Cytotoxic effects of topotecan combined with various anticancer agents in human cancer cell lines

BACKGROUND: Topotecan (TPT) is a topoisomerase I poison that exhibits antineoplastic activity. Analysis of the cytotoxic effects of combinations of TPT and other anticancer agents has been limited. PURPOSE: We assessed the cytotoxic effects produced by combinations of TPT and other antineoplastic agents in experiments involving multiple human cancer cell lines of diverse histologic origins. METHODS: The cytotoxic effects of various antimetabolites (fluorouracil, methotrexate, or cytarabine), antimicrotubule agents (vincristine or paclitaxel [Taxol]), DNA alkylating agents (melphalan, bis[chloroethyl]nitrosourea [BCNU], or 4-hydroperoxycyclophosphamide [4HC]), and a DNA-platinating agent (cisplatin), alone and in combination with TPT, were measured in clonogenic (i.e., colony-forming) assays. HCT8 ileocecal adenocarcinoma, A549 non-small-cell lung carcinoma, NCI-H82ras(H) lung cancer, T98G glioblastoma, and MCF-7 breast cancer cell lines were used in these assays. The data were analyzed by the median effect method, primarily under the assumption that drug mechanisms of action were mutually nonexclusive (i.e., completely independent of one another). For each level of cytotoxicity (ranging from 5% to 95%), a drug combination index (CI) was calculated. A CI less than 1 indicated synergy (i.e., the effect of the combination was greater than that expected from the additive effects of the component agents), a CI equal to 1 indicated additivity, and a CI greater than 1 indicated antagonism (the effect of the combination was less than that expected from the additive effects of the component agents). RESULTS: When the mechanisms of drug action were assumed to be mutually nonexclusive, virtually all CIs for combinations of TPT and either antimetabolites or antimicrotubule agents revealed cytotoxic effects that were less than additive. The CIs calculated at low-to-intermediate levels of cytotoxicity for combinations of TPT and the DNA alkylating agents melphalan, BCNU, and 4HC also showed drug effects that were less than additive; in most cases, however, nearly additive or even synergistic effects were observed with these same drug combinations at high levels of cytotoxicity (i.e., at > or = 90% inhibition of colony formation). Results obtained with combinations of TPT and cisplatin varied according to the cell line examined. With A549 cells, less than additive effects were seen at low-to-intermediate levels of cytotoxicity, and more than additive effects were seen at high levels of cytotoxicity. With NCI-H82ras(H) cells, synergy was observed over most of the cytotoxicity range. CONCLUSIONS AND IMPLICATIONS: TPT cytotoxicity appears to be enhanced more by combination with certain DNA-damaging agents than by combination with antimetabolites or antimicrotubule agents. Interactions between TPT and other drugs can vary depending on the cell type examined. Further investigation is required to determine the basis of the observed effects and to determine whether these in vitro findings are predictive of results obtained in vivo.     

Diagnosing attention disorders in a virtual classroom

The virtual classroom provides an efficient and scalable tool for conducting attention testing. The University of Southern California integrated media systems center and digital media works have partnered to develop virtual reality technology applications for the study, assessment, and rehabilitation of cognitive and functional processes. This work primarily focuses on the development of systems that address the special needs of clinical populations with central nervous system dysfunctions such as brain injury, learning disabilities, or neurological disorders.     

Review of The elderly in rural society: Every fourth elder.

Reviews the book, The elderly in rural society: Every fourth elder edited by Raymond T. Coward and Gary R. Lee (1985). Until recently, the gerontological literature has had a decidedly urban bias. This book is an important effort to fill the knowledge gap concerning the rural elderly and is a useful reference for students, academicians, service providers, and policy makers who share a concern for America's rural elderly. For many of the more than 59.5 million rural residents of this country, the romanticized vision of a tranquil and prosperous rural lifestyle has been replaced by the realities of economic deprivation, inadequate housing, and unaddressed physical and mental health problems. This book brings together a wealth of current information to understand these realities better. In addition to the editors, 16 distinguished contributors, primarily from the fields of sociology and social work, examine rural-urban differences and the implication of those differences for the rural elderly population. Chapters cover demographics, socioeconomic considerations, physical and mental health status, housing characteristics, family and community relationships, and the development and delivery of health and human services to the elderly in rural society. This book helps service providers to understand and be sensitive to the value system and social ecology of rural areas so that they can address real rather than assumed needs more effectively. Overall, the book is comprehensive and well-written and can serve as a resource for students and professionals from a variety of disciplines, including rehabilitation psychology, who may work with, live with, help, or study the rural elderly. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Autonomic control of skeletal muscle vasodilation during exercise

