Structure-activity relationship models for rat carcinogenesis and assessing the role mutagens play in model predictivity.

We previously demonstrated that fragment based cat-SAR carcinogenesis models consisting solely of mutagenic or non-mutagenic carcinogens varied greatly in terms of their predictive accuracy. This led us to investigate how well the rat cancer cat-SAR model predicted mutagens and non-mutagens in their learning set. Four rat cancer cat-SAR models were developed: Complete Rat, Transgender Rat, Male Rat and Female Rat, with leave-one-out (LOO) validation concordance values of 69%, 74%, 67% and 73%, respectively. The mutagenic carcinogens produced concordance values in the range 69-76% compared with only 47-53% for non-mutagenic carcinogens. As a surrogate for mutagenicity, comparisons between single site and multiple site carcinogen SAR models were analysed. The LOO concordance values for models consisting of 1-site, 2-site and 4+-site carcinogens were 66%, 71% and 79%, respectively. As expected, the proportion of mutagens to non-mutagens also increased, rising from 54% for 1-site to 80% for 4+-site carcinogens. This study demonstrates that mutagenic chemicals, in both SAR learning sets and test sets, are influential in assessing model accuracy. This suggests that SAR models for carcinogens may require a two-step process in which mutagenicity is first determined before carcinogenicity can be accurately predicted.

Chemical structure determines target organ carcinogenesis in rats.

SAR models were developed for 12 rat tumour sites using data derived from the Carcinogenic Potency Database. Essentially, the models fall into two categories: Target Site Carcinogen-Non-Carcinogen (TSC-NC) and Target Site Carcinogen-Non-Target Site Carcinogen (TSC-NTSC). The TSC-NC models were composed of active chemicals that were carcinogenic to a specific target site and inactive ones that were whole animal non-carcinogens. On the other hand, the TSC-NTSC models used an inactive category also composed of carcinogens but to any/all other sites but the target site. Leave one out (LOO) validations produced an overall average concordance value for all 12 models of 0.77 for the TSC-NC models and 0.73 for the TSC-NTSC models. Overall, these findings suggest that while the TSC-NC models are able to distinguish between carcinogens and non-carcinogens, the TSC-NTSC models are identifying structural attributes that associate carcinogens to specific tumour sites. Since the TSC-NTSC models are composed of active and inactive compounds that are genotoxic and non-genotoxic carcinogens, the TSC-NTSC models may be capable of deciphering non-genotoxic mechanisms of carcinogenesis. Together, models of this type may also prove useful in anticancer drug development since they essentially contain chemical moieties that target a specific tumour site.

Mammary carcinogen-protein binding potentials: novel and biologically relevant structure-activity relationship model descriptors.

Previously, SAR models for carcinogenesis used descriptors that are essentially chemical descriptors. Herein we report the development of models with the cat-SAR expert system using biological descriptors (i.e., ligand-receptor interactions) rat mammary carcinogens. These new descriptors are derived from the virtual screening for ligand-receptor interactions of carcinogens, non-carcinogens, and mammary carcinogens to a set of 5494 target proteins. Leave-one-out validations of the ligand mammary carcinogen-non-carcinogen model had a concordance between experimental and predicted results of 71%, and the mammary carcinogen-non-mammary carcinogen model was 72% concordant. The development of a hybrid fragment-ligand model improved the concordances to 85 and 83%, respectively. In a separate external validation exercise, hybrid fragment-ligand models had concordances of 81 and 76%. Analyses of example rat mammary carcinogens including the food mutagen and oestrogenic compound PhIP, the herbicide atrazine, and the drug indomethacin; the ligand model identified a number of proteins associated with each compound that had previously been referenced in Medline in conjunction with the test chemical and separately with association to breast cancer. This new modelling approach can enhance model predictivity and help bridge the gap between chemical structure and carcinogenic activity by descriptors that are related to biological targets.

Lone mothers are at higher risk for cardiovascular disease compared with partnered mothers. Data from the National Health and Nutrition Examination Survey III (NHANES III).

