Targeting PI3K/Akt/mTOR Pathway Identifies Differential Expression and Functional Role of IL8 in Liver Cancer Stem Cell Enrichment.
Activation of the PI3K/Akt/mTOR pathway is an important signaling mechanism involved in the development and the progression of liver cancer stem cell (LCSC) population during acquired Sorafenib resistance in advanced hepatocellular carcinoma (HCC). Therefore, identification of novel therapeutic targets involving this pathway and acting on LCSCs is highly essential. Here, we analyzed the bioactivities and the molecular pathways involved in the action of small-molecule PI3K/Akt/mTOR pathway inhibitors in comparison with Sorafenib, DNA intercalators, and DAPT (CSC inhibitor) on CD133/EpCAM-positive LCSCs. Sorafenib and DNA intercalators lead to the enrichment of LCSCs, whereas Rapamycin and DAPT significantly reduced CD133/EpCAM positivity. Sequential treatment with Rapamycin followed by Sorafenib decreased the ratio of LCSCs as well as their sphere formation capacity, as opposed to Sorafenib alone. Under the stress of the inhibitors, differential expression analysis of 770 cancer pathway genes using network-based systems biology approach singled out IL8 expression association with LCSCs. Furthermore, IL8 secretion and LCSC enrichment ratio was also positively correlated. Following IL8 inhibition with its receptor inhibitor Reparixin or siRNA knockdown, LCSC features of HCC cells were repressed, and sensitivity of cells to Sorafenib increased significantly. Furthermore, inflammatory cytokines (IL8, IL1β, and IL11) were also upregulated upon treatment with HCC-approved kinase inhibitors Sorafenib and Regorafenib. Hence, chemotherapeutic stress alters inflammatory cytokine gene expression in favor of hepatic CSC population survival. Autocrine IL8 signaling is identified as a critical event, and its inhibition provides a promising complimentary therapeutic approach for the prevention of LCSC population enrichment.


Lifetime occupational exposure to dusts, gases and fumes is associated with bronchitis symptoms and higher diffusion capacity in COPD patients.
Occupational exposure to dusts, gases and fumes has been associated with reduced FEV1 and sputum production in COPD patients. The effect of occupational exposure on other characteristics of COPD, especially those reflecting emphysema, has not been studied in these patients. We studied 338 patients hospitalized for a first exacerbation of COPD in 9 Spanish hospitals, obtaining full occupational history in a face-to-face interview; job codes were linked to a job exposure matrix for semi-quantitative estimation of exposure to mineral/biological dust, and gases/fumes for each job held. Patients underwent spirometry, diffusing capacity testing and analysis of gases in stable conditions. Quality of life, dyspnea and chronic bronchitis symptoms were determined with a questionnaire interview. A high- resolution CT scan was available in 133 patients. 94% of the patients included were men, with a mean age of 68(8.5) years and a mean FEV1% predicted 52 (16). High exposure to gases or fumes was associated with chronic bronchitis, and exposure to mineral dust and gases/fumes was associated with higher scores for symptom perception in the St. George's questionnaire. No occupational agent was associated with a lower FEV1. High exposure to all occupational agents was associated with better lung diffusion capacity, in long-term quitters. In the subgroup with CT data, patients with emphysema had 18% lower DLCO compared to those without emphysema. In our cohort of COPD patients, high exposure to gases or fumes was associated with chronic bronchitis, and high exposure to all occupational agents was consistently associated with better diffusion capacity in long-term quitters.


Toxicity and Resistance Potential of Selected Fungicides to Galactomyces and Penicillium spp. Causing Postharvest Fruit Decays of Citrus and Other Crops.
A diverse collection of isolates of Galactomyces citri-aurantii and G. geotrichum, the causal pathogens of sour rots of citrus and other fruit crops, respectively, was evaluated for sensitivity to demethylation-inhibiting (DMI) fungicides of the triazole group. Propiconazole was found to be highly effective in reducing mycelial growth of both species in vitro. For 139 isolates of G. citri-aurantii, a mean effective concentration for 50% reduction of mycelial growth (EC50 value) of 0.34 μg/ml was determined; whereas, for 33 isolates of G. geotrichum, this value was 0.14 μg/ml. In a comparison of additional DMI fungicides, mean EC50 values for 60 isolates of G. citri-aurantii and 20 isolates of G. geotrichum, were 0.27 and 0.17 μg/ml for cyproconazole, 0.25 and 0.14 μg/ml for metconazole, and 1.16 and 0.73 μg/ml for tebuconazole, respectively. Propiconazole was also highly active against mycelial growth of imazalil-sensitive isolates of Penicillium digitatum, the pathogen that causes green mold of citrus, with a mean EC50 value of 0.008 μg/ml for 63 isolates. Imazalil-resistant isolates of this fungus were cross-resistant to propiconazole. When G. citri-aurantii and P. digitatum were grown at selected pH values between 3 and 9, inhibition by propiconazole occurred over the entire pH range. The fungicide was most effective at pH 5 when compared with the non-fungicide-amended control grown at the same pH. In laboratory mass platings of single-spore isolates sensitive to propiconazole onto selective media, isolates with an up to 81.6-fold decrease in sensitivity to the fungicide were recovered for P. digitatum. For G. geotrichum, isolates with an approximately twofold decrease in sensitivity were obtained. No isolates with reduced sensitivity were recovered for G. citri-aurantii. Propiconazole is currently being registered for postharvest use on citrus and other crops, and the information provided will be valuable in monitoring of fungicide resistance and in designing effective fungicide application strategies.


Axo-Glia Interaction Preceding CNS Myelination Is Regulated by Bidirectional Eph-Ephrin Signaling.
In the central nervous system, myelination of axons is required to ensure fast saltatory conduction and for survival of neurons. However, not all axons are myelinated, and the molecular mechanisms involved in guiding the oligodendrocyte processes toward the axons to be myelinated are not well understood. Only a few negative or positive guidance clues that are involved in regulating axo-glia interaction prior to myelination have been identified. One example is laminin, known to be required for early axo-glia interaction, which functions through α6β1 integrin. Here, we identify the Eph-ephrin family of guidance receptors as novel regulators of the initial axo-glia interaction, preceding myelination. We demonstrate that so-called forward and reverse signaling, mediated by members of both Eph and ephrin subfamilies, has distinct and opposing effects on processes extension and myelin sheet formation. EphA forward signaling inhibits oligodendrocyte process extension and myelin sheet formation, and blocking of bidirectional signaling through this receptor enhances myelination. Similarly, EphB forward signaling also reduces myelin membrane formation, but in contrast to EphA forward signaling, this occurs in an integrin-dependent manner, which can be reversed by overexpression of a constitutive active β1-integrin. Furthermore, ephrin-B reverse signaling induced by EphA4 or EphB1 enhances myelin sheet formation. Combined, this suggests that the Eph-ephrin receptors are important mediators of bidirectional signaling between axons and oligodendrocytes. It further implies that balancing Eph-ephrin forward and reverse signaling is important in the selection process of axons to be myelinated.


Menadione triggers cell death through ROS-dependent mechanisms involving PARP activation without requiring apoptosis.
Low levels of reactive oxygen species (ROS) can function as redox-active signaling messengers, whereas high levels of ROS induce cellular damage. Menadione generates ROS through redox cycling, and high concentrations trigger cell death. Previous work suggests that menadione triggers cytochrome c release from mitochondria, whereas other studies implicate the activation of the mitochondrial permeability transition pore as the mediator of cell death. We investigated menadione-induced cell death in genetically modified cells lacking specific death-associated proteins. In cardiomyocytes, oxidant stress was assessed using the redox sensor RoGFP, expressed in the cytosol or the mitochondrial matrix. Menadione elicited rapid oxidation in both compartments, whereas it decreased mitochondrial potential and triggered cytochrome c redistribution to the cytosol. Cell death was attenuated by N-acetylcysteine and exogenous glutathione or by overexpression of cytosolic or mitochondria-targeted catalase. By contrast, no protection was observed in cells overexpressing Cu,Zn-SOD or Mn-SOD. Overexpression of antiapoptotic Bcl-X(L) protected against staurosporine-induced cell death, but it failed to confer protection against menadione. Genetic deletion of Bax and Bak, cytochrome c, cyclophilin D, or caspase-9 conferred no protection against menadione-induced cell death. However, cells lacking PARP-1 showed a significant decrease in menadione-induced cell death. Thus, menadione induces cell death through the generation of oxidant stress in multiple subcellular compartments, yet cytochrome c, Bax/Bak, caspase-9, and cyclophilin D are dispensable for cell death in this model. These studies suggest that multiple redundant cell death pathways are activated by menadione, but that PARP plays an essential role in mediating each of them.


Response of captive skunks to microencapsulated tetracycline.
A captive striped skunk (Mephitis mephitis) study was conducted between February and June 2004 at the United States Department of Agriculture, Animal and Plant Health Inspection Service, Wildlife Services National Wildlife Research Center, Fort Collins, Colorado, USA. The main objective was to determine the percentage of adult striped skunks that were marked after consuming placebo oral rabies vaccine (ORV) baits containing 100 mg of an experimental microencapsulated (coated microparticle) tetracycline hydrochloride biomarker. Biomarkers were identified in the canine teeth and mandibles of five of five skunks that consumed an ORV bait. A second objective was to determine if the microencapsulated tetracycline was resistant to photochemical conversion from tetracycline to epitetracycline. After 15 days of exposure, conversion from tetracycline to epitetracycline concentration in the microencapsulated product (mean 1.9% conversion, SD=1.24) was significantly less (P=0.006) than the pure-grade tetracycline powder (mean 7.5% conversion, SD=1.37). Results support the use of microencapsulated tetracycline hydrochloride as a biomarker in circumstances where the use of conventional powdered tetracycline hydrochloride is not feasible due to ORV bait design constraints.


