Equations for O2 and CO2 solubilities in saline and plasma: combining temperature and density dependences.
Solubilities of respiratory gasses in water, saline, and plasma decrease with rising temperatures and solute concentrations. Henry's Law, C = α·P, states that the equilibrium concentration of a dissolved gas is solubility times partial pressure. Solubilities in the water of a solution depend on temperature and the content of other solutes. Blood temperatures may differ more than 20°C between skin and heart, and an erythrocyte will undergo that range as blood circulates. The concentrations of O2 and CO2 are the driving forces for diffusion, exchanges, and for reactions. We provide an equation for O2 and CO2 solubilities, α, that allows for continuous changes in temperature, T, and solution density, ρ, in dynamically changing states:[Formula: see text]This two-exponential expression with a density scalar γ, and a density exponent β, accounts for solubility changes due to density changes of an aqueous solution. It fits experimental data on solubilities in water, saline, and plasma over temperatures from 20 to 40°C, and for plasma densities, ρsol up to 1.020 g/ml with ~0.3% error. The amounts of additional bound O2 (to Hb) and CO2 (bicarbonate and carbamino) depend on the concentrations in the local water space and the reaction parameters. During exercise, solubility changes are large; both ρsol and T change rapidly with spatial position and with time. In exercise hemoconcentration plasma, ρsol exceeds 1.02, whereas T may range over 20°C. The six parameters for O2 and the six for CO2 are constants, so solubilities are calculable continuously as T and ρsol change.NEW & NOTEWORTHY Solubilities for oxygen and carbon dioxide are dependent on the density of the solution, on temperature, and on the partial pressure. We provide a brief equation suitable for hand calculators or mathematical modeling, accounting for these factors over a wide range of temperatures and solution densities for use in rapidly changing conditions, such as extreme exercise or osmotic transients, with better than 0.5% accuracy.


Effects of exercise on diastasis of the rectus abdominis muscle in the antenatal and postnatal periods: a systematic review.
Diastasis of the rectus abdominis muscle (DRAM) is common during and after pregnancy, and has been related to lumbopelvic instability and pelvic floor weakness. Women with DRAM are commonly referred to physiotherapists for conservative management, but little is known about the effectiveness of such strategies. To determine if non-surgical interventions (such as exercise) prevent or reduce DRAM. EMBASE, Medline, CINAHL, PUBMED, AMED and PEDro were searched. Studies of all designs that included any non-surgical interventions to manage DRAM during the ante- and postnatal periods were included. Methodological quality was assessed using a modified Downs and Black checklist. Meta-analysis was performed using a fixed effects model to calculate risk ratios (RR) and 95% confidence intervals (CI) where appropriate. Eight studies totalling 336 women during the ante- and/or postnatal period were included. The study design ranged from case study to randomised controlled trial. All interventions included some form of exercise, mainly targeted abdominal/core strengthening. The available evidence showed that exercise during the antenatal period reduced the presence of DRAM by 35% (RR 0.65, 95% CI 0.46 to 0.92), and suggested that DRAM width may be reduced by exercising during the ante- and postnatal periods. The papers reviewed were of poor quality as there is very little high-quality literature on the subject. Based on the available evidence and quality of this evidence, non-specific exercise may or may not help to prevent or reduce DRAM during the ante- and postnatal periods.


The regulation of seasonal changes in food intake and body weight.
Seasonal rhythms of body weight, reflecting altered food intake, energy storage and expenditure, are a common feature of mammals inhabiting temperate and arctic latitudes. They have evolved so that predictable annual changes in the external environment can be anticipated and animals can adjust their physiology and behaviour in preparation for the changing demands of the seasons. These long-term changes in energy balance are not simply effected by the brain centres and peptidergic pathways known to underlie short-term homeostatic regulation. Screens of altered gene expression in Siberian hamsters comparing the anabolic summer state in long photoperiods and the catabolic 'winter' state in short photoperiods have identified differential gene expression in the hypothalamus. The majority of gene expression changes are confined to two restricted areas: the dorsomedial posterior arcuate nucleus, and the ventral ependymal layer of the third ventricle. Functions encoded by these 'seasonal' genes include thyroid hormone metabolism, retinoic acid and histaminergic signalling, and VGF and secretogranin production. The changes in thyroid hormone availability that are brought about by differential activity of deiodinase enzymes are of particular importance because experimental manipulation of central thyroid levels can prevent seasonal cyclicity. Given the importance of thyroid hormone in the initial development of the brain, we hypothesise that thyroid hormone-dependent plasticity of hypothalamic connections and neurogenesis underlie seasonal cycles of food intake and body weight.


A randomised study comparing the effectiveness of acupuncture or morphine versus the combination for the relief of dyspnoea in patients with advanced non-small cell lung cancer and mesothelioma.
Dyspnoea is one of the commonest symptoms of lung cancer. Opioids can reduce dyspnoea. This study investigates acupuncture for relief of breathlessness in lung cancer. We performed a single-centre, randomised phase II study of 173 patients with non-small cell lung cancer or mesothelioma with dyspnoea score of ≥4 on visual analogue scale (VAS). Randomisation was to acupuncture alone (A), morphine alone (M) or both (AM). Acupuncture was administered at upper sternal, thoracic paravertebral, trapezius trigger points and LI4. Manubrial semi-permanent acupuncture studs were inserted and massaged when symptomatic. Arm A patients received rescue morphine. Primary end-point was proportion of patients achieving ≥1.5 improvement in VAS dyspnoea at 4 h. Measurements continued to day 14 and included VAS relaxation, line analogue rating (Lar) anxiety, hospital anxiety and depression and European Organisation for Research and Treatment of Cancer quality-of-life scores. Dyspnoea VAS improved ≥1.5 in 74%, 60% and 66% of arms A, M and AM, respectively, and was maintained in 45% at 2 weeks. There was no statistically significant difference between arms. VAS relaxation improved in arms A (1.06 points) and AM (1.48 points) compared to arm M (-0.19 points, p<0.001). At 7 d, the Lar anxiety score improved in arm A (1.5 points), arm AM (1.2 points) and arm M (no change, p=0.003). Fewer patients received at least one morphine dose in arm A compared with arm M or AM (21% versus 87% versus 87%, respectively, p<0.001). A, M and AM were effective in relieving dyspnoea. Acupuncture relieved anxiety and was morphine sparing, providing an alternative to morphine.


Bullying and Delinquency: The Impact of Anger and Frustration.
Few studies have explored whether individuals who are bullied at school or online are more likely to engage in delinquent behavior. Even less is known about whether negative emotions (i.e., anger or frustration)-as a result of being victimized-mediate the relationships between being bullied or cyberbullied and delinquency (as predicted by Agnew's general strain theory). The current study uses data from a national sample of 2,670 middle and high school students in the United States. Results indicate that youth who were bullied or cyberbullied, and who experience negative emotions as a result, are more likely to engage in delinquency. Negative emotions did not mediate the relationship between bullying and delinquency; however, they did partly mediate the relationship between cyberbullying and delinquency. The findings indicate that being bullied matters more in explaining delinquent behavior than the negative emotions that may result. Implications for research and policy are discussed in light of these findings.


Blood loss in infants and children for open heart operations: albumin 5% versus fresh-frozen plasma in the prime.
Infants and children undergoing cardiopulmonary bypass become substantially hemodiluted secondary to the volume used to prime the oxygenator. Fresh-frozen plasma has been included in the prime to lessen dilution of clotting factors and correspondingly minimize blood loss and transfusions. We prospectively randomized 56 patients weighing 10 kg or less who required cardiopulmonary bypass to receive either one unit of fresh-frozen plasma or 200 mL of albumin 5% in the prime. After protamine administration, samples for prothrombin time, fibrinogen, platelet count, and thromboelastogram were obtained. Mediastinal chest tube drainage and transfusion requirements were documented. There were no significant differences between groups regarding demographic or surgical characteristics. Blood loss during the first 24 hours was similar in both groups, but total transfusions were significantly greater in those who received fresh-frozen plasma instead of albumin 5% in the prime (8.0 +/- 4.2 versus 6.1 +/- 4.5 U, respectively; p = 0.035). Post hoc analyses suggest that for cyanotic patients and patients undergoing complex operations, fresh-frozen plasma in the prime results in less blood loss than albumin 5%. Substitution of albumin 5% for fresh-frozen plasma in the prime of acyanotic patients weighing 10 kg or less who undergo noncomplex operations requiring cardiopulmonary bypass significantly reduces perioperative transfusions without increasing blood loss. Further investigation is needed to determine whether increased blood loss is associated with increased transfusions when albumin 5% is substituted for fresh-frozen plasma in the prime of infants and children who are cyanotic or undergoing complex operations.


Neuroprotective Effects of Pomegranate Juice against Parkinson's Disease and Presence of Ellagitannins-Derived Metabolite-Urolithin A-In the Brain.
Pomegranate juice is a rich source of ellagitannins (ETs) believed to contribute to a wide range of pomegranate's health benefits. While a lot of experimental studies have been devoted to Alzheimer disease and hypoxic-ischemic brain injury, our knowledge of pomegranate's effects against Parkinson's disease (PD) is very limited. It is suggested that its neuroprotective effects are mediated by ETs-derived metabolites-urolithins. In this study, we examined the capability of pomegranate juice for protection against PD in a rat model of parkinsonism induced by rotenone. To evaluate its efficiency, assessment of postural instability, visualization of neurodegeneration, determination of oxidative damage to lipids and α-synuclein level, as well as markers of antioxidant defense status, inflammation, and apoptosis, were performed in the midbrain. We also check the presence of plausible active pomegranate ETs-derived metabolite, urolithin A, in the plasma and brain. Our results indicated that pomegranate juice treatment provided neuroprotection as evidenced by the postural stability improvement, enhancement of neuronal survival, its protection against oxidative damage and α-synuclein aggregation, the increase in mitochondrial aldehyde dehydrogenase activity, and maintenance of antiapoptotic Bcl-xL protein at the control level. In addition, we have provided evidence for the distribution of urolithin A to the brain.


