Phosphoinositide 3-kinase inhibits megalin-mediated transcytosis of thyroglobulin across thyroid epithelial cells at a post-sorting level.
Phosphoinositide 3-kinase (PI3-K) is implicated in various cellular processes involving signaling, including intracellular trafficking. PI3-K has been shown to play a part in both receptor- and non-receptor-mediated transcytosis across cultured kidney cells and undifferentiated thyroid cells. To investigate the role of PI3-K in transcytosis of thyroglobulin (Tg) across differentiated cultured Fisher rat thyroid cells (FRTL-5 cells) - a process known to be mediated by megalin, a member of the low-density lipoprotein receptor family. We studied the effect of the microbial product wortmannin, a specific inhibitor of PI3-K, on transcytosis of Tg across FRTL-5 cells. Transcytosis experiments were performed using FRTL-5 cells cultured as tight layers on filters in the upper chamber of dual chambered devices, with megalin expression exclusively on the upper cell surface. Tg was added to the upper chamber and cells were incubated at 37 degrees C. Transcytosed Tg was measured in fluids collected from the lower chamber. To study the role of PI3-K, cells were pre-incubated with wortmannin. Pre-incubation of FRTL-5 cells with wortmannin did not affect Tg binding and uptake, but resulted in a considerable increase in Tg transcytosis (by 40-75%, depending on the concentration of wortmannin), suggesting that PI3-K exerts an inhibitory effect on Tg transcytosis. In experiments in which a monoclonal antibody against megalin was used to reduce Tg transcytosis, pre-incubation with wortmannin did not increase Tg transcytosis from its reduced levels, indicating that PI3-K is involved in the megalin-mediated pathway. Wortmannin did not affect the extent of release of tri-iodothyronine from exogenously added Tg by FRTL-5 cells, which was used as a measure of Tg degradation in the lysosomal pathway, indicating that the effect of PI3-K on transcytosis occurs after diversion of Tg from the lysosomal pathway. PI3-K exerts an inhibitory role on megalin-mediated Tg transcytosis across cultured thyroid cells. PI3-K action takes place at a post-sorting level, after Tg bypassing of the lysosomal pathway.


Red ginseng relieves the effects of alcohol consumption and hangover symptoms in healthy men: a randomized crossover study.
Heavy drinking causes hangover symptoms, because the action of alcohol dehydrogenase forms acetaldehyde, which is metabolized by acetaldehyde dehydrogenase into acetate. Red ginseng shows positive effects on alcohol metabolism in animal studies. We investigated the effects of red ginseng on relieving alcohol and hangover symptoms in 25 healthy men in a randomized crossover study. At each visit (0, 1, and 2 weeks), the subjects drank 100 mL whiskey (40% alcohol) and either 100 mL water or 100 mL of a 0.321 mg mL(-1) red ginseng anti-hangover drink (RGD). We took blood samples periodically until 240 min after alcohol consumption, and we investigated the blood profiles, alcohol levels, and acetaldehyde levels. We also measured anthropometric parameters, expiratory air-alcohol levels, and hangover symptoms. The plasma alcohol concentrations within the RGD group were significantly lower than those within the placebo group after 30 min (p = 0.002), 45 min (p = 0.016), and 60 min (p = 0.009); the areas under the response curves revealed a positive effect of RGD (p = 0.051). Furthermore, the expiratory alcohol concentration was significantly lower after 30 min (p = 0.005) and 60 min (p = 0.065), and the areas under the response curves (p = 0.058) likewise revealed a positive effect of RGD. The plasma acetaldehyde level was significantly elevated at 120 min (p = 0.020), but the areas under the response curves showed a similar trend (p = 0.054). While the plasma acetaldehyde concentration slightly increased, the RGD showed positive effects on hangover symptoms. Considering the reduction of plasma alcohol levels, expiratory concentrations, and hangover severity, we conclude that red ginseng relieves the symptoms of alcohol hangover.


Assessing the external validity of a randomized controlled trial of anthelminthics in mothers and their children in Entebbe, Uganda.
The 'external validity' of randomized controlled trials is an important measure of quality, but is often not formally assessed. Trials concerning mass drug administration for helminth control are likely to guide public health policy and careful interpretation of their context is needed. We aimed to determine how representative participants in one such trial were of their community. We explore implications for trial interpretation and resulting public health recommendations. The trial assessed was the Entebbe Mother and Baby Study (EMaBS), a trial of anthelminthic treatment during pregnancy and early childhood. In a novel approach for assessing external validity, we conducted a two-stage cluster sample community survey within the trial catchment area and compared characteristics of potentially-eligible community children with characteristics of children participating in the trial. A total of 173 children aged three to five-years-old were surveyed from 480 households. Of children surveyed, we estimated that mothers of 60% would have been eligible for recruitment, and of these, 31% had actually been enrolled. Children surveyed were compared to 199 trial children in the same age group reviewed at annual trial visits during the same time period. There were significant differences in ethnicity between the trial participants and the community children, and in socioeconomic status, with those in the trial having, on average, more educated parents and higher maternal employment. Trial children were less likely to have barefoot exposure and more likely to use insecticide-treated bed nets. There were no significant differences in numbers of reported illness events over the last year. The trial had not enrolled all eligible participants, and those enrolled were of higher socioeconomic status, and had lower risk of exposure to the parasitic infections targeted by the trial interventions. It is possible the trial may have underestimated the absolute effects of anthelminthic treatment during pregnancy and early childhood, although the fact that there were no differences in reported incidence of common infectious diseases (one of the primary outcomes of EMaBS) between the two groups provides reassurance. Concurrent community surveys may be an effective way to test the external validity of trials. ISRCTN32849447, registered 22 July 2005.


Salvia miltiorrhiza enhances the survival of mesenchymal stem cells under ischemic conditions.
To validate the enhanced therapeutic effect of Salvia miltiorrhiza Bunge (SM) for brain ischemic stroke through the anti-apoptotic and survival ability of mesenchymal stem cells (MSCs). The viability and the expression level of cell apoptotic and survival-related proteins in MSCs by treatment of SM were assessed in vitro. In addition, the infarcted brain region and the behavioural changes after treatment of MSCs with SM were confirmed in rat middle cerebral artery occlusion (MCAo) models. We demonstrated that SM attenuates apoptosis and improves the cell viability of MSCs. In the rat MCAo model, the recovery of the infarcted region and positive changes of behaviour are observed after treatment of MSCs with SM. The therapy using SM enhances the therapeutic effect for brain ischemic stroke by promoting the survival of MSCs. This synergetic effect thereby proposes a new experimental approach of traditional Chinese medicine and stem cell-based therapies for patients suffering from a variety of diseases.


Transcription-dependent nuclear-cytoplasmic trafficking is required for the function of the von Hippel-Lindau tumor suppressor protein.
Mutation of the von Hippel-Lindau tumor suppressor gene (vhl) causes the von Hippel-Lindau cancer syndrome as well as sporadic renal clear cell carcinoma. To pursue our study of the intracellular localization of VHL protein in relation to its function, we fused VHL to the green fluorescent protein (GFP) to produce the VHL-GFP fusion protein. Like VHL, VHL-GFP binds to elongins B and C and Cullin-2 and regulates target gene product levels, including levels of vascular endothelial growth factor and glucose transporter 1. VHL-GFP localizes predominantly to the cytoplasm, with some detectable nuclear signal. Inhibition of transcription by actinomycin D or 5,6-dichlorobenzimidazole riboside (DRB) causes VHL to be redistributed to the nucleus. A cellular fusion assay was used to demonstrate that inhibition of transcription induces a decrease in the nuclear export rate of VHL. The dependence of transcription for trafficking is lost with a deletion of exon 2, a region with a mutation causing a splice defect in the VHL gene in sporadic renal clear cell carcinoma. Addition of a strong nuclear export signal (NES) derived from the Rev protein results in complete nuclear exclusion and abrogates the redistribution of VHL-GFP-NES into the nucleus upon inhibition of transcription. Leptomycin B, which inhibits NES-mediated nuclear export, reverts the distribution of VHL-GFP-NES to that of VHL-GFP and restores sensitivity to actinomycin D and DRB. Uncoupling of VHL-GFP trafficking to transcription either by an exon 2 deletion or fusion to NES abolishes VHL function. We suggest that VHL function requires not only nuclear or cytoplasmic localization, but also exon 2-mediated transcription-dependent trafficking between these two cellular compartments.


Evaluation by dual energy X-ray absorptiometry of changed bone density in metastatic bone sites as a consequence of systemic treatment.
Fourteen cancer patients with bone metastases from various primary malignancies were submitted to repeated dual X-ray absorptiometry (DEXA) scan before and after systemic antineoplastic treatments. In the nine patients with lytic lesions the Bone Mineral Density (BMD) increased after chemotherapy + pamidronate in four (by +11.2%, +7.5%, +5.0% and +6.6%, respectively), decreased in four (by -19.9%, -8.1%, -7.5%, and -7.0%, respectively) and remained unchanged in one. BMD changes paralleled variations in painful symptomatology and biochemical markers. In patients with blastic metastases the BMD on target metastatic lesions did not change after hormone therapy or chemotherapy in one case but showed a significant increase in four. BMD increase was associated to bone pain improvement and PSA decrease in two cases, and with a worsening in skeletal pain and/or serum PSA in the remaining two. Our data suggest that BMD evaluation by DEXA instrument may be a reliable tool in assessing the response of bone metastases to treatment.


Do pain characteristics guide selection for multimodal pain rehabilitation?
To determine whether self-reported pain measures are associated with selection for multimodal or multidisciplinary rehabilitation (MMR) and whether this selection is influenced by sex. Cross-sectional cohort study. A total of 1,226 women and 464 men with chronic pain conditions from 2 university hospitals. Drawing from the Swedish Quality Registry for Pain Rehabilitation (SQRP), data on pain, psychological symptoms, function, health, and activity/participation were collected. Multiple logistic regression was used to investigate association of pain measures with selection for MMR (no/yes) after multidisciplinary assessment. Covariates were: age, educational level, anxiety, depression, working status, and several pain measures. High pain intensity in the previous week (odds ratio (OR) 0.92; 95% confidence interval (CI) 0.86-0.99) and high pain severity (Multidimensional Pain Inventory) (OR 0.83; 95% CI 0.74-0.95) were negatively associated with selection for MMR, whereas higher number of pain quadrants was positively associated with selection for MMR. Similar results were obtained for women, but none of the measures was predictive for men. This practice-based study showed that higher scores on self-reported pain were not associated with selection for MMR, and in women there was a negative association for higher pain intensity and pain severity. Thus, other factors than pain determine whether patients are selected for MMR.


