Differential Motor Unit Changes after Endurance or High-Intensity Interval Training.
Using a novel technique of high-density surface EMG decomposition and motor unit (MU) tracking, we compared changes in the properties of vastus medialis and vastus lateralis MU after endurance (END) and high-intensity interval training (HIIT). Sixteen men were assigned to the END or the HIIT group (n = 8 each) and performed six training sessions for 14 d. Each session consisted of 8-12 × 60-s intervals at 100% peak power output separated by 75 s of recovery (HIIT) or 90-120 min continuous cycling at ~65% V˙O2peak (END). Pre- and postintervention, participants performed 1) incremental cycling to determine V˙O2peak and peak power output and 2) maximal, submaximal (10%, 30%, 50%, and 70% maximum voluntary contraction [MVC]), and sustained (until task failure at 30% MVC) isometric knee extensions while high-density surface EMG signals were recorded from the vastus medialis and vastus lateralis. EMG signals were decomposed (submaximal contractions) into individual MU by convolutive blind source separation. Finally, MU were tracked across sessions by semiblind source separation. After training, END and HIIT improved V˙O2peak similarly (by 5.0% and 6.7%, respectively). The HIIT group showed enhanced maximal knee extension torque by ~7% (P = 0.02) and was accompanied by an increase in discharge rate for high-threshold MU (≥50% knee extension MVC) (P < 0.05). By contrast, the END group increased their time to task failure by ~17% but showed no change in MU discharge rates (P > 0.05). HIIT and END induce different adjustments in MU discharge rate despite similar improvements in cardiopulmonary fitness. Moreover, the changes induced by HIIT are specific for high-threshold MU. For the first time, we show that HIIT and END induce specific neuromuscular adaptations, possibly related to differences in exercise load intensity and training volume.


Ion channel formation by synthetic analogues of staphylococcal delta-toxin.
Ion channel formation by three analogues of staphylococcal delta-toxin, an amphipathic and alpha-helical channel-forming peptide, has been evaluated by measurement of ionic currents across planar lipid bilayers. Replacement of beta-branched, hydrophobic residues by leucine and movement of a tryptophan residue from the hydrophilic to the hydrophobic face of the helix does not significantly alter ion channel activity. Removal of the N-terminal blocking group combined with the substitution of glycine-10 by leucine changes the single channel properties of delta-toxin, without altering macroscopic conductance/voltage behaviour. Truncation of the N-terminus by three residues results in complete loss of channel-forming activity. These changes in channel-forming properties upon altering the peptide sequence do not mirror changes in haemolytic activity. The results lend support to the proposal that channel formation and haemolysis are distinct events. Channel properties are discussed in the context of a model in which the pore is formed by a bundle of approximately parallel transbilayer helices.


A single splice site mutation in human-specific ARHGAP11B causes basal progenitor amplification.
The gene ARHGAP11B promotes basal progenitor amplification and is implicated in neocortex expansion. It arose on the human evolutionary lineage by partial duplication of ARHGAP11A, which encodes a Rho guanosine triphosphatase-activating protein (RhoGAP). However, a lack of 55 nucleotides in ARHGAP11B mRNA leads to loss of RhoGAP activity by GAP domain truncation and addition of a human-specific carboxy-terminal amino acid sequence. We show that these 55 nucleotides are deleted by mRNA splicing due to a single C→G substitution that creates a novel splice donor site. We reconstructed an ancestral ARHGAP11B complementary DNA without this substitution. Ancestral ARHGAP11B exhibits RhoGAP activity but has no ability to increase basal progenitors during neocortex development. Hence, a single nucleotide substitution underlies the specific properties of ARHGAP11B that likely contributed to the evolutionary expansion of the human neocortex.


Speech pathologist practice patterns for evaluation and management of suspected cricopharyngeal dysfunction.
Speech pathologists are often the first professionals to identify signs of a cricopharyngeal (CP) dysfunction and make recommendations for further care. There are many care options for patients with CP dysfunction, but it is unclear how certain interventions are used in practice. A paper-based survey employing two clinical cases involving suspected CP dysfunction (Case 1 with adequate pharyngeal strength and Case 2 with coexisting pharyngeal weakness) was sent to members of American Speech-Language Hearing Association's Special Interest Group 13. Respondents ranked the order of management approaches (swallowing therapy, further evaluation, and referral to another medical professional) and selected specific interventions under each approach that they would recommend for each case. Completed surveys from 206 respondents were entered into analysis. The majority of the respondents recommended swallowing therapy as a first approach for each case (Case 1: 64 %; Case 2: 88 %). The most prevalent swallowing exercises recommended were the Shaker (73 %), effortful swallow (62 %), and Mendelsohn maneuver (53 %) for Case 1 and effortful swallow (92 %), Shaker (84 %), and tongue-hold swallow (73 %) for Case 2. 76 % of respondents recommended a referral for Case 1, while 38 % recommended the same for Case 2. Respondents with access to more types of evaluative tools were more likely to recommend further evaluation, and those with access to only videofluoroscopy were less likely to recommend further evaluation. However, the high degree of variability in recommendations reflects the need for best practice guidelines for patients with signs of CP dysfunction.


A Single Dose of Marine Chlorella vulgaris Increases Plasma Concentrations of Lutein, β-Carotene and Zeaxanthin in Healthy Male Volunteers.
The beneficial health effects of Chlorella vulgaris have been associated with the presence of several nutrients and antioxidants, including carotenoids. However, the in vivo bioavailability of Chlorella is still poorly evaluated. In this work, a human intervention study was conducted in 11 healthy men to evaluate the bioavailability of carotenoids within 3 days after the intake of a single dose (6 g) of dried marine Chlorella vulgaris containing lutein (7.08 mg), β-carotene (1.88 mg) and zeaxanthin (1.47 mg). Subjects were instructed to follow a low carotenoid diet during the experimental phase, starting 1 week earlier. On the day of the experiment, dried microalgae formulated in vegetarian hard capsules were ingested, and blood samples were collected up to 72 h for the analysis of plasma carotenoids concentration by high-performance liquid chromatography with diode-array detection. For all carotenoids, the estimated AUC and Cmax values were significantly different from zero (p < 0.05), indicating that a single dose of marine Chlorella vulgaris increased plasma concentrations of lutein (Cmin-corrected AUC = 1002 µg·h/L, Cmax = 20.4 µg/L), β-carotene (AUC = 1302 µg·h/L, Cmax = 34.9 µg/L) and zeaxanthin (AUC = 122.2 µg·h/L, Cmax = 3.4 µg/L). The bioavailability of other compounds, namely, polyunsaturated fatty acids and trace elements, was also assessed post-prandial for the first time, showing that linoleic acid, docosahexaenoic acid and iodine were absorbed after microalgae intake. These findings support the use of Chlorella vulgaris as a source of carotenoids, PUFA and essential trace elements with associated health benefits.


2,4-D adsorption to biochars: effect of preparation conditions on equilibrium adsorption capacity and comparison with commercial activated carbon literature data.
Batch isotherm experiments were conducted with chars to study adsorption of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D). Chars generated from corncobs, bamboo and wood chips in a laboratory pyrolyzer at 400-700 °C were compared with traditional kiln charcoals collected from villages in S/SE Asia and with activated carbons (ACs). 2,4-D uptake by laboratory chars obtained from bamboo and wood chips after 14 h of pyrolysis at 700 °C, from wood chips after 96 h of pyrolysis at 600 °C, and one of the field-collected chars (basudha) was comparable to ACs. H:C and O:C ratios declined with pyrolysis temperature and duration while surface area increased to >500 m(2)/g. Increasing pyrolysis intensity by increasing temperature and/or duration of heating was found to positively influence adsorption capacity yield (mg(2,4-D/g(feedstock))) over the range of conditions studied. Economic analysis showed that high temperature chars can be a cost-effective alternative to ACs for water treatment applications.


Understanding due discretion of judgment in Catholic marriage courts.
Psychiatrists and psychologists provide consultation to the Catholic Church's marriage courts. Operating under the Church's legal code, these tribunals assess the validity of weddings that have ended in divorce. This report describes one of the standards used for this purpose, the lack of due discretion of judgment, which is concerned with the maturity, understanding, and appreciation that the couple brought to the ceremony. This normal capacity is vulnerable to various mental illnesses, which if present with sufficient severity may nullify the marriage vows as seen by the Church (though not necessarily by the state). Such a finding results in freedom to marry again despite the Church's ban on divorce, provided that due discretion of judgment is regained. Case examples and discussion of the assessment process for due discretion of judgment prepare the consultant to apply psychiatric findings to this unique and urgent legal issue.


Ab initio and NBO studies of methyl internal rotation in 1-methyl-2(1H)-quinolinone: effect of aromatic substitution to 1-methyl-2(1H)-pyridone.
1-methyl-2(1H)-quinolinone (MeQone) forms the framework of several hundred alkaloid molecules both natural and synthetic being used for various biological applications. From chemical structure point of view, the molecules can also be seen as an aromatic ring fused to 1-methyl-2(1H)-pyridone (1-MPY). In this work, we present theoretical investigations on internal rotation of methyl group in MeQone in light of 1-MPY. We looked into the change in the three-fold (V3) methyl internal rotation barrier resulted from the aromatic ring substitution to 1-MPY. The V3 term in two molecules were calculated using density functional theory and Hartree-Fock theory with different basis sets. MeQone has calculated V3 term (in S0 state) three times higher in magnitude compared with that of 1-MPY. The role of aromatic substitution in increase of V3 term is investigated using natural bond orbital (NBO) analyses. In the NBO analysis, it is found that the aromatic ring as highly delocalized π-system lowers the magnitude of hyperconjugation energy in MeQone compared with 1-MPY. This is due to the extension of delocalization of π-electrons to pyridone ring which lowers the orbital overlap. However, the Lewis energy increases substantially and make the overall barrier energy higher in MeQone compared with 1-MPY. From our study, we conclude that in the molecules such as 1-MPY and MeQone where the methyl group has two single bonds vicinal to it, the overall hyperconjugation energy is always barrier forming with nonlocal interactions playing significant role. Also, the Lewis energy plays the decisive role in barrier formation, and its magnitude can be tuned by tuning the π-electron delocalization. We have also looked into the change in methyl group conformation upon electronic excitation to S1 state. In 1-MPY, the methyl group rotated by 60° upon excitation whereas in MeQone, there was no conformational change. Strong π*-σ* interaction in LUMO in top-of-barrier conformation is responsible for the change in the methyl group conformation in 1-MPY, whereas same π*-σ* interaction in LUMO of minimum energy conformation results in unchanged excited state conformation in MeQone. Graphical abstract.


