The association between driving time and unhealthy lifestyles: a cross-sectional, general population study of 386 493 UK Biobank participants.

BACKGROUND: Driving is a common type of sedentary behaviour; an independent risk factor for poor health. The study explores whether driving is also associated with other unhealthy lifestyle factors. METHODS: In a cross-sectional study of UK Biobank participants, driving time was treated as an ordinal variable and other lifestyle factors dichotomized into low/high risk based on guidelines. The associations were explored using chi-square tests for trend and binary logistic regression. RESULTS: Of the 386 493 participants who drove, 153 717 (39.8%) drove <1 h/day; 140 140 (36.3%) 1 h/day; 60 973 (15.8%) 2 h/day; and 31 663 (8.2%) ≥3 h/day. Following adjustment for potential confounders, driving ≥3 h/day was associated with being overweight/obese (OR = 1.74, 95% CI: 1.64-1.85), smoking (OR = 1.48, 95% CI: 1.37-1.63), insufficient sleep (1.70, 95% CI: 1.61-1.80), low fruit/vegetable intake (OR = 1.26, 95% CI: 1.18-1.35) and low physical activity (OR = 1.05, 95% CI: 1.00-1.11), with dose relationships for the first three, but was not associated with higher alcohol consumption (OR = 0.94, 95% CI: 0.87-1.02). CONCLUSIONS: Sedentary behaviour, such as driving, is known to have an independent association with adverse health outcomes. It may have additional impact mediated through its effect on other aspects of lifestyle. People with long driving times are at higher risk and might benefit from targeted interventions.

Motion-guided attention promotes adaptive communications during social navigation.

Animals are capable of enhanced decision making through cooperation, whereby accurate decisions can occur quickly through decentralized consensus. These interactions often depend upon reliable social cues, which can result in highly coordinated activities in uncertain environments. Yet information within a crowd may be lost in translation, generating confusion and enhancing individual risk. As quantitative data detailing animal social interactions accumulate, the mechanisms enabling individuals to rapidly and accurately process competing social cues remain unresolved. Here, we model how motion-guided attention influences the exchange of visual information during social navigation. We also compare the performance of this mechanism to the hypothesis that robust social coordination requires individuals to numerically limit their attention to a set of n-nearest neighbours. While we find that such numerically limited attention does not generate robust social navigation across ecological contexts, several notable qualities arise from selective attention to motion cues. First, individuals can instantly become a local information hub when startled into action, without requiring changes in neighbour attention level. Second, individuals can circumvent speed-accuracy trade-offs by tuning their motion thresholds. In turn, these properties enable groups to collectively dampen or amplify social information. Lastly, the minority required to sway a group's short-term directional decisions can change substantially with social context. Our findings suggest that motion-guided attention is a fundamental and efficient mechanism underlying collaborative decision making during social navigation.

Alternatively spliced mdm2 transcripts with loss of p53 binding domain sequences: transforming ability and frequent detection in human cancer.

The mdm2 oncogene encodes a 90-kilodalton nuclear phosphoprotein that binds and inactivates the p53 tumor suppressor protein. Here we report the observation of five alternatively spliced mdm2 gene transcripts in a range of human cancers and their absence in normal tissues. Transfection of NIH 3T3 cells with each of these forms gave foci of morphologically transformed cells. A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding, consistent with partial deletion of sequences encoding the p53 binding domain, but retain carboxyterminal zinc-finger domains. These observations suggest a reassessment of the transforming mechanisms of mdm2 and its relation to p53.

Parathyroid hormone effects in rats treated with diphosphonate.

The ability of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP; 40 milligrams per kilogram of body weight per day) to reduce the hypercalcemic effect of parathyroid hormone in thyroparathyroidectomized rats was confirmed. However, treatment with this large dose of EHDP enhanced the hypophosphatemic effect of a low dose of parathyroid hormone (10 international units per100 grams of body weight), apparently by promoting the renal excretion of phosphate. The data suggest that EHDP may have a direct effect on the renal action of parathyroid hormone and, in this way, may also affect vitamin D metabolism by the kidney.

Collective motion in animal groups from a neurobiological perspective: the adaptive benefits of dynamic sensory loads and selective attention.

We explore mechanisms associated with collective animal motion by drawing on the neurobiological bases of sensory information processing and decision-making. The model uses simplified retinal processes to translate neighbor movement patterns into information through spatial signal integration and threshold responses. The structure provides a mechanism by which individuals can vary their sets of influential neighbors, a measure of an individual's sensory load. Sensory loads are correlated with group order and density, and we discuss their adaptive values in an ecological context. The model also provides a mechanism by which group members can identify, and rapidly respond to, novel visual stimuli.