Lone mothers are a disadvantaged population, with research in several countries indicating that they experience low levels of physical and mental health. While research has demonstrated a socioeconomic gradient for cardiovascular disease (CVD), little research has explored lifestyle and clinical risk for CVD and prevalence of CVD events in lone mothers. The purpose of this study is (1) to compare select CVD lifestyle risks (smoking, obesity, physical activity), health, and relevant sociodemographic variables in partnered versus lone mothers; (2) to examine the relationship between partner status and having experienced a CVD event (myocardial infarction [MI], congestive heart failure [CHF], stroke). Data from the U.S. National Health and Nutrition Examination Survey III (NHANES III) included 1,446 women over 60 years with one or more children less than 17 years old. Lone mothers included women who were widowed, divorced, separated, never married, or married without the spouse living in the household (n = 623; weighted sample represents n = 3,904,450). Partnered mothers included women who reported living as married or married with the spouse in the household (n = 832; weighted sample represents n = 8,614,362). Weighted logistic regression was used to compare the prevalence of CVD risk factors in lone (43%) ver sus partnered (57%) mothers. Multivariate modeling was used to examine the relationship between partner status, CVD risks, and Coronary Heart Disease (CHD) events. Compared with partnered mothers, lone mothers were less educated and reported lower levels of income, health, and social support; and they were more likely to report non-White ethnicity. Lone mothers were more likely to be current smokers, overweight or obese, and physically active than partnered mothers. Those with clinical risks for CVD, including diabetes, elevated C-reactive protein, hypercholesterolemia, or hypertension, or all of these were more likely to be lone mothers. After adjusting for age, we found that mothers who had experienced a CVD event (MI, CHF, or stroke) were 3.3 times more likely to be a lone mother than a partnered mother (95% confidence interval (CI) 3.24, 3.31). Lone mothers are at increased risk for CVD. Health professionals and lone mothers should collaborate in the development of programs and policies not only to reduce lone mothers' risk for CVD, but also improve their conditions of living.

Development of an information-intensive structure-activity relationship model and its application to human respiratory chemical sensitizers.

Structure-activity relationship (SAR) models are recognized as powerful tools to predict the toxicologic potential of new or untested chemicals and also provide insight into possible mechanisms of toxicity. Models have been based on physicochemical attributes and structural features of chemicals. We describe herein the development of a new SAR modeling algorithm called cat-SAR that is capable of analyzing and predicting chemical activity from divergent biological response data. The cat-SAR program develops chemical fragment-based SAR models from categorical biological response data (e.g. toxicologically active and inactive compounds). The database selected for model development was a published set of chemicals documented to cause respiratory hypersensitivity in humans. Two models were generated that differed only in that one model included explicate hydrogen containing fragments. The predictive abilities of the models were tested using leave-one-out cross-validation tests. One model had a sensitivity of 0.94 and specificity of 0.87 yielding an overall correct prediction of 91%. The second model had a sensitivity of 0.89, specificity of 0.95 and overall correct prediction of 92%. The demonstrated predictive capabilities of the cat-SAR approach, together with its modeling flexibility and design transparency, suggest the potential for its widespread applicability to toxicity prediction and for deriving mechanistic insight into toxicologic effects.

Wave-energy patterns in carotid, brachial, and radial arteries: a noninvasive approach using wave-intensity analysis.

The study of wave propagation at different points in the arterial circulation may provide useful information regarding ventriculoarterial interactions. We describe a number of hemodynamic parameters in the carotid, brachial, and radial arteries of normal subjects by using noninvasive techniques and wave-intensity analysis (WIA). Twenty-one normal adult subjects (14 men and 7 women, mean age 44 +/- 6 yr) underwent applanation tonometry and pulsed-wave Doppler studies of the right common carotid, brachial, and radial arteries. After ensemble averaging of the pressure and flow-velocity data, local hydraulic work was determined and a pressure-flow velocity loop was used to determine local wave speed. WIA was then applied to determine the magnitude, timings, and energies of individual waves. At all sites, forward-traveling (S) and backward-traveling (R) compression waves were observed in early systole. In mid- and late systole, forward-traveling expansion waves (X and D) were also seen. Wave speed was significantly higher in the brachial (6.97 +/- 0.58 m/s) and radial (6.78 +/- 0.62 m/s) arteries compared with the carotid artery (5.40 +/- 0.34 m/s; P < 0.05). S-wave energy was greatest in the brachial artery (993.5 +/- 87.8 mJ/m2), but R-wave energy was greatest in the radial artery (176.9 +/- 19.9 mJ/m2). X-wave energy was significantly higher in the brachial and radial arteries (176.4 +/- 32.7 and 163.2 +/- 30.5 mJ/m2, respectively) compared with the carotid artery (41.0 +/- 9.4 mJ/m2; P < 0.001). WIA illustrates important differences in wave patterns between peripheral arteries and may provide a method for understanding ventriculo-arterial interactions in the time domain.