Interferon gamma plays a critical role in induced cell death of effector T cell: a possible third mechanism of self-tolerance.
We have used anti-T cell monoclonal antibodies (mAbs) as mimic ligands to study the effects of T cell receptor (TCR) ligation of cloned T helper type 1 cells in the presence or absence of accessory cells. Our results demonstrate that ligation of the TCR in the absence of accessory cells rapidly induces cell death. Cell death can be prevented by addition of spleen adherent cells, leading to strong clonal expansion. Induced cell death is inhibited by cyclosporin A and by anti-interferon gamma (IFN-gamma), and is restored by adding exogenous recombinant IFN-gamma to cyclosporin A-treated cells. These results demonstrate that IFN-gamma plays a critical role in cell death induced by anti-TCR mAbs in the absence of costimulatory cells. We propose that induced cell death of active effector T cells provides a third mechanism of tolerance in addition to intrathymic deletion of developing autoreactive T cells and peripheral inactivation of mature, naive T cells.


Absorbed EVELISA: a diagnostic test with improved specificity for Johne's disease in cattle.
The use of enzyme-linked immunosorbent assays (ELISAs) is recommended for Johne's disease (JD) control in dairy herds. In 2006, we developed a novel ELISA test for JD, named EVELISA (ELISA using ethanol extract of Mycobacterium avium subsp. paratuberculosis), which showed higher sensitivity than commercial ELISA tests. To further investigate the performance of EVELISA, we obtained 38 serum samples from cattle in a JD-free herd with suspected cases of serological false-positive reactions. When these samples were tested using the EVELISA and a commercial ELISA test, more than 70% of the samples were falsely identified as JD positive. Antibodies in the serum samples reacted strongly with antigens of various environmental mycobacteria, suggesting the presence of cross-reactive antibodies in the samples. The possible cross reactions in the EVELISA were inhibited markedly by the use of Mycobacterium phlei antigens for antibody absorption. When these samples were tested, 8 samples were classified as positive for JD by the EVELISA with the antibody absorption, whereas 27 samples were classified as positive for JD by the commercial ELISA. For an estimation of tentative sensitivity and specificity, the ELISA tests were performed on 38 serum samples from JD-negative herds with no suspected cases of serological false-positive reaction and 68 samples from cattle diagnosed as positive for M. avium subsp. paratuberculosis infection by fecal culture test. Sensitivity and specificity of the EVELISA with preabsorption of serum with M. phlei ("ethanol vortex absorbed-ELISA" or EVA-ELISA) were estimated to be 97.1% and 100%, respectively, whereas those of the commercial ELISA were 48.5% and 97.4%, respectively. Further, in 85 fecal culture-negative cattle in JD-positive herds, higher sensitivity of the EVA-ELISA than the commercial ELISA was demonstrated by a Bayesian analysis. This study indicates that the EVA-ELISA may form a basis for a sensitive diagnostic test with a higher level of specificity than that of the current commercial ELISA test.


Tissue engineered constructs for peripheral nerve surgery.
Tissue engineering has been defined as "an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function or a whole organ". Traumatic peripheral nerve injury resulting in significant tissue loss at the zone of injury necessitates the need for a bridge or scaffold for regenerating axons from the proximal stump to reach the distal stump. A review of the literature was used to provide information on the components necessary for the development of a tissue engineered peripheral nerve substitute. Then, a comprehensive review of the literature is presented composed of the studies devoted to this goal. Extensive research has been directed toward the development of a tissue engineered peripheral nerve substitute to act as a bridge for regenerating axons from the proximal nerve stump seeking the distal nerve. Ideally this nerve substitute would consist of a scaffold component that mimics the extracellular matrix of the peripheral nerve and a cellular component that serves to stimulate and support regenerating peripheral nerve axons. The field of tissue engineering should consider its challenge to not only meet the autograft "gold standard" but also to understand what drives and inhibits nerve regeneration in order to surpass the results of an autograft.


Psychosocial factors are linked to functional gastrointestinal disorders: a population based nested case-control study.
It is widely accepted based on volunteer studies that levels of psychological distress are similar in those with functional gastrointestinal (GI) disorders and health in the community, while increased psychological distress in outpatients is largely explained by health-care seeking. To determine if psychological distress, life event stress, or social support is associated with functional GI disorders in a population-based study. A nested case-control study was performed by first mailing a self-report bowel disease questionnaire to a random sample of Olmsted County, Minnesota, aged 20-50 yr. All persons who reported symptoms of nonulcer dyspepsia (NUD) or irritable bowel syndrome (IBS) (cases), or an absence of GI symptoms (controls), were invited to complete a series of validated questionnaires designed to measure psychological distress, life event stress, social support, current symptoms, and physician visits. 103 subjects with functional GI disorders and 119 controls participated (85% of eligible). Functional GI disorders were more likely to be reported by those with higher scores on each of the nine SCL-90-R scales used to measure psychological distress (except phobic anxiety), and those with more negative and total life event stress. In a multiple logistic regression model (including age and gender), somatization, interpersonal sensitivity, and total life event stress were independently associated with functional GI disorders. Findings were similar when subjects with the IBS and NUD were analyzed separately compared to controls. Contrary to current dogma, psychosocial factors were significantly associated with functional GI disorders in this community sample. This suggests that these factors may be involved in the etiopathogenesis rather than just driving health-care utilization.


Prepared Disappearing Ink and Deciphering of Documents.
Disappearing inks can be used for forgeries in many fields. In this study, thymolphthalein indicator solution was prepared as a disappearing ink. A total of 54 different solutions containing thymolphthalein were prepared at six different concentrations and nine different pH values. Among the prepared solutions, 0.16 g/50 mL and 0.32 g/65 mL thymolphthalein at pH 14 were the optimum solutions that were not distinguishable from regular ink when applied to promissory note. Fountain pens were filled with the abovementioned ink solutions and applied to promissory notes for experimental purposes. After 40 h, ink residues were not visible on promissory notes written with the ink with the optimum pH (pH = 14) value. To decipher the entries that disappeared, an instrumental method (Video Spectral Comparator-8000) and a chemical method (using NH3 vapor) were used, succeeded at 0.32 g/65 mL, but failed at 0.16 g/50 mL thymolphthalein. Therefore, NH3 had to be sprayed for 0.16 g/50 mL with negligible harm.


Peace, a MYB-like transcription factor, regulates petal pigmentation in flowering peach 'Genpei' bearing variegated and fully pigmented flowers.
Flowering peach Prunus persica cv. Genpei bears pink and variegated flowers on a single tree. The structural genes involved in anthocyanin biosynthesis were expressed strongly in pink petals but only very weakly or not at all in variegated petals. A cDNA clone encoding a MYB-like gene, isolated from pink petals was strongly expressed only in pink petals. Introduction of this gene, via biolistics gave magenta spots in the white areas of variegated petals, therefore this gene was named as Peace (peach anthocyanin colour enhancement). Differences in Peace expression determine the pattern of flower colouration in flowering peach. The R2R3 DNA-binding domain of Peace is similar to those of other plant MYBs regulating anthocyanin biosynthesis. Key amino acids for tertiary structure and the motif for interaction with bHLH proteins were conserved in Peace. Phylogenetic analysis indicates that Peace is closely related to AtMYB123 (TT2), which regulates proanthocyanidin biosynthesis in Arabidopsis, and to anthocyanin regulators in monocots rather than to regulators in dicots. This is the first report that a TT2-like R2R3 MYB has been shown to regulate anthocyanin biosynthesis.


The resveratrol tetramer (-)-hopeaphenol inhibits type III secretion in the gram-negative pathogens Yersinia pseudotuberculosis and Pseudomonas aeruginosa.
Society faces huge challenges, as a large number of bacteria have developed resistance towards many or all of the antibiotics currently available. Novel strategies that can help solve this problem are urgently needed. One such strategy is to target bacterial virulence, the ability to cause disease e.g., by inhibition of type III secretion systems (T3SSs) utilized by many clinically relevant gram-negative pathogens. Many of the antibiotics used today originate from natural sources. In contrast, most virulence-blocking compounds towards the T3SS identified so far are small organic molecules. A recent high-throughput screening of a prefractionated natural product library identified the resveratrol tetramer (-)-hopeaphenol as an inhibitor of the T3SS in Yersinia pseudotuberculosis. In this study we have investigated the virulence blocking properties of (-)-hopeaphenol in three different gram-negative bacteria. (-)-Hopeaphenol was found to have micromolar activity towards the T3SSs in Yersinia pseudotuberculosis and Pseudomonas aeruginosa in cell-based infection models. In addition (-)-hopeaphenol reduced cell entry and subsequent intracellular growth of Chlamydia trachomatis.


Sibling cooperation in earwig families provides insights into the early evolution of social life.
The evolutionary transition from solitary to social life is driven by direct and indirect fitness benefits of social interactions. Understanding the conditions promoting the early evolution of social life therefore requires identification of these benefits in nonderived social systems, such as animal families where offspring are mobile and able to disperse and will survive independently. Family life is well known to provide benefits to offspring through parental care, but research on sibling interactions generally focused on fitness costs to offspring due to competitive behaviors. Here we show experimentally that sibling interactions also reflect cooperative behaviors in the form of food sharing in nonderived families of the European earwig, Forficula auricularia. Food ingested by individual offspring was transferred to their siblings through mouth-to-anus contacts and active allo-coprophagy. These transfers occurred in both the presence and the absence of the tending mothers, even though the direct contact with the mothers limited sibling food sharing. Neither food deprivation or relatedness influenced the total amount of transferred food, but relatedness affected frass release and the behavioral mechanisms mediating food sharing. Related offspring obtained food predominately through allo-coprophagy, whereas unrelated offspring obtained food through mouth-to-anus contacts. Overall, this study emphasizes that sibling cooperation may be a key process promoting the early evolution of social life.


