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Biomedical subjects

E M Mills

Publications and source records attributed to E M Mills.

At least 19 recordsLinked to original sources
PubMed2005

Enhancement of cyanide-induced mitochondrial dysfunction and cortical cell necrosis by uncoupling protein-2.

Uncoupling protein 2 (UCP-2) is expressed in the inner mitochondrial membrane and modulates mitochondrial function by partially uncoupling oxidative phosphorylation, and it has been reported to modulate cell death. Cyanide is a potent neurotoxin that inhibits complex IV to alter mitochondrial function to induce neuronal death. In primary rat cortical cells KCN produced an apoptotic death at 200-400 microM. Higher concentrations of potassium cyanide (KCN) (500-600 microM) switched the mode of death from apoptosis to necrosis. In necrotic cells, ATP levels were severely depleted as compared to cortical cells undergoing apoptosis. To determine if UCP-2 expression could alter KCN-induced cell death, cells were transiently transfected with full-length human UCP-2 cDNA (UCP-2+). Overexpression switched the mode of death produced by KCN (400 microM) from apoptosis to necrosis. The change in cell death was mediated by impaired mitochondrial function as reflected by a marked decrease of ATP levels and reduction in mitochondrial membrane potential. RNA interference or transfection with a dominant interfering mutant blocked the necrotic response observed in UCP-2+ cells. Additionally, treatment of UCP-2+ cells with cyclosporin A blocked necrosis, indicating the involvement of mitochondrial permeability pore transition in the necrotic death. These results show that increased expression of UCP-2 alters the response to a potent mitochondrial toxin by switching the mode of cell death from apoptosis to necrosis. It is concluded that UCP-2 levels influence cellular responses to cyanide-induced mitochondrial dysfunction.

Animals↗
PubMed1999

Differential susceptibility of brain areas to cyanide involves different modes of cell death.

We have demonstrated that cyanide (KCN) induces selective degeneration of dopaminergic neurons in mice and apoptotic cell death in cultured neurons. In the present study the mode of cyanide-induced cell death was determined in the susceptible brain areas. Mice were treated with KCN (6 mg/kg ip) or vehicle (saline) twice daily for 1 to 12 days. After 3 days of KCN treatment, two separate lesions were observed in coronal brain sections. Widespread DNA fragmentation in parietal and suprarhinal regions of the motor cortex was observed by the in situ terminal deoxynucleotide transferase nick-end labeling (TUNEL) technique. Pyknosis and chromatin condensation, morphological hallmarks of apoptotic cells, were observed in TUNEL-positive regions. On the other hand, in the substantia nigra (SN), KCN produced a progressive, bilateral necrotic lesion that was evident by 3 days of treatment. The SN lesion was circumscribed by a prominent ring of glial infiltration, as determined by glial-acidic fibrillary protein (GFAP) immunostaining. The extent of the SN lesion steadily increased with treatment duration, and DNA fragmentation was not observed over the 1- to 12-day period. On the other hand, cortical apoptosis was not associated with necrotic cell loss or astrogliosis. Pretreatment of animals with the antioxidant alpha-phenyl-tert-butyl nitrone (PBN) for 7 days prior to and during 3 days of KCN administration markedly reduced cortical DNA fragmentation whereas the PBN treatment did not influence the SN necrosis or astrocytic gliosis. Except for moderate GFAP immunostaining in corpus callosum, other brain areas were not affected by cyanide. It is concluded that KCN-induced neuronal loss involves selective activation of necrosis or apoptosis in different neuronal populations, and involves divergent mechanisms and sensitivity to antioxidants.

Animals↗
PubMed1998

Nerve growth factor treatment prevents the increase in superoxide produced by epidermal growth factor in PC12 cells.

Stimulation of pheochromocytoma (PC12) cells with the mitogen epidermal growth factor (EGF) produced a rapid and robust accumulation of intracellular reactive oxygen species (ROS), an accumulation which, in other systems, has been shown to be essential for mitogenesis. Brief pretreatment of the cells with nerve growth factor (NGF) suppressed the EGF-mediated ROS increase. EGF failed to produce elevations in ROS in a PC12 variant stably expressing a dominant-negative p21(ras) construct (PC12-N17) or in cells pretreated with the MEK inhibitor PD098059. NGF failed to suppress the increase in ROS in the PC12 variant nnr5, which lacks p140(trk) receptors. The suppression of the increase in ROS by NGF was restored in nnr5 cells stably expressing p140(trk) (nnr5-trk), but NGF failed to prevent the increase in ROS in nnr cells expressing mutant p140(trk) receptors that lack binding sites for Shc and phospholipase Cgamma. Among several inhibitors of superoxide-generating enzymes, only the lipoxygenase inhibitor, nordihydroguaiaretic acid reduced EGF-mediated ROS accumulation. The inhibitory action of NGF on ROS production was mimicked by the nitric oxide donor, sodium nitroprusside, and was blocked by an inhibitor of nitric-oxide synthetase, L-nitroarginine methyl ester. These results suggest a novel mechanism for the rapid interruption of mitogenic signaling by the neurotrophin NGF.