Structure-activity approach to the identification of environmental estrogens: the MCASE approach.

A sizable number of environmental contaminants and natural products have been found to possess hormonal activity and have been termed endocrine-disrupting chemicals. Due to the vast number (estimated at about 58,000) of environmental contaminants, their potential to adversely affect the endocrine system, and the paucity of health effects data associated with them, the U.S. Congress was led to mandate testing of these compounds for endocrine-disrupting ability. Here we provide evidence that a computational structure-activity relationship (SAR) approach has the potential to rapidly and cost effectively screen and prioritize these compounds for further testing. Our models were based on data for 122 compounds assayed for estrogenicity in the ESCREEN assay. We produced two models, one for relative proliferative effect (RPE) and one for relative proliferative potency (RPP) for chemicals as compared to the effects and potency of 17beta-estradiol. The RPE and RPP models achieved an 88 and 72% accurate prediction rate, respectively, for compounds not in the learning sets. The good predictive ability of these models and their basis on simple to understand 2-D molecular fragments indicates their potential usefulness in computational screening methods for environmental estrogens.

The MODEL project: a scoring system to manage demand for cataract and joint replacement surgery.

Cataract surgery and joint replacement are highly cost-effective procedures; however, their availability is inequitable and doctors lack guidance on whom to refer and treat. We investigated the feasibility of using a scoring system to assess patients' suitability for operation. Wefound acceptable correlations between the scores ofgeneral practitioners and surgeons for both procedures. Scoring systems can be used in a consistent way bygeneralpractitioners and surgeons, and can make a contribution towards matching patients' needs with available treatment capacity.

University of Washington and partners' program to teach middle school students about neuroscience and science careers.

The Making Connections, Making Choices program is a multidisciplinary, neuroscience-focused project aimed at middle-school students and teachers primarily throughout Washington State and also across the country. The three components--the Summer Institute (for teacher training), the Brain Power Van (to visit schools and provide neuroscience education), and the speakers' bureau (to train clinicians and researchers to provide effective class-room and public talks and to schedule engagements)--work together to foster enriching, interactive science education experiences for students and teachers. The program has been funded by the National Center for Research Resources at the National Institutes of Health since 1991. Each year the aspect of it described in this article reaches 30-35 schools, with a total of more than 1,000 students and 80 teachers, plus another 30-40 teachers each summer. The program seeks to (1) enhance middle-school students' science knowledge, (2) help science teachers improve their science knowledge and teaching, (3) increase understanding and appreciation of biomedical research, (4) increase understanding of why animals are used in research, and (5) promote students' interest in science careers, especially the interest of students from groups underrepresented in science. Periodic evaluations showed that students exposed to the program scored higher on tests of neuroscience knowledge and had more interest in health science careers than did control groups of non-exposed students. The authors argue an important aspect of the program is that it has a broad focus and is multidisciplinary.

Stages of exercise behavior change at two time periods following coronary artery bypass graft surgery.

A sedentary lifestyle is the most prevalent coronary heart disease risk factor in the United States. It is a challenge for healthcare providers to promote the adoption and maintenance of regular exercise as a lifestyle change in sedentary individuals. For this effort to be effective, research on exercise behavior and the processes that promote the desired behavior is needed. Using the Transtheoretical Model of Change (TMC), this study was aimed at describing and comparing short- and long-term regular exercise behavior and the change processes used in the different stages, with subjects after coronary artery bypass graft (CABG) surgery. Questionnaires were sent to 253 patients aged 60 years and older at 4 to 6 months and 22 to 26 months after CABG surgery. The study findings indicate that 67% of the subjects had become long-term regular exercisers. However, there were more subjects who had begun exercise shortly after the surgery than at the 2-year point. The data suggest that health promotion efforts may be more cost-effective and efficient if focused on educating the smaller percentage of post-CABG surgery patients in the pre-regular-exercise stages. In addition, relapse prevention may be needed to maintain exercise adherence. This study also demonstrates that exercise behavior can be easily categorized into stages with the use of four questions. However, an instrument to evaluate the processes of exercise behavior change needs to be developed specifically for the older population.

An electromyographic marker for neuroleptic-induced akathisia: preliminary measures of sensitivity and specificity.