Continuation of the genetic divergence of ecological speciation by spatial environmental heterogeneity in island endemic plants.
Divergent selection plays a critical role not only as a speciation driver but also in maintaining post-speciation divergence. In the absence of direct evidence, ancestral interspecific gene flow between incipient species can reflect ancient selective pressure for ecological speciation. In the present study, two late-Pleistocene diverged species endemic to Taiwan, Scutellaria playfairii and S. tashiroi, were spatially and ecologically partitioned with partial overlap. Multilocus genome-scan analyses and in silico evaluation revealed ancestral interspecific gene flow but distinct genetic compositions, implying that adaptive divergence contributed to their speciation. Ecological niche modeling and principal component analysis suggested incomplete divergent niches between the two species; the species distribution is therefore consistent with Hutchinson's metaphor of multidimensional hypervolume niches rather than attributable to a single factor. Constraint ordination analysis supported this inference of a combination of variables explaining the genetic structure. The rare occurrence of hybrids in the sympatric population suggested hybrid breakdown, providing further evidence of divergent selection blocking gene flow. The correlation of environmental variables with integrated genetic components demonstrated that environmental heterogeneity maintains the species and population differentiation. This study highlights the importance of environmental heterogeneity and divergent selection for the rapid speciation and recent diversification of island plants.


Wet-spinning of PEDOT:PSS/functionalized-SWNTs composite: a facile route toward production of strong and highly conducting multifunctional fibers.
With the aim of fabricating multifunctional fibers with enhanced mechanical properties, electrical conductivity and electrochemical performance, we develop wet-spinning of composite formulation based on functionalized PEG-SWNT and PEDOT:PSS. The method of addition and loading are directly correlated to the quality and the ease of spinnability of the formulation and to the mechanical and electrical properties of the resultant fibers. Both the fiber modulus (Y) and strength (σ) scaled linearly with PEG-SWNT volume fraction (Vf). A remarkable reinforcement rate of dY/dVf = 417 GPa and dσ/dVf = 4 GPa were obtained when PEG-SWNTs at Vf ≤ 0.02. Further increase of PEG-SWNTs loading (i.e. up to Vf 0.12) resulted in further enhancements up to 22.8 GPa and 254 MPa in Modulus and ultimate stress, respectively. We also show the enhancement of electrochemical supercapacitor performance of composite fibers. These outstanding mechanical, electrical and electrochemical performances place these fibers among the best performing multifunctional composite fibers.


New therapeutic effects of cilostazol in patients with ischemic disorders.
Cilostazol (CIL) is effective for the treatment of patients with peripheral arterial disease (PAD). CIL is an orally administered drug with multiple effects, including anti-platelets aggregation, favorable functions on plasmatic lipids and vasodilator ones, but how these effects might be related to improvement in patients walking affected by PAD is not fully understood. The latest data demonstrate that nitric oxide (NO) is induced by CIL through endothelial nitric oxide synthase (eNOS) activation via a cyclic-AMP (cAMP)/ protein kinase A (PKA)- and PI3K/Akt- dependent mechanism. This mechanism is also responsible for the vasodilatation dependent on endothelium which characterized patients receiving CIL. Other investigators have found that CIL notably reduces the exercise-induced host-inflammatory response in PAD patients, and consequently it improves lipid hydroperoxides and cell-adhesion molecule levels. We recently reported that CIL is able to cause neoangiogenesis in vivo by stimulating the production of proangiogenic proteins, such as vascular endothelial growth factor (VEGF), that increase levels of Endothelial progenitor cells (EPCs) and the formation of new blood vessels. The mechanisms of action of this drug are several and are not clear and established. The objective of the present review is to analyze the existing data about the therapeutic effects of CIL, with the purpose of providing practical indications about this topic for the management of subjects affected by ischemic disorders.


Climatic adaptation and species status in the lawn ground cricket : III. Ovipositor length.
The cricket tentatively identified as Pteronemobius taprobanensis shows a stepwise pattern of latitudinal variation in ovipositor length. Abrupt elongation of ovipositor at about 28° N marks the replacement of the subtropical form by the temperate form. The latter maintains almost a constant ovipositor length up to about 35° N within the bivoltine area. Further north in the univoltine area, an ascending cline extends to about 39° N, beyond which no further increase occurs. The ovipositor length adjusted for body size shows a northeastward increase in each of the univoltine and bivoltine areas, though this tendency is less clear in the latter. The optimum length of ovipositor would vary with the relative amounts of gain (due to the protection of eggs in the soil) and loss (due to the metabolic cost and the difficulty to emerge from the soil) in fitness. If so, it may be predicted that a longer ovipositor would be selected for, when the metabolic cost and the risk at hatching are smaller, the environmental pressure in the egg stage is stronger, and the egg stage lasts longer. The last parameter seems to be mainly responsible for the observed association of the type of life cycle with the geographic pattern of variation in ovipositor length.


Parameterizing state-space models for infectious disease dynamics by generalized profiling: measles in Ontario.
Parameter estimation for infectious disease models is important for basic understanding (e.g. to identify major transmission pathways), for forecasting emerging epidemics, and for designing control measures. Differential equation models are often used, but statistical inference for differential equations suffers from numerical challenges and poor agreement between observational data and deterministic models. Accounting for these departures via stochastic model terms requires full specification of the probabilistic dynamics, and computationally demanding estimation methods. Here, we demonstrate the utility of an alternative approach, generalized profiling, which provides robustness to violations of a deterministic model without needing to specify a complete probabilistic model. We introduce novel means for estimating the robustness parameters and for statistical inference in this framework. The methods are applied to a model for pre-vaccination measles incidence in Ontario, and we demonstrate the statistical validity of our inference through extensive simulation. The results confirm that school term versus summer drives seasonality of transmission, but we find no effects of short school breaks and the estimated basic reproductive ratio (0) greatly exceeds previous estimates. The approach applies naturally to any system for which candidate differential equations are available, and avoids many challenges that have limited Monte Carlo inference for state-space models.


Pain REduction with bone metastases STereotactic radiotherapy (PREST): A phase III randomized multicentric trial.
Palliative antalgic treatments represent an issue for clinical management and a challenge for scientific research. Radiotherapy (RT) plays a central role. Techniques such as stereotactic body radiotherapy (SBRT) were largely investigated in several phase 2 studies with good symptom response, becoming widely adopted. However, evidence from randomized, direct comparison of RT and SBRT is still lacking. The PREST trial was designed as an interventional study without medicinal treatment. It is a phase 3, open-label, multicentric trial randomized 1:1. Inclusion criteria include painful spinal bone metastases presenting with a pain level > 4 (or > 1 if being treated with an analgesic) on the Numeric Rating Scale (NRS); expected intermediate/high prognosis (greater than 6 months) according to the Mizumoto prognostic score; low spine instability neoplastic score (SINS) sores (< 7); magnetic resonance imaging (MRI) assessment of the bulky lesion. Patients will be assigned to either standard conventional radiotherapy involving 4 Gy × 5 fractions (fx) to the whole involved vertebra or SBRT by intensity modulated radiotherapy with simultaneous integrated boost (IMRT-SIB) involving 7 Gy × 3 fx to the whole involved vertebra + 10 Gy × 3 fx on the macroscopic lesion (gross tumor volume (GTV)). In the experimental arm, the GTV will be contoured by registration with baseline MRI. The primary endpoint is overall pain reduction, defined in terms of variation between baseline and 3-month evaluation; pain will be measured using the NRS. Secondary endpoints include pain control duration; retreatment rates (after a minimum interval of 1 month); local control assessed with RECIST criteria; symptom progression free survival; progression-free survival; overall survival; and quality of life (at 0, 30, and 90 days). Accrual of 330 lesions is planned. The experimental arm is expected to have an improvement in overall pain response rates of 15% with respect to the standard arm (60% according to Chow et al. (Int J Radiat Oncol Biol Phys. 82(5):1730-7, 2012)). ClinicalTrials.gov, NCT03597984 . Registered on July 2018.


Is necropsy a valid monitor of clinical diagnosis performance?
To improve the validity of comparisons between clinical and postmortem diagnoses when postmortem diagnosis is used to monitor clinical diagnosis performance. Analysis of elementary examples. Sensitivity and specificity of clinical and postmortem diagnoses and confirmation and agreement rates. Sensitivity and specificity permit valid comparisons of clinical and postmortem diagnoses among different procedures, sites, or times whereas agreement and confirmation rates may be misleading. Estimates of sensitivity and specificity, however, can be severely distorted by factors such as non-random selection of cases for necropsy or by unrecognised errors in postmortem diagnosis. Such distortion may be minimised by (a) estimating the likely magnitude of errors in postmortem diagnosis, (b) specifying standard conditions for performing necropsies, and (c) ensuring an unbiased sample of moderate size rather than a large biased sample. Sensitivity and specificity should be used as measures of agreement between clinical and postmortem diagnoses. Monitoring of clinical diagnosis performance by necropsy surveys requires ensuring accuracy of pathological examinations and validity of study design and analysis.


