Impairment of the context preexposure facilitation effect in juvenile rats by neonatal alcohol exposure is associated with decreased Egr-1 mRNA expression in the prefrontal cortex.
The context preexposure facilitation effect (CPFE) is a variant of contextual fear conditioning in which learning about the context (preexposure) and associating the context with a shock (training) occur on separate occasions. The CPFE is sensitive to a range of neonatal alcohol doses (Murawski & Stanton, 2011). The current study examined the impact of neonatal alcohol on Egr-1 mRNA expression in the infralimbic (IL) and prelimbic (PL) subregions of the mPFC, the CA1 of dorsal hippocampus (dHPC), and the lateral nucleus of the amygdala (LA), following the preexposure and training phases of the CPFE. Rat pups were exposed to a 5.25 g/kg/day single binge-like dose of alcohol (Group EtOH) or were sham intubated (SI; Group SI) over postnatal days (PD) 7-9. In behaviorally tested rats, alcohol administration disrupted freezing. Following context preexposure, Egr-1 mRNA was elevated in both EtOH and SI groups compared with baseline control animals in all regions analyzed. Following both preexposure and training, Group EtOH displayed a significant decrease in mPFC Egr-1 mRNA expression compared with Group SI. However, this decrease was greatest after training. Training day decreases in Egr-1 expression were not found in LA or CA1 in Group EtOH compared with Group SI. A second experiment confirmed that the EtOH-induced training-day deficits in mPFC Egr-1 mRNA expression were specific to groups which learned contextual fear (vs. nonassociative controls). Thus, memory processes that engage the mPFC during the context-shock association may be most susceptible to the teratogenic effects of neonatal alcohol. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Semiconductor-laser-pumped, cw mode-locked Nd:phosphate glass laser oscillator and regenerative amplifier.
An all-diode-pumped Nd:glass mode-locked laser oscillator and regenerative amplifier are described. The oscillator produces a train of 58-psec transform-limited pulses at a 113.6-MHz repetition rate. The output of the oscillator is amplified by a regenerative amplifier. The pulse energy at the input of the amplifier is 39 pJ. The amplifier provides a gain of 51 dB, producing 5.4-microJ pulses at a repetition rate of 355 Hz. The amplifier produces no measurable broadening of the pulse.


High-field FMRI reveals brain activation patterns underlying saccade execution in the human superior colliculus.
The superior colliculus (SC) has been shown to play a crucial role in the initiation and coordination of eye- and head-movements. The knowledge about the function of this structure is mainly based on single-unit recordings in animals with relatively few neuroimaging studies investigating eye-movement related brain activity in humans. The present study employed high-field (7 Tesla) functional magnetic resonance imaging (fMRI) to investigate SC responses during endogenously cued saccades in humans. In response to centrally presented instructional cues, subjects either performed saccades away from (centrifugal) or towards (centripetal) the center of straight gaze or maintained fixation at the center position. Compared to central fixation, the execution of saccades elicited hemodynamic activity within a network of cortical and subcortical areas that included the SC, lateral geniculate nucleus (LGN), occipital cortex, striatum, and the pulvinar. Activity in the SC was enhanced contralateral to the direction of the saccade (i.e., greater activity in the right as compared to left SC during leftward saccades and vice versa) during both centrifugal and centripetal saccades, thereby demonstrating that the contralateral predominance for saccade execution that has been shown to exist in animals is also present in the human SC. In addition, centrifugal saccades elicited greater activity in the SC than did centripetal saccades, while also being accompanied by an enhanced deactivation within the prefrontal default-mode network. This pattern of brain activity might reflect the reduced processing effort required to move the eyes toward as compared to away from the center of straight gaze, a position that might serve as a spatial baseline in which the retinotopic and craniotopic reference frames are aligned.