Outcome of patients with cyanotic congenital heart disease undergoing a second systemic-to-pulmonary artery shunt.
Multiple systemic-to-pulmonary artery shunts often represent a deviation from the initial management strategy for cyanotic congenital heart disease. This study analysed the outcome in patients undergoing a second shunt. Between 1965 and 1998, 80 patients required a second shunt. Patient age ranged from 11 days to 11.2 years at the initial shunt, and 4 months to 25.6 years at the second shunt. The interval between shunts ranged from 11 days to 19.6 years. The patient survival rates at 1, 6, 12, 60 and 120 months following the second shunt were 95.0 +/- 2.4%, 92.5+/-3.0%, 87.4+/-3.7%. 82.4+/-4.5% and 74.8+/-5.8%, respectively. Although excess pulmonary flow was not encountered after the second shunt, mode and incidence of morbidity were otherwise similar to the first one. Between 9 months and 7.5 years after the second shunt, 24 patients underwent successful definitive repair. Multivariable analysis identified pulmonary atresia (p=0.027) and a short (<1 year) interval between the two shunts (p=0.034) as the independent risk factors for long-term shunt failure. Single ventricle physiology (p=0.002) and a central approach for the second shunt (p=0.016) were independent risk factors for lack of application, or failure of intracardiac definitive repair. A significant limitation in longevity and quality of life is common in patients requiring a second shunt, especially those associated with pulmonary atresia, the single ventricle physiology heart, or ungraftably hypoplastic contralateral branch pulmonary artery to the first shunt. Since excess pulmonary blood flow leading to congenital heart failure and/or ventricular diastolic dysfunction is unlikely, all patients who preclude definitive repair due to decreased pulmonary blood flow even after the first shunt should be shunted again.


Epidemiology and trends of gastrointestinal cancer in Iran (2004-2008).
Gastrointestinal (GI) cancer is among the most common cancers in Iran. The main purpose of this study was to evaluate changes in the time trends of stomach, colon and rectum, and esophageal cancer during the past decade in Iran. In this cross-sectional study, the study population was all cases of GI cancers diagnosed in Iran between 2004 and 2008. Cancer incidence data for the years 2004-2008 were obtained from the cancer registry system of the Ministry of Health. All incidence rates were directly age standardized to the world standard population. Age-Satndardized incidence rate (ASR)per 105 persons was calculated using direct standardization and the world standard population. The crude rate was calculated in this study. Data were analyzed using SPSS (version 17) and Microsoft Office Excel 2007. During the 2004-2008 period, the ASR and crude rates of GI cancers, including esophagus, stomach, colon and rectum, among males were 5.05, 15.02, and 8.29 and 4.01, 11.81, and 6.4, respectively, and among females were 6.52, 7.055, and 7.75 and 4.40, 4.85, and 5.49, respectively. The most common cancers in women were colon and rectum, and stomach cancer had the highest incidence in males. In this study, most cases of stomach cancer were adenocarcinoma adenocarcinoma (Nos) in both women and men. The most common type of colorectal cancer was adenocarcinoma, which was greater in men than women. The most common type of esophageal cancer was squamous cell carcinoma in both sexes. The north and northwestern regions of Iran have the highest risk of GI cancer. According to this study, a significant increase was observed in the incidence of cancers in the north and western regions of Iran. Hence, screening and early detection programs are highly recommended in these high-risk areas.


Building-site camps and extended work hours: A two-week monitoring of self-reported physical exertion, fatigue, and daytime sleepiness.
Large-scale construction work often requires people to work longer daily hours and more than the ordinary five days in a row. In order to minimize transportation times and optimize the use of personnel, workers are sometimes asked to live in temporary building-site camps in the proximity of the work site. However, little is known about the biological and psychological effects of this experience. The objective of the present study was to investigate whether exposure to long work hours and extended workweeks while living in building-site camps in between work shifts was associated with a build-up of increased complaints of poor sleep, daytime sleepiness, physical exertion, and fatigue across a two-week work cycle. Two groups of construction workers were examined. The camp group of 13 participants (mean age: 42+/-11 S.D. yrs) lived in building-site camps and worked extended hours (between 07:00 and 18:00 h) and extended workweeks (six days in a row, one day off, five days in a row, nine days off). The home group of 16 participants (mean age 40+/-9 yrs) worked ordinary hours between 07:00 and 15:00 h and returned home after each workday. Self-ratings of daytime sleepiness (Karolinska Sleepiness Scale), physical exertion (Borg CR-10), and mood were obtained six or seven times daily during two workweeks. Fatigue ratings were obtained once daily in the evening, and ratings of sleep disturbances were obtained once daily in the morning with the Karolinska Sleep Diary. Data were evaluated in a repeated measures design. The results showed that both groups reported a similar level of daytime sleepiness, physical exertion, and mood across workdays and time points within a workday (all three-way interactions had p>0.898). Although the home group reported earlier wake-up times, the pattern of sleep disturbance ratings across the workdays did not differ between the groups. Both groups reported few sleep disturbances and good mood. However, the camp group reported higher physical exertion already at the start of work and showed a more gentle increase in ratings during the work shift and a smaller decline between the end of work and bedtime. The camp group also reported higher fatigue scores than the home group. However, none of the groups showed signs of increasing ratings in the progress of the two workweeks. For both groups, the ratings of daytime sleepiness formed a U-shaped pattern, with the highest scores at awakening and at bedtime. Yet, the camp group reported higher daytime sleepiness than the home group at lunch break and at the second break in the afternoon. In conclusion, there were no signs of fatigue build-up or accumulation of daytime sleepiness, physical exertion, or sleep disturbances in either group. Despite the fact that the camp group showed some signs of having trouble in recuperating in between work shifts, as indicated by the higher physical exertion ratings at the start of work, higher fatigue scores, and higher daytime sleepiness, the results constitute no real foundation for altering the camp group's current work schedule and living arrangements.


Pain management for total hip arthroplasty.
Total hip arthroplasty (THA) has been shown to improve long-term quality of life, although the immediate postoperative period can be associated with intense postoperative pain that hampers rehabilitation. Effective postoperative analgesia is paramount in the recovery period. The understanding and collaboration of the orthopaedic surgeon and the pain-management physicians will improve the perioperative outcome of THA. Appropriate pain management can reduce the associated total direct medical costs for lower extremity joint replacement surgeries by reducing hospital stays and the services needed during hospitalization. Factors contributing to the shorter lengths of stay include homogenous entities such as regular staff and continuity of nursing care, the use of timely and up-to-date information including expectations on a short stay, functional discharge criteria, early mobilization, and the use of a multimodal analgesia approach centered on opioid sparing.


Fellowship training, workload, fatigue and physical stress: a prospective observational study.
Fatigue in physician trainees may compromise patient safety and the well-being of the trainees and limit the educational opportunities provided by training programs. Anecdotal evidence suggests that the on-call workload and physical demands experienced by trainees are significant despite duty-hour regulation and support from nursing staff, other trainees and staff physicians. We measured the workload and the level of fatigue and physical stress of 11 senior fellows during 35 shifts in the critical care unit at the Hospital for Sick Children in Toronto. We determined number of rostered hours, number of admissions and discharges, number and type of procedures, nurse:patient ratios and related measures of workload. Fellows self-reported the number of pages they received and the amount of time they slept. We estimated physical stress by using a commercially available pedometer to measure the distance walked, by using ambulatory electrocardiographic monitoring to determine arrhythmias and by determining urine specific gravity and ketone levels to estimate hydration. The number of rostered hours were within current Ontario guidelines. The mean shift duration was 25.5 hours (range 24-27 hours). The fellows worked on average 69 hours (range 55-106) per week. On average during a shift, the fellows received 41 pages, were on non-sleeping breaks for 1.2 hours, slept 1.9 hours and walked 6.3 km. Ketonuria was found in participants in 7 (21%) of the 33 shifts during which it was measured. Arrhythmia (1 atrial, 1 ventricular) or heart rate abnormalities occurred in all 6 participants. These fellows were the most senior in-house physician for a mean of 9.4 hours per shift and were responsible for performing invasive procedures in two-thirds of their shifts. Established Canadian and proposed American guidelines expose trainees to significant on-call workload, physical stress and sleep deprivation.


Topographic characteristics of optic disc hemorrhage in primary open-angle glaucoma.
To investigate the topographic characteristics of optic disc hemorrhage (DH) and the factors associated with DH area in POAG. We enrolled 128 POAG eyes (with DH) of 128 patients consecutively. Digital red-free retinal nerve fiber layer (RNFL) photographs and digital color stereo disc photographs of the enrolled eyes were reviewed, and the DH locations were measured. The DH area was calculated based on RNFL deviation map/RNFL photographs overlay image. Disc hemorrhages were most common in the inferotemporal inferior sector (58.0%) and the disc rim (40.6%) in terms of octant and proximal location, respectively. In a multivariate analysis, a larger DH area was associated with older age (P < 0.01), use of acetylsalicylic acid (P = 0.03), lower cup-to-disc ratio (P < 0.01), and lower baseline IOP (P = 0.01). In normal-baseline IOP-POAG eyes (n = 88), the overall DH area and length of maximum radial extent of DH were larger than in high-baseline IOP-POAG eyes (n = 40) (P = 0.04 and 0.03, respectively). In POAG eyes, DH was larger in area and longer in length in cases of normal-baseline IOP than in cases of high-baseline IOP. This suggests the possibility that previous studies' findings of higher DH prevalence and incidence in normal-baseline IOP-POAG eyes were partially affected by these topographic characteristics, which make DH more easily detectable.


A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response.
DNA damage and the elicited cellular response underlie the etiology of tumorigenesis and ageing. Yet, how this response integrates inputs from cells' environmental cues remains underexplored. Here we report that the BMP-Smad1 pathway, which is essential for embryonic development and tissue homeostasis, has an important role in the DNA damage response and oncogenesis. On genotoxic stress, Atm phosphorylates BMPs-activated Smad1 in the nucleus on S239, which disrupts Smad1 interaction with protein phosphatase PPM1A, leading to enhanced activation and upregulation of Smad1. Smad1 then interacts with p53 and inhibits Mdm2-mediated p53 ubiquitination and degradation to regulate cell proliferation and survival. Enhanced Smad1 S239 phosphorylation, and Smad1 mutations causing S239 substitution were detected in oesophageal and gastric cancer samples, respectively. These findings suggest that BMP-Smad1 signalling participates in the DNA damage response via the Atm-p53 pathway, thus providing a molecular mechanism whereby BMP-Smad1 loss-of-function leads to tumorigenesis, for example, juvenile polyposis and Cowden syndromes.


