The cost-effectiveness and return-on-investment of a combined social and physical environmental intervention in office employees.

This study explored the cost-effectiveness and return-on-investment of a combined social and physical environmental worksite health promotion program compared with usual practice, and of both intervention conditions separately. Participants were randomized to the combined intervention (n = 92), social environmental intervention (n = 118), physical environmental intervention (n = 96), or control group (n = 106). The social environmental intervention consisted of group motivational interviewing and the physical environmental intervention of workplace modifications. Both interventions were aimed at improving physical activity and relaxation. Effects included need for recovery (NFR), general vitality and job satisfaction. Cost-effectiveness analyses were performed from the societal and employer's perspective, and return-on-investment analyses from the employer's perspective. Compared with usual practice, the combined intervention was significantly more effective in improving NFR (-8.4;95% CI:-14.6;-2.2) and significantly more expensive to the employer (3102; 95%CI:598;5969). All other between-group differences were non-significant. For NFR, the combined intervention became the preferred option at willingness-to-pays of ≥€170/point improvement (society) and ≥€300/point improvement (employer). For general vitality and job satisfaction, the interventions' maximum probabilities of cost-effective were low (≤0.55). All interventions had a negative return-on-investment. The combined intervention may be cost-effective for NFR depending on the decision-makers' willingness-to-pay. Both separate interventions are not cost-effective for NFR. All interventions were neither cost-effective for general vitality and job satisfaction, nor cost-saving to the employer.

Cost-effectiveness of a distance lifestyle counselling programme among overweight employees from a company perspective, ALIFE@Work: a randomized controlled trial.

OBJECTIVE: The objective of this study was to determine whether a lifestyle intervention with individual counselling was cost-effective for reducing body weight compared with usual care from a company perspective. PARTICIPANTS: Overweight employees were recruited and randomly assigned to the intervention groups, either phone or Internet, or the control group. METHODS: The intervention was based on a cognitive behavioural approach and addressed physical activity and diet. Self-reported body weight was collected at baseline and 12 months follow-up. Intervention costs and costs of sick leave days based on gross and net lost productivity days (GLPDs/NLPDs) obtained from the participating companies were calculated. Missing data were imputed using multiple imputation techniques. Uncertainty surrounding the differences in costs and the incremental cost-effectiveness ratios (ICER) was estimated by bootstrapping techniques, and presented on cost-effectiveness planes and cost-effectiveness acceptability curves. RESULTS: No statistically significant differences in total costs were found between the intervention groups and control group, though mean total costs in both intervention groups tended to be higher than those in the control group. The ICER of the Internet group compared with the control group was €59 per kilogram of weight loss based on GLPD costs. The probability of cost effectiveness of the Internet intervention was 45% at a willingness-to-pay of €0 per extra kilogram weight loss and 75% at a willingness-to-pay of €1500 per extra kilogram body weight loss. Comparable results were found for the phone intervention. CONCLUSIONS: The intervention was not cost effective in comparison with usual care from the company perspective. Due to the large amount of missing data, it is not possible to draw firm conclusions.

Systematic review on the financial return of worksite health promotion programmes aimed at improving nutrition and/or increasing physical activity.

This systematic review summarizes the current evidence on the financial return of worksite health promotion programmes aimed at improving nutrition and/or increasing physical activity. Data on study characteristics and results were extracted from 18 studies published up to 14 January 2011. Two reviewers independently assessed the risk of bias of included studies. Three metrics were (re-)calculated per study: the net benefits, benefit cost ratio (BCR) and return on investment (ROI). Metrics were averaged, and a post hoc subgroup analysis was performed to compare financial return estimates between study designs. Four randomized controlled trials (RCTs), 13 non-randomized studies (NRSs) and one modelling study were included. Average financial return estimates in terms of absenteeism benefits (NRS: ROI 325%, BCR 4.25; RCT: ROI -49%, BCR 0.51), medical benefits (NRS: ROI 95%, BCR 1.95; RCT: ROI -112%, BCR -0.12) or both (NRS: ROI 387%, BCR 4.87; RCT: ROI -92%, BCR 0.08) were positive in NRSs, but negative in RCTs. Worksite health promotion programmes aimed at improving nutrition and/or increasing physical activity generate financial savings in terms of reduced absenteeism costs, medical costs or both according to NRSs, whereas they do not according to RCTs. Since these programmes are associated with additional types of benefits, conclusions about their overall profitability cannot be made.

