Theory of mind in utterance interpretation: the case from clinical pragmatics.
The cognitive basis of utterance interpretation is an area that continues to provoke intense theoretical debate among pragmatists. That utterance interpretation involves some type of mind-reading or theory of mind (ToM) is indisputable. However, theorists are divided on the exact nature of this ToM-based mechanism. In this paper, it is argued that the only type of ToM-based mechanism that can adequately represent the cognitive basis of utterance interpretation is one which reflects the rational, intentional, holistic character of interpretation. Such a ToM-based mechanism is supported on conceptual and empirical grounds. Empirical support for this view derives from the study of children and adults with pragmatic disorders. Specifically, three types of clinical case are considered. In the first case, evidence is advanced which indicates that individuals with pragmatic disorders exhibit deficits in reasoning and the use of inferences. These deficits compromise the ability of children and adults with pragmatic disorders to comply with the rational dimension of utterance interpretation. In the second case, evidence is presented which suggests that subjects with pragmatic disorders struggle with the intentional dimension of utterance interpretation. This dimension extends beyond the recognition of communicative intentions to include the attribution of a range of cognitive and affective mental states that play a role in utterance interpretation. In the third case, evidence is presented that children and adults with pragmatic disorders struggle with the holistic character of utterance interpretation. This serves to distort the contexts in which utterances are processed for their implicated meanings. The paper concludes with some thoughts about the role of theorizing in relation to utterance interpretation.


Involvement of angiotensin II type 2 receptor (AT2R) signaling in human pancreatic ductal adenocarcinoma (PDAC): a novel AT2R agonist effectively attenuates growth of PDAC grafts in mice.
We have recently discovered the potential involvement of angiotensin II type 2 receptor (AT2R) signaling in pancreatic cancer using AT2R deficient mice. To examine the involvement of AT2R expression in human PDAC, expressions of AT2R as well as the major angiotensin II receptor (type 1 receptor, AT1R) in human PDAC and adjacent normal tissue was evaluated by immunohistochemistry and real time PCR using surgically dissected human PDAC specimens. In immunohistochemical analysis, relatively strong AT1R expression was detected consistently in both normal pancreas and PDAC areas, whereas moderate AT2R expression was detected in 78.5% of PDAC specimens and 100% of normal area of the pancreas. AT1R, but not AT2R, mRNA levels were significantly higher in the PDAC area than in the normal pancreas. AT2R mRNA levels showed a negative correlation trend with overall survival. In cell cultures, treatment with a novel AT2R agonist significantly attenuated both murine and human PDAC cell growth with negligible cytotoxicity in normal epithelial cells. In a mouse study, administrations of the AT2R agonist in tumor surrounding connective tissue markedly attenuated growth of only AT2R expressing PAN02 murine PDAC grafts in syngeneic mice. The AT2R agonist treatment induced apoptosis primarily in tumor cells but not in stromal cells. Taken together, our findings offer clinical and preclinical evidence for the involvement of AT2R signaling in PDAC development and pinpoint that the novel AT2R agonist could serve as an effective therapeutic for PDAC treatment.


Blood lead level and risk of asthma.
Asthma and lead poisoning are prevalent among urban children in the United States. Lead exposure may be associated with excessive production of immunoglobulin E, possibly increasing asthma risk and contributing to racial disparities. The objective of this study was to examine racial differences in the association of blood lead level (BLL) to risk of developing asthma. We established and followed a cohort prospectively to determine asthma onset, using patient encounters and drug claims obtained from hospital databases. Participants were managed care enrollees with BLL measured and documented at 1-3 years of age. We used multiple variable analysis techniques to determine the relationship of BLL to period prevalent and incident asthma. Of the 4,634 children screened for lead from 1995 through 1998, 69.5% were African American, 50.5% were male, and mean age was 1.2 years. Among African Americans, BLL > or = 5 and BLL > or = 10 microg/dL were not associated with asthma. The association of BLL > or = 5 microg/dL with asthma among Caucasians was slightly elevated, but not significant [adjusted hazard ratio (adjHR) = 1.4; 95% confidence interval (CI), 0.7-2.9; p = 0.40]. Despite the small number of Caucasians with high BLL, the adjHR increased to 2.7 (95% CI, 0.9-8.1; p = 0.09) when more stringent criteria for asthma were used. When compared with Caucasians with BLL < 5 microg/dL, African Americans were at a significantly increased risk of asthma regardless of BLL (adjHR = 1.4-3.0). We conclude that an effect of BLL on risk of asthma for African Americans was not observed. These results demonstrate the need for further exploration of the complex interrelationships between race, asthma phenotype, genetic susceptibilities, and socioenvironmental exposures, including lead.


Automatic imitation in budgerigars.
A fully automated procedure, involving computer-controlled stimulus presentation and computer-recorded response measurement, was used for the first time to study imitation in non-human animals. After preliminary training to peck and step on a manipulandum, budgerigars were given a discrimination task in which they were rewarded with food for pecking during observation of pecking and for stepping during observation of stepping (Compatible group), or for pecking while observing stepping and for stepping while observing pecking (Incompatible group). The Incompatible group, which had to counter-imitate for food reward, showed weaker discrimination performance than the Compatible group. This suggests that, like humans, budgerigars are subject to 'automatic imitation'; they cannot inhibit online the tendency to imitate pecking and/or stepping, even when imitation of these behaviours interferes with the performance of an ongoing task. The difference between the two groups persisted over 10 test sessions, but the Incompatible group eventually acquired the discrimination, making more counter-imitative than imitative responses in the final sessions. These results are consistent with the associative sequence learning model, which suggests that, across species, the development of imitation and the mirror system depends on sensorimotor experience and phylogenetically ancient mechanisms of associative learning.


Nuance and Noise: Lessons Learned From Longitudinal Aggregated Assessment Data.
Competency-based medical education requires frequent assessment to tailor learning experiences to the needs of trainees. In 2012, we implemented the McMaster Modular Assessment Program, which captures shift-based assessments of resident global performance. We described patterns (ie, trends and sources of variance) in aggregated workplace-based assessment data. Emergency medicine residents and faculty members from 3 Canadian university-affiliated, urban, tertiary care teaching hospitals participated in this study. During each shift, supervising physicians rated residents' performance using a behaviorally anchored scale that hinged on endorsements for progression. We used a multilevel regression model to examine the relationship between global rating scores and time, adjusting for data clustering by resident and rater. We analyzed data from 23 second-year residents between July 2012 and June 2015, which yielded 1498 unique ratings (65 ± 18.5 per resident) from 82 raters. The model estimated an average score of 5.7 ± 0.6 at baseline, with an increase of 0.005 ± 0.01 for each additional assessment. There was significant variation among residents' starting score (y-intercept) and trajectory (slope). Our model suggests that residents begin at different points and progress at different rates. Meta-raters such as program directors and Clinical Competency Committee members should bear in mind that progression may take time and learning trajectories will be nuanced. Individuals involved in ratings should be aware of sources of noise in the system, including the raters themselves.


Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL.
The reasons for the cellular specificity and slow progression of motoneuron diseases such as ALS are still poorly understood. We previously described a motoneuron-specific cell death pathway downstream of the Fas death receptor, in which synthesis of nitric oxide (NO) is an obligate step. Motoneurons from ALS model mice expressing mutant SOD1 showed increased susceptibility to exogenous NO as compared with controls. Here, we report a signaling mechanism whereby NO leads to death of mutant, but not control, motoneurons. Unexpectedly, exogenous NO triggers expression of Fas ligand (FasL) in cultured motoneurons. In mutant SOD1(G93A) and SOD1(G85R), but not in control motoneurons, this up-regulation results in activation of Fas, leading through Daxx to phosphorylation of p38 and further NO synthesis. This Fas/NO feedback amplification loop is required for motoneuron death in vitro. In vivo, mutant SOD1(G93A) and SOD1(G85R) mice show increased numbers of positive motoneurons and Daxx nuclear bodies weeks before disease onset. Moreover, FasL up-regulation is reduced in the presence of transgenic dominant-negative Daxx. We propose that chronic low-level activation of the Fas/NO feedback loop may underlie the motoneuron loss that characterizes familial ALS and may help to explain its slowly progressive nature.


Post-warmup strategies to maintain body temperature and physical performance in professional rugby union players.
We compared the effects of using passive-heat maintenance, explosive activity or a combination of both strategies during the post-warmup recovery time on physical performance. After a standardised warmup, 16 professional rugby union players, in a randomised design, completed a counter-movement jump (peak power output) before resting for 20 min and wearing normal-training attire (CON), wearing a passive heat maintenance (PHM) jacket, wearing normal attire and performing 3 × 5 CMJ (with a 20% body mass load) after 12 min of recovery (neuromuscular function, NMF), or combining PHM and NMF (COMB). After 20 min, participants completed further counter-movement jump and a repeated sprint protocol. Core temperature (Tcore) was measured at baseline, post-warmup and post-20 min. After 20 min of recovery, Tcore was significantly lower under CON and NMF, when compared with both PHM and COMB (P < 0.05); PHM and COMB were similar. Peak power output had declined from post-warmup under all conditions (P < 0.001); however, the drop was less in COMB versus all other conditions (P < 0.05). Repeated sprint performance was significantly better under COMB when compared to all other conditions. Combining PHM with NMF priming attenuates the post-warmup decline in Tcore and can positively influence physical performance in professional rugby union players.


Barriers experienced by people with disabilities participating in income-generating activities. A case of a sheltered workshop in Bloemfontein, South Africa.
People with disabilities often participate in income-generating activities (IGAs) in sheltered workshop in South Africa. However, they face many barriers that limit their ability to participate effectively in economic activities hosted by the workshops. To illustrate the barriers that limit the participation of people with disabilities in IGAs in a sheltered workshop. A qualitative exploratory single case study was conducted in a sheltered workshop. Eighteen participants, age 22 to 52 years with various disabilities were purposively sampled. Observations and semi-structured interview guides were used to generate data. Verbatim transcription was used after which content analysis was applied to identify ideas and concepts relating to barriers experienced by people with disabilities participating in IGAs. Some of the barriers participants experienced included institutional barriers (ability to use working tools, inability to concentrate for long periods, lack of funds, language barriers, lack of motivation, activities that are not stimulating and lack of artistry skills) and attitudinal barriers (exclusion from decision making) These barriers had an adverse influence on their performance in IGAs. The study found eight different barriers that existed in a sheltered workshop which limited the participation of the people with disabilities that attended the workshop. This information can be used to develop strategies to address each barrier and promote increased participation of the individual thereby improving their quality of life.


