Mobilizing Older Adults: Harnessing the Potential of Smart Home Technologies. Contribution of the IMIA Working Group on Smart Homes and Ambient Assisted Living.

OBJECTIVES: This paper highlights the potential of smart home applications to not only assess mobility determinants for older adults in the home environment but also provide the opportunity for tailored interventions. METHODS: We present a theoretical framework for assessing mobility parameters and utilizing this information to enable behavior change based on the Health Belief Model. We discuss examples that showcase the potential of smart home systems to not only measure but also improve mobility for community dwelling older adults. RESULTS: Mobility is a complex construct that cannot be addressed with a single monitoring approach or a single intervention. Instead, tailored interventions that address specific needs and behaviors of individuals and take into consideration preferences of older adults and potentially their social network are needed to effectively enforce positive behavior change. Smart home systems have the ability to capture details of one's daily living that could otherwise not be easily obtained; however, such data repositories alone are not sufficient to improve clinical outcomes if appropriate mechanisms for data mining and analysis, as well as tailored response systems are not in place. CONCLUSIONS: Unleashing the potential of smart home applications to measure and improve mobility has the potential of transforming elder care and providing potentially cost-effective tools to support independence for older adults. A technologically driven smart home application can maximize its clinical relevance by pursuing interactive features that can lead to behavior change.

Experimental models of traumatic brain injury: do we really need to build a better mousetrap?

Approximately 4000 human beings experience a traumatic brain injury each day in the United States ranging in severity from mild to fatal. Improvements in initial management, surgical treatment, and neurointensive care have resulted in a better prognosis for traumatic brain injury patients but, to date, there is no available pharmaceutical treatment with proven efficacy, and prevention is the major protective strategy. Many patients are left with disabling changes in cognition, motor function, and personality. Over the past two decades, a number of experimental laboratories have attempted to develop novel and innovative ways to replicate, in animal models, the different aspects of this heterogenous clinical paradigm to better understand and treat patients after traumatic brain injury. Although several clinically-relevant but different experimental models have been developed to reproduce specific characteristics of human traumatic brain injury, its heterogeneity does not allow one single model to reproduce the entire spectrum of events that may occur. The use of these models has resulted in an increased understanding of the pathophysiology of traumatic brain injury, including changes in molecular and cellular pathways and neurobehavioral outcomes. This review provides an up-to-date and critical analysis of the existing models of traumatic brain injury with a view toward guiding and improving future research endeavors.

Delayed inhibition of Nogo-A does not alter injury-induced axonal sprouting but enhances recovery of cognitive function following experimental traumatic brain injury in rats.

Traumatic brain injury causes long-term neurological motor and cognitive deficits, often with limited recovery. The inability of CNS axons to regenerate following traumatic brain injury may be due, in part, to inhibitory molecules associated with myelin. One of these myelin-associated proteins, Nogo-A, inhibits neurite outgrowth in vitro, and inhibition of Nogo-A in vivo enhances axonal outgrowth and sprouting and improves outcome following experimental CNS insults. However, the involvement of Nogo-A in the neurobehavioral deficits observed in experimental traumatic brain injury remains unknown and was evaluated in the present study using the 11C7 monoclonal antibody against Nogo-A. Anesthetized, male Sprague-Dawley rats were subjected to either lateral fluid percussion brain injury of moderate severity (2.5-2.6 atm) or sham injury. Beginning 24 h post-injury, monoclonal antibody 11C7 (n=17 injured, n=6 shams included) or control Ab (IgG) (n=16 injured, n=5 shams included) was infused at a rate of 5 microl/h over 14 days into the ipsilateral ventricle using osmotic minipumps connected to an implanted cannula. Rats were assessed up to 4 weeks post-injury using tests for neurological motor function (composite neuroscore, and sensorimotor test of adhesive paper removal) and, at 4 weeks, cognition was assessed using the Morris water maze. Hippocampal CA3 pyramidal neuron damage and corticospinal tract sprouting, using an anterograde tracer (biotinylated dextran amine), were also evaluated. Brain injury significantly increased sprouting from the uninjured corticospinal tract but treatment with monoclonal antibody 11C7 did not further increase the extent of sprouting nor did it alter the extent of CA3 cell damage. Animals treated with 11C7 showed no improvement in neurologic motor deficits but did show significantly improved cognitive function at 4 weeks post-injury when compared with brain-injured, IgG-treated animals. To our knowledge, the present findings are the first to suggest that (1) traumatic brain injury induces axonal sprouting in the corticospinal tract and this sprouting may be independent of myelin-associated inhibitory factors and (2) that post-traumatic inhibition of Nogo-A may promote cognitive recovery unrelated to sprouting in the corticospinal tract or neuroprotective effects on hippocampal cell loss following experimental traumatic brain injury.

