Cancer cell-selective induction of mitochondrial stress and immunogenic cell death by PT-112 in human prostate cell lines.

PT-112 is a novel immunogenic cell death (ICD)-inducing small molecule currently under Phase 2 clinical development, including in metastatic castration-resistant prostate cancer (mCRPC), an immunologically cold and heterogeneous disease state in need of novel therapeutic approaches. PT-112 has been shown to cause ribosome biogenesis inhibition and organelle stress followed by ICD in cancer cells, culminating in anticancer immunity. In addition, clinical evidence of PT-112-driven immune effects has been observed in patient immunoprofiling. Given the unmet need for immune-based therapies in prostate cancer, along with a Phase I study (NCT#02266745) showing PT-112 activity in mCRPC patients, we investigated PT-112 effects in a panel of human prostate cancer cell lines. PT-112 demonstrated cancer cell selectivity, inhibiting cell growth and leading to cell death in prostate cancer cells without affecting the non-tumorigenic epithelial prostate cell line RWPE-1 at the concentrations tested. PT-112 also caused caspase-3 activation, as well as stress features in mitochondria including ROS generation, compromised membrane integrity, altered respiration, and morphological changes. Moreover, PT-112 induced damage-associated molecular pattern (DAMP) release, the first demonstration of ICD in human cancer cell lines, in addition to autophagy initiation across the panel. Taken together, PT-112 caused selective stress, growth inhibition and death in human prostate cancer cell lines. Our data provide additional insight into mitochondrial stress and ICD in response to PT-112. PT-112 anticancer immunogenicity could have clinical applications and is currently under investigation in a Phase 2 mCRPC study.

Rise and fall of sea ice production in the Arctic Ocean's ice factories.

The volume, extent and age of Arctic sea ice is in decline, yet winter sea ice production appears to have been increasing, despite Arctic warming being most intense during winter. Previous work suggests that further warming will at some point lead to a decline in ice production, however a consistent explanation of both rise and fall is hitherto missing. Here, we investigate these driving factors through a simple linear model for ice production. We focus on the Kara and Laptev seas-sometimes referred to as Arctic "ice factories" for their outsized role in ice production, and train the model on internal variability across the Community Earth System Model's Large Ensemble (CESM-LE). The linear model is highly skilful at explaining internal variability and can also explain the forced rise-then-fall of ice production, providing insight into the competing drivers of change. We apply our linear model to the same climate variables from observation-based data; the resulting estimate of ice production over recent decades suggests that, just as in CESM-LE, we are currently passing the peak of ice production in the Kara and Laptev seas.

A sea change in our view of overturning in the subpolar North Atlantic.

To provide an observational basis for the Intergovernmental Panel on Climate Change projections of a slowing Atlantic meridional overturning circulation (MOC) in the 21st century, the Overturning in the Subpolar North Atlantic Program (OSNAP) observing system was launched in the summer of 2014. The first 21-month record reveals a highly variable overturning circulation responsible for the majority of the heat and freshwater transport across the OSNAP line. In a departure from the prevailing view that changes in deep water formation in the Labrador Sea dominate MOC variability, these results suggest that the conversion of warm, salty, shallow Atlantic waters into colder, fresher, deep waters that move southward in the Irminger and Iceland basins is largely responsible for overturning and its variability in the subpolar basin.

Patterns of soft drink consumption and primary tooth extractions in Queensland children.

BACKGROUND: The authors examined the association of patterns of soft drink consumption and primary tooth extractions in Queensland children aged 12 years or less. METHODS: Data were gathered through the Child Health Surveys conducted by Queensland Health in 2003 and 2008. The analysis allowed for various demographic characteristics using logistic regression analysis. RESULTS: The data in both surveys showed an increased risk of tooth extraction in children who had a greater frequency and amount of soft drink consumption, and those that consumed soft drink between meals. In 2008, the percentage of children that had soft drink daily or several times a week had decreased, with an increase in those that never had soft drink. CONCLUSIONS: To reduce the risk of primary tooth extraction due to decay, this paper recommends the continuing moderation of soft drink consumption frequency and the consumption of soft drinks with, rather than between, meals.

Risk of Chlamydia trachomatis infection during pregnancy: effectiveness of guidelines-based screening in identifying cases.