Expansion of Pathogenic Cardiac Macrophages in Immune Checkpoint Inhibitor Myocarditis.
Immune checkpoint inhibitors (ICIs), antibodies targeting PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1) or CTLA4 (cytotoxic T-lymphocyte-associated protein 4), have revolutionized cancer management but are associated with devastating immune-related adverse events including myocarditis. The main risk factor for ICI myocarditis is the use of combination PD-1 and CTLA4 inhibition. ICI myocarditis is often fulminant and is pathologically characterized by myocardial infiltration of T lymphocytes and macrophages. Although much has been learned about the role of T-cells in ICI myocarditis, little is understood about the identity, transcriptional diversity, and functions of infiltrating macrophages. We used an established murine ICI myocarditis model (Ctla4+/-Pdcd1-/- mice) to explore the cardiac immune landscape using single-cell RNA-sequencing, immunostaining, flow cytometry, in situ RNA hybridization, molecular imaging, and antibody neutralization studies. We observed marked increases in CCR2 (C-C chemokine receptor type 2)+ monocyte-derived macrophages and CD8+ T-cells in this model. The macrophage compartment was heterogeneous and displayed marked enrichment in an inflammatory CCR2+ subpopulation highly expressing Cxcl9 (chemokine [C-X-C motif] ligand 9), Cxcl10 (chemokine [C-X-C motif] ligand 10), Gbp2b (interferon-induced guanylate-binding protein 2b), and Fcgr4 (Fc receptor, IgG, low affinity IV) that originated from CCR2+ monocytes. It is important that a similar macrophage population expressing CXCL9, CXCL10, and CD16α (human homologue of mouse FcgR4) was expanded in patients with ICI myocarditis. In silico prediction of cell-cell communication suggested interactions between T-cells and Cxcl9+Cxcl10+ macrophages by IFN-γ (interferon gamma) and CXCR3 (CXC chemokine receptor 3) signaling pathways. Depleting CD8+ T-cells, macrophages, and blockade of IFN-γ signaling blunted the expansion of Cxcl9+Cxcl10+ macrophages in the heart and attenuated myocarditis, suggesting that this interaction was necessary for disease pathogenesis. These data demonstrate that ICI myocarditis is associated with the expansion of a specific population of IFN-γ-induced inflammatory macrophages and suggest the possibility that IFN-γ blockade may be considered as a treatment option for this devastating condition.


Modestobacter multiseptatus gen. nov., sp. nov., a budding actinomycete from soils of the Asgard Range (Transantarctic Mountains).
Oligotrophic PYGV medium, inoculated with soils from Linnaeus Terrace (1600 m, Antarctica), yielded four aerobic actinomycetes with short rods, multiple and irregular septa and often motile buds. Cells were 1.0-2.8 x 1.0-3.0 microm and colonies were beige to pink. The isolates were nearly identical in physiological and biochemical tests. Three strains grew from 0 degrees C to 25-28 degrees C, but one was psychrophilic with a maximum growth temperature of 20 degrees C. Carbon sources utilized were D-glucose, D-galactose, lactose, sucrose or mannitol; malate, succinate, fumarate, pyruvate or glutarate were decarboxylated aerobically. Peptone and yeast extract were the preferred nitrogen sources. Nitrate was reduced aerobically or anaerobically. Cell walls contained meso-diaminopimelic acid, glutamate, alanine, glycine, galactose, glucose and ribose. Major fatty acids of strains AA-802, -824, -825 and -826T were n18:1, i16:0 and ai17:0. Major respiratory quinones were MK-9(H4) and MK-8(H4). Polar lipids were diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylinositol. Phosphatidylglycerol was found in most strains. The DNA G+C contents were 68-70 mol%. In 16S rDNA analyses, similarity values obtained for 500 nucleotides from the 5' terminus were > 99.5%. Almost complete sequences from AA-826T and -825 were 99.9% similar. Strain AA-826T belonged to a novel cluster of desert soil and rock isolates within the Geodermatophilaceae and was equidistantly related to members of Geodermatophilus and to a Blastococcus lineage. The four isolates represent a new genus, Modestobacter gen. nov., with Modestobacter multiseptatus sp. nov. as the type species. The type strain, Modestobacter multiseptatus AA-826T, was deposited in the DSMZ as DSM 44406T.


Third-order lensless ghost diffraction with classical fully incoherent light.
We theoretically demonstrate third-order lensless ghost diffraction by using a fully classical incoherent light source in which the light beam is detected by two detectors. The resolution and visibility of the obtained diffraction pattern are discussed. It is shown that the resolution of third-order ghost diffraction is determined by the transverse correlation length in the detection plane, while the visibility is affected by the ratio of the transverse length of the imaged object and the transverse size of the light source. Furthermore, we discuss the similarities and differences of second- and third-order lensless ghost diffraction.


Tylosema esculentum extractives and their bioactivity.
The investigation of Tylosema esculentum (Morama) husks, cotyledons, and tuber yielded griffonilide 2, compound 1, griffonin 3, gallic acid 4, protocatechuic acid 5, β-sitosterol 6, behenic acid 7, oleic acid 8, sucrose 9, 2-O-ethyl-α-D-glucopyranoside 10, kaempferol 11 and kaempferol-3-O-β-D-glucopyranoside 12. The structures of the isolates were determined by NMR, HR-TOF EIMS, IR and UV-vis spectroscopy, and by comparison with literature data. The husk EtOAc and n-butanol extracts demonstrated >90% DPPH radical scavenging activity at concentrations of 25, 50 and 250 μg/mL. Furthermore the husk extracts showed higher total phenolic content (233 mg GAE/g). The extractives exhibited minimum inhibitory quantities of 50-100 μg or no activity against Staphylococcus aureus, Escherichia coli, Bacillus subtilis, Pseudomonas aeruginosa and Candida albicans. The tuber extracts were inactive against Caco-2 and Hela cell lines, while the husk extracts showed low activity against Caco-2 and Vero cell line with IC(50) values >400 μg/mL. The GC-MS analysis showed the beans and tuber non-polar (n-hexane) extracts major constituents as fatty acids.


BAK overexpression mediates p53-independent apoptosis inducing effects on human gastric cancer cells.
BAK (Bcl-2 homologous antagonist/killer) is a novel pro-apoptotic gene of the Bcl-2 family. It has been reported that gastric tumors have reduced BAK levels when compared with the normal mucosa. Moreover, mutations of the BAK gene have been identified in human gastrointestinal cancers, suggesting that a perturbation of BAK-mediated apoptosis may contribute to the pathogenesis of gastric cancer. In this study, we explored the therapeutic effects of gene transfer mediated elevations in BAK expression on human gastric cancer cells in vitro. Eukaryotic expression vector for the BAK gene was constructed and transferred into gastric cancer cell lines, MKN-45 (wild-type p53) and MKN-28 (mutant-type p53). RT-PCR and Western Blotting detected cellular BAK gene expression. Cell growth activities were detected by MTT colorimetry and flow cytometry, while apoptosis was assayed by electronic microscopy and TUNEL. Western Blotting and colorimetry investigated cellular caspase-3 activities. BAK gene transfer could result in significant BAK overexpression, decreased in vitro growth, cell cycle G0/G1 arrest, and induced apoptosis in gastric cancer cells. In transferred cells, inactive caspase-3 precursor was cleaved into the active subunits p20 and p17, during BAK overexpression-induced apoptosis. In addition, this process occurred equally well in p53 wild-type (MKN-45), or in p53 mutant-type (MKN-28) gastric cancer cells. The data presented suggests that overexpression of the BAK gene can lead to apoptosis of gastric cancer cells in vitro, which does not appear to be dependent on p53 status. The action mechanism of BAK mediated apoptosis correlates with activation of caspase-3. This could be served as a potential strategy for further development of gastric cancer therapies.


Phylogenetic identification of lateral genetic transfer events.
Lateral genetic transfer can lead to disagreements among phylogenetic trees comprising sequences from the same set of taxa. Where topological discordance is thought to have arisen through genetic transfer events, tree comparisons can be used to identify the lineages that may have shared genetic information. An 'edit path' of one or more transfer events can be represented with a series of subtree prune and regraft (SPR) operations, but finding the optimal such set of operations is NP-hard for comparisons between rooted trees, and may be so for unrooted trees as well. Efficient Evaluation of Edit Paths (EEEP) is a new tree comparison algorithm that uses evolutionarily reasonable constraints to identify and eliminate many unproductive search avenues, reducing the time required to solve many edit path problems. The performance of EEEP compares favourably to that of other algorithms when applied to strictly bifurcating trees with specified numbers of SPR operations. We also used EEEP to recover edit paths from over 19,000 unrooted, incompletely resolved protein trees containing up to 144 taxa as part of a large phylogenomic study. While inferred protein trees were far more similar to a reference supertree than random trees were to each other, the phylogenetic distance spanned by random versus inferred transfer events was similar, suggesting that real transfer events occur most frequently between closely related organisms, but can span large phylogenetic distances as well. While most of the protein trees examined here were very similar to the reference supertree, requiring zero or one edit operations for reconciliation, some trees implied up to 40 transfer events within a single orthologous set of proteins. Since sequence trees typically have no implied root and may contain unresolved or multifurcating nodes, the strategy implemented in EEEP is the most appropriate for phylogenomic analyses. The high degree of consistency among inferred protein trees shows that vertical inheritance is the dominant pattern of evolution, at least for the set of organisms considered here. However, the edit paths inferred using EEEP suggest an important role for genetic transfer in the evolution of microbial genomes as well.


isoMETLIN: a database for isotope-based metabolomics.
The METLIN metabolite database has become one of the most widely used resources in metabolomics for making metabolite identifications. However, METLIN is not designed to identify metabolites that have been isotopically labeled. As a result, unbiasedly tracking the transformation of labeled metabolites with isotope-based metabolomics is a challenge. Here, we introduce a new database, called isoMETLIN (http://isometlin.scripps.edu/), that has been developed specifically to identify metabolites incorporating isotopic labels. isoMETLIN enables users to search all computed isotopologues derived from METLIN on the basis of mass-to-charge values and specified isotopes of interest, such as (13)C or (15)N. Additionally, isoMETLIN contains experimental MS/MS data on hundreds of isotopomers. These data assist in localizing the position of isotopic labels within a metabolite. From these experimental MS/MS isotopomer spectra, precursor atoms can be mapped to fragments. The MS/MS spectra of additional isotopomers can then be computationally generated and included within isoMETLIN. Given that isobaric isotopomers cannot be separated chromatographically or by mass but are likely to occur simultaneously in a biological system, we have also implemented a spectral-mixing function in isoMETLIN. This functionality allows users to combine MS/MS spectra from various isotopomers in different ratios to obtain a theoretical MS/MS spectrum that matches the MS/MS spectrum from a biological sample. Thus, by searching MS and MS/MS experimental data, isoMETLIN facilitates the identification of isotopologues as well as isotopomers from biological samples and provides a platform to drive the next generation of isotope-based metabolomic studies.