Neurogenic fever after traumatic brain injury: an epidemiological study.

OBJECTIVES: To determine the incidence of neurogenic fever (NF) in a population of patients in the acute phase following severe traumatic brain injury (TBI); to identify factors associated with the development of NF following severe TBI in adults. METHODS: Charts of patients admitted from 1996 to 1999 with severe TBI at a large, urban mid-Atlantic teaching hospital were retrospectively evaluated based on diagnostic criteria for each episode of hyperthermia to determine the diagnosis of NF. Data were collected regarding mechanism and area of injury, severity of injury, and demographic factors to determine potential predictors of NF. RESULTS: Diffuse axonal injury (DAI) (OR 9.06, 95% CI 0.99 to 82.7) and frontal lobe injury of any type (OR 6.68, 95% CI 1.1 to 39.3) are independently predictive of an increased risk of development of NF following severe TBI. The presence of a skull fracture and lower initial Glasgow Coma Score (GCS) were individual predictors of development of NF, but did not contribute to the final model. CONCLUSIONS: These findings examine known and novel risk factors for this phenomenon in comparison to previously published literature on NF. A set of predictor variables was identified to help clinicians target patients at high risk for development of NF following severe TBI. It is hoped that earlier diagnosis and appropriate intervention for fever in the TBI patient will lead to improved outcomes.

Allium chemistry: synthesis, natural occurrence, biological activity, and chemistry of Se-alk(en)ylselenocysteines and their gamma-glutamyl derivatives and oxidation products.

Syntheses are reported for gamma-glutamyl Se-methylselenocysteine (Sa), selenolanthionine (16), Se-1-propenylselenocysteine (Gd), Se-2-methyl-2-propenyl-L-selenocysteine (6e), and Se-2-propynyl-L-selenocysteine (6f). Oxidation of 8a and Se-methylselenocysteine (Ga) gives methaneseleninic acid (24), characterized by X-ray crystallography, and dimethyl diselenide (25). Oxidation of Se-2-propenyl-L-selenocysteine (6c) gives allyl alcohol and 3-seleninoalanine (22). Compound 22 is also formed on oxidation of 16 and selenocystine (4). Oxidation of 6d gives 2-[(E,Z)-1-propenylseleno]propanal (36). These oxidations occur by way of selenoxides, detected by chromatographic and spectroscopic methods. The natural occurrence of many of the Se-alk(en)ylselenocysteines and their gamma-glutamyl derivatives and oxidation products is discussed. Three homologues of the potent cancer chemoprevention agents 6a and 6c, namely 6d-f, were evaluated for effects on cell growth, induction of apoptosis, and DNA-damaging activity using two murine mammary epithelial cell lines. Although each compound displays a unique profile of activity, none of these compounds (Gd-f) is likely to exceed the chemopreventive efficacy of selenocysteine Se-conjugates Ga and 6c.

Molecular mechanisms associated with Se-allylselenocysteine regulation of cell proliferation and apoptosis.