Our goal was to define the risk factors for Chlamydia trachomatis (CT) infection among pregnant women at a large urban medical centre. In a retrospective study, clinical records at a US maternity unit from July 2005 through February 2008 were reviewed. The study population included all pregnant women with a singleton newborn of at least 20 weeks gestation and antenatal care information. Logistic regression was used to analyse the association between a positive CT test and demographic, behavioural and prenatal care variables. A total of 2127 women were included in this analysis. The prevalence of CT infection was 4.7%. Cases were more likely to be younger, black and single. Other risk factors included tobacco use and Neisseria gonorrhoeae infection. Our findings suggest that factors other than age may impact upon the diagnosis of CT in pregnant women and that a more comprehensive testing strategy should be considered.

Chlamydia trachomatis infection during pregnancy and the risk of preterm birth: a case-control study.

Our goal was to define the risks of preterm birth associated with Chlamydia trachomatis (CT) and other sexually transmitted infections (STIs) among pregnant women. We accessed clinical records from July 2005 to February 2008. The study population included all pregnant women who gave birth to a singleton newborn of at least 20 weeks' gestation, and who had antenatal care information. We estimated the impact of CT and other STI on the odds of preterm birth using logistic regression. Overall, 2127 women were included in this analysis. The prevalence of CT infection was 4.7%. CT diagnosis was not associated with preterm birth. In conclusion, this study did not find an association between CT and preterm birth. The lack of an association may be explained by early treatment. Future studies evaluating the timing of screening for STIs may help clarify whether pregnant women would benefit more from earlier screening.

An ecological approach to development in children with prenatal drug exposure.

Knowledge about the effects of prenatal drug exposure on early development is reviewed within an ecological framework. The intersecting influences on maternal and child behavior in the early caregiving environment are considered, and similarities reported for drug-exposed children and other high-risk groups are noted. Data from a sample of 90 dyads are used to explore the impact of maternal stress, social support, and depression on children's behavior problems. Strategies for enhancing developmental outcomes in this population are discussed.

Cultural and familial influences that maintain the negative meaning of alcohol.

OBJECTIVE: The purpose of this overview is to highlight the ways that cultural and familial factors may buffer children and adolescents from initiating alcohol use. METHOD: This article uses the findings from studies of black and Hispanic adolescent and adult alcohol use to identify potentially important cultural and familial variables that buffer these groups from early alcohol use and misuse, abuse or dependence. RESULTS: We begin with the notion that negative beliefs regarding alcohol and its effects protect young children from early alcohol involvement. We then consider how, for blacks and Hispanics, family structure, parent-child interaction patterns and value orientations function to maintain these negative belief schemas, thereby protecting children and adolescents from involvement with alcohol. CONCLUSIONS: We conclude by emphasizing the importance of studying "nonmainstream" groups who are more likely to abstain from alcohol use. In doing this, research can more easily identify those family practices that produce the negative beliefs about alcohol consumption and thereby prevent early experimentation and adolescent alcohol abuse.

Applications of acute phase reactants in infectious diseases.

The elevation of acute phase reactants (APRs) is a nonspecific host response to infection, inflammation, and tissue injury. The major biologic function of APRs is to restore homeostasis and to improve survival. Measuring the alterations in APRs can be a useful clinical marker when an infection or inflammatory response is suspected. Serum levels of reactants like fibrinogen and complement proteins increase as part of the inflammatory response, but the increase is trivial and does not contribute to the differential diagnosis or the evaluation of therapeutic responsiveness. By contrast, C-reactive protein (CRP) concentrations increase markedly with acute invasive infections which parallel the severity of inflammation or tissue injury. This advantage makes CRP a useful marker for the presence of disease, response to therapy, and ultimate recovery.

Possible precursors of gender drinking differences.

This study explored the responses of sixth graders to a recently developed alcohol expectancy scale and a drinking attitude question. While factor analyses yielded the same "positive" and "negative" factors previously identified in scale construction, no significant gender differences were observed on scale items or factors. However, sixth grade males responded more favorably than their female counterparts to the general attitude item regarding alcohol consumption. Results also revealed that while male attitudes were related significantly to whether they reported observing adult intoxication in the home, female attitudes were not. Results are discussed in terms of their implication for the origins of initial male-female drinking behavior differences.