Hemidystrophic Thorax Mimicking Scoliosis.
We regularly use Angle of Trunk Rotation (ATR) measurements for scoliosis screening and also for clinical follow-up of our scoliosis patients under treatment. In some patients, when ATR measurements exceed the screening threshold but without a significant degree of curvature on the X-ray (Cobb angle), a Hemidystrophic Thorax (HDT) is diagnosed. The purpose of this paper was to present a case series of patients with this kind of thoracic deformity because this may be mimicking scoliosis to a significant degree. This case series is a consecutive series of patients where the first author detected a hemidystrophic thorax instead of or in combination with scoliosis. A 3D scan of the trunk was made and adjusted to the coordinates in order to achieve an upright orientation of the upper trunk. The scan was scaled in order to determine certain anatomic landmarks, as performed in preparation for bracing. The scan was cut horizontally at the xiphoid level and the plane at this level was analysed visually in order to detect deformations that were different to the typical scoliotic deformations in the horizontal plane. Seven cases were analysed and described in more detail. The condition of HDT may lead to significant rib humps that mimic scoliosis. According to our case series, mild scoliosis can also be associated with HDT. HDT, according to the cases presented in this study, seems to be a relatively benign deformity. Long-term observations are necessary before a final conclusion can be drawn with respect to prognosis.


Is running an analogue of anorexia nervosa? An empirical study of obligatory running and anorexia nervosa.
A recent report suggested that compulsive runners share a common set of psychological traits and behavioral dispositions with patients with anorexia nervosa. In an effort to objectively assess the similarity between anorexia nervosa and obligatory running, 43 runners and 24 patients with anorexia nervosa completed the Minnesota Multiphasic Personality Inventory (MMPI). Results indicated that the obligatory runners generally scored within the normal range, while the anorectic patients did not. The anorectic patients obtained more pathological scores than the runners on eight of the ten clinical subscales of the MMPI. Fifty percent of the anorectic patients obtained elevations on three or more of the MMPI subscales, while no runners obtained more than two scale elevations. Depression (scale 2) and psychopathy (scale 4) were particularly prevalent in the anorectic group. We conclude that obligatory runners do not suffer from the same degree of psychopathology as do patients with anorexia nervosa.


Registration of physical space to laparoscopic image space for use in minimally invasive hepatic surgery.
While laparoscopes are used for numerous minimally invasive (MI) procedures, MI liver resection and ablative surgery is infrequently performed. The paucity of cases is due to the restriction of the field of view by the laparoscope and the difficulty in determining tumor location and margins under video guidance. By merging MI surgery with interactive, image-guided surgery (IIGS), we hope to overcome localization difficulties present in laparoscopic liver procedures. One key component of any IIGS system is the development of accurate registration techniques to map image space to physical or patient space. This manuscript focuses on the accuracy and analysis of the direct linear transformation (DLT) method to register physical space with laparoscopic image space on both distorted and distortion-corrected video images. Experiments were conducted on a liver-sized plastic phantom affixed with 20 markers at various depths. After localizing the points in both physical and laparoscopic image space, registration accuracy was assessed for different combinations and numbers of control points (n) to determine the quantity necessary to develop a robust registration matrix. For n = 11, average target registration error (TRE) was 0.70 +/- 0.20 mm. We also studied the effects of distortion correction on registration accuracy. For the particular distortion correction method and laparoscope used in our experiments, there was no statistical significance between physical to image registration error for distorted and corrected images. In cases where a minimum number of control points (n = 6) are acquired, the DLT is often not stable and the mathematical process can lead to high TRE values. Mathematical filters developed through the analysis of the DLT were used to prospectively eliminate outlier cases where the TRE was high. For n = 6, prefilter average TRE was 17.4 +/- 153 mm for all trials; when the filters were applied, average TRE decreased to 1.64 +/- 1.10 mm for the remaining trials.


Cardiothoracic Surgery Residency Training in Surgical Ablation for Atrial Fibrillation.
As no standardized curriculum exists for training cardiothoracic surgery residents in surgical ablation for atrial fibrillation there is potential for variation in operative technique, patient selection, and overall application. Thus we sought to assess the exposure of current residents in order to identify areas for improvement in their education. A survey was emailed to residents inquiring about their training experience in surgical ablation for atrial fibrillation. Residents were asked about case volume, procedural variety, and guideline-based clinical scenarios where they felt ablation would be appropriate. Residents were also queried about their abilities to perform various lesion sets and overall satisfaction with training. The respondents performed a median of five cases during training with pulmonary vein isolation the most common lesion set. Seventy seven percent of residents are unable to independently perform a bi-atrial (Cox-Maze IV) lesion set. Residents are neutral regarding their satisfaction with training in surgical ablation for atrial fibrillation. The findings of low case volume, incomplete lesion set use, and lack of training satisfaction suggests residents are being insufficiently exposed to surgical ablation of atrial fibrillation. These findings should inform educators on the importance of a more thorough experience during training given the increasing prevalence of atrial fibrillation and the need for appropriate and durable surgical intervention.


Primary Palliative Care for Emergency Medicine (PRIM-ER): Protocol for a Pragmatic, Cluster-Randomised, Stepped Wedge Design to Test the Effectiveness of Primary Palliative Care Education, Training and Technical Support for Emergency Medicine.
Emergency departments (ED) care for society's most vulnerable older adults who present with exacerbations of chronic disease at the end of life, yet the clinical paradigm focuses on treatment of acute pathologies. Palliative care interventions in the ED capture high-risk patients at a time of crisis and can dramatically improve patient-centred outcomes. This study aims to implement and evaluate Primary Palliative Care for Emergency Medicine (PRIM-ER) on ED disposition, healthcare utilisation and survival in older adults with serious illness. This is the protocol for a pragmatic, cluster-randomised stepped wedge trial to test the effectiveness of PRIM-ER in 35 EDs across the USA. The intervention includes four core components: (1) evidence-based, multidisciplinary primary palliative care education; (2) simulation-based workshops; (3) clinical decision support; and (4) audit and feedback. The study is divided into two phases: a pilot phase, to ensure feasibility in two sites, and an implementation and evaluation phase, where we implement the intervention and test the effectiveness in 33 EDs over 2 years. Using Centers for Medicare and Medicaid Services (CMS) data, we will assess the primary outcomes in approximately 300 000 patients: ED disposition to an acute care setting, healthcare utilisation in the 6 months following the ED visit and survival following the index ED visit. Analysis will also determine the site, provider and patient-level characteristics that are associated with variation in impact of PRIM-ER. Institutional Review Board approval was obtained at New York University School of Medicine to evaluate the CMS data. Oversight will also be provided by the National Institutes of Health, an Independent Monitoring Committee and a Clinical Informatics Advisory Board. Trial results will be submitted for publication in a peer-reviewed journal. NCT03424109; Pre-results.


Participation in the College of American Pathologists Laboratory Accreditation Program Decreases Variability in B-Lymphoblastic Leukemia and Plasma Cell Myeloma Flow Cytometric Minimal Residual Disease Testing: A Follow-up Survey.
Minimal residual disease (MRD) testing by flow cytometry is ubiquitous in hematolymphoid neoplasm monitoring, especially B-lymphoblastic leukemia (B-ALL), for which it provides predictive information and guides management. Major heterogeneity was identified in 2014. Subsequently, new Flow Cytometry Checklist items required documentation of the sensitivity determination method and required lower level of detection (LLOD) inclusion in final reports. This study assesses Laboratory Accreditation Program (LAP) participation and new checklist items' impact on flow cytometry MRD testing. To survey flow cytometry laboratories about MRD testing for B-ALL and plasma cell myeloma. In particular, enumerate the laboratories performing MRD testing, the proportion performing assays with very low LLODs, and implementation of new checklist items. Supplemental questions were distributed in the 2017-A mailing to 548 flow cytometry laboratories subscribed to the College of American Pathologists FL3 Proficiency Testing Survey (Flow Cytometry-Immunophenotypic Characterization of Leukemia/Lymphoma). The percentage of laboratories performing MRD studies has significantly decreased since 2014. Wide ranges of LLOD and collection event numbers were reported for B-ALL and plasma cell myeloma. Most laboratories determine LLOD by using dilutional studies and include it in final reports; a higher proportion of LAP participants used these practices than nonparticipants. Several MRD testing aspects vary among laboratories receiving FL3 Proficiency Testing materials. After the survey in 2014, new checklist items were implemented. As compared to 2014, fewer laboratories are performing MRD studies. While LLOD remains heterogeneous, a high proportion of LAP subscribers follow the new checklist requirements and, overall, target LLOD recommendations from disease-specific working groups are met.