Isolation and characterization of a low-abundance splice variant from the human cytomegalovirus major immediate-early gene region.
The major immediate-early (IE) gene region of human cytomegalovirus (HCMV) encodes several proteins as a result of differential RNA splicing events. By expression vector cloning of HCMV IE mRNA, we isolated and characterized a cDNA for a novel splice variant from the major IE gene region. The RNA product is a derivative of the IE55 mRNA and contains an additional splice from nucleotides 170,635 to 170,307 in the IE2 gene region (UL122), resulting in a 1.4-kb mRNA. The predicted open reading frame codes for a 164-amino-acid protein with a calculated molecular mass of 18 kDa (IE18). Mung bean nuclease analysis and PCR were used to characterize expression of IE18 mRNA in HCMV-infected cells. While the 1.4-kb mRNA was detected in infected human fibroblasts in the presence of a protein synthesis inhibitor, it was not detectable during a normal infection. However, the 1.4-kb mRNA was readily detected in infected human monocyte-derived macrophages at IE times. These results suggest that the novel IE18 mRNA exhibits cell type-specific expression indicating differential regulation of the major IE gene region in different permissive cell types.


Patient retention gifts in clinical trials - undue inducement or justified motivational tools?
The use of retention gifts in clinical trials has been controversial, with some ethicists maintaining that such gifts represent undue inducement to the trial participants. A study was conducted at TREAD Research, a site-managed organisation based at Tygerberg Hospital, in which 302 participants completed a questionnaire that focused on their opinion with regard to such gifts. The results suggest that these gifts do not influence patients to participate in a clinical trial or influence them to remain on a trial should they wish to withdraw. However, they do act as a useful motivational tool and trial participants appreciate them.


Hybrid computational phantoms of the 15-year male and female adolescent: applications to CT organ dosimetry for patients of variable morphometry.
Currently, two classes of the computational phantoms have been developed for dosimetry calculation: (1) stylized (or mathematical) and (2) voxel (or tomographic) phantoms describing human anatomy through mathematical surface equations and three-dimensional labeled voxel matrices, respectively. Mathematical surface equations in stylized phantoms provide flexibility in phantom design and alteration, but the resulting anatomical description is, in many cases, not very realistic. Voxel phantoms display far better anatomical realism, but they are limited in terms of their ability to alter organ shape, position, and depth, as well as body posture. A new class of computational phantoms--called hybrid phantoms-takes advantage of the best features of stylized and voxel phantoms-flexibility and anatomical realism, respectively. In the current study, hybrid computational phantoms representing reference 15-year male and female body anatomy and anthropometry are presented. For the male phantom, organ contours were extracted from the University of Florida (UF) 14-year series B male voxel phantom, while for the female phantom, original computed tomography (CT) data from two 14-year female patients were used. Polygon mesh models for the major organs and tissues were reconstructed for nonuniform rational B-spline (NURBS) surface modeling. The resulting NURBS/polygon mesh models representing body contour and internal anatomy were matched to anthropometric data and reference organ mass data provided by the Centers for Disease Control and Prevention (CDC) and the International Commission on Radiation Protection (ICRP), respectively. Finally, two hybrid 15-year male and female phantoms were completed where a total of eight anthropometric data categories were matched to standard values within 4% and organ masses matched to ICRP data within 1% with the exception of total skin. To highlight the flexibility of the hybrid phantoms, 10th and 90th weight percentile 15-year male and female phantoms were further developed from the 50th percentile phantoms through adjustments in the body contour to match the total body masses given in CDC pediatric growth curves. The resulting six NURBS phantoms, male and female phantoms representing their 10th, 50th, and 90th weight percentiles, were used to investigate the influence of body fat distributions on internal organ doses following CT imaging. The phantoms were exposed to multislice chest and abdomen helical CT scans, and in-field organ absorbed doses were calculated. The results demonstrated that the use of traditional stylized phantoms yielded organ dose estimates that deviate from those given by the UF reference hybrid phantoms by up to a factor of 2. The study also showed that use of reference, or 50th percentile, phantoms to assess organ doses in underweight 15-year-old children would not lead to significant organ dose errors (typically less than 10%). However, more significant errors were noted (up to approximately 30%) when reference phantoms are used to represent overweight children in CT imaging dosimetry. These errors are expected to only further increase as one considers CT organ doses in overweight and obese individuals of the adult patient population, thus emphasizing the advantages of patient-sculptable phantom technology.


Localization of human mesenchymal stem cells from umbilical cord blood and their role in repair of diabetic foot ulcers in rats.
The aim of this study is to explore the localization of human mesenchymal stem cells from umbilical cord matrix (hMSCs-UC) and the role of these cells in the repair of foot ulcerate tissue in diabetic foot ulcers in rats. A diabetic rat model was established by administering Streptozotocin. Diabetic foot ulceration was defined as non-healing or delayed-healing of empyrosis on the dorsal hind foot after 14 weeks. hMSCs-UC were delivered through the left femoral artery. We evaluated the localization of hMSCs-UC and their role in tissue repair in diabetic foot ulcers by histological analysis, PCR, and immunohistochemical staining. A model for diabetes was established in 54 out of 60 rats (90% success rate) and 27 of these rats were treated with hMSCs-UC. The area of ulceration was significantly and progressively reduced at 7 and 14 days following treatment with hMSCs-UC. This gross observation was strongly supported by the histological changes, including newly developed blood vessels and proliferation of inflammatory cells at 3 days post-treatment, significant increase in granulation tissue at 7 days post-treatment and squamous epithelium or stratified squamous epithelium at 14 days post-treatment. Importantly, human leukocyte antigen type-I (HLA-1) was confirmed in ulcerated tissue by RT-PCR. The expression of cytokeratin 19 was significantly increased in diabetic model rats, with no detectable change in cytokeratin 10. Additionally, both collagens I and III increased in model rats treated with hMSCs-UC, but the ratio of collagen I/III was less significant in treated rats compared with control rats. These results suggest that hMSCs-UC specifically localize to the target ulcerated tissue and may promote the epithelialization of ulcerated tissue by stimulating the release of cytokeratin 19 from keratinocytes and extracellular matrix formation.


Spectroscopic and theoretical insights into sequence effects of aminofluorene-induced conformational heterogeneity and nucleotide excision repair.
A systematic spectroscopic and computational study was conducted in order to probe the influence of base sequences on stacked (S) versus B-type (B) conformational heterogeneity induced by the major dG adduct derived from the model carcinogen 7-fluoro-2-aminofluorene (FAF). We prepared and characterized eight 12-mer DNA duplexes (-AG*N- series, d[CTTCTAG*NCCTC]; -CG*N- series, d[CTTCTCG*NCCTC]), in which the central guanines (G*) were site-specifically modified with FAF with varying flanking bases (N = G, A, C, T). S/B heterogeneity was examined by CD, UV, and dynamic 19F NMR spectroscopy. All the modified duplexes studied followed a typical dynamic exchange between the S and B conformers in a sequence dependent manner. Specifically, purine bases at the 3'-flanking site promoted the S conformation (G > A > C > T). Simulation analysis showed that the S/B energy barriers were in the 14-16 kcal/mol range. The correlation times (tau = 1/kappa) were found to be in the millisecond range at 20 degrees C. The van der Waals energy force field calculations indicated the importance of the stacking interaction between the carcinogen and neighboring base pairs. Quantum mechanics calculations showed the existence of correlations between the total interaction energies (including electrostatic and solvation effects) and the S/B population ratios. The S/B equilibrium seems to modulate the efficiency of Escherichia coli UvrABC-based nucleotide excision repair in a conformation-specific manner: i.e., greater repair susceptibility for the S over B conformation and for the -AG*N- over the -CG*N- series. The results indicate a novel structure-function relationship, which provides insights into how bulky DNA adducts are accommodated by UvrABC proteins.


Assessment of different screening methods for selecting palaeontological bone samples for peptide sequencing.
Ancient proteomics is being applied to samples dating further and further back in time, with many palaeontological specimens providing protein sequence data for phylogenetic analysis as well as protein degradation studies. However, fossils are a precious material and proteomic analysis is destructive and costly. In this paper we consider three different techniques (ATR-FTIR, MALDI-ToF MS and chiral AA analysis) to screen fossil material for potential protein preservation, aiming to maximise the proteomic information recovered and saving costly time consuming analyses which may produce low quality results. It was found that splitting factor and C/P indices from ATR-FTIR were not a reliable indicator of protein survival as they are confounded by secondary mineralisation of the fossil material. Both MALDI-ToF MS and chiral AA analysis results were able to successfully identify samples with surviving proteins, and it is suggested that one or both of these analyses be used for screening palaeontological specimens. SIGNIFICANCE: This study has shown both chiral amino acid analysis and MALDI-ToF MS are reliable screening methods for predicting protein survival in fossils. Both these methods are quick, cheap, minimally destructive (1 mg and 15 mg respectively) and can provide crucial additional information about the endogeneity of the surviving proteins. It is hoped that the use of these screening methods will encourage the examination of a wide range of palaeontological specimens for potential proteomic analysis. This in turn will give us a better understanding of protein survival far back in time and under different environmental conditions.