Depression and risk of stroke morbidity and mortality: a meta-analysis and systematic review.
Several studies have suggested that depression is associated with an increased risk of stroke; however, the results are inconsistent. To conduct a systematic review and meta-analysis of prospective studies assessing the association between depression and risk of developing stroke in adults. A search of MEDLINE, EMBASE, and PsycINFO databases (to May 2011) was supplemented by manual searches of bibliographies of key retrieved articles and relevant reviews. We included prospective cohort studies that reported risk estimates of stroke morbidity or mortality by baseline or updated depression status assessed by self-reported scales or clinician diagnosis. Two independent reviewers extracted data on depression status at baseline, risk estimates of stroke, study quality, and methods used to assess depression and stroke. Hazard ratios (HRs) were pooled using fixed-effect or random-effects models when appropriate. Associations were tested in subgroups representing different participant and study characteristics. Publication bias was evaluated with funnel plots and Begg test. The search yielded 28 prospective cohort studies (comprising 317,540 participants) that reported 8478 stroke cases (morbidity and mortality) during a follow-up period ranging from 2 to 29 years. The pooled adjusted HRs were 1.45 (95% CI, 1.29-1.63; P for heterogeneity <.001; random-effects model) for total stroke, 1.55 (95% CI, 1.25-1.93; P for heterogeneity = .31; fixed-effects model) for fatal stroke (8 studies), and 1.25 (95% CI, 1.11-1.40; P for heterogeneity = .34; fixed-effects model) for ischemic stroke (6 studies). The estimated absolute risk differences associated with depression were 106 cases for total stroke, 53 cases for ischemic stroke, and 22 cases for fatal stroke per 100,000 individuals per year. The increased risk of total stroke associated with depression was consistent across most subgroups. Depression is associated with a significantly increased risk of stroke morbidity and mortality.


The RANO Leptomeningeal Metastasis Group proposal to assess response to treatment: lack of feasibility and clinical utility and a revised proposal.
A scorecard to evaluate magnetic resonance imaging (MRI) findings during the course of leptomeningeal metastases (LM) has been proposed by the Response Assessment in Neuro-Oncology (RANO) group. To explore the feasibility of the Leptomeningeal Assessment in Neuro-Oncology (LANO) scorecard, cerebrospinal MRIs of 22 patients with LM from solid tumors were scored by 10 neuro-oncologists and 9 neuroradiologists at baseline and at follow-up after treatment. Raters were blinded for clinical data including treatment. Agreement between raters of single items was evaluated using a Krippendorff alpha coefficient. Agreement between numerical parameters such as scores for changes between baseline and follow-up and total scores was evaluated by determining the intraclass coefficient of correlation. Most raters experienced problems with the instructions of the scorecard. No acceptable alpha concordance coefficient was obtained for the rating of single items at baseline or follow-up. The most concordant ratings were obtained for spinal nodules. The concordances were worst for brain linear leptomeningeal enhancement and cranial nerve enhancement. Discordance was less prominent among neuroradiologists than among neuro-oncologists. High variability was also observed for evaluating changes between baseline and follow-up and for total scores. Assessing response of LM by MRI remains challenging. Central imaging review is therefore indispensable for clinical trials. Based on the present results, we propose a new, simplified scorecard that will require validation using a similar approach as pursued here. The main challenges are to define measurable versus nonmeasurable (target) lesions and measures of change that allow assessment of response.