Guidelines for the management of vulvodynia.

These guidelines for the management of vulvodynia have been prepared by the British Society for the Study of Vulval Diseases Guideline Group. They present evidence-based guidance for treatment, with identification of the strength of evidence available at the time of preparation of the guidelines.

Long-term outcomes of an abstinence-based, small-group pregnancy prevention program in New York City schools.

CONTEXT: Despite drops in U.S. teenage birthrates, questions continue to arise about how best to reduce the country's adolescent birthrate. School-based programs continue to be considered one of the best ways to reach adolescents at risk of early sexual activity. METHODS: A total of 312 students completed a pretest, a posttest and a follow-up one year after the posttest: 125 who had participated in a 3-4-month-long abstinence-based small-group intervention led by trained social workers, and 187 in a comparison group that received no special services. RESULTS: There were few significant differences between the intervention and comparison groups at posttest. At the one-year follow-up, however, intervention students had significantly better scores on locus of control, their relationship with their parents and (among males only) their attitudes about the appropriateness of teenage sex. Measures of depression, self-esteem, intentions to have sex, attitudes toward teenage pregnancy and various behaviors did not differ significantly between groups. By the time of the one-year follow-up, there was no difference between study groups among females in the initiation of sexual intercourse. Among the males, initiation of sexual intercourse appeared to be higher in the intervention group than in the comparison group, but the difference was not statistically significant. Positive outcomes were especially limited among students who were already sexually active at the start of the study, a finding that emphasizes the difficulties of reaching adolescents who are already at high risk for pregnancy CONCLUSIONS: A small-group abstinence-based intervention focusing on mental health can have some impact on adolescents' attitudes and relationships (particularly with their parents). Long-term evaluations are important for determining the effects of an intervention, as it is difficult to change adolescent risk behavior.

Human interleukin-2 production in insect (Trichoplusia ni) larvae: effects and partial control of proteolysis.

Many eukaryotic proteins have been successfully expressed in insect cells infected with a baculovirus in which the foreign gene has been placed under the control of a viral promoter. This system can be costly at large scale due to the quality of virus stock, problems of oxygen transfer, and severity of large-scale contamination. To circumvent this problem, we have investigated the expression of a foreign protein, human interleukin-2 (IL-2), in insect larvae, Trichoplusia ni, infected with the baculovirus Autographa californica nuclear polyhedrosis virus (AcNPV). The IL-2 gene was placed under control of the p10 promoter so that the polyhedra remained intact for efficient primary infection. From our results, it was clear that early infection limited larval growth and late infection delayed product production until near pupation, hence infection timing was important. Also, the harvest time was crucial for obtaining high yield, because IL-2 production had a sharp optimal peak with a time of occurrence dependent on both temperature and the initial amount of infection virus. Specifically, we found that, by raising the infection temperature to 30 degrees C, we more than doubled the protein productivity. Furthermore, a significant concern of the larvae/baculovirus expression system has been the large amount of protease produced by the larvae, which adversely affects the protein yield. Therefore, we screened several protease inhibitors and characterized the larval protease specificity and timing to attenuate their impact. This report elucidates and delineates the factors that most directly impact protein yield in the larvae expression system, using IL-2 as a model.

Phenotype of chromosome 14-linked familial Alzheimer's disease in a large kindred.

We report the clinical and neuropathological features of chromosome 14-linked familial Alzheimer's disease (14qFAD) in affected members of the L family. Some clinical information on all 16 known affected individuals and detailed neuropathological findings in 6 family members were available for review. Common features of the phenotype of 14qFAD in the L family included onset of dementia before the age of 50, early progressive aphasia, early-appearing myoclonus and generalized seizures, paratonia, cortical atrophy, numerous and extensive senile plaques and neurofibrillary tangles, and prominent amyloid angiopathy. Descriptions of phenotypic features were available for six additional recently defined 14q-linked FAD kindreds: the findings in four of them (FAD4, FAD2, A, B) indicated a relatively consistently shared 14qFAD phenotype, conforming closely with the specific clinical and neuropathological characteristics noted in the L family. Comparisons also suggested several ostensible phenotypic variants in 14qFAD: (1) In two 14q-linked kindreds (SNW/FAD3, FAD1), affected individuals in some instances were noted to survive to age 70 or beyond and the mean age at onset (> 49 years) in these two kindreds was somewhat higher than in their five 14qFAD counterparts (< 48 years in each); (2) in the SNW/FAD3 kindred, seizures and myoclonus were absent in all 10 subjects examined; and (3) cerebellar amyloid plaques were variably present within and among several 14qFAD kindreds. Comparisons with phenotypic features recently detailed in three kindreds (TOR3, F19, ROM) with codon 717 amyloid precursor protein gene mutations (i.e., APP717 FAD) suggested several distinctions: Prominent progressive aphasia, myoclonus, seizures, and paratonia were all apparently less prevalent in APP717 FAD, with language function predominantly spared over the initial disease course. The extent of homogeneity and heterogeneity in the clinical and neuropathological phenotype of 14q-linked FAD and its possible meaningful distinctions from the phenotypes of APP717 FAD await further determination.

