Non-classical light generated by quantum-noise-driven cavity optomechanics.
Optomechanical systems, in which light drives and is affected by the motion of a massive object, will comprise a new framework for nonlinear quantum optics, with applications ranging from the storage and transduction of quantum information to enhanced detection sensitivity in gravitational wave detectors. However, quantum optical effects in optomechanical systems have remained obscure, because their detection requires the object's motion to be dominated by vacuum fluctuations in the optical radiation pressure; so far, direct observations have been stymied by technical and thermal noise. Here we report an implementation of cavity optomechanics using ultracold atoms in which the collective atomic motion is dominantly driven by quantum fluctuations in radiation pressure. The back-action of this motion onto the cavity light field produces ponderomotive squeezing. We detect this quantum phenomenon by measuring sub-shot-noise optical squeezing. Furthermore, the system acts as a low-power, high-gain, nonlinear parametric amplifier for optical fluctuations, demonstrating a gain of 20 dB with a pump corresponding to an average of only seven intracavity photons. These findings may pave the way for low-power quantum optical devices, surpassing quantum limits on position and force sensing, and the control and measurement of motion in quantum gases.


Exercise intensity does not effect body composition change in untrained, moderately overfat women.
To determine whether exercise intensity effects a change in body composition. Twelve untrained, moderately overfat, weight-stable women were randomly assigned to a high-intensity (80% VO2max) or low-intensity (50% VO2max) exercise group. Subjects trained four times per week for 12 weeks in monitored sessions, with a duration sufficient to expend 300 kcal. During this time, subjects were instructed to maintain their normal diet and activity patterns. Pretesting and posttesting included measurement of height, weight, body fat (via hydrostatic weighing), seven skinfold sites, seven circumference sites, and VO2max. Results were analyzed using the Student's t test and paired samples t test. Posttesting revealed no significant between-group differences for change in weight, percent body fat, fat mass, fat-free mass, sum of skinfold measurements, or sum of circumference measurements. Mean weight loss was 0.7 lb for the high-intensity group (P = .55) and 3.3 lb for the low-intensity group (P = .03). Hydrostatic data revealed that each group lost an identical amount of fat (5.0 lb), but the high-intensity group gained more than twice as much fat-free mass (4.3 vs 1.8 lb). The greater increase in fat-free mass by the high-intensity group explains why the low-intensity group had a greater absolute weight loss. This study suggests that fat loss is a function of energy expended rather than exercise intensity. Therefore, if fat loss is the goal and time is limited, persons should exercise safely at as high an intensity as tolerable to expend as much energy as possible during their allotted time.


Caregiver outcomes of the REACH-HF multicentre randomized controlled trial of home-based rehabilitation for heart failure with reduced ejection fraction.
Caregivers frequently provide support to people living with long-term conditions. However, there is paucity of evidence of interventions that support caregivers in their role. Rehabilitation EnAblement in Chronic Heart Failure (REACH-HF) is a novel home-based, health-professional-facilitated, self-management programme for patients with heart failure (HF) and their caregivers. Based on the random allocation of individual adult patients with reduced ejection fraction (HFrEF) and left ventricular ejection fraction <45% within the past five years, the caregiver of patients was allocated to receive the REACH-HF intervention over 12 weeks (REACH-HF group) or not (control group). Caregiver outcomes were generic health-related quality of life (EQ-5D-5L), Family Caregiver Quality of Life Scale questionnaire (FamQol), Caregiver Burden Questionnaire HF (CBQ-HF), Caregiver Contribution to Self-care of HF Index questionnaire (CC-SCHFI) and Hospital Anxiety and Depression Scale (HADS). Outcomes were compared between groups at 4, 6 and 12 months follow-up. Twenty caregivers receiving REACH-HF were purposively selected for qualitative interviews at 4 and 12 months. Compared with controls (44 caregivers), the REACH-HF group (53 caregivers) had a higher mean CC-SCHFI confidence score at 12 months (57.5 vs 62.8, adjusted mean difference: 9.3, 95% confidence interval: 1.8-16.8, p = 0.016). No significant between group differences were seen in other caregiver outcomes. Qualitative interviews showed that most caregivers who received the REACH-HF intervention made positive changes to how they supported the HF patient they were caring for, and perceived that they had increased their confidence in the caregiver role over time. Provision of the REACH-HF intervention for caregivers of HF patients improved their confidence of self-management and was perceived for some to be helpful in supporting their caregiver role.


Impact of a leptin single nucleotide polymorphism and zilpaterol hydrochloride on growth and carcass characteristics in finishing steers.
A total of 4,178 steers (mean initial BW = 403.9 ± 16.04 kg) were used to test the interactive effects, if any, of leptin R25C genotypes (CC, CT, or TT) and zilpaterol hydrochloride (ZH) feeding duration on growth performance and carcass traits. Steers were blocked by arrival at the feed yard, genotyped for the leptin SNP, allotted to genotype-specific pens (90 steers/pen), and assigned randomly within genotype and block to 0 or 21 d of dietary ZH. All pens within a block were slaughtered on the same day (132.1 ± 10.9 d on feed). Final BW of steers fed ZH was 6.0 kg heavier (P = 0.008), and ZH-fed steers had greater (P = 0.003) ADG than steers not fed ZH. Feeding ZH decreased DMI in steers with increased frequency of the T allele (9.67, 9.53, and 9.28 kg/d for CC, CT, and TT, respectively), but DMI increased with the frequency of the T allele (9.68, 9.90, and 10.1 kg for CC, CT, and TT, respectively) when ZH was not fed (leptin genotype × ZH, P = 0.011). At the conclusion of the study, ultrasonic fat was greatest for TT steers (11.4 ± 0.28 mm) and least (P = 0.003) for CC steers (11.0 ± 0.25 mm). Regardless of ZH-feeding duration, TT steers produced a greater (P = 0.006) percentage of USDA yield grade (YG) 4 or higher carcasses (5.4 vs. 2.7%) and a lesser (P = 0.006) percentage of YG 1 carcasses (17.7 vs. 26.8%) than CC steers. In addition, ZH-fed steers produced a greater (P < 0.001) percentage of USDA YG 1 carcasses (25.9 vs. 16.2%) and a lesser (P < 0.001) percentage of YG 4 or higher carcasses (1.6 vs. 6.0%) than steers fed the control diet. Marbling scores and the percentage of carcasses grading USDA Choice and Prime were greater in TT than CC steers when fed diets devoid of ZH, but both marbling and quality grades did not differ among leptin genotypes when fed ZH for 21 d (leptin genotype × ZH, P ≤ 0.03). The amount of HCW gain tended to be less (P = 0.095) for steers of the TT genotype (12.7 kg) than either CC (16.3 kg) or CT (17.0 kg) genotypes. Results indicated that leptin R25C genotype impacted most traits associated with fatness whereas feeding ZH for 21 d affected HCW and ADG positively but impacted feed intake, marbling, and USDA quality grades negatively.


Short term effects of air pollution on mortality in the city of Lyon, France, 1985-90.
The short term association between daily mortality and ambient air pollution in the city of Lyon, France (population, 410,000) between 1985 and 1990 was assessed using time series analysis. This study followed the standardised design and statistical analysis (Poisson regression) that characterise the APHEA project. Four categories of cause of death were studied: total (minus external causes), respiratory, cardiovascular, and digestive causes (as a control condition). No association was found with any cause of death for nitrogen dioxide (NO2) and ozone (O3), nor, for any pollutant, for digestive conditions. Sulphur dioxide (SO2) and, to a much lesser degree, suspended particles (PM13), were significantly related to mortality from respiratory and cardiovascular conditions. The relative risk (RR) of respiratory deaths associated with a 50 micrograms/m3 increment of mean daily SO2 over the whole period was 1.22 (95% CI 1.05, 1.40); the RR for cardiovascular deaths was 1.54 (1.22, 1.96). The corresponding RRs for PM13 were 1.04 (1.00, 1.09) for respiratory mortality and 1.04 (0.99, 1.10) for cardiovascular deaths. The effects of particulates were slightly increased during the cold season. When particulates concentrations were greater than 60 micrograms/m3, the joint SO2 effect was increased, suggesting some interaction between the two pollution indicators. These results agree with other studies showing an association between particulate pollution and daily mortality; however, they also suggest the noxious effect of SO2.


Sex differences in ET-1 receptor expression and Ca2+ signaling in the IMCD.
The inner medullary collecting duct (IMCD) is the nephron segment with the highest production of endothelin-1 (ET-1) and the greatest expression of ET-1 receptors that function to adjust Na(+) and water balance. We have reported that male rats have reduced natriuresis in response to direct intramedullary infusion of ET-1 compared with female rats. Our aim was to determine whether alterations of ET-1 receptor expression and downstream intracellular Ca(2+) signaling within the IMCD could account for these sex differences. IMCDs from male and female rats were isolated for radioligand binding or microdissected for intracellular Ca(2+) ([Ca(2+)]i) measurement by fluorescence imaging of fura-2 AM. IMCD from male and female rats had similar ETB expression (655 ± 201 vs. 567 ± 39 fmol/mg protein, respectively), whereas male rats had significantly higher ETA expression (436 ± 162 vs. 47 ± 29 fmol/mg protein, respectively; P < 0.05). The [Ca(2+)]i response to ET-1 was significantly greater in IMCDs from male compared with female rats (288 ± 52 vs. 118 ± 32 AUC, nM × 3 min, respectively; P < 0.05). In IMCDs from male rats, the [Ca(2+)]i response to ET-1 was significantly blunted by the ETA antagonist BQ-123 but not by the ETB antagonist BQ-788 (control: 137 ± 27; BQ-123: 53 ± 11; BQ-788: 84 ± 25 AUC, nM × 3 min; P < 0.05), consistent with greater ETA receptor function in male rats. These data demonstrate a sex difference in ETA receptor expression that results in differences in ET-1 Ca(2+) signaling in IMCD. Since activation of ETA receptors is thought to oppose ETB receptor activation, enhanced ETA function in male rats could limit the natriuretic effects of ETB receptor activation.