Intrauterine cocaine and crack exposure: neonatal outcome.

OBJECTIVE: Adverse health effects are associated with intrauterine cocaine exposure. The purpose of this study was to investigate the impact of fetal cocaine and crack exposure on neonatal outcome. STUDY DESIGN: We enrolled 386 mother-infant pairs, including 130 matched control pairs, in the study. The course of pregnancy and delivery was followed and neonatal outcome was assessed by physical and neurologic examination, as well as by the Brazelton Neonatal Behavioral Assessment Scale and the Neonatal Stress Scale. RESULTS: The cocaine-exposed neonates had significantly more adverse effects than the matched control infants. Birth weight, length, and head circumference were significantly lower in the cocaine- and crack-exposed infants (p < or = 0.001). There were significantly more premature infants (p < or = 0.007) in this group. They demonstrated significant abnormalities on the neurologic examination (p < or = 0.001), inferior performance on the Brazelton Neonatal Behavioral Assessment Scale (p < or = 0.001), and higher scores on the Neonatal Stress Scale (p < or = 0.001). Predictors of negative neonatal outcome were maternal age (p < or = 0.02), poor paternal relationship with the mother (p < or = 0.002), crack use (p < or = 0.004), cocaine use (p < or = 0.009), and marijuana use (p < or = 0.05). CONCLUSION: The single most important predictor of neonatal outcome is the frequency, quantity, and type of cocaine used.

Cognitive function, iron status, and hemoglobin concentration in obese dieting women.

OBJECTIVE: To determine the relationships between cognitive function and iron status in dieting obese women. DESIGN: Longitudinal weight loss study (repeated measures within-subject design) with 3 weeks of baseline, 15 weeks of 50% caloric restriction, and 3 weeks of weight stabilization. Dietary iron was fed at twice the US Recommended Dietary Allowance with half of the iron from food sources and half from an oral supplement. SETTING: This was a free-living study with the exception that subjects came to the research center for one meal per day and were provided all other meals and snacks to take home. SUBJECTS: Healthy, premenopausal, obese women (mean BMI=31.5) were recruited through local newspaper, poster and radio advertising. Twenty-four women volunteers were recruited and 14 completed the study. MEASUREMENTS: Cognitive function, iron and hematological status, height, body weights and body composition were measured at baseline; at weeks 5, 10, and 15 of the energy restriction period; and at the end of weight stabilization. Computerized cognitive tests included: Bakan vigilance task, two finger tapping, simple reaction time, immediate word recall, and a focused attention task. Iron status and hematological measures included: serum iron, total iron binding capacity (TIBC), transferrin saturation, serum ferritin, hemoglobin (Hb), hematocrit, red cell count, MCV, MCH, MCHC, and RDW. RESULTS: A significant reduction in Hb, hematocrit, and red blood cell count occurred across the study. Hb at the end of the study was positively correlated (r=0.72, P < 0.01) with mean performance on a measure of sustained attention. Transferrin saturation also correlated positively to sustained attention task performance for those subjects whose Hb declined across the study (r=0.86, P < 0.01). CONCLUSIONS: These findings suggest that dieting diminishes iron status in obese women, even when sufficient dietary iron is available, and that the inability to sustain attention may be an early sign of developing iron deficiency in dieting women.

Effect of weight loss on bone mineral content and bone mineral density in obese women.

Studies of body-composition changes during weight loss have had conflicting results with regard to changes in bone mineral content (BMC) and bone mineral density (BMD). We examined BMC and BMD for changes during weight loss. Fourteen women enrolled in a 15-wk weight loss program. Dual-energy X-ray absorptiometry (DXA) measures of the total body were made at baseline (T1), the midpoint of weight loss (T2), and at the end of weight loss (T3). Body weight changed significantly throughout the 15 wk, declining from a high of 89.7+/-3.6 to 74.1+/-3.2 kg. Fat-free mass declined initially (47.8+/-1.7 kg at T1, 45.7+/-1.4 kg at T2, and 46.0+/-1.5 kg at T3) and then stabilized. Fat mass changed significantly during the study (39.2 kg at T1, 32.4 kg at T2, and 29.3 kg at T3). No significant differences were observed in BMC or bone areal measurement during the study. However, BMD declined significantly from baseline (1.217 g/cm2 at T1, 1.197 g/cm2 at T2, and 1.200 g/cm2 at T3). The changes in BMC and BA were in opposite directions, resulting in a significant decline in BMD without a loss of BMC. These data suggest that changes in BMD observed with weight loss may be the result of a lack of instrument sensitivity when body weight and composition change and are simply an artifact and not a physiologic change in BMD. Further research is needed to determine the full effect of weight loss on BMC, bone area, and BMD.