Animals↗
PubMed1998

Bcl-2 and Bcl-xL in peroxide-resistant A549 and U87MG cells.

Overexpression of the bcl-2 and the related bcl-xL protooncogene proteins enhance cell survival by inhibiting apoptosis induced by many agents including oxidants. Whether these proteins contribute to survival in oxidant-resistant cells is not known. The current study assessed the expression of bcl-2 and bcl-xL proteins in human glioblastoma U87MG cells and human lung adenocarcinoma A549 cells selected for resistance to 0, 50, 100, 200, and 400 microM H2O2 by exposure to this oxidant one time each passage for 9 months. When examined 7 to 32 days after cessation of peroxide exposure (times when peroxide resistance was maintained), bcl-2 protein levels were significantly increased in most peroxide-resistant U87MG cells. However, the increase was not dose dependent and was not accompanied by an increase in mRNA levels. A549 cells did not express significant levels of bcl-2 protein, although bcl-2 mRNA was detectable. A549 cells expressed large amounts of bcl-xL and immunohistochemistry demonstrated extensive localization of this protein around the nucleus. However, expression of this protein was not altered in peroxide-resistant lines nor was bcl-2 protein increased to a measurable level. U87MG cells also expressed bcl-xL but it was not altered in peroxide-resistant cells. Although the increased bcl-2 protein in peroxide-resistant U87MG cells may contribute to their oxidant tolerance, the lack of a dose-response relationship, the failure to induce bcl-xL protein, and the absence of any bcl-2 or bcl-xL protein induction in peroxide-resistant A549 cells suggest these genes are not primary factors in oxidant resistance.

Drug Resistance, Neoplasm↗
PubMed1998

Falls risk factors in an acute-care setting: a retrospective study.

Research findings have been contradictory regarding risk factors for falls in the acute-care setting. Identification of factors that place individuals at risk of falling in this setting are a priority because falls result in high morbidity and mortality and thus increased healthcare costs. The purpose of this study was to extend knowledge beyond the known risk factors of age and medical diagnosis by comparing the characteristics of 301 adults who fell while hospitalized with a matched sample of adults who did not fall while hospitalized. A descriptive, retrospective, comparative design was used. The fall and non-fall group were matched on age and primary medical diagnosis at the time of discharge. Data were collected from hospital incident reports and medical records. Logistic regression for matched groups identified 5 risk factors, as follows. Incontinence. The odds of falling were 11.3 (CI = 3.85, 33.05) times greater for those who were incontinent than for those who were not incontinent. Long hospital stay. The odds of falling were 9.9 (CI = 4.89, 19.88) times greater for those hospitalized 19 days or longer than for those hospitalized less than 19 days. Dependency for ambulation. The odds of falling were 6 (CI = 2.83, 12.84) times greater for those who were dependent for ambulation than for those who were independent. Independency for hygiene. The odds of falling were 2.5 (CI = 1.23, 4.88) times greater for those who were independent for hygiene than for those who were dependent. Lack of regular exercise. The odds of falling were twice as high (CI = 1.00, 3.82) for those who did not exercise regularly as for those who exercised regularly. These findings suggest that ongoing assessment may be more important than the admission assessment in identifying risk factors for falls in the acute-care setting. No 2 studies have found exactly the same set of risk factors, although some findings are consistent across studies. This suggests that those risk factors that are consistent across studies may identify persons who are at the greatest risk for falls and that other risk factors for falls are specific to a patient population.

Accidental Falls↗
PubMed1997

Reactive oxygen species generated by cyanide mediate toxicity in rat pheochromocytoma cells.

Peroxide formation has been implicated in impairment of motor function by cyanide which occurs in both animals and man. The present study employs the neuronal model, rat pheochromocytoma (PC12) cells to evaluate peroxidation as a toxic mechanism of cyanide. Confocal imaging shows that peroxides form within a few seconds in cell cytoplasm after cyanide exposure and continue to accumulate over a period of several minutes. Peroxide generation by cyanide is decreased to about 50% by phospholipase A2 inhibitors indicating involvement of arachidonic acid in the oxidative process. Also antioxidant defense enzymes (CuZn superoxide dismutase and especially catalase) in PC12 cells are inhibited by cyanide. It appears that peroxide accumulation after cyanide treatment involves both inhibition of breakdown and increased production. Furthermore, both peroxide accumulation and cell death induced by cyanide in PC12 cells are blocked by an antioxidant (ascorbate). These data support the hypothesis that the cytotoxic action of cyanide is related in part to an oxidative process.

Amitrole↗
PubMed1997

Circumstances and consequences of falls in independent community-dwelling older adults.

