Multiplicity of control in the basal ganglia: computational roles of striatal subregions.
The basal ganglia, in particular the striatum, are central to theories of behavioral control, and often identified as a seat of action selection. Reinforcement learning (RL) models--which have driven much recent experimental work on this region--cast striatum as a dynamic controller, integrating sensory and motivational information to construct efficient and enriching behavioral policies. Befitting this informationally central role, the BG sit at the nexus of multiple anatomical 'loops' of synaptic projections, connecting a wide range of cortical and subcortical structures. Numerous pioneering anatomical studies conducted over the past several decades have meticulously catalogued these loops, and labeled them according to the inferred functions of the connected regions. The specific cotermina of the projections are highly localized to several different subregions of the striatum, leading to the suggestion that these subregions perform complementary but distinct functions. However, until recently, the dominant computational framework outlined only a bipartite, dorsal/ventral, division of striatum. We review recent computational and experimental advances that argue for a more finely fractionated delineation. In particular, experimental data provide extensive insight into unique functions subserved by the dorsomedial striatum (DMS). These functions appear to correspond well with theories of a 'model-based' RL subunit, and may also shed light on the suborganization of ventral striatum. Finally, we discuss the limitations of these ideas and how they point the way toward future refinements of neurocomputational theories of striatal function, bringing them into contact with other areas of computational theory and other regions of the brain.


Genetic and environmental contributions to alcohol dependence risk in a national twin sample: consistency of findings in women and men.
Genetic influences on alcoholism risk are well-documented in men, but uncertain in women. We tested for gender differences in genetic influences on, and risk-factors for, DSM-III-R alcohol dependence (AD). Diagnostic follow-up interviews were conducted in 1992-3 by telephone with twins from an Australian twin panel first surveyed in 1980-82 (N = 5889 respondents). Data were analysed using logistic regression models. Significantly higher twin pair concordances were observed in MZ compared to DZ same-sex twin pairs in women and men, even when data were weighted to adjust for over-representation of well-educated respondents, and for selective attrition. AD risk was increased in younger birth cohorts, in Catholic males or women reporting no religious affiliation, in those reporting a history of conduct disorder or major depression and in those with high Neuroticism, Social Non-conformity, Toughmindedness, Novelty-Seeking or (in women only) Extraversion scores; and decreased in 'Other Protestants', weekly church attenders, and university-educated males. Controlling for these variables, however, did not remove the significant association with having an alcoholic MZ co-twin, implying that much of the genetic influence on AD risk remained unexplained. No significant gender difference in the genetic variance in AD was found (64% heritability, 95% confidence interval 32-73%). Genetic risk-factors play as important a role in determining AD risk in women as in men. With the exception of certain sociocultural variables such as religious affiliation, the same personality, sociodemographic and axis I correlates of alcoholism risk are observed in women and men.


Nonalcoholic fatty liver disease is associated with coronary artery calcification.
Nonalcoholic fatty liver disease (NAFLD) is related to risk factors of coronary artery disease, such as dyslipidemia, diabetes, and metabolic syndrome, which are closely linked with visceral adiposity. The aim of this study was to investigate whether NAFLD was associated with coronary artery calcification (CAC), which is used as a surrogate marker for coronary atherosclerosis independent of computed tomography (CT)-measured visceral adiposity. Out of 5,648 subjects who visited one of our health screening centers between 2003 and 2008, we enrolled 4,023 subjects (mean age, 56.9 ± 9.4 years; 60.7% males) without known liver disease or a history of ischemic heart disease. CAC score was evaluated using the Agatston method. On univariate analysis, the presence of CAC (score >0) was significantly associated with age, sex, body mass index, aspartate aminotransferase, alanine aminotransferase, high-density lipoprotein cholesterol, triglycerides, and increased risk of diabetes, hypertension, smoking, and NAFLD. Increasing CAC scores (0, <10, 10-100, ≥ 100) were associated with higher prevalence of NAFLD (odds ratio [OR], 1.84; 95% confidence interval [CI], 1.61-2.10; P<0.001). Multivariable ordinal regression analysis was adjusted for traditional risk factors, and CT-measured visceral adipose tissue area in a subgroup of subjects showed that the increased CAC scores were significantly associated with the presence of NAFLD (OR, 1.28, 95% CI, 1.04-1.59; P = 0.023) independent of visceral adiposity. Patients with NAFLD are at increased risk for coronary atherosclerosis independent of classical coronary risk factors, including visceral adiposity. These data suggest that NAFLD might be an independent risk factor for coronary artery disease.


Characterization of the O-polysaccharide structure of lipopolysaccharide from Actinobacillus actinomycetemcomitans serotype b.
We previously reported that the serotype b antigen of Actinobacillus actinomycetemcomitans is a constituent of the polysaccharide region of lipopolysaccharide (LPS) and contains significant amount of the neutral sugars rhamnose and fucose (M. Wilson and R. Schifferle, Infect. Immun. 59:1544-1551, 1991). In the present study, we determined the structure of the O antigen of A. actinomycetemcomitans Y4 (serotype b) LPS. Aqueous phase LPS was obtained from a phenol-water extract of A. actinomycetemcomitans Y4. This material was found to react with rabbit polyclonal antiserum to serotype b but not with antisera specific for other A. actinomycetemcomitans serotypes. Analyses revealed that the O polysaccharide of Y4 LPS consists of a polymer of trisaccharide repeating units composed of D-Fuc, AL-Rha, and D-GalNAc residues. An identical structure was obtained for the O polysaccharide of LPS from A. actinomycetemcomitans JP2, another serotype b strain. These results indicate that the serotype b antigen of A. actinomycetemcomitans is defined by a trisaccharide repeating unit present in the O polysaccharide of LPS.


Vegetative buffers for fan emissions from poultry farms: 2. ammonia, dust and foliar nitrogen.
This study evaluated the potential of trees planted around commercial poultry farms to trap ammonia (NH(3)) and dust or particulate matter (PM). Norway spruce, Spike hybrid poplar, hybrid willow, and Streamco purpleosier willow were planted on five commercial farms from 2003 to 2004. Plant foliage was sampled in front of the exhaust fans and at a control distance away from the fans on one turkey, two laying hen, and two broiler chicken farms between June and July 2006. Samples were analyzed for dry matter (DM), nitrogen (N), and PM content. In addition, NH(3) concentrations were measured downwind of the exhaust fans among the trees and at a control distance using NH(3) passive dosi-tubes. Foliage samples were taken and analyzed separately based on plant species. The two layer farms had both spruce and poplar plantings whereas the two broiler farms had hybrid willow and Streamco willow plantings which allowed sampling and species comparisons with the effect of plant location (control vs. fan). The results showed that NH(3) concentration h(- 1) was reduced by distance from housing fans (P < or = 0.0001), especially between 0 m (12.01 ppm), 11.4 m (2.59 ppm), 15 m (2.03 ppm), and 30 m (0.31 ppm). Foliar N of plants near the fans was greater than those sampled away from the fans for poplar (3.87 vs. 2.56%; P < or = 0.0005) and hybrid willow (3.41 vs. 3.02%; P < or = 0.05). The trends for foliar N in spruce (1.91 vs. 1.77%; P = 0.26) and Streamco willow (3.85 vs. 3.33; P = 0.07) were not significant. Pooling results of the four plant species indicated greater N concentration from foliage sampled near the fans than of that away from the fans (3.27 vs. 2.67%; P < or = 0.0001). Foliar DM concentration was not affected by plant location, and when pooled the foliar DM of the four plant species near the fans was 51.3% in comparison with 48.5% at a control distance. There was a significant effect of plant location on foliar N and DM on the two layer farms with greater N and DM adjacent to fans than at a control distance (2.95 vs. 2.15% N and 45.4 vs. 38.2% DM, respectively). There were also significant plant species effects on foliar N and DM with poplar retaining greater N (3.22 vs. 1.88%) and DM (43.7 vs. 39.9%) than spruce. The interaction of location by species (P < or = 0.005) indicated that poplar was more responsive in terms of foliar N, but less responsive for DM than spruce. The effect of location and species on foliar N and DM were not clear among the two willow species on the broiler farms. Plant location had no effect on plant foliar PM weight, but plant species significantly influenced the ability of the plant foliage to trap PM with spruce and hybrid willow showing greater potential than poplar and Streamco willow for PM(2.5)(0.0054, 0.0054, 0.0005, and 0.0016 mg cm(- 2); P < or = 0.05) and total PM (0.0309, 0.0102, 0.0038, and 0.0046 mg cm(- 2), respectively; P < or = 0.001). Spruce trapped more dust compared to the other three species (hybrid willow, poplar, and Streamco willow) for PM(10) (0.0248 vs. 0.0036 mg cm(- 2); P < or = 0.0001) and PM(> 10) (0.0033 vs. 0.0003 mg cm(- 2); P = 0.052). This study indicates that poplar, hybrid willow, and Streamco willow are appropriate species to absorb poultry house aerial NH(3)-N, whereas spruce and hybrid willow are effective traps for dust and its associated odors.


Immunization of human HIV-seronegative volunteers with recombinant p17/p24:Ty virus-like particles elicits HIV-1 p24-specific cellular and humoral immune responses.
To evaluate the immune response to HIV-1 p24 generated in vivo by p17/p24:Ty virus-like particles (p17/p24:Ty-VLP) by examining the lymphoproliferative and antibody (Ab) responses to HIV-1 p24, as well as Gag-specific cytotoxic T lymphocytes (CTL), in HIV-seronegative volunteers immunized with hybrid p17/p24:Ty-VLP. Sixteen HIV-seronegative volunteers were immunized with p17/p24:Ty-VLP at two dose levels (100 or 500 micrograms) and monitored for the following 48 weeks for production of anti-p24 and anti-p17 Ab, in vitro lymphoproliferative responses to HIV-1 p24 and p17, and in vitro CTL responses to HIV-1 Gag. Twelve out of the 16 volunteers had significant p24-specific proliferative responses, with volunteers on the higher dose schedule exhibiting earlier proliferative responses than those on the lower dose schedule. Proliferative responses in both volunteer groups were similar in overall magnitude but appeared at different times during the immunization schedule. Anti-p24 Ab were detected in six out of the nine individuals in the lower dose group and in five out of the seven in the higher dose group. There was a good correlation between the presence of p24-specific Ab and the detection of lymphoproliferative responses to the p24 protein in peripheral blood mononuclear cells isolated from the same individuals. Anti-p17 Ab were detected in five volunteers. No Gag-specific CTL responses were detected. We conclude that hybrid HIV-1 p17/p24:Ty-VLP are capable of inducing both cellular and humoral immunity to HIV-1 Gag p17 and p24 components and are worthy of further study as a potential HIV immunotherapeutic.