[High mobility group box 1 is increased in children with acute lymphocytic leukemia and stimulates the release of tumor necrosis factor-alpha in leukemic cell].
Cytokine mediated cell immunity is the main mode of anti-tumor immunity in organism, and the disequilibrium of cytokine network is the main cause of tumor cells escaping immunologic surveillance. High mobility group box 1 (HMGB1), a nuclear protein, has recently been identified as an important mediator of local and systemic inflammatory diseases when released into the extracellular milieu. In the present study, the investigators explored the clinical significance of alteration in the serum levels of HMGB1 in childhood acute lymphocytic leukemia (ALL) and the mechanism of HMGB1-induced tumor necrosis factor (TNF)-alpha secretion in leukemic cells. The serum levels of HMGB1 in healthy children and childhood ALL were assayed by Western blotting. K562 leukemic cells were stimulated with recombinant HMGB1 protein in vitro, and the secretion of TNF-alpha was determined by using ELISA. The effects of HMGB1 on activation of p38, c-Jun amino-terminal kinase (JNK), and extracellular-signal regulated protein kinase (ERK) and mitogen-activated protein kinase (MAPK) in K562 cells were assayed by using Western blotting. The effects of inhibitors specific for the MAPK on HMGB1-induced TNF-alpha secretion were assayed by using ELISA. The serum levels of HMGB1 were significantly higher in ALL initial treatment group (n = 15, 43.78 +/- 4.62 microg/ml) than those in healthy control group (n = 15, 0.60 +/- 0.48 microg/ml, P < 0.01) and ALL complete remission group (n = 15, 0.89 +/- 0.62 microg/ml, P < 0.01). No significant difference was found between the healthy control group and ALL complete remission group in HMGB1 levels (P > 0.05). TNF-alpha started to become detectable at 2 h and was still increasing at 16 h after HMGB1 (1 microg/ml) treatment in K562 cell culture. TNF-alpha was also secreted from K562 cells in a dose-dependent manner after HMGB1 (1 ng/ml-1 microg/ml) exposure. HMGB1 induced the phosphorylation of p38, JNK and ERK in k562 cells. Inhibitors specific for the JNK (SP600125), MEK (PD98059), and p38 MAPK (SB203580), abrogated HMGB1-induced TNF-alpha secretion. The measurement of serum HMGB1 is helpful to evaluate the prognosis of the childhood ALL. HMGB1 stimulates leukemic cells to secrete TNF-alpha through a MAPK-dependent mechanism.


The effects of ageing on dental pulp stem cells, the tooth longevity elixir.
Stem cells are essential for tissue homeostasis and regeneration throughout the lifespan of multicellular organisms. The decline in stem cell function during advanced age is associated with a reduced regenerative potential of tissues that leads to an increased frequency of diseases. Age-related changes also occur in the dental pulp that represents a reliable model tissue, with high regenerative capability, for studying senescence mechanisms. However, little information is available concerning the effects of ageing on dental stem-cell function. In this mini-review, recent data on how the molecular and functional alterations that accumulate in stem cell populations during ageing result in modifications of dental pulp physiology are discussed. Changes that accumulate during ageing such as how reduction of pulp chamber volume, decreased vascular supply and modifications to the stem cell niches affect stem cell functions and, therefore, dental pulp regenerative potential in response to various stressful agents. Dental pulp cells from aged individuals are still metabolically active and secrete pro-inflammatory and matrix-degrading molecules. Furthermore, miRNAs and exosomes derived from dental pulp stem cells constitute an attractive source of nanovesicles for the treatment of age-related dental pathologies. Further investigation of the epigenetic alterations in dental pulp stem cells, accumulating during ageing, might reveal crucial information for potential stem cell-based therapeutic approaches in the elderly.


Engineering of biologically active living heart valve leaflets using human umbilical cord-derived progenitor cells.
This study demonstrates the engineering of biologically active heart valve leaflets using prenatally available human umbilical cord-derived progenitor cells as the only cell source. Wharton's Jelly-derived cells and umbilical cord blood-derived endothelial progenitor cells were subsequently seeded on biodegradable scaffolds and cultured in a biomimetic system under biochemical or mechanical stimulation or both. Depending on the stimulation, leaflets showed mature layered tissue formation with functional endothelia and extracellular matrix production comparable with that of native tissues. This demonstrates the feasibility of heart valve leaflet fabrication from prenatal umbilical cord-derived progenitor cells as a further step in overcoming the lack of living autologous replacements with growth and regeneration potential for the repair of congenital malformation.


Elemental compositions and ages of lunar samples by nondestructive gamma-ray spectrometry.
A gamma-ray spectrometry system with low background was used to determine the radioactivity of crystalline rocks, breccias, and fine material. Nuclides identified were (40)K, (232)Th, (238)U, (7)Be, (22)Na (26)A1, (44)Ti, (46)Sc, (48)V, (52)Mn, (54)Mn, and (56)Co. Concentrations of K, Th, and U ranged between 480 and 2550, 1.01 and 3.30, and 0.26 and 0.83 parts per million, respectively. Concentrations of thorium and uranium were those of terrestrial basalts, while the potassium concentrations were near values for chondrites. Products of low-energy nuclear reactions showed pronounced concentration gradients at rock surfaces. Concentrations of K and of (22)Na determined here were combined with concentrations of rare gases to estimate gas-retention ages and cosmic-ray exposure ages with ranges of 2200 to 3200 and 34 to 340 million years, respectively, for three rocks.


Discrimination among similar looking noisy color patches using Margin Setting.
The goal of discrimination of one color from many other similar-appearing colors even when the colored objects show substantial variation or noise is of obvious import. We show how to accomplish that using a technique called Margin Setting. It is possible not only to have very low error rates but also to have some control over the types of errors that do occur. Robust spectral filtering prior to spatial pattern recognition allows subsequent filtering processes to be based on conventional coherent optical correlation that can be done monochromatically.


Associations between both legacy and alternative per- and polyfluoroalkyl substances and glucose-homeostasis: The Isomers of C8 health project in China.
Epidemiological studies on the associations of legacy per- and polyfluoroalkyl substances (PFASs) and glucose homeostasis remain discordant. Understanding of PFAS alternatives is limited, and few studies have reported joint associations of PFASs and PFAS alternatives. To investigate associations of novel PFAS alternatives (chlorinated perfluoroalkyl ether sulfonic acids, Cl-PFESAs and perfluorobutanoic acid, PFBA) and two legacy PFASs (Perfluorooctanoic acid, PFOA and perfluorooctane sulfonate, PFOS) with glucose-homeostasis markers and explore joint associations of 13 legacy and alternative PFASs with the selected outcomes. We used cross-sectional data of 1,038 adults from the Isomers of C8 Health Project in China. Associations of PFASs and PFAS alternatives with glucose-homeostasis were explored in single-pollutant models using generalized linear models with natural cubic splines for PFASs. Bayesian Kernel Machine Regression (BKMR) models were applied to assess joint associations of exposures and outcomes. Sex-specific analyses were also conducted to evaluate effect modification. After adjusting for confounders, both legacy (PFOA, PFOS) and alternative (Cl-PFESAs and PFBA) PFASs were positively associated with glucose-homeostasis markers in single-pollutant models. For example, in the total study population, estimated changes with 95% confidence intervals (CI) of fasting glucose at the 95th percentile of 6:2Cl-PFESA and PFOS against the thresholds were 0.90 (95% CI: 0.59, 1.21) and 0.44 (95% CI: 0.26, 0.62). Positive joint associations were found in BKMR models with 6:2Cl-PFESA contributing most. Sex-specific associations existed in both single- and multi-pollutant models. Legacy and alternative PFASs were positively associated with glucose-homeostasis markers. 6:2Cl-PFESA was the primary contributor. Sex-specific associations were also identified. These results indicate that joint associations and effect modification should be considered in risk assessment. However, further studies are recommended to strengthen our findings and to elucidate the mechanisms of action of legacy and alternative PFASs.


Diabetic db/db mice exhibit central nervous system and peripheral molecular alterations as seen in neurological disorders.
The db/db mouse is a widely used preclinical model in diabetes research. Recent studies have shown that these mice also display aspects of psychosis and depression-like behaviors as seen in some psychiatric disorders. Here, we have performed multiplex immunoassay and liquid chromatography mass spectrometry profiling of the plasma and brain samples from db/db and control mice to identify altered pathways, which could be related to these behavioral abnormalities. This is the first study to carry out profiling of the brain proteome in this model. Plasma from the db/db mice had increased levels of leptin and insulin, decreased levels of peptide YY, glucagon and prolactin and alterations in inflammation-related proteins, compared with control mice. Frontal cortex tissue from the db/db mice showed changes in proteins involved in energy metabolism, cellular structure and neural functioning, and the hippocampus had changes in proteins involved in the same pathways, with additional effects on cellular signalling proteins. The overlap of these findings with effects seen in type 2 diabetes, schizophrenia, major depressive disorder and Alzheimer's disease might contribute to a common endophenotype seen in metabolic and neurological disorders.


How Plastic Is the Brain after a Stroke?
Stroke is a common problem, and with an aging population, it is likely to become more so. Outcomes from stroke are wide ranging from death to complete recovery, but the majority result in severe motor impairments that affect quality of life and become a burden on health care systems, family, and friends. Therapeutically, removal of thromboses can greatly improve outcomes, but for many stroke sufferers, the only currently available therapy is rehabilitative training in which spared brain areas and fiber tracts are strengthened and trained to take over new functions. Experimental data in animals show that this is in part based on changes in the connectivity of the brain and spinal cord and on the growth of new nerve fiber branches, a process called structural plasticity. So, just how plastic is the brain after a stroke? In this review, we explore the factors that affect plasticity after strokes, such as age and the overall size and location of the lesion. We discuss the peri-infarct area as extensive research has shown that processes occurring there are likely to be involved mechanistically in plastic changes in cortical circuitry. Finally, we review promising interventions being tested preclinically and discuss those that have been translated into clinical research.


Clinical manifestations of HIV infected children.
Heterosexual contact is the predominant mode of transmission among adults in India with an increasing number of women of childbearing age becoming infected with HIV. Consequently, children in India increasingly getting infected, primarily from vertical transmission. A retrospective review of the profile of HIV infected children attending an HIV clinic in South India is reported. All HIV-infected children under 15 years of age at the time of first presentation and managed at this center between June 1996 and June 2000 are included in this report. Socio-demographic characteristics and clinical manifestation were collected in a precoded proforme. A complete physical examination and baseline laboratory investigations were performed at entry into the clinic and at subsequent follow-up. Fifty-eight HIV-infected children were included: thirty-nine (67.2%) were male with mean age 4 years. Perinatal transmission was the predominant mode of HIV acquisition (67%). Common clinical manifestations in these children at presentation included oral candidiasis (43%), pulmonary tuberculosis (35%), recurrent respiratory infections (26%), bacterial skin infection (21%), papulo-pruritic dermatitis (19%), hepatosplenomegaly and lymphadenopathy (14%) each and chronic diarrhea (7%). An understanding of the epidemiology of pediatric HIV infection may reveal opportunities to reduce and perhaps eliminate perinatal transmission. Knowledge of clinical manifestations in this setting will help physicians meet the management challenges presented by HIV infected children.