Constraint of the translational diffusion of a membrane glycoprotein by its external domains.

The translational diffusion of wild-type and underglycosylated molecules of a membrane-integral glycoprotein the Ld class I major histocompatibility complex (MHC) antigen has been measured. The Ld mutant molecules, which lack one or more glycosylation sites, had larger translational diffusion coefficients, D, than did wild-type Ld molecules glycosylated at three sites. The increase in D is linear with loss of glycosylation. The highest value of D approaches that for translational diffusion of molecules constrained only by viscosity of the membrane lipid bilayer. These results indicate that the external portions of cell surface glycoproteins interact significantly with other nearby molecules.

Aproliferin: a modulator of proliferative potential.

Cellular differentiation proceeds through a series of steps in which cells undergo modifications in cellular phenotype and proliferative potential. Differentiation has been extensively studied in 3T3-T mesenchymal stem cells and growth arrest, non-terminal and terminal differentiation have been identified as three distinct stages in the adipocyte differentiation of these cells. The terminal stage of differentiation is associated with irreversible loss of proliferative potential and commitment to the expression of the adipocyte phenotype. A protein has been partially purified from human plasma that can induce the transition of 3T3-T adipocytes from the non-terminal to the terminal state of differentiation. This protein, designated aproliferin, has a mol. wt of approximately 45,000 and is trypsin, acid and heat labile. Induction of terminal differentiation by aproliferin is associated with changes in the synthesis of a limited number of cellular proteins. The ability of aproliferin to induce terminal differentiation in non-terminally differentiated cells is highly specific as a wide variety of pharmacological and biochemical agents do not mimic the effects of this agent. Apoliferin may be one of an emerging class of molecules which can affect differentiation and induce irreversible changes in cell function.

Polypeptide changes associated with loss of proliferative potential during the terminal event in differentiation.

The differentiation of murine mesenchymal stem cells occurs in nonterminal and terminal phases. In previous reports we established the characteristics of nonterminally differentiated cells and showed that transition from the nonterminal to the terminal state of differentiation can be induced by human plasma. We also showed that this transition is blocked by protein synthesis inhibitors and other pharmacological agents. In this paper, we have employed two-dimensional gel electrophoresis to evaluate changes in specific polypeptides that are induced when cells lose proliferative capacity associated with the terminal event in differentiation. Using silver staining procedures for analysis of electrophoretograms, we detected only seven major polypeptide differences between nonterminally differentiated and terminally differentiated cells. Six polypeptides were expressed only in preparations of terminally differentiated cells; these included two polypeptides identified in cytosolic fractions and four polypeptides identified in nuclear fractions. One polypeptide was also found to be selectively expressed only in nuclear fractions of nonterminally differentiated cells. Based on these observations we conclude that the loss of proliferative potential that occurs during the terminal event in mesenchymal stem cell differentiation is associated with changes in the composition of a limited number of specific polypeptides. We suggest that one or more of these polypeptides may be important in the regulation of cellular proliferation.

Aproliferin--a human plasma protein that induces the irreversible loss of proliferative potential associated with terminal differentiation.

