Assessing Conformance with Benford's Law: Goodness-Of-Fit Tests and Simultaneous Confidence Intervals.

Benford's Law is a probability distribution for the first significant digits of numbers, for example, the first significant digits of the numbers 871 and 0.22 are 8 and 2 respectively. The law is particularly remarkable because many types of data are considered to be consistent with Benford's Law and scientists and investigators have applied it in diverse areas, for example, diagnostic tests for mathematical models in Biology, Genomics, Neuroscience, image analysis and fraud detection. In this article we present and compare statistically sound methods for assessing conformance of data with Benford's Law, including discrete versions of Cramér-von Mises (CvM) statistical tests and simultaneous confidence intervals. We demonstrate that the common use of many binomial confidence intervals leads to rejection of Benford too often for truly Benford data. Based on our investigation, we recommend that the CvM statistic Ud(2), Pearson's chi-square statistic and 100(1 - α)% Goodman's simultaneous confidence intervals be computed when assessing conformance with Benford's Law. Visual inspection of the data with simultaneous confidence intervals is useful for understanding departures from Benford and the influence of sample size.

Transcription factors that mediate epithelial-mesenchymal transition lead to multidrug resistance by upregulating ABC transporters.

Development of multidrug resistance (MDR) is a major deterrent in the effective treatment of metastatic cancers by chemotherapy. Even though MDR and cancer invasiveness have been correlated, the molecular basis of this link remains obscure. We show here that treatment with chemotherapeutic drugs increases the expression of several ATP binding cassette transporters (ABC transporters) associated with MDR, as well as epithelial-mesenchymal transition (EMT) markers, selectively in invasive breast cancer cells, but not in immortalized or non-invasive cells. Interestingly, the mere induction of an EMT in immortalized and non-invasive cell lines increased their expression of ABC transporters, migration, invasion, and drug resistance. Conversely, reversal of EMT in invasive cells by downregulating EMT-inducing transcription factors reduced their expression of ABC transporters, invasion, and rendered them more chemosensitive. Mechanistically, we demonstrate that the promoters of ABC transporters carry several binding sites for EMT-inducing transcription factors, and overexpression of Twist, Snail, and FOXC2 increases the promoter activity of ABC transporters. Furthermore, chromatin immunoprecipitation studies revealed that Twist binds directly to the E-box elements of ABC transporters. Thus, our study identifies EMT inducers as novel regulators of ABC transporters, thereby providing molecular insights into the long-standing association between invasiveness and MDR. Targeting EMT transcription factors could hence serve as novel strategies to curb both metastasis and the associated drug resistance.

Behavioral and psychological symptoms of dementia and caregivers' stress appraisals: intra-individual stability and change over short-term observations.

Dementia is commonly associated with memory loss, but Behavioral and Psychological Symptoms of Dementia (BPSD) such as disruptive behaviors, agitation, and problems with mood, usually have a more significant impact on caregivers' stress. It is known that BPSD and caregivers' stress reactions vary in frequency over the long-term course of dementia, however little is known about the variability over the short-term. The current study included 85 people with dementia and their primary caregivers assessed over three months. Caregivers used a 24-hour log on multiple, consecutive days to report behavioral symptoms of dementia on seven domains of behavior, as well as their stress reactions for each domain. Using latent growth curve analysis, most BPSD and caregiver stress appraisals were found to be, on average, stable over the three-month time frame. For many BPSD and stress appraisal models, however, intra-individual differences in rate of change were significantly different from the mean trend, indicating behaviors and stress are not stable over three months when assessed at the level of the individual. Covariates were used to explain individual differences in rates of change; however few variables were significantly associated with intra-individual short-term change over time.

Employed family caregivers of cognitively impaired elderly: an examination of role strain and depressive symptoms.