Analysis of preexistent vertebral rotation in the normal infantile, juvenile, and adolescent spine.
Vertebral rotation was systematically analyzed in the normal, nonscoliotic thoracic spine of children aged 0 to 16 years. Subgroups were created to match the infantile, juvenile, and adolescent age groups according to the criteria of the Scoliosis Research Society. To determine whether a distinct pattern of vertebral rotation in the transverse plane exists in the normal, nonscoliotic infantile, juvenile, and adolescent spine. We assume that, once the spine starts to deteriorate into a scoliotic deformity, it will follow a preexisting rotational pattern. Recently, we identified a rotational pattern in the normal nonscoliotic adult spine that corresponds to the most common curve types in adolescent idiopathic scoliosis. In infantile idiopathic scoliosis, curves are typically left sided and boys are affected more often than girls, whereas in adolescent idiopathic scoliosis, the thoracic curve is typically right sided and predominantly girls are affected. The present study is the first systematic analysis of vertebral rotation in the normal children's spine. Vertebral rotation in the transverse plane of T2-T12 was measured by using a semiautomatic method on 146 computed tomographic scans of children (0-16 years old) without clinical or radiologic evidence of spinal pathology. Scans were mainly made for reasons such as recurrent respiratory tract infections, malignancies, or immune disorders. Vertebral rotational patterns were analyzed in the infantile (0-3-year-old), juvenile (4-9-year-old), and adolescent (10-16-year-old) boys and girls. In the infantile spine, vertebrae T2-T6 were significantly rotated to the left (P < 0.001). In the juvenile spine, T4 was significantly rotated to the left. In the adolescent spine, T6-T12 were significantly rotated to the right (P ≤ 0.001). Rotation to the left was more pronounced in infantile boys than in the girls (P = 0.023). In juvenile and adolescent children, no statistical differences in rotation were found between the sexes. These data support the hypothesis that the direction of the spinal curve in idiopathic scoliosis is determined by the built-in rotational pattern that the spine exhibits at the time of onset. The well-known predominance of right-sided thoracic curves in adolescent idiopathic scoliosis and left-sided curves in infantile idiopathic scoliosis can be explained by the observed patterns of vertebral rotation that preexist at the corresponding age.


Cohort profile: design and methods in the eye and vision consortium of UK Biobank.
To describe the rationale, methods and research potential of eye and vision measures available in UK Biobank. UK Biobank is a large, multisite, prospective cohort study. Extensive lifestyle and health questionnaires, a range of physical measures and collection of biological specimens are collected. The scope of UK Biobank was extended midway through data collection to include assessments of other measures of health, including eyes and vision. The eye assessment at baseline included questionnaires detailing past ophthalmic and family history, measurement of visual acuity, refractive error and keratometry, intraocular pressure (IOP), corneal biomechanics, spectral domain optical coherence tomography (OCT) of the macula and a disc-macula fundus photograph. Since recruitment, UK Biobank has collected accelerometer data and begun multimodal imaging data (including brain, heart and abdominal MRI) in 100 000 participants. Dense genotypic data and a panel of 20 biochemistry measures are available, and linkage to medical health records for the full cohort has begun. A total of 502 665 people aged between 40 and 69 were recruited to participate in UK Biobank. Of these, 117 175 took part in baseline assessment of vision, IOP, refraction and keratometry. A subgroup of 67 321 underwent OCT and retinal photography. The introduction of eye and vision measures in UK Biobank was accompanied by intensive training, support and a data monitoring quality control process. UK Biobank is one of the largest prospective cohorts worldwide with extensive data on ophthalmic diseases and conditions. Data collection is an ongoing process and a repeat of the baseline assessment including the questionnaires, measurements and sample collection will be performed in subsets of 25 000 participants every 2-3 years. The depth and breadth of this dataset, coupled with its open-access policy, will create a powerful resource for all researchers to investigate the eye diseases in later life.


Outcomes in syncope research: a systematic review and critical appraisal.
Syncope is the common clinical manifestation of different diseases, and this makes it difficult to define what outcomes should be considered in prognostic studies. The aim of this study is to critically analyze the outcomes considered in syncope studies through systematic review and expert consensus. We performed a systematic review of the literature to identify prospective studies enrolling consecutive patients presenting to the Emergency Department with syncope, with data on the characteristics and incidence of short-term outcomes. Then, the strengths and weaknesses of each outcome were discussed by international syncope experts to provide practical advice to improve future selection and assessment. 31 studies met our inclusion criteria. There is a high heterogeneity in both outcome choice and incidence between the included studies. The most commonly considered 7-day outcomes are mortality, dysrhythmias, myocardial infarction, stroke, and rehospitalisation. The most commonly considered 30-day outcomes are mortality, haemorrhage requiring blood transfusion, dysrhythmias, myocardial infarction, pacemaker or implantable defibrillator implantation, stroke, pulmonary embolism, and syncope relapse. We present a critical analysis of the pros and cons of the commonly considered outcomes, and provide possible solutions to improve their choice in ED syncope studies. We also support global initiatives to promote the standardization of patient management and data collection.


Alcohol consumption and risk of heart failure: the Atherosclerosis Risk in Communities Study.
Alcohol is a known cardiac toxin and heavy consumption can lead to heart failure (HF). However, the relationship between moderate alcohol consumption and risk for HF, in either men or women, remains unclear. We examined 14 629 participants of the Atherosclerosis Risk in Communities (ARIC) study (54 ± 6 years, 55% women) without prevalent HF at baseline (1987-89) who were followed for 24 ± 1 years. Self-reported alcohol consumption was assessed as the number of drinks/week (1 drink = 14 g of alcohol) at baseline, and updated cumulative average alcohol intake was calculated over 8.9 ± 0.3 years. Using multivariable Cox proportional hazards models, we examined the relation of alcohol intake with incident HF and assessed whether associations were modified by sex. Overall, most participants were abstainers (42%) or former drinkers (19%), with 25% reporting up to 7 drinks per week, 8% reporting ≥7 to 14 drinks per week, and 3% reporting ≥14-21 and ≥21 drinks per week, respectively. Incident HF occurred in 1271 men and 1237 women. Men consuming up to 7 drinks/week had reduced risk of HF relative to abstainers (hazard ratio, HR 0.80, 95% CI 0.68-0.94, P = 0.006); this effect was less robust in women (HR 0.84, 95% CI 0.71-1.00, P = 0.05). In the higher drinking categories, the risk of HF was not significantly different from abstainers, either in men or in women. In the community, alcohol consumption of up to 7 drinks/week at early-middle age is associated with lower risk for future HF, with a similar but less definite association in women than in men. These findings suggest that despite the dangers of heavy drinking, modest alcohol consumption in early-middle age may be associated with a lower risk for HF.


Gene-specific modulation of TAF10 function by SET9-mediated methylation.
SET9 is a member of the SET domain-containing histone methyltransferase family that can specifically methylate histone 3 at lysine 4 position. Although nucleosomal histones are poor substrates for SET9, the active enzyme can stimulate activator-induced transcription. Here, we show that SET9 can monomethylate the TBP-associated factor TAF10 at a single lysine residue located at the loop 2 region within the putative histone-fold domain of the protein. Methylated TAF10 has an increased affinity for RNA polymerase II, pointing to a direct role of this modification in preinitiation complex formation. Reporter assays and studies on TAF10 null F9 cells expressing a methylation-deficient TAF10 mutant revealed that SET9-mediated methylation of TAF10 potentiates transcription of some but not all TAF10-dependent genes. This gene specificity correlated with SET9 recruitment. The promoter-specific effects of SET9-methylated TAF10 may have important implications regarding the biological function of SET domain-containing lysine methylases, whose primary targets have been presumed to be histones.


Estimation of the possible scale for holographic switches with liquid-crystal displays.
Simulating the positions of output beams under the assumption that a liquid-crystal display acts as a binary phase modulator reveals that the number of the outputs increases almost linearly with the square root of the number of pixels assigned to an input. This result is confirmed by experiments, and it is estimated that 1016 outputs can be obtained when the number of pixels is 700 × 700. Holographic switches with liquid-crystal displays are therefore suitable for large-scale switches.


Increased ultraviolet sensitivity and chromosomal instability related to P53 function in the xeroderma pigmentosum variant.
The xeroderma pigmentosum (XP) variant (XPV) is a form of XP that has normal excision repair but shows defective DNA replication after UV irradiation. In developing various transformed fibroblast cell lines from these patients, we have found that there are significant phenotypic changes in transformed cells that seem to correlate with inactivation of p53. After transformation with SV40, XPV cell lines are only slightly UV sensitive, like their primary counterparts, but their sensitization with caffeine and the induction of sister chromatid exchanges (SCEs) by UV irradiation are greatly enhanced. After transformation by HPV16 E7, which targets the retinoblastoma cell cycle regulatory gene, there is no change in the UV sensitivity of XPV cells; but, when transformed by HPV16 E6 or E6 and E7 combined, there is a large increase in UV sensitivity and in the induction of SCEs. These changes are not associated with any detectable changes in the reactivation of an externally irradiated luciferase expression vector, the excision of cyclobutane pyrimidine dimers from bulk DNA, or unscheduled DNA synthesis and, therefore, do not involve excision repair. We suggest that if SCEs represent homologous recombination between sister chromatids, then in the absence of p53 function, the DNA chain arrest typical of UV-damaged XPV cells initiates strand exchange during recovery. In untransformed cells with normal p53, the preferred mode of recovery would then be replication bypass. The symptoms of elevated solar carcinogenesis in XPV patients may, therefore, be associated with increased genomic instability in cells of the skin in which p53 is inactivated by UV-induced mutations.


Monocyte differentiation is controlled by MyD88 after mouse orthotopic lung transplantation.
In lung grafts, ischemia-reperfusion signals rapidly induce the recruitment and differentiation of host monocytes into macrophages and dendritic cells. The nature of ischemia-reperfusion signals are antigen independent, but have been hypothesized to initiate Toll-like receptor (TLR) and interleukin (IL)-1R-mediated signaling pathways that are thought to potentiate alloimmune responses. We wondered whether MyD88, an adaptor molecule critical for both TLR and IL-1R-mediated inflammatory responses, regulated monocyte differentiation in a mouse model of vascularized orthotopic lung transplantation. Orthotopic left lung transplants were performed in the following syngeneic combinations: CD45.1(+) B6 --> CD45.2(+) MyD88(-/-) and CD45.1(+) B6 --> CD45.2(+) B6. One day later, recipient-derived dendritic cells and macrophage numbers were assessed in the bronchiolar lavage by FACS analysis. Compared with the bronchiolar lavage of wildtype recipients, MyD88(-/-) recipients had lower numbers of dendritic cells in lung graft airways that were of recipient origin. Lower numbers of newly differentiated lung graft dendritic cells was coincident with the appearance of higher numbers of undifferentiated monocytes in the lung airways of MyD88(-/-) recipients as compared with wild-type recipients. Moreover, adoptive transfer experiments demonstrated that MyD88(-/-) monocytes were poorer at differentiating into lung dendritic cells as compared with wild-type monocytes. Taken together, these data show that MyD88 regulates graft-infiltrating monocyte differentiation and suggests a mechanism by which TLR/IL-1R-signaling pathways control adaptive responses in lung allografts through controlling monocyte fate.