[Fluoride intake and excretion in children of Hermosillo, Sonora, Mexico].
To estimate the fluoride intake and urinary excretion among 8-9 year-old school children. A cross-sectional study was conducted from February to November 1997. Study subjects were 31 male children from Hermosillo, Mexico, living in three neighborhoods with different drinking water fluoride levels. Fluoride intake was measured through water intake and collection of food samples ingested in 24 hr. Fluoride excretion was measured in 24-hour urine samples. The fluoride concentration was measured by the potentiometer method using a fluoride-specific ion electrode. Statistically significant differences of fluoride levels in drinking water were found in the 3 different neighborhoods: 2.77, 0.78 and 0.54 mg/L, respectively (p < 0.01). The daily mean intake of fluoride for the neighborhood with the highest fluoride level was 5.41 mg/d, while mean intakes for the other two neighborhoods were 2.31 and 1.51 mg/d, respectively. Thirty-two percent of the children had fluoride intake above the recommendation values for this age group; sixty per cent of these children lived in the neighborhood with the highest fluoride level. Drinking water accounted for 63% of total fluoride intake, and the mean water intake was 1.8 liters. The mean excretion of fluoride was 1.61 mg/24 hours (range 0.18 to 8.1 mg/24 hr). Stepwise multiple regression showed an association between drinking water fluoride and fluoride urinary excretion (R2 = 0.56 p < 0.001). Fluoride intake in the neighborhood with the highest fluoride level was twice the daily recommended value for 8-9 year-old children. Drinking water was the main source of fluoride intake. The English version of this paper is available at: http://www.insp.mx/salud/index.html.


Semiquantitative Parameters in PSMA-Targeted PET Imaging with [18F]DCFPyL: Impact of Tumor Burden on Normal Organ Uptake.
In this study, we aimed to quantitatively investigate the biodistribution of [18F]DCFPyL in patients with prostate cancer (PCa) and to determine whether uptake in normal organs correlates with an increase in tumor burden. Fifty patients who had been imaged with [18F]DCFPyL positron emission tomography/computed tomography (PET/CT) were retrospectively included in this study. Forty of 50 (80 %) demonstrated radiotracer uptake on [18F]DCFPyL PET/CT compatible with sites of PCa. Volumes of interests (VOIs) were set on normal organs (lacrimal glands, parotid glands, submandibular glands, liver, spleen, and kidneys) and on tumor lesions. Mean standardized uptake values corrected to lean body mass (SULmean) and mean standardized uptake values corrected to body weight (SUVmean) for normal organs were assessed. For the entire tumor burden, SULmean/max, SUVmean, tumor volume (TV), and the total activity in the VOI were obtained using tumor segmentation. A Spearman's rank correlation coefficient was used to investigate correlations between normal organ uptake and tumor burden. There was no significant correlation between TV with the vast majority of the investigated organs (lacrimal glands, parotid glands, submandibular glands, spleen, and liver). Only the kidney showed significant correlation: With an isocontour threshold at 50 %, left kidney uptake parameters correlated significantly with TV (SUVmean, ρ = - 0.214 and SULmean, ρ = - 0.176, p < 0.05, respectively). Only a minimal sink effect with high tumor burden in patients imaged with [18F]DCFPyL was observed. Other factors, such as a high intra-patient variability of normal organ uptake, may be a much more important consideration for personalized dosimetry with PSMA-targeted therapeutic agents structurally related to [18F]DCFPyL than the tumor burden.


Genome-wide analysis of two-component systems and prediction of stress-responsive two-component system members in soybean.
In plants, the two-component systems (TCSs) play important roles in regulating diverse biological processes, including responses to environmental stress stimuli. Within the soybean genome, the TCSs consist of at least 21 histidine kinases, 13 authentic and pseudo-phosphotransfers and 18 type-A, 15 type-B, 3 type-C and 11 pseudo-response regulator proteins. Structural and phylogenetic analyses of soybean TCS members with their Arabidopsis and rice counterparts revealed similar architecture of their TCSs. We identified a large number of closely homologous soybean TCS genes, which likely resulted from genome duplication. Additionally, we analysed tissue-specific expression profiles of those TCS genes, whose data are available from public resources. To predict the putative regulatory functions of soybean TCS members, with special emphasis on stress-responsive functions, we performed comparative analyses from all the TCS members of soybean, Arabidopsis and rice and coupled these data with annotations of known abiotic stress-responsive cis-elements in the promoter region of each soybean TCS gene. Our study provides insights into the architecture and a solid foundation for further functional characterization of soybean TCS elements. In addition, we provide a new resource for studying the conservation and divergence among the TCSs within plant species and/or between plants and other organisms.


Extracellular clusterin promotes neuronal network complexity in vitro.
Clusterin (apolipoprotein J), a highly conserved amphiphatic glycoprotein and chaperone, has been implicated in a wide range of physiological and pathological processes. As a secreted protein, clusterin has been shown to act extracellularly where it is involved in lipid transportation and clearance of cellular debris. Intracellularly, clusterin may regulate signal transduction and is upregulated after cell stress. After neural injury, clusterin may be involved in nerve cell survival and postinjury neuroplasticity. In this study, we investigated the role of extracellular clusterin on neuronal network complexity in vitro. Quantitative analysis of clustrin-treated neuronal cultures showed significantly higher network complexity. These findings suggest that in addition to previously demonstrated neuroprotective roles, clusterin may also be involved in neuronal process formation, elongation, and plasticity.


Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis.
Oral daily (2.5 mg) and intermittent ibandronate (between-dose interval of >2 months), delivering a similar cumulative exposure, were evaluated in 2946 osteoporotic women with prevalent vertebral fracture. Significant reduction in incident vertebral fracture risk by 62% and 50%, respectively, was shown after 3 years. This is the first study to prospectively show antifracture efficacy for the intermittent administration of a bisphosphonate. Bisphosphonates are important therapeutics in postmenopausal osteoporosis. However, they are currently associated with stringent dosing instructions that may impair patient compliance and hence therapeutic efficacy. Less frequent, intermittent administration may help to overcome these deficiencies. This study assessed the efficacy and safety of oral ibandronate administered either daily or intermittently with a dose-free interval of >2 months. This randomized, double-blind, placebo-controlled, parallel-group study enrolled 2946 postmenopausal women with a BMD T score < or = -2.0 at the lumbar spine in at least one vertebra (L1-L4) and one to four prevalent vertebral fractures (T4-L4). Patients received placebo or oral ibandronate administered either daily (2.5 mg) or intermittently (20 mg every other day for 12 doses every 3 months). After 3 years, the rate of new vertebral fractures was significantly reduced in patients receiving oral daily (4.7%) and intermittent ibandronate (4.9%), relative to placebo (9.6%). Thus, daily and intermittent oral ibandronate significantly reduced the risk of new morphometric vertebral fractures by 62% (p = 0.0001) and 50% (p = 0.0006), respectively, versus placebo. Both treatment groups also produced a statistically significant relative risk reduction in clinical vertebral fractures (49% and 48% for daily and intermittent ibandronate, respectively). Significant and progressive increases in lumbar spine (6.5%, 5.7%, and 1.3% for daily ibandronate, intermittent ibandronate, and placebo, respectively, at 3 years) and hip BMD, normalization of bone turnover, and significantly less height loss than in the placebo group were also observed for both ibandronate regimens. The overall population was at low risk for osteoporotic fractures. Consequently, the incidence of nonvertebral fractures was similar between the ibandronate and placebo groups after 3 years (9.1%, 8.9%, and 8.2% in the daily, intermittent, and placebo groups, respectively; difference between arms not significant). However, findings from a posthoc analysis showed that the daily regimen reduces the risk of nonvertebral fractures (69%; p = 0.012) in a higher-risk subgroup (femoral neck BMD T score < -3.0). In addition, oral ibandronate was well tolerated. Oral ibandronate, whether administered daily or intermittently with an extended between-dose interval of >2 months, is highly effective in reducing the incidence of osteoporotic fractures in postmenopausal women. This is the first time that significant fracture efficacy has been prospectively shown with an intermittently administered bisphosphonate in the overall study population of a randomized, controlled clinical trial. Thus, oral ibandronate holds promise as an effective and convenient alternative to current bisphosphonate therapies.


Matrix Gla protein polymorphism, but not concentrations, is associated with radiographic hand osteoarthritis.
Factors associated with mineralization and osteophyte formation in osteoarthritis (OA) are incompletely understood. Genetic polymorphisms of matrix Gla protein (MGP), a mineralization inhibitor, have been associated clinically with conditions of abnormal calcification. We therefore evaluated the relationship of MGP concentrations and polymorphisms at the MGP locus to hand OA. Ours was an ancillary study to a 3-year randomized trial assessing the effect of vitamin K supplementation on vascular calcification and bone loss among community-dwelling elders. We studied participants who had serum MGP concentration measured and DNA genotyped for 3 MGP genetic polymorphisms (rs1800802, rs1800801, and rs4236), and who had hand radiographs. We evaluated the cross-sectional associations of serum MGP and the 3 MGP genetic polymorphisms, respectively, with radiographic hand OA using logistic regression with generalized estimating equations, adjusting for potential confounders. Radiographic hand OA in ≥ 1 joint was present in 71% of the 376 participants (mean age 74 years, mean body mass index 28 kg/m(2), 59% women). No significant association between serum MGP concentrations and radiographic hand OA was found [adjusted OR 1.0 (ref), 1.40, 1.21, and 1.21 for quartiles 1-4, respectively]. Homozygosity of the rs1800802 minor allele was associated with 0.56 times lower prevalence of hand OA compared with having ≥ 1 major allele at this locus (95% CI 0.32-0.99, p = 0.046). There may be an association between hand OA and genetic polymorphism at the MGP locus that is not reflected by total MGP serum concentrations. Further studies are warranted to replicate and elucidate potential mechanisms underlying these observed associations.