Increased rates of trimethoprim resistance in uncomplicated urinary tract infection: cause for concern?
To assess changes in trimethoprim resistance over 2 years in bacteria causing uncomplicated urinary tract infections (UTIs) presenting to a representative group of general practitioners (GPs) in Christchurch. Seventy-six randomly selected GPs in Christchurch (the Christchurch Sentinel network) participated in the study. Using the same methodology as in the previously reported 2000 collection, midstream urine (MSU) samples were prospectively collected for standard microbiological analysis on all women between the ages of 16 and 50 years presenting with symptoms of dysuria and frequency and who had positive dipstick testing for either nitrites, leucocytes, or both. MSUs were submitted for bacterial colony counts and resistance testing of isolates present in numbers >105 cfu/ml of urine. 216 dipstick positive specimens were collected in the survey period; 105 of these fulfilled criteria for significant bacteriuria. Trimethoprim resistance was found in 16 (15.2%) overall, with a resistance rate for Escherichia coli (E. coli) to trimethoprim of 17.7%. When compared to the proportions of organisms resistant in the 2000 study, there were apparent but non significant increases in the total resistance among pathogens (+6.7%) and E. coli resistance (+5.8%). Rates of antibiotic resistance of all organisms to nitrofurantoin (2.9%) and norfloxacin (0.95%) remain low. There was a statistically significant increase in resistance among all women presenting with symptoms and a positive dipstick test (+5.3%; 95% CI: 1.5%-9.1%). For a woman in this age group presenting with symptoms of urinary tract infection and a positive dipstick test, we estimate that her probability of having a trimethoprim-resistant organism in 2002 was 7.4% compared with 2.7% in 2000. Trimethoprim resistance of E. coli causing uncomplicated UTI appears to be rising in Christchurch. This may reflect the promotion and extensive use of this agent as first-line treatment. Whilst these data indicate that trimethoprim remains a reasonable first-line empiric treatment in this condition, this may change if trimethoprim resistance continues to rise. The apparent increase over a relatively short period (2-3 years) demonstrates the importance of regular surveillance. A third study is required to confirm whether this is a significant trend.


Candida rugosa, an emerging fungal pathogen with resistance to azoles: geographic and temporal trends from the ARTEMIS DISK antifungal surveillance program.
Candida rugosa is a fungus that appears to be emerging as a cause of infection in some geographic regions. We utilized the extensive database of the ARTEMIS DISK Antifungal Surveillance Program to describe the geographic and temporal trends in the isolation of C. rugosa from clinical specimens and the in vitro susceptibilities of 452 isolates to fluconazole and voriconazole. C. rugosa accounted for 0.4% of 134,715 isolates of Candida, and the frequency of isolation increased from 0.03% to 0.4% over the 6.5-year study period (1997 to 2003). C. rugosa was most common in the Latin American region (2.7% versus 0.1 to 0.4%). Decreased susceptibility to fluconazole (40.5% susceptible) was observed in all geographic regions; however, isolates from Europe and North America were much more susceptible (97 to 100%) to voriconazole than those from other geographic regions (55.8 to 58.8%). C. rugosa was most often isolated from blood and urine in patients hospitalized at the Medical and Surgical inpatient services. Notably, bloodstream isolates were the least susceptible to both fluconazole and voriconazole. C. rugosa should be considered, along with the established pathogens Candida krusei and Candida glabrata, as a species of Candida with reduced susceptibility to the azole antifungal agents.


Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA.
In senescent cells, specialized domains of transcriptionally silent senescence-associated heterochromatic foci (SAHF), containing heterochromatin proteins such as HP1, are thought to repress expression of proliferation-promoting genes. We have investigated the composition and mode of assembly of SAHF and its contribution to cell cycle exit. SAHF is enriched in a transcription-silencing histone H2A variant, macroH2A. As cells approach senescence, a known chromatin regulator, HIRA, enters PML nuclear bodies, where it transiently colocalizes with HP1 proteins, prior to incorporation of HP1 proteins into SAHF. A physical complex containing HIRA and another chromatin regulator, ASF1a, is rate limiting for formation of SAHF and onset of senescence, and ASF1a is required for formation of SAHF and efficient senescence-associated cell cycle exit. These data indicate that HIRA and ASF1a drive formation of macroH2A-containing SAHF and senescence-associated cell cycle exit, via a pathway that appears to depend on flux of heterochromatic proteins through PML bodies.


Can computer navigation-assisted surgery reduce the risk of an intralesional margin and reduce the rate of local recurrence in patients with a tumour of the pelvis or sacrum?
We hypothesised that the use of computer navigation-assisted surgery for pelvic and sacral tumours would reduce the risk of an intralesional margin. We reviewed 31 patients (18 men and 13 women) with a mean age of 52.9 years (13.5 to 77.2) in whom computer navigation-assisted surgery had been carried out for a bone tumour of the pelvis or sacrum. There were 23 primary malignant bone tumours, four metastatic tumours and four locally advanced primary tumours of the rectum. The registration error when using computer navigation was < 1 mm in each case. There were no complications related to the navigation, which allowed the preservation of sacral nerve roots (n = 13), resection of otherwise inoperable disease (n = 4) and the avoidance of hindquarter amputation (n = 3). The intralesional resection rate for primary tumours of the pelvis and sacrum was 8.7% (n = 2): clear bone resection margins were achieved in all cases. At a mean follow-up of 13.1 months (3 to 34) three patients (13%) had developed a local recurrence. The mean time alive from diagnosis was 16.8 months (4 to 48). Computer navigation-assisted surgery is safe and has reduced our intralesional resection rate for primary tumours of the pelvis and sacrum. We recommend this technique as being worthy of further consideration for this group of patients.


Self-reported vitamin supplementation in early pregnancy and risk of miscarriage.
Miscarriage is a common and poorly understood adverse pregnancy outcome. In this study, the authors sought to evaluate the relation between self-reported use of prenatal vitamins in early pregnancy and the risk of miscarriage. Between 2000 and 2008, 4,752 US women were prospectively enrolled in Right From the Start. Information about vitamin use was obtained from a first-trimester interview. Discrete-time hazard models were used, candidate confounders were assessed, and the following variables were included in the model: study site, maternal age, gravidity, marital status, education, race/ethnicity, smoking, and use of progesterone in early pregnancy. Approximately 95% of participants reported use of vitamins during early pregnancy. A total of 524 women had a miscarriage. In the final adjusted model, any use of vitamins during pregnancy was associated with decreased odds of miscarriage (odds ratio = 0.43, 95% confidence interval: 0.30, 0.60) in comparison with no exposure. These results should be viewed in the context of a potentially preventive biologic mechanism mitigated by possible confounding by healthy behaviors and practices that are also associated with vitamin supplement use during pregnancy.


Out of Cuba: overwater dispersal and speciation among lizards in the Anolis carolinensis subgroup.
Overwater dispersal and subsequent allopatric speciation contribute importantly to the species diversity of West Indian Anolis lizards and many other island radiations. Here we use molecular phylogenetic analyses to assess the contribution of overwater dispersal to diversification of the Anolis carolinensis subgroup, a clade comprising nine canopy-dwelling species distributed across the northern Caribbean. Although this clade includes some of the most successful dispersers and colonists in the anole radiation, the taxonomic status and origin of many endemic populations have been ambiguous. New mitochondrial and nuclear DNA sequences from four species occurring on small islands or island banks (Anolis brunneus, Anolis longiceps, Anolis maynardi, Anolis smaragdinus) and one species from the continental United States (A. carolinensis) are presented and analysed with homologous sequences sampled from related species on Cuba (Anolis allisoni and Anolis porcatus). Our analyses confirm that all five non-Cuban species included in our study represent distinct, independently evolving lineages that warrant continued species recognition. Moreover, our results support Ernest Williams's hypothesis that all of these species originated by overseas colonization from Cuban source populations. However, contrary to Williams's hypothesis of Pleistocene dispersal, most colonization events leading to speciation apparently occurred earlier, in the late Miocene-Pliocene. These patterns suggest that overwater dispersal among geologically distinct islands and island banks is relatively infrequent in anoles and has contributed to allopatric speciation. Finally, our results suggest that large Greater Antillean islands serve as centres of origin for regional species diversity.


Role for highly regulated rep gene expression in adeno-associated virus vector production.
Recent success achieving long-term in vivo gene transfer without a significant immune response by using adeno-associated virus (AAV) vectors (X. Xiao, J. Li, and R. J. Samulski, J. Virol. 70:8098-8108, 1996) has encouraged further development of this vector for human gene therapy. Currently, studies focus on the generation of high-titer vectors by using the two-plasmid helper-vector system in adenovirus (Ad)-infected cells. To examine the effects of the AAV replication (rep) genes on recombinant AAV (rAAV) vector production, we have constructed a series of AAV helper plasmids that contain strong heterologous promoters in place of the endogenous p5 promoter. Although high-level rep gene expression was achieved, rAAV DNA failed to replicate in the absence of Ad infection. Moreover, unregulated overexpression of Rep78/68 led to substantially lower rAAV yields in the presence of Ad (10(4-5) versus 10(7-8)). In contrast, under similar conditions, reduced Rep78/68 expression resulted in much higher rAAV yields (10(9)). Molecular characterization showed that overexpression of the rep gene decreased rAAV DNA replication and severely inhibited capsid (cap) gene expression. Interestingly, a reduced rep level enhanced cap gene expression and supported normal rAAV DNA replication. These studies suggest a critical role for regulated rep gene expression in rAAV production and have facilitated the development of a new AAV helper plasmid that increases vector production eightfold over currently used constructs.


Prenatal exposure to the contaminant perfluorooctane sulfonate elevates lipid peroxidation during mouse fetal development but not in the pregnant dam.
Perfluorooctane sulfonate (PFOS), a member of the perfluorinated chemical family, has been convincingly demonstrated to affect lipid metabolism in animals and humans and readily crosses the placenta to exert its effects on the developing fetuses. While its exact mechanism is still not clear, PFOS exposure has long been suggested to exert its toxicity via oxidative stress and/or altered gene expression. Levels of PFOS and malondialdehyde in various organs and cell cultures have been widely determined as general indicators of non-specific lipid peroxidation after PFOS exposure. In this study, the oxidation of precise polyunsaturated fatty acids and their metabolites, derived from enzymatic and non-enzymatic pathways was determined following PFOS exposure in both adult and maternal/fetal mice. CD-1 mice were exposed to 3 mg/kg body weight/day of PFOS in corn oil by oral gavage until late gestation (GD17). We demonstrated that lipid peroxidation was particularly and exclusively affected in fetuses exposed to PFOS, but this was not the case in the maternal mice, where limited effects were observed in the enzymatic oxidation pathway. In this study, we demonstrated that PFOS-induced lipid peroxidation might have a greater impact in free radical generation in fetuses than in dams and could be responsible for affecting fetal development. In addition, antioxidant enzymes, such as superoxide dismutase and catalase, appeared to maintain oxidative stress homeostasis partially in adult mice exposed to PFOS. Taken together, our results might elucidate the mechanism of how PFOS induces oxidative stress in vivo.