Graphene-porphyrin single-molecule transistors.
We demonstrate a robust graphene-molecule-graphene transistor architecture. We observe remarkably reproducible single electron charging, which we attribute to insensitivity of the molecular junction to the atomic configuration of the graphene electrodes. The stability of the graphene electrodes allow for high-bias transport spectroscopy and the observation of multiple redox states at room-temperature.


Clinical outcomes of 4-point scleral fixated 1-piece hydrophobic acrylic equiconvex intraocular lens using polytetrafluoroethylene suture.
To report the visual outcomes and complications of scleral fixated intraocular lenses (IOLs) using Gore-Tex suture. The current study is a retrospective noncomparative case series including patients who underwent scleral fixation of IOL (Akreos AO60) using Gore-Tex suture from August 2015 to March 2017 at a university teaching center. Primary outcome measures were visual acuity and complications at last follow-up. The current study included 49 eyes of 48 patients. Mean follow-up duration postsurgery was 6.9 months (range: 0.9-29.4 months). The indications for secondary IOL surgery were dislocated IOL in 16/49 (33%), subluxed IOL in 9/49 (18%), dislocated or subluxed crystalline lens in 9/49 (18%), traumatic cataract in 8/49 (16%), and complicated cataract surgery in 7/49 (14%). Mean best-corrected logMAR visual acuity improved from 1±0.7 (20/200 Snellen equivalent) preoperatively to 0.5±0.5 (20/63 Snellen equivalent) at last follow-up. There were no intraoperative complications noted. Early postoperative complications included significant persistent corneal edema (longer than 1 week) in 4/49 (8.2%), ocular hypertension (intraocular pressure ≥25 mmHg) in 8/49 (16.3%), hypotony (intraocular pressure ≤5 mmHg) in 6/49 (12.2%), cystoid macular edema 3/21 (6.1%), IOL tilt 2/49 (4.1%), hyphema in 2/49 (4.1%), and vitreous hemorrhage in 5/49 (4.8%). There was one case of recurrent retinal detachment. One patient presented with an erosion of the Gore-Tex suture through the conjunctiva resulting in a purulent scleritis 6 months after the initial surgery, and was managed with removal of the IOL, debridement, and cryotherapy. Forty-one of 49 patients completed 3-month follow-up, among which visual acuity improved, deteriorated, or remained same compared to baseline in 27/49 (55.1%), 8/49 (16.3%), and 6/49 (12.2%) eyes, respectively. In the current study, visual acuity outcomes were generally favorable. The complications were largely transient. Significant complications included a suture-related infection, which required removal of the IOL, and a recurrence of a retinal detachment.


Health Research Using Facebook to Identify and Recruit Pregnant Women Who Use Electronic Cigarettes: Internet-Based Nonrandomized Pilot Study.
Participant recruitment is often a challenge, particularly enrolling individuals with relatively rare characteristics. The wide reach of social media may provide a mechanism to overcome these challenges. This paper aimed to provide information to researchers who seek to recruit participants from rare populations using social media for studies with demanding protocols. We aimed to describe a pilot study protocol that identified and enrolled pregnant women (second or third trimester) who were exclusive users of electronic cigarettes (e-cigarettes). We have described the recruitment methods, time, and cost; examined advertisement types that were more or less successful; discussed participant retention and relationship management; and described the process of collecting biological data. In an open-access, nonrandomized pilot study, we placed Facebook advertisements that were selectively targeting women who were likely to be pregnant and interested in e-cigarettes or vaping. The advertisements invited individuals to complete a fully automated eligibility screener based on Qualtrics. Eligible participants were asked to (1) complete a Web-based survey that collected detailed information on the use of e-cigarettes, including the exact type of device and electronic liquid, (2) report the frequency and intensity of e-cigarette use for 3 months before pregnancy and during each trimester, and (3) provide a saliva specimen for a nicotine biomarker assay. We collected a photograph of each participant's e-cigarette device, 8 weeks after the mother's due date, to allow corroboration of the self-report and the baby's birth weight and gestational age from the participant's physician. Participants were recruited between August 19 and October 26, 2017. We enrolled 20 participants in 2 months at a cost of US $3421.28. Baseline data were collected for all 20 participants. Of the 20 women enrolled, 16 provided a saliva sample, 4 provided a photo of the e-cigarette device, and 10 provided physician contact information. Of the 10 physicians contacted by mail, 6 responded with information on the participants and their babies. Study findings suggest that Facebook's targeting criteria should focus on e-cigarette users to maximize advertisement exposure of potentially eligible women. In addition, saliva sample collection was feasible among pregnant women (second or third trimester) who were exclusive e-cigarette users, but obtaining photographs and physician reports was problematic and called for further refinement. These lessons are likely useful to others who are seeking to use social media to recruit participants from rare populations into studies with demanding protocols.


Taxol metabolism. Isolation and identification of three major metabolites of taxol in rat bile.
The elimination of nonradioactive taxol in bile and urine was investigated in the rat after administration via the caudal vein (10 mg/kg). As in humans, no metabolites of taxol were detected by HPLC in rat urine, and only 10% of the injected taxol was recovered in urine over a 24-hr period. In contrast, 11.5% and 29% of the injected taxol was recovered in rat bile as unchanged taxol and metabolites, respectively. Among the nine taxol metabolites detected by HPLC, the side chain at C13, which is required for pharmacological activity, had been removed in only one minor metabolite, baccatin III. The chemical structures of the two major hydroxylated metabolites were determined by mass spectrometry (fast atom bombardment and desorption chemical ionization) and 1H-NMR spectroscopy. One was a taxol derivative hydroxylated on the phenyl group at C3' of the side chain at C13, while the other corresponded to a taxol derivative hydroxylated in the m-position on the benzoate of the side chain at C2. Although these two major taxol metabolites were as active as taxol in preventing cold microtubule disassembly, they were, respectively, 9 and 39 times less cytotoxic as taxol on in vitro L1210 leukemia growth. These results show for the first time that there is a significant hepatic metabolism of taxol.


Translation initiation factors eIF3 and HCR1 control translation termination and stop codon read-through in yeast cells.
Translation is divided into initiation, elongation, termination and ribosome recycling. Earlier work implicated several eukaryotic initiation factors (eIFs) in ribosomal recycling in vitro. Here, we uncover roles for HCR1 and eIF3 in translation termination in vivo. A substantial proportion of eIF3, HCR1 and eukaryotic release factor 3 (eRF3) but not eIF5 (a well-defined "initiation-specific" binding partner of eIF3) specifically co-sediments with 80S couples isolated from RNase-treated heavy polysomes in an eRF1-dependent manner, indicating the presence of eIF3 and HCR1 on terminating ribosomes. eIF3 and HCR1 also occur in ribosome- and RNA-free complexes with both eRFs and the recycling factor ABCE1/RLI1. Several eIF3 mutations reduce rates of stop codon read-through and genetically interact with mutant eRFs. In contrast, a slow growing deletion of hcr1 increases read-through and accumulates eRF3 in heavy polysomes in a manner suppressible by overexpressed ABCE1/RLI1. Based on these and other findings we propose that upon stop codon recognition, HCR1 promotes eRF3·GDP ejection from the post-termination complexes to allow binding of its interacting partner ABCE1/RLI1. Furthermore, the fact that high dosage of ABCE1/RLI1 fully suppresses the slow growth phenotype of hcr1Δ as well as its termination but not initiation defects implies that the termination function of HCR1 is more critical for optimal proliferation than its function in translation initiation. Based on these and other observations we suggest that the assignment of HCR1 as a bona fide eIF3 subunit should be reconsidered. Together our work characterizes novel roles of eIF3 and HCR1 in stop codon recognition, defining a communication bridge between the initiation and termination/recycling phases of translation.


Turnover of rod photoreceptor outer segments. II. Membrane addition and loss in relationship to light.
The rate of disk addition to rod outer segments (ROS) varies widely in Xenopus laevis tadpoles kept in cyclic light (12L:12D). When measured as radioactive band (3H-band) displacement during the 2nd day after injection of [3H]leucine, 75% of the daily increment of displacement occurred during the first 8 h of light. During the same interval, the number of open disks at the ROS base increased more than threefold. During the last 8 h of darkness, 3H-band displacement was undetectable and the number of open disks was reduced. These observations suggest the possibility that disk addition may occur discontinuously. During the 3rd and 4th days after injection of [3H]leucine, maximal displacement of the 3H-band occurred later in the day than on the 2nd day, its movement no longer corresponding to the increase in open disks. This delay in 3H-band displacement may reflect a time delay as a result of propagation of compressive stress in an elastic ROS system. Maximal disk loss from ROS as reflected in counts of phagosomes in the pigment epithelium occurred within 1 h of light exposure, and phagosome counts remained high for 4 h before declining to a low level in darkness. Modified lighting regimes affected the daily rhythms of shedding and disk addition differently, suggesting that control mechanisms for the two processes are not directly coupled. During 3 days in darkness, disk addition was reduced 50% compared to controls (12L:12D), whereas shedding was reduced by about 40%. Although reduced in level, shedding occurred as a free-running circadian rhythm. There was no evidence of rhythmicity of disk addition in darkness. In constant light, the rate of disk addition was not different from controls, but shedding was reduced by about 80% after the 1st day. This resulted in a 21% increase in ROS length. Among animals kept on a 2.5L:21.5D cycle, the rate of disk addition was reduced by 40% while shedding was maintained near control levels, resulting in a slight decrease in ROS length. These observations indicate that normal shedding requires alternating light and darkness, and that the daily rhythm of disk addition is due primarily to daily stimulation by light.


Liver Transplantation for Acute Intermittent Porphyria.
Recurrent attacks of acute intermittent porphyria (AIP) result in poor quality of life and significant risks of morbidity and mortality. Liver transplantation (LT) offers a cure, but published data on outcomes after LT are limited. We assessed the pretransplant characteristics, complications, and outcomes for patients with AIP who received a transplant. Data were collected retrospectively from the European Liver Transplant Registry and from questionnaires sent to identified transplant and porphyria centers. We studied 38 patients who received transplants in 12 countries from 2002 to 2019. Median age at LT was 37 years (range, 18-58), and 34 (89%) of the patients were women. A total of 9 patients died during follow-up, and 2 patients were retransplanted. The 1-year and 5-year overall survival rates were 92% and 82%, which are comparable with other metabolic diseases transplanted during the same period. Advanced pretransplant neurological impairment was associated with increased mortality. The 5-year survival rate was 94% among 19 patients with moderate or no neuropathy at LT and 83% among 10 patients with severe neuropathy (P = 0.04). Pretransplant renal impairment was common. A total of 19 (51%) patients had a GFR < 60 mL/minute. Although few patients improved their renal function after LT, neurological impairments improved, and no worsening of neurological symptoms was recorded. No patient had AIP attacks after LT, except for a patient who received an auxiliary graft. LT is a curative treatment option for patients with recurrent attacks of AIP. Severe neuropathy and impaired renal function are common and increase the risk for poor outcomes. If other treatment options fail, an evaluation for LT should be performed early.