Lifting without seeing: the role of vision in perceiving and acting upon the size weight illusion.
Our expectations of an object's heaviness not only drive our fingertip forces, but also our perception of heaviness. This effect is highlighted by the classic size-weight illusion (SWI), where different-sized objects of identical mass feel different weights. Here, we examined whether these expectations are sufficient to induce the SWI in a single wooden cube when lifted without visual feedback, by varying the size of the object seen prior to the lift. Participants, who believed that they were lifting the same object that they had just seen, reported that the weight of the single, standard-sized cube that they lifted on every trial varied as a function of the size of object they had just seen. Seeing the small object before the lift made the cube feel heavier than it did after seeing the large object. These expectations also affected the fingertip forces that were used to lift the object when vision was not permitted. The expectation-driven errors made in early trials were not corrected with repeated lifting, and participants failed to adapt their grip and load forces from the expected weight to the object's actual mass in the same way that they could when lifting with vision. Vision appears to be crucial for the detection, and subsequent correction, of the ostensibly non-visual grip and load force errors that are a common feature of this type of object interaction. Expectations of heaviness are not only powerful enough to alter the perception of a single object's weight, but also continually drive the forces we use to lift the object when vision is unavailable.


Connexin hemichannels and cell death as measures of bovine COC vitrification success.
Vitrification of immature germinal vesicle-stage oocytes is a promising method in assisted reproduction but is associated with reduced developmental potential and low birth rates. Cumulus-oocyte complexes (COCs) express several connexins that form hexameric hemichannels, which interact head to head to create a gap junction or exist as unopposed free hemichannels. The latter are normally closed but open under stress conditions and may exert detrimental effects. We determined whether minimizing hemichannel opening and cell death during vitrification could improve COC quality. Bovine immature COCs underwent vitrification, storage and warming, followed by dye uptake to assess hemichannel opening and TUNEL staining to detect cell death. Based on these scores, we optimized the procedure by tuning the equilibration time, temperature, cryoprotectant concentration and extracellular Ca2+ concentration and assessed its impact on maturation, cleavage and blastocyst formation after parthenogenetic activation. We found that the major stressor resides in the cooling/warming phase of the vitrification procedure and observed that hemichannel opening and cell death in cumulus cells measure different aspects of cell stress. Optimization of the hemichannel and cell death readouts demonstrated that combined minimal hemichannel opening/cell death gave the highest cleavage rates but had no effect on maturation and blastocyst formation. Neither hemichannel nor cell death optimization performed better than the non-optimized protocol, leading to the conclusion that cell stress factors other than those detected by hemichannel dye uptake or TUNEL positivity are involved.


Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression.
Alzheimer's disease (AD) is a complex, neurodegenerative disease characterized by the impairment of cognitive function in elderly individuals. In a recent global gene expression study of APP transgenic mice, we found elevated expression of mitochondrial genes, which we hypothesize represents a compensatory response because of mitochondrial oxidative damage caused by the over-expression of mutant APP and/or amyloid beta (Abeta). We investigated this hypothesis in a series of experiments examining what forms of APP and Abeta localize to the mitochondria, and whether the presence of these species is associated with mitochondrial dysfunction and oxidative damage. Using immunoblotting, digitonin fractionation, immunofluorescence, and electron microscopy techniques, we found a relationship between mutant APP derivatives and mitochondria in brain slices from Tg2576 mice and in mouse neuroblastoma cells expressing mutant human APP. Further, to determine the functional relationship between mutant APP/Abeta and oxidative damage, we quantified Abeta levels, hydrogen peroxide production, cytochrome oxidase activity and carbonyl proteins in Tg2576 mice and age-matched wild-type (WT) littermates. Hydrogen peroxide levels were found to be significantly increased in Tg2576 mice when compared with age-matched WT littermates and directly correlated with levels of soluble Abeta in Tg2576 mice, suggesting that soluble Abeta may be responsible for the production of hydrogen peroxide in AD progression in Tg2576 mice. Cytochrome c oxidase activity was found to be decreased in Tg2576 mice when compared with age-matched WT littermates, suggesting that mutant APP and soluble Abeta impair mitochondrial metabolism in AD development and progression. An increase in hydrogen peroxide and a decrease in cytochrome oxidase activity were found in young Tg2576 mice, prior to the appearance of Abeta plaques. These findings suggest that early mitochondrially targeted therapeutic interventions may be effective in delaying AD progression in elderly individuals and in treating AD patients.


The role of matched controls in building an evidence base for hospital-avoidance schemes: a retrospective evaluation.
To test whether two hospital-avoidance interventions altered rates of hospital use: "intermediate care" and "integrated care teams." Linked administrative data for England covering the period 2004 to 2009. This study was commissioned after the interventions had been in place for several years. We developed a method based on retrospective analysis of person-level data comparing health care use of participants with that of prognostically matched controls. Individuals were linked to administrative datasets through a trusted intermediary and a unique patient identifier. Participants who received the intermediate care intervention showed higher rates of unscheduled hospital admission than matched controls, whereas recipients of the integrated care team intervention showed no difference. Both intervention groups showed higher rates of mortality than did their matched controls. These are potentially powerful techniques for assessing impacts on hospital activity. Neither intervention reduced admission rates. Although our analysis of hospital utilization controlled for a wide range of observable characteristics, the difference in mortality rates suggests that some residual confounding is likely. Evaluation is constrained when performed retrospectively, and careful interpretation is needed.


Immunopositivity for histone macroH2A1 isoforms marks steatosis-associated hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Prevention and risk reduction are important and the identification of specific biomarkers for early diagnosis of HCC represents an active field of research. Increasing evidence indicates that fat accumulation in the liver, defined as hepatosteatosis, is an independent and strong risk factor for developing an HCC. MacroH2A1, a histone protein generally associated with the repressed regions of chromosomes, is involved in hepatic lipid metabolism and is present in two alternative spliced isoforms, macroH2A1.1 and macroH2A1.2. These isoforms have been shown to predict lung and colon cancer recurrence but to our knowledge, their role in fatty-liver associated HCC has not been investigated previously. We examined macroH2A1.1 and macroH2A1.2 protein expression levels in the liver of two murine models of fat-associated HCC, the high fat diet/diethylnistrosamine (DEN) and the phosphatase and tensin homolog (PTEN) liver specific knock-out (KO) mouse, and in human liver samples of subjects with steatosis or HCC, using immunoblotting and immunohistochemistry. Protein levels for both macroH2A1 isoforms were massively upregulated in HCC, whereas macroH2A1.2 was specifically upregulated in steatosis. In addition, examination of human liver samples showed a significant difference (p<0.01) in number of positive nuclei in HCC (100% of tumor cells positive for either macroH2A1.1 or macroH2A1.2), when compared to steatosis (<2% of hepatocytes positive for either isoform). The steatotic areas flanking the tumors were highly immunopositive for macroH2A1.1 and macroH2A1.2. These data obtained in mice and humans suggest that both macroH2A1 isoforms may play a role in HCC pathogenesis and moreover may be considered as novel diagnostic markers for human HCC.


Plasma pro-atrial natriuretic peptide to estimate fluid balance during open and robot-assisted esophagectomy: a prospective observational study.
It remains debated how much fluid should be administered during surgery. The atrial natriuretic peptide precursor proANP is released by atrial distension and deviations in plasma proANP are reported associated with perioperative fluid balance. We hypothesized that plasma proANP would decrease when the central blood volume is compromised during the abdominal part of robot-assisted hybrid (RE) esophagectomy and that a positive fluid balance would be required to maintain plasma proANP. Patients undergoing RE (n = 25) or open (OE; n = 25) esophagectomy for gastroesophageal cancer were included consecutively in this prospective observational study. Plasma proANP was determined repetitively during esophagectomy to allow for distinction between the abdominal and thoracic part of the procedure. The RE group was 15° head up tilted during the abdominal procedure. The blood loss was 250 (150-375) (RE) and 600 ml (390-855) (OE) (p = 0.01), but the two groups of patients were provided with a similar positive fluid balance: 1705 (1390-1983) vs. 1528 ml (1316-1834) (p = 0.4). However, plasma proANP decreased by 21% (p < 0.01) during the abdominal part of RE carried out during moderate head-up tilt, but only by 11% (p = 0.01) during OE where the patients were supine. Plasma proANP and fluid balance were correlated in the RE-group (r = 0.5 (0.073-0.840), p = 0.02) and tended to correlate in the OE group (r = 0.4 (-0.045-0.833), p = 0.08). The results support that plasma proANP decreases when the central blood volume is compromised and suggest that an about 2200 ml surplus administration of crystalloid is required to maintain plasma proANP during esophagectomy. Clinicaltrials.gov ( NCT02077673 ). Registered retrospectively February 12th 2014.


Recovery of upper extremity sensorimotor system acuity in baseball athletes after a throwing-fatigue protocol.
Research indicates that upper extremity fatigue hampers sensorimotor system acuity. However, no investigators have observed recovery of upper extremity acuity after fatigue. To observe recovery of active position reproduction acuity in overhead throwers after a throwing-fatigue protocol. Single-session, repeated-measures design. University musculoskeletal laboratory. Sixteen healthy collegiate baseball players (age = 21.0 +/- 1.6 years, height = 175.8 +/- 10.2 cm, mass = 82.8 +/- 4.3 kg). Subjects threw a baseball with maximum velocity (every 5 seconds) from a single knee. Every 20 throws, subjects rated their upper extremity exertion on a Borg scale until reporting a level of more than 14. We used an electromagnetic tracking system to measure active multijoint position reproduction acuity at 5 intervals: prefatigue; immediately postfatigue; and after 4, 7, and 10 minutes of recovery. Blindfolded subjects reproduced their arm-cocked and ball-release positions. Dependent variables were 3-dimensional variable errors of scapulothoracic, glenohumeral, elbow, and wrist joints; endpoint (ie, hand) position error represented overall upper extremity acuity. The independent variable was time (measured prefatigue and at 4 postfatigue intervals). Fatigue significantly affected acuity of scapulothoracic, glenohumeral, and elbow joints and endpoint error for both positions (P < .001). Fatigue significantly affected wrist acuity only for ball release (P < .001). For arm-cocked reproduction, each measure of acuity, except that of the glenohumeral joint, recovered by 7 minutes; for ball release, each measure of acuity recovered within 4 minutes (P > .05). The sensorimotor system deficits that we observed after fatigue recovered within 7 minutes in most upper extremity joints. Glenohumeral arm-cocked position reproduction acuity failed to recover within 10 minutes. Research indicates that overhead throwers are vulnerable in this position to the capsulolabral injuries commonly observed in throwing athletes. Future researchers should explore this relationship and the effectiveness of exercises aimed at enhancing sensorimotor system acuity and endurance.