This paper compares employed and non-employed caregivers of cognitively impaired elderly family members. Using two competing positions derived from role theory, role conflict and role expansion, we explored whether holding the positions of both caregiver and worker led to greater role overload and psychological role conflict, or provided an outlet that helps caregivers better manage the demands placed on them. We found no differences between employed and non-employed caregivers on measures of role overload, worry and strain, and depression. For working caregivers, however, greater conflict on the job was associated with higher role overload and worry and strain while beneficial work experiences were only weakly associated with lower role overload and worry and strain. There was an interaction effect between positive work experiences and role overload when predicting depressive symptoms. These results provide some support for role conflict, but also suggest that caregivers may vary considerably in how they adapt to multiple roles.

Balancing parent care with other roles: interrole conflict of adult daughter caregivers.

This study examined interrole conflict experienced by 278 women who simultaneously occupied 4 roles: parent care provider, mother to children at home, wife, and employee. Compared with women who experienced no conflict between parent care and their other roles, women reporting parent care conflict tended to have fewer socio-economic resources, to have older children, and to be caring for parents with greater impairment. Women who reported conflicts between parent care and employment were older; had more education; had marriages of longer duration; and had older, more self-sufficient children than women who reported conflict between the parent care role and the mother role. Some evidence was found for the hypothesis that interrole conflict between parent care and other roles mediates the relationship between parent care stress and psychosocial well-being. Results suggest that one way parent care stress exerts its deleterious effects on the well-being of adult daughters is through the incompatible pressures of parent care and other roles.

Comparisons of African American and White women in the parent care role.

Little is known about African American women's experiences providing care to impaired older relatives. This study investigated potential differences in depressive symptomatology, parent care stress and rewards, parent care mastery, and the quality of the parent care relationship between 261 White and 56 African American daughters and daughters-in-law who were providing care for an impaired parent or parent-in-law. Multivariate analysis of variance, controlling for significant background characteristics and interrelationships among caregiving experiences, revealed that African American women reported less stress and more rewards in the parent care role than White women did. Race did not have a significant effect on caregivers' depressive symptomatology, parent care mastery, or the quality of their relationship with the parent. However, this research demonstrates the importance of examining a broad range of caregiving experiences in order to detect both similarities and differences between African American and White caregivers.

Response to warfarin and other oral anticoagulants: effects of disease states.

BACKGROUND: Warfarin is associated with numerous drug and food interactions, and much attention has been appropriately focused on this subject. Because several disease states may also affect response to oral anticoagulants, we present a summary of the literature. METHODS: We searched MEDLINE for original articles on the effect of disease states on response to warfarin. RESULTS: Liver disease and thyroid dysfunction are well-documented as affecting warfarin response. Further study is needed to establish whether febrile illness, congestive heart failure, and other disease states enhance the effect of warfarin in some patients. CONCLUSION: Careful monitoring of anticoagulant therapy in patients with diseases that have the potential to affect warfarin response could increase safety and efficacy of this important agent.

Predictors of institutionalization of cognitively impaired elders: family help and the timing of placement.

Although predictors of nursing home placement have attracted a good deal of attention in gerontological research, the type and amount of family assistance offered to caregivers prior to institutionalization has not been extensively examined. This study analyzed the impact of family help on the timing of placement among cognitively impaired care recipients. Using longitudinal data from the Adult Day Care Collaborative Study, an event-history analysis was performed to determine the effects of family help after sociodemographic characteristics, caregiving stressors, and indicators of caregiver well-being were taken into account. Results showed that caregivers were far less likely to institutionalize their relatives when family members provided overnight help and assisted with activities of daily living care. These findings suggest that specific types of family help play an important role in delaying nursing home placement among older adults suffering from dementia.

Centrality of women's multiple roles: beneficial and detrimental consequences for psychological well-being.