Abnormal epigenetic changes during differentiation of human skeletal muscle stem cells from obese subjects.
Human skeletal muscle stem cells are important for muscle regeneration. However, the combined genome-wide DNA methylation and expression changes taking place during adult myogenesis have not been described in detail and novel myogenic factors may be discovered. Additionally, obesity is associated with low relative muscle mass and diminished metabolism. Epigenetic alterations taking place during myogenesis might contribute to these defects. We used Infinium HumanMethylation450 BeadChip Kit (Illumina) and HumanHT-12 Expression BeadChip (Illumina) to analyze genome-wide DNA methylation and transcription before versus after differentiation of primary human myoblasts from 14 non-obese and 14 obese individuals. Functional follow-up experiments were performed using siRNA mediated gene silencing in primary human myoblasts and a transgenic mouse model. We observed genome-wide changes in DNA methylation and expression patterns during differentiation of primary human muscle stem cells (myoblasts). We identified epigenetic and transcriptional changes of myogenic transcription factors (MYOD1, MYOG, MYF5, MYF6, PAX7, MEF2A, MEF2C, and MEF2D), cell cycle regulators, metabolic enzymes and genes previously not linked to myogenesis, including IL32, metallothioneins, and pregnancy-specific beta-1-glycoproteins. Functional studies demonstrated IL-32 as a novel target that regulates human myogenesis, insulin sensitivity and ATP levels in muscle cells. Furthermore, IL32 transgenic mice had reduced insulin response and muscle weight. Remarkably, approximately 3.7 times more methylation changes (147,161 versus 39,572) were observed during differentiation of myoblasts from obese versus non-obese subjects. In accordance, DNMT1 expression increased during myogenesis only in obese subjects. Interestingly, numerous genes implicated in metabolic diseases and epigenetic regulation showed differential methylation and expression during differentiation only in obese subjects. Our study identifies IL-32 as a novel myogenic regulator, provides a comprehensive map of the dynamic epigenome during differentiation of human muscle stem cells and reveals abnormal epigenetic changes in obesity.


Recruitment of release sites underlies chemical presynaptic potentiation at hippocampal mossy fiber boutons.
Synaptic plasticity is a cellular model for learning and memory. However, the expression mechanisms underlying presynaptic forms of plasticity are not well understood. Here, we investigate functional and structural correlates of presynaptic potentiation at large hippocampal mossy fiber boutons induced by the adenylyl cyclase activator forskolin. We performed 2-photon imaging of the genetically encoded glutamate sensor iGluu that revealed an increase in the surface area used for glutamate release at potentiated terminals. Time-gated stimulated emission depletion microscopy revealed no change in the coupling distance between P/Q-type calcium channels and release sites mapped by Munc13-1 cluster position. Finally, by high-pressure freezing and transmission electron microscopy analysis, we found a fast remodeling of synaptic ultrastructure at potentiated boutons: Synaptic vesicles dispersed in the terminal and accumulated at the active zones, while active zone density and synaptic complexity increased. We suggest that these rapid and early structural rearrangements might enable long-term increase in synaptic strength.


Functional magnetic resonance imaging findings in Meares-Irlen syndrome: a pilot sudy.
To investigate patterns of functional magnetic resonance imaging (fMRI) activation during sentence reading before and after wearing color-tinted lenses. A total of 15 Meares-Irlen syndrome patients with a mean age of 23.4 years (range, 13 to 42 years) with no history of neurological or psychiatric disorders were scanned using a 3T MR scanner (Siemens, Tim-Trio, Germany). Each patient underwent two sessions of fMRI imaging (before and after MISViS color-tinted lens application). The fMRI paradigm included a block design of 20 seconds of rest (cross), 20 seconds of activation (sentence reading), and ten blocks (a total of 200 echo-planar image volumes) repeated for each session. Data preprocessing and analyses were performed using the SPM8 software package. The reading speed of patients improved more than 20% while wearing the selected lenses. When compared to the before-lens session, the after-lens session identified significant regions of activation in the left middle and superior temporal gyri (paired t-test; maximal z score, 5.38; Montreal Neurological Institute coordinate, -60 / -39 / 0; threshold at p < 0.05; corrected for multiple comparisons using family-wise error). No region of activation at the same threshold was found in the before-lens session as compared to the after-lens session. In the current study, we confirmed activation in the left middle and superior temporal gyri during sentence reading after wearing color-tinted lenses. These results could explain the effectiveness of color-tinted lenses in patients with Meares-Irlen syndrome.


Unintended pregnancy and low birthweight in Ecuador.
This study assessed the relationship between unintended pregnancy and infant birthweight in Ecuador, differentiating between unwanted and mistimed pregnancies. Analyses focused on a subsample of women (n = 2490) interviewed in the 1994 Ecuador Demographic and Maternal-Child Health Survey. Logistic regression was used to assess the relationship between pregnancy intention status and low birthweight after control for other factors. Infants from unwanted pregnancies were more likely than infants from planned pregnancies to have low birthweight (odds ratio = 1.64, 95% confidence interval = 1.22, 2.20). Mistimed pregnancy was not associated with low birthweight. Unwanted pregnancy, but not mistimed pregnancy, is associated with low birthweight in Ecuador. Further research is needed to understand the mechanism through which pregnancy intention status affects birthweight.


