Defining a role for sphingosine kinase 1 in p53-dependent tumors.

p53 is a crucial tumor suppressor that is mutated or deleted in a majority of cancers. Exactly how p53 prevents tumor progression has proved elusive for many years; however, this information is crucial to define targets for chemotherapeutic development that can effectively restore p53 function. Bioactive sphingolipids have recently emerged as important regulators of proliferative, apoptotic and senescent cellular processes. In this study, we demonstrate that the enzyme sphingosine kinase 1 (SK1), a critical enzyme in the regulation of the key bioactive sphingolipids ceramide, sphingosine and sphingosine-1-phosphate (S1P), serves as a key downstream target for p53 action. Our results show that SK1 is proteolysed in response to genotoxic stress in a p53-dependent manner. p53 null mice display elevation of SK1 levels and a tumor-promoting dysregulation of bioactive sphingolipids in which the anti-growth sphingolipid ceramide is decreased and the pro-growth sphingolipid S1P is increased. Importantly, deletion of SK1 in p53 null mice completely abrogated thymic lymphomas in these mice and prolonged their life span by ~30%. Deletion of SK1 also significantly attenuated the formation of other cancers in p53 heterozygote mice. The mechanism of p53 tumor suppression by loss of SK1 is mediated by elevations of sphingosine and ceramide, which in turn were accompanied by increased expression of cell cycle inhibitors and tumor cell senescence. Thus, targeting SK1 may restore sphingolipid homeostasis in p53-dependent tumors and provide insights into novel therapeutic approaches to cancer.

Motion analysis of the glenohumeral joint during activities of daily living.

The shoulder complex has a larger range of motion (ROM) than any other joint complex in the human body, leaving it prone to numerous injuries. Objective kinematic analysis could yield useful functional insights that may assist clinical practice. Non-invasive optoelectronic motion analysis techniques have been used to assess the shoulders of five healthy subjects performing ROM tasks and 10 functional tasks of daily living. The four most demanding tasks - touching the side and back of the head, brushing the opposite side of the head, lifting an object to shoulder height and lifting an object to head height, required 78%, 60%, 61% and 71%, respectively, of the glenohumeral elevation necessary for full abduction in the scapular plane for the 10 shoulders. This has implications for clinical practice where maximum arm elevation is commonly used to determine a patient's ability to return to work and other everyday activities.

Dynamic tracking of the scapula using skin-mounted markers.

The shoulder complex is prone to numerous pathologies and instabilities due to its large range of motion. The extent of injury is assessed through a series of observations and physical examinations. It is hypothesized that objective kinematic analysis of the shoulder could yield useful functional insights to aid clinical practice. Non-invasive motion analysis techniques to monitor shoulder function have been developed using passive markers; however, accurate measurement of scapula kinematics is problematic because of overlying tissue. The scapula locator is the accepted standard by which alternative non-invasive techniques of scapula tracking are validated. In this study, the viability of using skin-mounted markers to measure dynamic scapula movement is determined. Complete kinematic descriptions of ten healthy shoulders were obtained. Elevations of the glenohumeral joint were similar with both techniques, indicating that the skin marker method is suitable for gathering functional glenohumeral data. The main differences of note are seen at the scapulothoracic articulation where the skin marker method underestimated lateral rotation by more than 50 degrees at maximum elevation. However, the correlation between the two approaches is greater than 0.7, suggesting that it may be possible to derive linear regression models to predict dynamic scapulothoracic lateral rotation accurately using skin-mounted scapula markers.

Accuracy of reporting nosocomial infections in intensive-care-unit patients to the National Nosocomial Infections Surveillance System: a pilot study.