Growth factor receptor-Src-mediated suppression of GRK6 dysregulates CXCR4 signaling and promotes medulloblastoma migration.
Metastasis in medulloblastoma (MB) is associated with poor survival. Recent genetic studies revealed MB to comprise distinct molecular subgroups, including the sonic hedgehog (SHH) subgroup that exhibits a relatively high rate of progression. To identify targeted therapeutics against metastasis, a better understanding of the regulation of MB cell migration is needed. G protein-coupled receptor kinases (GRKs) have been implicated in cancer metastasis through their regulation of G-protein coupled receptors (GPCRs) involved in growth factor (GF)-mediated cell migration. However, the specific roles and regulation of GRKs in MB have not been investigated. Microarray mRNA analysis was performed for GRKs, GPCRs, and GFs in 29 human MB, and real time RT-PCR was used to detect GRK6 expression in MB cells. Lenti- or retro-virus infection, and siRNA or shRNA transfection, of MB cells was used to overexpress and knockdown target genes, respectively. Western blot was used to confirm altered expression of proteins. The effect of altered target protein on cell migration was determined by Boyden chamber assay and xCELLigence migration assays. We observed co-overexpression of PDGFRA, CXCR4, and CXCL12 in the SHH MB subtype compared to non-SHH MB (5, 7, and 5-fold higher, respectively). GRK6, which typically acts as a negative regulator of CXCR4 signaling, is downregulated in MB, relative to other GRKs, while the percentage of GRK6 expression is lower in MB tumors with metastasis (22%), compared to those without metastasis (43%). In SHH-responsive MB cells, functional blockade of PDGFR abolished CXCR4-mediated signaling. shPDGFR transfected MB cells demonstrated increased GRK6 expression, while PDGF or 10% FBS treatment of native MB cells reduced the stability of GRK6 by inducing its proteosomal degradation. Overexpression or downregulation of Src, a key mediator of GF receptor/PDGFR signaling, similarly inhibited or induced GRK6 expression, respectively. siRNA downregulation of GRK6 enhanced CXCR4 signaling and promoted MB migration, while lentiviral-GRK6 overexpression suppressed CXCR4 signaling, potentiated the effect of AMD3100, a CXCR4 antagonist, and impaired migration. Our findings demonstrate a novel mechanism of GF receptor/PDGFR-Src-mediated dysregulation of CXCR4 signaling that promotes MB cell migration, which could potentially be exploited for therapeutic targeting in SHH MB.


Magnetic Resonance Imaging of the Temporomandibular Joint at 7.0 T Using High-Permittivity Dielectric Pads: A Feasibility Study.
The aims of this study were to show feasibility and to quantitatively and qualitatively evaluate the use of high-permittivity dielectric pads for imaging the temporomandibular joint (TMJ) at 7.0 T. This study is an institutional review board-approved study with written informed consent. Ten asymptomatic volunteers (20 TMJs) were magnetic resonance imaged using a 32-channel head coil at 7.0 T (Achieva; Philips Healthcare, the Netherlands) with and without high-permittivity dielectric pads consisting of barium titanate in deuterated suspension. Imaging protocol consisted of an oblique sagittal proton density-weighted turbo-spin echo sequence. For quantitative evaluation, B1 maps and voxelwise signal-to-noise ratio (SNR) maps were calculated. For qualitative evaluation, 2 readers assessed the visibility of anatomical structures of the TMJ and overall image quality on a 5-point Likert scale from 1 (excellent visibility) to 5 (not visible) in consensus. Quantitative and qualitative measurements were compared between images acquired with and without pads. Imaging the TMJ using dielectric pads was feasible in all volunteers. The quantitative analysis showed locally higher B1+ and higher SNR in the area covering the TMJ for the scans performed with dielectric pads compared with those without pads (SNR: mean [SD] pads, 12.38 [3.18]; mean [SD] no pads, 6.60 [0.72]). The qualitative analysis showed significantly better visibility and delineation of clinically relevant anatomical structures of the TMJ, including temporomandibular disc, bilaminar zone, mandibular fossa, mandibular condyle, and pterygoid muscle. In addition, observers judged overall image quality as better for images taken with pads compared with those taken without pads (mean [SD] pads, 1.40 [0.50]; mean [SD] no pads, 4.25 [0.78]). The application of high-permittivity dielectric pads improves the local B1+ field and thus the SNR, optimizing TMJ magnetic resonance imaging at 7.0 T.


Identification of specific contacts in T3 RNA polymerase-promoter interactions: kinetic analysis using small synthetic promoters.
The T7, T3, and SP6 RNA polymerases recognize very similar, yet distinct, promoter sequences. The high homology among the promoter sequences suggests that differential promoter recognition must derive from relatively small changes in the protein. Steady-state kinetic analyses of transcription from the T3 consensus promoter and from promoters modified in the region critical to specific recognition reveal details concerning which functional groups contribute to this recognition. Modifications include base pair substitutions, single base substitutions (mismatches), and simple functional group modifications at unique sites in the promoter. The results show that T3 RNA polymerase recognizes the amino group on the nontemplate cytidine in the major groove at position -10, while the identity of the base on the template strand is less critical to binding. In contrast, recognition at position -11 allows a greater range of modifications and seems to have a more complex recognition. The results do not seem to be consistent with a single recognition contact at this position; however, some groups may be ruled out as simple recognition contacts. While major groove modifications weaken binding at positions -10 and -11, the removal of an exocyclic amino group from the minor groove at either position does not disrupt binding, further supporting a model for promoter recognition in which the enzyme binds to one face of closed duplex DNA in this region. The effects of these changes in the DNA structure on the kinetics of initiation are compared to complementary results from the T7 system.


A genetic system for Clostridium ljungdahlii: a chassis for autotrophic production of biocommodities and a model homoacetogen.
Methods for genetic manipulation of Clostridium ljungdahlii are of interest because of the potential for production of fuels and other biocommodities from carbon dioxide via microbial electrosynthesis or more traditional modes of autotrophy with hydrogen or carbon monoxide as the electron donor. Furthermore, acetogenesis plays an important role in the global carbon cycle. Gene deletion strategies required for physiological studies of C. ljungdahlii have not previously been demonstrated. An electroporation procedure for introducing plasmids was optimized, and four different replicative origins for plasmid propagation in C. ljungdahlii were identified. Chromosomal gene deletion via double-crossover homologous recombination with a suicide vector was demonstrated initially with deletion of the gene for FliA, a putative sigma factor involved in flagellar biogenesis and motility in C. ljungdahlii. Deletion of fliA yielded a strain that lacked flagella and was not motile. To evaluate the potential utility of gene deletions for functional genomic studies and to redirect carbon and electron flow, the genes for the putative bifunctional aldehyde/alcohol dehydrogenases, adhE1 and adhE2, were deleted individually or together. Deletion of adhE1, but not adhE2, diminished ethanol production with a corresponding carbon recovery in acetate. The double deletion mutant had a phenotype similar to that of the adhE1-deficient strain. Expression of adhE1 in trans partially restored the capacity for ethanol production. These results demonstrate the feasibility of genetic investigations of acetogen physiology and the potential for genetic manipulation of C. ljungdahlii to optimize autotrophic biocommodity production.


Multiscale pulse dynamics in communication systems with strong dispersion management.
The evolution of an optical pulse in a strongly dispersion-managed fiber-optic communication system is studied. The pulse is decomposed into a fast phase and a slowly evolving amplitude. The fast phase is calculated exactly, and a nonlocal equation for the evolution of the amplitude is derived. In the limit of weak dispersion management the equation reduces to the nonlinear Schrödinger equation. A class of stationary solutions of this equation is obtained; they represent pulses with a Gaussian-like core and exponentially decaying oscillatory tails, and they agree with direct numerical solutions of the full system.


Greater involvement and diversity of Internet gambling as a risk factor for problem gambling.
Concerns that Internet gambling has elevated the prevalence of problem gambling have not been substantiated; however, evidence suggests a subgroup of Internet gamblers do experience higher rates of gambling harms. Greater overall involvement in gambling appears to be predictive of harms. The purpose of this study was to examine differences between Internet gamblers with a single or multiple online gambling accounts, including their gambling behaviours, factors influencing their online gambling and risk of experiencing gambling problems. Internet gamblers (3178) responding to an online survey that assessed their gambling behaviour, and use of single or multiple online gambling accounts. Results revealed that multiple account holders were more involved gamblers, gambling on more activities and more frequently, and had higher rates of gambling problems than single account holders. Multiple account holders selected gambling sites based on price, betting options, payout rates and game experience, whereas single account holders prioritized legality and consumer protection features. Results suggest two different types of Internet gamblers: one motivated to move between sites to optimize preferred experiences with a tendency to gamble in a more volatile manner; and a smaller, but more stable group less influenced by promotions and experiences, and seeking a reputable and safe gambling experience. As the majority of Internet gamblers use multiple accounts, more universal responsible gambling strategies are needed to assist gamblers to track and control their expenditure to reduce risks of harm.


Increased incidence of invasive bacterial disease in chronic obstructive pulmonary disease compared to the general population--a population based cohort study.
Innate defence mechanisms of the airways are impaired in chronic obstructive pulmonary disease (COPD), predisposing patients to lower respiratory tract infections, but less is known about the association with other infections. In this population-based cohort study, we investigated the associations between COPD and invasive bacterial disease by comparing incidence rates of bacteraemia in COPD patients and randomly selected reference individuals from the general population. In this population based cohort study all patients with COPD, ≥40 years of age, who were discharged from hospitals in southern Sweden between 1990 and 2003 were identified in the Swedish Inpatient Register (n = 15,403). Age and gender matched reference individuals were randomly selected from the general population. Records were cross-referenced to the microbiological databases covering the region, 1990-2010. The hazard ratios (HR) of bloodstream infections and hospitalisations for infections were estimated by Cox proportional hazards regression. We found that individuals with COPD had a 2.5-fold increased incidence of bacteraemia compared to the reference individuals from the general population adjusted for other co-morbidity and socio-economic status (hazard ratio: 2.5, 95% confidence interval: 2.2-2.7). The increased incidence of bacteraemia was paralleled by an increased incidence of hospitalisation for non-respiratory infections, i.e., skin infections, pyelonephritis, or septic arthritis. Despite higher absolute rates of bloodstream infections among COPD patients than among the general population, the distribution of different pathogens was similar. In summary this population-based study shows COPD is associated with an increased incidence of invasive bacterial infections compared to the general population, indicating a general frailty of acquiring severe infections in addition to the specific susceptibility to infections of respiratory origin. The underlying contributory factors (e.g. smoking, corticosteroid use, co-morbid diseases or a frailty inherent to COPD itself) need to be disentangled in further studies.