Se-allylselenocysteine (ASC) has been shown to inhibit mammary carcinogenesis in vivo and cell growth in vitro. However, little is known about the molecular events that account for these effects. The goal of the present study was to use a mouse hyperplastic mammary epithelial cell line, TM12, to investigate the underlying mechanism(s) associated with ASC regulation of cell proliferation and apoptosis. Cells were treated with 50 microM ASC and assessed after 3, 6 and 12 h of exposure. A significant inhibition of cell proliferation, as measured by BrdU incorporation into DNA, was observed within 3 h of ASC treatment. This inhibitory effect was slightly magnified at the later time points. The induction of apoptosis was also rapid, and progressed from a 1.3-fold increase at 3 h to a 4.4-fold increase at 12 h. Consistent with these cellular events, the levels of phosphorylated Rb protein were greatly reduced at all times points. The other accompanying changes included increases in P53, P21 and P27. Collectively, the results demonstrate for the first time that ASC is able to cause an immediate response in the expression of cell cycle regulatory proteins that favor an arrest in proliferation and an augmentation in apoptosis.

Control of rat mammary epithelium proliferation by conjugated linoleic acid.

Past research showed that mammary gland morphogenesis in the pubescent rat was retarded by the feeding of conjugated linoleic acid (CLA). A major objective of the present study was to examine the proliferative activity and the expression of cell cycle regulatory proteins in the developing mammary epithelium of rats fed a mixture of CLA isomers (primarily as free fatty acid c9, t11-CLA and t10,c12-CLA) or a highly enriched natural source of c9,t11-CLA (as triacylglycerol in butterfat). In both experiments, the diets, with or without CLA, were started at weaning and continued for four weeks. The two CLA preparations were equally effective in suppressing bromodeoxyuridine labeling and the expression of cyclin D1 and cyclin A (determined by immunohistochemistry) in the terminal end buds and alveolar clusters of the mammary epithelium while it undergoes extensive ductal branching during pubescence. There was a trend of an increase, although not statistically significant, in the proportion of cells expressing the p16 and p27 cdk inhibitors. A separate experiment was designed to evaluate the effect of c9,t11-CLA (as a free fatty acid of > 90% purity) treatment on the rate of proliferation of the mammary epithelium as the animal matured from weanling to adult. The bromodeoxyuridine labeling data indicated that the mammary epithelium appeared to lose its sensitivity to CLA control of proliferation as it completely filled the fat pad and became quiescent. These observations suggest that the responsiveness of mammary epithelial cells to CLA intervention may be dependent on their proliferative status.

Effect of the aromatase inhibitor vorozole on estrogen and progesterone receptor content of rat mammary carcinomas induced by 1-methyl-1-nitrosourea.

Vorozole, a nonsteroidal aromatase inhibitor, impedes the post-initiation stage of chemically induced mammary carcinogenesis. While various aspects of vorozole's effects on mammary carcinoma development have been investigated, little attention has been directed to determining the estrogen receptor (ER) and progesterone receptor (PR) content of mammary carcinomas that arise despite vorozole treatment. Female Sprague-Dawley rats were given an i.p. injection of 50mg MNU/kg body weight at 21 days of age and placed on diet supplemented with 0 or 3 mg vorozole/kg, which had no effect on mammary tumor development. Histologically confirmed carcinomas were evaluated for ER and PR by immunohistochemistry. In the control group, 78.8% of carcinomas were ER positive with an ER content ranging from 13.8 to 40.0%, similar to ER content of mammary ductal epithelial cells from non-carcinogen treated animals. PR content ranged from 4.4 to 45.2% and also was similar to levels of PR observed in ductal epithelial cells. ER was not correlated with PR in mammary carcinomas (r = 0.05, p > 0.80), whereas there was a significant correlation in ductal epithelium (r = 0.86, p = 0.006). In vorozole-treated rats, no ER negative carcinomas were observed and overall ER expression by vorozole was elevated (p < 0.03). All carcinomas from vorozole-treated rats expressed PR (2.5-60.2%) and correlation between ER and PR content was numerically greater in carcinomas from vorozole-treated animals (r = 0.42, p = 0.09). These data, which are considered hypothesis generating, provide evidence that low doses of vorozole in the diet select for mammary carcinomas with an increased ER positive phenotype.

In vitro effects of Se-allylselenocysteine and Se-propylselenocysteine on cell growth, DNA integrity, and apoptosis.