Electrophysiological signatures of intentional social coordination in the 10-12 Hz range.
This study sought to investigate the effects of manipulating social coordination on brain synchronization/de-synchronization in the mu band. Mu activation is associated with understanding and coordinating motor acts and may play a key role in mediating social interaction. Members of a dyad were required to interact with one another in a rhythmic finger movement coordination task under various instructions: intrinsic where each member of the dyad was instructed to maintain their own and ignore their partner's movement; in-phase where they were asked to synchronize with their partner's movement; and anti-phase where they were instructed to syncopate with their partner's movement. EEG and movement data were recorded simultaneously from both subjects during all three tasks and a control condition. Log power ratios of EEG activity in the active conditions versus control were used to assess the effect of task context on synchronization/de-synchronization in the mu spectral domain. Results showed clear and systematic modulation of mu band activity in the 10-12 Hz range as a function of coordination context. In the left hemisphere general levels of alpha-mu suppression increased progressively as one moved from intrinsic through in-phase to anti-phase contexts but with no specific central-parietal focus. In contrast the right hemisphere displayed context-specific changes in the central-parietal region. The intrinsic condition showed a right synchronization which disappeared with the in-phase context even as de-synchronization remained greater in the left hemisphere. Anti-phase was associated with larger mu suppression in the right in comparison with left at central-parietal region. Such asymmetrical changes were highly correlated with changing behavioral dynamics. These specific patterns of activation and deactivation of mu activity suggest that localized neural circuitry in right central-parietal regions mediates how individuals interpret the movements of others in the context of their own actions. A right sided mechanism in the 10-12 Hz range appears to be involved in integrating the mutual information among the members of a dyad that enables the dynamics of social interaction to unfold in time.


Contrast-enhanced MRI and routine single photon emission computed tomography (SPECT) perfusion imaging for detection of subendocardial myocardial infarcts: an imaging study.
Myocardial infarcts are routinely detected by nuclear imaging techniques such as single photon emission computed tomography (SPECT) myocardial perfusion imaging. A newly developed technique for infarct detection based on contrast-enhanced cardiovascular magnetic resonance (CMR) has higher spatial resolution than SPECT. We postulated that this technique would detect infarcts missed by SPECT. We did contrast-enhanced CMR and SPECT examinations in 91 patients with suspected or known coronary artery disease. All CMR and SPECT images were scored, using a 14-segment model, for the presence, location, and spatial extent of infarction. To compare each imaging modality to a gold standard, we also acquired contrast-enhanced CMR and SPECT images in 12 dogs with, and three dogs without, myocardial infarction as defined by histochemical staining. In animals, contrast-enhanced CMR and SPECT detected all segments with nearly transmural infarction (>75% transmural extent of the left-ventricular wall). CMR also identified 100 of the 109 segments (92%) with subendocardial infarction (<50% transmural extent of the left-ventricular wall), whereas SPECT identified only 31 (28%). SPECT and CMR showed high specificity for the detection of infarction (97% and 98%, respectively). In patients, all segments with nearly transmural infarction, as defined by contrast-enhanced CMR, were detected by SPECT. However, of the 181 segments with subendocardial infarction, 85 (47%) were not detected by SPECT. On a per patient basis, six (13%) individuals with subendocardial infarcts visible by CMR had no evidence of infarction by SPECT. SPECT and CMR detect transmural myocardial infarcts at similar rates. However, CMR systematically detects subendocardial infarcts that are missed by SPECT.


Epidemiologic studies of glyphosate and non-cancer health outcomes: a review.
The United States (US) Environmental Protection Agency (EPA) and other regulatory agencies around the world have registered glyphosate as a broad-spectrum herbicide for use on multiple food and non-food use crops. To examine potential health risks in humans, we searched and reviewed the literature to evaluate whether exposure to glyphosate is associated causally with non-cancer health risks in humans. We also reviewed biomonitoring studies of glyphosate to allow for a more comprehensive discussion of issues related to exposure assessment and misclassification. Cohort, case-control and cross-sectional studies on glyphosate and non-cancer outcomes evaluated a variety of endpoints, including non-cancer respiratory conditions, diabetes, myocardial infarction, reproductive and developmental outcomes, rheumatoid arthritis, thyroid disease, and Parkinson's disease. Our review found no evidence of a consistent pattern of positive associations indicating a causal relationship between any disease and exposure to glyphosate. Most reported associations were weak and not significantly different from 1.0. Because accurate exposure measurement is crucial for valid results, it is recommended that pesticide-specific exposure algorithms be developed and validated.


Digital Screen Time During the COVID-19 Pandemic: Risk for a Further Myopia Boom?
To review the impact of increased digital device usage arising from lockdown measures instituted during the COVID-19 pandemic on myopia and to make recommendations for mitigating potential detrimental effects on myopia control. Perspective. We reviewed studies focused on digital device usage, near work, and outdoor time in relation to myopia onset and progression. Public health policies on myopia control, recommendations on screen time, and information pertaining to the impact of COVID-19 on increased digital device use were presented. Recommendations to minimize the impact of the pandemic on myopia onset and progression in children were made. Increased digital screen time, near work, and limited outdoor activities were found to be associated with the onset and progression of myopia, and could potentially be aggravated during and beyond the COVID-19 pandemic outbreak period. While school closures may be short-lived, increased access to, adoption of, and dependence on digital devices could have a long-term negative impact on childhood development. Raising awareness among parents, children, and government agencies is key to mitigating myopigenic behaviors that may become entrenched during this period. While it is important to adopt critical measures to slow or halt the spread of COVID-19, close collaboration between parents, schools, and ministries is necessary to assess and mitigate the long-term collateral impact of COVID-19 on myopia control policies.


Robust and efficient multi-frequency temporal phase unwrapping: optimal fringe frequency and pattern sequence selection.
Temporal phase unwrapping (TPU) is an essential algorithm in fringe projection profilometry (FPP), especially when measuring complex objects with discontinuities and isolated surfaces. Among others, the multi-frequency TPU has been proven to be the most reliable algorithm in the presence of noise. For a practical FPP system, in order to achieve an accurate, efficient, and reliable measurement, one needs to make wise choices about three key experimental parameters: the highest fringe frequency, the phase-shifting steps, and the fringe pattern sequence. However, there was very little research on how to optimize these parameters quantitatively, especially considering all three aspects from a theoretical and analytical perspective simultaneously. In this work, we propose a new scheme to determine simultaneously the optimal fringe frequency, phase-shifting steps and pattern sequence under multi-frequency TPU, robustly achieving high accuracy measurement by a minimum number of fringe frames. Firstly, noise models regarding phase-shifting algorithms as well as 3-D coordinates are established under a projector defocusing condition, which leads to the optimal highest fringe frequency for a FPP system. Then, a new concept termed frequency-to-frame ratio (FFR) that evaluates the magnitude of the contribution of each frame for TPU is defined, on which an optimal phase-shifting combination scheme is proposed. Finally, a judgment criterion is established, which can be used to judge whether the ratio between adjacent fringe frequencies is conducive to stably and efficiently unwrapping the phase. The proposed method provides a simple and effective theoretical framework to improve the accuracy, efficiency, and robustness of a practical FPP system in actual measurement conditions. The correctness of the derived models as well as the validity of the proposed schemes have been verified through extensive simulations and experiments. Based on a normal monocular 3-D FPP hardware system, our method enables high-precision unambiguous 3-D shape measurement with the highest fringe frequency up to 180 by using only 7 fringe patterns achieving a depth precision ∼ 38μm across a field of view of 400 × 300 × 400 mm.


Quantification of hydroxyl radical-derived oxidation products in peptides containing glycine, alanine, valine, and proline.
Proteins are a major target for oxidation due to their abundance and high reactivity. Despite extensive investigation over many years, only limited quantitative data exist on the contributions of different pathways to the oxidation of peptides and proteins. This study was designed to obtain quantitative data on the nature and yields of oxidation products (alcohols, carbonyls, hydroperoxides, fragment species) formed by a prototypic oxidant system (HO(•)/O(2)) on small peptides of limited, but known, amino acid composition. Peptides composed of Gly, Ala, Val, and Pro were examined with particular emphasis on the peptide Val-Gly-Val-Ala-Pro-Gly, a repeat motif in elastin with chemotactic activity and metalloproteinase regulation properties. The data obtained indicate that hydroperoxide formation occurs nonrandomly (Pro > Val > Ala > Gly) with this inversely related to carbonyl yields (both peptide-bound and released). Multiple alcohols are generated at both side-chain and backbone sites. Backbone fragmentation has been characterized at multiple positions, with sites adjacent to Pro residues being of major importance. Summation of the product concentrations provides clear evidence for the occurrence of chain reactions in peptides exposed to HO(•)/O(2), with the overall product yields exceeding that of the initial HO(•) generated.