Increased dialysate MCP-1 is associated with cardiovascular mortality in peritoneal dialysis patients: a prospective observational study.
The aim of this study was to investigate the association between the dialysate MCP-1 (dMCP-1) and systemic inflammatory and nutritional markers in peritoneal dialysis (PD) patients. In addition, we examined the prognostic value of dMCP-1 on all-cause or cardiovascular mortality in these patients. We prospectively followed 169 prevalent PD patients from April 1st 2008 to December 31st 2012. At baseline, dMCP-1 and serum biochemical parameters including high sensitivity CRP (hs-CRP) and albumin were checked. All-cause mortality and cause of death were evaluated during the follow-up period. Based on the median level of dMCP-1, patients were classified as either low or high dMCP-1 groups. Mean age, hs-CRP, and D/Pcr ratio at 4 h were significantly higher, while serum albumin levels and %lean body mass (LBM) were significantly lower in the high dMCP-1 group. During the mean follow-up period of 47.7 months, all-cause mortality and cardiovascular mortality rate were significantly higher in the high dMCP-1 group (9.6 and 6.3 per 100 person-years, respectively) compared to the low dMCP-1 group (5.1 and 3.1 per 100 person-years, respectively; p = 0.021, 0.038). In multivariate Cox analysis, high dMCP-1 was a significant independent predictor of all-cause mortality (hazard ratio: 1.83, 95% confidence interval: 1.03-3.24, p = 0.039). dMCP-1 levels are closely correlated with nutritional and systemic inflammatory markers in PD patients. In addition, increased dMCP-1 is significantly associated with higher all-cause and cardiovascular mortality. These findings suggest that local peritoneal inflammation could contribute to poor clinical outcomes in PD patients.


The development of an innovative, theory-driven, psychoeducational HIV/STI prevention intervention for heterosexually active black adolescents with mental illnesses.
Sexually transmitted infections (STIs), including human immunodeficiency virus (HIV), continue to disproportionately affect Black adolescents. Those experiencing the psychological sequelae of mental illnesses are at increased risk. Here, we outline the development of an HIV/STI prevention intervention for heterosexually-active Black adolescents with mental illnesses. This research was guided by a psychosocial expansion of the Theory of Planned Behavior, nested within a broader social determinants of health framework. A youth community advisory board provided study oversight. Heterosexually-active Black adolescents aged 14 to 17 were recruited from community-based outpatient mental health providers for focus groups, surveys and two "dress rehearsals" of the intervention protocol (N = 68). The qualitative and quantitative findings indicated that knowledge, attitudes and skills related to consistent condom use, reduced number of sexual partners, routine HIV/STI testing, abstinence and emotion regulation were important areas to target. These elicitation data provided insight on the context of HIV/STI risk for the study population, and were used to develop the intervention content. "Project GOLD: We are Kings and Queens" was designed to be delivered over two days (three hours per day), with eight, 45-minute modules. The activities address behaviors, as well as cognitive, emotional, psychological and social processes associated with HIV/STI risk. Alongside evidence-based HIV/STI prevention strategies (e.g., sexual partner communication skills), the intervention activities are rooted in principles of Cognitive Behavioral Therapy. Dress rehearsal participants were in favor of the intervention and provided feedback on activity length, gender and cultural relevance, and strategies to sustain attention; this information was used to finalize the curriculum. In partnership with the community, we developed a theoretically-driven, gender and culturally relevant, developmentally and psychologically appropriate HIV/STI prevention program. Our ultimate goal is to standardize sexual health assessment and intervention in outpatient mental health treatment settings to meet sexual health needs in this underserved population.


Clinical and genomic landscape of gastric cancer with a mesenchymal phenotype.
Gastric cancer is a heterogeneous cancer, making treatment responses difficult to predict. Here we show that we identify two distinct molecular subtypes, mesenchymal phenotype (MP) and epithelial phenotype (EP), by analyzing genomic and proteomic data. Molecularly, MP subtype tumors show high genomic integrity characterized by low mutation rates and microsatellite stability, whereas EP subtype tumors show low genomic integrity. Clinically, the MP subtype is associated with markedly poor survival and resistance to standard chemotherapy, whereas the EP subtype is associated with better survival rates and sensitivity to chemotherapy. Integrative analysis shows that signaling pathways driving epithelial-to-mesenchymal transition and insulin-like growth factor 1 (IGF1)/IGF1 receptor (IGF1R) pathway are highly activated in MP subtype tumors. Importantly, MP subtype cancer cells are more sensitive to inhibition of IGF1/IGF1R pathway than EP subtype. Detailed characterization of these two subtypes could identify novel therapeutic targets and useful biomarkers for prognosis and therapy response.


Intratumoral radioimmunotherapy of a human colon cancer xenograft using a sustained-release gel.
Low tumor uptake and normal tissue toxicity limit the efficacy of RIT for the treatment of solid tumors. In this study, an intratumoral injectable gel drug delivery system for local administration of RIT was evaluated using the LS174T human colon cancer xenograft model in SCID mice. The injectable gel is a collagen-based drug delivery system designed for intratumoral (i.t.) administration, which has previously been shown to enhance drug retention at the injection site and reduce systemic drug exposure. We compared the local (tumor) retention and biodistribution of 111In-labeled NR-LU-10 monoclonal antibody given i.t. in the injectable gel versus simple aqueous solution. 111In gel given i.t. and 111In-NR-LU-10 given intraperitoneally (i.p.) were used as controls. The results showed that tumors treated with 111In-NR-LU-10 gel maintained the highest levels of radioactivity for up to 96 h. At 48 h after the administration of 111In-NR-LU-10 gel i.t., 111In-NR-LU-10 solution i.t., 111In gel i.t., or 111In-NR-LU-10 i.p., the level of radioactivity remaining in each gram of tumor was 98, 49, 45, and 16% of the injected dose, respectively. It was estimated that if 100 microCi of 90Y-NR-LU-10 were administered similarly, tumor treated with 90Y-NR-LU-10 gel i.t. would receive a dose of 90.0 Gy, whereas normal tissues in the same animal would receive a dose of approximately 2.43 Gy. In contrast, if 90Y-NR-LU-10 were delivered i.p., a comparable tumor would receive a dose of 16.8 Gy and corresponding normal tissues would receive 3.36 Gy. Consistent with these estimates, enhanced antitumor efficacy was observed when 90Y-NR-LU-10 gel was administered i.t. Tumor growth delay time was 6.9-fold (P < 0.01) longer in these animals (14.4 days) than in animals treated with 90Y-NR-LU-10 i.p. (2.1 days). Systemic toxicity was also significantly reduced in gel-treated animals as monitored by loss of body weight. This study demonstrated that intratumoral delivery of 90Y-NR-LU-10 gel markedly increased the retention of the radioisotope in tumors, enhanced the antitumor efficacy, and reduced systemic toxicity compared to systemic administration of the radiolabeled antibody. This injectable gel drug delivery system may allow for improvement in the therapeutic index for RIT.


Atherosclerosis in diabetes mellitus: role of inflammation.
Inflammation plays a central role in the pathophysiology of atherosclerosis, starting from initiation, through progression and ultimately the thrombotic complications of atherosclerosis. Diabetes mellitus is a major risk factor for atherosclerosis. Hyperglycemia-induced endothelial dysfunctions, along with hypercoagulable potential of diabetes mellitus, accelerate the process of atherothrombotic complications. Therefore, clinically feasible markers to monitor subtle systemic inflammatory burden and specific add-on therapy for the same constitute need of the present day. The understanding of the concept of inflammation in diabetes-accelerated atherosclerosis can be used practically to predict future cardiovascular risk by evaluating inflammatory biomarkers and to design clinical trials making inflammation as a therapeutic target.


Herbal panacea: The need for today in dentistry.
Among ancient civilizations, India has been known to be a rich repository of medicinal plants. Herbal extracts have been used in traditional medicine for several thousand years. Some plants contain phytochemicals that have effects on the body. The use of phytotherapy is staging a comeback and an era of herbal renaissance is being revolutionized all over the globe. Herbs are a class of plants that are devoid of the woody tissue characteristic of shrubs or trees and have been known for their aromatic, flavoring, and medicinal values over the past centuries. Since the birth of contemporary practices, many have turned away from herbal therapies in favor of synthetic drugs. But these synthetic medicines can alter microbiota and have several side effects. However, the blind dependence on synthetics is over and people are returning to the naturals with the hope of safety and security. Hence, the search for alternative natural products continue. This review includes a few herbs, which can be used in dentistry as alternatives to allopathic medicines.


Eye can see what you want: posterior intraparietal sulcus encodes the object of an actor's gaze.
In a social setting, seeing Sally look at a clock means something different to seeing her gaze longingly at a slice of chocolate cake. In both cases, her eyes and face might be turned rightward, but the information conveyed is markedly different, depending on the object of her gaze. Numerous studies have examined brain systems underlying the perception of gaze direction, but less is known about the neural basis of perceiving gaze shifts to specific objects. During fMRI, participants observed an actor look toward one of two objects, each occupying a distinct location. Video stimuli were sequenced to obtain repetition suppression (RS) for object identity, independent of spatial location. In a control condition, a spotlight highlighted one of the objects, but no actor was present. Observation of the human actor's gaze compared with the spotlight engaged frontal, parietal, and temporal cortices, consistent with a broad action observation network. RS for gazed object in the human condition was found in posterior intraparietal sulcus (pIPS). RS for highlighted object in the spotlight condition was found in middle occipital, inferior temporal, medial fusiform gyri, and superior parietal lobule. These results suggest that human pIPS is specifically sensitive to the type object that an observed actor looks at (tool vs. food), irrespective of the observed actor's gaze location (left vs. right). A general attention or lower-level object feature processing mechanism cannot account for the findings because a very different response pattern was seen in the spotlight control condition. Our results suggest that, in addition to spatial orienting, human pIPS has an important role in object-centered social orienting.


Different Mechanisms May Exist for HBsAg Synthesis and Secretion During Various Phases of Chronic Hepatitis B Virus Infection.
BACKGROUND The aim of this study was to characterize the expression and secretion of hepatitis B surface-antigen (HBsAg) in the hepatocytes of hepatitis B virus (HBV)-infected patients at different phases of infection; as such, the association of intrahepatic HBsAg expression with virological markers and the histological characteristics were analyzed. MATERIAL AND METHODS 302 chronic HBV infection patients who had not received antiviral therapy were stratified by HBeAg status. The proportion of HBsAg-positive cells was used as an indicator for HBsAg expression level. RESULTS In HBeAg-positive patients, there was a significant correlation between serum HBsAg and serum HBV DNA levels (r=0.569, p<0.001). Intrahepatic HBsAg expression and serum HBsAg level in HBeAg-positive patients were higher than those in HBeAg-negative patients (p=0.002 and p<0.001, respectively). A significant correlation between serum HBsAg level and intrahepatic HBsAg expression was found in HBeAg-negative patients (r=0.377, p<0.001), but not in HBeAg-positive patients (r=0.051, p=0.557). Very interestingly, the correlation between serum HBsAg level and HBsAg expression in hepatocytes gradually increased along with disease progression through the immune-tolerant, immune-clearance, inactive, and recovery phases of HBV infection (r=-0.184, 0.068, 0.492, and 0.575; and p=0,238, 0,722, 0.012, and 0.002, respectively). CONCLUSIONS Different mechanisms may be involved in HBsAg synthesis and secretion in different phases of chronic HBV infection.