Impact of climatic and other environmental changes on food production and population health in the coming decades.
World population will reach an estimated nine billion by 2050. Given this factor and continued economic development in today's low-income countries, the total global demand for food will increase approximately threefold over the coming half-century. Meanwhile, against this background, newly-occurring global environmental changes such as climate change are anticipated to affect food production. Other incipient large-scale environmental changes likely to affect food production include stratospheric O3 depletion, the accelerating loss of biodiversity (with knock-on effects on crop and livestock pest species) and the perturbation of several of the great elemental cycles of N and S. The ways in which these various environmental influences affect the production of food (crops and livestock on land, and wild and cultivated fisheries) are complex and interactive. Uncertainties therefore persist about how global climate change is likely to affect world and regional food production. On balance, recent modelling-based estimates indicate that, in the medium to longer term, if not over the next several decades, climate change is likely to affect crop yields adversely, especially in food-insecure regions. The prospect of increased climatic variability further increases the risks to future food production. Given these possible though uncertain adverse impacts of climatic and other environmental changes on world food production, there is a need to apply the Precautionary Principle. There are finite, and increasingly evident, limits to agro-ecosystems and to wild fisheries. Our capacity to maintain food supplies for an increasingly large and increasingly expectant world population will depend on maximising the efficiency and sustainability of production methods, incorporating socially-beneficial genetic biotechnologies, and taking pre-emptive action to minimise detrimental ecologically-damaging global environmental changes.


Clinicopathologic correlation in PGRN mutations.
Frontotemporal dementia (FTD) has been linked to the microtubule associated protein tau (MAPT) gene region of chromosome 17. However, many chromosome-17 linked FTLDs do not have MAPT mutations or tau protein deposits, but have ubiquitin positive, tau and alpha-synuclein negative inclusions. Mutations in the progranulin (PGRN) gene, located 1.7 Mb from MAPT at 17q21.31, were recently discovered in some of these individuals. The pathologic phenotype in all cases has thus far included ubiquitinated neuronal intranuclear inclusions (NIIs) and neuronal cytoplasmic inclusions (NCIs). PGRN mutation analysis was performed in 12 individuals. Informed consent was obtained from next of kin under an IRB-approved protocol. We compared clinical and pathologic findings in those cases with and without PGRN mutations. PGRN mutations were found in four patients, two with clinical FTD and a positive family history, and two with clinical primary progressive aphasia (PPA), one with and one without a family history. All four cases with, and five of eight cases without, PGRN mutations had ubiquitinated NCIs and NIIs. Brains of individuals with PGRN mutations are associated with more frequent frontal NCIs and dystrophic neurites, less frequent dentate gyrus NCIs, and more frequent striatal NIIs than FTLD-U cases without PGRN mutations. PGRN mutations at 17q21 may occur in apparently sporadic frontotemporal lobar dementia with ubiquitinated inclusions cases and in cases presenting with either primary progressive aphasia or the behavioral variant of frontotemporal dementia. Some cases without PGRN mutations also have ubiquitinated neuronal intranuclear inclusions. Clinicopathologic differences are observed among individuals with and without PGRN mutations.


On the origin of sorption hysteresis in cellulosic materials.
Moisture sorption and moisture sorption hysteresis of carbohydrates are phenomena which affect the utilisation of products made thereof. Although extensively studied, there is still no consensus regarding the mechanisms behind sorption hysteresis. Attempts have been made to link the behaviour to molecular properties, in particular to softening properties, and the moisture sorption hysteresis has therefore here been investigated by modifying cellulosic fibres to affect their softening properties. The results show that the moisture sorption hysteresis diminishes with decreasing softening temperature, and was even completely absent at the higher degrees of modification. The moisture sorption characteristics also changed from a type II sorption to a more type III sorption behaviour, a feature more prominent the higher the degree of modification and the higher the temperature. For the highest degree of modification studied the sorption characteristics changed from sorbing less water the higher the temperature to sorbing more water with increasing temperature.


Quantitative Trait Locus Mapping of Flowering Time and Maturity in Soybean Using Next-Generation Sequencing-Based Analysis.
Soybean (Glycine max L.) is a major legume crop that is mainly distributed in temperate regions. The adaptability of soybean to grow at relatively high latitudes is attributed to natural variations in major genes and quantitative trait loci (QTLs) that control flowering time and maturity. Identification of new QTLs and map-based cloning of candidate genes are the fundamental approaches in elucidating the mechanism underlying soybean flowering and adaptation. To identify novel QTLs/genes, we developed two F8:10 recombinant inbred lines (RILs) and evaluated the traits of time to flowering (R1), maturity (R8), and reproductive period (RP) in the field. To rapidly and efficiently identify QTLs that control these traits, next-generation sequencing (NGS)-based QTL analysis was performed. This study demonstrates that only one major QTL on chromosome 4 simultaneously controls R1, R8, and RP traits in the Dongnong 50 × Williams 82 (DW) RIL population. Furthermore, three QTLs were mapped to chromosomes 6, 11, and 16 in the Suinong 14 × Enrei (SE) RIL population. Two major pleiotropic QTLs on chromosomes 4 and 6 were shown to affect flowering time, maturity, and RP. A QTL influencing RP was identified on chromosome 11, and QTL on chromosome 16 was associated with time to flowering responses. All these QTLs contributed to soybean maturation. The QTLs identified in this study may be utilized in fine mapping and map-based cloning of candidate genes to elucidate the mechanisms underlying flowering and soybean adaptation to different latitudes and to breed novel soybean cultivars with optimal yield-related traits.


Chemokine MIP-2/CXCL2, acting on CXCR2, induces motor neuron death in primary cultures.
Chemokines are implicated in many diseases of the central nervous system (CNS). Although their primary role is to induce inflammation through the recruitment of leukocytes by their chemotactic activity, they may also have direct effects on neuronal cells. We evaluated the expression of CXCR1 and CXCR2 and investigated the effect of CXCR2 activation by the agonist MIP-2 (CXCL2) on primary cultured motor neurons. To specifically assess the role of CXCR2 in the neurotoxicity induced by MIP-2, we used the CXCR1/2 inhibitor reparixin and studied the effect of the chemokine on motor neuron cultures from CXCR2-deficient mice. Primary motor neurons prepared from rat or mouse embryos were treated with MIP-2 and reparixin. Motor neuron viability and receptor expression were assessed by immunocytochemical techniques. Rat primary motor neurons expressed CXCR2 receptors and recombinant rat MIP-2 induced dose-dependent neurotoxicity. This neurotoxicity was counteracted by reparixin, a specific CXCR1/2 inhibitor, and was not observed in motor neurons from CXCR2-deficient mice. CXCR2 activation might directly contribute to motor neuron degeneration. Thus, chemokines acting on CXCR2, including IL-8, may have direct pathogenic effects in CNS diseases, independent of the induction of leukocyte migration.


Scapular kinematics during shoulder elevation performed with and without elastic resistance in men without shoulder pathologies.
Controlled laboratory study using within-group comparisons. Objectives To compare scapular kinematics between active and resisted shoulder elevation performed in the sagittal (flexion), frontal (abduction), and scapular (scapular abduction) planes. Several studies have documented scapular kinematics during arm elevation against an external load; however, there is little information on how scapular kinematics change with loading provided by elastic bands, an exercise approach often used in the clinic. Thirty-two men without shoulder pathology participated in the study. The level of resistance to be used for each individual was determined prior to data collection and standardized by perceived effort on a Borg scale. Three-dimensional scapular kinematics were recorded with an electromagnetic tracking device in all 3 planes of shoulder elevation for both the unloaded (active) and loaded (resisted) conditions. Data for scapular kinematics were analyzed at 30°, 60°, 90°, and 120° of humerothoracic elevation and lowering. Comparisons between loading conditions were made using analysis-of-variance models. In general, for all 3 planes of movement, the scapula was more downwardly rotated and anteriorly tilted during the elevation phase and more so during the lowering phase of shoulder elevation when performed against elastic resistance. While some of the statistically significant differences might not have been large enough to be considered clinically meaningful, some values were of a magnitude similar to previously reported differences between healthy and symptomatic individuals. The changes in scapular motion during the loaded condition were relatively small in this population with normal scapular motion, but they were in a direction that would be considered to have potential to lead to injuries, suggesting caution when using these exercises in individuals with poor scapular control.


Network of Cancer Genes (NCG 3.0): integration and analysis of genetic and network properties of cancer genes.
The identification of a constantly increasing number of genes whose mutations are causally implicated in tumor initiation and progression (cancer genes) requires the development of tools to store and analyze them. The Network of Cancer Genes (NCG 3.0) collects information on 1494 cancer genes that have been found mutated in 16 different cancer types. These genes were collected from the Cancer Gene Census as well as from 18 whole exome and 11 whole-genome screenings of cancer samples. For each cancer gene, NCG 3.0 provides a summary of the gene features and the cross-reference to other databases. In addition, it describes duplicability, evolutionary origin, orthology, network properties, interaction partners, microRNA regulation and functional roles of cancer genes and of all genes that are related to them. This integrated network of information can be used to better characterize cancer genes in the context of the system in which they act. The data can also be used to identify novel candidates that share the same properties of known cancer genes and may therefore play a similar role in cancer. NCG 3.0 is freely available at http://bio.ifom-ieo-campus.it/ncg.


