbital meningioma is reported. There were 11 women and four men, with a mean age of 46 years. The mean duration between the first and second operations was 46 months. Progressive proptosis without neurological deficit was the most common symptom. All tumors were large at the time of reoperation and involved the greater and lesser wings of the sphenoid bone and the orbit. Aggressive resection in all patients resulted in no deaths and only slight morbidity, with the exception of one patient who developed blindness 24 hours after surgery due to central retinal artery occlusion. Fourteen patients were improved cosmetically and one patient, treated early in the series, had persistent proptosis due to inadequate bone removal. No attempt was made to remove tumor within the cavernous sinus in patients who were neurologically normal. Although postoperative imaging demonstrated complete gross excision of tumor in nine patients, 10 underwent conventional radiation therapy for residual tumor visualized at the time of surgery in the dura of the superior orbital fissure, the cavernous sinus, or the basal optic canal. Although this study is inconclusive and requires further long-term documentation, no recurrences have been seen to date in the follow-up period, ranging from 16 to 95 months. The following important points are discussed: 1) the failure by experienced surgeons to radically excise bone, tumor, and involved dura at the first operation; 2) the importance of early aggressive therapy, depending upon the patient's age and medical condition; 3) the almost invariable intracranial dural involvement, which at times was seen only by gadolinium-enhanced magnetic resonance imaging and not visualized on computerized tomography; 4) an illustrated stepwise surgical technique for complete resection through a small craniotomy without the need for complicated reconstruction of the orbit or temporal fossa; 5) the role of radiation therapy when removal is incomplete or deemed hazardous because of cavernous sinus involvement; and 6) the excellent cosmetic results possible with minimal morbidity and no mortality.