Despite extensive investigation, the control of blood flow during dynamic exercise is not fully understood. The purpose of this study was to determine whether beta-adrenergic or muscarinic receptors are involved in the vasodilation in exercising skeletal muscle. Six mongrel dogs were instrumented with ultrasonic flow probes on both external iliac arteries and with a catheter in a branch of one femoral artery. The dogs exercised on a treadmill at 6 miles/h while drugs were injected intra-arterially into one hindlimb. Isoproterenol (0.2 microg) or acetylcholine (1 microg) elicited increases in iliac blood flow of 89.8 +/- 14.4 and 95.6 +/- 17.4%, respectively, without affecting systemic blood pressure or blood flow in the contralateral iliac artery. Intra-arterial propranolol (1 mg) or atropine (500 microg) had no effect on iliac blood flow, although they abolished the isoproterenol and acetylcholine-induced increases in iliac blood flow. These data indicate that exogenous activation of beta-adrenergic or muscarinic receptors in the hindlimb vasculature increases blood flow to dynamically exercising muscle. More importantly, because neither propranolol nor atropine affected iliac blood flow, we conclude that beta-adrenergic and muscarinic receptors are not involved in the control of blood flow to skeletal muscle during moderate steady-state dynamic exercise in dogs.     

alpha1-adrenergic-receptor responsiveness in skeletal muscle during dynamic exercise

Attenuation of sympathetic vasoconstriction (sympatholysis) in working muscles during dynamic exercise is controversial. One potential mechanism is a reduction in alpha1-adrenergic-receptor responsiveness. The purpose of this study was to examine alpha1-adrenergic-receptor-mediated vasoconstriction in resting and working skeletal muscles by using intra-arterial infusions of a selective agonist. Seven mongrel dogs were instrumented chronically with flow probes on the external iliac arteries of both hindlimbs and a catheter in one femoral artery. A selective alpha1-adrenergic-receptor agonist (phenylephrine) was infused as a bolus into the femoral artery catheter at rest and during exercise. All dogs ran on a motorized treadmill at two exercise intensities (3 and 6 miles/h). Intra-arterial infusions of the same effective concentration of phenylephrine elicited reductions in vascular conductance of 76 +/- 4, 76 +/- 6, and 67 +/- 5% (P > 0.05) at rest, 3 miles/h, and 6 miles/h, respectively. Systemic blood pressure and blood flow in the contralateral iliac artery were unaffected by phenylephrine. These results do not demonstrate an attenuation of vasoconstriction to a selective alpha1-agonist during exercise and do not support the concept of sympatholysis.     

Special care units for people with Alzheimer's disease. Only for the privileged few?

The number of Special Care Units (SCUs) for people with Alzheimer's disease (AD) in nursing homes have increased dramatically in the past 10 years. Despite the rapid increase in number of SCUs and the concern that most SCUs report higher costs than traditional nursing home units where residents with AD are integrated with cognitively intact residents, the evaluation of costs has been largely unsystematic and noncomparative. Studies are urgently needed to assess comparative costs so that administrators and policy makers can make informed decisions. This article reviews studies that examine the costs of care in SCUs and presents cost-related data comparing the outcomes of care for residents with AD on a SCU and on traditional units in one long-term care setting.     