The B subunit of the DNA polymerase alpha-primase complex in Saccharomyces cerevisiae executes an essential function at the initial stage of DNA replication.
The four-subunit DNA polymerase alpha-primase complex is unique in its ability to synthesize DNA chains de novo, and some in vitro data suggest its involvement in initiation and elongation of chromosomal DNA replication, although direct in vivo evidence for a role in the initiation reaction is still lacking. The function of the B subunit of the complex is unknown, but the Saccharomyces cerevisiae POL12 gene, which encodes this protein, is essential for cell viability. We have produced different pol12 alleles by in vitro mutagenesis of the cloned gene. The in vivo analysis of our 18 pol12 alleles indicates that the conserved carboxy-terminal two-thirds of the protein contains regions that are essential for cell viability, while the more divergent NH2-terminal portion is partially dispensable. The characterization of the temperature-sensitive pol12-T9 mutant allele demonstrates that the B subunit is required for in vivo DNA synthesis and correct progression through S phase. Moreover, reciprocal shift experiments indicate that the POL12 gene product plays an essential role at the early stage of chromosomal DNA replication, before the hydroxyurea-sensitive step. A model for the role of the B subunit in initiation of DNA replication at an origin is presented.


Location of an immunizing determinant within polypeptide VP1 of type O aphthovirus.
VP1 is the only structural polypeptide of aphthovirus able to stimulate the production of neutralizing antibody. The region of VP1 responsible for this activity was located by testing various proteolytic fragments of VP1 for their ability to compete for virus-specific antibodies in serum raised against the intact polypeptide. No antigenic activity could be detected in VP1 fragments isolated from trypsin-treated virus. Controlled digestion revealed that trypsin cleaved VP1 in four places in a preferred order, whereas chymotrypsin cut at a maximum of two sites. The initial cuts by the two proteases were made very close to each other, and in each case resulted in a greatly reduced affinity of the VP1 fragments for virus-specific antibodies in anti-VP1 serum. In contrast, aphthovirus was resistant to Staphylococcus aureus V8 protease, and treatment of isolated VP1 with this protease generated a peptide of mol. wt. 8500 which competed efficiently with virus for antiserum to VP1 and for an absorbed antiviral serum specific for trypsin-sensitive sites. The results indicate that these antisera interact specifically with aphthovirus at a single antigenic determinant located on VP1 approximately two-thirds of the way along the polypeptide sequence.


Relationship between FRA11F and 11q13 gene amplification in oral cancer.
Common fragile sites (CFS) are nonstaining gaps or breaks in chromosomes that are expressed under conditions inducing replicative stress. CFS have been suggested to play a role in epithelial cancers by their association with loss of heterozygosity, loss of gene expression, and/or gene amplification in the form of homogeneously staining regions (hsrs). In oral squamous-cell carcinomas (OSCC), amplification of chromosomal band 11q13 occurs in the form of an hsr. We suggested previously that CFS flanking 11q13 may be susceptible to breakage induced by tobacco or other carcinogens and/or human papillomavirus, promoting formation of the 11q13 amplicon. Examination of OSCC cell lines with 11q13 amplification using fluorescence in situ hybridization showed loss of FRA11F sequences, whereas cell lines without 11q13 amplification displayed an intact FRA11F site. Cell lines with more complex 11q rearrangements expressed FRA11F in the form of an inverted duplication, characteristic of breakage-fusion-bridge cycles. Our findings suggest that gene amplification involving chromosomal band 11q13 in OSCC may be initiated by breakage at FRA11F.


The role of TCF3 as potential master regulator in blastemal Wilms tumors.
Wilms tumors are the most common type of pediatric kidney tumors. While the overall prognosis for patients is favorable, especially tumors that exhibit a blastemal subtype after preoperative chemotherapy have a poor prognosis. For an improved risk assessment and therapy stratification, it is essential to identify the driving factors that are distinctive for this aggressive subtype. In our study, we compared gene expression profiles of 33 tumor biopsies (17 blastemal and 16 other tumors) after neoadjuvant chemotherapy. The analysis of this dataset using the Regulator Gene Association Enrichment algorithm successfully identified several biomarkers and associated molecular mechanisms that distinguish between blastemal and nonblastemal Wilms tumors. Specifically, regulators involved in embryonic development and epigenetic processes like chromatin remodeling and histone modification play an essential role in blastemal tumors. In this context, we especially identified TCF3 as the central regulatory element. Furthermore, the comparison of ChIP-Seq data of Wilms tumor cell cultures from a blastemal mouse xenograft and a stromal tumor provided further evidence that the chromatin states of blastemal cells share characteristics with embryonic stem cells that are not present in the stromal tumor cell line. These stem-cell like characteristics could potentially add to the increased malignancy and chemoresistance of the blastemal subtype. Along with TCF3, we detected several additional biomarkers that are distinctive for blastemal Wilms tumors after neoadjuvant chemotherapy and that may provide leads for new therapeutic regimens.


Post-Surgical Clinical Monitoring of Soft Tissue Wound Healing in Periodontal and Implant Surgery.
Clinical features of surgical soft tissue wound healing in dentistry have been rarely discussed in the international literature. The aim of the present paper is to highlight both the main clinical findings of surgical wound healing, especially in periodontal and implant dentistry, and the wound healing monitoring procedures which should be followed. Wound inspection after careful food and plaque debridement is the essential part of wound healing monitoring. Periodontal and peri-implant probing should be performed only after tissue healing has been completed and not on a weekly basis in peri-implant tissue monitoring. Telephone follow-up and patient self-assessment scales can also be used the days following surgery to monitor the most common surgical complications such as pain, swelling, bleeding, and bruising. Wound healing monitoring is an important concern in all surgical procedures since it allows to identify signs or/and symptoms possibly related to surgical complications.


Laparoscopic Roux-en-Y gastric bypass: defining the learning curve.
Increasing numbers of laparoscopic surgeons are performing laparoscopic Roux-en-Y gastric bypass (LGB). Our aim was to determine the length of the learning curve for a skilled laparoscopic surgeon. The study population consisted of the first 225 consecutive LGB procedures attempted by one laparoscopic surgeon (HJS). Outcome parameters included mortality, morbidity, operative time, and conversion to an open procedure. Average operative time decreased from 189 min (first 75 patients) to 125 minutes (last 75 patients). Most of the improvement in operative time occurred over the first 75 patients. The perioperative complication rate decreased from 32% (first 75 patients) to 15% (second and third groups of 75 patients). Complication rates did not significantly decrease after the first 75 patients. Low mortality and conversion rates were achieved early in the series. Low mortality rates and low conversion rates can be achieved early in the learning curve for LGB. Complication rates plateau after approximately 75 LGBs, and operative times decrease substantially over the initial 75 cases. Operative times continue to decrease at a slower rate beyond 75 cases.


Specificity of the stress electrocardiogram during adenosine myocardial perfusion imaging in patients taking digoxin.
In patients taking digoxin, the exercise electrocardiogram has a lower specificity for detecting coronary artery disease. However, the effect of digoxin on adenosine-induced ST-segment depression is unknown. The purpose of this study was to evaluate the specificity of the electrocardiogram during adenosine myocardial perfusion imaging in patients taking digoxin. Between May 1991 and September 1997, patients (n = 99) taking digoxin who underwent adenosine stress imaging with thallium-201 or technetium-99m sestamibi and coronary angiography within 3 months were retrospectively identified. Exclusion criteria included prior myocardial infarction, coronary artery angioplasty or bypass surgery, left bundle branch block, paced ventricular rhythm, or significant valvular disease. Twelve-lead electrocardiograms were visually interpreted at baseline, during adenosine infusion, and during the recovery period. The stress electrocardiogram was considered positive if there was > or =1 mm additional horizontal or downsloping ST-segment depression or elevation 0.08 seconds after the J-point compared with the baseline tracing. ST-segment depression and/or elevation occurred in 24 of 99 patients. There were only 2 false-positive stress electrocardiograms, yielding a specificity of 87% and positive predictive value of 92%. All 8 patients with > or =2 mm ST segment depression had multivessel disease by coronary angiography. ST-segment depression or elevation during adenosine myocardial perfusion imaging in patients taking digoxin is highly specific for coronary artery disease. Marked (> or =2 mm) ST-segment depression and/or ST-segment elevation is associated with a high likelihood of multivessel disease.


Substance Abuse Recovery after Experiencing Homelessness and Mental Illness: Case Studies of Change Over Time.
OBJECTIVE: This paper addresses how consumers with dual diagnosis, who were formerly homeless but are now living in supportive housing, understand their recovery from substance abuse (i.e., substance abuse or dependence). Specifically, this study examined: What can be learned about substance abuse recovery from consumers considered to be doing well; how past substance abuse fits into their present-day narratives; and how (if at all) policies of harm reduction versus abstinence are regarded as affecting recovery efforts. METHODS: As part of a federally-funded qualitative study, 38 individuals who met criteria for having achieved a measure of success in mental health recovery were purposively sampled from two supportive housing agencies - one using a harm reduction and the other an abstinence model. Researchers conducted in-depth interviews and used case study analysis, the latter including the development of case summaries and data matrices, to focus on substance abuse recovery in the larger context of participants' lives. RESULTS: Recovery from substance abuse was depicted as occurring either through discrete decisions or gradual processes; achieving recovery was distinct from maintaining recovery. Emergent themes related to achievement included: (a) pivotal events and people (b) maturation, and (c) institutionalization. Central themes to maintaining recovery were: (a) housing, (b) self-help, and (c) the influence of significant others. CONCLUSIONS: These findings capture a complex picture of overcoming substance abuse that largely took place outside of formal treatment and was heavily dependent on broader contexts. Equally important is that consumers themselves did not necessarily view substance abuse recovery as a defining feature of their life story. Indeed, recovery from substance abuse was seen as overcoming one adversity among many others during their troubled life courses.


Younger age and antibody induction increase the risk for infection in pediatric renal transplantation: a NAPRTCS report.
Infections now exceed rejection as a cause of hospitalization in the first 2 years post-renal transplantation. We analyzed data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) to determine risks for hospitalization for infection (HI), either bacterial (HBI) or viral (HVI). 3106 children transplanted between 1996 and 2002 with 2-year follow-up were analyzed. Univariate and multivariate logistic regression analyses identified factors for cause-specific hospitalization. 23.4% experienced HBI, 23.9% HVI; 8.9% were hospitalized for both. Children 0-1 years age at transplant had higher rates of HI (64.2%), HBI (40.3%) and HVI (43.3%) compared to >12 years (31%, 17.5% and 18.9%, p < 0.0001). In comparison to no induction, patients receiving monoclonal or polyclonal antibody were more likely to have HI (>42% vs. 34.0%), HBI (>24% vs. 21%) or HVI (>29% vs. 21%, all p < 0.003) but had equivalent graft survival (p = NS). Higher rates of HI, HBI and HVI were also seen with prophylactic antimicrobial use and with >5 transfusions pretransplant. Since antibody induction in recent era was not associated with better graft or patient survival but was associated with more HI and HVI, the need for routine antibody induction in children needs to be reassessed.