OBJECTIVE: To assess the accuracy of nosocomial infections data reported on patients in the intensive-care unit by nine hospitals participating in the National Nosocomial Infections Surveillance (NNIS) System. DESIGN: A pilot study was done in two phases to review the charts of selected intensive-care-unit patients who had nosocomial infections reported to the NNIS System. The charts of selected high- and low-risk patients in the same cohort who had no infections reported to the NNIS System also were included. In phase I, trained data collectors reviewed a sample of charts for nosocomial infections. Retrospectively detected infections that matched with previously reported infections were deemed to be true infections. In phase II, two Centers for Disease Control and Prevention (CDC) epidemiologists reexamined a sample of charts for which a discrepancy existed. Each sampled infection either was confirmed or disallowed by the epidemiologists. Confirmed infections also were deemed to be true infections. True infections from both phases were used to estimate the accuracy of reported NNIS data by calculating the predictive value positive, sensitivity, and specificity at each major infection site and the "other sites." RESULTS: The data collectors examined a total of 1,136 patients' charts in phase I. Among these charts were 611 infections that the study hospitals had reported to the CDC. The data collectors retrospectively matched 474 (78%) of the prospectively identified infections, but also detected 790 infections that were not reported prospectively. Phase II focused on the discrepant infections: the 137 infections that were identified prospectively and reported but not detected retrospectively, and the 790 infections that were detected retrospectively but not reported previously. The CDC epidemiologists examined a sample of 113 of the discrepant reported infections and 369 of the discrepant detected infections, and estimated that 37% of all discrepant reported infections and 43% of all discrepant detected infections were true infections. The predictive value positive for reported bloodstream infections, pneumonia, surgical-site infection, urinary tract infection, and other sites was 87%, 89%, 72%, 92%, and 80%, respectively; the sensitivity was 85%, 68%, 67%, 59%, and 30%, respectively; and the specificity was 98.3%, 97.8%, 97.7%, 98.7%, and 98.6%, respectively. CONCLUSIONS: When the NNIS hospitals in the study reported a nosocomial infection, the infection most likely was a true infection, and they infrequently reported conditions that were not infections. The hospitals also identified and reported most of the nosocomial infections that occurred in the patients they monitored, but accuracy varied by infection site. Primary bloodstream infection was the most accurately identified and reported site. Measures that will be taken to improve the quality of the infection data reported to the NNIS System include reviewing the criteria for definitions of infections and other data fields, enhancing communication between the CDC and NNIS hospitals, and improving the training of surveillance personnel in NNIS hospitals.

Evaluation of infection control measures in preventing the nosocomial transmission of multidrug-resistant Mycobacterium tuberculosis in a New York City hospital.

OBJECTIVE: To evaluate the efficacy of Centers for Disease Control and Prevention (CDC)-recommended infection control measures implemented in response to an outbreak of multidrug-resistant (MDR) tuberculosis (TB). DESIGN: Retrospective cohort studies of acquired immunodeficiency syndrome (AIDS) patients and healthcare workers. The study period (January 1989 through September 1992) was divided into period I, before changes in infection control; period II, after aggressive use of administrative controls (eg, rapid placement of TB patients or suspected TB patients in single-patient rooms); and period III, while engineering changes were made (eg, improving ventilation in TB isolation rooms). SETTING: A New York City hospital that was the site of one of the first reported outbreaks of MDR-TB among AIDS patients in the United States. PARTICIPANTS: All AIDS patients admitted during periods I and II. Healthcare workers on nine inpatient units with TB patients and six without TB patients. RESULTS: The epidemic (38 patients) waned during period II and only one MDR-TB patient presented during period III. The MDR-TB attack rate among AIDS patients hospitalized on the same ward on the same days as an infectious MDR-TB patient was 8.8% (19 of 216) during period I, decreasing to 2.6% (5 of 193; P = 0.01) during period II. In a small group of healthcare workers with tuberculin skin test data, conversions during periods II through III were higher on wards with than without TB patients (5 of 29 versus 0 of 15; P = 0.15), although the difference was not statistically significant. CONCLUSIONS: Transmission of MDR-TB among AIDS patients decreased markedly after enforcement of readily implementable administrative measures, ending the outbreak. However, tuberculin skin-test conversions among healthcare workers may not have been prevented by these measures. CDC guidelines for prevention of nosocomial transmission of TB should be implemented fully at all US hospitals.