Effect of Bt maize and soil insecticides on yield, injury, and rootworm survival: implications for resistance management.
A 2-yr field experiment was conducted to determine the effects on Diabrotica spp. (Coleoptera: Chrysomelidae) of an insecticidal seed treatment (Poncho 1250, (AI)/clothianidin) and a granular insecticide (Aztec 2.1G, (AI)/tebupirimphos and cyfluthrin) alone and in combination with maize producing the insectidical toxin Cry3Bb1 derived from the bacterium Bacillus thuringiensis (Bt). Yields for Bt maize plots were significantly greater than for non-Bt maize; however, insecticides did not significantly affect yield. Insecticides significantly decreased root injury in non-Bt maize plots, but there were no significant differences in root injury between Bt maize with or without either insecticide. Maize producing the Bt toxin Cry3Bb1 and the soil-applied insecticide Aztec significantly decreased survival of western corn rootworm (Diabrotica virgifera virgifera LeConte), while only Bt maize significantly decreased survival of the northern corn rootworm (Diabrotica barberi Smith & Lawrence). For both species, Bt maize and each of the insecticides delayed emergence. In the absence of density-dependent mortality, Bt maize imposed 71 and 80% reduction in survival on the western corn rootworm and the northern corn rootworm, respectively. The data from this study do not support combining insecticide with Bt maize because the addition of insecticide did not increase yield or reduce root injury for Bt maize, and the level of rootworm mortality achieved with conventional insecticide was likely too low to delay the evolution of Bt resistance. In addition, delays in emergence from Bt maize combined with insecticides could promote assortative mating among Bt-selected individuals, which may hasten resistance evolution.


Patients who challenge.
Individuals have different values. They seek to express their individuality even when receiving medical care. It is a part of modern medical practice and respect for patient autonomy to show respect for different values. We give an account of what it means to respect different values and challenging patients in medical practice. Challenging choices are often choices which are perceived by many to be either irrational or against a person's interests, such as engaging in harmful or excessively risky activities. When the medical profession is involved in such choices, the basic medical principle of acting in a person's best interests is challenged. Often doctors refuse to respect controversial choices on paternalistic grounds. We should all respect and facilitate the controversial choices of competent individuals, subject to resource limitations, our own and others well-being and autonomy, and the public interest. But more importantly, sometimes such choices make for a better, more autonomous life. Sometimes, such choices reflect considerations of global well-being or altruism, or idiosyncratic attitudes to risk. Sometimes, they reflect unusual values. However, in some other cases, controversial choices are irrational and are not expressions of our autonomy. Doctors should assist patients to make rational if individual choices. The patient also bears the responsibility for bringing his beliefs to the attention of the clinician.


Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation.
Tribbles pseudokinase-3 (TRIB3) has been proposed to act as an inhibitor of AKT although the precise molecular basis of this activity and whether the loss of TRIB3 contributes to cancer initiation and progression remain to be clarified. In this study, by using a wide array of in vitro and in vivo approaches, including a Trib3 knockout mouse, we demonstrate that TRIB3 has a tumor-suppressing role. We also find that the mechanism by which TRIB3 loss enhances tumorigenesis relies on the dysregulation of the phosphorylation of AKT by the mTORC2 complex, which leads to an enhanced phosphorylation of AKT on Ser473 and the subsequent hyperphosphorylation and inactivation of the transcription factor FOXO3. These observations support the notion that loss of TRIB3 is associated with a more aggressive phenotype in various types of tumors by enhancing the activity of the mTORC2/AKT/FOXO axis.


Stable changes in CD4+ T lymphocyte miRNA expression after exposure to HIV-1.
MicroRNAs (miRNAs) inhibit HIV-1 expression by either modulating host innate immunity or by directly interfering with viral mRNAs. We evaluated the expression of 377 miRNAs in CD4(+) T cells from HIV-1 élite long-term nonprogressors (éLTNPs), naive patients, and multiply exposed uninfected (MEU) patients, and we observed that the éLTNP patients clustered with naive patients, whereas all MEU subjects grouped together. The discriminatory power of miRNAs showed that 21 miRNAs significantly differentiated éLTNP from MEU patients and 23 miRNAs distinguished naive from MEU patients, whereas only 1 miRNA (miR-155) discriminated éLTNP from naive patients. We proposed that miRNA expression may discriminate between HIV-1-infected and -exposed but negative patients. Analysis of miRNAs expression after exposure of healthy CD4(+) T cells to gp120 in vitro confirmed our hypothesis that a miRNA profile could be the result not only of a productive infection but also of the exposure to HIV-1 products that leave a signature in immune cells. The comparison of normalized Dicer and Drosha expression in ex vivo and in vitro condition revealed that these enzymes did not affect the change of miRNA profiles, supporting the existence of a Dicer-independent biogenesis pathway.


Smoking patterns among primary school students in Turkey.
Cigarette smoking continues to be a threat to global health. The number of cigarettes smoked per person tends to increase each year, and the age of starting seems to be dropping. The research related to cigarette smoking conducted among young people generally studied high school or university students. However, studies have shown that students usually start smoking during the primary school period out of curiosity or imitation. The purpose of the present study was to find the prevalence of cigarette smoking among primary school students and the reasons for starting smoking, and to determine the characteristics of cigarette smoking of their parents. This study was conducted among 17 primary schools chosen according to their socioeconomic situations in different municipality districts in Turkey, with 9,408 students participating. Data were obtained by questionnaire. The mean age to start smoking was 11.7 +/- 1.6; 82.9% of the students who took part in this study had never smoked before, 13.4% had tried smoking at least once, and 3.7% had been smoking regularly. The biggest reason for smoking was just curiosity or imitation. It was determined that a risk factor for students to start smoking was parents who smoke. The 17% smoking rate among primary school students was high in our opinion and prevention studies initiated. In addition, the effects of cigarette-smoking parents on students who start smoking should also be considered.


Two Drosophila regulatory genes, deformed and the Broad-Complex, share common functions in development of adult CNS, head, and salivary glands.
Deformed (Dfd), a homeotic selector gene required for segment identity in the head, and the Broad-Complex (BR-C), a steroid hormone-regulated locus required for metamorphosis of the epidermis and multiple internal tissues, are members of distinct genetic regulatory hierarchies. Their protein products contain DNA-binding domains (of the homeodomain and zinc-finger variety, respectively) and are believed to act by regulating the transcription of target genes. In this study we demonstrate that Dfd and BR-C mutants dying during metamorphosis share defects of CNS reorganization, ventral adult head development, and adult salivary gland morphogenesis. Specifically, the shared phenotypes are (i) failure to separate the subesophageal ganglion (SEG) from the thoracic ganglion (TG); (ii) structural and functional abnormalities of the proboscis and maxillary palps, innervated by the SEG; and (iii) failure of the adult salivary glands to extend into the thorax. Experiments performed with a conditional allele demonstrate that Dfd+ function during either larval life or metamorphosis is sufficient to rescue the SEG-TG separation phenotype. BR-C;Dfd double mutants show synergistic enhancement of the ventral head defects. This genetic interaction suggests that the segment identity and steroid hormone-sensitive regulatory hierarchies intersect during postembryonic development.


An inverse relationship between autoimmune liver diseases and Strongyloides stercoralis infection.
A case-control study was undertaken to describe the prevalence of Strongyloides stercoralis infection among patients with autoimmune liver diseases, such as primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH), and primary sclerosing cholangitis (PSC). This study covered 4,117 patients who were admitted to hospitals in Okinawa, Japan, between 1988 and 2006. During this period, 538 patients had the following chronic liver diseases: PBC, AIH, PSC, chronic viral hepatitis group, and alcoholic liver disease. The other 3,579 patients who were hospitalized and underwent parasitologic tests served as controls. The frequency of S. stercoralis infection in the autoimmune liver diseases group (1.0%) was lower than that found in the control group (7.0%; P = 0.0063). None of the female patients with PBC born before 1955 had S. stercoralis infection, which was also statistically significant (P = 0.045). We hypothesized that immunomodulation by S. stercoralis infection may lower the incidence of autoimmune liver disease.


Pulmonary function in young and older athletes and untrained men.
This study compared the lung volumes and pulmonary functions of older endurance-trained athletes with those of healthy sedentary age-matched controls, young athletes, and young untrained men to determine whether training affects the age-associated changes in these variables. Despite large differences in maximal 02 consumption (VO2max), the older athletes and their sedentary peers had similar values for all pulmonary variables when expressed as absolute values. However, because the older athletes were shorter than the older sedentary men, their vital capacity, total lung capacity (TLC), and forced expiratory volume in 1 s were significantly larger than those of the older sedentary men when normalized for age and height; the average values for maximal voluntary ventilation and residual volume (RV) were also larger in the older athletes when normalized for age and height, but the differences were not significant. The young trained and untrained men did not differ in any of these measures. TLC was the only pulmonary variable that was the same in the young and older men; RV and the RV-to-TLC ratio were larger, whereas all other pulmonary function and volume measures were lower in the older men compared with the younger men. The older athletes were the only group whose lung volumes and pulmonary function measures were all, except for RV, substantially greater than expected based on their age and height. Thus prolonged strenuous endurance training in these older highly trained endurance athletes appears to have altered the decline in pulmonary function and volumes associated with aging.


Energy-conversion properties of vapor-liquid-solid-grown silicon wire-array photocathodes.
Silicon wire arrays, though attractive materials for use in photovoltaics and as photocathodes for hydrogen generation, have to date exhibited poor performance. Using a copper-catalyzed, vapor-liquid-solid-growth process, SiCl4 and BCl3 were used to grow ordered arrays of crystalline p-type silicon (p-Si) microwires on p+-Si(111) substrates. When these wire arrays were used as photocathodes in contact with an aqueous methyl viologen(2+/+) electrolyte, energy-conversion efficiencies of up to 3% were observed for monochromatic 808-nanometer light at fluxes comparable to solar illumination, despite an external quantum yield at short circuit of only 0.2. Internal quantum yields were at least 0.7, demonstrating that the measured photocurrents were limited by light absorption in the wire arrays, which filled only 4% of the incident optical plane in our test devices. The inherent performance of these wires thus conceptually allows the development of efficient photovoltaic and photoelectrochemical energy-conversion devices based on a radial junction platform.