Increased cardiovascular risk after pre-eclampsia in women with dysglycaemia.
Compared with women with uncomplicated pregnancies, women with a history of pre-eclampsia have two to five times the risk of cardiovascular disease. It is not known whether this risk is related to albuminuria, a known cardiovascular risk factor that is part of the definition of pre-eclampsia and that often persists after delivery. Our objective was to determine if the high risk of cardiovascular disease in women with pre-eclampsia is accounted for by known cardiovascular risk factors including albuminuria. We performed a cross-sectional analysis of 4080 dysglycaemic women enrolled in a large randomized controlled trial who provided an obstetric history and had at least one delivery. Blood pressure, height, weight, waist circumference and hip circumference were measured. An oral glucose tolerance test, lipids, an electrocardiogram and an albumin/creatinine ratio from a first morning urine sample were obtained. There were 3613 women with no history of pre-eclampsia during their pregnancies, 108 with severe pre-eclampsia and 359 with non-severe pre-eclampsia. Women with a history of severe pre-eclampsia had higher rates of previous cardiovascular disease than women with non-severe pre-eclampsia or women without pre-eclampsia (87, 72 and 72%, P = 0.0019). The high risk of previous cardiovascular disease in women with a history of severe pre-eclampsia (odds ratio 2.67, 95% CI 1.52-4.70) persisted after adjustment for albuminuria (odds ratio 2.74, 95% CI 1.55-4.83) and also after adjusting for other covariates including albuminuria (odds ratio 3.03, 95% CI 1.69-5.44). Even after accounting for cardiovascular risk factors including albuminuria, a history of severe pre-eclampsia is independently associated with a threefold higher risk of cardiovascular disease.


Quality of life impairment associated with body dissatisfaction in a general population sample of women.
In order to elucidate the individual and community health burden of body dissatisfaction (BD), we examined impairment in quality of life associated with BD in a large, general population sample of women. Self-report measures of BD, health-related quality of life (SF-12 Physical and Mental Component Summary scales) and subjective quality of life (WHOQOL-BREF Psychological Functioning and Social Relationships subscales) were completed by 5,255 Australian women aged 18 to 42 years. Most participants (86.9%) reported some level of dissatisfaction with their weight or shape and more than one third (39.4%) reported moderate to marked dissatisfaction. Higher levels of BD were associated with poorer quality of life for all items of both quality of life measures, the degree of impairment being proportional to the degree of BD. Associations were strongest for items tapping mental health and psychosocial functioning, although greater BD was associated with substantially increased risk of impairment in certain aspects of physical health even when controlling for body weight. Post-hoc analysis indicated that the observed associations between BD and quality of life impairment were not accounted for by an association between BD and eating disorder symptoms. In women, BD is associated with marked impairment in aspects of quality of life relating to mental health and psycho-social functioning and at least some aspects of physical health, independent of its association with body weight and eating disorder symptoms. Greater attention may need to be given to BD as a public health problem. The fact that BD is "normative" should not be taken to infer that it is benign.


Gene set bagging for estimating the probability a statistically significant result will replicate.
Significance analysis plays a major role in identifying and ranking genes, transcription factor binding sites, DNA methylation regions, and other high-throughput features associated with illness. We propose a new approach, called gene set bagging, for measuring the probability that a gene set replicates in future studies. Gene set bagging involves resampling the original high-throughput data, performing gene-set analysis on the resampled data, and confirming that biological categories replicate in the bagged samples. Using both simulated and publicly-available genomics data, we demonstrate that significant categories in a gene set enrichment analysis may be unstable when subjected to resampling. We show our method estimates the replication probability (R), the probability that a gene set will replicate as a significant result in future studies, and show in simulations that this method reflects replication better than each set's p-value. Our results suggest that gene lists based on p-values are not necessarily stable, and therefore additional steps like gene set bagging may improve biological inference on gene sets.


Natural Salicylates and Their Roles in Human Health.
Salicylic acid (SA) is a plant hormone which plays a crucial role in the plant defense against various pathogens and abiotic stresses. Increasing reports suggest that this phenolic compound and its derivatives, collectively termed salicylates, not only regulate plant defense but also have beneficial effects on human health. Both natural and synthetic salicylates are known to have multiple targets in humans, thereby exhibiting various appreciating pharmacological roles, including anti-inflammatory, anticancer, neuroprotective, antidiabetic effects, and so on. The role of some salicylates, such as acetylsalicylic acid (aspirin), 5-aminosalicylic acid (mesalazine), and amorfrutins in human diseases has been well studied in vitro. However, their clinical significance in different diseases is largely unknown. Based on recent studies, five natural salicylates, including amorfrutin, ginkgolic acid, grifolic acid, tetrahydrocannabinolic acid, and cannabidiolic acid, showed potential roles in different challenging human diseases. This review summarizes together some of the recent information on multitarget regulatory activities of these natural salicylates and their pharmacological roles in human health.


Blood doping--a literature review.
There is increasing evidence that the technique of reinfusing an athlete's stored blood prior to competition to improve performance has been used on many occasions. Although early experimental results were controversial and the precise mechanism by which the technique improves performance is still debated, there is now strong evidence that if the blood doping produces a sufficient rise in total red cell mass there are significant improvements in physiological variables such as maximum oxygen uptake, lactate buffering and thermoregulation. These physiological changes are matched by improvements in endurance performance. These may persist in diminishing degree for several weeks, but have to be weighed against the detraining effect produced by the repeated venesection required to obtain an adequate amount of stored blood for autologous reinfusion. Experimental evidence suggests that the transient increase in blood volume and cardiac output following reinfusion is too short lived to be of any real importance and the major effect is related to the increase in total red blood cell mass and haemoglobin enabling an increased transport of oxygen and therefore a potentially greater reserve of blood which can be diverted to non-exercising tissues to improve thermoregulation. The increased red cell mass also improves lactate buffering. Although these benefits have been shown in several studies the increases in performance and measured physiological parameters do not bear a direct relationship to the changes in haematological variables. Blood doping is of considerable importance, not only as an abuse of fair competition, but also because of the light it throws on the physiological limits to endurance performance. It has reawakened controversy as to whether oxygen transport is the limiting factor in endurance.


The antidepressant drugs fluoxetine and duloxetine produce anxiolytic-like effects in a schedule-induced polydipsia paradigm in rats: enhancement of fluoxetine's effects by the α2 adrenoceptor antagonist yohimbine.
Similar to the time-course for treating depression, several weeks of administration are required for serotonin (5-HT) reuptake inhibitors to produce anxiolytic effects. Previous studies with the schedule-induced polydipsia paradigm (a putative preclinical anxiety model) have shown that repeated administration of antidepressant drugs is necessary to produce a suppression of polydipsia, which is interpreted as an anxiolytic-like effect. The present study sought to expand past findings by evaluating the selective 5-HT reuptake inhibitor (SSRI) fluoxetine and the 5-HT-norepinephrine reuptake inhibitor duloxetine in the schedule-induced polydipsia paradigm with rats. Dose combinations of the α2 adrenoceptor antagonist yohimbine with fluoxetine were also explored to determine whether α2 adrenoceptor antagonism could enhance the anxiolytic-like effects produced by an SSRI. Fluoxetine and duloxetine significantly reduced water intake over the course of daily administrations. Daily treatment with the combination of fluoxetine and yohimbine produced a significantly greater reduction in water intake than fluoxetine alone. The present results confirmed previous findings that inhibition of 5-HT reuptake reduces water consumption in this paradigm. The results for the α2 antagonist yohimbine (in combination with fluoxetine) also indicate that α2 adrenoceptor antagonism may significantly enhance anxiolytic-like effects of SSRIs.


Hepatocellular Neoplasms Arising in Association With Androgen Use.
Correlation between androgen use and hepatocellular neoplasia is well established. However, there are no detailed studies of the histopathology and immunohistochemical/molecular profile of these tumors. We studied 9 patients with androgen-associated hepatocellular neoplasms. In addition to histology, immunostains for liver fatty acid-binding protein, β-catenin, glutamine synthetase, C-reactive protein, and serum amyloid A were utilized for tumor subtyping. Molecular testing using Solid Tumor Targeted Cancer Panel was performed on 3 cases. The neoplasms were predominantly seen in male individuals (7/9). Two patients (22%) had multifocal lesions. All lesions had architectural and 4/9 had cytologic atypia. Cholestasis was present in 6/9 cases. Reticulin was focally disrupted in 5/9 cases. Given the clinical setting, all lesions were classified as well-differentiated hepatocellular neoplasms of uncertain malignant potential. In cases with follow-up (6/9 cases, 67%), there were no recurrences or metastases. On the basis of the immunoprofile, 7 (78%) cases were β-catenin activated (including 1 hepatic adenoma with concurrent hepatocyte nuclear factor 1α inactivation) and 2 (22%) had inflammatory phenotype. Somatic mutations in CTNNB1 were detected in all 3 tested cases (all β-catenin activated by immunostain), all involving exon-3. Our data indicate that androgen-associated hepatocellular neoplasms most often develop in male individuals and always show some degree of atypia and/or focal reticulin disruption. Most are β-catenin activated, often harboring CTNNB1 exon-3 mutations, and a minority is inflammatory type. Although β-catenin and inflammatory pathways likely play a role in pathogenesis, the heterogenous molecular profile suggests there are other (yet to be characterized) primary oncogenic mechanisms in this unique tumor type.


What attracts students to interprofessional education and other health care reform initiatives?
An international consensus has emerged that interprofessional education (IPE) and other health care reforms are necessary to address the increasing complexity of patients' health needs. Despite overwhelming barriers to its system-wide implementation, health professional students worldwide have organized themselves to promote IPE and have achieved considerable attention. This study seeks to offer insights into what attracts students to IPE and other health care reform initiatives and how advocates of change can stimulate this interest. Using a qualitative research methodology, 69 students representing 25 disciplines from 22 institutions across North America were interviewed and surveyed on why and how they became interested in IPE. Students were attracted to the possibility of enhancing patient care (n=17), advancing their careers (n=17) and learning more about the issue (n=15). The participating students first became involved in IPE after they joined a student organization (n=21), attended an IPE conference (n=10) or received personal encouragement to do so from a dean (n=2), instructor (n=3), school administrator (n=7) or peer (n=11). These findings point to several strategies that advocates can use to capitalize on the potential of student advocacy to gain support for IPE and new health care innovations. This study is the first of its kind to delineate how clinicians, educators, researchers and policymakers can attract students to health care reform initiatives. This work can inform the strategic efforts of advocates to make the idea of IPE and health care reform more attractive to students (as both learners and leaders) and enlist their help in achieving it in the future.