Deep brain stimulation of the medial forebrain bundle elevates striatal dopamine concentration without affecting spontaneous or reward-induced phasic release.
Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) induces rapid improvement of depressive symptoms in patients suffering from treatment-refractory major depressive disorder (MDD). It has been hypothesized that activation of the dopamine (DA) system contributes to this effect. To investigate whether DBS in the MFB affects DA release in the striatum, we combined DBS with fast-scan cyclic voltammetry (FSCV) in freely moving rats. Animals were implanted with a stimulating electrode at the border of the MFB and the ventral tegmental area, and a FSCV microelectrode in the ventromedial striatum to monitor extracellular DA during the acute onset of DBS and subsequent continued stimulation. DBS onset induced a significant increase in extracellular DA concentration in the ventromedial striatum that was sustained for at least 40s. However, continued DBS did not affect amplitude or frequency of so-called spontaneous phasic DA transients, nor phasic DA release in response to the delivery of unexpected food pellets. These findings suggest that effects of DBS in the MFB are mediated by an acute change in extracellular DA concentration, but more research is needed to further explore the potentially sustained duration of this effect. Together, our results provide both support and refinement of the hypothesis that MFB DBS activates the DA system: DBS induces an increase in overall ambient concentration of DA, but spontaneous or reward-associated more rapid, phasic DA dynamics are not enhanced. This knowledge improves our understanding of how DBS affects brain function and may help improve future therapies for depressive symptoms.


Strong hydrogen bond between glutamic acid 46 and chromophore leads to the intermediate spectral form and excited state proton transfer in the Y42F mutant of the photoreceptor photoactive yellow protein.
In the Y42F mutant of photoactive yellow protein (PYP) the photoreceptor is in an equilibrium between two dark states, the yellow and intermediate spectral forms, absorbing at 457 and 390 nm, respectively. The nature of this equilibrium and the light-induced protonation and structural changes in the two spectral forms were characterized by transient absorption, fluorescence, FTIR, and pH indicator dye experiments. In the yellow form, the oxygen of the deprotonated p-hydroxycinnamoyl chromophore is linked by a strong low-barrier hydrogen bond to the protonated carboxyl group of Glu46 and by a weaker one to Thr50. Using FTIR, we find that the band due to the carbonyl of the protonated side chain of Glu46 is shifted from 1736 cm(-1) in wild type to 1724 cm(-1) in the yellow form of Y42F, implying a stronger hydrogen bond with the deprotonated chromophore in Y42F. The FTIR data suggest moreover that in the intermediate spectral form the chromophore is protonated and Glu46 deprotonated. Flash spectroscopy (50 ns-10 s) shows that the photocycles of the two forms are essentially the same except for a transition around 5 mus that has opposite signs in the two forms and is due to the chemical relaxation between the two dark states. The two cycles are coupled, likely by excited state proton transfer. The Y42F cycle differs from wild type by the occurrence of a new intermediate with protonated chromophore between the usual I(1) and I(2) intermediates which we call I(1)H (370 nm). Transient fluorescence measurements indicate that in I(1)H the chromophore retains the orientation it had in I(1). Transient proton uptake occurs with a time constant of 230 mus and a stoichiometry of 1. No proton uptake was associated however with the formation of the I(1)H intermediate and the relaxation of the yellow/intermediate equilibrium. These protonation changes of the chromophore thus occur intramolecularly. The chromophore-Glu46 hydrogen bond in Y42F is shorter than in wild type, since the adjacent chromophore-Y42 hydrogen bond is replaced by a longer one with Thr50. This facilitates proton transfer from Glu46 to the chromophore in the dark by lowering the barrier, leading to the protonation equilibrium and causing the rapid light-induced proton transfer which couples the cycles.


The potential for deprescribing in a palliative oncology patient population: a cross-sectional study.
The use of preventive medication in palliative oncology patients may be inappropriate due to limited life expectancy. Deprescribing tools are available but time-consuming and not always tailored to this specific population. Our primary goal was to identify potentially inappropriate medications (PIMs) in palliative oncology patients with a life expectancy of up to 2 years using an adapted deprescribing tool. Our secondary aim was to identify patient characteristics associated with the presence of PIMs. Oncology patients with a life expectancy of up to 2 years were included cross-sectionally. An adapted deprescribing tool was developed to identify PIMs. Logistic regression was used to identify factors associated with having PIMs. A total of 218 patients were included in this study of which 56% had at least one PIM with a population mean of 1.1 PIM per patient. Most frequently defined PIMs were antihypertensive drugs and gastric acid inhibitors. Identification of PIMs by review took an estimated 5-10 min per patient. Polypharmacy, age >65 years and inpatient/outpatient status were found to be associated with having at least one PIM. Deprescribing is possible in more than half of palliative oncology patients with a life expectancy of up to 2 years. The adapted deprescribing tool used is non-time consuming and suitable for palliative oncology patients, regardless of age.


Fast and precise Laguerre-Gaussian beam steering with acousto-optic deflectors.
Novel fluorescence microscopy techniques and two-color laser direct imaging photolithography methods that enable resolution an order of magnitude beyond the diffraction limit require Laguerre-Gaussian beams and a fast and precise laser beam steering device to obtain images and produce microstructures. An acousto-optic deflector (AOD) is a suitable choice and provides high-speed random access beam positioning with subnanometer precision as well as beam intensity control in a single element. In high-resolution applications, the impact of an AOD on beam quality plays a major role. We study the transfer function of an AOD for a fundamental Gaussian and a doughnut-shaped Laguerre-Gaussian beam by measuring the beam quality as a function of the diffraction angle after passing through the device. It is demonstrated that an AOD introduces negligible distortion and degradation to the beam profile and is therefore highly suitable for use in super-resolution imaging and photolithography techniques where manipulation of Laguerre-Gaussian doughnut-shaped beams is required.


Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants.
Establishing the age of each mutation segregating in contemporary human populations is important to fully understand our evolutionary history and will help to facilitate the development of new approaches for disease-gene discovery. Large-scale surveys of human genetic variation have reported signatures of recent explosive population growth, notable for an excess of rare genetic variants, suggesting that many mutations arose recently. To more quantitatively assess the distribution of mutation ages, we resequenced 15,336 genes in 6,515 individuals of European American and African American ancestry and inferred the age of 1,146,401 autosomal single nucleotide variants (SNVs). We estimate that approximately 73% of all protein-coding SNVs and approximately 86% of SNVs predicted to be deleterious arose in the past 5,000-10,000 years. The average age of deleterious SNVs varied significantly across molecular pathways, and disease genes contained a significantly higher proportion of recently arisen deleterious SNVs than other genes. Furthermore, European Americans had an excess of deleterious variants in essential and Mendelian disease genes compared to African Americans, consistent with weaker purifying selection due to the Out-of-Africa dispersal. Our results better delimit the historical details of human protein-coding variation, show the profound effect of recent human history on the burden of deleterious SNVs segregating in contemporary populations, and provide important practical information that can be used to prioritize variants in disease-gene discovery.


Development and validation of oral health-related early childhood quality of life tool for North Indian preschool children.
The purpose of this study was to develop a reliable instrument [Oral Health related Early Childhood Quality of Life (OH- ECQOL) scale] for measuring oral health related quality of life (OHrQoL) in preschool children in North Indian population. Four pediatric dentists evaluated a pool of 65 items from various QoL questionnaires to assess their relevance to Indian population. These items were discussed with eight independent pediatric dentists and two community dentists who were not a part of this study to assess relevance of these items to preschool age children based on their comprehensiveness and clarity. Based on their responses and feedback a modified pool of items was developed and administered to a convenience sample of 20 parents who rated these items according to their relevance. The test retest reliability was evaluated on another sample of 20 parents of 2-5 year old children. The final questionnaire comprised of 16 items (12 child and 4 family). This was administered to 300 parents of 24-71 months old children divided on the basis of early childhood caries to assess its reliability and validity. OH-ECQOL scores were significantly associated with parental ratings of their child's general and oral health, and the presence of dental disease in the child. Cronbach's alpha was 0.862, and the ICC for test-retest reliability was 0.94. The OH-ECQOL proved reliable and valid tool for assessing the impact of oral disorders on the quality of life of preschool children in Northern India.


Data visualization literacy: Definitions, conceptual frameworks, exercises, and assessments.
In the information age, the ability to read and construct data visualizations becomes as important as the ability to read and write text. However, while standard definitions and theoretical frameworks to teach and assess textual, mathematical, and visual literacy exist, current data visualization literacy (DVL) definitions and frameworks are not comprehensive enough to guide the design of DVL teaching and assessment. This paper introduces a data visualization literacy framework (DVL-FW) that was specifically developed to define, teach, and assess DVL. The holistic DVL-FW promotes both the reading and construction of data visualizations, a pairing analogous to that of both reading and writing in textual literacy and understanding and applying in mathematical literacy. Specifically, the DVL-FW defines a hierarchical typology of core concepts and details the process steps that are required to extract insights from data. Advancing the state of the art, the DVL-FW interlinks theoretical and procedural knowledge and showcases how both can be combined to design curricula and assessment measures for DVL. Earlier versions of the DVL-FW have been used to teach DVL to more than 8,500 residential and online students, and results from this effort have helped revise and validate the DVL-FW presented here.


Rhabdomyolysis.
Rhabdomyolysis is a syndrome involving the breakdown of skeletal muscle causing myoglobin and other intracellular proteins and electrolytes to leak into the circulation. The development of rhabdomyolysis is associated with a wide variety of diseases, injuries, medications and toxins. While the exact mechanisms responsible for all the causes are not fully understood, it is clear that muscle damage can occur from direct injury or by metabolic inequalities between energy consumption and energy production. Rhabdomyolysis is diagnosed by elevations in serum creatine phosphokinase (CPK), and while there is no established serum level cut-off, many clinicians use five times the upper limit of normal ( approximately 1000 U/l). Rhabdomyolysis can be complicated by acute renal failure (occurring in 4%-33% of patients), compartment syndrome, cardiac dysrhythmias via electrolyte abnormalities, and disseminated intravascular coagulopathy. The mainstay of treatment is hospitalisation with aggressive intravenous fluid (IVF) resuscitation with the correction/prevention of electrolyte abnormalities. There are additional adjunctive therapies to IVF, such as alkalinisation of the urine with sodium bicarbonate, diuretic therapy or combinations of both; however the lack of large randomised control studies concerning the benefits of these treatments makes it difficult to make strong recommendations for or against their use in the treatment of rhabdomyolysis. Regardless of these controversies, the overall prognosis for rhabdomyolysis is favourable when treated with early and aggressive IVF resuscitation, and full recovery of renal function is common. Irrespective of the cause of rhabdomyolysis the mortality rate may still be as high as 8%. This is a comprehensive review of the pathophysiology, diagnosis, complications and treatment options for rhabdomyolysis.