Submicron polyacrolein particles in situ embedded with upconversion nanoparticles for bioassay.
We report a new surface modification approach of upconversion nanoparticles (UCNPs) structured as inorganic hosts NaYF4 codoped with Yb(3+) and Er(3+) based on their encapsulation in a two-stage process of precipitation polymerization of acrolein under alkaline conditions in the presence of UCNPs. The use of tetramethylammonium hydroxide both as an initiator of acrolein polymerization and as an agent for UCNP hydrophilization made it possible to increase the polyacrolein yield up to 90%. This approach enabled the facile, lossless embedment of UCNPs into the polymer particles suitable for bioassay. These particles are readily dispersible in aqueous and physiological buffers, exhibiting excellent photoluminescence properties, chemical stability, and also allow the control of particle diameters. The feasibility of the as-produced photoluminescent polymer particles mean-sized 260 nm for in vivo optical whole-animal imaging was also demonstrated using a home-built epi-luminescence imaging system.


Impaired NLRP3 inflammasome activity during fetal development regulates IL-1β production in human monocytes.
Interleukin-1β (IL-1β) production is impaired in cord blood monocytes. However, the mechanism underlying this developmental attenuation remains unclear. Here, we analyzed the extent of variability within the Toll-like receptor (TLR)/NLRP3 inflammasome pathways in human neonates. We show that immature low CD14 expressing/CD16(pos) monocytes predominate before 33 weeks of gestation, and that these cells lack production of the pro-IL-1β precursor protein upon LPS stimulation. In contrast, high levels of pro-IL-1β are produced within high CD14 expressing monocytes, although these cells are unable to secrete mature IL-1β. The lack of secreted IL-1β in these monocytes parallels a reduction of NLRP3 induction following TLR stimulation resulting in a lack of caspase-1 activity before 29 weeks of gestation, whereas expression of the apoptosis-associated speck-like protein containing a CARD and function of the P2×7 receptor are preserved. Our analyses also reveal a strong inhibitory effect of placental infection on LPS/ATP-induced caspase-1 activity in cord blood monocytes. Lastly, secretion of IL-1β in preterm neonates is restored to adult levels during the neonatal period, indicating rapid maturation of these responses after birth. Collectively, our data highlight important developmental mechanisms regulating IL-1β responses early in gestation, in part due to a downregulation of TLR-mediated NLRP3 expression. Such mechanisms may serve to limit potentially damaging inflammatory responses in a developing fetus.


Maintenance of High Genome Integrity over Vegetative Growth in the Fairy-Ring Mushroom Marasmius oreades.
Most mutations in coding regions of the genome are deleterious, causing selection to favor mechanisms that minimize the mutational load over time [1-5]. DNA replication during cell division is a major source of new mutations. It is therefore important to limit the number of cell divisions between generations, particularly for large and long-lived organisms [6-9]. The germline cells of animals and the slowly dividing cells in plant meristems are adaptations to control the number of mutations that accumulate over generations [9-11]. Fungi lack a separated germline while harboring species with very large and long-lived individuals that appear to maintain highly stable genomes within their mycelia [8, 12, 13]. Here, we studied genomic mutation accumulation in the fairy-ring mushroom Marasmius oreades. We generated a chromosome-level genome assembly using a combination of cutting-edge DNA sequencing technologies and re-sequenced 40 samples originating from six individuals of this fungus. The low number of mutations recovered in the sequencing data suggests the presence of an unknown mechanism that works to maintain extraordinary genome integrity over vegetative growth in M. oreades. The highly structured growth pattern of M. oreades allowed us to estimate the number of cell divisions leading up to each sample [14, 15], and from this data, we infer an incredibly low per mitosis mutation rate (3.8 × 10-12 mutations per site and cell division) as one of several possible explanations for the low number of identified mutations.


Supplemental intravenous crystalloids for the prevention of postoperative nausea and vomiting: quantitative review.
Hypovolaemia after overnight fasting is believed to exacerbate postoperative nausea and vomiting (PONV). However, data on the efficacy of supplemental i.v. crystalloids for PONV prophylaxis are conflicting. We performed a literature search using CENTRAL, MEDLINE, EMBASE, CINAHL, and Web of Science. We included prospective randomized controlled trials that reported PONV event rates in patients receiving supplemental i.v. crystalloids or a conservative fluid regimen after elective surgery under general anaesthesia. Studies were evaluated with regard to random sequence generation, allocation concealment, blinding of participants, personnel, and outcome assessment, incomplete outcome data, and selective reporting. We identified 15 trials (n=787 crystalloids; n=783 conservative fluids). Compared with conservative fluids, i.v. crystalloids reduced the risk of early postoperative nausea (PON) (relative risk 0.73, 95% confidence interval 0.59-0.89; P=0.003), late PON (0.41, 0.22-0.76; P=0.004), and overall PON (0.66, 0.46-0.95; P=0.02). I.V. crystalloids did not reduce the risk of early postoperative vomiting (POV) (0.66, 0.37-1.16; P=0.16) or late POV (0.52, 0.25-1.11; P=0.09), but did reduce overall POV (0.48, 0.29-0.79; P=0.004). I.V. crystalloids did not reduce the risk of early PONV (0.74, 0.49-1.12; P=0.16), but did reduce the risk of late PONV (0.27, 0.13-0.54; P<0.001) and overall PONV (0.59, 0.42-0.84; P=0.003). I.V. crystalloids reduced the need for antiemetic rescue treatment (0.56, 0.45-0.68; P<0.001). In summary, supplemental i.v. crystalloids were associated with a lower incidence of several PONV outcomes. However, a number of PONV outcomes failed to reach statistical significance, perhaps due to the lack of power. Thus, studies sufficiently powered for the less frequent outcomes (e.g. POV) are required.


Examining the relationship between home literacy environment and neural correlates of phonological processing in beginning readers with and without a familial risk for dyslexia: an fMRI study.
Developmental dyslexia is a language-based learning disability characterized by persistent difficulty in learning to read. While an understanding of genetic contributions is emerging, the ways the environment affects brain functioning in children with developmental dyslexia are poorly understood. A relationship between the home literacy environment (HLE) and neural correlates of reading has been identified in typically developing children, yet it remains unclear whether similar effects are observable in children with a genetic predisposition for dyslexia. Understanding environmental contributions is important given that we do not understand why some genetically at-risk children do not develop dyslexia. Here, we investigate for the first time the relationship between HLE and the neural correlates of phonological processing in beginning readers with (FHD+, n = 29) and without (FHD-, n = 21) a family history of developmental dyslexia. We further controlled for socioeconomic status to isolate the neurobiological mechanism by which HLE affects reading development. Group differences revealed stronger correlation of HLE with brain activation in the left inferior/middle frontal and right fusiform gyri in FHD- compared to FHD+ children, suggesting greater impact of HLE on manipulation of phonological codes and recruitment of orthographic representations in typically developing children. In contrast, activation in the right precentral gyrus showed a significantly stronger correlation with HLE in FHD+ compared to FHD- children, suggesting emerging compensatory networks in genetically at-risk children. Overall, our results suggest that genetic predisposition for dyslexia alters contributions of HLE to early reading skills before formal reading instruction, which has important implications for educational practice and intervention models.


Is measurement of renal function necessary for all trauma patients before iodinated contrast administration?
The purpose of this study was to identify factors at the time of presentation which could quickly exclude or identify renal dysfunction in blunt trauma patients, thus negating serum measurement of renal function prior to contrast-enhanced imaging and expediting care. Patients, >18 years old, without renal failure, presenting after blunt trauma, with serum creatinine measured at presentation, were retrospectively studied at a single center. Variables recorded at presentation including vitals, mechanism, and past medical history were analyzed using multivariate regression analysis to identify independent predictors of abnormal renal function. From 2009 to 2015, a total of 1099 patients met the inclusion criteria. Of those, 75 (6.8%) had renal dysfunction at presentation. Patients with renal dysfunction had a mean age of 74.3 (SD 15.5) years old, and 57.3% were male. Multivariate analysis identified independent predictors of renal dysfunction at presentation as age ≥ 61 (p < 0.001), hypotension (p = 0.02), and diabetes (p = 0.02). The presence of a single identified factor had an 85% sensitivity for renal dysfunction and a 98.5% negative predictive value. Impaired renal function at presentation was infrequent in our trauma cohort. Trauma patients who were normotensive, under the age of 61, and without diabetes were unlikely to have impaired renal function at presentation. In the urgent setting of trauma, patients without these comorbidities are likely safe to forgo screening of renal function prior to contrast-enhanced imaging.


Two-wavelength sinusoidal phase/modulating laser-diode interferometer insensitive to external disturbances.
We describe a two-wavelength laser-diode interferometer that is insensitive to external disturbances such as fluctuations in the wavelength of the laser diode and mechanical vibrations of the optical components. In sinusoidal phase-modulating interferometry this insensitivity is easily obtained by controlling the injection current of the laser diode with a feedback control system. Using an equivalent wavelength of 152 microm provided by two single-frequency laser diodes, we can measure the distance, rotation angle, and surface profile measurements with great accuracy.


Increased oxidative damage to membrane lipids following surgery for breast cancer.
To evaluate the level of oxidative damage to membrane lipids due to the breast cancer surgery in the early postoperative period. Blood samples were collected on the preoperative day and 24 hours postoperatively in 71 women operated for breast cancer, and preoperatively in 38 female patients with benign breast tumour. Lipid peroxidation (LPO) in the blood samples was estimated by measuring the concentrations of malondialdehyde+4-hydroxyalkenals (MDA+4-HDA) with spectrophotometry. tumour site, tumour histological findings, cancer stage, grade, tumour volume, state of lymph nodes, type of surgery for breast, type of surgery for axilla. Blood LPO level was similar in breast cancer patients and benign tumour patients (2.01±0.46 nmol/ml vs. 1.92±0.39 nmol/ml, respectively; p>0.05). In cancer patients, MDA+4-HDA increased on the first postoperative day, i.e. from 2.01±0.46 nmol/ml to 2.58±0.98 nmol/ml (p=0.0001). In women with benign breast tumour, LPO did not relate to the histological finding (p=0.8915). In the breast cancer group, preoperative LPO did not correlate with age, tumour volume and number of metastatic lymph nodes. Level of MDA+4-HDA was similar in stages I/II (2.03±0.46 nmol/ml) compared to stages III/IV (1.69±0.26 nmol/ml, p=0.1521). Consequently, levels of MDA+4-HDA did not relate to disease stage (p=0.1364). Surgery for breast cancer causes peripheral increase in oxidative damage to macromolecules in the early postoperative period. Therefore, perioperative antioxidant supplementation should be considered.