Identification of new urinary gamma-hydroxybutyric acid markers applying untargeted metabolomics analysis following placebo-controlled administration to humans.
Gamma-hydroxybutyrate (GHB) is a short-chain fatty acid that occurs naturally in the mammalian brain and is prescribed as a medication against narcolepsy or used as a drug of abuse. Particularly, its use as a knock-out drug in cases of drug-facilitated crimes is of major importance in forensic toxicology. Because of its rapid metabolism and resulting narrow detection windows (<12 hours in urine), detection of GHB remains challenging. Thus, there is an urgent call for new markers to improve the reliable detection of GHB use. In the framework of a randomized, placebo-controlled, crossover study in 20 healthy male volunteers, urine samples obtained 4.5 hours post-administration were submitted to untargeted mass spectrometry [MS, quadrupole time of flight (QTOF)] analysis to identify possible new markers of GHB intake. MS data from four different analytical methods (reversed phase and hydrophilic interaction liquid chromatography; positive and negative electrospray ionization) were filtered for significantly changed features applying univariate and multivariate statistics. From the resulting 42 compounds of interest, 8 were finally identified including conjugates of GHB with carnitine, glutamate, and glycine as well as the endogenous compounds glycolate and succinylcarnitine. While GHB conjugates were only detectable in the GHB, but not in the placebo group, glycolate and succinylcarnitine were present in both groups albeit significantly increased through GHB intake. Untargeted metabolomics proved as a suitable tool for the non-hypothesis driven identification of new GHB markers. However, more studies on actual concentrations, detection windows, and stability will be necessary to assess the suitability of these markers for routine application.


Hepatitis B virus DNA integration in a sequence homologous to v-erb-A and steroid receptor genes in a hepatocellular carcinoma.
Hepatitis B virus (HBV) is clearly involved in the aetiology of human hepatocellular carcinoma (HCC) and the finding of HBV DNA integration into human liver DNA in almost all HCCs studied suggested that these integrated viral sequences may be involved in liver oncogenesis. Several HBV integrations in different HCCs and HCC-derived cell lines have been analysed after molecular cloning without revealing any obvious role for HBV. From a comparison of a HBV integration site present in a particular HCC with the corresponding unoccupied site in the non-tumorous tissue of the same liver, we now report that HBV integration places the viral sequence next to a liver cell sequence which bears a striking resemblance to both an oncogene (v-erb-A) and the supposed DNA-binding domain of the human glucocorticoid receptor and human oestrogen receptor genes. We suggest that this gene, usually silent or transcribed at a very low level in normal hepatocytes, becomes inappropriately expressed as a consequence of HBV integration, thus contributing to the cell transformation.


Zinc-iron, but not zinc-alone supplementation, increased linear growth of stunted infants with low haemoglobin.
Zinc supplementation has been shown to benefit linear growth. However the effect may depend on whether zinc is the most limiting nutrient. This study aims to investigate the effect of supplementation with zinc-given alone or with iron and vitamin-A in improving infantsf micronutrient status and linear growth. The study was a double-blind-community-intervention study involving 800 infants aged 3-6 months in rural East Lombok, West Nusa Tenggara. Syrup consisting of zinc-alone, Zn (10 mg/d), zinc+iron, Zn+Fe (10 mg/d of each), zinc+iron+vitamin-A, Zn+Fe+vit.A (10 mg/d of each zinc and iron plus 1,000 IU vitamin-A), or placebo were given daily for six months. Outcomes measured were length, weight, and micronutrient status (haemoglobin, se-rum zinc, ferritin and retinol). Zn+Fe and Zn+Fe+vit.A supplementations benefit zinc and iron status of the sub-jects, while Zn-alone supplementation disadvantaged haemoglobin and iron status. The highest increment in vi-tamin A and haemoglobin status was shown in Zn+Fe+vit.A group. An effect on linear growth was observed among initially-stunted subjects in Zn+Fe and Zn+Fe+vit.A groups who grew 1.1-1.5 cm longer than placebo. On the other hand, in the Zn-alone group, mean height-for-age Z-score decreased to a greater extent than placebo. The between-group difference in HAZ among initially-stunted subjects was significant after four months sup-plementation. While the difference was not significant in follow-up after 6 months, the pattern remained the same where means height-for-age Z-score in Zn+Fe+vit.A and Zn+Fe groups were higher than placebo and Zn-alone groups. Given the low haemoglobin/iron status of the subjects, zinc supplementation would have positive effect on growth if the low haemoglobin/iron status is also addressed and corrected.


Dynamic regulation of SCG10 in regenerating axons after injury.
Peripheral axons can re-extend robustly after nerve injury. Soon after a nerve crush regenerating axons grow through the nerve segment distal to the lesion in close proximity to distal axons that are still morphologically and molecularly preserved. Hence, following the progress of regenerating axons necessitates markers that can distinguish between regenerating and degenerating axons. Here, we show that axonal levels of superior cervical ganglion 10 (SCG10) are dynamically regulated after axonal injury and provide an efficient method to label regenerating axons. In contrast to the rapid loss of SCG10 in distal axons (Shin et al., 2012b), we report that SCG10 accumulates in the proximal axons within an hour after injury, leading to a rapid identification of the lesion site. The increase in SCG10 levels is maintained during axon regeneration after nerve crush or nerve repair and allows for more selective labeling of regenerating axons than the commonly used markers growth-associated protein 43 (GAP43) and YFP. SCG10 is preferentially expressed in regenerating sensory axons rather than motor axons in the sciatic nerve. In a mouse model of slow Wallerian degeneration, SCG10 labeling remains selective for regenerating axons and allows for a quantitative analysis of delayed regeneration in this mutant. Taken together, these data demonstrate the utility of SCG10 as an efficient and selective marker of sensory axon regeneration.


High TWIST1 mRNA expression is associated with poor prognosis in lymph node-negative and estrogen receptor-positive human breast cancer and is co-expressed with stromal as well as ECM related genes.
The TWIST homolog 1 (TWIST1) is a transcription factor that induces epithelial to mesenchymal transition (EMT), a key process in metastasis. The purpose of this study was to investigate whether TWIST1 expression predicts disease progression in a large breast cancer cohort with long-term clinical follow-up, and to reveal the biology related to TWIST1 mediated disease progression. TWIST1 mRNA expression level was analyzed by quantitative real-time reverse polymerase chain reaction (RT-PCR) in 1,427 primary breast cancers. In uni- and multivariate analysis using Cox regression, TWIST1 mRNA expression level was associated with metastasis-free survival (MFS), disease-free survival (DFS) and overall survival (OS). Separate analyses in lymph node-negative patients (LNN, n = 778) who did not receive adjuvant systemic therapy, before and after stratification into estrogen receptor (ER)-positive (n = 552) and ER-negative (n = 226) disease, were also performed. The association of TWIST1 mRNA with survival endpoints was assessed using Kaplan-Meier analysis. Using gene expression arrays, genes showing a significant Spearman rank correlation with TWIST1 were used to identify overrepresented Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG)-annotated biological pathways. Increased mRNA expression level of TWIST1 analyzed as a continuous variable in both uni- and multivariate analysis was associated with shorter MFS in all patients (hazard ratio (HR): 1.17, 95% confidence interval, (95% CI):1.09 to 1.26; and HR: 1.17, 95% CI: 1.08 to 1.26; respectively), in LNN patients (HR: 1.22, 95% CI: 1.09 to 1.36; and HR: 1.21, 95% CI: 1.07 to 1.36; respectively) and in the ER-positive subgroup of LNN patients (HR: 1.34, 95% CI: 1.17 to 1.53; and HR: 1.32, 95% CI: 1.14 to 1.53; respectively). Similarly, high TWIST1 expression was associated with shorter DFS and OS in all patients and in the LNN/ER-positive subgroup. In contrast, no association of TWIST1 mRNA expression with MFS, DFS or OS was observed in ER-negative patients. Genes highly correlated with TWIST1 were significantly enriched for cell adhesion and ECM-related signaling pathways. Furthermore, TWIST1 mRNA was highly expressed in tumor stroma and positively related to tumor stromal content (P <0.001). TWIST1 mRNA expression is an independent prognostic factor for poor prognosis in LNN/ER-positive breast cancer. The biological associations suggest an involvement of the tumor microenvironment in TWIST1's adverse role in breast cancer.


Big-pharmaceuticalisation: clinical trials and Contract Research Organisations in India.
The World Trade Organisation's Trade Related Intellectual Property Rights [TRIPS] agreement aimed to harmonise intellectual property rights and patent protection globally. In India, the signing of this agreement resulted in a sharp increase in clinical trials since 2005. The Indian government, along with larger Indian pharmaceutical companies, believed that they could change existing commercial research cultures through the promotion of basic research as well as attracting international clinical trials, and thus create an international level, innovation-based drug industry. The effects of the growth of these outsourced and off-shored clinical trials on local commercial knowledge production in India are still unclear. What has been the impact of the increasing scale and commercialisation of clinical research on corporate science in India? In this paper we describe Big-pharmaceuticalisation in India, whereby the local pharmaceutical industry is moving from generic manufacturing to innovative research. Using conceptual frameworks of pharmaceuticalisation and innovation, this paper analyses data from research conducted in 2010-2012 and describes how Contract Research Organisations (CROs) enable outsourcing of randomised control trials to India. Focussing on twenty-five semi-structured interviews CRO staff, we chart the changes in Indian pharmaceutical industry, and implications for local research cultures. We use Big-pharmaceuticalisation to extend the notion of pharmaceuticalisation to describe the spread of pharmaceutical research globally and illustrate how TRIPS has encouraged a concentration of capital in India, with large companies gaining increasing market share and using their market power to rewrite regulations and introduce new regulatory practices in their own interest. Contract Research Organisations, with relevant, new, epistemic skills and capacities, are both manifestations of the changes in commercial research cultures, as well as the vehicles to achieve them. These changes have reinvigorated public concerns that stress not only access to new medicines but also the 'price' of innovation on research participants.


Spectroscopic photoacoustic microscopy using a photonic crystal fiber supercontinuum source.
Photoacoustic microscopy (PAM) provides high resolution images with excellent image contrast based on optical absorption. The compact size and high repetition rate of pulsed microchip lasers make them attractive sources for PAM. However, their fixed wavelength output precludes their use in spectroscopic PAM. We are developing a tunable optical source based on a microchip laser that is suitable for spectroscopic PAM. Pulses from a 6.6 kHz repetition rate Q-switched Nd:YAG microchip laser are sent through a photonic crystal fiber with a zero dispersion wavelength at 1040 nm. The highly nonlinear optical propagation produces a supercontinuum spectrum spanning 500-1300 nm. A tunable band pass filter selects the desired wavelength band from the supercontinuum. Our PAM system employs optical focusing and a 25 MHz spherically focused detection transducer. En-face imaging experiments were performed at seven different wavelengths from 575 to 875 nm. A simple discriminant analysis of the multiwavelength photoacoustic data produces images that clearly distinguish the different absorbing regions of ink phantoms. These results suggest the potential of this compact tunable source for spectroscopic photoacoustic microscopy.


CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.
3-methylglutaconic aciduria (3-MGA-uria) is a nonspecific finding associated with mitochondrial dysfunction, including defects of oxidative phosphorylation. 3-MGA-uria is classified into five groups, of which one, type IV, is genetically heterogeneous. Here we report five children with a form of type IV 3-MGA-uria characterized by cataracts, severe psychomotor regression during febrile episodes, epilepsy, neutropenia with frequent infections, and death in early childhood. Four of the individuals were of Greenlandic descent, and one was North American, of Northern European and Asian descent. Through a combination of homozygosity mapping in the Greenlandic individuals and exome sequencing in the North American, we identified biallelic variants in the caseinolytic peptidase B homolog (CLPB). The causative variants included one missense variant, c.803C>T (p.Thr268Met), and two nonsense variants, c.961A>T (p.Lys321*) and c.1249C>T (p.Arg417*). The level of CLPB protein was markedly decreased in fibroblasts and liver of affected individuals. CLPB is proposed to function as a mitochondrial chaperone involved in disaggregation of misfolded proteins, resulting from stress such as heat denaturation.


Investigations of an optimal inhaler technique with the use of urinary salbutamol excretion as a measure of relative bioavailability to the lung.
A simple non-invasive method, in which a urine sample is taken 30 minutes after drug administration, has previously been shown to be a measure of the relative bioavailability of salbutamol to the lungs. This technique has been used to determine an optimal inhaler technique with commercially available metered dose inhalers (MDI). Ten healthy subjects were trained in the use of MDIs. Each inhaled 4 x 100 micrograms salbutamol in a series of experiments to examine the relative bioavailability to the lung after different respiratory manoeuvres. Urine collection intervals were 0-0.5 hours and 0.5-24 hours after administration. There was significantly greater elimination of unchanged salbutamol 30 minutes after administration, indicating a greater relative bioavailability of salbutamol to the lungs after (1) exhaling gently to residual volume rather than to functional residual capacity before inhalation; (2) slow inhalation (10 l/min) compared with fast inhalation (50 l/min); (3) breath holding for 10 seconds after inhalation compared with no breath holding. All patient information leaflets and healthcare personnel should standardise the instructions given to patients and should adopt the inhalation method proposed.


Nucleic acid programmable protein array a just-in-time multiplexed protein expression and purification platform.
Systematic study of proteins requires the availability of thousands of proteins in functional format. However, traditional recombinant protein expression and purification methods have many drawbacks for such study at the proteome level. We have developed an innovative in situ protein expression and capture system, namely NAPPA (nucleic acid programmable protein array), where C-terminal tagged proteins are expressed using an in vitro expression system and efficiently captured/purified by antitag antibodies coprinted at each spot. The NAPPA technology presented in this chapter enable researchers to produce and display fresh proteins just in time in a multiplexed high-throughput fashion and utilize them for various downstream biochemical researches of interest. This platform could revolutionize the field of functional proteomics with it ability to produce thousands of spatially separated proteins in high density with narrow dynamic rand of protein concentrations, reproducibly and functionally.


Circulating tumour-derived DNA and RNA markers in blood: a tool for early detection, diagnostics, and follow-up?
Lung cancer is the most common cause of cancer death in developed countries. The prognosis is poor with only 10-15% of patients surviving 5 years after diagnosis. This dismal prognosis is attributed to the lack of efficient diagnostic methods for early detection and lack of successful treatment for metastatic disease. Within the last decade, rapid advances in molecular biology and radiology have provided a rational basis for improving early detection and patients' outcome. A non-invasive blood test effective in detecting preneoplastic changes or early lung cancer in high risk individuals has been perceived as a holy grail by cancer researchers. The introduction of polymerase chain reaction (PCR)-based technology in the late 1980s and its refinement over the last 10 years have allowed us to detect and quantify extremely small amounts of tumour-derived nucleic acids. This has led to an increased knowledge of the molecular pathogenesis of lung cancer and a basis for the use of DNA and RNA markers in blood for early cancer detection, diagnostics, and follow-up. Common genetic alterations in lung carcinogenesis are already well known. We reviewed published literature on DNA and RNA in plasma or serum in lung cancer patients up to 2004, with particular emphasis on reports published since 1995. Twenty-two clinical studies have evaluating the role of DNA and RNA aberrations in the blood of lung cancer patients. A total of 1618 (range 10-163/study) cases and 595 (range 10-120/study) control cases were evaluated, and overall plasma/serum abnormalities were found in 43% (range 0-78%) of cases and 0.8% of healthy controls. For (1) total DNA and gene expression levels, 61% (range 53-71%) of cases and 0.9% of controls; (2) oncogene mutations, 16% (range 0-30%) and 0%; (3) microsatellite alterations, 46% (range 24-71%) and 21% (controls with non-malignant pulmonary disease); (4) promoter methylation, 42% (range 5-73%) and 0%; (5) tumour-related RNAs, 54% (range 39-78%) and 6%. In general, the studies contain small series of lung cancer patients and even smaller or missing case control groups. The analysis of circulating DNA or RNA in plasma is a promising non-invasive diagnostic tool, requiring only a limited blood sample. Its wide applicability and potential importance will possibly lead to increasing clinical impact in the near future. However, large prospective clinical studies are needed to validate and standardise any tests for DNA or RNA alteration in plasma or serum of high risk individuals or patients with established lung cancer.


The five-factor gambling motivation model.
Pathological gambling is a serious social issue, but the underlying psychological motivations are poorly understood. This study developed a five-factor gambling motivation model. The five factors that motivate gambling (socialization, amusement, avoidance, excitement, and monetary motives) were derived from study data obtained from 240 college students. The structure of the five-factor model was confirmed by factor analysis of responses from 234 frequent gamblers. We then compared the "monetary motive version" of this model with the "parallel version" to determine which model more accurately describes how the five factors influence gambling. The monetary motive model holds that amusement, excitement, and avoidance motives influence gambling severity only through mediation of the monetary motive. The parallel model proposes that the five motives all independently influence gambling severity. We found that the avoidance and excitement motives did not have direct effects on gambling severity, but the monetary motive showed a direct positive influence. Thus the monetary motive model was more effective than the parallel model in explaining the influence of specific gambling motives on gambling severity. These findings may help in the improvement of therapy for pathological gambling.


Response kinetics in the complex chemotaxis signalling pathway of Rhodobacter sphaeroides.
Chemotaxis is one of the best-characterized signalling systems in biology. It is the mechanism by which bacteria move towards optimal environments and is implicated in biofilm formation, pathogenesis and symbiosis. The properties of the bacterial chemosensory response have been described in detail for the single chemosensory pathway of Escherichia coli. We have characterized the properties of the chemosensory response of Rhodobacter sphaeroides, an α-proteobacterium with multiple chemotaxis pathways, under two growth conditions allowing the effects of protein expression levels and cell architecture to be investigated. Using tethered cell assays, we measured the responses of the system to step changes in concentration of the attractant propionate and show that, independently of the growth conditions, R. sphaeroides is chemotactic over at least five orders of magnitude and has a sensing profile following Weber's Law. Mathematical modelling also shows that, as E. coli, R. sphaeroides is capable of showing fold-change detection (FCD). Our results indicate that general features of bacterial chemotaxis such as the range and sensitivity of detection, adaptation times, adherence to Weber's Law and the presence of FCD may be integral features of chemotaxis systems in general, regardless of network complexity, protein expression levels and cellular architecture across different species.


The effects of a home-based arm ergometry exercise programme on physical fitness, fatigue and activity in polio survivors: protocol for a randomised controlled trial.
Many Polio survivors have reduced mobility, pain and fatigue, which make access to conventional forms of aerobic exercise difficult. Inactivity leads to increased risk of health problems, many of which are prevalent among Polio survivors. Aerobic exercise programmes in Polio survivors should utilise stable muscle groups and should be designed to minimise exacerbation of pain and fatigue. A home-based arm ergometry aerobic exercise programme may represent an affordable and accessible exercise modality, incorporating exercise prescription principles in this group. This is a prospective, single blinded, randomised controlled trial. There are two arms; exercise intervention using arm ergometers and control. Polio survivors meeting eligibility criteria will be recruited and randomly allocated to intervention or control groups. Participants allocated to the intervention group will receive a small arm ergometer and a polar heart rate monitor. They will carry out a home-based moderate intensity (50-70% HRMax) aerobic exercise programme for eight weeks, following instruction by the treating physiotherapist. Assessments will occur at baseline and after eight weeks and will include tests of physical fitness, activity, energy cost of walking, fatigue and quality of life. Clinically feasible assessment tools including the Six Minute Arm Test, the Physical Activity Scale for People with Physical Disabilities questionnaire, the Physiological Cost Index, Fatigue Severity Scale and the SF-36v2 will be utilised. The efficacy of a home-based arm ergometry programme in Polio survivors will be examined. No previous trial has examined such a programme using a wide range of outcome measures pertinent to Polio survivors. This study will provide new information on the impact of arm ergometry on physical fitness, activity, body composition, fatigue, pain, muscle strength, and health related quality of life. Also, the study will provide information, which at present is lacking, on safety of aerobic exercise in Polio, as potential negative outcomes of activity including loss of muscle strength, increased pain and fatigue will be closely monitored.


Rheumatoid arthritis-associated polymorphisms at 6q23 are associated with radiological damage in autoantibody-positive RA.
Recent studies have identified 6q23 as an important susceptibility locus for rheumatoid arthritis (RA), with risk alleles at 3 single-nucleotide polymorphisms combining to give an effect size greater than that of these markers individually. We investigated whether these polymorphisms are also associated with disease severity measured by radiological damage. We studied 927 patients from a cross-sectional RA cohort. Median Larsen scores (LS) read from radiographs taken at study entry were compared by genotype at rs6920220, rs13207033, and rs5029937 according to a dominant model using negative binomial regression with stratification for autoantibody status. Median LS was associated with genotype at rs6920220 [LS 31 GG vs 36 GA/AA (p=0.02) in cyclic citrullinated peptide+ (CCP) RA] and rs13020220 [LS 37 GG vs 29 GA/AA (p=0.02) in CCP+ RA] only in autoantibody-positive RA, with no association at rs5029937. Association was stronger for these markers in combination [LS 28 vs 42 for lowest vs highest risk genotype combination in rheumatoid factor positivity (p=0.007), LS 28 vs 37 for anti-CCP+ (p=0.01)]. Established RA risk markers at 6q23 are associated also with radiographic severity in autoantibody-positive RA; as for susceptibility, the association for these markers in combination is stronger than that for markers alone.