Active video games and energy balance in male adolescents: a randomized crossover trial.
Active video games (AVGs) have been shown to acutely increase energy expenditure when compared with seated video games; however, the influence of AVGs on compensatory adjustments in energy intake and expenditure is largely unknown. The aim was to examine the acute effects of AVGs on energy intake and expenditure. With the use of a randomized crossover design, 26 male adolescents (mean ± SD age: 14.5 ± 1.4 y) completed three 1-h experimental conditions: resting control, seated video game play (Xbox 360; Microsoft), and AVG play (Kinect Adventures on Xbox 360) followed by an ad libitum lunch. A validated food menu was used to assess food intake immediately after the conditions and for the remainder of the day, and a dietary record was used for the subsequent 3-d period. Energy expenditure was measured by using portable indirect calorimetry throughout each experimental condition, and an accelerometer was used to assess the subsequent 3-d period. Appetite sensations were assessed by using visual analog scales at different time points during the testing day. The primary outcomes were acute (immediately after the conditions and 24-h) and short-term (3-d) energy intake and expenditure. Energy expenditure was significantly higher (~145%; P < 0.001) during the AVG condition than during the resting control and seated video game conditions; however, no significant differences in energy expenditure were observed 24 h (~6%; P > 0.49) and 3 d after the experimental conditions (~3%; P > 0.82). No significant differences were observed in absolute energy intake immediately after the conditions (~2%; P > 0.94) or in absolute energy intake 24 h (~5%; P > 0.63) and 3 d (~9%; P > 0.53) after the experimental conditions. Finally, appetite sensations were similar between conditions at all time points (P > 0.05). The increase in energy expenditure promoted by a single session of Kinect AVG play is not associated with increased food intake but is compensated for after the intervention, resulting in no measurable change in energy balance after 24 h. These results suggest that the potential of Kinect to reduce the energy gap underlying weight gain is offset within 24 h in male adolescents. This trial was registered at clinicaltrials.gov as NCT01655901.


Individuals susceptible to lung adenocarcinoma defined by combined HLA-DQA1 and TERT genotypes.
Adenocarcinoma (ADC) is the commonest histological type of lung cancer, and its weak association with smoking indicates the necessity to identify high-risk individuals for targeted screening and/or prevention. By a genome-wide association study (GWAS), we identified an association of polymorphisms in the 6p21.31 locus containing four human leukocyte antigen (HLA) class II genes with lung ADC risk. DQA1*03 of the HLA-DQA1 gene was defined as a risk allele with odds ratio (OR) of 1.36 [95% confidence interval (CI) = 1.21-1.54, P = 5.3 x 10(-7)] by analysis of 1656 ADC cases and 1173 controls. DQA1*03 and the minor allele for a polymorphism, rs2736100, in TERT, another lung cancer susceptibility locus identified in recent GWASs on Europeans and Americans, were indicated to independently contribute to ADC risk with per allele OR of 1.43 (95% CI = 1.31-1.56, P = 7.8 x 10(-16)). Individuals homozygous both for the DQA1*03 and minor TERT alleles were defined as high-risk individuals with an OR of 4.76 (95% CI = 2.53-9.47, P = 4.2 x 10(-7)). The present results indicated that individuals susceptible to lung ADC can be defined by combined genotypes of HLA-DQA1 and TERT.


Sales impact of displaying alcoholic and non-alcoholic beverages in end-of-aisle locations: an observational study.
In-store product placement is perceived to be a factor underpinning impulsive food purchasing but empirical evidence is limited. In this study we present the first in-depth estimate of the effect of end-of-aisle display on sales, focussing on alcohol. Data on store layout and product-level sales during 2010-11 were obtained for one UK grocery store, comprising detailed information on shelf space, price, price promotion and weekly sales volume in three alcohol categories (beer, wine, spirits) and three non-alcohol categories (carbonated drinks, coffee, tea). Multiple regression techniques were used to estimate the effect of end-of-aisle display on sales, controlling for price, price promotion, and the number of display locations for each product. End-of-aisle display increased sales volumes in all three alcohol categories: by 23.2% (p = 0.005) for beer, 33.6% (p < 0.001) for wine, and 46.1% (p < 0.001) for spirits, and for three non-alcohol beverage categories: by 51.7% (p < 0.001) for carbonated drinks, 73.5% (p < 0.001) for coffee, and 113.8% (p < 0.001) for tea. The effect size was equivalent to a decrease in price of between 4% and 9% per volume for alcohol categories, and a decrease in price of between 22% and 62% per volume for non-alcohol categories. End-of-aisle displays appear to have a large impact on sales of alcohol and non-alcoholic beverages. Restricting the use of aisle ends for alcohol and other less healthy products might be a promising option to encourage healthier in-store purchases, without affecting availability or cost of products.


Large-scale exploration of gene-gene interactions in prostate cancer using a multistage genome-wide association study.
Recent genome-wide association studies have identified independent susceptibility loci for prostate cancer that could influence risk through interaction with other, possibly undetected, susceptibility loci. We explored evidence of interaction between pairs of 13 known susceptibility loci and single nucleotide polymorphisms (SNP) across the genome to generate hypotheses about the functionality of prostate cancer susceptibility regions. We used data from Cancer Genetic Markers of Susceptibility: Stage I included 523,841 SNPs in 1,175 cases and 1,100 controls; Stage II included 27,383 SNPs in an additional 3,941 cases and 3,964 controls. Power calculations assessed the magnitude of interactions our study is likely to detect. Logistic regression was used with alternative methods that exploit constraints of gene-gene independence between unlinked loci to increase power. Our empirical evaluation demonstrated that an empirical Bayes (EB) technique is powerful and robust to possible violation of the independence assumption. Our EB analysis identified several noteworthy interacting SNP pairs, although none reached genome-wide significance. We highlight a Stage II interaction between the major prostate cancer susceptibility locus in the subregion of 8q24 that contains POU5F1B and an intronic SNP in the transcription factor EPAS1, which has potentially important functional implications for 8q24. Another noteworthy result involves interaction of a known prostate cancer susceptibility marker near the prostate protease genes KLK2 and KLK3 with an intronic SNP in PRXX2. Overall, the interactions we have identified merit follow-up study, particularly the EPAS1 interaction, which has implications not only in prostate cancer but also in other epithelial cancers that are associated with the 8q24 locus.


HIV/AIDS-related stigma in South African alcohol-serving venues and its potential impact on HIV disclosure, testing and treatment-seeking behaviours.
Alcohol-serving venues in South Africa are sites for high-risk behaviours that may lead to HIV transmission. Prevention and treatment interventions are sorely needed in these settings, but HIV-related stigma may limit their effectiveness. This study explored expressions of stigma among alcohol-serving venue patrons in Cape Town and examined the potential impact of stigma on HIV disclosure, testing and treatment-seeking behaviours. A total of 92 in-depth interviews with male and female, black and coloured patrons were conducted. Transcripts were analysed via memo-writing and diagramming techniques. Many participants mentioned knowing other patrons living with HIV/AIDS (PLWH), and this visibility of HIV impacted expressions of HIV-related stigma. Participants discussed four forms of HIV-related stigma in the venues: fearing PLWH, fearing HIV acquisition, blaming others for spreading HIV and isolating PLWH. HIV visibility and expressions of HIV-related stigma, particularly fear of isolation, influenced participants' willingness to disclose their status. HIV-related stigma in the venues also appeared to indirectly influence testing and treatment-seeking behaviour outside the venue. Results suggest that efforts to change norms and reduce expressions of HIV-related stigma in alcohol-serving venues are necessary to successfully deliver tailored HIV prevention interventions and increase uptake of HIV testing and care in this important social setting.


Leukocyte telomere length and late-life depression.
Depressive disorders have been associated with increased risk for aging-related diseases, possibly as a consequence of accelerated cellular aging. Cellular aging, indexed by telomere length (TL) shortening, has been linked to depression in adults younger than 60 years; however, it remains unclear whether this is the case in late-life depression (age >60 years). The objective of this study was to assess differences in TL between persons with current late-life depression and never-depressed comparisons and to examine the association between characteristics of late-life depression and TL. In this cross-sectional study using the Netherlands Study of Depression in Older Persons, 355 persons with current late-life depression and 128 never-depressed comparisons, aged 60-93 years (mean age [SD]: 70.5 [7.4] years, 65% women), were recruited through primary care and mental healthcare. Late-life depression was established using a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-based structured psychiatric interview. Leukocyte TL, expressed in base pairs (bp), was determined in fasting blood samples by performing quantitative polymerase chain reaction. Mean TL did not differ between depressed persons (bp [SD]: 5,035 [431]) and never-depressed (bp [SD]: 5,057 [729]) comparisons. Further, TL was not associated with severity, duration, and age at onset of depression; comorbid anxiety disorders; anxiety symptoms; apathy severity; antidepressant use; benzodiazepine use; cognitive functioning; and childhood trauma. Late-life depression was not associated with increased cellular aging. This absent association, which contradicts observations in younger adults, may be due to the potential larger heterogenic nature of late-life depression and lifetime cumulative exposure to other TL-damaging factors, possibly overruling effects of late-life depression.