Mortality before and after initiation of a computerized physician order entry system in a critically ill pediatric population.
A worrisome increase in mortality has been reported recently following the initiation of a computerized physician order entry (CPOE) system in a critically ill pediatric transport population. We tested the hypothesis that such a mortality increase did not occur after the initiation of CPOE in a pediatric population that was directly admitted to the neonatal and pediatric intensive care units at Montefiore Medical Center during two 6-month periods before CPOE and one 6-month period immediately after CPOE was initiated. Mortality in the pre- and post-CPOE time periods was compared, and adjustment for potentially confounding covariates was performed. The pediatric and neonatal intensive care units at Montefiore Medical Center. All patients admitted from the emergency room or operating room or as transfers from other institutions directly to the pediatric and neonatal intensive care units at Montefiore Medical Center. None. Overall, 29 (3.16%) of the 917 patients in the pre-CPOE period and nine (2.41%) of the 374 patients in the post-CPOE period died during their hospital stay (p = .466). The power to detect the hypothesized mortality increase was 81.7%. The variables that remained significant risk factors for mortality after adjustment were shock (odds ratio, 9.41; 95% confidence interval, 2.90-30.49), prematurity (odds ratio, 3.57; 95% confidence interval, 1.74-7.30), male gender (odds ratio, 3.31; 95% confidence interval, 1.47-7.69), or a hematologic/oncologic diagnosis (odds ratio, 3.14; 95% confidence interval, 1.44-6.86). Post-CPOE initiation status remained unassociated with mortality after adjusting for all covariates (odds ratio, 0.71; 95% confidence interval, 0.32-1.57). Mortality did not increase during CPOE initiation.


Reproductive and hormonal factors and risk of lung cancer in women: a prospective cohort study.
Several lines of evidence suggest that endocrine factors may play a role in the development of lung cancer, but the evidence is limited and inconsistent. We investigated the association of reproductive and hormonal factors with risk of lung cancer in the National Breast Screening Study, which included 89,835 Canadian women aged 40-59 years at recruitment between 1980 and 1985. Linkages to national cancer and mortality databases provided data on cancer incidence and deaths from all causes, respectively, with follow-up ending between 1998 and 2000. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between hormonal factors and lung cancer. During a mean of 16.4 years of follow-up, we observed 750 incident lung cancer cases. After adjustment for covariates, parous women were not at increased risk of lung cancer (HR = 1.18, 95% CI 0.94-1.47) relative to nulliparous women; however, there was a modest increase in risk with increasing parity, reaching a HR of 1.42, 95% CI 1.06-1.88 in women who had 5 or more live births (p for trend 0.02). Among parous women, age at first live birth was inversely associated with risk. Women who had their first live birth at age 30 or older were at reduced risk relative to women who had their first live birth below age 23 (HR 0.68, 95% CI 0.50-0.93, p for trend 0.004). These associations did not differ by age at enrollment (40-49 vs. 50-59 years old), but were somewhat strengthened when attention was restricted to never smokers. Ever use of exogenous hormones showed little association with lung cancer risk; however, long-term users of hormone replacement therapy were at slightly increased risk. Our results add to the limited existing evidence that certain reproductive and hormonal factors may be associated with lung cancer risk in women.


Germline Genetic Association between Stromal Interaction Molecule 1 (STIM1) and Clinical Outcomes in Breast Cancer Patients.
Among all cancers in women, breast cancer has the highest incidence. The mortality of breast cancer is highly associated with metastasis. Migration and malignant transformation of cancer cells have been reported to be modulated by store-operated calcium (SOC) channels, which control calcium signaling and cell proliferation pathways. Stromal interaction molecule 1 (STIM1) is a calcium sensor in the endoplasmic reticulum, triggering the activation of store-operated calcium signaling. However, the clinical relevance of STIM1 in breast cancer is still unclear. Here, we recruited 348 breast cancer patients and conducted a genetic association study to address this question. Four tagging germline single nucleotide variants (SNVs) in STIM1 were selected and RNA sequencing data of 525 breast cancer samples from The Cancer Genome Atlas (TCGA) database were evaluated. The results show that rs2304891 and rs3750996 were correlated with clinical stage of breast cancer. Expression quantitative trait loci (eQTL) analysis indicated that risk G allele of STIM1 contributed to the higher expression of STIM1. In addition, we found an increased risk of rs2304891 G allele and rs3750996 A allele in estrogen receptor (ER) positive and progesterone receptor (PR) positive patients. In conclusion, our results suggest that germline SNV, rs2304891 and rs3750996 as well as STIM1 expression are important biomarkers for the prediction of clinical outcomes in breast cancer patients.


Histologic analysis of the hernia sac: current practices based on a survey of IPEG members.
Inguinal hernia repair is one of the most common operations performed by pediatric surgeons. Although the practice of sending the hernia sac for histologic examination after routine hernia repair is common, the indications and practice patterns for this have not been evaluated. The objective of this survey was to determine practice patterns and indications for histologic analysis of the pediatric inguinal hernia sac. A 9-question online survey was sent to all members of the International Pediatric Endosurgery Group (IPEG). A Kruskal-Wallis test was used to determine whether practice patterns of sending the hernia sac for histologic evaluation were associated with respondent characteristics. The chi-squared test with Yates's correction was used where appropriate. The survey was completed by 315 IPEG members, for a response rate of 54.4%. Hernia sacs were sent for histologic evaluation always by 23.9%, often by 5.1%, rarely by 17.5%, and never by 53.5%. The respondent characteristics were not associated with whether or not specimens were sent for histology review. Of the 128 who reported sending the inguinal hernia sac, the most common reasons were hospital/state requirements (47.6%), followed by routine practice (25.7%) and concern for missed pathology (24.2%). The majority of IPEG respondents report never sending the inguinal hernia sac for histologic analysis. Of those that do, most are influenced by hospital/state requirements. The value of sending the hernia sac after routine inguinal hernia repair should be validated if it is to remain an institutional requirement.


A sampling theory of selectively neutral alleles in a subdivided population.
Ewens' sampling distribution is investigated for a structured population. Samples are assumed to be taken from a single subpopulation that exchanges migrants with other subpopulations. A complete description of the probability distribution for such samples is not a practical possibility but an equilibrium approximation can be found. This approximation extracts the information necessary for constructing a continuous approximation to the complete distribution using known values of the distribution and its derivatives in randomly mating populations. It is shown that this approximation is as complete a description of a single biologically realistic subpopulation as is possible given standard uncertainties about the actual size of the migration rates, relative sizes of each of the subpopulations and other factors that might affect the genetic structure of a subpopulation. Any further information must be gained at the expense of generality. This approximation is used to investigate the effect of population subdivision on Watterson's test of neutrality. It is known that the infinite allele, sample distribution is independent of mutation rate when made conditional on the number of alleles in the sample. It is shown that the conditional, infinite allele, sample distribution from this approximation is also independent of population structure and hence Watterson's test is still approximately valid for subdivided populations.


Systemic delivery of umbilical cord blood cells for stroke therapy: a review.
This review paper summarizes relevant studies, discusses potential mechanisms of transplanted cell-mediated neuroprotection, and builds a case for the need to establish outcome parameters that are critical for transplantation success. In particular, we outline the advantages and disadvantages of systemic delivery of human umbilical cord blood (HUCB) cells in the field of cellular transplantation for treating ischemic stroke. A MEDLINE/PubMed systematic search of published articles in peer-reviewed journals over the last 25 years was performed focusing on the theme of HUCB as donor graft source for transplantation therapy in neurological disorders with emphasis on stroke. Ischemic stroke remains a leading cause of human death and disability. Although stroke survivors may gain spontaneous partial functional recovery, they often suffer from sensory-motor dysfunction, behavioral/neurological alterations, and various degrees of paralysis. Currently, limited clinical intervention is available to prevent ischemic damage and restore lost function in stroke victims. Stem cells from fetal tissues, bone marrow, and HUCB has emerged in the last few years as a potential cell transplant cell source for ischemic stroke, because of their capability to differentiate into multiple cell types and the possibility that they may provide trophic support for cell survival, tissue repair, and functional recovery. A growing number of studies highlight the potential of systemic delivery of HUCB cells as a novel therapeutic approach for stroke. However, additional preclinical studies are warranted to reveal the optimal HUCB transplant regimen that is safe and efficacious prior to proceeding to large-scale clinical application of these cells for stroke therapy.


Chimeric human opsins as optogenetic light sensitisers.
Human opsin-based photopigments have great potential as light-sensitisers, but their requirement for phototransduction cascade-specific second messenger proteins may restrict their functionality in non-native cell types. In this study, eight chimeric human opsins were generated consisting of a backbone of either a rhodopsin (RHO) or long-wavelength-sensitive (LWS) opsin and intracellular domains from Gq/11-coupled human melanopsin. Rhodopsin/melanopsin chimeric opsins coupled to both Gi and Gq/11 pathways. Greater substitution of the intracellular surface with corresponding melanopsin domains generally showed greater Gq/11 activity with a decrease in Gi activation. Unlike melanopsin, rhodopsin and rhodopsin/melanopsin chimeras were dependent upon exogenous chromophore to function. By contrast, wild-type LWS opsin and LWS opsin/melanopsin chimeras showed only weak Gi activation in response to light, whilst Gq/11 pathway activation was not detected. Immunocytochemistry (ICC) demonstrated that chimeric opsins with more intracellular domains of melanopsin were less likely to be trafficked to the plasma membrane. This study demonstrates the importance of Gα coupling efficiency to the speed of cellular responses and created human opsins with a unique combination of properties to expand the range of customised optogenetic biotools for basic research and translational therapies.