Interleukin-10 protects lipopolysaccharide-induced neurotoxicity in primary midbrain cultures by inhibiting the function of NADPH oxidase.
The role of anti-inflammatory cytokines in Parkinson's disease is not completely understood. In this study, using mesencephalic neuron-glia cultures, we report that both pretreatment and post-treatment of rat mesencephalic neuron-glia cultures with interleukin (IL)-10, a natural immune modulator, reduced lipopolysaccharide (LPS)-induced DA neurotoxicity. The main purpose of this study was to elucidate the molecular mechanism underlying IL-10-elicited neuroprotection. IL-10 significantly inhibited LPS-induced production of tumor necrosis factor-alpha, nitric oxide, and extracellular superoxide in microglia cells. In addition, using reconstituted neuron and glia cell cultures, IL-10 was shown to be neuroprotective only in the presence of microglia. More importantly, IL-10 failed to protect DA neurons in cultures from mice lacking NADPH oxidase (PHOX), a key enzyme for extracellular superoxide production in immune cells, suggesting the critical role of PHOX in IL-10 neuroprotection. This conclusion was further supported by the finding that IL-10 inhibited LPS-induced translocation of the cytosolic subunit of NADPH oxidase p47(phox) to the membrane. When the Janus tyrosine kinase (JAK) 1 signaling pathway was blocked, IL-10 failed to attenuate LPS-induced superoxide production, indicating that the JAK1 signaling cascade mediates the inhibitory effect of IL-10. Together, our results suggest that IL-10 inhibits LPS-induced DA neurotoxicity through the inhibition of PHOX activity in a JAK1-dependent mechanism.


Home or hospital for people with dementia and one or more other multimorbidities: What is the potential to reduce avoidable emergency admissions? The HOMEWARD Project Protocol.
Older people with multimorbidities frequently access 999 ambulance services. When multimorbidities include dementia, the risk of ambulance use, accident and emergency (A&E) attendance and hospital admission are all increased, even when a condition is treatable in the community. People with dementia tend to do poorly in the acute hospital setting and hospital admission can result in adverse outcomes. This study aims to provide an evidence-based understanding of how older people living with dementia and other multimorbidities are using emergency ambulance services. It will also provide evidence of how paramedics make decisions about taking this group of patients to hospital, and what resources would allow them to make more person-focused decisions to enable optimal patient care. METHODS AND ANALYSIS: Phase 1: retrospective data analysis: quantitative analysis of ambulance service data will investigate: how often paramedics are called to older people with dementia; the amount of time paramedics spend on scene and the frequency with which these patients are transported to hospital. Phase 2: observational case studies: detailed case studies will be compiled using qualitative methods, including non-participant observation of paramedic decision-making, to understand why older people with multimorbidities including dementia are conveyed to A&E when they could be treated at home or in the community. Phase 3: needs analysis: nominal groups with paramedics will investigate and prioritise the resources that would allow emergency, urgent and out of hours care to be effectively delivered to these patients at home or in a community setting. Approval for the study has been obtained from the Health Research Authority (HRA) with National Health Service (NHS) Research Ethics Committee approval for phase 2 (16/NW/0803). The dissemination strategy will include publishing findings in appropriate journals, at conferences and in newsletters. We will pay particular attention to dissemination to the public, dementia organisations and ambulance services.


Comparative study of natural antioxidants - curcumin, resveratrol and melatonin - in cadmium-induced oxidative damage in mice.
The present study was designed to examine the antioxidative effect of curcumin, resveratrol and melatonin pre-treatment on cadmium-induced oxidative damage and cadmium distribution in an experimental model in mice. Male CD mice were treated once daily for 3 days with curcumin (50mg/kg b.w., p.o.), resveratrol (20mg/kg b.w., p.o.) or melatonin (12mg/kg, p.o.), dispersed in 0.5% methylcellulose. One hour after the last dose of antioxidants cadmium chloride was administered (7mg/kg b.w., s.c.) to pre-treated animals and control animals receiving methylcellulose. At 24th h after Cd administration the lipid peroxidation (LP - expressed as malondialdehyde production), reduced glutathione (GSH), catalase (CAT) and glutathione peroxidase (GPx) were estimated in liver homogenates. Cadmium concentration was measured in the liver, kidneys, testes and brain by AAS. Cadmium chloride administration to mice induced hepatic lipid peroxidation (to 133%, p<0.001), decreased GSH content (to 65%, p<0.001) and inhibited catalase (to 68%, p<0.001) and GPx activity (to 60%, p<0.001) in the liver. Curcumin, resveratrol and melatonin oral pre-treatment completely prevented the Cd-induced lipid peroxidation and Cd-induced inhibition of GPx hepatic activity. Resveratrol was effective against Cd-induced inhibition of catalase activity (p<0.001). The decrease in hepatic GSH level was not prevented by curcumin, resveratrol or melatonin pre-treatment. In mice treated with antioxidants alone the level of LP, GSH, GPx or CAT was not different from control levels. The pre-treatment with antioxidants did not affect cadmium distribution in the tissues of Cd-intoxicated mice. The results demonstrate that curcumin, resveratrol and melatonin pre-treatment effectively protect against cadmium-induced lipid peroxidation and ameliorate the adverse effect of cadmium on antioxidant status without any reduction in tissue Cd burden.


Cannabinoids: a new approach for pain control?
To analyze available data related to the use of cannabinoids in medicine, with a special focus on pain management in cancer. The use of cannabis for medical purposes is growing but there are still numerous questions to be solved: effectiveness, safety, and specific indications. There is considerable variation between countries in the approaches taken, reflecting a variety of historical and cultural factors and despite few randomized controlled studies using natural cannabinoids, there is a trend to state that the use of cannabis should be taken seriously as a potential treatment of cancer-related pain. Cannabidiol, a nontoxic phytocannabinoid with few side-effects is promising in various indications in medicine. The endocannabinoid system is a potential therapeutic target. Cannabinoids may be considered as potential adjuvant in cancer-related pain management. Cannabidiol appears to be the drug of choice. Analgesic trial designs should evolve to get closer to real-life practice and to avoid biases.


Cardiac magnetic resonance spectroscopy.
This review describes recent advances in cardiac magnetic resonance spectroscopy (MRS). MRS allows noninvasive characterization of the metabolic state of cardiac muscle, in both animal and human models. Recent experimental MRS studies have allowed new insights into the essential role of energetics in heart failure. Various new studies suggest a rapidly growing role of MRS for phenotyping new genetically modified mouse models, and recent methodologic advances include development of absolute quantification of high-energy phosphates, measurement of ATP turnover rates and thermodynamic parameters (such as free ADP and free energy change of ATP hydrolysis), and improved acquisition sequences. New patient studies demonstrate the potential value of MRS as a clinical diagnostic tool in patients with ischemic heart disease, heart failure, cardiac transplantation, valve disease, and genetic cardiomyopathy.


Biostimulation of iron reduction and subsequent oxidation of sediment containing Fe-silicates and Fe-oxides: effect of redox cycling on Fe(III) bioreduction.
Sediment containing a mixture of iron (Fe)-phases, including Fe-oxides (mostly Al-goethite) and Fe-silicates (illites and vermiculite) was bioreduced in a long-term flow through column experiment followed by re-oxidation with dissolved oxygen. The objective of this study was (a) to determine the nature of the re-oxidized Fe(III), and (b) to determine how redox cycling of Fe would affect subsequent Fe(III)-bioavailability. In addition, the effect of Mn on Fe(III) reduction was explored.(57)Fe-Mössbauer spectroscopy measurements showed that biostimulation resulted in partial reduction (20%) of silicate Fe(III) to silicate Fe(II) while the reduction of goethite was negligible. Furthermore, the reduction of Fe in the sediment was uniform throughout the column. When, after biostimulation, 3900 pore volumes of a solution containing dissolved oxygen was pumped through the column over a period of 81 days, approximately 46% of the reduced silicate Fe(II) was re-oxidized to silicate Fe(III). The Mössbauer spectra of the re-oxidized sample were similar to that of pristine sediment implying that Fe-mineralogy of the re-oxidized sediment was mineralogically similar to that of the pristine sediment. In accordance to this, batch experiments showed that Fe(III) reduction occurred at a similar rate although time until Fe(II) buildup started was longer in the pristine sediment than re-oxidized sediment under identical seeding conditions. This was attributed to oxidized Mn that acted as a temporary redox buffer in the pristine sediment. The oxidized Mn was transformed to Mn(II) during bioreduction but, unlike silicate Fe(II), was not re-oxidized when exposed to oxygen.


Medical student education program in Alzheimer's disease: the PAIRS Program.
As life expectancy increases, dementia incidence will also increase, creating a greater need for physicians well-trained to provide integrated geriatric care. However, research suggests medical students have limited knowledge or interest in pursuing geriatric or dementia care. The purpose of this study is to evaluate the PAIRS Program and its effectiveness in enhancing medical education as a service-learning activity and replication model for the Buddy ProgramTM. Between 2007 and 2011, four consecutive classes of first year Boston University School of Medicine students (n = 45; 24 ± 3 years, 58% female, 53% White) participated in a year-long program in which they were paired with a patient with early-stage Alzheimer's disease (AD). Assessments included pre- and post-program dementia knowledge tests and a post-program reflective essay. Program completion was 100% (n = 45). A paired-sample t-test revealed a modest improvement in dementia knowledge post-program (p < 0.001). Using qualitative coding methods, 12 overarching themes emerged from the students' reflective essays, such as observing care partner burden, reporting a human side to AD, reporting experiences from the program that will impact future clinical practice, and obtaining a greater understanding of AD. Quantitative and qualitative findings suggest that the PAIRS Program can enhance the acquisition of knowledge, skills, and positive attitudes regarding geriatric healthcare in future generations of physicians, a skill set that is becoming increasingly relevant in light of the rapidly aging population. Furthermore, results suggest that The Buddy ProgramTM model can be successfully replicated.


A novel genetic- and cell-based tool for assessing the efficacy and toxicity of anticancer drugs in vitro.
To develop an in vitro tool for assessing the efficacy and toxicity of anticancer drugs using mixed culture containing both tumor and non-tumor cells. Such in vitro tool should have high application potential in drug-screening and personalized cancer care. Fibroblasts were spiked as non-tumor cells into tumor cells of an established line. The mixed culture was treated with a test drug at various concentrations. After the treatment, DNA was prepared directly from the survived adhesive cells in the wells of the 96-well plates using a simple and inexpensive method, and subjected to digital PCR for measuring relative copy numbers of a target gene NF1 to that of a reference gene RPP30. The NF1 gene is known to be heterozygously deleted in these tumor cells while the RPP30 gene has two copies in both tumor and non-tumor cells. Using the NF1/ RPP30 ratios resulting from the dual digital PCR assay, the proportions of tumor cells were calculated for each drug concentration. Digital PCR confirmed that the tumor cells have only one copy of the NF1 gene while the non-tumor fibroblasts have two copies. By contrast, both types of cells have two copies of the reference gene RPP30. Using the ratio of the two genes, we successfully calculated the proportion of tumor cells which decreased as the dose of the test drug increased up to a certain concentration, indicating that the drug is more effective for the tumor cells than for the non-tumor cells in this dose-range. At the highest dose, we observed a slight increase in the proportion of tumor cells, likely reflecting the toxic effect of the drug on both tumor and non-tumor cells. This pilot study demonstrated the feasibility of a genetic- and cell-based tool for testing efficacy and toxicity of anticancer drugs in vitro. The promising results suggest that additional efforts are merited, for further development since such a tool will likely have high application potential (1) in drug discovery where it enables simultaneously assessing therapeutic effect on target cells and toxic effect on non-target cells, and (2) in personalized adjuvant chemotherapy where multiple drugs can be tested in primary cultures derived from surgically removed tumor.