The 3D Structural Architecture of the Human Hand Area Is Nontopographic.
The functional topography of the human primary somatosensory cortex hand area is a widely studied model system to understand sensory organization and plasticity. It is so far unclear whether the underlying 3D structural architecture also shows a topographic organization. We used 7 Tesla (7T) magnetic resonance imaging (MRI) data to quantify layer-specific myelin, iron, and mineralization in relation to population receptive field maps of individual finger representations in Brodman area 3b (BA 3b) of human S1 in female and male younger adults. This 3D description allowed us to identify a characteristic profile of layer-specific myelin and iron deposition in the BA 3b hand area, but revealed an absence of structural differences, an absence of low-myelin borders, and high similarity of 3D microstructure profiles between individual fingers. However, structural differences and borders were detected between the hand and face areas. We conclude that the 3D structural architecture of the human hand area is nontopographic, unlike in some monkey species, which suggests a high degree of flexibility for functional finger organization and a new perspective on human topographic plasticity.SIGNIFICANCE STATEMENT Using ultra-high-field MRI, we provide the first comprehensive in vivo description of the 3D structural architecture of the human BA 3b hand area in relation to functional population receptive field maps. High similarity of precise finger-specific 3D profiles, together with an absence of structural differences and an absence of low-myelin borders between individual fingers, reveals the 3D structural architecture of the human hand area to be nontopographic. This suggests reduced structural limitations to cortical plasticity and reorganization and allows for shared representational features across fingers.


Comparative metabolism and disposition of furfural and furfuryl alcohol in rats.
The comparative metabolism and disposition of furfural (FAL) and furfuryl alcohol (FOL) were investigated following oral administration of approximately 0.001, 0.01, and 0.1 of the LD50, corresponding to approximately 0.127, 1.15, and 12.5 mg/kg for FAL and 0.275, 2.75, and 27.5 mg/kg for FOL. At all doses studied, at least 86-89% of the dose of FAL or FOL was absorbed from the gastrointestinal tract. FAL and FOL were extensively metabolized prior to excretion. The major route of excretion was in urine, where 83-88% of the dose was excreted, whereas 2-4% was excreted in the feces. Approximately 7% of the dose from rats treated with FAL at 12.5 mg/kg was exhaled as 14CO2. At 72 hr following administration, the pattern of tissue distribution of radioactivity was similar for both FAL and FOL. Liver and kidney contained the highest, and brain the lowest concentrations of radioactivity. Generally, the concentrations of radioactivity in tissues were proportional to the dose. Almost all of the urinary radioactivity was tentatively identified. No FAL or FOL was detected in urine. Furoylglycine was the major urinary metabolite (73-80% of dose), and furoic acid (1-6%) and furanacrylic acid (3-8%) were the minor metabolites following treatment with either FAL or FOL. Therefore, the initial step in the metabolism of FAL and FOL involves the oxidation to furoic acid, which is excreted unchanged and decarboxylated to form 14CO2, conjugated with glycine, or condensed with acetic acid.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of single versus multiple courses of antenatal corticosteroids on maternal and neonatal outcome.
Treatment of pregnant mothers with a single course of antenatal corticosteroids significantly reduces neonatal mortality and morbidity. Multiple weekly courses are often given. However, the safety and efficacy of repeated courses of antenatal corticosteroids have not been adequately studied. A retrospective study was performed for 609 mothers and their 713 infants who were treated with 1 to 12 courses of antenatal corticosteroids. Data for 369 singleton preterm infants born at < or =34 weeks' gestation, 210 multiple gestations, and 134 infants delivered at > or =35 weeks' gestation were analyzed separately. The incidence of respiratory distress syndrome was 45% for single-course and 35% for multiple-course groups (P =.005; odds ratio, 0.44; 95% confidence interval, 0.25-0.79). The multiple-course group also had significantly less patent ductus arteriosus (20% vs 13%; P =.016). Incidence of death before discharge and other neonatal morbidities were similar. The multiple-course group had a reduction of 0.46 +/- 0.19 cm in head circumference at birth (P =.013) when adjusted for gestational age and preeclampsia. The 2 groups had similar birth weights. Infants born at > or =35 weeks' gestation, multiple-gestation infants, and infants who were born >7 days after the last corticosteroid dose had similar outcomes, regardless of the number of courses they received. Mothers treated with multiple courses compared with a single course had a significantly higher incidence of postpartum endometritis (P =.013), even though they had a lower incidence of prolonged rupture of membranes (24% vs 33%, P =.06) and similar cesarean delivery rates. Exposure to multiple courses of antenatal corticosteroids compared with a single course resulted in a significant reduction in the incidence of respiratory distress syndrome in singleton preterm infants delivered within a week of the last corticosteroid dose. This was associated with a reduction in birth head circumference and an increased incidence of maternal endometritis. Whether the potential benefits of repeated therapy clearly outweigh the risks will ultimately be determined in randomized prospective controlled trials.


Ticagrelor Removal by CytoSorb® in Patients Requiring Emergent or Urgent Cardiac Surgery: A UK-Based Cost-Utility Analysis.
Acute coronary syndrome patients receiving dual antiplatelet therapy who need emergent or urgent cardiac surgery are at high risk of major bleeding, which can impair postoperative outcomes. CytoSorb®, a blood purification technology based on adsorbent polymer, has been demonstrated to remove ticagrelor from blood during on-pump cardiac surgery. The aim of this study was to evaluate the cost utility of intraoperative removal of ticagrelor using CytoSorb versus usual care among patients requiring emergent or urgent cardiac surgery in the UK. A de novo decision analytic model, based on current treatment pathways, was developed to estimate the short- and long-term costs and outcomes. Results from randomised clinical trials and national standard sources such as National Health Service (NHS) reference costs were used to inform the model. Costs were estimated from the NHS and Personal Social Services perspective. Deterministic and probabilistic sensitivity analyses (PSAs) explored the uncertainty surrounding the input parameters. In emergent cardiac surgery, intraoperative removal of ticagrelor using CytoSorb was less costly (£12,933 vs. £16,874) and more effective (0.06201vs. 0.06091 quality-adjusted life-years) than cardiac surgery without physiologic clearance of ticagrelor over a 30-day time horizon. For urgent cardiac surgery, the use of CytoSorb was less costly than any of the three comparators-delaying surgery for natural washout without adjunctive therapy, adjunctive therapy with short-acting antiplatelet agents, or adjunctive therapy with low-molecular-weight heparin. Results from the PSAs showed that CytoSorb has a high probability of being cost saving (99% in emergent cardiac surgery and 53-77% in urgent cardiac surgery, depending on the comparators). Cost savings derive from fewer transfusions of blood products and re-thoracotomies, and shorter stay in the hospital/intensive care unit. The implementation of CytoSorb as an intraoperative intervention for patients receiving ticagrelor undergoing emergent or urgent cardiac surgery is a cost-saving strategy, yielding improvement in perioperative and postoperative outcomes and decreased health resource use.


Effect of a gradually increasing temperature on the behavioural and physiological response of juvenile Hippocampus erectus: Thermal preference, tolerance, energy balance and growth.
The physiological and behavioural responses of ectotherms to temperature is strongly dependent on the individuals' previous thermal history. Laboratory based studies investigating the mechanisms of thermoregulation in marine ectotherms, however, rarely consider key temporal elements of thermal exposure, such as the rate at which temperature changes. We tested the hypothesis that juvenile seahorses, Hippocampus erectus, from a tropical coastal lagoon in Yucatan, Mexico, would exhibit variations in physiological and behavioural descriptors of thermoregulation when submitted to contrasting regimes during 30 days: temperature constant at 25 °C (C 25); gradually increasing 1 °C every 5 days from 25 to 30 °C (GI 25-30); and constant at 30 °C (C 30). Immediately after exposure, critical maximum temperature, thermal preference, oxygen consumption, partial energy balance, growth rate and survival of seahorses were measured. Seahorses exposed to GI 25-30 showed a significantly higher critical thermal maxima (37.8 ± 0.9 °C), preference (28.7 ± 0.4 °C), growth (1.10 ± 0.49%) and survival (97.6%) than those exposed to C 30 (36.5 ± 1, 29.4 ± 0.3 °C, 0.48 ± 0.32%, 73.8%, respectively). Both high temperature regimes induced metabolic depression, but ramping resulted in a greater amount of energy assimilated (278.9 ± 175.4 J g-1 day-1) and higher energy efficiency for growth (89.8%) than constant exposure to 30 °C (115.4 ± 63.4 J g-1 day-1, 65.3%, respectively). Gradually increasing temperature allowed physiological mechanisms of thermal adjustment to take place, reflecting the capacity of juvenile H. erectus to respond to environmental change. Despite its advantage, this capacity is limited in time, since the cumulative effect of thermal exposure affected metabolic performance, eventually compromising survival. The study of seahorse response to thermal variations in the context of ocean warming needs to consider the temporal elements of thermal exposure to foresee its vulnerability under future scenarios.


Conformal geometry and its applications on 3D shape matching, recognition, and stitching.
Three-dimensional shape matching is a fundamental issue in computer vision with many applications such as shape registration, 3D object recognition, and classification. However, shape matching with noise, occlusion, and clutter is a challenging problem. In this paper, we analyze a family of quasi-conformal maps including harmonic maps, conformal maps, and least-squares conformal maps with regards to 3D shape matching. As a result, we propose a novel and computationally efficient shape matching framework by using least-squares conformal maps. According to conformal geometry theory, each 3D surface with disk topology can be mapped to a 2D domain through a global optimization and the resulting map is a diffeomorphism, i.e., one-to-one and onto. This allows us to simplify the 3D shape-matching problem to a 2D image-matching problem, by comparing the resulting 2D parametric maps, which are stable, insensitive to resolution changes and robust to occlusion, and noise. Therefore, highly accurate and efficient 3D shape matching algorithms can be achieved by using the above three parametric maps. Finally, the robustness of least-squares conformal maps is evaluated and analyzed comprehensively in 3D shape matching with occlusion, noise, and resolution variation. In order to further demonstrate the performance of our proposed method, we also conduct a series of experiments on two computer vision applications, i.e., 3D face recognition and 3D nonrigid surface alignment and stitching.