Radical prostatectomy findings in patients in whom active surveillance of prostate cancer fails.
Little data are available on radical prostatectomy findings in men who experience disease progression following active surveillance. A total of 470 men in our active surveillance program underwent annual repeat needle biopsies to look for progression defined as any Gleason pattern grade 4/5, more than 50% cancer on any core or cancer in more than 2 cores. Slides were available for review in 48 of 51 radical prostatectomies with progression. The average time between the first prostate biopsy and radical prostatectomy was 29.5 months (range 13 to 70), with 44% and 75% of the patients showing progression by the second and third biopsy, respectively. There were 31 (65%) organ confined cases, of which 25 (52%) were Gleason score 6. Of 48 cases 17 (35%) had extraprostatic extension, 3 had seminal vesicle/lymph node involvement and 7 (15%) had positive margins. Mean total tumor volume was 1.3 cm(3) (range 0.02 to 10.8). Of the 48 tumors 13 (27%) were potentially clinically insignificant (organ confined, dominant nodule less than 0.5 cm(3), no Gleason pattern 4/5) and 19% (5 of 26) of the radical prostatectomies with a dominant tumor nodule less than 0.5 cm(3) demonstrated extraprostatic extension, 4 with Gleason pattern 4. All 10 tumors with a dominant nodule greater than 1 cm(3) were located predominantly anteriorly. Most progression after active surveillance occurs 1 to 2 years after diagnosis suggesting undersampling of more aggressive tumor rather than progression of indolent tumor. Even with progression most tumors have favorable pathology (27% potentially insignificant). A small percentage of men have advanced stage disease (pT3b or N1). The anterior region should be sampled in men on active surveillance.


An integrative architecture for general intelligence and executive function revealed by lesion mapping.
Although cognitive neuroscience has made remarkable progress in understanding the involvement of the prefrontal cortex in executive control, the broader functional networks that support high-level cognition and give rise to general intelligence remain to be well characterized. Here, we investigated the neural substrates of the general factor of intelligence (g) and executive function in 182 patients with focal brain damage using voxel-based lesion-symptom mapping. The Wechsler Adult Intelligence Scale and Delis-Kaplan Executive Function System were used to derive measures of g and executive function, respectively. Impaired performance on these measures was associated with damage to a distributed network of left lateralized brain areas, including regions of frontal and parietal cortex and white matter association tracts, which bind these areas into a coordinated system. The observed findings support an integrative framework for understanding the architecture of general intelligence and executive function, supporting their reliance upon a shared fronto-parietal network for the integration and control of cognitive representations and making specific recommendations for the application of the Wechsler Adult Intelligence Scale and Delis-Kaplan Executive Function System to the study of high-level cognition in health and disease.


Antipsychotic medication use in nursing homes: a proposed measure of quality.
The potential misuse of antipsychotic medications (APMs) is an ongoing quality concern in nursing homes (NHs), especially given recent black box warnings and other evidence regarding the risk of APMs when used in NH populations. One mechanism regulators could use is public reporting of APM use by NHs; however, there is currently no agreed-upon measure of guideline-inconsistent APM use. In this paper, we describe a proposed measure of quality of APM use that is based on Centers for Medicare and Medicaid Services (CMS) Interpretive Guidelines, Food and Drug Administration (FDA) indications for APMs, and severity of behavioral symptoms. The proposed measure identifies NH residents who receive an APM but do not have an approved indication for APM use. We demonstrate the feasibility of this measure using data from Medicaid-eligible long-stay residents aged 65 years and older in seven states. Using multivariable logistic regressions, we compare it to the current CMS Nursing Home Compare quality measure. We find that nearly 52% of residents receiving an APM lack indications approved by CMS/FDA guidelines compared with 85% for the current CMS quality measure. APM guideline-inconsistent use rates vary significantly across resident and facility characteristics, and states. Only our measure correlates with another quality indicator in that facilities with higher deficiencies have significantly higher odds of APM use. Predictors of inappropriate use are found to be consistent with other measures of NH quality, supporting the validity of our proposed measure. The proposed measure provides an important foundation to improve APM prescribing practices without penalizing NHs when there are limited alternative treatments available.


X-Y translocations and sex differentiation.
Translocations involving the X and Y chromosomes are often associated with anomalies of gonadal development. Transfer of Yp sequences, including the testis-determining SRY gene, to the terminal portion of the short arm of the X chromosome is associated with 46,XX maleness and in rare cases 46,XX true hermaphroditism. Three classes of XX males have been defined on the basis of the extent of Y material transferred to the X chromosome. In one class, the transfer of material involves aberrant recombination between two highly homologous genes, PKRX and PKRY, and there is evidence to suggest that this interchange is influenced by the Y chromosome background. Other types of X-Y translocations associated with anomalies of sex differentiation include Xp-Yq translocations, which result in a functional disomy of Xp sequences including the DSS locus and are associated with 46,XY complete or partial gonadal dysgenesis. In rare cases Yp-Xq translocations have been described in association with 46,XX maleness.


Panel 1: Epidemiology and Diagnosis.
Objective To create a literature review between 2011 and June 1, 2015, on advances in otitis media (OM) epidemiology and diagnosis (including relevant audiology studies). Data Sources Electronic search engines (PubMed, EMBASE, and Cochrane Library) with a predefined search strategy. Review Methods Articles with appropriate epidemiologic methodology for OM, including acute mastoiditis and eustachian tube dysfunction. Items included OM worldwide and in high-risk populations, OM-related hearing loss, news in OM diagnostics, prenatal risk factors and comorbidities, postnatal risk factors, genetics, microbiological epidemiology, guidelines, and quality of life. Conclusions Diagnostic evidence and genetic studies are increasing; guidelines are introduced worldwide; and there is evidence of benefit of pneumococcal conjugate vaccines. New risk factors and comordities are identified in the study period, and quality of life is affected in children and their families. Implications for Practice Chronic suppurative OM occurs worldwide and contributes to lifelong hearing loss. Uniform definitions are still lacking and should be provided. An association between HIV and chronic suppurative OM has been found. Tympanometry is recommended for diagnosis, with or without pneumatic otoscopy. Video otoscopy, algorithms, and validated questionnaires may assist clinicians. Childhood obesity is associated with OM. Heritability accounts for 20% to 50% of OM diagnoses. OM-prone children seem to produce weaker immunologic responses to pneumococcal conjugate vaccines. Clinicians tend to individualize treatment without adhering to guidelines.


Novel Monte Carlo approach quantifies data assemblage utility and reveals power of integrating molecular and clinical information for cancer prognosis.
Current clinical practice in cancer stratifies patients based on tumour histology to determine prognosis. Molecular profiling has been hailed as the path towards personalised care, but molecular data are still typically analysed independently of known clinical information. Conventional clinical and histopathological data, if used, are added only to improve a molecular prediction, placing a high burden upon molecular data to be informative in isolation. Here, we develop a novel Monte Carlo analysis to evaluate the usefulness of data assemblages. We applied our analysis to varying assemblages of clinical data and molecular data in an ovarian cancer dataset, evaluating their ability to discriminate one-year progression-free survival (PFS) and three-year overall survival (OS). We found that Cox proportional hazard regression models based on both data types together provided greater discriminative ability than either alone. In particular, we show that proteomics data assemblages that alone were uninformative (p = 0.245 for PFS, p = 0.526 for OS) became informative when combined with clinical information (p = 0.022 for PFS, p = 0.048 for OS). Thus, concurrent analysis of clinical and molecular data enables exploitation of prognosis-relevant information that may not be accessible from independent analysis of these data types.


Climate change-related migration and infectious disease.
Anthropogenic climate change will have significant impacts on both human migration and population health, including infectious disease. It will amplify and alter migration pathways, and will contribute to the changing ecology and transmission dynamics of infectious disease. However there has been limited consideration of the intersections between migration and health in the context of a changing climate. This article argues that climate-change related migration - in conjunction with other drivers of migration - will contribute to changing profiles of infectious disease. It considers infectious disease risks for different climate-related migration pathways, including: forced displacement, slow-onset migration particularly to urban-poor areas, planned resettlement, and labor migration associated with climate change adaptation initiatives. Migration can reduce vulnerability to climate change, but it is critical to better understand and respond to health impacts - including infectious diseases - for migrant populations and host communities.


Atypical presentation of disseminated intravascular coagulation with synchronous peripheral venous thromboembolism and arterial gangrene in a pancreatic cancer patient: a case report.
Cancer is a prothrombotic state and anticancer therapies are often complicated by vascular events. The risk of developing thromboembolic events is substantially increased in patients with pancreatic cancer. One possible presentation of vascular events in pancreatic cancer is disseminated intravascular coagulation (DIC). In our case a patient with a diagnosis of pancreatic cancer initially presented with thrombosis and received low molecular weight heparin (LMWH) in addition to standard chemotherapy regimen. He was thought to have DIC by assessment of clinical and laboratory findings. Clinically, thrombosis was first located in the left femoral vein and encountered at right femoral artery after three weeks. This pattern was an unusual presentation of DIC. Subclinical DIC is common in patients presenting with pancreatic cancer and is considered a 'poor' prognostic factor. Acute DIC, on the other hand is a potentially mortal condition.


Genomic and phenotypic analyses of multidrug-resistant Acinetobacter baumannii NCCP 16007 isolated from a patient with a urinary tract infection.
Polymyxin B (PMB) is increasingly used as a last-line antibiotic; however, the emergence of PMB resistance is a serious threat to global health. Here, a total of 40 Acinetobacter baumannii clinical isolates were collected to screen for PMB-resistant strains. Several clinical isolates including NCCP 16007 were far more resistant to PMB (MIC: 128-256 μg/ml) than the ATCC 17978 strain (MIC: 2 μg/ml) and appeared to possess resistance to broad-spectrum antibiotics including meropenem and 12 others. Four highly PMB-resistant strains possessed point mutations in the histidine kinase PmrB, leading to an increased expression of pmrC encoding a phosphoethanolamine transferase. Whole-genome analyses revealed that the NCCP 16007 stain had acquired two additional copies of the pmrC gene with phage integrase and 13 antibiotic resistance genes (ARGs) from other pathogens, including Klebsiella pneumoniae and Pseudomonas aeruginosa. The GC ratios of the ARGs (50-60%) were higher than that of the chromosomal backbone (39.06%), further supporting the horizontal gene transfer of ARGs. Comparative genomics with other multidrug-resistant A. baumannii strains revealed that the NCCP 16007 strain has many additional ARGs and has lost several virulence factors including Csu pili and heme oxygenase but exhibited high pathogenicity in Galleria mellonella-infection models. The observation of condensed biofilm through confocal and scanning electron microscopy suggested that the NCCP 16007 strain may possess high adhesion capacity during urinary tract infection. Therefore, our genomic and phenotypic analyses suggested that the multidrug-resistant A. baumannii NCCP 16007 strain possesses high genome plasticity, natural transformation ability, and pathogenicity.