A systematic review of Bayesian articles in psychology: The last 25 years.
Although the statistical tools most often used by researchers in the field of psychology over the last 25 years are based on frequentist statistics, it is often claimed that the alternative Bayesian approach to statistics is gaining in popularity. In the current article, we investigated this claim by performing the very first systematic review of Bayesian psychological articles published between 1990 and 2015 (n = 1,579). We aim to provide a thorough presentation of the role Bayesian statistics plays in psychology. This historical assessment allows us to identify trends and see how Bayesian methods have been integrated into psychological research in the context of different statistical frameworks (e.g., hypothesis testing, cognitive models, IRT, SEM, etc.). We also describe take-home messages and provide "big-picture" recommendations to the field as Bayesian statistics becomes more popular. Our review indicated that Bayesian statistics is used in a variety of contexts across subfields of psychology and related disciplines. There are many different reasons why one might choose to use Bayes (e.g., the use of priors, estimating otherwise intractable models, modeling uncertainty, etc.). We found in this review that the use of Bayes has increased and broadened in the sense that this methodology can be used in a flexible manner to tackle many different forms of questions. We hope this presentation opens the door for a larger discussion regarding the current state of Bayesian statistics, as well as future trends. (PsycINFO Database Record


Increased morbid risk for schizophrenia-related disorders in relatives of schizotypal personality disordered patients.
To evaluate whether probands from a clinical sample diagnosed as having DSM-III schizotypal and/or paranoid personality disorder have a familial relationship to the schizophrenia-related disorders, the morbid risk for schizophrenia-related disorders and other psychiatric disorders were evaluated in the first-degree relatives of patients with schizotypal and/or paranoid personality disorder and compared with the corresponding risk for these disorders in the first-degree relatives of patients with other non-schizophrenia-related personality disorders. The morbid risk for all schizophrenia-related disorders, and specifically for schizophrenia-related personality disorders, was significantly greater among the relatives of the probands with schizotypal and/or paranoid personality disorder than among the relatives of probands with other personality disorder. The morbid risk for other psychiatric disorders did not differ significantly between the first-degree relatives of the schizotypal/paranoid personality disorder and the other personality disorder control proband samples. These results suggest a specific familial association between schizophrenia-related disorders, particularly schizophrenia-related personality disorders, and clinically diagnosed schizotypal patients.


Retinal detachment in England: database studies of trends over time and geographical variation.
Retinal detachment (RD) is one of the most common of ophthalmic emergencies in the UK. Our aim was to study trends over time and regional variation in rates of RD in England. Hospital admission rates for RD were analysed using the Hospital In-Patient Enquiry, Hospital Episode Statistics and the Oxford record linkage study between 1968 and 2011. Record linkage was used, when possible, to distinguish between episodes of care and individual people. Person-based rates from the 1960s to mid-1990s (only available in the Oxford data) were broadly stable. From 1999, the annual person-based rate increased significantly, from 13.4 in 1999 (13.1 to 13.8) to 15.4 in 2011 (15.1 to 15.7). Most, if not all, of the increase was an increase in people with diabetes mellitus. RD rates, comparing local authority (LA) areas, ranged from 10.3 (9.0 to 11.6) to 22.4 per 100,000 (19.9 to 25.1) over the period 1999-2011. The rate of RD by LA showed almost no association with social deprivation (r(2)=0.01) or with the proportion of people in each LA who were Black (r=0.04), Asian (r =-0.03) or born outside the UK (r=0.02). Admission rates seem to have increased in recent years. This increase is probably attributable to an increase in the prevalence of diabetes, and so an increase in RD associated with diabetes. Understanding trends over time, and geographical variation, in RD will help match capacity in retinal surgery with need for treatment of RD.


The global burden of alveolar echinococcosis.
Human alveolar echinococcosis (AE) is known to be common in certain rural communities in China whilst it is generally rare and sporadic elsewhere. The objective of this study was to provide a first estimate of the global incidence of this disease by country. The second objective was to estimate the global disease burden using age and gender stratified incidences and estimated life expectancy with the disease from previous results of survival analysis. Disability weights were suggested from previous burden studies on echinococcosis. We undertook a detailed review of published literature and data from other sources. We were unable to make a standardised systematic review as the quality of the data was highly variable from different countries and hence if we had used uniform inclusion criteria many endemic areas lacking data would not have been included. Therefore we used evidence based stochastic techniques to model uncertainty and other modelling and estimating techniques, particularly in regions where data quality was poor. We were able to make an estimate of the annual global incidence of disease and annual disease burden using standard techniques for calculation of DALYs. Our studies suggest that there are approximately 18,235 (CIs 11,900-28,200) new cases of AE per annum globally with 16,629 (91%) occurring in China and 1,606 outside China. Most of these cases are in regions where there is little treatment available and therefore will be fatal cases. Based on using disability weights for hepatic carcinoma and estimated age and gender specific incidence we were able to calculate that AE results in a median of 666,434 DALYs per annum (CIs 331,000-1.3 million). The global burden of AE is comparable to several diseases in the neglected tropical disease cluster and is likely to be one of the most important diseases in certain communities in rural China on the Tibetan plateau.


NCBO Ontology Recommender 2.0: an enhanced approach for biomedical ontology recommendation.
Ontologies and controlled terminologies have become increasingly important in biomedical research. Researchers use ontologies to annotate their data with ontology terms, enabling better data integration and interoperability across disparate datasets. However, the number, variety and complexity of current biomedical ontologies make it cumbersome for researchers to determine which ones to reuse for their specific needs. To overcome this problem, in 2010 the National Center for Biomedical Ontology (NCBO) released the Ontology Recommender, which is a service that receives a biomedical text corpus or a list of keywords and suggests ontologies appropriate for referencing the indicated terms. We developed a new version of the NCBO Ontology Recommender. Called Ontology Recommender 2.0, it uses a novel recommendation approach that evaluates the relevance of an ontology to biomedical text data according to four different criteria: (1) the extent to which the ontology covers the input data; (2) the acceptance of the ontology in the biomedical community; (3) the level of detail of the ontology classes that cover the input data; and (4) the specialization of the ontology to the domain of the input data. Our evaluation shows that the enhanced recommender provides higher quality suggestions than the original approach, providing better coverage of the input data, more detailed information about their concepts, increased specialization for the domain of the input data, and greater acceptance and use in the community. In addition, it provides users with more explanatory information, along with suggestions of not only individual ontologies but also groups of ontologies to use together. It also can be customized to fit the needs of different ontology recommendation scenarios. Ontology Recommender 2.0 suggests relevant ontologies for annotating biomedical text data. It combines the strengths of its predecessor with a range of adjustments and new features that improve its reliability and usefulness. Ontology Recommender 2.0 recommends over 500 biomedical ontologies from the NCBO BioPortal platform, where it is openly available (both via the user interface at http://bioportal.bioontology.org/recommender , and via a Web service API).


Are dual-purpose hens less fearful than conventional layer hybrids?
Excessive fear in farm animals can lead to chronic stress and thus impair animal welfare. In laying hens, fear responses in several behavioural tests have also been associated with the occurrence of feather pecking. The aim of the present study was to comparatively assess fear-related responses of conventional layer hybrids (Lohmann Brown plus, LB+) and dual-purpose hens (Lohmann Dual, LD), which seem to be less prone to injurious pecking. A novel object (NO) and an avoidance distance (AD) test were carried out in both hybrids at a group level and at different ages during the laying period in order to measure their fear-related responses. On most study days, more LD hens approached the NO and they approached it sooner than the LB+ hens. Similarly, the LD hens retreated at smaller distances from a human being in the AD test. The results indicate that dual-purpose hens act less fearful in the performed behavioural tests compared with conventional layer hybrids. Therefore, dual-purpose hens might experience less stress during daily management routines, which would affect animal welfare positively.


Enhanced endocannabinoid-mediated modulation of rostromedial tegmental nucleus drive onto dopamine neurons in Sardinian alcohol-preferring rats.
The progressive predominance of rewarding effects of addictive drugs over their aversive properties likely contributes to the transition from drug use to drug dependence. By inhibiting the activity of DA neurons in the VTA, GABA projections from the rostromedial tegmental nucleus (RMTg) are well suited to shift the balance between drug-induced reward and aversion. Since cannabinoids suppress RMTg inputs to DA cells and CB1 receptors affect alcohol intake in rodents, we hypothesized that the endocannabinoid system, by modulating this pathway, might contribute to alcohol preference. Here we found that RMTg afferents onto VTA DA neurons express CB1 receptors and display a 2-arachidonoylglycerol (2-AG)-dependent form of short-term plasticity, that is, depolarization-induced suppression of inhibition (DSI). Next, we compared rodents with innate opposite alcohol preference, the Sardinian alcohol-preferring (sP) and alcohol-nonpreferring (sNP) rats. We found that DA cells from alcohol-naive sP rats displayed a decreased probability of GABA release and a larger DSI. This difference was due to the rate of 2-AG degradation. In vivo, we found a reduced RMTg-induced inhibition of putative DA neurons in sP rats that negatively correlated with an increased firing. Finally, alcohol failed to enhance RMTg spontaneous activity and to prolong RMTg-induced silencing of putative DA neurons in sP rats. Our results indicate functional modifications of RMTg projections to DA neurons that might impact the reward/aversion balance of alcohol attributes, which may contribute to the innate preference observed in sP rats and to their elevated alcohol intake.