Two previously unevaluated selenium compounds, Se-allylselenocysteine (ASC) and Se-propylselenocysteine (PSC), have been shown recently to be active in the chemoprevention of experimentally induced mammary carcinogenesis. Other than their potential as chemopreventive agents, little is known about the pharmacological properties of these compounds. In this article, we report on the in vitro effects of ASC and PSC on cell growth inhibition, apoptosis, and the induction of DNA damage. The effects of ASC and PSC were examined in two mouse mammary epithelial cell lines derived from mammary hyperplasias. These cell lines, designated TM2H and TM12, have mutant or wild-type p53, respectively. It was observed that ASC but not PSC reduced, in a concentration- and time-dependent manner, the number of adherent cells in culture, and this suppressive effect was more prominent in TM12 than in TM2H cells. ASC was also found to induce alkaline-labile DNA damage and the oxidation of pyrimidines, and it also increased the rate of apoptosis. These changes were not seen by exposure to PSC or the sulfur analog of ASC. However, additional data obtained from the intact rat mammary gland suggest that the loss of DNA integrity induced by ASC might not be manifest in vivo at doses of ASC that inhibit carcinogenesis.

In vitro and in vivo studies of methylseleninic acid: evidence that a monomethylated selenium metabolite is critical for cancer chemoprevention.

Previous research suggested that the beta-lyase-mediated production of a monomethylated selenium metabolite from Se-methylselenocysteine is a key step in cancer chemoprevention by this agent. In an attempt to affirm the concept, the present study was designed to evaluate the activity of methylseleninic acid, a compound that represents a simplified version of Se-methylselenocysteine without the amino acid moiety, thereby obviating the need for beta-lyase action. The in vitro experiments showed that methylseleninic acid was more potent than Se-methylselenocysteine in inhibiting cell accumulation and inducing apoptosis in TM12 (wild-type p53) and TM2H (nonfunctional p53) mouse mammary hyperplastic epithelial cells, and these effects were not attributable to DNA damage, as determined by the comet assay. In general, methylseleninic acid produced a more robust response at one-tenth the concentration of Se-methylselenocysteine. It is possible that these cell lines may have only a modest ability to generate a monomethylated selenium species from Se-methylselenocysteine via the beta-lyase enzyme. In contrast, methylseleninic acid already serves as a preformed active monomethylated metabolite, and this could be an underlying reason why methylseleninic acid acts more rapidly and exerts a more powerful effect than Se-methylselenocysteine in vitro. Interestingly, the distinction between these two compounds disappeared in vivo, where their cancer chemopreventive efficacies were found to be very similar to each other [in both methylnitrosourea and dimethylbenz(a)anthracene rat mammary tumor models]. The beta-lyase enzyme is present in many tissues; thus, animals have an ample capacity to metabolize Se-methylselenocysteine systemically. Therefore, Se-methylselenocysteine would be expected to behave like methylseleninic acid if beta-lyase is no longer a limiting factor. Taken together, the present in vitro and in vivo results provide strong evidence in support of our earlier hypothesis that a monomethylated selenium metabolite is important for cancer chemoprevention. Methylseleninic acid could be an excellent tool, especially for molecular mechanism studies in cell culture, and some of these attributes are discussed.

Plasma xanthophyll carotenoids correlate inversely with indices of oxidative DNA damage and lipid peroxidation.