Local and global influences on protein turnover in neurons and glia.
Regulation of protein turnover allows cells to react to their environment and maintain homeostasis. Proteins can show different turnover rates in different tissue, but little is known about protein turnover in different brain cell types. We used dynamic SILAC to determine half-lives of over 5100 proteins in rat primary hippocampal cultures as well as in neuron-enriched and glia-enriched cultures ranging from <1 to >20 days. In contrast to synaptic proteins, membrane proteins were relatively shorter-lived and mitochondrial proteins were longer-lived compared to the population. Half-lives also correlate with protein functions and the dynamics of the complexes they are incorporated in. Proteins in glia possessed shorter half-lives than the same proteins in neurons. The presence of glia sped up or slowed down the turnover of neuronal proteins. Our results demonstrate that both the cell-type of origin as well as the nature of the extracellular environment have potent influences on protein turnover.


Potent and prolonged hypoglycemic activity of an oral insulin--Tat mixture in diabetic mice.
Trans-activator of transcription (Tat) is a cell penetrating peptide which can translocate and carry macromolecular cargoes through cell membranes. This study investigated the hypoglycemic activity of orally delivered insulin - Tat mixture in alloxan-induced diabetic mice. The mixtures of insulin and Tat at 1:1, 1:3 and 1:6 molar ratios were given orally at the insulin doses ranging from 1-200 IU/kg. The fasting blood glucose (FBG) levels were measured at initial, 1, 2, 4, 6, and 12 h after administration. At 1:3 molar ratio of the mixture and after 12 h of administration, insulin at 200 IU/kg showed the highest with prolonged hypoglycemic activity of 74.0±10.3% FBG reduction (2.18 folds of subcutaneously injected (SC) insulin). Free insulin administered orally did not show any hypoglycemic activity. The mixtures at the insulin doses of 100 and 50 IU/kg also showed potent FBG reduction of 73.8±8.2 and 71.3±16.9% at 12 h after administration (2.18 and 2.10 folds of SC insulin, respectively). After incubation with Mono-Mac-6 cells, only the -mixtures but not the free insulin showed intra-cellular insulin uptake, indicating the insulin penetration through the cell membranes via Tat. In simulated gastric fluid, the insulin content in the mixture was not found, demonstrating the degradation of insulin in the gastric environments. Insulin may be absorbed at upper gastrointestinal tract facilitated by Tat. The potent and prolonged hypoglycemic activity of insulin co-administered orally with Tat can be further developed as an effective oral insulin delivery system.


Insights into behavioral vulnerability to differential sleep pressure and circadian phase from a functional ADA polymorphism.
Sleep loss affects human behavior in a nonuniform manner, depending on the cognitive domain and also the circadian phase. Besides, evidence exists about stable interindividual variations in sleep loss-related performance impairments. Despite this evidence, only a few studies have considered both circadian phase and neurobehavioral domain when investigating trait-like vulnerability to sleep manipulation. By applying a randomized, crossover design with 2 sleep pressure conditions (40 h sleep deprivation vs. 40 h multiple naps), we investigated the influence of a human adenosine deaminase (ADA) polymorphism (rs73598374) on several behavioral measures throughout nearly 2 circadian cycles. Confirming earlier studies, we observed that under sleep deprivation the previously reported vulnerable G/A-allele carriers felt overall sleepier than G/G-allele carriers. As expected, this difference was no longer present when sleep pressure was reduced by the application of multiple naps. Concomitantly, well-being was worse in the G/A genotype under sleep loss when compared to the nap protocol, and n-back working memory performance appeared to be specifically susceptible to sleep-wake manipulation in this genotype. When considering psychomotor vigilance performance, however, a higher sensitivity to sleep-wake manipulation was detected in homozygous participants, but specifically at the end of the night and only for optimal task performance. Although these data are based on a small sample size and hence require replication (12 G/A- and 12 G/G-allele carriers), they confirm the assumption that interindividual differences regarding the effect of sleep manipulation highly depend on the cognitive task and circadian phase, and thus emphasize the necessity of a multimethodological approach. Moreover, they indicate that napping might be suitable to counteract endogenously heightened sleep pressure depending on the neurobehavioral domain.


Elucidating the Underlying Functional Mechanisms of Breast Cancer Susceptibility Through Post-GWAS Analyses.
Genome-wide association studies (GWAS) have identified more than 170 single nucleotide polymorphisms (SNPs) associated with the susceptibility to breast cancer. Together, these SNPs explain 18% of the familial relative risk, which is estimated to be nearly half of the total familial breast cancer risk that is collectively explained by low-risk susceptibility alleles. An important aspect of this success has been the access to large sample sizes through collaborative efforts within the Breast Cancer Association Consortium (BCAC), but also collaborations between cancer association consortia. Despite these achievements, however, understanding of each variant's underlying mechanism and how these SNPs predispose women to breast cancer remains limited and represents a major challenge in the field, particularly since the vast majority of the GWAS-identified SNPs are located in non-coding regions of the genome and are merely tags for the causal variants. In recent years, fine-scale mapping studies followed by functional evaluation of putative causal variants have begun to elucidate the biological function of several GWAS-identified variants. In this review, we discuss the findings and lessons learned from these post-GWAS analyses of 22 risk loci. Identifying the true causal variants underlying breast cancer susceptibility and their function not only provides better estimates of the explained familial relative risk thereby improving polygenetic risk scores (PRSs), it also increases our understanding of the biological mechanisms responsible for causing susceptibility to breast cancer. This will facilitate the identification of further breast cancer risk alleles and the development of preventive medicine for those women at increased risk for developing the disease.


Multi-system neurorehabilitative strategies to restore motor functions following severe spinal cord injury.
Severe spinal cord injury (SCI) permanently abolishes motor functions caudal to the lesion. However, the neuronal machinery sufficient to produce standing and stepping is located below most SCI, and can be reactivated with training. Therefore, why do rats and humans fail to regain significant levels of motor control after a severe SCI? In this review, we argue that the lack of sustainable excitability in locomotor circuitries after SCI prevents the emergence of functional motor states during training, thus limiting the occurrence of activity-dependent plasticity in paralyzed subjects. In turn, we show that spinal rats trained with combinations of epidural electrical stimulation and monoamine agonists, which promote locomotor permissive states during rehabilitation, can regain coordinated stepping with full weight bearing capacities in the total absence of supraspinal influences. This impressive recovery of function relies on the ability of spinal circuitries to utilize multisensory information as a source of control and learning after the loss of brain input. We finally discuss the implication of these findings for the design of multi-system neurorehabilitative interventions capable of restoring some degree of function in humans with severe SCI.


Developing, Integrating, and Implementing Evidence-Informed Practice Curricula Throughout a Chinese Medicine Degree Program.
Objectives: To train faculty and develop curricula in evidence-informed practice (EIP) within a Chinese medicine degree program. Setting: Pacific College of Oriental Medicine (New York). Design: Faculty EIP training was undertaken through utilization of online EIP modules, and development and completion of a 3-credit (45 h) online Foundations of EIP course. This was supplemented by faculty meetings and one-on-one support from department chairs. Curriculum development was undertaken by an EIP Curriculum Committee. The committee followed a modified Delphi process to develop EIP course learning outcomes (CLOs), and to make changes to the College's clinic policies and procedures. EIP assignments were developed for each course in accordance with the CLO. Results: Ninety-one percent of the faculty and 97% of clinical supervisors received formal EIP training. Thirty-five percent of all didactic faculty, 38% of faculty teaching courses with EIP incorporated, and 30% of clinical supervisors completed 10 or more h of EIP training during this project. Faculty also received informal EIP training through participation in department and general faculty meetings. Seventy-three percent of the Master's degree curriculum, inclusive of 40 didactic courses and fifteen 60-h clinic shifts, were modified to incorporate EIP. EIP CLOs and corresponding assignments were developed. Clinic intake forms were modified to facilitate undertaking EIP in the College clinic. Issues related to how EIP is defined in conjunction with the nature of available scientific research in Chinese medicine required discussion and resolution. Conclusions: Training faculty and developing curricula in EIP within Chinese medicine colleges has unique challenges that must be factored into the strategies and processes. Factors that contributed to the success of this project were having faculty drive the process, integrating EIP content within existing curricula, gradual exposure, identifying champions, relating EIP to practice building, and openly discussing opposing perspectives.


OPEN DATA FOR DISCOVERY SCIENCE.
The modern healthcare and life sciences ecosystem is moving towards an increasingly open and data-centric approach to discovery science. This evolving paradigm is predicated on a complex set of information needs related to our collective ability to share, discover, reuse, integrate, and analyze open biological, clinical, and population level data resources of varying composition, granularity, and syntactic or semantic consistency. Such an evolution is further impacted by a concomitant growth in the size of data sets that can and should be employed for both hypothesis discovery and testing. When such open data can be accessed and employed for discovery purposes, a broad spectrum of high impact end-points is made possible. These span the spectrum from identification of de novo biomarker complexes that can inform precision medicine, to the repositioning or repurposing of extant agents for new and cost-effective therapies, to the assessment of population level influences on disease and wellness. Of note, these types of uses of open data can be either primary, wherein open data is the substantive basis for inquiry, or secondary, wherein open data is used to augment or enrich project-specific or proprietary data that is not open in and of itself. This workshop is concerned with the key challenges, opportunities, and methodological best practices whereby open data can be used to drive the advancement of discovery science in all of the aforementioned capacities.


The popliteal lymph node of the mouse: internal architecture, vascular distribution and lymphatic supply.
The architecture of the mouse popliteal lymph nodes differs from that shown in conventional diagrams. The cortical lymphoid tissue, rather than forming a continuous outer layer, is organised into one or two hemispherical aggregates which project towards the hilus. These aggregates are surrounded by medullary tissue which thus extends to large areas of the surface of the node. The vascular distribution in the lymphoid aggregates is relatively sparse and contrasts with the dense meshwork of capillaries and venules around them. It also contrasts with the high vascularity of medullary tissue. Arterial vessels, especially those of larger calibre, are predominantly seen in the hilar area of the node suggesting that there is extensive branching as the artery enters the node. Capillaries associated with the lymphoid aggregates are usually lined by continuous endothelium, while those in the medulla are generally of the fenestrated type. The microcirculation has an extensive venous capacity and many venous segments are high endothelium venules whose walls are permeated by lymphocytes. Each node receives one or two afferent lymphatic vessels and is drained by up to four or five efferent lymphatic vessels. In approximately half the nodes examined, there were extranodal communications between afferent and efferent lymphatic vessels allowing some lymph to bypass the node.