Effect of minoxidil on proliferation and apoptosis in dermal papilla cells of human hair follicle.
Minoxidil has been widely used to treat androgenetic alopecia, but little is known about its pharmacological activity or about the identity of its target cells in hair follicles. We hypothesized that minoxidil has direct effects on the proliferation and apoptosis of dermal papilla cells (DPCs) of human hair follicle. To elucidate the mechanism of topical minoxidil action in terms of stimulating hair growth. We evaluated cell proliferations in cultured DPCs by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and measured the expressions of extracellular signal-regulated kinase (ERK), Akt, Bcl-2, and Bax by Western blot. We also measured elongation of hair follicles in organ culture. Minoxidil significantly increased the proliferation of DPCs. The levels of ERK phosphorylation and of phosphorylated Akt increased significantly 1 h post-treatment; percentage increase of ERK phosphorylation was 287% at 0.1 microM and 351% at 1.0 microM of minoxidil, and that of Akt phosphorylation was 168% at 0.1 microM and 257% at 1.0 microM of minoxidil. 1.0 microM of minoxidil increased Bcl-2 expression over 150%, while 1.0 microM of minoxidil decreased Bax expression by more than 50%. Moreover, a significant elongation of individual hair follicles in organ culture was observed after adding minoxidil. Minoxidil promotes the survival of human DPCs by activating both ERK and Akt and by preventing cell death by increasing the ratio of Bcl-2/Bax. We suggest that minoxidil stimulates the growth of human hairs by prolonging anagen through these proliferative and anti-apoptotic effects on DPCs.


Probing Anti-inflammatory Properties Independent of NF-κB Through Conformational Constraint of Peptide-Based Interleukin-1 Receptor Biased Ligands.
Interleukin-1β (IL-1β) binds to the IL-1 receptor (IL-1R) and is a key cytokine mediator of inflammasome activation. IL-1β signaling leads to parturition in preterm birth (PTB) and contributes to the retinal vaso-obliteration characteristic of oxygen-induced retinopathy (OIR) of premature infants. Therapeutics targeting IL-1β and IL-1R are approved to treat rheumatoid arthritis; however, all are large proteins with clinical limitations including immunosuppression, due in part to inhibition of NF-κB signaling, which is required for immuno-vigilance and cytoprotection. The all-D-amino acid peptide 1 (101.10, H-d-Arg-d-Tyr-d-Thr-d-Val-d-Glu-d-Leu-d-Ala-NH2) is an allosteric IL-1R modulator, which exhibits functional selectivity and conserves NF-κB signaling while inhibiting other IL-1-activated pathways. Peptide 1 has proven effective in experimental models of PTB and OIR. Seeking understanding of the structural requirements for the activity and biased signaling of 1, a panel of twelve derivatives was synthesized employing the various stereochemical isomers of α-amino-γ-lactam (Agl) and α-amino-β-hydroxy-γ-lactam (Hgl) residues to constrain the D-Thr-D-Val dipeptide residue. Using circular dichroism spectroscopy, the peptide conformation in solution was observed to be contingent on Agl, Hgl, and Val stereochemistry. Moreover, the lactam mimic structure and configuration influenced biased IL-1 signaling in an in vitro panel of cellular assays as well as in vivo activity in murine models of PTB and OIR. Remarkably, all Agl and Hgl analogs of peptide 1 did not inhibit NF-κB signaling but blocked other pathways, such as JNK and ROCK2 phosphorylation contingent on structure and configuration. Efficacy in preventing preterm labor correlated with a capacity to block IL-1β-induced IL-1β synthesis. Furthermore, the importance of inhibition of JNK and ROCK2 phosphorylation for enhanced activity was highlighted for prevention of vaso-obliteration in the OIR model. Taken together, lactam mimic structure and stereochemistry strongly influenced conformation and biased signaling. Selective modulation of IL-1 signaling was proven to be particularly beneficial for curbing inflammation in models of preterm labor and retinopathy of prematurity (ROP). A class of biased ligands has been created with potential to serve as selective probes for studying IL-1 signaling in disease. Moreover, the small peptide mimic prototypes are promising leads for developing immunomodulatory therapies with easier administration and maintenance of beneficial effects of NF-κB signaling.


Insulinlike growth factor-binding protein modulates the growth response to insulinlike growth factor 1 by human gastric cancer cells.
This study determined whether the resistance to the mitogenic effect of insulinlike growth factor 1 (IGF-1) in AGS (we found that IGF-1 had almost no effect on the growth of AGS) cells is caused by the absence of IGF-1 receptor on the cells or by the interference of endogenous IGFs and IGF-binding protein (IGFBP). IGF-1 receptors were examined by radioligand binding assay. The protein in conditioned medium and the molecular weight of IGF-1 receptors on AGS cells were determined by affinity cross-linking with 125I-IGF-1 followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Messenger RNAs for IGF-1, IGF-2, and IGFBP-4 were detected by Northern analysis. AGS cells possessed a single class of high-affinity binding sites for IGF-1 (dissociation constant [Kd], 0.51), with a binding capacity approximately 4 x 10(4) sites per cell. The size of the alpha subunit of IGF-1 receptors on cell membranes was approximately 130 kilodaltons. des (1-3) IGF-1, a truncated IGF-1 with very low affinity to IGFBPs, stimulated AGS cell growth in dose-dependent fashion. The medium conditioned by AGS cells contained IGFBPs of 27-32 and 37-42 kilodaltons. AGS cells expressed messenger (mRNA) RNAs for IGF-2 and IGFBP-4 but not for IGF-1, whereas another gastric carcinoma cell line (SIIA), whose growth is stimulated by IGF-1, expressed mRNA IGF-2 but did not express mRNA for IGF-1 or IGFBP-4: The relative absence of growth response of AGS cells to IGF-1 is due to the endogenously produced IGFBPs sequestering IGF-1 and preventing receptor interaction.


Snake venomics of the Central American rattlesnake Crotalus simus and the South American Crotalus durissus complex points to neurotoxicity as an adaptive paedomorphic trend along Crotalus dispersal in South America.
We report a comparative venomic and antivenomic characterization of the venoms of newborn and adult specimens of the Central American rattlesnake, Crotalus simus, and of the subspecies cumanensis, durissus, ruruima, and terrificus of South American Crotalus durissus. Neonate and adult C. simus share about 50% of their venom proteome. The venom proteome of 6-week-old C. simus is predominantly made of the neurotoxic heterodimeric phospholipase A(2) (PLA(2) crotoxin) (55.9%) and serine proteinases (36%), whereas snake venom Zn(2+)-metalloproteinases (SVMPs), exclusively of class PIII, represent only 2% of the total venom proteins. In marked contrast, venom from adult C. simus comprises toxins from 7 protein families. A large proportion (71.7%) of these toxins are SVMPs, two-thirds of which belong to the PIII class. These toxin profiles correlate well with the overall biochemical and pharmacological features of venoms from adult (hemorrhagic) and newborn (neurotoxic) C. simus specimens. The venoms of the South American Crotalus subspecies belong to one of two distinct phenotypes. C. d. cumanensis exhibits high levels of SVMPs and low lethal potency (LD(50)), whereas C. d. subspecies terrificus, ruruima, and durissus have low SVMP activity and high neurotoxicity to mice. Their overall toxin compositions explain the outcome of envenomation by these species. Further, in all C. simus and C. durissus venoms, the concentration of neurotoxins (crotoxin and crotamine) is directly related with lethal activity, whereas lethality and metalloproteinase activity show an inverse relationship. The similar venom toxin profiles of newborn C. simus and adult C. durissus terrificus, ruruima, and durissus subspecies strongly suggests that the South American taxa have retained juvenile venom characteristics in the adult form (paedomorphism) along their North-South stepping-stone dispersal. The driving force behind paedomorphism is often competition or predation pressure. The increased concentration of the neurotoxins crotoxin and crotamine in South American rattlesnake venoms strongly argues that the gain of neurotoxicity and lethal venom activities to mammals may have represented the key axis along which overall venom toxicity has evolved during Crotalus durissus invasion of South America. The paedomorphic trend is supported by a decreasing LNC (lethal neurotoxicity coefficient, defined as the ratio between the average LD(50) of the venom and the crotoxin + crotamine concentration) along the North-South axis, coincident with the evolutionary dispersal pattern of the Neotropical rattlesnakes. The indistinguisable immunoreactivity patterns of Costa Rican and Venezuelan polyvalent antivenoms toward C. simus and C. durissus venoms strongly suggest the possibility of using these antivenoms indistinctly for the management of snakebites by adult C. simus and by certain C. d. cumanensis populations exhibiting a hemorrhagic venom phenotype. The antivenomic results also explain why the antivenoms effectively neutralize the hemorrhagic activity of adult C. simus venoms but does not protect against adult C. durissus sp. and newborn C. simus envenomations. The identification of evolutionary trends among tropical Crotalus, as reported here, may have an impact in defining the mixture of venoms for immunization to produce an effective pan-American anti-Crotalus antivenom.