Nasal Pneumococcal Density Is Associated with Microaspiration and Heightened Human Alveolar Macrophage Responsiveness to Bacterial Pathogens.
Rationale: Pneumococcal pneumonia remains a global health problem. Colonization of the nasopharynx with Streptococcus pneumoniae (Spn), although a prerequisite of infection, is the main source of exposure and immunological boosting in children and adults. However, our knowledge of how nasal colonization impacts on the lung cells, especially on the predominant alveolar macrophage (AM) population, is limited.Objectives: Using a controlled human infection model to achieve nasal colonization with 6B serotype, we investigated the effect of Spn colonization on lung cells.Methods: We collected BAL from healthy pneumococcal-challenged participants aged 18-49 years. Confocal microscopy and molecular and classical microbiology were used to investigate microaspiration and pneumococcal presence in the lower airways. AM opsonophagocytic capacity was assessed by functional assays in vitro, whereas flow cytometry and transcriptomic analysis were used to assess further changes on the lung cellular populations.Measurements and Main Results: AMs from Spn-colonized individuals exhibited increased opsonophagocytosis to pneumococcus (11.4% median increase) for approximately 3 months after experimental pneumococcal colonization. AMs also had increased responses against other bacterial pathogens. Pneumococcal DNA detected in the BAL samples of Spn-colonized individuals were positively correlated with nasal pneumococcal density (r = 0.71; P = 0.029). Similarly, AM-heightened opsonophagocytic capacity was correlated with nasopharyngeal pneumococcal density (r = 0.61, P = 0.025).Conclusions: Our findings demonstrate that nasal colonization with pneumococcus and microaspiration prime AMs, leading to brisker responsiveness to both pneumococcus and unrelated bacterial pathogens. The relative abundance of AMs in the alveolar spaces, alongside their potential for nonspecific protection, render them an attractive target for novel vaccines.


Clinicopathologic characteristics of malignant germ cell tumors in the ovaries of Korean women: a Korean Gynecologic Oncology Group Study.
From January 1995 to December 2000, medical records of 196 patients were collected from 14 hospitals nationwide and were reviewed retrospectively. We evaluated the clinicopathologic characteristics of malignant germ cell tumors in the ovaries of South Korean women and determined the prognostic factors affecting recurrence. The mean patient age was 23.8 years (range, 4-63 years), and the median follow-up period was 67 months (range, 1-128 months). The distribution of the International Federation of Gynecology and Obstetrics stage was as follows: 128 cases (65.3%) in stage I, 27 cases (13.8%) in stage II, 39 cases (19.9%) in stage III, and 2 cases (1.0%) in stage IV. Histologically, immature teratoma was the most common tumor type (n = 68), followed by dysgerminoma (n = 54), endodermal sinus tumor (n = 38), mixed form (n = 24), and choriocarcinoma (n = 12). A fertility-sparing operation was performed in 134 patients, staging operation in 43 patients, and hysterectomy and bilateral salpingo-oophorectomy in 19 patients. Postoperative chemotherapy was administered in 166 patients, and the most common regimen was bleomycin, etoposide, and cisplatin (n = 120). Recurrence was observed in 13 patients (6.8%) and was influenced by the stage of the tumor and patient age (>40 years). The 5-year survival rate was 96.7%. During the follow-up period, 20 patients had 22 pregnancies that resulted in 17 normal deliveries at term and 5 abortions. The results of this study demonstrate that most malignant germ cell tumors of the ovary in Korean women are detected in the early stage and have excellent survival outcomes with conservative operation and platinum-based chemotherapy.