Cellular proliferation is regulated not only by the action of growth factors and growth inhibitors whose effects are reversible but also by factors that induce the irreversible loss of proliferative potential associated with the terminal event in cellular differentiation. The authors have employed 3T3 T mesenchymal stem cells as a model system to study the terminal event in cellular differentiation because in these cells' distinct nonterminal and terminal states of differentiation can be identified and because transition from the nonterminal to the terminal states of differentiation can be induced by human plasma. In this paper is reported the 20,000-fold purification of a component of human plasma that induces the terminal event in differentiation. This factor is shown to have an apparent molecular weight of approximately 45,000 and an isoelectric point of approximately 7.6. It is trypsin-sensitive, acid and heat-labile, and is resistant to treatment with dithiothreitol and alkali. The ability of this human plasma protein to induce the irreversible loss of proliferative potential associated with the terminal event in differentiation serves as the basis for its designation "aproliferin." The data in this paper in addition show that no other pharmacologic or physiologic agents have been identified that can mimic the biologic effect of aproliferin. Therefore, aproliferin appears to be a functionally distinct protein in human plasma.

Hydrophobic adsorption chromatography to reduce nonspecific staining by rhodamine-labeled antibodies.

Rhodamine absorbed to protein was removed from rhodamine-conjugated antibody solutions by adsorption to hydrophobic macroporous beads (Bio-Beads SM-2) following gel permeation chromatography. This simple technique eliminated the contaminating free dye more effectively than gel filtration alone, but neither significantly reduced the level of fluorescently conjugated antibody nor altered the latter's binding characteristics. Passage of the fluorescent antibody solution over the SM-2 beads eliminated the high background of nonspecific staining caused by internalization of residual free dye.

Differentiation, dedifferentiation, and transdifferentiation of BALB/c 3T3 T mesenchymal stem cells: potential significance in metaplasia and neoplasia.

The expression of defects in the control of cellular differentiation is thought to be of etiological significance in the early stages of carcinogenesis. This possibility is supported by a variety of experimental studies including those that have established that metaplastic changes in cells can represent preneoplastic lesions in vivo. To evaluate this question in greater detail, we have used 3T3 T mesenchymal stem cells as a model system. These cells express certain characteristics of preneoplastic cells even though they can regulate their proliferation and even though they can undergo nonterminal and terminal differentiation into adipocytes. For example, they are immortal and aneuploid, and they show a proclivity to undergo spontaneous or induced neoplastic transformation compared to normal human cells. The question we sought to answer in the current experiments concerns whether predifferentiation growth arrest and/or nonterminal differentiation in such preneoplastic cells is completely reversible or whether these processes induce the expression of the new stable program that limits the cells' proliferative potential and reduces the cells' subsequent differentiation potential in a manner comparable to that which is thought to occur in normal stem cells. The results show that arrest at both the predifferentiation state and at the nonterminal differentiation state is a completely reversible phenomenon that does not limit the cells' subsequent growth or differentiation potential. In fact, the results show that, when nonterminally differentiated 3T3 T adipocytes are induced to dedifferentiate, they can subsequently redifferentiate into macrophages. We therefore suggest that preneoplasia as expressed in 3T3 T mesenchymal stem cells is associated with the expression of defects in the ability to integrally control cellular differentiation and proliferation. As a result, the data suggest that such cells express an increased proclivity to undergo metaplastic change and complete neoplastic transformation.

Effects of cell density and extracellular matrix on the lateral diffusion of major histocompatibility antigens in cultured fibroblasts.

We have studied the effect of cell density on the lateral diffusion of major histocompatibility (MHC) antigens in the plasma membranes of fibroblasts using fluorescence recovery after photobleaching. The percent recovery of fluorescence was decreased in fibroblasts grown in confluent cultures. While recovery of fluorescence was measurable in greater than 90% of the cells from sparse cultures, measurable recovery was detected in only 60-80% of the cells from dense cultures; no mobile antigens were detectable in 20-40% of cells examined. The diffusion coefficient on human skin fibroblast cells that did show recovery was the same for cells grown in sparse or dense conditions. In WI-38, VA-2, and c1 1d cultures the diffusion coefficients of mobile antigens were smaller in cells from dense cultures. Changes in lateral diffusion occurred with increased cell-cell contact and with age of cell culture but were not observed in growth-arrested cells or in sparse cells cultured in medium conditioned by confluent cells. Decreased mobile fractions of MHC antigens were observed when cells were plated on extracellular matrix materials derived from confluent cultures. Treatment of the extracellular matrix materials with a combination of proteolytic enzymes or by enzymes that degrade proteoglycans abolished this effect. Matrices produced by cells from other cell lines were less effective in inducing changes in mobile fractions and purified matrix components alone did not induce changes in lateral diffusion. Finally, there were no differences in the proportion of MHC antigens that were resistant to Triton X-100 extraction in sparse and dense cells. These results suggest that cell-cell interactions mediated through extracellular matrix materials can influence the lateral diffusion of at least part of the population of MHC antigens.