Wnt signaling in bone, kidney, intestine, and adipose tissue and interorgan interaction in aging.
Over the last two decades, it has become increasingly apparent that Wnt signaling plays a critical role in development and adult tissue homeostasis in multiple organs and in the pathogenesis of many diseases. In particular, a crucial role for Wnt signaling in bone development and bone tissue homeostasis has been well recognized. Numerous genome-wide association studies confirmed the importance of Wnt signaling in controlling bone mass. Moreover, ample evidence suggests that Wnt signaling is essential for kidney, intestine, and adipose tissue development and homeostasis. Recent emerging evidence demonstrates that Wnt signaling may play a fundamental role in the aging process of those organs. New discoveries show that bone is not only the major reservoir for calcium and phosphate storage, but also the largest organ with multiple functions, including mineral and energy metabolism. The interactions among bone, kidney, intestine, and adipose tissue are controlled and regulated by several endocrine signals, including FGF23, klotho, sclerostin, osteocalcin, vitamin D, and leptin. Since the aging process is characterized by structural and functional decline in almost all tissues and organs, understanding the Wnt signaling-related interactions among bone, kidney, intestine, and adipose tissue in aging may shed light on the pathogenesis of age-related diseases.


Substance use, criminal behaviour and psychiatric symptoms following childhood traumatic brain injury: findings from the ALSPAC cohort.
Recent research suggests a link between traumatic brain injury (TBI) in youth and later risk behaviour. We explored the association between mild TBI and psychiatric symptoms, substance use and criminal behaviour using data from a longitudinal birth cohort. Participants with mild TBI (n = 800), orthopaedic injuries (n = 2305) and no injuries (n = 8307) were identified from self and parent reports up to age 16 years. Self-report measures of substance use (alcohol, tobacco and cannabis) and criminal behaviours, and parent-reported psychiatric symptoms were collected at age 17 years. Analyses were adjusted for pre-birth and early childhood confounders. Participants with a TBI showed increased odds of hazardous alcohol use compared to those with no injury and those with an orthopaedic injury. Relative to those with no injury, participants with a TBI showed increased odds of problematic use of tobacco and cannabis, being in trouble with the police and having more parent-reported conduct problems. Sustaining either a TBI or an orthopaedic injury increased the odds of offending behaviour compared to having no injuries. There was no clear evidence of association between orthopaedic injury and the other risk outcomes. The increased odds of risk behaviour associated with TBI relative to no injury replicated previous research. However, the inclusion of a non-brain-related injury group adds evidence for a possible causal pathway between mild TBI in youth and later hazardous alcohol use only. This highlights the importance of including an additional negative control injury group in mild TBI research.


Pathogenic Impacts of Dysregulated Polycomb Repressive Complex Function in Hematological Malignancies.
Polycomb repressive complexes (PRCs) are epigenetic regulators that mediate repressive histone modifications. PRCs play a pivotal role in the maintenance of hematopoietic stem cells through repression of target genes involved in cell proliferation and differentiation. Next-generation sequencing technologies have revealed that various hematologic malignancies harbor mutations in PRC2 genes, such as EZH2, EED, and SUZ12, and PRC1.1 genes, such as BCOR and BCORL1. Except for the activating EZH2 mutations detected in lymphoma, most of these mutations compromise PRC function and are frequently associated with resistance to chemotherapeutic agents and poor prognosis. Recent studies have shown that mutations in PRC genes are druggable targets. Several PRC2 inhibitors, including EZH2-specific inhibitors and EZH1 and EZH2 dual inhibitors have shown therapeutic efficacy for tumors with and without activating EZH2 mutations. Moreover, EZH2 loss-of-function mutations appear to be attractive therapeutic targets for implementing the concept of synthetic lethality. Further understanding of the epigenetic dysregulation associated with PRCs in hematological malignancies should improve treatment outcomes.


Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease.
The scurfy mutant mouse strain suffers from a fatal lymphoproliferative disease leading to early death within 3-4 wk of age. A frame-shift mutation of the forkhead box transcription factor Foxp3 has been identified as the molecular cause of this multiorgan autoimmune disease. Foxp3 is a central control element in the development and function of regulatory T cells (T reg cells), which are necessary for the maintenance of self-tolerance. However, it is unclear whether dysfunction or a lack of T reg cells is etiologically involved in scurfy pathogenesis and its human correlate, the IPEX syndrome. We describe the generation of bacterial artificial chromosome-transgenic mice termed "depletion of regulatory T cell" (DEREG) mice expressing a diphtheria toxin (DT) receptor-enhanced green fluorescent protein fusion protein under the control of the foxp3 gene locus, allowing selective and efficient depletion of Foxp3+ T reg cells by DT injection. Ablation of Foxp3+ T reg cells in newborn DEREG mice led to the development of scurfy-like symptoms with splenomegaly, lymphadenopathy, insulitis, and severe skin inflammation. Thus, these data provide experimental evidence that the absence of Foxp3+ T reg cells is indeed sufficient to induce a scurfy-like phenotype. Furthermore, DEREG mice will allow a more precise definition of the function of Foxp3+ T reg cells in immune reactions in vivo.


Reviving the acid phosphatase test for prostate cancer.
Prostatic acid phosphatase (PAP) emerged as the world's first clinically useful tumor marker in the 1940s and 1950s. With the introduction of the prostate-specific antigen (PSA) test in the 1980s, which performed significantly better than PAP in terms of screening and monitoring response to treatment, PAP fell into disfavor. An increasing number of recent studies have identified PAP as a significant prognostic factor for patients with intermediate- and high-risk prostate cancer. PAP appears to be particularly valuable in predicting distant failure in higher-risk patients for whom high levels of local control are achieved with aggressive initial local treatment. As prostate cancer care becomes increasingly focused on identifying the minority of patients who would benefit from aggressive systemic therapy, a reevaluation of the potential contribution of the prostatic acid phosphatase test seems timely.


Relative incomes and rates of return for U.S. physicians.
Since 1967 the supply of physicians in the U.S. has been growing by more than 3 percent per annum. This, coupled with public insurer fee discounts, might have been expected to depress both the relative and absolute incomes of physicians in spite of growing insurance coverage and new technologies. Real incomes of physicians did decline at a 0.2 percent annual rate between 1967 and 1980, but this was apparently due to economy-wide events since the income trends for lawyers, dentists, and college graduates were virtually identical. Internal rates of return to undergraduate medical training remained high--between 14 and 17 percent in 1980. Specialty training became more profitable for internists, general surgeons, and obstetricians/gynecologists (all with 10-15 percent rates of return), while pediatricians continued to suffer a financial loss. While Medicare and Medicaid fee discounts have been criticized as inequitable, the programs are also shown to provide a 'hidden subsidy' to physicians during residency training, materially adding to rates of returns.


Sequential comprehensive chromosome analysis on polar bodies, blastomeres and trophoblast: insights into female meiotic errors and chromosomal segregation in the preimplantation window of embryo development.
What is the optimal stage from oocyte through preimplantation embryo development for biopsy and preimplantation genetic screening (PGS) to detect abnormal chromosome segregation patterns in eggs or embryos from advanced maternal age (AMA) patients? Testing at the polar body (PB) stage was the least accurate mainly due to the high incidence of post-zygotic events. This suggests that postponing the time of biopsy to the blastocyst stage of preimplantation embryo development may provide the most reliable results for PGS. In the PGS field there is an ongoing debate about the optimal biopsy stage for PGS. This is a result of the lack of understanding of how aneuploidy arises in the human embryo. To date, most of the cytogenetic data obtained during PGS investigations have been derived through the analysis of cells at isolated points in the preimplantation window, thus potentially missing critical information on chromosomal segregation. Understanding the chromosome segregation patterns during preimplantation development holds the potential to significantly increase the success rates of IVF. In this study, a sequential comprehensive chromosome analysis of both the PBs and the corresponding embryos at both the cleavage and the blastocyst stages is presented. This is a prospective longitudinal cohort study performed between October 2009 and August 2011 involving 9 infertile couples and 21 sets of complete comprehensive chromosomal screening data, including PB1, PB2, corresponding blastomeres and trophectoderm (TE) samples. Infertile couples undergoing IVF cycles with PGS where the female partner was older than 40 years and with a good response to controlled ovarian stimulation (>10 MII oocytes retrieved) were enrolled into the study. The exclusion criteria were (i) patients presenting with abnormal karyotype; (ii) specific ovarian pathologies including polycystic ovary syndrome, endometriosis grade III or higher and premature ovarian failure and (iii) severe male factor infertility (motile sperm count of <500 000/ml after preparation of a fresh ejaculate). The PBs, blastomere and TE samples were sequentially biopsied and analyzed by array comparative genomic hybridization (aCGH). The analysis of chromosome segregation patterns was performed to infer the origin of aneuploidy and to investigate the diagnostic accuracy of both PB and cleavage-stage PGS strategies. Twenty-one sets of complete data (PB1/PB2/blastomere/TE) including 84 aCGH experiments showed a pattern of multiple meiotic errors typically caused by sister chromatid separation errors and predominantly arising in the second meiotic division. Twenty-two of the 24 (91.7%) errors in the first meiotic division arose as a consequence of premature sister chromatid predivision. In half of these cases, the second meiotic division resulted in a balancing chromosome segregation event producing a normal female complement for that chromosome in the resulting embryo. Overall, only 62 out of 78 (79.5%) of the abnormal meiotic segregations had errors in the either one or both PBs consistent with the aneuploidies observed in their resulting embryos. Ten of the 21 (47.6%) embryos had aneuploidies other than female meiotic-derived ones, most of which detected on Day 3 and confirmed on Day 5 or 6 of embryo development (20/25) with chromosomal loss being three times more frequent than gains. Notably, as high as 20% of female-derived aneuploidies detected on PBs and confirmed on Day 3 were rescued at the blastocyst stage, mainly as a result of diploidization of trisomic chromosomes. On a per chromosome basis, the sensitivity in predicting blastocyst chromosomal complement was significantly lower for PB approach, 61.7%, compared with blastomeres analysis, 86.4% (P < 0.01). The study was limited to the analysis of oocytes and embryos from AMA patients. Thus, these findings apply only to this patient group. Comparisons with other patient populations including patients with different indications for PGS should be made in future research. In addition, higher resolution and/or more accurate chromosomal screening tests could be used in future studies to corroborate the current findings. These findings provide critical insights into the mechanisms causing errors during female meiosis and the preimplantation embryo development period to improve the design and treatment outcome of PGS.