Theorists have proposed that greater centrality (personal importance) of a social role is associated with better psychological well-being but that role centrality exacerbates the negative effects of stress in that same social role on well-being. The present study found evidence to support both hypotheses in a sample of 296 women who simultaneously occupied the roles of parent care provider, mother, wife, and employee. Greater centrality of all four roles was related to better psychological well-being. As predicted, wife centrality exacerbated the effects of wife stress on life satisfaction, and employee centrality exacerbated the effects of employee stress on depressive symptoms. Contrary to prediction, centrality of the mother role buffered women from the negative effects of mother stress on depressive symptoms. These findings point to an aspect of role identity that can benefit well-being but that has complex effects in the context of role stress.

Vitamin K to reverse excessive anticoagulation: a review of the literature.

We conducted an extensive literature review to evaluate the appropriate use, route, and dose of vitamin K to reverse excessive anticoagulation. Issues such as sample size, study design, different patient populations, and various study end points confounded results. Of 18 studies published, 8 enrolled 229 patients to evaluate parenteral vitamin K administration. Nine studies with 288 patients evaluated oral administration, and only 2 retrospective studies (280 patients) compared routes of administration. Reductions in international normalized ratios at 24 hours ranged from 21-42%, 47-86%, 25-67%, and 40-75% for temporary warfarin discontinuation alone, and intravenous, subcutaneous, and oral routes of vitamin K administration, respectively. Methodologically weak studies and indeterminate results plague interpretation of the literature on vitamin K. In general, results of this review support current guidelines for reversing excessive warfarin anticoagulation. However, it is important to realize that the quality of literature on which these recommendations are based is poor and that optimal dose and route of vitamin K administration remain unclear. Large, well-designed, randomized, controlled trials are necessary to define optimum management strategies for excessively anticoagulated patients.

Subcutaneous phytonadione for reversal of warfarin-induced elevation of the International Normalized Ratio.

The efficacy and safety of subcutaneous phytonadione in the treatment of patients with asymptomatic excessive International Normalized Ratio (INR) values secondary to warfarin therapy were evaluated. Patients at an outpatient anticoagulation clinic with an INR of 8 or more but less than 14 were given 1 mg of subcutaneous phytonadione, and patients with an INR of 14 or more but less than 20 received 2 mg. The patients were instructed to withhold warfarin therapy for the next 24 hours and to immediately report any bleeding complications. At subsequent visits, patients with an INR of 8 or more but less than 14 were given an additional 1 mg of subcutaneous phytonadione. Patients with an INR above 4.5 were instructed to withhold warfarin therapy for an additional 24 hours. Seventeen patients received the 1-mg dose (group 1), and four patients received the 2mg dose (group 2). In group 1, the mean INR reduction was 49% at 24 hours and 72% at 48 hours and the INR was below 4.5 in 93% of patients at 48 hours. In group 2, the mean INR reduction was 67% at 24 hours and 85% at 48 hours and the INR was below 4.5 in 100% of patients at 48 hours. In four group-1 patients and one group-2 patient, the INR fell below 2.0 at 48 hours. No patients reported hemorrhagic or thrombotic complications. Subcutaneous phytonadione safely lowered excessively high INR values caused by warfarin therapy.

Accuracy, clinical correlation, and patient acceptance of two handheld prothrombin time monitoring devices in the ambulatory setting.