Previous polysomnographic (PSG) investigations have reported a rhythmic electromyographic (EMG) pattern (0.5-3.0 cps) of leg movement activity in a subset of patients with neuroleptic-induced akathisia (NIA). It has been suggested that this EMG pattern may represent a pathophysiological correlate of NIA and thus have clinical utility as an objective marker for this condition. We present preliminary measures of sensitivity and specificity for this EMG pattern as a diagnostic marker for NIA for 26 neuroleptic-treated patients. The EMG marker yielded a diagnostic sensitivity of 68.9% and a specificity of 70.0%, falling just short of statistical significance (Fisher's exact test p = 0.06). Quantitative analysis of the EMG pattern revealed a significant positive correlation between the percentage of time the NIA marker occurred during wakefulness and corresponding chlorpromazine equivalent levels. Clinical demographic findings for true-positive, false-positive, true-negative, and false-negative groups are discussed. Overall findings suggest that this particular pattern of EMG marker activity observed in neuroleptic-treated patients during PSG and EMG studies is valuable in facilitating the diagnosis and monitoring treatment.

Fluoxetine-induced sleep disturbance in depressed patients.

Abnormal polysomnographic (PSG) features, most notably increased electromyographic (EMG) tone and eye movements during non-REM sleep have been observed during sleep in fluoxetine-treated depressed patients. However, the relationship between these PSG features and sleep disruption is unclear. Nine depressed patients treated with 10 to 80 mg of fluoxetine and six unmedicated, depressed patients were studied polysomnographically on two consecutive nights during which sleep parameters, transient arousals, and eye movements were measured. The fluoxetine group experienced a lower-average sleep efficiency index (SEI) and significantly more eye movements and arousals during non-REM sleep than the control group. Eye movement and arousal counts were significantly correlated. In addition, clinically significant periodic limb movement disorder (PLMD) was observed in 44% of the fluoxetine-treated group versus none of the control group. We conclude that a higher incidence of PLMD and frequent transient arousals associated with eye movements may be responsible in part for the complaint of insomnia made by patients treated with fluoxetine.

Effects of passive body heating on the sleep of older female insomniacs.

The purpose of this study was to evaluate passive body heating (PBH) as a treatment for insomnia in older adults. Polysomnographic recordings of older adults routinely show an increase in sleep fragmentation and a substantial decrease in slow-wave sleep (SWS) consistent with complaints of "lighter" more disturbed sleep. An increase in body temperature in young adults early in the evening by way of PBH has been shown to produce an increase in SWS in the early part of the sleep period. In a crossover design, nine female insomniacs (aged 60-72 yr) participated in two consecutive nights of PBH, involving hot (40-40.5 degrees C) and luke-warm (37.5-38.5 degrees C) baths 1.5 hours before bedtime. Significant improvement in sleep continuity and a trend toward an increase in SWS occurred after hot baths. Results of subjective measures showed that subjects experienced significantly "deeper" and more restful sleep after hot baths. In addition, hot baths resulted in a significant delay of temperature nadir in comparison to baseline nights.

Preoperative regional therapy for extremity sarcoma. A tricenter update.

BACKGROUND: Preoperative radiation with sensitizing doxorubicin has been popularized in the treatment of high grade sarcoma of the extremity. A multiinstitutional experience with this protocol that was initiated by the Southeastern Cancer Study Group in 1984 and maintained in three institutions was updated by the authors. METHODS: Patients with biopsied sarcoma had intraarterial infusion with doxorubicin hydrochloride (Adriamycin) 30 mg/24 hrs x 3 days and were allocated by the institution to receive radiation 30-35 Gy in 10 fractions or 46 Gy in 23-25 fractions followed by resection. Surgery was performed within 10 days or 30 days depending on the radiation dose. Postoperative chemotherapy was administered to 31 patients. RESULTS: Of 66 patients, 32 were female and 34 were male. The median age was 46 years (range, 14-77 years); 73% had lower and 27% had upper extremity tumors. There were 55 soft-tissue and 9 malignant bone tumors. Common types were malignant fibrous histiocytoma 20%; liposarcoma, 17%; synovial sarcoma 18%; and 14% were osteosarcoma. American Joint Committee on Cancer stages were: I, IIB (17%), IIIA/B (59%), and IIIC/4A (24%). Limb salvage surgery was performed on 60 patients including radical resection in 21 with extensive tumors, wide local excision in 30, and limited excision in 2 patients. Primary amputation was performed on four patients and delayed amputation in two because of wound complications. Three patients had pulmonary metastasectomy in conjunction with primary surgery (2 are long term survivors > 5 years). There were no postoperative deaths, but wound complications occurred in 41% of the patients. Overall survival and disease free survival at 5 years was 59 and 49%. One patient (1.5%) had local recurrence 9 years after resection of an extensive synovial sarcoma of the shoulder. This was resected with limb salvage techniques. Among 23 patients who failed primarily in the lung, the median survival was 7 months with 4 surviving more than 5 years, after demonstration of the pulmonary metastases. Multivariant analysis of prognostic factors showed that extent of disease and stage correlated with disease free survival, whereas only extent of surgical resection correlated with overall surgical survival. CONCLUSION: Combined therapy for extremity sarcoma in a multicenter setting using preoperative radiation with sensitizing chemotherapy and adequate resection was associated with an excellent local control rate (98.5%) and reasonable long term tumor control, although distant metastases continued to be a major challenge.