Cognitive effects of a long-term weight reducing diet.

OBJECTIVE: To investigate if long-term caloric restriction under controlled conditions adversely affects cognitive function in obese women. SUBJECTS: Healthy, premenopausal women between 23-42 y. Dieting group: n = 14. CONTROL GROUP: n = 11. DESIGN: Longitudinal weight loss study (repeated measures within-subject design) with 3 weeks of baseline, 15 weeks of 50% caloric restriction, and 3 weeks of weight stabilization. MEASUREMENTS: Computerized cognitive function tests (sustained attention, short-term memory, simple reaction time, motor performance and attentional focus), height, body weight, body composition (TOBEC) and behavioral questionnaires (Dutch Eating Behaviour Questionnaire, Eating Attitudes Test, and State-Trait Anxiety Inventory). RESULTS: Dieting women lost 12.3 +/- 5.5 kg (mean +/- s.d.) of body weight. Controlled long-term caloric restriction significantly slowed simple reaction time but did not diminish sustained attention, motor performance or immediate memory. Word recall performance significantly improved by 24% at the end of caloric restriction. CONCLUSIONS: The slowing of simple reaction time is a short-term and long-term consequence of caloric restriction. In contrast to previous short-term dieting studies, sustained attention and immediate memory were not impaired with long-term caloric restriction.

Vitamin B-6 requirement and status assessment: young women fed a depletion diet followed by a plant- or animal-protein diet with graded amounts of vitamin B-6.

The vitamin B-6 requirement of young women consuming a high-protein diet (1.55 g/kg body wt) and the effect of protein quality on this requirement was studied. In addition, the response of clinical, functional, and biochemical measures of vitamin B-6 nutriture to short-term depletion and step-wise repletion of vitamin B-6 were evaluated. Eight healthy young women resided in a metabolic unit and were fed a formula depletion diet (< 0.05 mg vitamin B-6/d) for 11-28 d followed by either an animal-protein (AP) or plant-protein (PP) diet with successively increasing vitamin B-6 intakes (0.5, 1.0, 1.5, and 2.0 mg/d) for periods of 14-21 d. Animal proteins were primarily from dairy and poultry sources and plant proteins were primarily from legumes. Vitamin B-6 status measures were assessed at weekly intervals. Results showed that a PP diet does not elevate the vitamin B-6 requirement over that required for an AP diet given the high amount of dietary protein used in this study. It was also found that 0.015 mg vitamin B-6/g protein intake normalized most biochemical indexes of vitamin B-6 status (including those indicative of functional status), and that 0.020 mg/g protein normalized all biochemical measures except total urinary vitamin B-6. Adding a margin of safety to either the 0.015 or 0.020 mg/g protein intake would raise the vitamin B-6 requirement for young women above the currently recommended dietary allowance of 0.016 mg/g protein.

Energy restriction decreases number of circulating natural killer cells and serum levels of immunoglobulins in overweight women.