Post hoc analysis of data obtained from a study designed to modulate oxidative damage by dietary intervention revealed consistently strong inverse correlations between plasma xanthophyll carotenoids and oxidative damage indices. Thirty-seven women participated in a 14-day dietary intervention that increased mean vegetable and fruit (VF) consumption to approximately 12 servings/day. An additional 10 subjects participated in an intervention that limited VF consumption to less than four servings per day. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) in DNA isolated from peripheral lymphocytes and 8-OHdG excreted in urine were measured as indices of oxidative DNA damage. Lipid peroxidation was assessed by measuring 8-epiprostaglandin F2alpha (8-EPG) in urine. Plasma levels of selected carotenoids were also determined, with the intention of using a-carotene as a biochemical index of VF consumption. Urinary 8-OHdG and 8-EPG were measured by ELISA, and plasma carotenoids were measured by high performance liquid chromatography. Lymphocyte 8-OHdG was measured by reverse phase high performance liquid chromatography with electrochemical detection. We observed that the structurally related xanthophyll carotenoids, lutein and beta-cryptoxanthin, which occur in dissimilar botanical families, were consistently inversely associated with these oxidative indices. Statistically significant inverse correlations were observed between plasma lutein and/or beta-cryptoxanthin levels and lymphocyte 8-OHdG and urinary 8-EPG. Moreover, an inverse correlation was observed between change in plasma xanthophylls and change in lymphocyte 8-OHdG concentration that occurred during the course of the study. These data lead us to hypothesize that lutein and beta-cryptoxanthin serve as markers for the antioxidant milieu provided by plants from which they are derived. Whether these carotenoids are directly responsible for the observed antioxidant phenomena merits further investigation.

A comparison of the histopathology of premalignant and malignant mammary gland lesions induced in sexually immature rats with those occurring in the human.

The injection of sexually immature female rats with 1-methyl-1-nitrosourea results in a rapid induction of premalignant and malignant mammary gland lesions within 35 days of carcinogen administration. This model affords the opportunity for investigators to study the process of mammary carcinogenesis over a very short latency and to investigate early events in this process. We have recently published on various aspects of this system including the histology of the lesions induced, the time frame of their occurrence, and their dependence on ovarian hormones for their maintenance and growth. In this report we present evidence that many aspects of the histopathology of mammary lesions in this model system are similar to those occurring in humans. We also discuss aspects of the human disease, which are not recapitulated in this model.

Selenium modulation of cell proliferation and cell cycle biomarkers in normal and premalignant cells of the rat mammary gland.

The present study was designed to assess the effect of Se-methylselenocysteine or triphenylselenonium chloride treatment on cell proliferation [bromodeoxyuridine (BrdUrd) labeling] and cell cycle biomarkers [proliferating cell nuclear antigen (PCNA), cyclin D1, and p27/Kip 1] in the intact mammary gland of rats. Immunohistochemical assays of the above end points were carried out in different morphological structures: (a) terminal end bud cells and alveolar cells of a maturing mammary gland undergoing active differentiation; and (b) premalignant mammary intraductal proliferations (IDPs) identified at 6 weeks after carcinogen dosing. Neither compound was found to affect BrdUrd labeling or the expression of cell cycle biomarkers in the normal terminal-end bud cells and alveolar cells. Se-methylselenocysteine reduced the total number of IDP lesions by approximately 60%. Interestingly, this was not accompanied by decreases in BrdUrd labeling or the proportion of IDP cells expressing PCNA and cyclin D1. An enhancement in the fraction of p27/Kip 1-positive IDP cells, however, was detected as a result of Se-methylselenocysteine treatment. Although triphenylselenonium chloride did not reduce the total number of IDPs, there were more of the smaller-sized lesions and fewer of the larger-sized lesions compared with those found in the control group. Triphenylselenonium chloride also significantly decreased the proportion of IDP cells incorporating the BrdUrd label or expressing PCNA and cyclin D1. The above findings suggest that early transformed cells are sensitive to selenium intervention, whereas normal proliferating cells are not. It is possible that Se-methylselenocysteine blocks carcinogenesis by a pathway that may not involve cell growth inhibition as a primary response; in contrast, triphenylselenonium chloride is likely to act by a cytostatic mechanism. The data also imply that selenium efficacy testing in intervention trials is possible with the use of biomarkers, provided that the appropriate biomarkers are matched with the selenium compound of interest and that the pathological characteristics of the cell population to be evaluated are taken into consideration.

Effect of fixation and epitope retrieval on BrdU indices in mammary carcinomas.