Increased complement activation in human type 1 diabetes pancreata.
Evidence supporting an association between complement (C) and type 1 diabetes (T1D) includes the identification of C-fixing islet cell autoantibodies in T1D sera and genetic associations with the major histocompatibility complex III C4 region on chromosome 6. Therefore, we investigated whether C activation was present in pancreata from those with or at increased risk (positive for T1D associated autoantibodies) for T1D. Immunohistochemical techniques were used to measure the C degradation product C4d in organ donor pancreata from patients with T1D and type 2 diabetes and autoantibody-positive and autoantibody-negative subjects. Median C4d antigen density differed across the groups (P < 0.0001) and was highest in patients with T1D. C4d immunostaining localized to the blood vessel endothelium and extracellular matrix surrounding blood vessels and exocrine ducts. Receiver operating characteristic analysis resulted in 81.8% sensitivity and 94.4% specificity for C4d staining. These data suggest that C activation is occurring within pancreata from patients with T1D and C4d may be a biomarker for T1D.


Immunoglobulin D (IgD)-deficient mice reveal an auxiliary receptor function for IgD in antigen-mediated recruitment of B cells.
To assess the role of immunoglobulin D (IgD) in vivo we generated IgD-deficient mice by gene targeting and studied B cell development and function in the absence of IgD expression. In the mutant animals, conventional and CD5-positive (B1) B cells are present in normal numbers, and the expression of the surface markers CD22 and CD23 in the compartment of conventional B cells indicates acquisition of a mature phenotype. As in wild-type animals, most of the peripheral B cells are resting cells. The IgD-deficient mice respond well to T cell-independent and -dependent antigens. However, in heterozygous mutant animals, B cells expressing the wild type IgH locus are overrepresented in the peripheral B cell pool, and T cell-dependent IgG1 responses are further dominated by B cells expressing the wild-type allele. Similarly, in homozygous mutant (IgD-deficient) animals, affinity maturation is delayed in the early primary response compared to control animals, although the mutants are capable of generating high affinity B cell memory. Thus, rather than being involved in major regulatory processes as had been suggested, IgD seems to function as an antigen receptor optimized for efficient recruitment of B cells into antigen-driven responses. The IgD-mediated acceleration of affinity maturation in the early phase of the T cell-dependent primary response may confer to the animal a critical advantage in the defense against pathogens.


Investigating the Effect of Personality, Internet Literacy, and Use Expectancies in Internet-Use Disorder: A Comparative Study between China and Germany.
Research on Internet-use Disorder (IUD) has increased rapidly, indicating its clinical and global importance. Past studies suggested cultural diversity regarding the prevalence of an IUD, e.g., between Asian and European countries. Additionally, it was found that personality factors, Internet-related cognitions and specific competences seem to influence IUD tendencies, but research lacks in cultural comparative studies regarding these mechanisms. This study focuses on differences between Germany and China regarding the above-mentioned characteristics. German (n = 411; M = 20.70 years, SD = 3.34 years) and Chinese participants (n = 410; M = 20.72 years, SD = 2.65 years) answered the short Internet Addiction Test, Big Five Inventories, the Internet-use Expectancies Scale, as well as the Internet Literacy Questionnaire. The results revealed higher occurrence of IUD symptoms in China. Furthermore, Chinese participants scored significantly higher on neuroticism and agreeableness, whereas German participants scored higher on extraversion and openness. Compared to German participants, Chinese showed higher expectancies to avoid negative feelings online and to be positively reinforced. Regarding Internet literacy, German participants indicated higher skills concerning the reflection and critical analysis of online content, whereas Chinese showed higher expertise in producing and interacting online. Further, simple slope analyses indicated that certain Internet literacy domains were related differentially to IUD symptoms in Germany and China. While Chinese participants with higher reflective skills indicated highest IUD symptoms, reflective skills revealed no effect in Germany. Additionally, higher self-regulative skills correlated with lower IUD symptoms in the German, but not in the Chinese sample. The results give a hint to potential cultural differences regarding IUD, especially on the predictive and protective role of Internet literacy domains.


NOS3 Glu298Asp genotype and blood pressure response to endurance training: the HERITAGE family study.
Endothelium-dependent vasodilation is a mechanism that may affect blood pressure response to endurance training. Because NO plays a central role in this process, the endothelial NO synthase gene is a good candidate for the regulation of exercise blood pressure. We investigated the associations between an endothelial NO synthase gene polymorphism (Glu298Asp) and endurance training-induced changes in resting and submaximal exercise blood pressure in 471 white subjects of the HERITAGE Family Study. Two submaximal exercise tests at 50 W were conducted both before and after a 20-week endurance training program. Steady-state exercise blood pressure was measured twice in each test with an automated unit. The Glu298Asp polymorphism was typed with a PCR-based method and digestion with BAN:II. Both systolic and diastolic blood pressure at 50 W decreased in response to the training program, whereas resting blood pressure remained unchanged. The decrease in diastolic blood pressure at 50 W was greater (P=0.0005, adjusted for age, gender, baseline body mass index, and baseline diastolic blood pressure at 50 W) in the Glu/Glu homozygotes (4.4 [SEM 0.4] mm Hg, n=187) than in the heterozygotes (3.1 [0.4] mm Hg, n=213) and the Asp/Asp homozygotes (1.3 [0.7] mm Hg, n=71). The genotype accounted for 2.3% of the variance in diastolic blood pressure at 50 W training response. Both the Glu298 homozygotes and the heterozygotes had a greater (P=0.013) training-induced reduction in rate-pressure product at 50 W than the Asp298 homozygotes. These data suggest that DNA sequence variation in the endothelial NO synthase gene locus is associated with the endurance training-induced decreases in submaximal exercise diastolic blood pressure and rate-pressure product in sedentary normotensive white subjects.


Parent-child relationships and ADHD symptoms: a longitudinal analysis.
Evidence both from psychological research and clinical intervention studies suggests that there are bidirectional influences between overt child behavior problems and parent-child relations. Very little research however, has considered the pattern of relations that exists between Attention Deficit Hyperactivity Disorder (ADHD) and the parent-child relationship within a longitudinal context. Using a longitudinal community sample from the United Kingdom which included 194 school aged children (46% male and 54% female) and both parents, this study examined the relationship between child ADHD symptoms and displays of rejection in the parent-child relationship. These relationships were investigated separately for mothers and fathers using cross-lagged panel correlation and reciprocal effects analysis. Mothers and fathers reported on ADHD symptoms and children reported on their feelings of rejection in the mother-child and father-child relationships. Results suggested differences in the direction of effects linking mother- and father-child rejection and child ADHD symptoms; with ADHD symptoms affecting the mother-child relationship and the converse pattern of effects noted for fathers. Implications for future research focusing on the link between ADHD symptoms and parent-child relationships are discussed.


Determination of netropsin-DNA binding constants from footprinting data.
A theory for deriving drug-DNA site binding constants from footprinting data is presented. Plots of oligonucleotide concentration, as a function of drug concentration, for various cutting positions on DNA are required. It is assumed that the rate of cleavage at each nucleotide position is proportional to the concentration of enzyme at that nucleotide and to the probability that the nucleotide is not blocked by drug. The probability of a nucleotide position not being blocked is calculated by assuming a conventional binding equilibrium for each binding site with exclusions for overlapping sites. The theory has been used to evaluate individual site binding constants for the antiviral agent netropsin toward a 139 base pair restriction fragment of pBR-322 DNA. Drug binding constants, evaluated from footprinting data in the presence of calf thymus DNA and poly(dGdC) as carrier and in the absence of carrier DNA, were determined by obtaining the best fit between calculated and experimental footprinting data. Although the strong sites on the fragment were all of the type (T.A)4, the value of the binding constant was strongly sequence dependent. Sites containing the dinucleotide sequence 5'-TA-3' were found to have significantly lower binding constants than those without this sequence, suggesting that an adenine-adenine clash produces a DNA structural alteration in the minor groove which discourages netropsin binding to DNA. The errors, scope, and limitations associated with the method are presented and discussed.


Age interactions in the development of naturally acquired immunity to Plasmodium falciparum and its clinical presentation.
Naturally acquired malaria immunity has many determinants and, in the absence of immunological markers of protection, studies assessing malaria incidence through clinical endpoints remain an approach to defining immunity acquisition. We investigated the role of age in disease incidence and the effects of chemoprophylaxis on clinical immunity development to Plasmodium falciparum during a randomised controlled trial. A total of 415 Tanzanian infants were randomly assigned to receive weekly malaria prophylaxis with Deltaprim (3.125 mg of pyrimethamine plus 25 mg of dapsone) or placebo between the ages of 2 and 12 mo. Children were followed up until 4 y of age. Uncomplicated febrile malaria, severe malaria, and anaemia morbidity were assessed through hospital-based passive surveillance. Compared with the group of control participants, there was a marked reduction in the incidence of clinical malaria, severe malaria, and anaemia in the group of children who had received chemoprophylaxis during the first year of life. After discontinuing the intervention, there was a significant increase in the incidence of clinical malaria for 2 y. The cumulative rates of clinical malaria, by age 4 y, were slightly higher in the group of children who had previously received chemoprophylaxis: 3.22 episodes versus 3.02 episodes in the group of control participants; rate difference 0.20 (95% confidence interval [CI]: -0.21 to 0.59). By age 4 y, the cumulative rates of severe malaria, however, were slightly lower in chemosuppressed children (0.47 versus 0.59) (rate difference -0.12 [95% CI: -0.27 to 0.03]). The number of episodes of anaemia was also slightly lower in chemosuppressed children by age 4 y: 0.93 episodes (95% CI: 0.79 to 0.97) versus 1.12 episodes in the group of control participants (95% CI: 0.97 to 1.28) (rate difference -0.19 [95% CI: -0.40 to 0.01]), respectively. Reducing exposure to P. falciparum antigens through chemoprophylaxis early in life can delay immunity acquisition. Infants appear to acquire immunity faster than older children, but have a higher risk of developing severe forms of malaria and anaemia. These findings provide insight on the interplay between immunity and exposure-reduction interventions.