A survey of coronary risk factors and B-type natriuretic peptide concentrations in cardiac nurses from Europe: do nurses still practice what they preach?
From a previous survey of cardiac nurses attending a scientific conference, we learned that these nurses adopted a healthier lifestyle than the general population. The aim of this study was to determine the overall profile of cardiac risk factors in a similar cohort and determine whether cardiac nurses continue to 'practice what they preach' in this regard. Secondly, we examined the practical value of screening a large cohort of individuals within a short time frame (total of 8 hours screening time) and determined the range of BNP concentrations within a 'healthy' cohort. Data on CHD risk factors were collected with a short self-report questionnaire. The sample consisted of 122 cardiac nurses from 19 countries attending a European cardiac nursing conference held in Stockholm. A venous blood sample was collected into a tube containing potassium ETDA. B-type natriuretic peptide was measured on-site with the use of a portable fluorescence immunoassay kit. Most participants were female (89%). Participants ranged in age from 23 to 60 years with a mean age of 41 (S.D. 9.4). Eleven percent - all female - reported they were current smokers, 27% (34) had a BMI >25 and 27% of the sample stated they did not exercise regularly. Almost half (48%) of the sample reported a family history of CHD. As expected, all BNP-values were within the normal range. There were significant differences in BNP on the basis of sex (P<0.05) and age (P<0.05) and a trend towards increasing BNP concentrations with progressively higher BMI scores (P=0.06). This study reconfirms the likelihood that many cardiac nurses heed their own advice on lifestyle modification to reduce cardiovascular risk and therefore provide a good role model for the promotion of primary and secondary prevention initiatives.


Lactulose and Melibiose Inhibit α-Synuclein Aggregation and Up-Regulate Autophagy to Reduce Neuronal Vulnerability.
Parkinson's disease (PD) is a neurodegenerative disease characterized by selective dopaminergic (DAergic) neuronal degeneration in the substantia nigra (SN) and proteinaceous α-synuclein-positive Lewy bodies and Lewy neuritis. As a chemical chaperone to promote protein stability and an autophagy inducer to clear aggregate-prone proteins, a disaccharide trehalose has been reported to alleviate neurodegeneration in PD cells and mouse models. Its trehalase-indigestible analogs, lactulose and melibiose, also demonstrated potentials to reduce abnormal protein aggregation in spinocerebellar ataxia cell models. In this study, we showed the potential of lactulose and melibiose to inhibit α-synuclein aggregation using biochemical thioflavin T fluorescence, cryogenic transmission electron microscopy (cryo-TEM) and prokaryotic split Venus complementation assays. Lactulose and melibiose further reduced α-synuclein aggregation and associated oxidative stress, as well as protected cells against α-synuclein-induced neurotoxicity by up-regulating autophagy and nuclear factor, erythroid 2 like 2 (NRF2) pathway in DAergic neurons derived from SH-SY5Y cells over-expressing α-synuclein. Our findings strongly indicate the potential of lactulose and melibiose for mitigating PD neurodegeneration, offering new drug candidates for PD treatment.


A model of ovulatory regulation examining the effects of insulin-mediated testosterone production on ovulatory function.
Polycystic ovary syndrome (PCOS), a common cause of infertility in women, is often accompanied by abnormal reproductive and metabolic hormone levels. Specifically, androgens such as testosterone are elevated in many PCOS women, and the syndrome itself is frequently associated with insulin resistance, which leads to hyperinsulinemia, i.e., elevated insulin. Although the precise role of insulin in ovulatory function is unclear, its role in ovulatory dysfunction is often linked to the effects of increased ovarian androgen production. We present a mathematical model of the menstrual cycle that incorporates regulation by the pituitary-ovarian axis and mechanisms of ovarian testosterone production. We determine a physiological role for testosterone in the normal ovulatory cycle and study the role of hyperinsulinemia in pathological regulation of the cycle. Model results indicate increased ovulatory disruption with elevated insulin-mediated testosterone production and suggest that variations in the response of ovarian follicles to essential signals can alter the degree to which hyperinsulinemia disrupts the ovulatory cycle. The model also provides insight into the various PCOS phenotypes and the severity of ovulatory dysfunction.


Availability and delivery of cardiac rehabilitation in the Eastern Mediterranean Region: How does it compare globally?
This study aimed to (1) confirm cardiac rehabilitation (CR) availability, (2) establish CR density and unmet need, as well as (3) the nature of programs in the Eastern Mediterranean Region (EMR), and (4) compare these (a) by EMR country and (b) to other countries. In this cross-sectional study, a survey was administered to CR programs globally. Cardiac associations and local champions facilitated program identification. CR need was based on Global Burden of Disease study ischemic heart disease (IHD) estimates. Of the 22 EMR countries, CR programs were identified in 12 (54.5%). Nine (75.0% country response rate) countries participated, and 24/49 (49.0% program response rate) surveys were initiated. There was 1 CR spot for every 104 incident IHD patients/year (versus 12 globally). One-third of responding programs were privately funded (n = 8; versus globally p < .001), and in 18 (75.0%) programs patients paid some or all of the cost out-of-pocket (versus n = 378, 36.3% globally; p < .001). Over 80% of programs accepted guideline-indicated patients. Nurses (n = 20, 95.2%), cardiologists (n = 18, 85.7%) and dietitians (n = 18, 85.7%) were the most common healthcare providers on CR teams (mean = 6.4 ± 2.2/program; 5.9 ± 2.8 globally, p = .18). On average, programs offered 8.9 ± 1.7/11 core components (versus 8.7 ± 1.9 globally, p = .90). These were most commonly initial assessment, management of risk factors, and patient education (n = 21, 100.0% for each), and least commonly return-to-work counselling (n = 15 71.4%). Mean dose was 27.0 ± 13.5 sessions (versus 28.7 ± 27.6 globally, p = .38). Seven (33.3%) programs offered some alternative models. CR is insufficiently implemented, with 2,079,283 more spots needed/year across the EMR. But where offered, CR is consistent with guidelines.


Pediatric tracheotomy: a 30-year experience.
The aim of this study was to investigate changes of pediatric tracheotomy practice over time. A retrospective analysis of all tracheotomies at the University Children's Hospital Zurich from January 1990 to December 2009 was performed. Data analyzed included the indication for tracheotomy, patient comorbidities, age, duration of cannulation, and complications. The second part of the study consisted of comparing our results with data from an earlier study done at the same institution by Simma et al. (Eur J Pediatr 1994;153:291-296) reviewing the patients with tracheotomies treated from 1979 to 1989. Between 1990 and 2009, 119 patients were included. The indication for tracheotomy was airway obstruction in 70% and prolonged ventilation in 30%. 70% of the patients were operated on before 1 year of age. Serious postoperative complications occurred in 25 patients (23%). There was one death related to tracheotomy. Successful decannulation was achieved in 60%, on average 28 months after tracheotomy. The decannulation rate in patients with airway obstruction was 74% compared to 52% for the patients in prolonged ventilation group; a statistically significant difference was observed (p < 0.05). The longitudinal analysis showed an increase of indications for prolonged ventilation and a trend toward decreased tracheotomy complications. Over 30 years, a shift in the indications of pediatric tracheotomy, with an increasing number of procedures performed for prolonged ventilation, was found. The tracheotomy-related mortality was under 1%. Tracheotomy remains a valid and safe option for pediatric patients. Level of evidence 2c.


Matrix Metalloproteinase-9 Production following Cardiopulmonary Bypass Was Not Associated with Pulmonary Dysfunction after Cardiac Surgery.
Cardiopulmonary bypass (CPB) causes release of matrix metalloproteinase- (MMP-) 9, contributing to pulmonary infiltration and dysfunction. The aims were to investigate MMP-9 production and associated perioperative variables and oxygenation following CPB. Thirty patients undergoing elective cardiac surgery were included. Arterial blood was sampled at 6 sequential points (before anesthesia induction, before CPB and at 2, 4, 6, and 24 h after beginning CPB) for plasma MMP-9 concentrations by ELISA. The perioperative laboratory data and variables, including bypass time, PaO2/FiO2, and extubation time, were also recorded. The plasma MMP-9 concentrations significantly elevated at 2-6 h after beginning CPB (P < 0.001) and returned to the preanesthesia level at 24 h (P = 0.23), with predominant neutrophil counts after surgery (P < 0.001). The plasma MMP-9 levels at 4 and 6 h were not correlated with prolonged CPB time and displayed no association with postoperative PaO2/FiO2, regardless of reduced ratio from preoperative 342.9 ± 81.2 to postoperative 207.3 ± 121.3 mmHg (P < 0.001). Elective cardiac surgery with CPB induced short-term elevation of plasma MMP-9 concentrations within 24 hours, however, without significant correlation with CPB time and postoperative pulmonary dysfunction, despite predominantly increased neutrophils and reduced oxygenation.


Method for absolute flatness measurement of optical surfaces.
To determine the absolute flatness deviations of optical surfaces, a novel method using two optical plates to achieve the absolute flatness test is presented. Absolute deviations of three surfaces, the rear surface of plate I and the front and rear surfaces of plate II, are obtained by four measurements. Wavefront error due to the inhomogeneity of plate II is measured beforehand and is then subtracted from the test results. Vertical profiles of the three surfaces are compared with the measurement results obtained by Zygo's three-flat application. Good agreement validates our method. The advantage of our method is that only one transmission flat is needed during the absolute test, which is especially useful for large-aperture interferometer calibration.


The Predicted Cross Value for Genetic Introgression of Multiple Alleles.
We consider the plant genetic improvement challenge of introgressing multiple alleles from a homozygous donor to a recipient. First, we frame the project as an algorithmic process that can be mathematically formulated. We then introduce a novel metric for selecting breeding parents that we refer to as the predicted cross value (PCV). Unlike estimated breeding values, which represent predictions of general combining ability, the PCV predicts specific combining ability. The PCV takes estimates of recombination frequencies as an input vector and calculates the probability that a pair of parents will produce a gamete with desirable alleles at all specified loci. We compared the PCV approach with existing estimated-breeding-value approaches in two simulation experiments, in which 7 and 20 desirable alleles were to be introgressed from a donor line into a recipient line. Results suggest that the PCV is more efficient and effective for multi-allelic trait introgression. We also discuss how operations research can be used for other crop genetic improvement projects and suggest several future research directions.