BACKGROUND: knowledge of the circumstances and consequences of falls in older adults is important for understanding the aetiology of falls as well as for effective clinical assessment and design of fall prevention strategies. Such data, however, are relatively scarce, especially in community-dwelling elders. METHOD: accidental falls (including their circumstances and consequences) occurring in 96 male and female participants between 60 and 88 years of age were monitored prospectively for 1 year. After the monitoring period, participants were divided into three groups based on fall status: non-fallers (n = 46), one-time fallers (n = 27) and recurrent fallers (n = 23). Frequency distributions were created for selected circumstances and consequences of falls and the prevalence of these consequences were examined. RESULTS: 50 participants (52%) fell during the 1 year period, amassing 91 falls. Trips and slips were the most prevalent causes of falls, accounting for 59% of falls. Falls most often occurred during the afternoon and while subjects walked on level or uneven surfaces. Fallers most commonly attributed falls to hurrying too much. Fractures resulted from five of the 91 falls and eight other falls resulted in soft tissue injuries that required treatment by a physician. There were no differences between one-time and recurrent fallers in the circumstances and consequences of falls. However, several notable differences were found between men (n = 20) and women (n = 30) who fell. Falls by men most often resulted from slips whereas falls by women most often resulted from trips. Moreover, women and men differed in the time of the year in which falls occurred, with men falling most often during winter and women during summer. CONCLUSIONS: the results of this study provide insight into the circumstances and consequences of falls among independent community-dwelling older adults and suggest some possible ways of preventing falls. Preventive services, however, should not solely target recurrent fallers, nor should the type of services necessarily differ for one-time and recurrent fallers.

Accidental Falls↗
PubMed1996

Cyanide-induced apoptosis and oxidative stress in differentiated PC12 cells.

Terminally differentiated PC12 cells are a useful neuron-like model for studying programmed cell death in response to nerve growth factor (NGF) deprivation. This in vitro model was used to investigate the mechanism by which cyanide-induced histotoxic hypoxia produces neuronal degeneration. Treatment of undifferentiated PC12 cells with 0.1 mM KCN for 24 h did not produce cell death. In contrast, treatment of differentiated PC12 cell cultures with 0.1 mM KCN for 24 h increased cell death by 43% when compared with control cultures, as measured by trypan blue dye exclusion and lactate dehydrogenase release assays. The Ca2+/Mg(2+)-dependent endonuclease inhibitor aurintricarboxylic acid and the transcriptional inhibitor actinomycin D partially attenuated hypoxic toxicity, suggesting roles for endonuclease activation and transcription in this model of neuronal death. Extracted DNA from cyanide-treated neurons demonstrated cleavage into oligonucleosomal fragments on gel electrophoresis. Transmission electron microscopic analysis showed morphological changes consistent with apoptotic cell death, including membrane blebbing and convolution, as well as chromatin condensation and margination to the nuclear membrane. Addition of either ascorbate or catalase to the cultures partially attenuated the loss of cell viability induced by cyanide, and decreased the incidence of apoptotic cells after treatment, based on the in situ detection of DNA strand breaks. The ability of cyanide to elevate intracellular oxidant species was determined by microfluorescence in differentiated PC12 cells loaded with the oxidant-sensitive dye 2',7'-dichlorofluorescin. Exposure of cells to 0.1 mM KCN produced a rapid generation of oxidants that was blocked approximately 50% by ascorbate or catalase. These observations indicate that cyanide induces apoptosis in terminally differentiated, and not undifferentiated, PC12 cells, and that antioxidants significantly reduce the incidence of cyanide-induced apoptosis.

Animals↗
PubMed1995

Physician recruitment after Hermann Hospital.

The state of physician recruitment changed after the Internal Revenue Service required Hermann Hospital to publish its closing agreement with the IRS. The closing agreement released the long-awaited IRS "Hospital Physician Recruitment Guidelines." The IRS' recently proposed revenue ruling provides additional insight on acceptable physician recruitment practices as well.

Guidelines as Topic↗
PubMed1993

Mammography use and outcomes in a community. The Greater Lansing Area Mammography Study.

BACKGROUND: Mammography is widely known to reduce morbidity and mortality from breast cancer, but a population-based assessment of mammography use and follow-up of mammography findings has not been reported previously. METHODS: An observational, population-based, follow-up study was conducted of all women having mammograms in the Greater Lansing, Michigan, metropolitan area, between June 1987 and June 1988. A total of 17,811 Greater Lansing women participated. The adherence of women to mammography screening guidelines was estimated, and mammography's utility to detect breast cancer was assessed through follow-up review of breast biopsy results. RESULTS: Thirty-seven percent of the expected number of women 35 years of age and older had mammograms. Adherence to screening guidelines declined with age, and less than 5% (302 of 6700) of women 55 years of age and older reporting having annual mammograms. Seventy-six percent of women reported that their physicians prompted the examination. The predictive value of a positive mammogram was 21.9% for women without symptoms and 32.4% for women with symptoms. Mammography's sensitivity and specificity for breast cancer detection were 71% and 98%, respectively. CONCLUSIONS: The study highlights the need to target mammography to women 50 years of age and older, underscores the importance of physicians in promoting mammography, and demonstrates the analytic value and limitation of mammography in clinical decision-making.

Adult↗