Concurrent sound segregation is enhanced in musicians.
The ability to segregate simultaneously occurring sounds is fundamental to auditory perception. Many studies have shown that musicians have enhanced auditory perceptual abilities; however, the impact of musical expertise on segregating concurrently occurring sounds is unknown. Therefore, we examined whether long-term musical training can improve listeners' ability to segregate sounds that occur simultaneously. Participants were presented with complex sounds that had either all harmonics in tune or the second harmonic mistuned by 1%, 2%, 4%, 8%, or 16% of its original value. The likelihood of hearing two sounds simultaneously increased with mistuning, and this effect was greater in musicians than nonmusicians. The segregation of the mistuned harmonic from the harmonic series was paralleled by an object-related negativity that was larger and peaked earlier in musicians. It also coincided with a late positive wave referred to as the P400 whose amplitude was larger in musicians than in nonmusicians. The behavioral and electrophysiological effects of musical expertise were specific to processing the mistuned harmonic as the N1, the N1c, and the P2 waves elicited by the tuned stimuli were comparable in both musicians and nonmusicians. These results demonstrate that listeners' ability to segregate concurrent sounds based on harmonicity is modulated by experience and provides a basis for further studies assessing the potential rehabilitative effects of musical training on solving complex scene analysis problems illustrated by the cocktail party example.


Effective Discipline to Raise Healthy Children.
Pediatricians are a source of advice for parents and guardians concerning the management of child behavior, including discipline strategies that are used to teach appropriate behavior and protect their children and others from the adverse effects of challenging behavior. Aversive disciplinary strategies, including all forms of corporal punishment and yelling at or shaming children, are minimally effective in the short-term and not effective in the long-term. With new evidence, researchers link corporal punishment to an increased risk of negative behavioral, cognitive, psychosocial, and emotional outcomes for children. In this Policy Statement, the American Academy of Pediatrics provides guidance for pediatricians and other child health care providers on educating parents about positive and effective parenting strategies of discipline for children at each stage of development as well as references to educational materials. This statement supports the need for adults to avoid physical punishment and verbal abuse of children.


Wheat grass juice may improve hematological toxicity related to chemotherapy in breast cancer patients: a pilot study.
Myelotoxicity induced by chemotherapy may become life-threatening. Neutropenia may be prevented by granulocyte colony-stimulating factors (GCSF), and epoetin may prevent anemia, but both cause substantial side effects and increased costs. According to non-established data, wheat grass juice (WGJ) may prevent myelotoxicity when applied with chemotherapy. In this prospective matched control study, 60 patients with breast carcinoma on chemotherapy were enrolled and assigned to an intervention or control arm. Those in the intervention arm (A) were given 60 cc of WGJ orally daily during the first three cycles of chemotherapy, while those in the control arm (B) received only regular supportive therapy. Premature termination of treatment, dose reduction, and starting GCSF or epoetin were considered as "censoring events." Response rate to chemotherapy was calculated in patients with evaluable disease. Analysis of the results showed that five censoring events occurred in Arm A and 15 in Arm B (P = 0.01). Of the 15 events in Arm B, 11 were related to hematological events. No reduction in response rate was observed in patients who could be assessed for response. Side effects related to WGJ were minimal, including worsening of nausea in six patients, causing cessation of WGJ intake. In conclusion, it was found that WGJ taken during FAC chemotherapy may reduce myelotoxicity, dose reductions, and need for GCSF support, without diminishing efficacy of chemotherapy. These preliminary results need confirmation in a phase III study.


Contemporaneous trace and body fossils from a late Pleistocene Lakebed in Victoria, Australia, allow assessment of bias in the fossil record.
The co-occurrence of vertebrate trace and body fossils within a single geological formation is rare and the probability of these parallel records being contemporaneous (i.e. on or near the same bedding plane) is extremely low. We report here a late Pleistocene locality from the Victorian Volcanic Plains in south-eastern Australia in which demonstrably contemporaneous, but independently accumulated vertebrate trace and body fossils occur. Bite marks from a variety of taxa are also present on the bones. This site provides a unique opportunity to examine the biases of these divergent fossil records (skeletal, footprints and bite marks) that sampled a single fauna. The skeletal record produced the most complete fauna, with the footprint record indicating a markedly different faunal composition with less diversity and the feeding traces suggesting the presence, amongst others, of a predator not represented by either the skeletal or footprint records. We found that the large extinct marsupial predator Thylacoleo was the only taxon apparently represented by all three records, suggesting that the behavioral characteristics of large carnivores may increase the likelihood of their presence being detected within a fossil fauna. In contrast, Diprotodon (the largest-ever marsupial) was represented only by trace fossils at this site and was absent from the site's skeletal record, despite its being a common and easily detected presence in late Pleistocene skeletal fossil faunas elsewhere in Australia. Small mammals absent from the footprint record for the site were represented by skeletal fossils and bite marks on bones.


Vertical transmission of hepatitis B virus during pregnancy and delivery in Denmark.
In Denmark, pregnant women have been screened for hepatitis B virus (HBV) since 2005, and children born to HBV-infected mothers offered hepatitis B immunoglobulin at birth, vaccination against HBV at birth and after 1, 2 and 12 months. The purpose of this study was to determine the risk of vertical HBV transmission in children born to mothers with chronic HBV infection, to investigate the antibody response in the children and to investigate possible maternal predictive risk factors for HBV transmission. Through the Danish Database for Hepatitis B and C, we identified 589 HBV-infected women who had given birth to 686 children, of whom 370 children were born to 322 women referred to hospital. 132 (36%) children, born to 109 mothers, were included in the study; 128 children had blood samples tested for HBsAg, anti-HBc (total), anti-HBs and HBV-DNA and four children had saliva samples tested for anti-HBc. We found vertical HBV transmission in Denmark to be 2.3% [95% CI: 0.5, 6.5], a high proportion of HBsAg-negative children with low levels of anti-HBs (18.4%) and a high proportion (15.2%) with resolved HBV infection. No maternal risk factor was statistically significantly associated with HBV vertical transmission. In a HBV low prevalence setting as Denmark, despite a national vaccination program, vertical HBV transmission occurred in 2.3% of children born to HBV-infected mothers. In addition, a high proportion of the children had insufficient anti-HBs levels and a high proportion had serological signs of resolved HBV infection.


Tramadol has a better potency ratio relative to morphine in neuropathic than in nociceptive pain models.
Treatment of neuropathic pain remains a challenge and the role of various analgesics in this setting is still debated. The effects of tramadol, an atypically acting analgesic with a combined opioid and monoaminergic mechanism of action, and morphine, a prototypical opioid, were tested in rat models of neuropathic and nociceptive pain. Cold allodynia and mechanical hypersensitivity, symptoms of neuropathic pain, were studied in rat models of mononeuropathic pain. Cold allodynia was analyzed in the chronic constriction injury (CCI) model and mechanical hypersensitivity was analyzed in the spinal nerve ligation (SNL) model. Heat-induced rat tail-flick latencies were determined as measure for nociceptive pain. Cold allodynia and mechanical hypersensitivity were strongly attenuated with similar absolute potency after intravenous administration of tramadol and morphine. The doses of drug that were calculated to result in 50% pain inhibition (ED(50)) for tramadol and morphine were 2.1 and 0.9 mg/kg, respectively, in CCI rats and 4.3 and 3.7 mg/kg, respectively, in SNL rats. In the tail-flick assay of acute nociception, the potency of the two drugs differed markedly, as seen by ED(50) values of 5.5 and 0.7 mg/kg intravenously for tramadol and morphine, respectively. Accordingly, the analgesic potency ratio (ED(50) tramadol/ED(50) morphine) of both compounds differed in neuropathic (potency ratio 2.3 in CCI and 1.2 in SNL) and nociceptive pain models (potency ratio 7.8), suggesting a relative increase in potency of tramadol in neuropathic pain compared with nociceptive pain. The results of this study are consistent with clinical data supporting the efficacy of opioids in neuropathic pain conditions, and furthermore suggest an additional contribution of the monoaminergic mechanism of tramadol in the treatment of neuropathic pain states.


Recovery in soccer: part I - post-match fatigue and time course of recovery.
In elite soccer, players are frequently required to play consecutive matches interspersed by 3 days and complete physical performance recovery may not be achieved. Incomplete recovery might result in underperformance and injury. During congested schedules, recovery strategies are therefore required to alleviate post-match fatigue, regain performance faster and reduce the risk of injury. This article is Part I of a subsequent companion review and deals with post-match fatigue mechanisms and recovery kinetics of physical performance (sprints, jumps, maximal strength and technical skills), cognitive, subjective and biochemical markers. The companion review will analyse recovery strategies used in contemporary professional soccer. Soccer involves many physically demanding activities including sprinting, changes in running speed, changes of direction, jumps and tackles, as well as technical actions such as dribbling, shooting and passing. These activities lead to a post-match fatigue that is linked to a combination of dehydration, glycogen depletion, muscle damage and mental fatigue. The magnitude of soccer match-induced fatigue, extrinsic factors (i.e. match result, quality of the opponent, match location, playing surface) and/or intrinsic factors (i.e. training status, age, gender, muscle fibre typology), potentially influence the time course of recovery. Recovery in soccer is a complex issue, reinforcing the need for future research to estimate the quantitative importance of fatigue mechanisms and identify influencing factors. Efficient and individualized recovery strategies may consequently be proposed.


Evaluation of multiparameter flow cytometry for the detection of breast cancer tumor cells in blood samples.
We comparatively evaluated different cytokeratin (CK) reagents analyzed by flow cytometry (FCM) for the identification of the best combination of DNA/CK staining for detecting minimal numbers of breast cancer cells in peripheral blood (PB). In 59 primary breast cancer tumors, we comparatively analyzed the reactivity for up to 6 different anti-CK reagents using multiparameter FCM: anti-CK7, anti-CK20, anti-pan-CK, anti-CK8/CK18, anti-CK8, and anti-CK18. Afterward, dilutional experiments of Michigan Cancer Foundation (MCF)7 breast cancer cells in PB were performed, and the sensitivity of a DNA/CK18 staining was evaluated. Our results showed that anti-CK18 reagents were those providing the brightest and more sensitive staining for primary breast cancer tumor cells by FCM. Dilutional experiments of MCF cells in PB showed that the DNA/anti-CK18 double staining was highly specific for the identification of epithelial cells; its sensitivity ranged between 10(-6) and 10(-7) (detection of 1 tumor cell among 10(6) to 10(7) nucleated blood cells). Combined assessment of DNA cell contents and reactivity for CK18 by FCM is a sensitive method for the specific identification of breast cancer cells in PB.