Polysomnographic characteristics of neuroleptic-induced akathisia.

To investigate nocturnal leg movement activity and other polysomnographic features in patients with neuroleptic-induced akathisia (NIA), all-night polysomnography was performed in nine patients with NIA and compared with nine healthy individuals and eight unmedicated patients with depression. Patients with NIA displayed a pattern of leg movement activity during sleep similar to healthy individuals and depressed patients. In addition, eight of nine patients with NIA exhibited 10- to 40-second bursts of increased leg muscle tone before sleep onset. Although the significance of this finding is unclear, it is possible that it may be a pathophysiological correlate of NIA.

Outer capsid glycoprotein vp7 is recognized by cross-reactive, rotavirus-specific, cytotoxic T lymphocytes.

Cytotoxic T lymphocytes (CTLs) generated in mice orally inoculated with rotaviruses lyse target cells infected with different rotavirus serotypes (cross-reactive CTLs). Using vaccinia virus recombinants expressing individual rotavirus proteins from two different rotavirus serotypes, we found that cross-reactive CTLs recognize target cells expressing outer capsid protein vp7 better than those expressing outer capsid protein vp4 or inner capsid protein vp6. These findings may be relevant to vaccine strategies which include immunization with reassortant rotaviruses or viral or bacterial vectors expressing individual rotavirus proteins. The region or regions of vp7 which are antigenically conserved among different rotavirus serotypes and recognized by cross-reactive CTLs remain to be determined.

Memory and distribution of virus-specific cytotoxic T lymphocytes (CTLs) and CTL precursors after rotavirus infection.

The gastrointestinal tract is constantly exposed to a variety of potentially invasive bacteria, viruses, and parasites. The first line of defense against these pathogens is the intestinal mucosal surface, which consists of epithelial cells, intraepithelial lymphocytes (IELs), mucus, and secretory immunoglobulins. In addition, the intestine is a rich source of lymphocytes located within Peyer's patches and the lamina propria. Little is known about the function, memory, trafficking, or origin of intestinal T lymphocytes after intestinal infection. We studied the murine cytotoxic T-lymphocyte (CTL) response to the intestinal pathogen rotavirus (simian strain RRV). Adult mice were inoculated orally or via the hind footpad with RRV; virus-specific cytotoxic activities in intestinal and nonintestinal lymphocyte populations were determined by 51Cr release assays. In addition, virus-specific CTL precursor (CTLp) frequencies were determined by limiting-dilution analysis. IELs containing rotavirus-specific cytotoxic activity were detected after oral but not footpad inoculation and expressed alpha/beta but not gamma/delta cell surface protein; virus-specific CTLs did not appear to arise from CTLp among IELs. In addition, the site at which RRV was presented to the immune system determined the site at which RRV-specific CTLp first appeared. Frequencies of rotavirus-specific CTLp detected in Peyer's patches were 25- to 30-fold greater after oral than after footpad inoculation. However, regardless of the route of inoculation, rotavirus-specific CTLp were distributed throughout the lymphoid system 21 days after infection. Implications of these findings for vaccine design are discussed.

EEG sleep in adolescents with major depression: the role of suicidality and inpatient status.

All night sleep EEG recordings were performed for three consecutive nights in 27 adolescents with a diagnosis of major depressive disorder (MDD) and 30 normal adolescent controls. Group comparisons between the entire MDD group and the normal controls revealed no significant diagnostic group differences for any of the major sleep variables. Analyses within subgroups of MDD adolescents, however, revealed heterogeneity of EEG sleep findings in association with suicidality and inpatient status. The findings of this study suggest that the discrepancies among the EEG sleep studies in adolescent MDD may be accounted for by the relative proportions of inpatients, suicidality, or bipolarity within the MDD sample being studied.