Studies on the pharmacokinetics and metabolism of a gamma-secretase inhibitor BMS-299897, and exploratory investigation of CYP enzyme induction.

BMS-299897 is a gamma-secretase inhibitor that was effective in reducing amyloid beta-peptide (A beta) in transgenic mice and guinea pigs. Therefore, pharmacokinetic and drug metabolism studies were conducted in animals to support its clinical development. The compound appeared to have low to intermediate total body clearance and was orally bioavailable (24-100%). The oral absorption of BMS-299897 from solid dosage forms appeared to be dissolution rate-limited. BMS-299897 was distributed into extravascular space (V(ss) >or= 1.3 l kg(-1)), including brain (brain-to-plasma ratio = 0.13-0.50). BMS-299897 appeared to be a P-glycoprotein (P-gp) substrate as the brain-to-plasma ratio was two-fold higher in the mdr1a knockout mouse as compared with the wild-type. Apparent autoinduction by BMS-299897 was observed in murine and rat efficacy and toxicity studies. In vitro, BMS-299897 was a weaker inducer of cytochrome P450 3A4 (CYP3A4) and a weaker transactivator of human pregnane X receptor (hPXR) as compared with rifampicin. Induction of human UGT1A and UGT2B was evaluated in primary human hepatocytes, but the results were inconclusive. A low potential for autoinduction in humans was predicted at a clinical dose of 250 mg and the prediction was consistent with the findings from a clinical multiple-dose study with BMS-299897 in probable Alzheimer's patients.

The predictive value of p53 and p33(ING1b) in patients with Dukes'C colorectal cancer.

OBJECTIVE: Identification of biological markers that may predict response to chemotherapy would allow the individualization of treatment by enabling selection of patients most likely to benefit from chemotherapy. The aims of this study were to determine whether p53 mutation status and p53 and p33(ING1b) protein expression can predict which patients with Dukes' C colorectal cancer following curative surgical resection respond to adjuvant chemotherapy with 5-fluorouracil (5-FU). METHOD: Patients with Dukes'C colorectal cancer (n = 41) were studied. DNA was extracted and analysed for p53 mutation using PCR-based direct DNA sequencing. Tumours were analysed for p53 protein expression by immunohistochemistry using DO-7 monoclonal antibody and for p33(ING1b) protein expression using GN1 monoclonal antibody. RESULTS: There was a significant association between p53 mutation status analysed by gene sequencing and overall and metastasis-free survival (P = 0.03 and 0.004, respectively, log-rank test). By contrast, no significant correlation was found between p53 and p33(ING1b) protein expression and overall or metastasis-free survival. CONCLUSION: In patients with Dukes'C colorectal cancer who underwent curative surgical resection of the primary tumour, followed by 5-FU-based adjuvant chemotherapy, p53 mutation status as assessed by gene sequencing is a significant predictor of overall and metastasis-free survival.

Effects of systemic administration of mirtazapine on respiratory muscle activity in sleeping rats.

Mirtazapine (MIRT) is an antidepressant with mixed noradrenergic and serotonergic effects in central nervous system. The present study was undertaken to assess whether MIRT can stimulate genioglossus muscle (GG) activity in the conscious, behaving rat. Nine male rats were chronically instrumented with GG and neck muscle EMG electrodes. EEG electrodes were implanted to acquire sleep stage. Results demonstrated a dose-dependent effect of MIRT on GG activity during sleep, although no changes reached statistical significance. Low dose MIRT (0.1 mg/kg) showed a slight increase in GG phasic activity. In contrast, higher doses of MIRT (0.5-1.0 mg/kg) tended to decrease GG activity relative to vehicle, in addition to decreasing total sleep time.

Exposure to tobacco smoke in utero or during early childhood and risk of hypomania: Prospective birth cohort study.

OBJECTIVES: Using data from a prospective birth cohort, we aimed to test for an association between exposure to tobacco smoke in utero or during early development and the experience of hypomania assessed in young adulthood. METHODS: We used data on 2957 participants from a large birth cohort (Avon longitudinal study of parents and children [ALSPAC]). The primary outcome of interest was hypomania, and the secondary outcome was "hypomania plus previous psychotic experiences (PE)". Maternally-reported smoking during pregnancy, paternal smoking and exposure to environmental tobacco smoke (ETS) in childhood were the exposures of interest. Multivariable logistic regression was used and estimates of association were adjusted for socio-economic, lifestyle and obstetric factors. RESULTS: There was weak evidence of an association between exposure to maternal smoking in utero and lifetime hypomania. However, there was a strong association of maternal smoking during pregnancy within the sub-group of individuals with hypomania who had also experienced psychotic symptoms (OR=3.45; 95% CI: 1.49-7.98; P=0.004). There was no association between paternal smoking, or exposure to ETS during childhood, and hypomania outcomes. CONCLUSIONS: Exposure to smoking in utero may be a risk factor for more severe forms of psychopathology on the mood-psychosis spectrum, rather than DSM-defined bipolar disorder.