Early Adolescent Alcohol Use: Are Sipping and Drinking Distinct?
Sipping alcohol is common during early adolescence, but research has ignored the distinction between sipping and drinking whole alcohol beverages, conflating the 2, or else simply classifying "sippers" as abstainers. Research has not addressed whether sippers are different to drinkers, in relation to variables known to be associated with adolescent alcohol consumption, or considered whether sipping and drinking behaviors may have quite different associations. Parent-child dyads (N = 1,823) were recruited in 3 states from Australian grade 7 classes. Multinomial logistic analyses compared adolescents who had only had a sip/taste of alcohol (sippers) with adolescents who had consumed at least a whole drink (drinkers) in the past 6 months. The multivariate model assessed a broad range of demographics, parenting practices, peer influences, and adolescent externalizing and internalizing behaviors, and controlled for school clustering. Compared to drinkers, sippers were less likely to come from 1-parent households (odds ratio [OR] = 0.59, 95% confidence interval [CI]: 0.35 to 0.98); less likely to come from low-socioeconomic status (SES) households (OR = 0.54, 95% CI: 0.31 to 0.94); more likely to come from families where parents provide stricter alcohol-specific rules (OR = 1.21, 95% CI: 1.11 to 1.32), stricter monitoring of the child's activities (OR = 1.10, 95% CI: 1.04 to 1.16), more consistent parenting practices (OR = 1.13, 95% CI: 1.05 to 1.23), and more positive family relationships (OR = 1.56, 95% CI: 1.02 to 2.43); and report having fewer substance-using peers (OR = 0.80, 95% CI: 0.70 to 0.91) and greater peer disapproval of any substance use (OR = 1.30, 95% CI: 1.19 to 1.42). After adjustment for confounders, the associations with household composition and SES were no longer significant, but the familial and peer associations remained significant in the multivariate analysis, χ(2) (40) = 1,493.06, p < 0.001. Sipping alcohol has different associations with known predictors of adolescent alcohol use than drinking whole beverages, and sipping may be a distinct or separable behavior. Future research should better define quantities of early consumption and assess the relationship between early sipping and drinking on long-term outcomes separately.


Current status and perspectives regarding the treatment of osteo-sarcoma: chemotherapy.
Osteosarcoma is the most common primary bone tumor in childhood and adolescence. The use of combination chemotherapy and surgery enables long-term survival in approximately 60-70% of cases. However, the necessity for surgery, the poor prognosis of patients with metastatic or recurrent disease (long-term survival in only about 20% of cases), and the lack of establishment of second-line chemotherapy suggest that improvements in chemotherapy are desperately needed. Currently, in an effort to extend the protocol with the chemotherapy drugs that already exist, high-dose chemotherapy with/without autologous peripheral blood stem cell transplantation, and tumor-targeted drug delivery systems are under investigation. Future drug developments will no doubt lie in the direction of immunotherapy and anti-angiogenic therapy, as well as the use of cytotoxic drugs. Identifying the genes and signal transduction pathways responsible for the development of osteosarcoma or for the occurrence of malignancy in cases of osteosarcoma will undoubtedly lead to the identification of pathway-specific agents, or possible gene therapy. Furthermore, as increased light is shed on the character of osetoblastic differentiation in osteosarcoma, this will certainly give rise to new treatments utilizing differentiation therapy. This article reviews the current status and perspectives regarding the treatment of osteosarcoma in terms of chemotherapy.


The ethics of HIV "cure" research: what can we learn from consent forms?
The advent of HIV "cure" research has generated enormous attention, but also concern about its potential to engender false hope, leading to overestimation of benefits and underestimation of risks, and about recruiting relatively healthy participants to studies with uncertain or serious risks. Currently, little is known about potential ethical problems in the ways that informed consent for HIV cure research is described to potential participants. As a first step to address this question, early phase, HIV "cure" research consent forms were analyzed to assess how study aims and potential risks and benefits are presented. Thirteen consent forms from a diverse group of clinical studies were selected to represent the major categories of cure research, including 11 interventional (gene transfer, vaccine intensification, treatment interruption, and latency reversing) and two observational. Consent forms were coded using seven categories, abstracting data on study purpose and design, participant selection criteria, presentation of risks and benefits of participation, and potential return of research results. Findings demonstrate variation and deficiencies that merit attention, but that can largely be addressed by turning to existing guidance about early phase research and specific study designs from other research contexts. The most challenging of these is ensuring that clear, specific, and consistent language is used to describe study aims, risks, benefits, and possible return of results. Informed consent for HIV "cure" research represents an opportunity to apply relevant existing guidance, measure the effectiveness of its application, and develop standardized best-practice policies for consent forms and processes.


Activation patterns in superficial layers of neocortex change between experiences independent of behavior, environment, or the hippocampus.
Previous work suggests that activation patterns of neurons in superficial layers of the neocortex are more sensitive to spatial context than activation patterns in deep cortical layers. A possible source of this laminar difference is the distribution of contextual information to the superficial cortical layers carried by hippocampal efferents that travel through the entorhinal cortex and subiculum. To evaluate the role that the hippocampus plays in determining context sensitivity in superficial cortical layers, behavior-induced expression of the immediate early gene Arc was examined in hippocampus-lesioned and control rats after exposing them to 2 distinct contexts. Contrary to expectations, hippocampal lesions had no observable effect on Arc expression in any neocortical layer relative to controls. Furthermore, another group of intact animals was exposed to the same environment twice, to determine the reliability of Arc-expression patterns across identical contextual and behavioral episodes. Although this condition included no difference in external input between 2 epochs, the significant layer differences in Arc expression still remained. Thus, laminar differences in activation or plasticity patterns are not likely to arise from hippocampal sources or differences in external inputs, but are more likely to be an intrinsic property of the neocortex.


Synovial fluid leukocyte apoptosis is inhibited in patients with very early rheumatoid arthritis.
Synovial leukocyte apoptosis is inhibited in established rheumatoid arthritis (RA). In contrast, high levels of leukocyte apoptosis are seen in self-limiting crystal arthritis. The phase in the development of RA at which the inhibition of leukocyte apoptosis is first apparent, and the relationship between leukocyte apoptosis in early RA and other early arthritides, has not been defined. We measured synovial fluid leukocyte apoptosis in very early arthritis and related this to clinical outcome. Synovial fluid was obtained at presentation from 81 patients with synovitis of < or = 3 months duration. The percentages of apoptotic neutrophils and lymphocytes were assessed on cytospin preparations. Patients were assigned to diagnostic groups after 18 months follow-up. The relationship between leukocyte apoptosis and patient outcome was assessed. Patients with early RA had significantly lower levels of neutrophil apoptosis than patients who developed non-RA persistent arthritis and those with a resolving disease course. Similarly, lymphocyte apoptosis was absent in patients with early RA whereas it was seen in patients with other early arthritides. The inhibition of synovial fluid leukocyte apoptosis in the earliest clinically apparent phase of RA distinguishes this from other early arthritides. The mechanisms for this inhibition may relate to the high levels of anti-apoptotic cytokines found in the early rheumatoid joint (e.g. IL-2, IL-4, IL-15 GMCSF, GCSF). It is likely that this process contributes to an accumulation of leukocytes in the early rheumatoid lesion and is involved in the development of the microenvironment required for persistent RA.


A trypanosome-soluble factor induces IP3 formation, intracellular Ca2+ mobilization and microfilament rearrangement in host cells.
Lysosomes are recruited to the invasion site during host cell entry by Trypanosoma cruzi, an unusual process suggestive of the triggering of signal transduction mechanisms. Previous studies showed that trypomastigotes, but not the noninfective epimastigotes, contain a proteolytically generated trypomastigote factor (PGTF) that induces intracellular free Ca2+ transients in several mammalian cell types. Using confocal time-lapse imaging of normal rat kidney (NRK) fibroblasts loaded with the Ca(2+)-sensitive dye fluo-3, we show that the initial intracellular free Ca(2+) concentration ([Ca2+]i) transient detected a few seconds after exposure to trypomastigote extracts is a result of Ca2+ release from intracellular stores. Removal of Ca2+ from the extracellular medium or inhibition of Ca2+ channels with NiCl2 did not affect the response to PGTF, while depletion of intracellular stores with thapsigargin abolished it. [Ca2+]i transients induced by PGTF were shown to be coupled to the activity of phospholipase C (PLC), since the specific inhibitor U73122 completely blocked the response, while its inactive analogue U73343 had no effect. In addition, polyphosphoinositide hydrolysis and inositol 1,4,5-trisphosphate (IP3) were detected upon cell stimulation with PGTF, suggesting the participation of IP3-sensitive intracellular Ca2+ channels. An immediate effect of the signaling induced by PGTF and live trypomastigotes was a rapid and transient reorganization of host cell microfilaments. The redistribution of F-actin appeared to be a direct consequence of increased [Ca2+]i, since thrombin and the Ca2+ ionophore ionomycin produced a similar effect, with a time course that corresponded to the kinetics of the elevation in [Ca2+]i. These observations support the hypothesis that PGTF-induced disassembly of the cortical actin cytoskeleton may play a role in T. cruzi invasion, by facilitating lysosome access to the invasion site. Taken together, our findings suggest that the proteolytically generated trypomastigote factor PGTF is a novel agonist that acts through the PLC/phosphoinositide signaling pathway of mammalian cells.


A novel tibial tuberosity advancement technique with cranial implant fixation (TTA CF): a pilot study in sheep.
Cranial cruciate ligament rupture is the most frequent orthopedic disorder in human and animals. An array of surgical techniques have been described to stabilize the stifle joint in dogs, including intraarticular stabilization, extraarticular stabilization, and tibial osteotomy techniques. Tibial plateau leveling osteotomy and tibial tuberosity advancement with a lot of modifications are the most common. In this study we report the possibility of fixing the novel titanium implant for tibial tuberosity advancement with two screws in a craniocaudal direction. The aim of our study was to improve the clinical benefit of the tibial tuberosity advancement surgical technique where an attempt was made to reduce the number of screws and obtain a strong implant fixation with minimal bone traumatization. This way of attachment allows to distribute the forces evenly on medial and lateral side of osteotomy gap. Tibial tuberosity advancement with cranial implant fixation was performed in four sheep. Complete radiographic and clinical follow up was recorded. All four sheep had a complete osteotomy line healing at a mean of 10 weeks postoperative (range 8-12 weeks). None of the animals had osteotomy gap healing grades of poor. Minor complication included the minimally cracked Maquet hole on the postoperative radiographs, without displacement of the tibial crest which occurred in 2 sheep. Major complication grade 1, major complication grade 2 and catastrophic were not found. The novel surgical technique for tibial tuberosity advancement with cranial implant fixation is technically comparable to the recent trend in tuberosity advancement techniques, where partial osteotomy of the cranial tibial tuberosity crest is performed. A cranial implant fixation allows to distribute the forces evenly on medial and lateral side of osteotomy gap, which may result in less number of major complications in dogs. A novel titanium implant decreases the tibial traumatisation by reducing the number of screws.