Regulation of the terminal event in cellular differentiation: biological mechanisms of the loss of proliferative potential.

Human plasma has been demonstrated to contain factors that induce the sequential expression of nonterminal and terminal adipocyte differentiation in 3T3 T mesenchymal stem cells. We now report the development of methods for the isolation of purified populations of nonterminally differentiated cells and terminally differentiated cells, and we show that it is possible to experimentally induce transition from the nonterminal to the terminal state of differentiation. With this model system it is therefore now possible to examine the biological and molecular processes associated with the terminal event in differentiation, i.e., the irreversible loss of proliferative potential. In this regard, we demonstrate that transition from the nonterminal to terminal state of differentiation is a complex metabolic process that consists of at least two steps and that this process can be triggered by pulse exposure to an inducer for approximately 12 h but that approximately 24-48 h is required for the process to be completed. The data also establish that induction of the terminal event in differentiation requires protein synthesis but not RNA and DNA synthesis. These and additional results suggest that loss of proliferative potential associated with the terminal event in cellular differentiation is a distinct regulatory process, and we suggest that defects in this regulatory process may be of etiological significance in the pathogenesis of specific human diseases, especially cancer.

Defective control of terminal differentiation and its role in carcinogenesis in the 3T3 T proadipocyte stem cell line.

The expression of defects in the control of terminal cellular differentiation has been implicated to be of etiological significance in the pathogenesis of cancer. However, it has not been established whether or not additional defects in the control of cellular differentiation and proliferation are required for the expression of the completely transformed phenotype. We therefore developed four clones of proadipocyte stem cells that express a single specific defect that limits their capacity to undergo the terminal phase in differentiation. The value of these clones is emphasized by the fact that they show no defects in their ability to regulate nonterminal differentiation or proliferation relative to native nontransformed proadipocyte stem cells. Terminal differentiation-defective clones were therefore assayed to determine if they express the completely transformed phenotype. The results show that differentiation-defective stem cells are not tumorigenic in vivo and do not grow in soft agar, which is an in vitro assay for expression of the transformed phenotype by murine mesenchymal cells. These data are interpreted to support the conclusion that the expression of defects in the control of the terminal phase of differentiation per se is not adequate to induce complete neoplastic transformation.

Biological mechanisms for the loss of the differentiated phenotype by non-terminally differentiated adipocytes.

The differentiation of 3T3 T proadipocyte stem cells is controlled at two related yet distinct states in the G1 phase of the cell cycle. They are designated GD and GD'. GD is the G1 state at which cells must growth arrest prior to differentiation, and GD' is the G1 state at which non-terminal differentiation occurs. Cells arrested at the GD and GD' states have distinct characteristics; yet cells at both states can mediate the integrated control of cellular proliferation and differentiation. In this paper we report on studies designed to further characterize the relationship of these two states, specifically to determine whether non-terminally differentiated GD'-arrested cells can be induced to lose the adipocyte phenotype and revert to the GD state. We report that retinoic acid (RA) and methyl isobutyl xanthine (MIX) can induce non-terminally differentiated GD'-arrested cells to lose the adipocyte phenotype without undergoing DNA synthesis. Such cells that have lost the adipocyte phenotype are also shown to remain in the G1 phase of the cell cycle and to reacquire most of the characteristics of GD-arrested cells. Most importantly, they demonstrate the capacity to redifferentiate without DNA synthesis. We therefore conclude that when non-terminally differentiated GD'-arrested cells are induced to lose the adipocyte phenotype they do indeed revert to the GD state and they thereby become more responsive to environmental influences which can further regulate the integrated control of cellular proliferation and differentiation.

Mechanisms for the initiation and promotion of carcinogenesis: a review and a new concept.

Carcinogenesis in humans is a multistage process, and the two major stages have been designated initiation and promotion. Although the biochemical basis for initiation and promotion remains to be established, recent research has provided important insights into potentially significant biologic mechanisms. These data are reviewed, and a new concept of carcinogenesis is presented. This concept suggests that the initiation of carcinogenesis may result from cellular immortalization and the development of defects in the integrated control of stem cell proliferation and differentiation and that the promotion of carcinogenesis may result when such initiated stem cells develop aberrant autoregulatory growth-control properties.