Loop-mediated isothermal amplification method targeting the TTS1 gene cluster for detection of Burkholderia pseudomallei and diagnosis of melioidosis.
Melioidosis is a severe infection caused by Burkholderia pseudomallei. The timely implementation of effective antimicrobial treatment requires rapid diagnosis. Loop-mediated isothermal amplification (LAMP) targeting the TTS1 gene cluster was developed for the detection of B. pseudomallei. LAMP was sensitive and specific for the laboratory detection of this organism. The lower limit of detection was 38 genomic copies per reaction, and LAMP was positive for 10 clinical B. pseudomallei isolates but negative for 5 B. thailandensis and 5 B. mallei isolates. A clinical evaluation was conducted in northeast Thailand to compare LAMP to an established real-time PCR assay targeting the same TTS1 gene cluster. A total of 846 samples were obtained from 383 patients with suspected melioidosis, 77 of whom were subsequently diagnosed with culture-confirmed melioidosis. Of these 77 patients, a positive result was obtained from one or more specimens by PCR in 26 cases (sensitivity, 34%; 95% confidence interval [CI], 23.4 to 45.4%) and by LAMP in 34 cases (sensitivity, 44%; 95% CI, 32.8 to 55.9%) (P = 0.02). All samples from 306 patients that were culture negative for B. pseudomallei were negative by PCR (specificity, 100%; 95% CI, 98.8 to 100%), but 5 of 306 patients (1.6%) were positive by LAMP (specificity, 98.4%; 95% CI, 96.2 to 99.5%) (P = 0.03). The diagnostic accuracies of PCR and LAMP were 86.7% (95% CI, 82.9 to 89.9%) and 87.5% (95% CI, 83.7 to 90.6%), respectively (P = 0.47). Both assays were very insensitive when applied to blood samples; PCR and LAMP were positive for 0 and 1 of 44 positive blood cultures, respectively. The PCR and LAMP assays evaluated here are not sufficiently sensitive to replace culture in our clinical setting.


Functional Anatomy of the Inferior Longitudinal Fasciculus: From Historical Reports to Current Hypotheses.
The inferior longitudinal fasciculus (ILF) is a long-range, associative white matter pathway that connects the occipital and temporal-occipital areas of the brain to the anterior temporal areas. In view of the ILF's anatomic connections, it has been suggested that this pathway has a major role in a relatively large array of brain functions. Until recently, however, the literature data on these potential functions were scarce. Here, we review the key findings of recent anatomic, neuromodulation, and neuropsychological studies. We also summarize reports on how this tract is disrupted in a wide range of brain disorders, including psychopathologic, neurodevelopmental, and neurologic diseases. Our review reveals that the ILF is a multilayered, bidirectional tract involved in processing and modulating visual cues and thus in visually guided decisions and behaviors. Accordingly, sudden disruption of the ILF by neurologic insult is mainly associated with neuropsychological impairments of visual cognition (e.g., visual agnosia, prosopagnosia, and alexia). Furthermore, disruption of the ILF may constitute the pathophysiologic basis for visual hallucinations and socio-emotional impairments in schizophrenia, as well as emotional difficulties in autism spectrum disorder. Degeneration of the ILF in neurodegenerative diseases affecting the temporal lobe may explain (at least in part) the gradual onset of semantic and lexical access difficulties. Although some of the functions mediated by the ILF appear to be relatively lateralized, observations from neurosurgery suggest that disruption of the tract's anterior portion can be dynamically compensated for by the contralateral portion. This might explain why bilateral disruption of the ILF in either acute or progressive disease is highly detrimental in neuropsychological terms.


Cord blood Lin(-)CD45(-) embryonic-like stem cells are a heterogeneous population that lack self-renewal capacity.
Human umbilical cord blood (hUCB) has been proposed to contain not only haematopoietic stem cells, but also a rare pluripotent embryonic-like stem cell (ELSc) population that is negative for hematopoietic markers (Lin(-)CD45(-)) and expresses markers typical of pluripotent cells. The aim of this work was to isolate, characterise and expand this ELSc fraction from hUCB, as it may provide a valuable cell source for regenerative medicine applications. We found that we could indeed isolate a Lin(-)CD45(-) population of small cells (3-10 µm diameter) with a high nucleus to cytoplasm ratio that expressed the stem cell markers CD34 and CXCR4. However, in contrast to some previous reports, this fraction was not positive for CD133. Furthermore, although these cells expressed transcripts typical of pluripotent cells, such as SOX2, OCT3/4, and NANOG, they were not able to proliferate in any of the culture media known to support stem cell growth that we tested. Further analysis of the Lin(-)CD45(-) population by flow cytometry showed the presence of a Lin(-)CD45(-)Nestin(+) population that were also positive for CD34 (20%) but negative for CXCR4. These data suggest that the Lin(-)CD45(-) stem cell fraction present in the cord blood represents a small heterogeneous population with phenotypic characteristics of stem cells, including a Lin(-)CD45(-)Nestin(+) population not previously described. This study also suggests that heterogeneity within the Lin(-)CD45(-) cell fraction is the likely explanation for differences in the hUCB cell populations described by different groups that were isolated using different methods. These populations have been widely called "embryonic-like stem cell" on the basis of their phenotypical similarity to embryonic stem cells. However, the fact they do not seem to be able to self-renew casts some doubt on their identity, and warns against defining them as "embryonic-like stem cell" at this stage.


What makes bodies beautiful.
Health and beauty are the most important physical ideals. This paper seeks to compare and contrast these ideals, based on a value theory of human abilities. Health is comprehended as a potential ability to act grounded in bodily functions. Beauty is explained as a symbolising reference to happiness, physical beauty as a combination of organic orientation to purpose and virtuous orientation to action. Physical beauty is the implicit symbolic expression of mental and physical health. This teleological theory is tested and exemplified using current stereotypes such as youthfulness, slimness and shapeliness.


Characteristics of Pediatric Rapid Response Systems: Results From a Survey of PRIS Hospitals.
Many hospitals use rapid response systems (RRSs) to identify and intervene on hospitalized children at risk for deterioration. To describe RRS characteristics across hospitals in the Pediatric Research in Inpatient Settings (PRIS) network. We developed the survey through a series of prospective respondent, expert, and cognitive interviews. One institutional expert per PRIS hospital (n = 109) was asked to complete the web survey. We summarized responses using descriptive statistics with a secondary analysis of univariate associations between RRS characteristics and perceived effectiveness. The response rate was 72% (79 of 109). Respondents represented diverse hospital types and were primarily physicians (97%) with leadership roles in care escalation. Many hospitals used an early warning score (77%) for identification with variable characteristics (46% automated versus 54% full or partially manual calculation; inputs included vital signs [98%], physical examination findings [88%], diagnoses [23%], medications [19%], and diagnostic tests [14%]). Few incorporated a validated prediction model (9%). Similarly, many RRSs used a rapid response team for intervention (93%) with variable team composition (respiratory therapists [94%], ICU nurses [93%], ICU providers [67%], and pharmacists [27%]). Some used the early warning score to trigger the rapid response team (50%). Only a few staffed a clinician to proactively surveil hospitalized children for risk of deterioration (18%), and these tended to be larger hospitals (annual admissions 12 000 vs 6000, P = .007). Most responding experts stated their RRSs improved patient outcomes (92%). RRS characteristics varied across PRIS hospitals.


Differential vulnerabilities of urethral afferents in diabetes and discovery of a novel urethra-to-urethra reflex.
Urethral reflexes are important regulators of micturition, and impairment of urethral afferent neuronal function may disrupt coordinated bladder and urethral activity, thereby contributing to voiding dysfunction in lower urinary tract disorders. Chemical stimulation by intraurethral irritant solution perfusion was used to determine whether urethral afferent neuronal function is altered in diabetes mellitus (DM). Sprague-Dawley rats were studied 10 wk after streptozotocin injection to induce DM or vehicle alone. Escalating doses of capsaicin (0.1-30 microM) or acetic acid (0.01-1%; AA) were perfused intraurethrally while recording isovolumetric bladder activity, urethral perfusion pressure, and electromyography of the external urethral sphincter (EUS-EMG). Some rats were additionally treated with alpha-bungarotoxin, hexamethonium, or bilateral transection of the sensory branches of the pudendal nerves (PudSNx). Intraurethral capsaicin inhibited bladder contractions in six out of seven control rats but not in any of six DM rats. Low-frequency oscillations (LFOs) of intraurethral pressure were observed in five out of six control rats with capsaicin-induced bladder inhibition. In contrast, intraurethral AA inhibited bladder contractions and enhanced tonic EUS-EMG activity in six out of six control and five out of six DM rats. LFOs occurred in four out of six control and three of five DM rats with AA-induced bladder inhibition. Chemically induced bladder inhibition and LFOs were not prevented by alpha-bungarotoxin but were eliminated by PudSNx and hexamethonium. Finally, LFOs were followed by phasic EUS activity. These findings show that DM affects urethral afferent neurons differentially, compromising those expressing TRPV1 receptors. Urethral smooth muscle LFOs are neurogenically mediated and induce EUS activity, revealing the existence of a hitherto undescribed reflex pathway: a smooth-to-striated muscle urethra-to-urethra reflex.


All-optical three-dimensional mapping of 180 degrees domains hidden in a BaTiO(3) crystal.
We present three-dimensional, high-contrast maps of 180 degrees domains hidden inside photorefractive crystals of BaTiO(3). Some domains are columns that run the entire length of the crystal, whereas others are short needles that begin predominantly on the -c surface but disappear inside the crystal bulk.


Searching for an optimal hand hygiene bundle: a meta-analysis.
Many studies have evaluated bundled interventions to improve hand hygiene compliance. However, there are few evidence-based recommendations on optimal interventions for implementation. We aimed to systematically review all studies on interventions to improve hand hygiene compliance to evaluate existing bundles and identify areas of promise to target high-quality studies. Adjusted risk ratios were pooled to assess common bundles. Of the 8148 studies evaluated, 6 randomized controlled trials and 39 quasi-experimental studies met inclusion criteria. Three studies evaluated the interventions education, reminders, feedback, administrative support, and access to alcohol-based hand rub as a bundle, which was associated with improved hand hygiene compliance (pooled odds ratio [OR], 1.82; 95% confidence interval [CI], 1.69-1.97). Another bundle of education, reminders, and feedback evaluated in 3 studies was associated with improved compliance (pooled OR, 1.47; 95% CI, 1.12-1.94). These bundles should be further studied using high-quality study designs and compared with other interventions.