Athletics and osteoarthritis

Athletes, and an increasing number of middle aged and older people who want to participate in athletics, may question whether regular vigorous physical activity increases their risk of developing osteoarthritis. To answer this, the clinical syndrome of osteoarthritis must be distinguished from periarticular soft tissue pain associated with activity and from the development of osteophytes. Sports that subject joints to repetitive high levels of impact and torsional loading increase the risk of articular cartilage degeneration and the resulting clinical syndrome of osteoarthritis. However, moderate habitual exercise does not increase the risk of osteoarthritis; selected sports improve strength and mobility in older people and people with mild and moderate osteoarthritis. People with abnormal joint anatomy or alignment, previous significant joint injury or surgery, joint instability, above-average body weight, disturbances of joint or muscle innervation or inadequate muscle strength probably have increased risk of osteoarthritis. These people and those with early osteoarthritis can benefit from regular physical activity, but they should have a careful evaluation of their joint structure and function before participation. They should consider measures that decrease the intensity and frequency of impact and torsional loading of joints, including use of sports equipment that decreases joint impact loading, maintaining or improving muscle strength, tone, and general conditioning so that muscle contractions help protect joints from injury and high impact, and decreasing body weight.     

Unity in diversity. Outcomes of the Geropsychiatric Nursing Survey

The 264 persons who responded to the geropsychiatric nursing survey were diverse in both preparation and practice arenas. They remained up-to-date in the field through journals, certification and professional memberships, and they supported clinical geropsychiatric nursing research and the need to develop standards in geropsychiatric nursing education. Finally, these nurse respondents expressed a wide variety of policy, practice and educational concerns, most related to improved care for geropsychiatric patients and their families. Obviously, limitations exist to the generalizability of these survey results. First, respondents to this survey, which appeared in two journals, may not be representative of the overall geropsychiatric nursing population. Additionally, the methods for summarizing the survey results are not scientific. However, these results enable us to develop a picture of the geropsychiatric nursing community and provide a foundation for understanding the population and its characteristics.     

Small-scale, hydrogen-oxidizing-denitrifying bioreactor for treatment of nitrate-contaminated drinking water

Nitrate removal by hydrogen-coupled denitrification was examined using flow-through, packed-bed bioreactors to develop a small-scale, cost effective system for treating nitrate-contaminated drinking-water supplies. Nitrate removal was accomplished using a Rhodocyclus sp., strain HOD 5, isolated from a sole-source drinking-water aquifer. The autotrophic capacity of the purple non-sulfur photosynthetic bacterium made it particularly adept for this purpose. Initial tests used a commercial bioreactor filled with glass beads and countercurrent, non-sterile flow of an autotrophic, air-saturated, growth medium and hydrogen gas. Complete removal of 2 mM nitrate was achieved for more than 300 days of operation at a 2-h retention time. A low-cost hydrogen generator/bioreactor system was then constructed from readily available materials as a water treatment approach using the Rhodocyclus strain. After initial tests with the growth medium, the constructed system was tested using nitrate-amended drinking water obtained from fractured granite and sandstone aquifers, with moderate and low TDS loads, respectively. Incomplete nitrate removal was evident in both water types, with high-nitrite concentrations in the bioreactor output, due to a pH increase, which inhibited nitrite reduction. This was rectified by including carbon dioxide in the hydrogen stream. Additionally, complete nitrate removal was accomplished with wastewater-impacted surface water, with a concurrent decrease in dissolved organic carbon. The results of this study using three chemically distinct water supplies demonstrate that hydrogen-coupled denitrification can serve as the basis for small-scale remediation and that pilot-scale testing might be the next logical step.     

Renal hemodynamic responses to dynamic exercise in rabbits

Cardiovascular hemodynamics, including renal blood flow, were measured in rabbits with one intact and one denervated kidney during various intensities of treadmill exercise. Within the first 10 s of exercise, there was rapid vasoconstriction in the innervated kidney associated with decreases in renal blood flow (range -10 to -17%). The vasoconstriction in the innervated kidney was evident at all workloads and was intensity dependent. There was no significant vasoconstriction or change in renal blood flow (range 0.5 to -3.1%) in the denervated kidney at the onset of exercise. However, a slowly developing vasoconstriction occurred in the denervated kidney as exercise progressed to 2 min at all workloads. Examination of responses to exercise performed under alpha-adrenergic blockade with phentolamine (5 mg/kg iv) revealed that the vasoconstriction in the innervated kidney at the onset of exercise and the delayed vasoconstriction in the denervated kidney were due primarily to activation of alpha-adrenergic receptors. In addition, a residual vasoconstriction was also present in the innervated kidney after alpha-adrenergic blockade, suggesting that, during exercise, activation of other renal vasoconstrictor mechanisms occurs which is dependent on the presence of renal nerves.