Mst1/2 kinases restrain transformation in a novel transgenic model of Ras driven non-small cell lung cancer.
Non-small cell lung cancer remains a highly lethal malignancy. Using the tamoxifen inducible Hnf1b:CreERT2 (H) transgenic mouse crossed to the LsL-KrasG12D (K) transgenic mouse, we recently discovered that an Hnf1b positive cell type in the lung is sensitive to adenoma formation when expressing a mutant KrasG12D allele. In these mice, we observe adenoma formation over a time frame of three to six months. To study specificity of the inducible Hnf1b:CreERT2 in the lung, we employed lineage tracing using an mTmG (G) reporter allele. This technique revealed recombined, GFP+ cells were predominantly SPC+. We further employed this technique in HKG mice to determine Hnf1b+ cells give rise to adenomas that express SPC and TTF1. Review of murine lung tissue confirmed a diagnosis of adenoma and early adenocarcinoma, a pathologic subtype of non-small cell lung cancer. Our expanded mouse model revealed loss of Mst1/2 promotes aggressive lung adenocarcinoma and large-scale proteomic analysis revealed upregulation of PKM2 in the lungs of mice with genetic deletion of Mst1/2. PKM2 is a known metabolic regulator in proliferating cells and cancer. Using a human lung adenocarcinoma cell line, we show pharmacologic inhibition of Mst1/2 increases the abundance of PKM2, indicating genetic loss or pharmacologic inhibition of Mst1/2 directly modulates the abundance of PKM2. In conclusion, here we report a novel model of non-small cell lung cancer driven by a mutation in Kras and deletion of Mst1/2 kinases. Tumor development is restricted to a subset of alveolar type II cells expressing Hnf1b. Our data show loss of Mst1/2 regulates levels of a potent metabolic regulator, PKM2.


Influence of rhythmic grouping on duration perception: a novel auditory illusion.
This study investigated a potential auditory illusion in duration perception induced by rhythmic temporal contexts. Listeners with or without musical training performed a duration discrimination task for a silent period in a rhythmic auditory sequence. The critical temporal interval was presented either within a perceptual group or between two perceptual groups. We report the just-noticeable difference (difference limen, DL) for temporal intervals and the point of subjective equality (PSE) derived from individual psychometric functions based on performance of a two-alternative forced choice task. In musically untrained individuals, equal temporal intervals were perceived as significantly longer when presented between perceptual groups than within a perceptual group (109.25% versus 102.5% of the standard duration). Only the perceived duration of the between-group interval was significantly longer than its objective duration. Musically trained individuals did not show this effect. However, in both musically trained and untrained individuals, the relative difference limens for discriminating the comparison interval from the standard interval were larger in the between-groups condition than in the within-group condition (7.3% vs. 5.6% of the standard duration). Thus, rhythmic grouping affected sensitivity to duration changes in all listeners, with duration differences being harder to detect at boundaries of rhythm groups than within rhythm groups. Our results show for the first time that temporal Gestalt induces auditory duration illusions in typical listeners, but that musical experts are not susceptible to this effect of rhythmic grouping.


Fresh autologous pericardium for leaflet perforation repair in mitral valve infective endocarditis.
There is clear evidence that mitral valve (MV) repair is superior to replacement for MV infective endocarditis (IE). Leaflet perforation is a common pathologic finding in MV IE, and leaflet patch repair with glutaraldehyde-treated autologous or bovine pericardium is the currently accepted method of MV repair. In the present study, fresh autologous pericardium (FAP) was used universally to treat leaflet perforation in MV IE, and the mid-term clinical and echocardiographic outcomes were determined. Between 2002 and 2009, a total of 20 patients with leaflet perforations from MV IE underwent patch repair with FAP. Follow up echocardiography was performed in a core laboratory. There was one operative death (5%) secondary to sepsis, and three late deaths (15%). Late echocardiograms were available for review from 16 of the 19 patients (84%) who survived surgery. The mean time to follow up echocardiography was 793 +/- 663 days. The mitral regurgitation (MR) grade was mild or less in 14/16 patients (88%), moderate in one patient (6%), and severe in one patient (6%). The mean gradient was 4.8 +/- 2.7 mmHg, and the ejection fraction was preserved in all patients (63 +/- 4%). No expansion, retraction or calcification of the patches was observed. Freedom from reoperation, reinfection and thromboembolism was 100%. Fresh autologous pericardium for MV leaflet patch repair in IE is associated with good mid-term valve function. Given the association between late calcification and the glutaraldehyde treatment of bioprosthetic valves and this favorable experience, it is believed that FAP is an acceptable alternative for leaflet repair in MV IE.


TTP/HUS: observational studies generate hypotheses that lead to randomized controlled trials.
Thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS) is a disease syndrome, and its history exemplifies how small observational studies lead to hypotheses that spawn randomized control trials (RCTs). Moschowitz's original case report coupled with the case findings of Bukowski and Byrne led to the RCT of Rock and the Canadian Apheresis Group that proved plasma exchange was superior to plasma infusion for the treatment of adults with TTP/HUS. Our single case report of continuous plasma exchange coupled with the observations about the pathogenic role of von Willebrand multimer protease of Tsai and Furlan strengthened by a 25-year observational study of plasma exchange treatment for TTP/HUS has led to a proposal to initiate a new RCT.


LDLR expression and localization are altered in mouse and human cell culture models of Alzheimer's disease.
Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common form of dementia. The major molecular risk factor for late-onset AD is expression of the epsilon-4 allele of apolipoprotein E (apoE), the major cholesterol transporter in the brain. The low-density lipoprotein receptor (LDLR) has the highest affinity for apoE and plays an important role in brain cholesterol metabolism. Using RT-PCR and western blotting techniques we found that over-expression of APP caused increases in both LDLR mRNA and protein levels in APP transfected H4 neuroglioma cells compared to H4 controls. Furthermore, immunohistochemical experiments showed aberrant localization of LDLR in H4-APP neuroglioma cells, Abeta-treated primary neurons, and in the PSAPP transgenic mouse model of AD. Finally, immunofluorescent staining of LDLR and of gamma- and alpha-tubulin showed a change in LDLR localization preferentially away from the plasma membrane that was paralleled by and likely the result of a disruption of the microtubule-organizing center and associated microtubule network. These data suggest that increased APP expression and Abeta exposure alters microtubule function, leading to reduced transport of LDLR to the plasma membrane. Consequent deleterious effects on apoE uptake and function will have implications for AD pathogenesis and/or progression.


With that diet, you will go far: trait-based analysis reveals a link between rapid range expansion and a nitrogen-favoured diet.
Recent global change has had a substantial influence on the distribution of organisms, and many species are currently expanding their ranges. To evaluate the underlying processes, long-term data with good geographic resolution are essential. One important but generally overlooked data source is offered by the taxon-specific national catalogues of first provincial records that are kept in many countries. Here, we use such data to quantify trait-based influences on range expansion in Swedish butterflies and moths between 1973 and 2010. Of 282 species meeting pre-defined quality criteria, 170 expanded their northern range margin, with a mean expansion rate of 2.7 km per year. The analyses demonstrate that habitat and diet generalists, forest species and species active during warm conditions have expanded their ranges more rapidly than other species. Notably, range expansion in diet specialists was positively related to a nitrogen-favoured larval diet, an effect not found among oligo- or polyphagous species. In contrast to the general view, this shows that specialist species can undergo rapid range expansion. We suggest that increased areas of nitrogen-rich habitat, and increased availability of a nitrogen-favoured diet, are among the most important drivers of range expansions, potentially having far-reaching consequences for a wide variety of organisms.


Treatment of dysthymia with sertraline: a double-blind, placebo-controlled trial in dysthymic patients without major depression.
The selective serotonin reuptake inhibitor sertraline has been shown to be efficacious and well tolerated for the treatment of major depressive disorder. Relatively few trials, however, have examined the role of pharmacotherapy in dysthymia without concurrent major depression. The current investigation focuses on the use of sertraline for the treatment of dysthymia. In this 12-week, multicenter, double-blind study, 310 patients with a DSM-III-R diagnosis of dysthymic disorder without concurrent major depression were randomly assigned to receive either sertraline (N = 158) or placebo (N = 152). Sertraline was initiated at a dose of 50 mg daily, with titration permitted to a maximum of 200 mg daily. The primary evaluation criteria were the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorder Version (SIGH-SAD), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) scales. Mean percentage reductions for the intent-to-treat population in SIGH-SAD scores were 44.6% for the sertraline-treated group and 33.2% for the placebo-treated group (p = .03); MADRS scores, 43.6% and 33.0% (p = .02); and CGI-S scores, 32.8% and 22.8% (p = .02). A significantly greater proportion of the sertraline-treated group was classified as responders (defined for HAM-D and MADRS scores as a 50% score reduction and for CGI-I as a score of 1 or 2 by the final visit) and remitters (SIGH-SAD score < or = 8) relative to the placebo-treated group by the final visit. In addition, sertraline-treated patients experienced greater improvements in all 9 domains of the Battelle Quality of Life Questionnaire than placebo-treated patients did, with a significant difference observed in favor of sertraline in 8 of the 9 domains. The life satisfaction and social interaction quality of life domains showed significantly greater response in sertraline responders compared with placebo SIGH-SAD responders. Sertraline was well tolerated. Thirteen percent of the sertraline-treated group versus 8% of the placebo-treated group withdrew from therapy owing to adverse events (p = .14). Sertraline is efficacious and well tolerated in the short-term treatment of dysthymia without concurrent major depression.


Extensive identification and analysis of conserved small ORFs in animals.
There is increasing evidence that transcripts or transcript regions annotated as non-coding can harbor functional short open reading frames (sORFs). Loss-of-function experiments have identified essential developmental or physiological roles for a few of the encoded peptides (micropeptides), but genome-wide experimental or computational identification of functional sORFs remains challenging. Here, we expand our previously developed method and present results of an integrated computational pipeline for the identification of conserved sORFs in human, mouse, zebrafish, fruit fly, and the nematode C. elegans. Isolating specific conservation signatures indicative of purifying selection on amino acid (rather than nucleotide) sequence, we identify about 2,000 novel small ORFs located in the untranslated regions of canonical mRNAs or on transcripts annotated as non-coding. Predicted sORFs show stronger conservation signatures than those identified in previous studies and are sometimes conserved over large evolutionary distances. The encoded peptides have little homology to known proteins and are enriched in disordered regions and short linear interaction motifs. Published ribosome profiling data indicate translation of more than 100 novel sORFs, and mass spectrometry data provide evidence for more than 70 novel candidates. Taken together, we identify hundreds of previously unknown conserved sORFs in major model organisms. Our computational analyses and integration with experimental data show that these sORFs are expressed, often translated, and sometimes widely conserved, in some cases even between vertebrates and invertebrates. We thus provide an integrated resource of putatively functional micropeptides for functional validation in vivo.