Tetraspanin CD82 Associates with Trafficking Vesicle in Muscle Cells and Binds to Dysferlin and Myoferlin.
Tetraspanins organize protein complexes at the cell membrane and are responsible for assembling diverse binding partners in changing cellular states. Tetraspanin CD82 is a useful cell surface marker for prospective isolation of human myogenic progenitors and its expression is decreased in Duchenne muscular dystrophy (DMD) cell lines. The function of CD82 in skeletal muscle remains elusive, partly because the binding partners of this tetraspanin in muscle cells have not been identified. CD82-associated proteins are sought to be identified in human myotubes via mass spectrometry proteomics, which identifies dysferlin and myoferlin as CD82-binding partners. In human dysferlinopathy (Limb girdle muscular dystrophy R2, LGMDR2) myogenic cell lines, expression of CD82 protein is near absent in two of four patient samples. In the cell lines where CD82 protein levels are unaffected, increased expression of the ≈72 kDa mini-dysferlin product is identified using an antibody recognizing the dysferlin C-terminus. These data demonstrate that CD82 binds dysferlin/myoferlin in differentiating muscle cells and its expression can be affected by loss of dysferlin in human myogenic cells.


Lung Transplantation for Lymphangioleiomyomatosis in Japan.
Lung transplantation has been established as the definitive treatment option for patients with advanced lymphangioleiomyomatosis (LAM). However, the prognosis after registration and the circumstances of lung transplantation with sirolimus therapy have never been reported. In this national survey, we analyzed data from 98 LAM patients registered for lung transplantation in the Japan Organ Transplantation Network. Transplantation was performed in 57 patients as of March 2014. Survival rate was 86.7% at 1 year, 82.5% at 3 years, 73.7% at 5 years, and 73.7% at 10 years. Of the 98 patients, 21 had an inactive status and received sirolimus more frequently than those with an active history (67% vs. 5%, p<0.001). Nine of twelve patients who remained inactive as of March 2014 initiated sirolimus before or while on a waiting list, and remained on sirolimus thereafter. Although the statistical analysis showed no statistically significant difference, the survival rate after registration tended to be better for lung transplant recipients than for those who awaited transplantation (p = 0.053). Lung transplantation is a satisfactory therapeutic option for advanced LAM, but the circumstances for pre-transplantation LAM patients are likely to alter with the use of sirolimus.


Ampullary cancer in a patient with familial adenomatous polyposis - a rare case report and current status of management.
Familial adenomatous polyposis (FAP) is an inherited autosomal dominant disorder. Extracolonic manifestations are seen quite often. As prophylactic colectomy has become a standard care in FAP patients, the concerns over the development of associated extracolonic malignancies have become more prevalent. The authors report a case of a patient with the history of subtotal colectomy because of FAP with the development of adenocarcinoma of papilla of Vater twenty-six years later. A radical procedure in form of proximal pancreaticoduodenectomy was indicated. Variable endoscopic surveillance protocols and treatment strategies have been proposed concerning the management of duodenal and periampullary lesions. In case of periampullary malignancies, the radical surgical resection offers the only chance for cure and the only option that may safeguard the long‑term survival (Fig. 2, Ref. 30). Keywords: ampulla of Vater, bile duct, obstructive jaundice, pancreatoduodenectomy, periampullary tumors.


Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status.
Retrospective studies suggest that p53 alteration is prognostic for recurrence in patients with urothelial bladder cancer and predictive for benefit from combination methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) adjuvant chemotherapy. Patients with pT1/T2N0M0 disease whose tumors demonstrated ≥ 10% nuclear reactivity on centrally performed immunohistochemistry for p53 were offered random assignment to three cycles of adjuvant MVAC versus observation; p53-negative patients were observed. By using a log-rank test with one-sided α = .05 and β = .10, 190 p53-positive patients were planned to be randomly assigned to detect an absolute improvement in probability of recurring by 3 years from 0.50 to 0.30. A total of 521 patients were registered, 499 underwent p53 assessment, 272 (55%) were positive, and 114 (42%) were randomly assigned. Accrual was halted on the basis of the data and safety monitoring board review of a futility analysis. Overall 5-year probability of recurring was 0.20 (95% CI, 0.16 to 0.24) with no difference on the basis of p53 status. Only 67% of patients randomly assigned to MVAC received all three cycles with 12 patients receiving no treatment. There was no difference in recurrence in the randomly assigned patients (hazard ratio, 0.78; 95% CI, 0.29 to 2.08; P = .62). Neither the prognostic value of p53 nor the benefit of MVAC chemotherapy in patients with p53-positive tumors was confirmed, but the high patient refusal rate, lower than expected event rate, and failures to receive assigned therapy severely compromised study power.


Increasing power to predict mild cognitive impairment conversion to Alzheimer's disease using hippocampal atrophy rate and statistical shape models.
Identifying mild cognitive impairment (MCI) subjects who will convert to clinical Alzheimer's disease (AD) is important for therapeutic decisions, patient counselling and clinical trials. Hippocampal volume and rate of atrophy predict clinical decline at the MCI stage and progression to AD. In this paper, we create p-maps from the differences in the shape of the hippocampus between 60 normal controls and 60 AD subjects using statistical shape models, and generate different regions of interest (ROI) by thresholding the p-maps at different significance levels. We demonstrate increased statistical power to classify 86 MCI converters and 128 MCI stable subjects using the hippocampal atrophy rates calculated by the boundary shift integral within these ROIs.


One size fits all? Promoting condom use for sexually transmitted infection prevention among heterosexual young adults.
The aims of this exploratory qualitative study were to increase our understanding of heterosexual young adults' knowledge and beliefs about sexually transmitted infections (STIs) other than HIV, to explore their beliefs about the factors that influence condom use for STI prevention, and to explore their ideas about how best to promote condom use for STI prevention. Data came from a qualitative study that used 11 group discussions with 53 heterosexual men and women aged 18-25. Respondents thought that STI infection and unplanned pregnancy were equally likely, but were less concerned about STIs than unplanned pregnancy. Respondents gave several reasons for their low levels of concern about STIs. They also suggested several means to promote condom use for STI prevention. They supported multi-faceted condom promotion campaigns, using multiple styles of communication and a variety of media. The range of suggestions given by participants suggests that rather than employing a 'one size fits all' strategy, a variety of different approaches are needed to promote condom use for STI prevention.


The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease.
Colorectal cancer (CRC) is the second most frequent cancer in developed countries. Newfoundland has the highest incidence of CRC in Canada and the highest rate of familial CRC yet reported in the world. To determine the impact of mutations in known CRC susceptibility genes and the contribution of the known pathways to the development of hereditary CRC, an incident cohort of 750 patients with CRC (708 different families) from the Newfoundland population was studied. Microsatellite instability (MSI) testing was performed on tumours, together with immunohistochemistry analysis for mismatch repair (MMR) genes. Where indicated, DNA sequencing and multiplex ligation-dependent probe amplifications of MMR genes and APC was undertaken. DNA from all patients was screened for MUTYH mutations. The presence of the BRAF variant, p.V600E, and of MLH1 promoter methylation was also tested in tumours. 4.6% of patients fulfilled the Amsterdam criteria (AC), and an additional 44.6% fulfilled the revised Bethesda criteria. MSI-high (MSI-H) was observed in 10.7% (n=78) of 732 tumours. In 3.6% (n=27) of patients, CRC was attributed to 12 different inherited mutations in six known CRC-related genes associated with chromosomal instability or MSI pathways. Seven patients (0.9%) carried a mutation in APC or biallelic mutations in MUTYH. Of 20 patients (2.7%) with mutations in MMR genes, 14 (70%) had one of two MSH2 founder mutations. 17 of 28 (61%) AC families did not have a genetic cause identified, of which 15 kindreds fulfilled the criteria for familial CRC type X (FCCTX). Founder mutations accounted for only 2.1% of cases and this was insufficient to explain the high rate of familial CRC. Many of the families classified as FCCTX may have highly penetrant mutations segregating in a Mendelian-like manner. These families will be important for identifying additional CRC susceptibility loci.


Widespread Genotype-Phenotype Correlations in Intellectual Disability.
Background: Linking genotype to phenotype is a major aim of genetics research, yet the underlying biochemical mechanisms of many complex conditions continue to remain elusive. Recent research provides evidence that relevant gene-phenotype associations are discoverable in the study of intellectual disability (ID). Here we expand on that work, identifying distinctive gene interaction modules with unique enrichment patterns reflective of associated clinical features in ID. Methods: Two hundred twelve forms of monogenic ID were curated according to comorbidities with autism and epilepsy. These groups were further subdivided according to secondary clinical manifestations of complex vs. simple facial dysmorphia and neurodegenerative-like features due to their clinical prominence, modest symptom overlap, and probable etiological divergence. An aggregate gene interaction ID network for these phenotype subgroups was discovered via a public database of known gene interactions: protein-protein, genetic, and mRNA coexpression. Additional annotation resources (Gene Ontology, Human Phenotype Ontology, TRANSFAC/JASPAR, and KEGG/WikiPathways) were utilized to assess functional and phenotypic enrichment patterns within subgroups. Results: Phenotypic analysis revealed high rates of complex facial dysmorphia in ID with comorbid autism. In contrast, neurodegenerative-like features were overrepresented in ID with epilepsy. Network analysis subsequently showed that gene groups divided according to clinical features of interest resulted in distinctive interaction clusters, with unique functional enrichments according to gene set. Conclusions: These data suggest that specific comorbid and secondary clinical features in ID are predictive of underlying genotype. In summary, ID form unique clusters, which are comprised of individual conditions with remarkable genotypic and phenotypic overlap.


Jazz drummers recruit language-specific areas for the processing of rhythmic structure.
Rhythm is a central characteristic of music and speech, the most important domains of human communication using acoustic signals. Here, we investigated how rhythmical patterns in music are processed in the human brain, and, in addition, evaluated the impact of musical training on rhythm processing. Using fMRI, we found that deviations from a rule-based regular rhythmic structure activated the left planum temporale together with Broca's area and its right-hemispheric homolog across subjects, that is, a network also crucially involved in the processing of harmonic structure in music and the syntactic analysis of language. Comparing the BOLD responses to rhythmic variations between professional jazz drummers and musical laypersons, we found that only highly trained rhythmic experts show additional activity in left-hemispheric supramarginal gyrus, a higher-order region involved in processing of linguistic syntax. This suggests an additional functional recruitment of brain areas usually dedicated to complex linguistic syntax processing for the analysis of rhythmical patterns only in professional jazz drummers, who are especially trained to use rhythmical cues for communication.