The relationship of body fat content to deep muscle temperature and isometric endurance in man.
1. The relationship between body fat content, isometric endurance and deep muscle temperature was assessed in eight male and female volunteers trained to static effort. 2. Muscle temperature, measured in the belly of the brachioradialis muscle, was found to be directly related to the subject's body fat content. 3. Associated with a reduction in body fat content, there was a marked decrease in deep muscle temperature and an increase in isometric endurance of the hand-grip muscles; no change in strength was noted. 4. Conversely, an increase in body fat content resulted in an increase in deep muscle temperature and a decrease in isometric endurance. 5. When muscle temperature was stabilized before and after weight loss by immersing the forearm in water at 37 degrees C, a reduction in body fat no longer influenced endurance. 6. It was concluded that the change in isometric endurance associated with either loss or gain of weight can be accounted for entirely by the changes in muscle temperature.


The Ethics of Error in Medicine.
The practice of medicine forces medical practitioners to make difficult and challenging choices on a daily basis. On the one hand we are obligated to cure with every resource available, while on the other hand we put the patient at risk because our treatments are flawed. To understand the ethics of error in medicine, its moral value, and the effects, error must first be defined. However, definition of error remains elusive, and its incidence has been extraordinarily difficult to quantify. Yet, a health care system that acknowledges error as a consequence of normative ethical practice must create systems to minimize error. Error reduction, in turn, should attempt to decrease patient harm and improve the entire health care system. We discuss a number of ethical and moral considerations that arise from practicing medicine despite anticipated error.


Identification of G protein-coupled receptor kinase 2 phosphorylation sites responsible for agonist-stimulated delta-opioid receptor phosphorylation.
Agonist-induced receptor phosphorylation is an initial step in opioid receptor desensitization, a molecular mechanism of opioid tolerance and dependence. Our previous research suggested that agonist-induced delta-opioid receptor (DOR) phosphorylation occurs at the receptor carboxyl terminal domain. The current study was carried out to identify the site of DOR phosphorylation during agonist stimulation and the kinases catalyzing this reaction. Truncation (Delta15) or substitutions (T358A, T361A, and S363G single or triple mutants) at the DOR cytoplasmic tail caused 80 to 100% loss of opioid-stimulated receptor phosphorylation, indicating that T358, T361, and S363 all contribute and are cooperatively involved in agonist-stimulated DOR phosphorylation. Coexpression of GRK2 strongly enhanced agonist-stimulated phosphorylation of the wild-type DOR (WT), but Delta15 or mutant DOR (T358A/T361A/S363G) failed to show any detectable phosphorylation under these conditions. These results demonstrate that T358, T361, and S363 are required for agonist-induced and GRK-mediated receptor phosphorylation. Agonist-induced receptor phosphorylation was severely impaired by substitution of either T358 or S363 with aspartic acid residue, but phosphorylation of the T361D mutant was comparable with that of WT. In the presence of exogenously expressed GRK2, phosphorylation levels of T358D and S363D mutants were approximately half of that of WT, whereas significant phosphorylation of the T358/S363 double-point mutant was not detected. These results indicate that both T358 and S363 residues at the DOR carboxyl terminus are capable of serving cooperatively as phosphate acceptor sites of GRK2 in vivo. Taken together, we have demonstrated that agonist-induced opioid receptor phosphorylation occurs exclusively at two phosphate acceptor sites (T358 and S363) of GRK2 at the DOR carboxyl terminus. These results represent the identification of the GRK phosphorylation site on an opioid receptor for the first time and demonstrate that GRK is the prominent kinase responsible for agonist-induced opioid receptor phosphorylation in vivo.


Soy protein consumption and bone mass in early postmenopausal Chinese women.
Recent interest has been shown in the potential beneficial effects of phytoestrogens on bone health. As the early years of menopause are a period of rapid bone loss, and the risk for osteoporosis increases substantially, the habitual intake of soy protein and isoflavones may play a role in the retardation of bone loss. This paper reports the results of the baseline cross-sectional analysis of the association between dietary soy protein intake and bone mineral density/content in a population-based study of Chinese women. The sample comprised 454 healthy Chinese women (mean age 55.1 +/- 3.57) within the first 12 years of postmenopause. We estimated the dietary intake of soy protein and isoflavones, and other key nutrients, including dietary protein and calcium, using the quantitative food frequency method. Bone mineral density (BMD) and content (BMC) at the spine, hip and total body were measured with a dual energy X-ray densitometer (Hologic 4500A). Soy protein consumption was categorized as quartiles of intake, and related to BMD values at the spine and hip, and BMC of total body. Stratified analyses were carried out among women within or at least 4 years postmenopausal. We observed few differences in BMD/BMC values among the intake quartiles in women within the first 4 years of menopause. However, among the later postmenopausal women, we noted a dose-response relationship with increasing higher BMD values at the trochanter, intertrochanter as well as the total hip and total body with increasing soy protein intake quartiles (P<0.05 from tests for trend). The BMD values differed by about 4-8% between the first and fourth soy protein intake quartiles. Though women from the fourth intake quartile had a 2.9% higher BMD value compared with those from the first intake quartile, the difference was not statistically significant. Stepwise multiple linear regression analyses showed the association between soy intake quartiles and hip BMD as well as total body BMC values remained after adjusting for body weight, which was retained in the final model. Analyses based on soy isoflavones content yielded similar results. This study demonstrated that, among women after the initial few years postmenopausal, soy protein/isoflavones intake had a modest but significant association with hip BMD as well as total body BMC. The effects of soy protein and soy isoflavones on bone health should be further explored in populations with habitual dietary soy intake.


Design of a robust thin-film interference filter for erbium-doped fiber amplifier gain equalization.
Gain-flattening filters (GFFs) are key wavelength division multiplexing components in fiber-optics telecommunications. Challenging issues in the design of thin-film GFFs were recently the subject of a contest organized at the 2001 Conference on Optical Interference Coatings. The interest and main difficulty of the proposed problem was to minimize the sensitivity of a GFF to simulated fabrication errors. A high-yield solution and its design philosophy are described. The approach used to control the filter robustness is explained and illustrated by numerical results.


Iterative generation of holograms on spatial light modulators.
Iterative learning procedures on a hybrid electro-optic system can be employed to generate holograms on inexpensive liquid-crystal-television spatial light modulators. The algorithm takes into account random electronic noise in the system and compensates for spatial-light-modulator distortions. Experimental results are given for the reconstruction of intensity distribution, and computer complex amplitude reconstruction.


Laser guided automated calibrating system for accurate bracket placement.
The basic premise of preadjusted bracket system is accurate bracket positioning. It is widely recognized that accurate bracket placement is of critical importance in the efficient application of biomechanics and in realizing the full potential of a preadjusted edgewise appliance. The purpose of this study was to design a calibrating system to accurately detect a point on a plane as well as to determine the accuracy of the Laser Guided Automated Calibrating (LGAC) System. To the lowest order of approximation a plane having two parallel lines is used to verify the accuracy of the system. On prescribing the distance of a point from the line, images of the plane are analyzed from controlled angles, calibrated and the point is identified with a laser marker. The image was captured and analyzed using MATLAB ver. 7 software (The MathWorks Inc.). Each pixel in the image corresponded to a distance of 1cm/413 (10 mm/413) = 0.0242 mm (L/P). This implies any variations in distance above 0.024 mm can be measured and acted upon, and sets the highest possible accuracy for this system. A new automated system is introduced having an accuracy of 0.024 mm for accurate bracket placement.


Correlation between quality of cardiopulmonary resuscitation and self-efficacy measured during in-hospital cardiac arrest simulation; preliminary results.
The concept of self-assess it's a central mechanism in human agency for behavior change and should translate to desirable practice patterns. There are no many studies that have investigated the relationship between the perception of the ability to perform cardiopulmonary resuscitation (CPR) and the quality of the same. The aim of this work is to investigate the relation between physiological and psychosocial variables in cardiac resuscitation in order to improve the involvement and motivation of professionals in training courses. During the year 2012, 322 medical staff of Ospedale-Universitario of Parma were trained to basic life support defibrillation (BLSD). Before started the course the partecipants were randomly selected among the staff working in the same department to create a team of two persons and involved in a simulation that reproduced the first five minutes that occurs for a cardiac arrest in a medical or surgical department in our hospital before the intervention of the hospital emergency team. Before and after simulation to each participant was asked to answer a self-efficacy questionnaire on a 10-point scale on the management of cardiac. During simulation were registered the activation time of the emergency response system, hands-on time, defibrillation time, number of compression and correct compression rate. Activation time of the emergency response system was 70.52 ± 78.77 seconds. In 55 teams was not made the allert. The defibrillation time was 148.63 ± 58.43 seconds. In 44 teams the defibrillator were used within 120 seconds, in 36 (22.1%) it was not used. Hands-on time average was of 166.20 ± 62.9 seconds. The mean number of compression was 216.22 ± 115.57. The percentage of satisfactory compression was 9.97 ± 21.23 %. The level of self-efficacy was under the average for the 35.6%, while the 26.8% of the participants had a medium level of 5 and the 38.5% of the sample declared to feel an efficacy level included in 6-10. The sense of self efficacy after the simulation was constant in the 38.3% of the sample, while increased in the 30.5% and decreased in the 31.2%. We found no significant correlations between self-efficacy levels and specific results in scenario acting before simulation, instead, after the simulation the skills performances are much more correlated with self-efficacy. The medical staff reported an individual's perception of good efficacy in the management of simulation of cardiac arrest, but it does not correspond to a high skills. An open question is if and how these psychosocial variables may play a role in improving the quality of CPR and if knowledge of the low capacity to manage a cardiac arrest can be translated into the need for the medical staff to be regularly engaged in BLSD retraining.