Serum IGF-1 in the diagnosis of acromegaly and the profile of patients with elevated IGF-1 but normal glucose-suppressed growth hormone.
To report the utility of insulin-like growth factor-1 (IGF-1) as a single biomarker for establishing the diagnosis of acromegaly and to examine the clinical and biochemical profile of patients with an elevated IGF-1 in whom a diagnosis of acromegaly could not be confirmed by means of the oral glucose tolerance test (OGTT). Between the years 1999 and 2010, we identified 101 patients who underwent pituitary surgery and had histologically proven somatotroph adenomas (Group 1, Gr 1). We selected 149 patients with non-growth hormone (GH) secreting pituitary macroadenomas (Gr 2, n = 97) and microadenomas (Gr 3, n = 52) to serve as control subjects. In addition, we identified 34 patients with elevated IGF-1values in whom acromegaly could not subsequently be proven by the OGTT (Gr 4). IGF-1 was elevated in all patients with acromegaly prior to therapy with a median (range) standard deviation score (SDS) of +9.52 (+2.34 to +9.2), compared to SDS -1.46 (-2.91 to +2.17) and -1.22 (-2.8 to +1.58) in Gr 2 and 3, respectively (P<0.001). IGF-1 SDS values were +3.28 (+2.05 to +6.1), and IGF-1 was less than twice the upper limit of normal in all patients in Gr 4. OGTT was performed in 51 of the 101 acromegalic patients. The nadir GH in these patients was 4.01 (0.2 to 46.7) in comparison with 0.2 (<0.05 to 0.6) in Gr 4 (P<0.001). Elevated IGF-1 levels, alone, are sufficient to establish a diagnosis of acromegaly in the majority of clinically suspected cases. The OGTT may be useful to obtain corroborative evidence when there is modest elevation of IGF-1 with absent or equivocal clinical features.


Penetration of fluids into periodontal pockets using a powered toothbrush/irrigator device.
This study was a single-blind, randomized, controlled clinical trial. The researchers evaluated a powered brush/irrigating device (HydraBrush Oral Health System; OHS) for its safety and ability to deliver a solution to the bottom of 5-6 mm pockets, compared to rinsing alone with a solution following brushing with a powered toothbrush (Sonicare Elite 7800; SE). An evaluation technique to measure the quantity and quality of solution able to enter the pocket was also introduced in this project. Subjects were randomized in one of two-groups: brush plus simultaneous irrigation (OHS) versus brush plus rinsing (SE). Subjects used their devices at home for two weeks. At the measurement visit, subjects used the OHS to irrigate and brush simultaneously for 1 minute (30 seconds per each side of the mouth) with a 0.01% erythrosine disclosing solution in 10 oz of distilled water. Control subjects brushed for 2 minutes with a SE followed by a 1 minute rinse with an identical disclosing solution. A blinded evaluator collected six samples of approximately of 1 microL of sucular fluid from six 5-6 mm evaluation sites. This was accomplished by inserting a microcapillary tip with a 20 microL micropipette in the sulcus. Two-group repeated measures ANOVA was used to examine differences in two measures of the disclosing solution between OHS and SE subjects; the spectrometer reading of the disclosing solutions, and by visual inspection of the samples (positive/negative) to determine the presence or absence of solution in the samples. Subjects' diaries were collected. Bleeding and discomfort during the evaluation period was reported. Visually, OHS had a significantly greater proportion of solution taken from the base of 5-6 mm sites than the SE (p=0.0001). However, there was no statistical difference between the two groups (p=.1359) in the spectrophotometer readings. The experimental device is more efficient in delivering a solution to the base of 5-6 mm pockets than rinsing following use of a control powered toothbrush. Both devices have demonstrated they are safe and well accepted by patients. The technique developed provides a useful method for quantitative and qualitative studies of solutions from the base of periodontal pockets.


Evidence that miR168a contributes to salinity tolerance of Brassica rapa L. via mediating melatonin biosynthesis.
Melatonin is a master regulator of diverse biological processes, including plant's abiotic stress responses and tolerance. Despite the extensive information on the role of melatonin in response to abiotic stress, how plants regulate endogenous melatonin content under stressful conditions remains largely unknown. In this study, we computationally mined Expressed Sequence Tag (EST) libraries of salinity-exposed Chinese cabbage (Brassica rapa) to identify the most reliable differentially expressed miRNA and its target gene(s). In light of these analyses, we found that miR168a potentially targets a key melatonin biosynthesis gene, namely O-METHYLTRANSFERASE 1 (OMT1). Accordingly, molecular and physiochemical evaluations were performed in a separate salinity experiment using contrasting B. rapa genotypes. Then, the association between B. rapa salinity tolerance and changes in measured molecular and physiochemical characteristics was determined. Results indicated that the expression profiles of miR168a and OMT1 significantly differed between B. rapa genotypes. Moreover, the expression profiles of miR168a and OMT1 significantly correlated with more melatonin content, robust antioxidant activities, and better ion homeostasis during salinity stress. Our results suggest that miR168a plausibly mediates melatonin biosynthesis, mainly through the OMT1 gene, under salinity conditions and thereby contributes to the salinity tolerance of B. rapa. To our knowledge, this is the first report on the role of miR168a and OMT1 in B. rapa salinity response.


Cost-effectiveness of total hip and knee replacements for the Australian population with osteoarthritis: discrete-event simulation model.
Osteoarthritis constitutes a major musculoskeletal burden for the aged Australians. Hip and knee replacement surgeries are effective interventions once all conservative therapies to manage the symptoms have been exhausted. This study aims to evaluate the cost-effectiveness of hip and knee replacements in Australia. To our best knowledge, the study is the first attempt to account for the dual nature of hip and knee osteoarthritis in modelling the severities of right and left joints separately. We developed a discrete-event simulation model that follows up the individuals with osteoarthritis over their lifetimes. The model defines separate attributes for right and left joints and accounts for several repeat replacements. The Australian population with osteoarthritis who were 40 years of age or older in 2003 were followed up until extinct. Intervention effects were modelled by means of disability-adjusted life-years (DALYs) averted. Both hip and knee replacements are highly cost effective (AUD 5,000 per DALY and AUD 12,000 per DALY respectively) under an AUD 50,000/DALY threshold level. The exclusion of cost offsets, and inclusion of future unrelated health care costs in extended years of life, did not change the findings that the interventions are cost-effective (AUD 17,000 per DALY and AUD 26,000 per DALY respectively). However, there was a substantial difference between hip and knee replacements where surgeries administered for hips were more cost-effective than for knees. Both hip and knee replacements are cost-effective interventions to improve the quality of life of people with osteoarthritis. It was also shown that the dual nature of hip and knee OA should be taken into account to provide more accurate estimation on the cost-effectiveness of hip and knee replacements.


A sedge plant as the source of Kangaroo Island propolis rich in prenylated p-coumarate ester and stilbenes.
Propolis samples from Kangaroo Island, South Australia, were investigated for chemical constituents using high-field nuclear magnetic resonance spectral profiling. A type of propolis was found containing a high proportion of prenylated hydroxystilbenes. Subsequently, the botanical origin of this type of propolis was identified using a beehive propolis depletion method and analysis of flora. Ligurian honey bees, Apis mellifera ligustica Spinola, were found to produce propolis from resin exuded by the Australian native sedge plant Lepidosperma sp. Montebello (Cyperaceae). The plants, commonly known as sword sedge, were found to have resin that matched with the propolis samples identified as the most abundant propolis type on the island containing C- and O-prenylated tetrahydroxystilbenes (pTHOS) in addition to a small amount of prenylated p-coumarate. The isolation of five pTHOS not previously characterized are reported: (E)-4-(3-methyl-2-buten-1-yl)-3,4',5-trihydroxy-3'-methoxystilbene, (E)-2,4-bis(3-methyl-2-buten-1-yl)-3,3',4',5-tetrahydroxystilbene, (E)-2-(3-methyl-2-buten-1-yl)-3-(3-methyl-2-butenyloxy)-3',4',5-trihydroxystilbene, (E)-2,6-bis(3-methyl-2-buten-1-yl)-3,3',5,5'-tetrahydroxystilbene and (E)-2,6-bis(3-methyl-2-buten-1-yl)-3,4',5-trihydroxy-3'-methoxystilbene. A National Cancer Institute 60 human cell line anticancer screen of three of these compounds showed growth inhibitory activity. The large Australasian genus Lepidosperma is identified as a valuable resource for the isolation of substances with medicinal potential.


Defending genome integrity during DNA replication: a proposed role for RecQ family helicases.
The RecQ family of DNA helicases have been shown to be important for the maintenance of genomic integrity in all organisms analysed to date. In human cells, representatives of this family include the proteins defective in the cancer predisposition disorder Bloom's syndrome and the premature ageing condition, Werner's syndrome. Several pieces of evidence suggest that RecQ family helicases form associations with one or more of the cellular topoisomerases, and together these heteromeric complexes manipulate DNA structure to effect efficient DNA replication, genetic recombination, or both. Here, we propose that RecQ helicases are required for ensuring that structural abnormalities arising during replication, such as at sites where replication forks encounter DNA lesions, are corrected with high fidelity. In mutants defective in these proteins, not only is replication abnormal, but cells display aberrant responses to DNA-damaging agents or inhibitors of DNA synthesis. We suggest that RecQ helicases may be important for the integration of cellular responses to these insults, such as by linking cell cycle checkpoint responses to recombinational repair.


[Bodies, mummies and texts for an history of embalming in Italy].
In the early 80's, a systematic investigation was started of the series of mummies from Central and Southern Italy, in particular from important Renaissance depositions. Radiological exams were carried out on each individual, not only to determine the age at death of those subjects lacking any indication of age, but also to detect possible pathological findings. Furthermore, X-rays allow greater understanding of the techniques and the substances used for embalming, including the type of craniotomy, the partial or complete evisceration, and the identification of the embalming substances used to fill the body cavities. The great number of artificial mummies, examined by G. Fornaciari and his equipe, allowed the study of human embalming techniques, related to methods and procedures described by medical and non-medical authors in Early Modern age. The history of the art of mummification has been here reconstructed, from the 'clyster' techniques to the partial or total evisceration of the corpses, to the introvascular injection of drying and preserving liquors.