The role of oxidative products of nitrous oxide and the tumor necrosis factor alpha in dilated cardiomyopathy.
Dilated Cardiomyopathy (DCM) is a disease of the myocardium and one of the leading causes of death in patients with heart diseases. We explored the role of increased Nitric oxide and TNF-alpha on the pathogenesis and progression of DCM. 25 patients with DCM, and 20 apparently healthy age and sex matched controls, were studied. Patients were divided into 2 groups according to the presence or absence of pulmonary hypertension. All patients and controls were subjected to full cardiological assessment including plain chest x-ray, 12 lead ECG, and thorough 2D and Doppler echocardiography study. Laboratory investigations included measurement of plasma nitrite, nitrate and TNF-alpha levels. Plasma nitrite, nitrate and TNF-alpha concentrations were significantly elevated in DCM patients as compared to controls, and the elevation correlated with the decreasing functional status of the patients. It is concluded that plasma nitrite, nitrate, and TNF-alpha levels in DCM are not only linked to the severity of heart failure at presentation and during follow up, but also to the worsening of left ventricular function as evidenced by the decrease in ejection fraction and increase in end systolic and diastolic ventricular diameters during the echocardiography evaluation.


Potential role of bcl-2 as a suppressor of tumour angiogenesis in non-small-cell lung cancer.
It has been reported that genes regulating apoptosis may play a role in tumoral angiogenesis. This study examined the relationship between tumour vascularization, a measure of tumour angiogenesis, and bcl-2 and p53 expression in operable non-small-cell lung cancer (NSCLC). The relationship between bcl-2, p53 and tumour vascularization and epidermal-growth-factor-receptor(EGFR) and c-erbB-2 expression was also studied. Tissue sections from resected tumour specimens of 107 NSCLC patients were evaluated immunohistochemically for vascular grade and bcl-2, p53, EGFR and c-erbB-2 expression. bcl-2 expression was found in 20/107 (19%) cases and was associated with squamous-cell histology (p = 0.03). A strong inverse relationship was found between bcl-2 expression and vascular grade (p = 0.005). All c-erbB-2-positive cases were negative for bcl-2 expression (p = 0.01). Overall no association was found between c-erbB-2 expression and vascular grade. However, in bcl-2-negative cases positive c-erbB-2 expression correlated with low angiogenesis (p = 0.05). No relationship was found between p53 and EGFR expression and bcl-2, c-erbB-2 or vascular grade. The improved prognosis reported in bcl-2-positive NSCLC may be related to low tumour vascularization. The results suggest that the anti-apoptotic gene bcl-2 plays a role in regulating tumour angiogenesis. Since normal lung epithelium expresses bcl-2, a sequence of tumour progression involving loss of bcl-2, then activation of c-erbB-2 or increase in tumour vascularization is proposed.


Thioridazine: an old neuroleptic effective against totally drug resistant tuberculosis.
Globally, tuberculosis infections continue to increase their resistance to antibiotics. Multidrug resistant tuberculosis infections (MDR TB) have progressed to extensively drug resistance status (XDR TB) and the latter have evolved in some parts of the world to totally drug resistant (TDR TB) infections. MDR TB is difficult to treat successfully, and when therapy is ineffective, a single case can cost almost $500,000. When the infection is XDR TB therapy is mostly unsuccessful and is accompanied with high mortality. TDR TB-a yet to be defined infection, is resistant to all forms of therapy and mortality is almost certain. We have, over a period of 14 years, studied thioridazine (TZ) an old neuroleptic that we have shown to: i) have in vitro activity against all antibiotic resistant forms of Mycobacterium tuberculosis; ii) have activity against intracellular Mycobacterium tuberculosis regardless of its antibiotic resistance status; iii) cure the infected mouse of an antibiotic susceptible and MDR TB infections; and, iv) when used in combination with antibiotics used for therapy of tuberculosis, would render the organism significantly more susceptible. These studies have guided our Argentinian colleagues to treat successfully XDR TB infections with thioridazine in combination with three antibiotics to which the infection was initially resistant. This mini review will describe our further work and the mechanisms by which TZ alone and in combination with antibiotics cures an XDR TB infection and why it is expected to cure TDR TB infections as well. The concepts presented are totally new and because they focus on the activation of killing by non-killing macrophages where Mycobacterium tuberculosis normally resides during infection, and coupled to the inhibition of efflux pumps which contribute to the antibiotic resistant status, effective therapy of any antibiotic resistant TB infection is possible. Because TZ is cheap and therefore affordable to any economically disadvantaged country, and will produce no harm when appropriate measures are taken, it is the ideal drug for immediate use in countries that have high frequencies of MDR, XDR and TDR TB infections.


Lack of a relationship between plasma PCSK9 concentrations and hepatic lipoprotein kinetics in obese people.
Obesity is associated with unfavorable alterations in plasma lipid concentrations. Data obtained from studies in cultured cells and rodent models show that Protein Convertase Subtilisn/Kexin 9 (PCSK9), a secreted protein that leads to degradation of LDL receptors in the liver, is an important regulator of plasma LDL cholesterol concentrations. Recent evidence suggests that PCSK9 may also regulate the very low density lipoprotein (VLDL) receptor expression and VLDL-triglyceride (TG) metabolism. The purpose of this study was to determine whether circulating PCSK9 concentrations are correlated with VLDL-triglyceride kinetics in obese people. Plasma PCSK9 concentration and VLDL-TG kinetics were evaluated in 39 nondiabetic, obese subjects (body mass index 36.9 ± 4.3 kg/m(2)). Body composition was assessed by using dual-energy x-ray absorptiometry, and VLDL-TG kinetics were assessed by using stable isotopically labeled tracer infusion. We found that plasma PCSK9 concentrations correlated significantly with percent body fat (r = 0.322, P = 0.046) and serum LDL-cholesterol concentrations (r = 0.333, P = 0.036), but not with VLDL-TG secretion rate (r = 0.083, P = 0.614) or clearance rate (r = 0.032, P = 0.845). These data suggest that PCSK9 is likely involved in LDL-cholesterol metabolism, but it is not a clinically important regulator of VLDL kinetics in obese individuals.


Association between dental implants in the posterior region and traumatic occlusion in the adjacent premolars: a long-term follow-up clinical and radiographic analysis.
The aim of this retrospective study was to determine the association between dental implants in the posterior region and traumatic occlusion in the adjacent premolars, using data collected during from 2002 to 2015. Traumatic occlusion in the adjacent premolars was assessed by examining clinical parameters (bleeding on probing, probing pocket depth, fremitus, and tooth mobility) and radiographic parameters (loss of supporting bone and widening of the periodontal ligament space) over a mean follow-up of 5 years. Clinical factors (gender, age, implant type, maxillary or mandibular position, opposing teeth, and duration of functional loading) were evaluated statistically in order to characterize the relationship between implants in the posterior region and traumatic occlusion in the adjacent premolars. The study inclusion criteria were met by 283 patients, who had received 347 implants in the posterior region. The incidence of traumatic occlusion in the adjacent premolars was significantly higher for splinted implants (P=0.004), implants in the maxillary region (P<0.001), and when implants were present in the opposing teeth (P<0.001). The other clinical factors of gender, age, and duration of functional loading were not significantly associated with traumatic occlusion. This study found that the risk of traumatic occlusion in the adjacent premolars increased when splinted implants were placed in the maxillary molar region and when the teeth opposing an implant also contained implants.


Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma.
KRAS mutations are found in approximately 25% of lung adenocarcinomas in Western countries and, as a group, have been strongly associated with cigarette smoking. These mutations are predictive of poor prognosis in resected disease as well as resistance to treatment with erlotinib or gefitinib. We determined the frequency and type of KRAS codon 12 and 13 mutations and characterized their association with cigarette smoking history in patients with lung adenocarcinomas. KRAS mutational analysis was done on 482 lung adenocarcinomas, 81 (17%) of which were obtained from patients who had never smoked cigarettes. KRAS mutations were found in 15% (12 of 81; 95% confidence intervals, 8-24%) of tumors from never smokers. Similarly, 22% (69 of 316; 95% confidence intervals, 17-27%) of tumors from former smokers, and 25% (21 of 85; 95% confidence intervals, 16-35%) of tumors from current smokers had KRAS mutations. The frequency of KRAS mutation was not associated with age, gender, or smoking history. The number of pack years of cigarette smoking did not predict an increased likelihood of KRAS mutations. Never smokers were significantly more likely than former or current smokers to have a transition mutation (G-->A) rather than the transversion mutations known to be smoking-related (G-->T or G-->C; P < 0.0001). Based on our data, KRAS mutations are not rare among never smokers with lung adenocarcinoma and such patients have a distinct KRAS mutation profile. The etiologic and biological heterogeneity of KRAS mutant lung adenocarcinomas is worthy of further study.


Use of Negative Pressure Wound Therapy on Closed Surgical Incision After Total Ankle Arthroplasty.
Wound healing problems of the anterior ankle incision are among the most common complications after total ankle arthroplasty, possibly resulting in exposure of the prostheses and infection. The aim of this study was to investigate the role of negative pressure wound therapy (NPWT) in decreasing the rate of wound healing problems after total ankle arthroplasty. This is a retrospective cohort study including consecutive patients who underwent total ankle arthroplasty by a single surgeon at a single institution between 2009 and 2013. The incisional negative pressure dressing was applied to all patients who underwent total ankle arthroplasty between 2012 and 2013 with a continuous application of -80 mm Hg negative pressure for 6 days postoperatively. The control group consisted of patients who underwent total ankle arthroplasty between 2009 and 2012 with a conventional nonadherent gauze dressing. Seventy-four patients were involved in this study: 37 in the control group and 37 in the incisional NPWT group. All patients tolerated the incisional NPWT to completion without any dressing failures or skin problems. Both groups showed similar distributions in demographics and perioperative risk factors for wound healing. There were 9 (24%) wound healing problems in the control group and 1 (3%) in the incisional NPWT group. Incisional NPWT was found to reduce wound healing problems with an odds ratio of 0.10 (95% CI, 0.01-0.50; P = .004). Our study demonstrated that there was a decreased incidence of wound healing problems following total ankle arthroplasty with incisional NPWT dressings. This is the first study evaluating the efficacy of incisional NPWT as an adjunct treatment for wound healing after total ankle arthroplasty. Level III, retrospective comparative study.


v-SNARE function in chromaffin cells.
Vesicle fusion is elementary for intracellular trafficking and release of signal molecules, thus providing the basis for diverse forms of intercellular communication like hormonal regulation or synaptic transmission. A detailed characterization of the mechanisms underlying exocytosis is key to understand how the nervous system integrates information and generates appropriate responses to stimuli. The machinery for vesicular release employs common molecular players in different model systems including neuronal and neuroendocrine cells, in particular members of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) protein family, Sec1/Munc18-like proteins, and other accessory factors. To achieve temporal precision and speed, excitable cells utilize specialized regulatory proteins like synaptotagmin and complexin, whose interplay putatively synchronizes vesicle fusion and enhances stimulus-secretion coupling. In this review, we aim to highlight recent progress and emerging views on the molecular mechanisms, by which constitutively forming SNAREpins are organized in functional, tightly regulated units for synchronized release. Specifically, we will focus on the role of vesicle associated membrane proteins, also referred to as vesicular SNAREs, in fusion and rapid cargo discharge. We will further discuss the functions of SNARE regulators during exocytosis and focus on chromaffin cell as a model system of choice that allows for detailed structure-function analyses and direct measurements of vesicle fusion under precise control of intracellular [Ca]i.