Adiposity among 132 479 UK Biobank participants; contribution of sugar intake vs other macronutrients.

Background: Policy makers are being encouraged to specifically target sugar intake in order to combat obesity. We examined the extent to which sugar, relative to other macronutrients, was associated with adiposity. Methods: We used baseline data from UK Biobank to examine the associations between energy intake (total and individual macronutrients) and adiposity [body mass index (BMI), percentage body fat and waist circumference]. Linear regression models were conducted univariately and adjusted for age, sex, ethnicity and physical activity. Results: Among 132 479 participants, 66.3% of men and 51.8% of women were overweight/obese. There was a weak correlation (r = 0.24) between energy from sugar and fat; 13% of those in the highest quintile for sugar were in the lowest for fat, and vice versa. Compared with normal BMI, obese participants had 11.5% higher total energy intake and 14.6%, 13.8%, 9.5% and 4.7% higher intake from fat, protein, starch and sugar, respectively. Hence, the proportion of energy derived from fat was higher (34.3% vs 33.4%, P < 0.001) but from sugar was lower (22.0% vs 23.4%, P < 0.001). BMI was more strongly associated with total energy [coefficient 2.47, 95% confidence interval (CI) 2.36-2.55] and energy from fat (coefficient 1.96, 95% CI 1.91-2.06) than sugar (coefficient 0.48, 95% CI 0.41-0.55). The latter became negative after adjustment for total energy. Conclusions: Fat is the largest contributor to overall energy. The proportion of energy from fat in the diet, but not sugar, is higher among overweight/obese individuals. Focusing public health messages on sugar may mislead on the need to reduce fat and overall energy consumption.

Determination of the prognostic value of cyclin D1 overexpression in breast cancer.

Cyclin D1 plays a critical role in the timing of the initiation of DNA synthesis in the normal cell cycle of mammalian cells. Deregulated expression of this protein has been seen in a variety of tumours either as a result of gene amplification or chromosomal translocation, in breast cancer and B cell malignancies respectively. In order to determine the role this putative oncoprotein plays in breast cancer, we have applied a new monoclonal antibody, recently produced in our laboratory, in an immunohistochemical study of 93 primary breast carcinomas. We show that approximately 28% of the cases displayed enhanced expression of the cyclin D1 protein. Furthermore, either cyclin D1, cyclin D3, or both, were expressed in 69% of cases, suggesting that overexpression of any one member of this family may relieve cancer cells of their mitogenic stimulatory requirement. In addition, we show that those patients whose breast cancers co-express cyclin D1 with either epidermal growth factor receptor (EGFR) or the retinoblastoma protein (pRB) have a significantly poorer prognosis in comparison to those expressing cyclin D1 alone. Our observations indicate that, in a subset of breast cancers, aberrant cyclin D1 expression is a contributory factor to tumorigenesis and in association with EGFR or pRB expression, identify those tumours which may require more aggressive therapy.

A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have well-known gastrointestinal and renal toxic reactions. Effects of NSAIDs on blood pressure are less appreciated. A meta-analysis was performed to determine the hypertensive effects of NSAIDs and rank them by magnitude of change in mean arterial pressure (MAP). METHODS: A literature search of published English-language studies of NSAIDs and their effects on blood pressure was done. Studies were included if they met the following criteria: (1) the studies were intervention studies; (2) NSAIDs at any dose or aspirin at doses of 1.5 g/d or greater were included; (3) documentation of blood pressure was provided; and (4) the studies were 24 hours in duration. Studies were excluded if 20% or more of their participants dropped out or if the dose of antihypertensive drugs was adjusted while the subjects were taking NSAIDs. The major outcome was change in MAP while patients were receiving NSAIDs. Each NSAID arm was extracted from its trial. Information on possible confounders, including subject age, trial quality, amount of dietary salt intake, and whether study subjects were hypertensive or normotensive, was recorded. We calculated the average change in MAP on each NSAID, adjusting for confounders. RESULTS: Fifty-four studies with 123 NSAID treatment arms met inclusion criteria. The mean age of subjects was 46 years. Of the 1324 participants, 1213 subjects (92%) were hypertensive. The effects of NSAIDs on blood pressure were found solely in hypertensive subjects. Among these, the increase in MAP after adjusting for amount of dietary salt intake was 3.59 mm Hg for indomethacin (57 treatment arms), 374 mm Hg for naproxen (four arms), and 0.49 mm Hg for piroxicam (four arms). The MAP decreased by 2.59 mm Hg for placebo (10 arms), 0.83 mm Hg for ibuprofen (six arms), 1.76 mm Hg for aspirin (four arms), and 0.16 mm Hg for sulindac (23 arms). The effects on MAP by using placebo, sulindac, and aspirin were statistically significantly different from indomethacin. CONCLUSIONS: In short-term use, NSAIDs vary considerably in their effect on blood pressure. Of the drugs studied, indomethacin and naproxen were associated with the largest increases in blood pressure. The average effects of piroxicam, aspirin, ibuprofen, and sulindac were negligible.