Loss of heterozygosity suggests tumor suppressor gene responsible for primary hepatocellular carcinoma.
Primary hepatocellular carcinoma (PHC), epidemiologically associated with chronic hepatitis B virus (HBV) infection, has historically been felt to be caused by the activation or introduction of an oncogene. However, transforming sequences from human PHC have not been reproducibly isolated. In this paper, evidence is presented that suggests PHC may result instead from the loss of an anti-oncogene. Seven of 12 human primary liver tumors tested against a panel of restriction fragment length polymorphisms (RFLPs) demonstrated loss of constitutional heterozygosity for markers on chromosome 4. Tumor and nontumor liver tissue were typed for 11 chromosome 4 RFLPs. In addition, at least one RFLP on nine other chromosomes (1, 2, 6, 7, 9, 11, 13, 14, and 17) was tested for allelic loss. Seven of nine tumors constitutionally heterozygous for chromosome 4q markers showed allele loss in tumor tissue. Six of the seven samples were jointly informative for both 4p and 4q markers. Five of the six demonstrated loss for only 4q RFLPs. In one individual, in which two samples were taken from distant locations within the same tumor, both samples showed loss of the same alleles. Among the other chromosomes informative for allele loss, one tumor showed changes on 13q. No other changes were observed in RFLPs located on the eight other chromosomes tested. These results indicate that an anti-oncogene may be located on 4q and suggest a mechanism for PHC and other cancers seroepidemiologically related to virus infection. Liver cancer caused by chronic HBV infection or other environmental agents may be linked through genetic events responsible for the loss of a tumor suppressor locus (anti-oncogene) located on chromosome 4.


Response of the pulmonary circulation to acute hypoxia in the growing pig.
In a previous article we have analyzed the structure of the growing pig lung and correlated the findings with cardiorespiratory function studies on the same animals (J. Appl. Physiol: Respirat. Environ. Exercise Physiol. 45: 806-817, 1978). The present study analyzes the pulmonary and systemic vascular responses to acute hypoxia in some of those animals at three ages, 2-4, 5-8, and 9-12 wk, the lung of the 12-wk-old pig being structurally similar to that of the adult. In all anesthetized animals, acute hypoxia (5 min 10% fractional inspired oxygen concentration) increased mean pulmonary arterial pressure (Ppa) and total pulmonary resistance (TPR). The increase over base line of Ppa was 41.3% in animals aged 2-4 wk; 83.0% in those aged 5-8 wk, and 136.9% in those aged 9-12 wk; for TPR the increase in the three age groups was 66.4, 92.4, and 138.9%, respectively. This difference in vasoactivity with age is associated with the progressive extension of smooth muscle into the intra-acinar arterial tree, which we have previously shown is an important feature of the structural remodeling that occurs during postnatal lung development in both man and swine.


Responses in the start of Betula (birch) pollen seasons to recent changes in spring temperatures across Europe.
A shift in the timing of birch pollen seasons is important because it is well known to be a significant aeroallergen, especially in NW Europe where it is a notable cause of hay fever and pollen-related asthma. The research reported in this paper aims to investigate temporal patterns in the start dates of Betula (birch) pollen seasons at selected sites across Europe. In particular it investigates relationships between the changes in start dates and changes in spring temperatures over approximately the last 20 years. Daily birch pollen counts were used from Kevo, Turku, London, Brussels, Zurich and Vienna, for the core period from 1982 to 1999 and, in some cases, from 1970 to 2000. The sites represent a range of biogeographical situations from just within the Arctic Circle through to North West Maritime and Continental Europe. Pollen samples were taken with Hirst-type volumetric spore traps. Weather data were obtained from the sites nearest to the pollen traps. The timing of birch pollen seasons is known to depend mostly on a non-linear balance between the winter chilling required to break dormancy, and spring temperatures. Pollen start dates and monthly mean temperatures for January through to May were compiled to 5-year running means to examine trends. The start dates for the next 10 years were calculated from regression equations for each site, on the speculative basis that the current trends would continue. The analyses show regional contrasts. Kevo shows a marked trend towards cooler springs and later starts. If this continues the mean start date will become about 6 days later over the next 10 years. Turku exhibits cyclic patterns in start dates. A current trend towards earlier starts is expected to continue until 2007, followed by another fluctuation. London, Brussels, Zurich and Vienna show very similar patterns in the trends towards earlier start dates. If the trend continues the mean start dates at these sites will advance by about 6 days over the next 10 years. Following this work, amendments will be needed to pollen calendars and local predictive models. It will also be important to assess the implications of earlier seasons for allergy sufferers.


Analysis of Racial/Ethnic Representation in Select Basic and Applied Cancer Research Studies.
Over the past decades, consistent studies have shown that race/ethnicity have a great impact on cancer incidence, survival, drug response, molecular pathways and epigenetics. Despite the influence of race/ethnicity in cancer outcomes and its impact in health care quality, a comprehensive understanding of racial/ethnic inclusion in oncological research has never been addressed. We therefore explored the racial/ethnic composition of samples/individuals included in fundamental (patient-derived oncological models, biobanks and genomics) and applied cancer research studies (clinical trials). Regarding patient-derived oncological models (n = 794), 48.3% have no records on their donor's race/ethnicity, the rest were isolated from White (37.5%), Asian (10%), African American (3.8%) and Hispanic (0.4%) donors. Biobanks (n = 8,293) hold specimens from unknown (24.56%), White (59.03%), African American (11.05%), Asian (4.12%) and other individuals (1.24%). Genomic projects (n = 6,765,447) include samples from unknown (0.6%), White (91.1%), Asian (5.6%), African American (1.7%), Hispanic (0.5%) and other populations (0.5%). Concerning clinical trials (n = 89,212), no racial/ethnic registries were found in 66.95% of participants, and records were mainly obtained from Whites (25.94%), Asians (4.97%), African Americans (1.08%), Hispanics (0.16%) and other minorities (0.9%). Thus, two tendencies were observed across oncological studies: lack of racial/ethnic information and overrepresentation of Caucasian/White samples/individuals. These results clearly indicate a need to diversify oncological studies to other populations along with novel strategies to enhanced race/ethnicity data recording and reporting.


An examination of the measurement of flow heterogeneity in striated muscle.
This review leads us to a number of conclusions and suggestions for further study. First, we find wide differences in the meaning of flow heterogeneity, arising as a result of the different methods used. These differences will have to be reconciled to form a comprehensive view of the role of heterogeneity in determining vascular function. Second, in the future, the meaning of heterogeneity must be clearly defined and related to a particular microvascular component, and it is imperative that the differences in scale of heterogeneity be appreciated when comparing data from various laboratories. These heterogeneities have different implications for function, and failure to distinguish among them leads to confusion. Third, the degree to which perfusion heterogeneity is regulated in the microcirculation remains in doubt. Reports of variations in flow heterogeneity in response to physiological stimuli are for the most part based on highly questionable indirect methods. Fourth, the heterogeneity that can be demonstrated at the capillary level within striated muscle does not appear to be large relative to the capacity for the microcirculation to exchange most diffusible solutes. Thus, the inferences regarding heterogeneity, as evidenced by diffusible indicators, are likely to be the result of different preparations, damage to the preparations, or perhaps large-scale heterogeneities in the tissue. An alternate possibility would be that the heterogeneity occurs at the microvascular level but reflects some other aspect of microcirculatory function, such as length or hematocrit heterogeneities, but not flow heterogeneities. Fifth, flow heterogeneity within microvessels implies important consequences for capillary exchange and tissue oxygenation. Heterogeneities of velocity of a magnitude comparable to those observed by direct visualization of microcirculation can clearly produce reductions in oxygen supply to small tissue regions of a degree that may limit oxygen delivery, and thereby, tissue function. Sixth, flow heterogeneity may also influence capillary hematocrit and/or red cell spacing by producing cell separation at bifurcations and a resultant reduction in mean capillary tube hematocrit. There is as yet no agreement on why and how these hematocrits influence tissue oxygenation and function. Although several hypotheses are advanced to explain the distribution of blood flow and red cells within microcirculation, each lacks a critical experimental test at present.(ABSTRACT TRUNCATED AT 400 WORDS)


Recovery from injury: the UK burden of injury multicentre longitudinal study.
To estimate the likelihood of recovery at 1, 4 and 12 months post injury and investigate predictors of recovery in injured people attending an emergency department (ED) or admitted to hospital in the UK. Participants completed questionnaires at recruitment and 1, 4 and 12 months post injury or until recovered. Data were collected on injury details, sociodemographic characteristics, general health prior to injury and recovery. We compared three age groups: 5-17, 18-64 and 65 years and above. Modified Poisson regression estimated the relative risk of recovery. Multivariable models were built using backward stepwise regression. Sensitivity analyses assessed the effect of missing data. We recruited 1517 participants, 55% (n=836) ED attenders and 44% (n=661) hospital admissions. By 1 month after injury, 28% (285/968) had fully recovered, 54% (440/820) at 4 months and 71% (523/738) at 12 months. Recovery was independently associated with gender, admission status, injury severity, body region injured and place of injury for 5-17 year olds and 18-64 year olds and with gender, admission status, injury severity and long-term illness for those aged 65+. Injury severity and hospital admission were associated with recovery across all age groups, but not at every time point in each age group. Other factors varied between age groups or time points. Results were generally robust to imputing missing data. A range of factors was found to predict recovery among injured people. These could be used to identify those at risk of delayed recovery and to inform the design of interventions to maximise recovery.