Inhibitory mechanisms of metallothionein on platelet aggregation in in vitro and platelet plug formation in in vivo experiments.
Metallothionein (MT) is a low-molecular-weight, cysteine-rich protein that contains heavy metals such as cadmium and zinc. The biological function of MT in platelets is not yet understood. Therefore, the aim of this study was to systematically examine the inhibitory mechanisms of metallothionein in platelet aggregation. In this study, metallothionein concentration-dependently (1-8 microM) inhibited platelet aggregation in human platelets stimulated by agonists. Metallothionein (4 and 8 microM) inhibited phosphoinositide breakdown in [3H]-inositol-labeled platelets, intracellular Ca+2 mobilization in Fura-2 AM-loaded platelets, and thromboxane A2 formation stimulated by collagen. In addition, metallothionein (4 and 8 microM) significantly increased the formation of cyclic GMP but not cyclic AMP in human platelets. Rapid phosphorylation of a protein of Mr 47,000 (P47), a marker of protein kinase C activation, was triggered by PDBu (100 nM). This phosphorylation was markedly inhibited by metallothionein (4 and 8 microM) in phosphorus-32-labeled platelets. In an in vivo thrombotic study, platelet thrombus formation was induced by irradiation of mesenteric venules in mice pretreated with fluorescein sodium. Metallothionein (6 microg/g) significantly prolonged the latency period for inducing platelet plug formation in mesenteric venules. These results indicate that the antiplatelet activity of metallothionein may involve the following pathways: (1) metallothionein may inhibit the activation of phospholipase C, followed by inhibition of phosphoinositide breakdown and thromboxane A2 formation, thereby leading to inhibition of intracellular Ca+2 mobilization; (ii) Metallothionein also activated the formation of cyclic GMP in human platelets, resulting in inhibition of platelet aggregation. The results strongly indicate that metallothionein provides protection against thromboembolism.


Comparing measured calcium and vitamin D intakes with perceptions of intake in Canadian young adults: insights for designing osteoporosis prevention education.
To identify the relationship between perceptions of Ca and vitamin D consumption and actual intakes to inform the design of osteoporosis prevention education. An FFQ was used to approximate usual monthly Ca and vitamin D intakes among a group of young Canadians. Qualitative interviews and a food card pile sort activity explored individuals' perceptions of nutrient intakes. The FFQ was used to assess nutrient adequacy for individual participants and the qualitative interviews and pile sort were analysed using thematic content analysis. Hamilton, Canada. Sixty participants aged 17-30 years, representing varying levels of educational attainment. Seventy-eight per cent of young adults who consumed inadequate vitamin D perceived their intake as adequate, compared with 57 % for Ca. Thematic analysis revealed three major themes that contributed to young adults' understandings of intake: belief their diet was correct, absence of symptoms and confusion over nutrient sources. The majority of participants perceived themselves as consuming adequate amounts of Ca and vitamin D, when they were actually consuming inadequate amounts according to FFQ findings. These perceptions were related to low engagement in prevention activities. Prevention education must motivate young adults to question the adequacy of their micronutrient intakes and design tailored programmes that are geared to a young adult audience.


Can we see living structure in a cell?
Colloid chemistry (kappa o lambda lambda alpha: glue, or gelatin) was introduced in 1861 after the discovery of protoplasm which exhibits gelatin-like properties. Some 80 years later, colloid chemistry (and with it, the concept of protoplasm) was largely abandoned. The membrane (pump) theory, according to which cell water and cell solute like K+ are free as in a dilute KCl solution, became dominant. Later studies revealed that rejecting the protoplasmic approach to cell physiology was not justified. Evidence against the membrane (pump) theory, on the other hand, has stood the test of time. In a new theory of the living cell called the association-induction (AI) hypothesis, the three major components of the living cell (water, proteins and K+) are closely associated; together they exist in a high-(negative)-energy-low entropy state called the living state. The bulk of cell water is adsorbed as polarized multilayers on some fully extended protein chains, and K+ is adsorbed singly on beta- and gamma-carboxyl groups carried on aspartic and glutamic residues of cell proteins. Extensive evidence in support of the AI hypothesis is reviewed. From an extension of the basic concepts of the AI hypothesis and the new knowledge on primary structure of the proteins, one begins to understand at long last what distinguishes gelatin from other proteins; in this new light, new definitions of protoplasm and of colloid chemistry have been introduced. With the return of the concept of protoplasm, living structure takes on renewed significance, linking cell anatomy to cell physiology. Finally, evidence is presented showing that electron microscopists have come close to seeing cell structure in its living state.


Progression-free survival is a surrogate for survival in advanced colorectal cancer.
The traditional end point for assessing efficacy of first-line chemotherapies for advanced cancer is overall survival (OS), but this end point requires prolonged follow-up and is potentially confounded by the effects of second-line therapies. We investigated whether progression-free survival (PFS) could be considered a valid surrogate for OS in advanced colorectal cancer. Individual patient data were available from 10 historical trials comparing fluouracil (FU) + leucovorin with either FU alone (1,744 patients) or with raltitrexed (1,345 patients) and from three validation trials comparing FU + leucovorin with or without irinotecan or oxaliplatin (1,263 patients). Correlation coefficients were estimated in historical trials between the end points of PFS and OS, and between the treatment effects on these end points. Treatment effects on OS were predicted in validation trials, and compared with the observed effects. In historical trials, 1,760 patients (57%) had progressed or died at 6 months, and 1,622 (52%) had died at 12 months. The rank correlation coefficient between PFS and OS was equal to 0.82 (95% CI, 0.82 to 0.83). The correlation coefficient between treatment effects on PFS and on OS ranged from 0.99 (95% CI, 0.94 to 1.04) when all trials were considered to 0.74 (95% CI, 0.44 to 1.04) after exclusion of one highly influential trial. In the validation trials, the observed OS hazard ratios were within the 95% prediction intervals. A hazard ratio of 0.77 or lower in terms of PFS would predict a benefit in terms of OS. PFS is an acceptable surrogate for OS in advanced colorectal cancer.


Contrasting the Influence of Cationic Amino Acids on the Viscosity and Stability of a Highly Concentrated Monoclonal Antibody.
To explain the effects of cationic amino acids and other co-solutes on the viscosity, stability and protein-protein interactions (PPI) of highly concentrated (≥200 mg/ml) monoclonal antibody (mAb) solutions to advance subcutaneous injection. The viscosities of ≥200 mg/ml mAb1 solutions with various co-solutes and pH were measured by capillary rheometry in some cases up to 70,000 s-1. The viscosities are analyzed in terms of dilute PPI characterized by diffusion interaction parameters (k D ) from dynamic light scattering (DLS). MAb stability was measured by turbidity and size exclusion chromatography (SEC) after 4 weeks of 40°C storage. Viscosity reductions were achieved by reducing the pH, or adding histidine, arginine, imidazole or camphorsulfonic acid, each of which contains a hydrophobic moiety. The addition of inorganic electrolytes or neutral osmolytes only weakly affected viscosity. Systems with reduced viscosities also tended to be Newtonian, while more viscous systems were shear thinning. Viscosity reduction down to 20 cP at 220 mg/ml mAb1 was achieved with co-solutes that are both charged and contain a hydrophobic interaction domain for sufficient binding to the protein surface. These reductions are related to the DLS diffusion interaction parameter, k D , only after normalization to remove the effect of charge screening. Shear rate profiles demonstrate that select co-solutes reduce protein network formation.


Ginger (Zingiber officinale Roscoe) elicits antinociceptive properties and potentiates morphine-induced analgesia in the rat radiant heat tail-flick test.
Ginger (Zingiber officinale Roscoe), a well-known spice plant, has been used traditionally in the treatment of a wide variety of ailments. It has been shown that ginger is a calcium channel blocker; however, its influence on morphine analgesic effects has not been elucidated. We examined the effect of ginger root extract on nociceptive threshold and morphine-induced analgesia in male Wistar rats. To determine the effect of ginger on morphine analgesia, ginger extract (200, 400, and 600 mg/kg i.p.) was injected before a subeffective dose of morphine (2.5 mg/kg i.p.). The radiant heat tail-flick test was used to assess the nociceptive threshold before and at different times after drug administration. Our results showed that ginger extract elicited a significant antinociceptive effect. In addition, in groups that received both morphine and ginger, the observed analgesia was higher than that in groups treated with either morphine or ginger extract alone. Thus, the data indicate that ginger extract has a beneficial influence on morphine analgesia and can be an efficacious adjunct for pain management.


Immunomodulatory and Antidiabetic Effects of a New Herbal Preparation (HemoHIM) on Streptozotocin-Induced Diabetic Mice.
Angelica gigas Nakai, Cnidium officinale Makino, and Paeonia japonica Miyabe) was developed to protect immune, hematopoietic, and self-renewal tissues against radiation. This study determined whether or not HemoHIM could alter hyperglycemia and the immune response in diabetic mice. Both nondiabetic and diabetic mice were orally administered HemoHIM (100 mg/kg) once a day for 4 weeks. Diabetes was induced by single injection of streptozotocin (STZ, 200 mg/kg, i.p.). In diabetic mice, HemoHIM effectively improved hyperglycemia and glucose tolerance compared to the diabetic control group as well as elevated plasma insulin levels with preservation of insulin staining in pancreatic β-cells. HemoHIM treatment restored thymus weight, white blood cells, lymphocyte numbers, and splenic lymphocyte populations (CD4(+) T and CD8(+) T), which were reduced in diabetic mice, as well as IFN-γ production in response to Con A stimulation. These results indicate that HemoHIM may have potential as a glucose-lowering and immunomodulatory agent by enhancing the immune function of pancreatic β-cells in STZ-induced diabetic mice.