Effects of weight and body mass index on bone mineral density in men and women: the Framingham study.

We evaluated the association of weight and bone mass in elderly male and female subjects of the Framingham osteoporosis study, a subset of the Framingham study cohort. By examining the differences in the correlations of weight with bone mass among men and women in weight-bearing and non-weight-bearing sites and weight change since early adulthood, we attempted to understand different ways in which weight or body mass index affects bone mass. During biennial examination 20 of the Framingham cohort (1988-1989), 693 women and 439 men (mean age 76 years) had proximal femur bone mineral density assessed by dualphoton absorptiometry (DPA) and radius bone mass assessed by single-photon absorptiometry. The majority of these subjects also had spine measurements by DPA. Subjects had been weighed repeatedly over 40 years. After adjusting for other factors affecting bone density, we found that both recent weight and body mass index explained a substantial proportion of the variance in bone mineral density for all sites in women (8.9-19.8% of total variance, all p < 0.01) and for only weight-bearing sites (femur and spine) in men (2.8-6.9% of total variance, all p < 0.01). For bone mineral density at the proximal radius, weight and body mass index accounted for < 1% of variance in men (p NS). Weight change since biennial examination 1 (1948-1951) was the strongest explanatory factor for bone mineral density among women at all sites, but weight change did not affect radius bone mineral density in men. The effect of weight and of weight change on bone mineral density was in general much less in men than in women. Our results suggest that the strong effect of weight on bone mineral density is due to load on weight-bearing bones sexes. The sex difference is unexplained but may be due to adipose tissue production of estrogen in women after menopause.

Bone mineral density in elderly men and women: results from the Framingham osteoporosis study.

Our study investigated bone mineral density of the proximal femur and ultradistal and proximal radius in a population of elderly men and women. The Framingham study started in 1948, following a population-based sample for evaluation of cardiovascular risk factors and events. During the 20th biennial Framingham examination (1988-89) we conducted the Framingham osteoporosis study, measuring bone mineral density in the proximal femur and distal and proximal radius for 1154 study participants. Ages ranged from 68 to 98 years, with a mean age of 76 years. Bone mineral density was measured using Lunar SP2 and DP3 densitometers. This cross-sectional study evaluates mean bone mineral density measurements at each site by 5 year age intervals for men and women, testing for trends in bone density with age. Analyses were repeated adjusting for weight and height. Among the 446 and 708 women, bone mineral density of the femur and bone mineral content of the proximal radius were inversely and significantly related to age in both sexes and were considerably higher in men than women at all sites. The linear decline with age group in our cross-sectional study remained after multivariate adjustment for height and weight. The ultradistal radius showed no significant correlation with age for either sex. There were significant correlations between the bone measurements made at different sites for both men and women (range in r = 0.27-0.89). Cross-sectional curves of bone mineral density with age showed no significant differences in slope between males and females.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlates of cortical bone mass among premenopausal and postmenopausal Japanese women.

Few studies have examined the multifactorial risk factors of bone mass in Asian populations. This cross-sectional study was designed to explore relationships between bone mass and environmental variables, including dietary and life-style factors, in Japanese women living in Japan. A total of 178 Japanese women completed the study: 89 premenopausal, ages 35-40, and 89 postmenopausal, ages 55-60. Midradial bone mineral content (MBMC) and bone mineral content per unit area, referred to as bone density (MBMD), were measured using single-photon absorptiometry. The major results of this investigation were the following: (1) The postmenopausal women differed significantly from the premenopausal women in having lower radial bone parameters, lower mean height, later age of menarche, and higher dietary intakes of carbohydrates, vegetables, and milk with a lower intake of caffeine. (2) Current protein intake was a positive correlate of MBMC in both groups. (3) Intake of vegetables (leafy green, yellow, orange, and white) and current milk intake were positively associated with MBMC in the postmenopausal women. (4) For the premenopausal women, irregular menstrual cycles was a negative correlate of MBMC, and for the postmenopausal women, years of menopause was negatively associated with MBMC and MBMD. Longitudinal studies are needed to establish more conclusively associations among diet, life-style, and reproductive history and bone mass of Japanese women.