Investigating early events in receptor binding and translocation of colicin E9 using synchronized cell killing and proteolytic cleavage.
Enzymatic colicins such as colicin E9 (ColE9) bind to BtuB on the cell surface of Escherichia coli and rapidly recruit a second coreceptor, either OmpF or OmpC, through which the N-terminal natively disordered region (NDR) of their translocation domain gains entry into the cell periplasm and interacts with TolB. Previously, we constructed an inactive disulfide-locked mutant ColE9 (ColE9(s-s)) that binds to BtuB and can be reduced with dithiothreitol (DTT) to synchronize cell killing. By introducing unique enterokinase (EK) cleavage sites in ColE9(s-s), we showed that the first 61 residues of the NDR were inaccessible to cleavage when bound to BtuB, whereas an EK cleavage site inserted at residue 82 of the NDR remained accessible. This suggests that most of the NDR is occluded by OmpF shortly after binding to BtuB, whereas the extreme distal region of the NDR is surface exposed before unfolding of the receptor-binding domain occurs. EK cleavage of unique cleavage sites located in the ordered region of the translocation domain or in the distal region of the receptor-binding domain confirmed that these regions of ColE9 remained accessible at the E. coli cell surface. Lack of EK cleavage of the DNase domain of the cell-bound, oxidized ColE9/Im9 complex, and the rapid detection of Alexa Fluor 594-labeled Im9 (Im9(AF)) in the cell supernatant following treatment of cells with DTT, suggested that immunity release occurred immediately after unfolding of the colicin and was not driven by binding to BtuB.


A combination of green tea, rhodiola, magnesium and B vitamins modulates brain activity and protects against the effects of induced social stress in healthy volunteers.
Magnesium (Mg), green tea and rhodiola extracts have, in isolation, been shown to possess stress and anxiety relieving effects. Green tea and rhodiola have been shown to modulate EEG oscillatory brain activity associated with relaxation and stress perception. The combined capacity of these ingredients to confer protective effects under conditions of acute stress has yet to be examined. We tested the hypothesis that a combination of Mg (with B vitamins) + green tea + rhodiola would acutely moderate the effects of stress exposure. A double blind, randomised, placebo controlled, parallel group design was employed (Clinicaltrials.gov:NCT03262376; 25/0817). One hundred moderately stressed adults received oral supplementation of either (i) Mg + B vitamins + green tea + rhodiola; (ii) Mg + B vitamins + rhodiola; (iii) Mg + B vitamins + green tea; or (iv) placebo. After supplementation participants were exposed to the Trier Social Stress Test. The effects of the study treatments on electroencephalogram (EEG) resting state alpha and theta, subjective state/mood, blood pressure, heart rate variability and salivary cortisol responses after acute stress exposure were assessed. The combined treatment significantly increased EEG resting state theta (p < .02) - considered indicative of a relaxed, alert state, attenuated subjective stress, anxiety and mood disturbance, and heightened subjective and autonomic arousal (p < .05). Mg, B vitamins, rhodiola and green tea extracts are a promising combination of ingredients that may enhance coping capacity and offer protection from the negative effects of stress exposure.Trial registration: ClinicalTrials.gov identifier: NCT03262376.


The HLA-C*04: 01/KIR2DS4 gene combination and human leukocyte antigen alleles with high population frequency drive rate of HIV disease progression.
The objective of this study is to identify human leukocyte antigen (HLA) class I and killer-cell immunoglobulin-like receptor (KIR) genotypes associated with different risks for HIV acquisition and HIV disease progression. A cross-sectional study of a cohort of 468 high-risk individuals (246 HIV-positive and 222 HIV-negative) from outpatient clinics in Lima (Perú). The cohort was high-resolution HLA and KIR-typed and analysed for potential differences in single-allele frequencies and allele combinations between HIV-positive and HIV-negative individuals and for associations with HIV viral load and CD4 cell counts in infected individuals. HLA class I alleles associated with a lack of viral control had a significantly higher population frequency than relatively protective alleles (P = 0.0093), in line with a rare allele advantage. HLA-A02 : 01 and HLA-C04 : 01 were both associated with high viral loads (P = 0.0313 and 0.0001, respectively) and low CD4 cell counts (P = 0.0008 and 0.0087, respectively). Importantly, the association between HLA-C04 : 01 and poor viral control was not due to its linkage disequilibrium with other HLA alleles. Rather, the coexpression of its putative KIR ligand KIR2DS4f was critically linked to elevated viral loads. These results highlight the impact of population allele frequency on viral control and identify a novel association between HLA-C04 : 01 in combination with KIR2DS4f and uncontrolled HIV infection. Our data further support the importance of the interplay of markers of the adaptive and innate immune system in viral control.