OBJECTIVE: To evaluate the accuracy, clinical correlation, ease of use, and patient acceptance of the Coaguchek and the ProTime Microcoagulation System as compared with standard laboratory methods for prothrombin time determination. METHODS: A total of 30 prothrombin times, expressed as international normalized ratios (INRs), were determined by each handheld device for comparison with standard laboratory testing. Accuracy was evaluated by calculating the absolute difference for each pair of INR values. Clinical correlation was defined as an INR obtained by the handheld monitor that would have resulted in the same therapeutic decision as the INR obtained by the standard laboratory method. Subjects were surveyed to determine which method of INR determination they preferred and their reasons for that preference. RESULTS: Accuracy was superior with the Coaguchek monitor. The absolute difference (mean +/- SD) in the laboratory and Coaguchek INRs was 0.28+/-0.23 (p = 0.96). The absolute difference (mean +/- SD) in the laboratory and the ProTime Microcoagulation System INRs was 0.56+/-0.34 (p < 0.001). For clinical correlation, two out of 24 (8.3%) INRs with the Coaguchek were sufficiently different from the laboratory INR to have resulted in a different therapeutic decision, compared with 12 out of 24 (50%) with the ProTime Microcoagulation System (p < 0.005). Of subjects surveyed, 77.8% preferred the finger stick method. CONCLUSIONS: The Coaguchek was superior to the ProTime Microcoagulation System in accuracy, clinical correlation, and ease of use. The study also showed that patients preferred capillary blood sampling by finger puncture over venipuncture for INR monitoring.

Longitudinal patterns of risk for depression in dementia caregivers: objective and subjective primary stress as predictors.

The present study examined how patterns of risk for depression over 1 year in 188 dementia caregivers (consistently asymptomatic, n = 88; consistently symptomatic, n = 40; changing risk, n = 60) could be predicted by objective (behavior problems of the relative) and subjective (role captivity and overload) primary stress. Results reveal that all primary stressors differentiated caregivers who remained at low levels of symptomatology over the course of 1 year from those who were at risk for experiencing a depressive disorder. In addition, caregivers' subjective experience of role captivity predicted the chronicity of risk. Findings extend prior caregiving research on patterns of depressive symptomatology by highlighting the relationship between subjective primary stressors and stability and change in caregivers' mental health.

Emotional support and well-being of midlife women: role-specific mastery as a mediational mechanism.

This study examined the relationships among emotional support, mastery, and well-being for 258 women who simultaneously occupied the roles of wife, mother, parent care provider, and employee. Its primary aim was to determine if a greater sense of mastery in each of these 4 roles could explain the relationship between emotional support from the partner or partners in the same role (the husband, children, impaired parent, or work supervisor) and better psychological well-being (less depressive symptomatology and more life satisfaction). Findings revealed that more emotional support from each of the 4 role partners was related to a greater sense of mastery in that same role. Furthermore, for each of the roles of wife, mother, and employee, role-specific mastery was a mediating mechanism in the relationship between support from the role partner or partners and better well-being.

Stress reduction for family caregivers: effects of adult day care use.

OBJECTIVES: This study reports the findings of an evaluation of the psychological benefits of use of adult day care by family caregivers assisting a relative with dementia. METHODS: The study used a quasi-experimental design in which caregivers in the treatment group used substantial amounts of services, whereas caregivers in a control group did not use day care at any point during the evaluation and only small amounts of other respite services. The evaluation was guided by the stress process model of caregiving which distinguishes between appraisals of primary stressors and well-being. RESULTS: Results after 3 months of day care use showed that the treatment group had significantly lower scores than the control group on two of the three measures of primary appraisals (overload and strain) and two of the three measures of well-being (depression and anger). Findings at one year showed that the treatment group had significantly lower scores on overload and depression than the control group. DISCUSSION: These results demonstrate that use of adult day care by caregivers of dementia patients results in lower levels of caregiving-related stress and better psychological well-being when compared to that of controls.

Mastery in women's multiple roles and well-being: adult daughters providing care to impaired parents.

The current study focused on 296 adult daughter caregivers who were simultaneously providing care to an impaired parent, mothers to children living at home, wives, and employees. How mastery (perceived competence and control) in each of these 4 roles was related to well-being was examined. Women experienced higher levels of mastery in the employee role than in any other role. After controlling for household income and dispositional optimism, only employee mastery contributed unique variance to physical health, but mastery in each of the 4 roles contributed unique variance to either depression or life satisfaction. Results also suggest that women's satisfaction with life was related to an accumulation of mastery across roles. The study expands previous research by revealing that mastery in women's additional roles can supplement the benefits of mastery stemming from parent care.