The effects of analytic software and scan analysis technique on the comparison of dual X-ray absorptiometry with dual photon absorptiometry of the hip in the elderly.

As part of a longitudinal comparison of bone mineral density (BMD) results originally obtained using a Lunar dual photon absorptiometry (DPA) scanner and later, using a Lunar dual X-ray absorptiometry (DXA) scanner, we compared femur results between DPA and DXA according to DXA analytic software (versions 1.3y and 1.4), and according to the method of placement of the femoral neck box (software algorithm or operator placement according to the appearance of the pair of images) in 58 elderly men and women. The mean BMD at each of three femoral sites was higher using DXA version 1.3y than DPA, but the use of software version 1.4 brought the BMD value closer to that of DPA at all sites. Of 58 scans, 12 (21%) were changed by the operator, resulting in an overall reduction in mean percent BMD difference between scan pairs of 79% (from 1.24% to 0.29%). Although the differences between the DPA/DXA software-driven analysis and the DPA/DXA operator-driven analysis appeared small (high r2 values and intra-class correlation coefficients), the increase in sample size that would be required for the same power to detect 2-year changes in BMD if the software-driven analysis was used instead of taking the time to perform the operator-driven analysis was 18%. The findings of this study highlight the need to account for upgrades in analytic software. Furthermore, we present a rational approach for the analysis of serial scans that has face validity and that results in smaller differences between pairs of scans performed on the same individual. The decision to adapt these methods must be based on the relative costs of reducing unwanted scan variability.

Identification and characterization of the ribosomal RNA-encoding genes in Clavibacter xyli subsp. cynodontis.

Clavibacter xyli subsp. cynodontis (Cxc) is a xylem-inhabiting bacterial endophyte of Bermudagrass. This organism is classified with Gram-positive, high G + C content, coryneform-actinomycete bacteria. Southern-blot analysis showed that Cxc contains only one copy of the ribosomal RNA-encoding genes (rRNA). A clone containing the rRNA genes was isolated from a genomic library of Cxc DNA cloned in the lambda EMBL3 vector. The gene cluster was partially sequenced, revealing the gene order 5'-16S-23S-5S-3', similar to that found in other prokaryotes. Low-resolution S1 mapping suggested multiple transcription start points of the rRNA operon.

Plant-based diets and bone health: nutritional implications.

Hip fracture incidence rates are predicted to increase dramatically in the first half of the 21st century, especially in Asia, Latin America, Africa, and the Middle East. These increased rates will result primarily from the effects of public health efforts to improve nutrition and infectious-disease control, both of which contribute to improved longevity of populations. An example of a rapid increase in hip fracture incidence rates has been reported in Hong Kong. Findings of studies there suggest that environmental changes, ie, westernization, urbanization, or both, are strongly related with declines in bone mineral density and increases in fractures. Hip fracture incidence rates in Western nations are typically increasing at much more modest rates than those in Hong Kong and other Asian nations. Epidemiologic investigations have identified multiple risk factors, including exposures earlier in life to adverse factors that are considered to contribute to the development of osteoporosis in both Western and Asian nations. The major risk factors are inadequate nutrition, limited physical activity, and low lifetime estrogen exposure. A dietary shift toward a more plant-based diet in Western nations may be beneficial to bone health, but is not likely to counter the adverse effects of limited physical activity and low estrogen exposure.

Dietary factors in bone health of elderly lactoovovegetarian and omnivorous women.

The relationships between dietary factors and radial bone indices of omnivorous (n = 287) and lactoovovegetarian (n = 88) postmenopausal women were investigated. Bone mineral content (BMC) and bone density (BD) were determined at mid and distal radius sites using a Norland single-beam bone densitometer. A quantitative food frequency questionnaire assessed usual current and long-term intakes. Multiple regression analyses showed that 1) vegetarianism was a positive contributor (p less than 0.05) to Mid BMC, 2) protein was a positive contributor (p less than 0.02) to Mid and Distal BMC, 3) phosphorus was a negative contributor (p less than 0.10) to Mid and Distal BMC and Mid BD, and 4) current calcium was not a significant contributor to any of the bone indices after age, body mass index, energy, protein, P, and vegetarianism were accounted for in the models. Estimations of long-term Ca intake and other nutrients are necessary if relationships between diet and bone are to be identified at any age period using cross-sectional epidemiological methods.