Studies in which 5-bromo-2'-deoxyuridine (BrdU) is used to quantify rates of cell proliferation are conducted prospectively. Therefore, the opportunity exists to select conditions that optimize detection of the BrdU epitope. The objective of this study was to quantify the extent to which the BrdU epitope was masked by formalin vs methacarn fixation in the assessment of cell proliferation. Mammary carcinomas from animals pulse-labeled with BrdU were trisected. A portion was frozen and the remaining two portions were fixed in 10% neutral buffered formalin or methacarn for 24 hr, processed, embedded in paraffin, and sections stained for incorporated BrdU using a peroxidase immunohistochemical staining technique. Antigen retrieval techniques also were applied to formalin-fixed sections. Fixation in methacarn gave the highest labeling index (16.4%), which was comparable to that observed in unfixed frozen sections (17.5%). Formalin fixation alone dramatically suppressed the labeling index (0.3%), which was only partially recovered using various antigen retrieval techniques (2.1-8.1%). Methacarn fixation is recommended for prospective studies in which BrdU detection is planned because of the quantitative recovery of epitope and the simplicity of the approach.

Reimbursement for acute care nurse practitioner services.

Until the passage of the Balanced Budget Act of 1997, acute care nurse practitioners could not be directly reimbursed for inpatient services provided to Medicare patients. With the enactment of this legislation, acute care nurse practitioners may now be directly compensated for care provided. The historical and contextual issues that surround reimbursement for nursing and advanced practice nursing services are reviewed to serve as a foundation for understanding the current Medicare reimbursement regulations. The implications of the Balanced Budget Act of 1997 for acute care nurse practitioners and their professional colleagues are critically examined. The language of the Balanced Budget Act of 1997 and the subsequent rules and regulations issued by the Health Care Financing Administration are reviewed with specific focus on implications for acute care nurse practitioners. The opportunities for reimbursement for services provided by acute care nurse practitioners are more extensive than ever before. Acute care nurse practitioners and their physician colleagues will be wise to become fully conversant with the changes in Medicare reimbursement regulations.

Classification of premalignant and malignant lesions developing in the rat mammary gland after injection of sexually immature rats with 1-methyl-1-nitrosourea.

Premalignant and malignant stages of mammary carcinogenesis can be rapidly induced by injecting female rats i.p. with 1-methyl-1-nitrosourea (MNU)3 at 21 days of age. In this paper, the characteristics of this model are briefly reviewed and the histology of the lesions induced is presented and compared to those that occur in humans. Malignant mammary lesions induced in rats injected with MNU at 21 days of age are compared with the lesions that develop when MNU is administered to 50-day-old female rats.

Activity of Se-allylselenocysteine in the presence of methionine gamma-lyase on cell growth, DNA integrity, apoptosis, and cell-cycle regulatory molecules.

Se-allylselenocysteine (ASC) is effective in inhibiting mammary epithelial cell growth in vitro and mammary carcinogenesis in vivo, but its mechanism is unknown. We recently reported that ASC reduces cell growth in a dose- and time-dependent manner, induces a loss of DNA integrity, and increases apoptosis. However, the level of ASC required for growth inhibition in vitro is 10- to 20-fold higher than that required in vivo. One possible explanation for this difference is that the cells used in in vitro studies have limited lyase activity required to release the allyl Se moiety from selenocysteine, whereas animals have abundant lyase activity in tissues. In the present study, we found that methionine gamma-lyase (MGL) added to culture medium containing ASC produced biological effects with lower levels of ASC, comparable to the selenium levels in plasma achieved during in vivo chemoprevention. The combination of 2.5 microM ASC and MGL inhibited the growth of TM12 cells and increased apoptosis without loss of DNA integrity. Treatment of TM12 cells with ASC and MGL resulted in an elevation of the protein levels of p53, Cip1/p21, and Kip1/p27, concomitant with a decrease in cyclins D1 and E and modest reductions in cyclin-dependent kinase inhibitors 4 and 2. Cells treated with ASC and MGL also showed decreased phosphorylation of retinoblastoma tumor-suppressor protein. Taken together, these results suggest that a physiologically relevant concentration of ASC with MGL exerts an inhibitory effect on cell growth and that this effect is likely to involve modulation of signaling pathways that suppress the phosphorylation of retinoblastoma tumor-suppressor protein.