Long-term hydroxychloroquine therapy improves the quality of sleep in patients with primary Sjögren's syndrome: a real-world study.
Patients with primary Sjögren's syndrome (pSS) often suffer from sleep disturbance. Studies suggest it may be related to symptoms, including xerostomia and dry eyes. Clinical studies have confirmed that hydroxychloroquine (HCQ) has a definite effect on pSS, but there is no clear report about its effect on sleep disorders in pSS patients. A total of 383 pSS patients were enrolled and followed up. The Pittsburgh Sleep Quality Index (PSQI) was used to evaluate the sleep quality of the patients, and the World Health Organization Quality of Life Brief Version (WHOQOL-BREF) scale was used to evaluate the quality of life (QoL) of patients. The European League assessed the patient's condition against Rheumatism Sjögren's syndrome patients reported index (ESSPRI). According to PSQI, patients were divided into two groups: good sleep group (GSG) and poor sleep group (PSG). The risk factors of sleep disorder are analyzed by univariate and multivariate analysis. The patients were further divided into HCQ-administered group and non-administered group, and the differences of baseline characteristics and outcome in follow-up between the two groups were compared. There were 208 patients with PSG (54.3%) and 175 patients with GSG (45.7%). Further, there is no statistical difference between the two groups in baseline data. Also, there were 112 cases (53.8%) and 118 cases (67.4%) taking HCQ in the two groups, respectively, P=0.007. Univariate and multivariate analysis showed that long-term use of HCQ, menopause, and income were related to sleep quality. The patients were divided into the HCQ-administered group (n=230) and non-administered group (n=153) according to whether they took HCQ. One hundred eighteen patients (51.3%) in the HCQ-administered group had a good sleep, and 58 patients in the non- administered group had a good sleep (37.9%), P<0.05. At followup, the PSQI of the two groups were 7.3±2.1 vs. 8.1±2.4, respectively, P<0.05 and the ESSPRI were 4.9±1.1 vs. 5.4±1.3, P<0.05. The QoL of the two groups of patients was statistically different in all four dimensions, P<0.05. Long-term use of HCQ can reduce the risk of sleep disturbance in patients with primary Sjögren's syndrome.


Effects of dark septate endophytes on tomato plant performance.
Non-mycorrhizal fungal root endophytes can be found in all natural and cultivated ecosystems, but little is known about their impact on plant performance. The impact of three mitosporic dark septate endophytes (DSE48, DSE49 and Leptodontidium orchidicola) on tomato plant characteristics was studied. Their effects on root and shoot growth, their influence on fruit yield and fruit quality parameters and their ability to diminish the impact of the pathogen Verticillium dahliae were investigated. While shoot biomass of young plants was enhanced between 10% and 20% by the endophytes DSE48 and L. orchidicola in one of two experiments and by DSE49 in both experiments, vegetative growth parameters of 24-week-old plants were not affected except a reproducible increase of root diameter by the isolate DSE49. Concerning fruit yield and quality, L. orchidicola could double the biomass of tomatoes and increased glucose content by 17%, but this was dependent on date of harvest and on root colonisation density. Additionally, the endophytes DSE49 and L. orchidicola decreased the negative effect of V. dahliae on tomato, but only at a low dosage of the pathogen. This indicates that the three dark septate endophytes can have a significant impact on tomato characters, but that the effects are only obvious at early stages of vegetative and generative development and currently too inconsistent to recommend the application of these DSEs in horticultural practice.


Subtle paranodal injury slows impulse conduction in a mathematical model of myelinated axons.
This study explores in detail the functional consequences of subtle retraction and detachment of myelin around the nodes of Ranvier following mild-to-moderate crush or stretch mediated injury. An equivalent electrical circuit model for a series of equally spaced nodes of Ranvier was created incorporating extracellular and axonal resistances, paranodal resistances, nodal capacitances, time varying sodium and potassium currents, and realistic resting and threshold membrane potentials in a myelinated axon segment of 21 successive nodes. Differential equations describing membrane potentials at each nodal region were solved numerically. Subtle injury was simulated by increasing the width of exposed nodal membrane in nodes 8 through 20 of the model. Such injury diminishes action potential amplitude and slows conduction velocity from 19.1 m/sec in the normal region to 7.8 m/sec in the crushed region. Detachment of paranodal myelin, exposing juxtaparanodal potassium channels, decreases conduction velocity further to 6.6 m/sec, an effect that is partially reversible with potassium ion channel blockade. Conduction velocity decreases as node width increases or as paranodal resistance falls. The calculated changes in conduction velocity with subtle paranodal injury agree with experimental observations. Nodes of Ranvier are highly effective but somewhat fragile devices for increasing nerve conduction velocity and decreasing reaction time in vertebrate animals. Their fundamental design limitation is that even small mechanical retractions of myelin from very narrow nodes or slight loosening of paranodal myelin, which are difficult to notice at the light microscopic level of observation, can cause large changes in myelinated nerve conduction velocity.


Landau Quantization of a Narrow Doubly-Folded Wrinkle in Monolayer Graphene.
Folding can be an effective way to tailor the electronic properties of graphene and has attracted wide study interest in finding its novel properties. Here we present the experimental characterizations of the structural and electronic properties of a narrow graphene wrinkle on a SiO2/Si substrate using scanning tunneling microscopy/spectroscopy. Pronounced and nearly equally separated conductance peaks are observed in the d I/d V spectra of the wrinkle. We attribute these peaks to pseudo-Landau levels (PLLs) that are caused by a gradient-strain-induced pseudomagnetic field up to about 42 T in the narrow wrinkle. The introduction of the gradient strain and thus the pseudomagnetic field can be ascribed to the lattice deformation. A doubly-folded structure of the wrinkle is suggested. Our density functional theory calculations show that the band structure of the doubly folded graphene wrinkle has a parabolic dispersion, which can well explain the equally separated PLLs. The effective mass of carriers is obtained to be about 0.02 me ( me: the rest mass of electron), and interestingly, it is revealed that there exists valley polarization in the wrinkle. Such properties of the strained doubly folded wrinkle may provide a platform to explore some exciting phenomena in graphene, like zero-field quantum valley Hall effect.


A global analysis of molecular markers and phenotypic traits in local chicken breeds in Taiwan.
Molecular and phenotypic data have been combined to characterize the genetic diversity of six local chicken breeds maintained with a long-term conservation programme. Hua-Tung, Hsin-Yi, Ju-Chi and Quemoy originated from Taiwan, Shek-Ki is from South China, and Nagoya is from Japan. Molecular tools included 24 microsatellite markers, melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor) (MC1R), the LEI0258 marker located within the major histocompatibility complex (MHC), and mitochondrial DNA. Performance was recorded on the same individuals for body weight, panting rate in summer and antibody response (antigens: Newcastle disease virus and sheep red blood cells). A multivariate method previously proposed for taxonomy was used to combine the different data sets. Melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor) and the MCW330 marker contributed the most to the first axis of the multiple coinertia analysis of molecular markers. Melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor) showed evidence of selection, probably related to its effect on feather colour. The MHC exhibited a large diversity, with 16 alleles of the LEI0258 marker. Immune response traits contributed the most to the principal component analysis of phenotypic data. Eight mitochondrial DNA haplotypes related to clades A, B, C and E were distributed across breeds and revealed an important contribution of Indian and European breeds to Ju-Chi, Quemoy and Hsin-Yi. Phenotypic data contributed less than molecular data to the combined analysis, and two markers, LEI0258 and LEI0228, contributed the most. The combined analysis could clearly discriminate all breeds, except Ju-Chi, which was similar to Quemoy for many criteria, except immune response.


Transcriptional analysis of the flagellar regulon of Salmonella typhimurium.
In Salmonella typhimurium, nearly 50 genes are involved in flagellar formation and function and constitute at least 13 different operons. In this study, we examined the transcriptional interaction among the flagellar operons by combined use of Mu d1(Apr Lac) cts62 and Tn10 insertion mutants in the flagellar genes. The results showed that the flagellar operons can be divided into three classes: class I contains only the flhD operon, which is controlled by the cAMP-CAP complex and is required for expression of all of the other flagellar operons; class II contains seven operons, flgA, flgB, flhB, fliA, fliE, fliF, and fliL, which are under control of class I and are required for the expression of class III; class III contains five operons, flgK, fliD fliC, motA, and tar. This ordered cascade of transcription closely parallels the assembly of the flagellar structure. In addition, we found that the fliD defect enhanced expression of the class III operons. This suggests that the fliD gene product may be responsible for repression of the class III operons in the mutants in the class II genes. These results are compared with the cascade model of the flagellar regulon of Escherichia coli proposed previously (Y. Komeda, J. Bacteriol. 170:1575-1581, 1982).


Probing transcription factor dynamics at the single-molecule level in a living cell.
Transcription factors regulate gene expression through their binding to DNA. In a living Escherichia coli cell, we directly observed specific binding of a lac repressor, labeled with a fluorescent protein, to a chromosomal lac operator. Using single-molecule detection techniques, we measured the kinetics of binding and dissociation of the repressor in response to metabolic signals. Furthermore, we characterized the nonspecific binding to DNA, one-dimensional (1D) diffusion along DNA segments, and 3D translocation among segments through cytoplasm at the single-molecule level. In searching for the operator, a lac repressor spends approximately 90% of time nonspecifically bound to and diffusing along DNA with a residence time of <5 milliseconds. The methods and findings can be generalized to other nucleic acid binding proteins.


Analysis of pulmonary inflammation and function in the mouse and baboon after exposure to Mycoplasma pneumoniae CARDS toxin.
Mycoplasma pneumoniae produces an ADP-ribosylating and vacuolating toxin known as the CARDS (Community Acquired Respiratory Distress Syndrome) toxin that has been shown to be cytotoxic to mammalian cells in tissue and organ culture. In this study we tested the ability of recombinant CARDS (rCARDS) toxin to elicit changes within the pulmonary compartment in both mice and baboons. Animals responded to a respiratory exposure to rCARDS toxin in a dose and activity-dependent manner by increasing the expression of the pro-inflammatory cytokines IL-1alpha, 1beta, 6, 12, 17, TNF-alpha and IFN-gamma. There was also a dose-dependent increase in several growth factors and chemokines following toxin exposure including KC, IL-8, RANTES, and G-CSF. Increased expression of IFN-gamma was observed only in the baboon; otherwise, mice and baboons responded to CARDS toxin in a very similar manner. Introduction of rCARDS toxin to the airways of mice or baboons resulted in a cellular inflammatory response characterized by a dose-dependent early vacuolization and cytotoxicity of the bronchiolar epithelium followed by a robust peribronchial and perivascular lymphocytic infiltration. In mice, rCARDS toxin caused airway hyper-reactivity two days after toxin exposure as well as prolonged airway obstruction. The changes in airway function, cytokine expression, and cellular inflammation correlate temporally and are consistent with what has been reported for M. pneumoniae infection. Altogether, these data suggest that the CARDS toxin interacts extensively with the pulmonary compartment and that the CARDS toxin is sufficient to cause prolonged inflammatory responses and airway dysfunction.