Palladium-catalysed atom-economical synthesis of conjugated dienals from terminal acetylenes and acrolein.
Conjugated (E,E)-dienals are versatile synthetic intermediates owing to their trifunctional, electrophilic nature and the prevalence of the (E,E)-diene in a wide range of functional molecules. It is shown herein that (E,E)-dienals can be readily prepared in two palladium-catalysed steps from simple, unactivated starting materials; terminal acetylenes and acrolein can be coupled via conjugate addition, followed by alkyne isomerisation. This procedure provides a highly atom-economical, redox-neutral and practical method to prepare a range of conjugated (E,E)-dienals in good yields and diastereoselectivities.


A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras.
TGFbeta can override the proliferative effects of EGF and other Ras-activating mitogens in normal epithelial cells. However, epithelial cells harboring oncogenic Ras mutations often show a loss of TGFbeta antimitogenic responses. Here we report that oncogenic Ras inhibits TGFbeta signaling in mammary and lung epithelial cells by negatively regulating the TGFbeta mediators Smad2 and Smad3. Oncogenically activated Ras inhibits the TGFbeta-induced nuclear accumulation of Smad2 and Smad3 and Smad-dependent transcription. Ras acting via Erk MAP kinases causes phosphorylation of Smad2 and Smad3 at specific sites in the region linking the DNA-binding domain and the transcriptional activation domain. These sites are separate from the TGFbeta receptor phosphorylation sites that activate Smad nuclear translocation. Mutation of these MAP kinase sites in Smad3 yields a Ras-resistant form that can rescue the growth inhibitory response to TGFbeta in Ras-transformed cells. EGF, which is weaker than oncogenic mutations at activating Ras, induces a less extensive phosphorylation and cytoplasmic retention of Smad2 and Smad3. Our results suggest a mechanism for the counterbalanced regulation of Smad2/Smad3 by TGFbeta and Ras signals in normal cells, and for the silencing of antimitogenic TGFbeta functions by hyperactive Ras in cancer cells.


Prevalence of mental disorders and torture among Tibetan refugees: a systematic review.
Many Tibetan refugees flee Tibet in order to escape physical and mental hardships, and to access the freedoms to practice their culture and religion. We aimed to determine the prevalence of mental illnesses within the refugee population and determine the prevalence of previous torture reported within this population. We performed a systematic literature search of 10 electronic databases from inception to May 2005. In addition, we searched the internet, contacted all authors of located studies, and contacted the Tibetan Government-in-exile, to locate unpublished studies. We included any study reporting on prevalence of mental illness within the Tibetan refugee populations. We determined study quality according to validation, translation, and interview administration. We calculated proportions with exact confidence intervals. Five studies that met our inclusion criteria (total n = 410). All studies were conducted in North India and 4 were specifically in adult populations. Four studies provided details on the prevalence of torture and previous imprisonment within the populations. The prevalence of post-traumatic stress disorder ranged from 11-23%, anxiety ranged from 25-77%, and major depression ranged from 11.5-57%. Our review indicates that the prevalence of serious mental health disorders within this population is elevated. The reported incidence of torture and imprisonment is a possible contributor to the illnesses. Non-government organizations and international communities should be aware of the human rights abuses being levied upon this vulnerable population and the mental health outcomes that may be associated with it.


Photon upconversion in organic nanoparticles and subsequent amplification by plasmonic silver nanowires.
The development of photonic materials with high photoluminescence is always a challenge in photochemistry and photophysics. Here we present a general approach for enhancing photon upconversion through aggregation and further via surface plasmon resonance (SPR). Luminescent nanoparticles from a tetraphenylethylene derivative were fabricated, showing excellent aggregation-induced emission (AIE) behavior. By mixing with a triplet sensitizer platinum octaethylporphyrin (PtOEP), aggregation-induced photon upconversion (iPUC) could be achieved, resulting in an enhancement of the emission. Blending such iPUC nanoparticles with silver nanowires (AgNWs), the upconverted emission intensity could be significantly amplified due to the SPR of AgNWs. Thus, the concepts of aggregation-induced emission (AIE), metal enhanced fluorescence (MEF) and aggregation-induced photon upconversion (iPUC) were successfully integrated and achieved.


Association of Pneumococcal Conjugate Vaccine Coverage With Pneumococcal Meningitis: An Analysis of French Administrative Areas, 2001-2016.
Geographic variations of invasive pneumococcal disease incidence and serotype distributions were observed after pneumococcal conjugate vaccine introduction at regional levels and among French administrative areas. The variations could be related to regional vaccine coverage (VC) variations that might have direct consequences for vaccination-policy impact on invasive pneumococcal disease, particularly pneumococcal meningitis (PM) incidence. We assessed vaccine impact from 2001 to 2016 in France by estimating the contribution of regional VC differences to variations of annual local PM incidence. Using a mixed-effect Poisson model, we showed that, despite some variations of VC among administrative areas, vaccine impact on vaccine-serotype PM was homogeneously confirmed among administrative areas. Compared with the prevaccine era, the cumulative VC impact on vaccine serotypes led, in 2016, to PM reductions ranging among regions from 87% (25th percentile) to 91% (75th percentile) for 7-valent pneumococcal conjugate vaccine serotypes and from 58% to 63% for the 6 additional 13-valent pneumococcal conjugate vaccine serotypes. Nonvaccine-serotype PM increases from the prevaccine era ranged among areas from 98% to 127%. By taking into account the cumulative impact of growing VC and VC differences, our analyses confirmed high vaccine impact on vaccine-serotype PM case rates and suggest that VC variations cannot explain PM administrative area differences.


Identifying the subtypes of cancer-related fatigue: results from the population-based PROFILES registry.
Little research has been done to identify possible cancer-related fatigue (CRF) subtypes and to classify cancer survivors accordingly. We aimed to identify CRF subtypes in a large population-based sample of (long term) stage I-III colorectal cancer survivors. We also identified factors associated with the CRF subtypes. Respondents completed the Multidimensional Fatigue Inventory and other validated questionnaires on anxiety and reduced positive affect (anhedonia), sleep quality, and lifestyle factors (body mass index and physical activity). Latent class analysis was used to derive the CRF subtypes. Factors associated with the derived CRF subtypes were determined with multinomial logistic regression. Three CRF classes were identified: class 1 (no fatigue and distress, n = 644, 56%), class 2 (low fatigue, moderate distress, n = 256, 22%), and class 3 (high fatigue, moderate distress, n = 256, 22%). Multinomial logistic regression results show that survivors in class 3 were more likely to be female, were treated with radiotherapy, have comorbid diabetes mellitus, and be overweight/obese than survivors in class 1 (reference). Survivors in classes 2 and 3 were also more likely to have comorbid heart condition, report poorer sleep quality, experience anhedonia, and report more anxiety symptoms when compared with survivors in class 1. Three distinct classes of CRF were identified which could be differentiated with sleep quality, anxiety, anhedonia, and lifestyle factors. The identification of CRF subtypes with distinct characteristics suggests that interventions should be targeted to the CRF subtype.


Action-oriented study circles facilitate efforts in nursing homes to "go from feeding to serving": conceptual perspectives on knowledge translation and workplace learning.
Background. Action-oriented study circles (AOSC) have been found to improve nutrition in 24 nursing homes in Sweden. Little, however, is known about the conceptual use of knowledge (changes in staffs' knowledge and behaviours). Methods. Qualitative and quantitative methods, structured questionnaires for evaluating participants' (working in nursing homes) experiences from study circles (n = 592, 71 AOSC) and for comparisons between AOSC participants (n = 74) and nonparticipants (n = 115). Finally, a focus group interview was conducted with AOSC participants (in total n = 12). Statistical, conventional, and directed content analyses were used. Results. Participants experienced a statistically significant increase in their knowledge about eating and nutrition, when retrospectively comparing before participating and after, as well as in comparison to non-participants, and they felt that the management was engaged in and took care of ideas regarding food and mealtimes to a significantly greater extent than non-participants. The use of AOSC was successful judging from how staff members had changed their attitudes and behaviours toward feeding residents. Conclusions. AOSC facilitates professional development, better system performance, and, as shown in previous studies, better patient outcome. Based on a collaborative learning perspective, AOSC manages to integrate evidence, context, and facilitation in the efforts to achieve knowledge translation in a learning organisation. This study has implications also for other care settings implementing AOSC.


Three-dimensional quantification of "still" points during normal facial movement.
This study investigated the 3-dimensional displacement of points on the face that were thought to be still during facial movement. These points are currently used to measure displacement of moving facial regions during assessment of normal facial movement and treatment interventions following facial nerve paralysis. It is, however, unknown if these places are "still" points. The Expert Vision Motion Analysis System was used to collect and analyze data on 42 normal subjects during facial movement. No point on the face was found to be still during facial expression. However, several points were present with very small movements for each individual expression. These were termed "reference" points. These small movements may be the result of system noise, physiological tremor, skin movement, or head-holder movement during facial expressions. Future studies of the displacement of the markers during facial movement in both normal subjects and patients with facial nerve paralysis may take into account the contribution of the "reference" point displacements to the overall facial movement.


Expression profiles of carcinosarcoma of the uterine corpus-are these similar to carcinoma or sarcoma?
Uterine carcinosarcoma (CS) is usually classified as uterine endometrial carcinoma (EC). However, CS is more aggressive even compared with high grade EC. CS is also reported to undergo epithelial to mesenchymal transition (EMT). In this study, we compared the gene expression profiles of CS, EC, and uterine sarcoma (US) and evaluated the role of EMT and chromosomal aberrations in CS tumor formation. Frozen tissues of 46 patients (14 CS, 24 EC, and 8 US) were included. The similarity was examined by Gene Set Enrichment Analysis (GSEA), Fisher's exact test, and clustering using "intrinsic gene set". We examined the expression of 39 EMT-related genes and evaluated TGF-beta signaling by phospho-SMAD2/3 (p-SMAD2/3) staining. Chromosomal regions differing between CS and EC were identified by chromosomal GSEA and comparative genomic hybridization (CGH) microarrays. Three statistical methods confirmed that CS resembled US rather than EC. Acquired markers of EMT were upregulated and attenuated markers of EMT were downregulated in CS. Immunohistochemistry showed that carcinomatous region of CS have higher expression of p-SMAD2/3 than EC (P = 0.008). Chromosomal GSEA showed that genes located at 19q13 had higher expression in CS. Furthermore, CGH microarray indicated that the TGFB1 locus at 19q13.1 was amplified in 4 of 7 samples. Based on the expression profile, CS resembles US rather than EC. TGF-beta signaling is activated in CS and chromosomal gains at 19q13, which includes the TGFB1 locus, suggest that this may contribute to high expression of TGF-beta and thereby EMT phenotype of CS.