We examined the effects of energy restriction on immune response and also compared the effects of low fat (LF, 18.6 E%) and high fat (HF, 40.7 E%) diets during energy restriction on immunological parameters. Ten overweight women were fed the HF diet for 42 days (P1) to maintain their body weights. For the next 84 days (P2), the energy intake was reduced to 50% of the intake during P1 for all the women, five of them were fed the HF diet and the other five the LF diet. For the last 35 days of the study (P3), subjects remained on their respective diets, but the energy intake was increased to maintain BW to the level reached at the end of energy restriction. Serum concentrations of IgG, IgA, IgM, C3 and C4, numbers of lymphocytes and their subsets, blastogenesis of peripheral blood mononuclear cells cultured with phytohemagglutinin, concanavalin A and protein A were determined several times during the study. Delayed hypersensitivity skin (DHS) response to seven recall antigens was determined towards the end of each study period. None of the parameters studied were different between the HF and LF dietary groups. During energy restriction the subjects lost an average of 7 kg in the LF group and 9 kg in the HF group. Energy restriction caused a significant (P < 0.005) decrease in the serum concentration of IgG, IgA, C3, and the number of circulating natural killer (NK) cells. An increase in energy intake during P3 reversed some of the decreases caused by energy restriction, but the levels did not return to pre-restriction levels during these 35 days of refeeding adequate dietary energy. The numbers of circulating lymphocytes and their subsets with the exception of NK cells, serum levels of IgM and C4, and the DHS response monitored 48 h after the application of antigens were not affected by energy restriction. Health status of the women in our study did not seem to be compromised; however, it could be compromised under more drastic restrictions or with moderate restrictions in high risk subjects.

Predicting total body water and extracellular fluid volumes from bioelectrical measurements of the human body.

Two biological impedance analyzers, a 50 kHz (RJL) and 20-100 kHz (BMA) instrument, and a total body electrical conductivity (TOBEC) instrument were used to estimate total body water (TBW), extracellular (ECF) and intracellular (ICF) fluid volumes by repeated measurements of 16 normal men (19-38 years old) to assess which, if any, would provide the best estimates. At 3-week intervals, TBW was determined by deuterium dilution, ECF by bromide dilution, ICF by difference (TBW-ECF) and lean body mass by density. Prediction equations were obtained by regression; predicted values for the body fluid volumes were calculated and the results were statistically evaluated. Both the TOBEC and the BMA provided rapid and reliable estimates for body fluid volumes with standard errors of the estimates of about 0.5-1.1 L for ECF, 1.0-1.8 L for TBW, and 1.0-1.3 L for ICF. Part of the error was attributable to standard tracer-dilution methods.

Brief communication: changes in thermogenesis and caloric efficiency with high and normal protein-reducing diets in women.

A pilot study with four women (40-60% above ideal weight, 32-42 years old) was conducted for 6 weeks of weight maintenance, 12 weeks at 50% calories (1000 and 1200 kcal/day) and 6 weeks of weight maintenance after weight loss. Two women consumed 17% and two 32% of their calories from protein during restriction; their energy metabolism and body composition changes were examined. The use of doubly labeled water for measuring energy expenditure during weight loss was evaluated. Although the 32% protein diet did not reduce lean body tissue loss, the apparent increased efficiency of calorie utilization compared to the 17% protein diet is worthy of further investigation. Thermic effect of a meal was greatly reduced in these women compared to previously reported responses. Further refinements of the doubly labeled water method are needed prior to application in weight loss studies.

Psychiatric mental health consultation and nursing in the United Arab Emirates.

1. Our "mission" was preparing psychiatric services for the anticipated high number of allied casualties; providing clinical, educational, and developmental support to the host nation; and maintaining diplomatic relations within the hospital and surrounding community. 2. Because of cultural differences, the hospital staff were uneasy about some of the inservice classes. US staff were taught the importance of refusing to succumb to "the illusion of color blindness." 3. With the support of the host, we took leadership in receiving and training the casualties of the war. Psychiatric services were provided to allied troops as well as the citizens of Dubai.

Resilient children: individual differences in developmental outcome of children born to drug abusers.

Since 1977, we have been following the neurobehavioral development of two groups of children: a group born to women on methadone maintenance and a drug-free comparison group. This study used the data on the children evaluated at 36 months of age to determine whether distinct patterns of developmental outcome can be identified, and which medical, familial, or environmental characteristics are associated with developmental differences. The children were clustered on four measures at 36 months: head circumference percentile, Merrill-Palmer Scale score, neurological evaluation, and referrals for developmental problems. Three distinct clusters emerged, with methadone children disproportionately frequent in Cluster 3, the group showing the poorest development. Comparisons of the clusters on a wide range of variables revealed consistent differences between Cluster 1 and Cluster 3 children in maternal responsiveness and incidence of neglect and family violence. These findings indicate that distinct developmental patterns do occur within this predominantly lower-class ghetto population; further, that children born to methadone-maintained women are more likely to show poor development. However, when the environment provides nurturance and stability, methadone children can show resilience and develop well.