The difference between actual and prescribed weight bearing of total hip patients with a trochanteric osteotomy: long-term vertical force measurements inside and outside the hospital.
To determine whether patients load the operated leg at a prescribed weight-bearing target load during postoperative recovery. A descriptive prospective study. Orthopedic clinic and patients' homes. Fifty patients who had undergone total hip arthroplasty (THA) with trochanteric osteotomy. Patients were verbally instructed by a physical therapist to perform partial weight bearing at a 10% body weight (BW) target load (n=33) or at a 50% BW target load (n=17). Mean peak load (%BW) and percentage of patients and mean percentage of steps below, equal to, and above the target load. Weight bearing was measured when patients walked with (condition 1) and without (condition 2) a physical therapist in the hospital and walked at home (condition 3). The mean peak load was significantly higher than the target in the 10% BW group for all 3 conditions (condition 1, 19.2% BW; condition 2, 20.0% BW; condition 3, 26.8% BW). In the 50% BW group, the mean peak load was significantly lower than the target in conditions 1 (28.1% BW) and 2 (32.5% BW). No significant difference in weight bearing was found when walking with or without a physical therapist (change in 10% BW, -0.1% BW; change in 50% BW, -3.17% BW). At home, the mean peak load was significantly larger compared with walking without a physical therapist in the hospital (change in 10% BW, -7.0% BW; change in 50% BW, -11.5% BW). Partial weight bearing at a specific target load was not achieved by patients with a THA when given verbal instructions. Especially when using a low target load and when walking at home with no supervision of a physical therapist, patients loaded the operated leg higher and more frequently above the target load. Other training methods (eg, biofeedback) have to be evaluated to use as training tools for partial weight bearing at specific target loads.


Image reconstruction via the finite Hilbert transform of the derivative of the backprojection.
An exact analytical image reconstruction method is presented for two-dimensional imaging. The method performs backprojection, the derivative and finite Hilbert transforms. This method can be applied to many imaging geometries. The backprojection procedure is imaging-geometry dependent, while the differentiation and the finite Hilbert transform procedures are identical for all imaging geometries. This algorithm is applicable to list-mode data in nuclear medicine, while other filtered backprojection algorithms cannot be applied directly to the list-mode data.


Monoclonal antibody specific for chicken DNA polymerase alpha associated with DNA primase.
Four monoclonal antibodies against chicken DNA polymerase alpha were obtained from mouse hybridomas (see ref. 1). Two of them, 4-2D and 4-8H, recognized different epitopes of the DNA polymerase alpha-DNA primase complex as determined by a competitive enzyme-linked immunosorbent assay. Antibody 4-8H partially (about 30%) neutralized the combined activity of primase-DNA polymerase alpha as well as the DNA polymerase alpha activity. In contrast, antibody 4-2D did not neutralize DNA polymerase alpha activity, but neutralized the primase-DNA polymerase alpha activity extensively (up to 80%). Furthermore, although an immunoaffinity column made with 4-8H antibody retained virtually all of the DNA polymerase alpha with and without associated primase, a column made with 4-2D antibody did not bind DNA polymerase alpha without the primase, but retained the enzyme associated with the primase. These results indicate that 4-8H monoclonal antibody is specific for DNA polymerase alpha and 4-2D monoclonal antibody is specific for the primase or a special structure present in the primase-DNA polymerase alpha complex.


Gamma knife radiosurgery for glossopharyngeal neuralgia: Marseille experience.
Although Gamma Knife radiosurgery (GKR) is widely recognized as an effective and minimally invasive treatment for intractable trigeminal neuralgia, its role in glossopharyngeal neuralgia (GPN) has not yet been determined. Between January 2002 and February 2009, 7 patients with medically intractable GPN were treated using GKR. Indication for GKR was the presence of medically intractable GPN, patient's refusal for open surgery or contraindication to microvascular decompression. Patients underwent preoperative investigation and were evaluated postoperatively with periodic assessment of pain relief and neurological function. Seven patients, 5 males and 2 females, with mean age 62 (range 36-83) presented with symptoms for an average of 28 months (range 8-72). Four patients had a neurovascular conflict. Patients were treated with a dose ranging from 60 to 80 Gy, targeted on the cisternal segment (n=2) or glossopharyngeal meatus (GPM) (n=5). Outcome was favorable with cure of GPN in 5 of 7 patients (71%) in the short-term (3 months post GKR) and 4 of 7 (57%) patients in the long term (> 7 months, mean 16 months). One patient required 2 treatments because of a recurrence of symptoms and was treated with a maximum doses of 60 and 70 Gy, respectively. There were no neurological complications. All patients with GPM as a target that received a dose greater than 75 Gy were cured at long-term follow-up. The 2 patients with cisternal segment as the target and received a dose lower than 70 Gy were not cured of their GPN. There were no neurological deficits involving the lower cranial nerves. It will be necessary to investigate the optimal radiation dose and target of GKR for GPN in order to achieve long-term pain relief.


Information resources to aid parental decision-making on when to seek medical care for their acutely sick child: a narrative systematic review.
To identify the effectiveness of information resources to help parents decide when to seek medical care for an acutely sick child under 5 years of age, including the identification of factors influencing effectiveness, by systematically reviewing the literature. 5 databases and 5 websites were systematically searched using a combination of terms on children, parents, education, acute childhood illness. A narrative approach, assessing quality via the Mixed Methods Appraisal Tool, was used due to non-comparable research designs. 22 studies met the inclusion criteria: 9 randomised control trials, 8 non-randomised intervention studies, 2 qualitative descriptive studies, 2 qualitative studies and 1 mixed method study. Consultation frequency (15 studies), knowledge (9 studies), anxiety/reassurance (7 studies), confidence (4 studies) satisfaction (4 studies) and antibiotic prescription (4 studies) were used as measures of effectiveness. Quality of the studies was variable but themes supported information needing to be relevant and comprehensive to enable parents to manage an episode of minor illness Interventions addressing a range of symptoms along with assessment and management of childhood illness, appeared to have the greatest impact on the reported measures. The majority of interventions had limited impact on consultation frequencies, No conclusive evidence can be drawn from studies measuring other outcomes. Findings confirm that information needs to be relevant and comprehensive to enable parents to manage an episode of minor illness. Incomplete information leaves parents still needing to seek help and irrelevant information appears to reduce parents' trust in the intervention. Interventions are more likely to be effective if they are also delivered in non-stressful environments such as the home and are coproduced with parents.


SU-D-217A-01: A High-Resolution in Vivo Molecular Imaging Technique Based on X- Ray Fluorescence.
Traditional molecular imaging techniques such as PET/SPECT have many limitations, including relatively low spatial resolution, short lifetime of radioisotope probes, limited availability due to reliance on cyclotron, relatively high dose, and lack of effective molecular probes for certain tumor cells. In this work we demonstrate the feasibility of a novel x- ray fluorescence molecular imaging (XFMI) technique using high-power carbon nanotube (CNT) x-ray array technology. The XFMI overcomes some limitations and will be a significant advance in molecular imaging technology for cancer drug development and cancer biology research. A testing chamber was constructed containing two Amptek energy-resolving detectors analyzing a copper collimated fluorescence beam placed opposite each other symmetric about the sample and perpendicular to the primary incoming x-ray beam, also using the copper collimator. Different concentrations of indium trichloride and iodine were tested to determine the minimum detectable concentration (MDC) for each. The MDC for indium was found to be 80 ug/mL and 100 ug/mL for iodine at 50 kVp, 30mAs (5 minutes imaging time). This is on the order of magnitude of the MDCs determined at large synchrotron facilities using XFI. Higher concentrations above 1mg/mL of both elements were detectable at 1.5 mAs (15 seconds). These results show that it is possible to not only measure low concentrations of the above elements, but also distinguish between similar L-alpha peaks. This allows for future work of obtaining 2D and 3D imaging to determine element types and concentrations diffused in different parts of the body. Carolina Center of Cancer Nanotechnology, University Cancer Research Fund.


Comparing post-operative human breast specimen radiograph and MRI in lesion margin and volume assessment.
The purpose of this research is to evaluate the potential for identifying malignant breast lesions and their margins on large specimen MRI, in comparison to specimen radiography and clinical dynamic contrast enhanced MRI (DCE-MRI). Breast specimens were imaged with an MR scanner immediately after surgery, with an IRB-approved protocol and with the patients' informed consent. Specimen sizes were at least 5 cm in diameter and approximately 1 to 4 cm thick. Coronal and axial gradient echo MR images without fat suppression were acquired over the whole specimens using a 9.4T animal scanner. Findings on specimen MRI were compared with findings on specimen radiograph, and their volumes were compared with measurements obtained from clinical DCE-MRI. The results showed that invasive ductal carcinoma (IDC) lesions were easily identified using MRI and the margins were clearly distinguishable from nearby tissue. However, ductal carcinoma in situ (DCIS) lesions were not clearly discernible and were diffused with poorly defined margins on MRI. Calcifications associated with DCIS were visualized in all specimens on specimen radiograph. There is a strong correlation between the maximum diameter of lesions as measured by radiograph and MRI (r = 0.93), as well as the maximum diameter measured by pathology and radiograph/MRI (r>0.75). The volumes of IDC measured on specimen MRI were slightly smaller than those measured on DCE-MRI. Imaging of excised human breast lumpectomy specimens with high magnetic field MRI provides promising results for improvements in lesion identification and margin localization for IDC. However, there are technical challenges in visualization of DCIS lesions. Improvements in specimen imaging are important, as they will provide additional information to standard radiographic analysis.