Mental health clinicians' beliefs about medicines, attitudes, and expectations of improved medication adherence in patients.
Nonadherence to antipsychotic medications remains a major factor in poor clinical outcomes. This study sought to identify clinician beliefs about patients who do not adhere to treatment, the clinicians' own beliefs about medicines, and the impact of beliefs on efforts to enhance patient adherence. In total, 292 clinicians responded to an anonymous questionnaire that included questions about their beliefs and their efforts to enhance adherence. Results indicated that clinicians' beliefs about their own adequacy to enhance adherence significantly predicted actual efforts to enhance adherence. Both pessimism about outcomes and empathy for the patient predicted outcome expectancy. It was concluded that enhancing clinicians' beliefs about working with nonadherent patients is a potentially important ingredient in efforts to improve patient adherence.


Indocyanine green fluorescence imaging during laparoscopic rectal cancer surgery could reduce the incidence of anastomotic leakage: a single institutional retrospective cohort study.
There is insufficient evidence on whether indocyanine green (ICG) fluorescence angiography can reduce the incidence of anastomotic leakage (AL). This retrospective cohort study aimed to evaluate the effect of ICG fluorescence angiography on AL rates in laparoscopic rectal cancer surgery at a single institution. Patients who underwent laparoscopic low anterior resection or intersphincteric resection with ICG fluorescence angiography (ICG group; n = 73) and patients who underwent a similar surgical procedure for rectal cancer without ICG fluorescence (non-ICG group; n = 114) were enrolled consecutively in this study. ICG fluorescence angiography was performed prior to transection of the proximal colon, and anastomosis was performed with sufficient perfusion using ICG fluorescence imaging. AL incidence was compared between both groups, and the risk factors for AL were analyzed. AL occurred in 3 (4.1%) and 14 (12.3%) patients in the ICG and non-ICG groups, respectively. In the ICG group, the median perfusion time from ICG injection was 34 s, and 5 patients (6.8%) required revision of the proximal transection line. None of the patients requiring revision of the proximal transection line developed AL. In univariate analysis, longer operating time (odds ratio: 2.758; 95% confidence interval: 1.023-7.624) and no implementation of ICG fluorescence angiography (odds ratio: 3.266; 95% confidence interval: 1.038-11.793) were significant factors associated with AL incidence, although the creation of a diverting stoma or insertion of a transanal tube was insignificant. ICG fluorescence angiography was associated with a significant reduction in AL during laparoscopic rectal cancer surgery. Changes in the surgical plan due to ICG fluorescence visibility may help improve the short-term outcomes of patients with rectal cancer.


Effect of 10% sodium ascorbate hydrogel and delayed bonding on shear bond strength of composite resin and resin-modified glass ionomer to bleached enamel.
The aim of this study was to comparatively investigate the neutralizing effect of antioxidant treatment and delayed bonding after bleaching with hydrogen peroxide on the shear bond strength of a composite resin (CR) and resin-modified glass ionomer (RmGI) to enamel. Ninety-six freshly extracted human 3rd molars with flat enamel surfaces were divided into six experimental groups (n=12/group) and two control groups (n=12/group). After initial preparation, specimens in Groups 1 and 5 (control groups) were not bleached and the buccal enamel surface of specimens were bonded immediately with CR and RmGI. The samples of the remaining groups were all bleached six hours a day for seven days consecutively. Immediately after bleaching, groups two and six specimens were bonded with CR and RmGI. Groups 3 and 7 specimens were immersed in distilled water at 37°C for 7 days and the specimens in Groups 4 and 8 were treated with 10% sodium ascorbate as an antioxidant agent after bleaching. Specimens in Groups 3 and 4 were bonded with CR and Groups 7 and 8 specimens were bonded with RmGI immediately. After specimens were bonded, the shear bond strength (SBS) was measured. The SBS data analyses were subjected to one-way analysis of variance (ANOVA) followed by Tukey test for comparison of specific mean values. The mean SBS value in Group 2 (immediately bonded with CR after bleaching) was significantly lower than other CR groups (P=0.045). RmGI did not bond to buccal enamel surface of specimens in group 6. There was no significant difference between other groups bonded with RmGI (P>0.05). Applying 10% sodium ascorbate hydrogel and one week delay before bonding resulted in reversal of reduced bond strength of CR and RmGI to bleached enamel.


Genomic profiling of inflammatory breast cancer: a review.
Inflammatory breast cancer (IBC) is a rare but aggressive form of breast cancer. Despite efforts in the past decade to delineate the molecular biology of IBC by applying high-throughput molecular profiling technologies to clinical samples, IBC remains insufficiently characterized. The reasons for that include limited sizes of the study population, heterogeneity with respect to the composition of the IBC and non-IBC control groups and technological differences across studies. In 2008, the World IBC Consortium was founded to foster collaboration between research groups focusing on IBC. One of the initial projects was to redefine the molecular profile of IBC using an unprecedented number of samples and search for gene signatures associated with survival and response to neo-adjuvant chemotherapy. Here, we provide an overview of all the molecular profiling studies that have been performed on IBC clinical samples to date.


Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology.
Regulated cell necrosis supports immune and anti-infectious strategies of the body; however, dysregulation of these processes drives pathological organ damage. Pseudomonas aeruginosa expresses a phospholipase, ExoU that triggers pathological host cell necrosis through a poorly characterized pathway. Here, we investigated the molecular and cellular mechanisms of ExoU-mediated necrosis. We show that cellular peroxidised phospholipids enhance ExoU phospholipase activity, which drives necrosis of immune and non-immune cells. Conversely, both the endogenous lipid peroxidation regulator GPX4 and the pharmacological inhibition of lipid peroxidation delay ExoU-dependent cell necrosis and improve bacterial elimination in vitro and in vivo. Our findings also pertain to the ExoU-related phospholipase from the bacterial pathogen Burkholderia thailandensis, suggesting that exploitation of peroxidised phospholipids might be a conserved virulence mechanism among various microbial phospholipases. Overall, our results identify an original lipid peroxidation-based virulence mechanism as a strong contributor of microbial phospholipase-driven pathology.


Human neoplasms elicit multiple specific immune responses in the autologous host.
Expression of cDNA libraries from human melanoma, renal cancer, astrocytoma, and Hodgkin disease in Escherichia coli and screening for clones reactive with high-titer IgG antibodies in autologous patient serum lead to the discovery of at least four antigens with a restricted expression pattern in each tumor. Besides antigens known to elicit T-cell responses, such as MAGE-1 and tyrosinase, numerous additional antigens that were overexpressed or specifically expressed in tumors of the same type were identified. Sequence analyses suggest that many of these molecules, besides being the target of a specific immune response, might be of relevance for tumor growth. Antibodies to a given antigen were usually confined to patients with the same tumor type. The unexpected frequency of human tumor antigens, which can be readily defined at the molecular level by the serological analysis of autologous tumor cDNA expression cloning, indicates that human neoplasms elicit multiple specific immune responses in the autologous host and provides diagnostic and therapeutic approaches to human cancer.


Clinical manifestations of telomere biology disorders in adults.
Telomere biology disorders (TBDs) are a spectrum of inherited bone marrow failure syndromes caused by impaired telomere function due to pathogenic germline variants in genes involved in telomere maintenance. TBDs can affect many organ systems and are often thought of as diseases of childhood. However, TBDs may present in mid- or even late adulthood with features similar to but not always the same as the childhood-onset TBDs. Adult-onset TBDs are often cryptic with isolated pulmonary, liver, or hematologic disease, or cancer, and may lack the classic disease-defining triad of abnormal skin pigmentation, nail dysplasia, and oral leukoplakia. Diagnostics include detection of very short leukocyte telomeres and germline genetic testing. Notably, adult-onset TBDs may show telomeres in the 1st to 10th percentile for age, and some cases may not have an identifiable genetic cause. TBD genetic etiology includes all modes of inheritance, with autosomal dominant the most frequent in adult-onset disease. Variable symptom onset due to incomplete penetrance, variable expressivity, and genetic anticipation add to the diagnostic challenges. Adult-onset TBDs are likely underrecognized, but their correct identification is of utmost importance, since affected patients are faced with numerous clinical complications, including but not limited to an increased risk of malignancies requiring close surveillance for early detection. Currently lung, liver, or hematopoietic cell transplants are the only curative therapeutic approaches but can be complicated by comorbidities, despite improved medical care. This review highlights the challenges of identifying adult-onset TBDs and addresses currently recommended clinical screening measures and therapy options.


Safety of trivalent inactivated influenza vaccine in children 6 to 23 months old.
Beginning with the winter season of 2004-2005, influenza vaccination has been recommended for all children 6 to 23 months old in the United States. However, its safety in young children has not been adequately studied in large populations. To screen for medically attended events in the clinic, emergency department, or hospital after administration of trivalent inactivated influenza vaccine in children 6 to 23 months old. Retrospective cohort using self-control analysis, with chart review of significant medically attended events at 8 managed care organizations in the United States that comprise the Vaccine Safety Datalink. Participants were all children in the Vaccine Safety Datalink cohort 6 to 23 months old who received trivalent inactivated influenza vaccine between January 1, 1991, and May 31, 2003 (45,356 children with 69,359 vaccinations). Any medically attended event significantly associated with trivalent inactivated influenza vaccine in risk windows 0 to 3 days, 1 to 14 days (primary analysis), 1 to 42 days, or 15 to 42 days after vaccination, compared with 2 control periods, one before vaccination and the second after the risk window. All individual ICD-9 codes as well as predefined aggregate codes were examined. Before chart review, only 1 diagnosis, gastritis/duodenitis, was more likely to occur in the 14 days after trivalent inactivated influenza vaccine (matched odds ratio [OR], 5.50; 95% confidence interval [CI], 1.22-24.81 for control period 1, and matched OR, 4.33; 95% CI, 1.23-15.21 for control period 2). Thirteen medically attended events were less likely to occur after trivalent inactivated influenza vaccine, including acute upper respiratory tract infection, asthma, bronchiolitis, and otitis media. After chart review, gastritis/duodenitis was not significantly associated with trivalent inactivated influenza vaccine (matched OR, 4.00; 95% CI, 0.85-18.84 for control period 1; matched OR, 3.34; 95% CI, 0.92-12.11 for control period 2). In the largest population-based study to date of the safety of trivalent inactivated influenza vaccine in young children, there were very few medically attended events, none of which were serious, significantly associated with the vaccine. This study provides additional evidence supporting the safety of universally immunizing all children 6 to 23 months old with influenza vaccine.