Purifying selection and genetic drift shaped Pleistocene evolution of the mitochondrial genome in an endangered Australian freshwater fish.
Genetic variation in mitochondrial genes could underlie metabolic adaptations because mitochondrially encoded proteins are directly involved in a pathway supplying energy to metabolism. Macquarie perch from river basins exposed to different climates differ in size and growth rate, suggesting potential presence of adaptive metabolic differences. We used complete mitochondrial genome sequences to build a phylogeny, estimate lineage divergence times and identify signatures of purifying and positive selection acting on mitochondrial genes for 25 Macquarie perch from three basins: Murray-Darling Basin (MDB), Hawkesbury-Nepean Basin (HNB) and Shoalhaven Basin (SB). Phylogenetic analysis resolved basin-level clades, supporting incipient speciation previously inferred from differentiation in allozymes, microsatellites and mitochondrial control region. The estimated time of lineage divergence suggested an early- to mid-Pleistocene split between SB and the common ancestor of HNB+MDB, followed by mid-to-late Pleistocene splitting between HNB and MDB. These divergence estimates are more recent than previous ones. Our analyses suggested that evolutionary drivers differed between inland MDB and coastal HNB. In the cooler and more climatically variable MDB, mitogenomes evolved under strong purifying selection, whereas in the warmer and more climatically stable HNB, purifying selection was relaxed. Evidence for relaxed selection in the HNB includes elevated transfer RNA and 16S ribosomal RNA polymorphism, presence of potentially mildly deleterious mutations and a codon (ATP6113) displaying signatures of positive selection (ratio of nonsynonymous to synonymous substitution rates (dN/dS) >1, radical change of an amino-acid property and phylogenetic conservation across the Percichthyidae). In addition, the difference could be because of stronger genetic drift in the smaller and historically more subdivided HNB with low per-population effective population sizes.


[Cloxacillin-susceptible Staphylococcus aureus with high MIC to glycopeptides. Ever we use cloxacillin?].
Staphylococcus aureus infections are yet an important cause of morbidity and mortality despite of numerous effective anti-staphylococcal antibiotics available. There has been an increasing incidence of methicillin-resistant strains which might have led to a wider use of vancomycin. This seems to ride alongside a covert progressive increase of S. aureus vancomycin minimum inhibitory concentration. In this way, the emergence of vancomycin-intermediate S. aureus (VISA) strains and heteroresistant-VISA has raised concern for the scarcity of alternative treatment options. Equally alarming, though fortunately less frequent, is the emergence of vancomycin-resistant S. aureus. Ultimately, various debate issues have arisen regarding the emergence of S. aureus strains with decreased vancomycin susceptibility, within the range still considered sensitive. These strains have shown a different clinical behaviour regardless of vancomycin use, both in methicillin resistant and sensitive S. aureus. The emergence of increasing vancomycin-resistance in S. aureus isolates, has stirred up the basis of therapeutic approach in staphylococcal infections. There is yet much to explore to better define the impact of higher vancomycin minimum inhibitory concentration in staphylococcal infections.


Beta-caryophyllene enhances wound healing through multiple routes.
Beta-caryophyllene is an odoriferous bicyclic sesquiterpene found in various herbs and spices. Recently, it was found that beta-caryophyllene is a ligand of the cannabinoid receptor 2 (CB2). Activation of CB2 will decrease pain, a major signal for inflammatory responses. We hypothesized that beta-caryophyllene can affect wound healing by decreasing inflammation. Here we show that cutaneous wounds of mice treated with beta-caryophyllene had enhanced re-epithelialization. The treated tissue showed increased cell proliferation and cells treated with beta-caryophyllene showed enhanced cell migration, suggesting that the higher re-epithelialization is due to enhanced cell proliferation and cell migration. The treated tissues also had up-regulated gene expression for hair follicle bulge stem cells. Olfactory receptors were not involved in the enhanced wound healing. Transient Receptor Potential channel genes were up-regulated in the injured skin exposed to beta-caryophyllene. Interestingly, there were sex differences in the impact of beta- caryophyllene as only the injured skin of female mice had enhanced re-epithelialization after exposure to beta-caryophyllene. Our study suggests that chemical compounds included in essential oils have the capability to improve wound healing, an effect generated by synergetic impacts of multiple pathways.


In-vivo activation of Raf-1 inhibits tumor growth and development in a xenograft model of human medullary thyroid cancer.
Apart from surgical resection, there are no effective therapies for medullary thyroid cancer, a neuroendocrine tumor derived from parafollicular C cells. We have previously shown that activation of raf-1 in TT-raf cells by estradiol suppresses tumor cell growth and calcitonin secretion in vitro. TT-raf cells are a human medullary thyroid cancer cell line that contains an estrogen-inducible raf-1 construct. The in-vivo effects of raf-1 activation in this cell line, however, have not been characterized. Therefore, we utilized TT or TT-raf cells in a murine subcutaneous xenograft model to study tumor development and growth. Activation of raf-1, in mice with TT-raf tumors, led to a significant decrease in medullary thyroid cancer tumor formation. Control groups, however, had a high rate of medullary thyroid cancer tumor development. These data indicate that raf-1 activation by estradiol treatment in this TT-raf xenograft model inhibited tumor development. Furthermore, to determine whether raf-1 activation could also inhibit the growth of established tumors, estradiol and control pellets were implanted after tumor development. The TT-raf group that received estradiol pellets showed an 8-fold decrease in tumor volume compared with the TT-raf control group. Taken together, these results suggest that in-vivo activation of raf-1 in a murine model of medullary thyroid cancer not only led to a reduction in tumor development, but also inhibited the growth of established tumors. These results suggest that strategies to activate the raf-1/MEK/ERK1/2 signaling pathway may be a viable approach to treat patients with metastatic medullary thyroid cancer.


Cardiopulmonary effects of three concentrations of isoflurane with or without mechanical ventilation and supramaximal noxious stimulation in New Zealand white rabbits.
To determine the cardiopulmonary effects of 3 doses of isoflurane, with and without controlled mechanical ventilation and noxious stimulation, in healthy adult New Zealand white rabbits. 6 adult female rabbits. Each rabbit was administered isoflurane in oxygen at each of 3 anesthetic doses (1.0, 1.5, or 2.0 times the published minimum alveolar concentration of 2.07%). At each anesthetic dose, blood gas and cardiopulmonary measurements were obtained before and during application of a supramaximal noxious stimulus. Effects of spontaneous and mechanical ventilation were assessed during separate anesthetic episodes. Mean ± SEM isoflurane concentrations used were 2.11 ± 0.04%, 3.14 ± 0.07%, and 4.15 ± 0.06%. During spontaneous ventilation, the rabbits' Paco2 and mixed venous Pco2 significantly increased with concomitant reductions in both arterial and mixed venous pH as isoflurane concentration increased. Cardiac output and vascular resistance did not change significantly. Noxious stimulation minimally affected measured cardiopulmonary variables. During mechanical ventilation, significant reductions in arterial blood pressures and cardiac output occurred with increasing isoflurane dose. Systemic vascular resistance index at the highest anesthetic dose was significantly lower than the value at the lowest anesthetic dose. During noxious stimulation, systolic arterial blood pressure and cardiac output significantly increased at the 2 lower isoflurane concentrations, but not at the highest concentration. In rabbits, isoflurane-induced dose-dependent cardiopulmonary depression was attributable to vasodilation and negative inotropy. At an isoflurane concentration of 4.15% with mechanical ventilation, cardiovascular depression was severe; use of unnecessarily high isoflurane concentrations in this species should be avoided.


The health care utilization of people in prison and after prison release: A population-based cohort study in Ontario, Canada.
Many people experience imprisonment each year, and this population bears a disproportionate burden of morbidity and mortality. States have an obligation to provide equitable health care in prison and to attend to care on release. Our objective was to describe health care utilization in prison and post-release for persons released from provincial prison in Ontario, Canada in 2010, and to compare health care utilization with the general population. We conducted a population-based retrospective cohort study. We included all persons released from provincial prison to the community in 2010, and age- and sex-matched general population controls. We linked identities for persons released from prison to administrative health data. We matched each person by age and sex with four general population controls. We examined ambulatory care and emergency department utilization and medical-surgical and psychiatric hospitalization, both in prison and in the three months after release to the community. We compared rates with those of the general population. The rates of all types of health care utilization were significantly higher in prison and on release for people released from prison (N = 48,861) compared to general population controls (N = 195,444). Comparing those released from prison to general population controls in prison and in the 3 months after release, respectively, utilization rates were 5.3 (95% CI 5.2, 5.4) and 2.4 (95% CI 2.4, 2.5) for ambulatory care, 3.5 (95% CI 3.3, 3.7) and 5.0 (95% CI 4.9, 5.3) for emergency department utilization, 2.3 (95% CI 2.0, 2.7) and 3.2 (95% CI 2.9, 3.5) for medical-surgical hospitalization, and 21.5 (95% CI 16.7, 27.7) and 17.5 (14.4, 21.2) for psychiatric hospitalization. Comparing the time in prison to the week after release, ambulatory care use decreased from 16.0 (95% CI 15.9,16.1) to 10.7 (95% CI 10.5, 10.9) visits/person-year, emergency department use increased from 0.7 (95% CI 0.6, 0.7) to 2.6 (95% CI 2.5, 2.7) visits/person-year, and hospitalization increased from 5.4 (95% CI 4.8, 5.9) to 12.3 (95% CI 10.1, 14.6) admissions/100 person-years for medical-surgical reasons and from 8.6 (95% CI 7.9, 9.3) to 17.3 (95% CI 14.6, 20.0) admissions/100 person-years for psychiatric reasons. Across care types, health care utilization in prison and on release is elevated for people who experience imprisonment in Ontario, Canada. This may reflect high morbidity and suboptimal access to quality health care. Future research should identify reasons for increased use and interventions to improve care.


Continuous relative phase variability during an exhaustive run in runners with a history of iliotibial band syndrome.
Previous research has proposed that a lack of variability in lower extremity coupling during running is associated with pathology. The purpose of the study was to evaluate lower extremity coupling variability in runners with and without a history of iliotibial band syndrome (ITBS) during an exhaustive run. Sixteen runners ran to voluntary exhaustion on a motorized treadmill while a motion capture system recorded reflective marker locations. Eight runners had a history of ITBS. At the start and end of the run, continuous relative phase (CRP) angles and CRP variability between strides were calculated for key lower extremity kinematic couplings. The ITBS runners demonstrated less CRP variability than controls in several couplings between segments that have been associated with knee pain and ITBS symptoms, including tibia rotation-rearfoot motion and rearfoot motion-thigh ad/abduction, but more variability in knee flexion/extension-foot ad/abduction. The ITBS runners also demonstrated low variability at heel strike in coupling between rearfoot motion-tibia rotation. The results suggest that runners prone to ITBS use abnormal segmental coordination patterns, particular in couplings involving thigh ad/abduction and tibia internal/external rotation. Implications for variability in injury etiology are suggested.