Emotional and physical intimacy in coping with lupus: women's dilemmas of disclosure and approach.

This study examined whether self-rated physical and emotional intimacy of 74 women with their heterosexual partner, during an illness episode of lupus, was related to their affect and relationship satisfaction. It was predicted that greater intimacy would be related to better psychosocial adjustment. Women who engaged in physically intimate behavior with their partner more often reported greater relationship satisfaction. Women who frequently avoided or who were often the initiators of physical intimacy, however, reported greater negative affect. Concerning emotional intimacy, women who disclosed more information about illness symptoms and women who concealed more information about their symptoms and feelings experienced the highest levels of negative affect. Results identify dilemmas that women with recurrent illness may face when trying to maintain intimacy during illness periods.

The interplay of work and caregiving: relationships between role satisfaction, role involvement, and caregivers' well-being.

This study applied theory from the general work and family literature to the dual roles of work and caregiving, in order to examine whether level of satisfaction and time involvement in each of these roles moderate the effects of stress in the other role on well-being. Respondents were 118 employed women who were providing care to an impaired parent or parent-in-law. As predicted, greater time involvement in work was found to buffer women from the negative effects of caregiving stress. Satisfaction with caregiving and satisfaction with work were directly associated with better well-being, beyond the effects of stress in both roles. However, women who experienced high levels of caregiving stress and who were highly satisfied with work were especially vulnerable to depression. These findings illustrate the importance of examining the effects of caregiving stress on well-being in the context of work-related experiences.

2-Cyclopropylindoloquinones and their analogues as bioreductively activated antitumor agents: structure-activity in vitro and efficacy in vivo.

A series of 2-cycloalkyl- and 2-alkyl-3-(hydroxymethyl)-1-methylindoloquinones and corresponding carbamates have been synthesized and substituted in the 5-position with a variety of substituted and unsubstituted aziridines. Cytotoxicity against hypoxic cells in vitro was dependent upon the presence of a 5-aziridinyl or a substituted aziridinyl substituent for 3-hydroxymethyl analogues. The activity of 5-methoxy derivatives was dependent upon the presence of a 3-(carbamoyloxy)methyl substituent. Increasing the steric bulk at the 2-position reduced the compounds' effectiveness against hypoxic cells. A 2-cyclopropyl substituent was up to 2 orders of magnitude more effective than a 2-isopropyl substituent, suggesting possible radical ring-opening reactions contributing to toxicity. Nonfused 2-cyclopropylmitosenes were more effective than related fused cyclopropamitosenes reported previously. The reduction potentials of the quinone/semiquinone one-electron couples were in the range -286 to -380 mV. The semiquinone radicals reacted with oxygen with rate constants 2-8 x 10(8) dm3 mol-1 s-1. The involvement of the two-electron reduced hydroquinone in the mediation of cytotoxicity is implicated. The most effective compounds in vitro were the 2-cyclopropyl and 5-(2-methylaziridinyl) derivatives, and of these, 5-(aziridin-1-yl)-2-cyclopropyl-3-(hydroxymethyl)-1-methylindole-4 ,7-dione (21) and 3-(hydroxymethyl)-5-(2-methylaziridin-1-yl)-1,2-dimethylindole+ ++-4,7-dione (54) were evaluated in vivo. Both compounds showed antitumor activity both as single agents and in combination with radiation, with some substantial improvements over EO9 (3) at maximum tolerated doses and as single agents against the RIF-1 tumor model and comparable efficacy in the KHT tumor model.

Synthesis and cytotoxic activity of indolyl thiazoles.

A number of indolyl thiazoles have been prepared and evaluated for their antitumor properties. The compounds were synthesized from the appropriate indole, building up the thiazole ring using the Hantzsch reaction. Cytotoxic activity was measured in the human breast cancer cell line SKBr3 using the MTT assay.