Update on Urological Management of Spina Bifida from Prenatal Diagnosis to Adulthood.
We review the current literature regarding urological management of spina bifida from prenatal diagnosis to adulthood. We searched MEDLINE(®), EMBASE(®) and PubMed(®) for English articles published through December 2014 using search terms "spina bifida," "spinal dysraphism" and "bladder." Based on review of titles and abstracts, 437 of 1,869 articles were identified as addressing topics related to open spina bifida in pediatric patients, or long-term or quality of life outcomes in adults with spina bifida. We summarize this literature to inform clinical guidelines and create a framework for disease management. The birth prevalence of spina bifida in the United States has recently plateaued at approximately 30 per 100,000. With improved management more individuals are surviving to adulthood, with an economic impact of $319,000 during the lifetime of an individual with spina bifida. Recent advances in prenatal surgery have demonstrated that prenatal closure of spina bifida is possible. To assess safety and efficacy, the National Institutes of Health sponsored Management of Myelomeningocele Study was undertaken, in which subjects were randomized to prenatal or postnatal closure. Until the urological results of this trial are published, the impact of prenatal intervention on future bladder function remains unclear. Controversy continues regarding the optimal use and timing of urodynamic studies, and the indications for initiation of clean intermittent catheterization and anticholinergics in infants and children. Many favor expectant management, while others argue for a more proactive approach. Based on the current literature, both approaches appear to protect the child from renal injury, although delayed intervention may increase rates of bladder augmentation. The current literature regarding this topic is difficult to interpret and compare due to heterogeneity of patient populations, variable outcome measures and lack of reporting of quality of life outcomes. Surgical intervention is indicated for those at risk for renal deterioration and/or is considered for children who fail to achieve satisfactory continence with medical management. Traditionally surgery concentrates on the bladder and bladder neck, and creation of catheterizable channels. For those with a hostile bladder, enterocystoplasty remains the gold standard for bladder augmentation, although use of bowel for augmentation remains suboptimal due to secondary complications, including increased risk of infections, metabolic abnormalities, neoplastic transformation and risk of life threatening perforation. Recent advances in tissue engineering technology may provide an alternative to traditional augmentation. However, recent results from phase II trials using current techniques to augment the bladder with engineered bladder tissue are disappointing. Catheterizable channels to the bladder and ascending colon further facilitate continence measures and promote independent care. While surgical reconstruction is clearly successful in improving continence, recent outcome studies have questioned the true impact of this type of surgery on quality of life. With improved survival transitional care issues, including health related independence, sexual health needs and development of a support system, are increasingly important. Transitional care remains a significant issue for which few public health measures are being quantitatively evaluated. Despite consensus regarding early urological involvement in the care of patients with spina bifida, controversy remains regarding optimal management. Major reconstructive urological surgeries still have a major role in the management of these cases to protect the upper urinary tract and to achieve continence. However, future studies are needed to better clarify the true impact on quality of life that these interventions have on patients and their families. Transition of urological care to adulthood remains a major avenue for improvement in disease management.


A case of persistent foot pain in a neurofibromatosis type I patient.
Introduction. This is the case of a young male patient who presented to his family physician with atypical left foot pain, which was extremely resistant to analgesia and caused significant disability. Despite extensive investigations, the cause of his pain was not identified until 18 months after his initial symptoms, when the official diagnosis of malignant peripheral nerve sheath tumour (MPNST) was made. Detailed review of the patient's past history established the diagnosis of type I neurofibromatosis (NF-1), previously undetected. Discussion. NF-1 is an autosomal dominant genetic disorder caused by loss of function mutations of the NF1 gene in chromosome 17. Patients with this condition are at increased risk for developing MPNSTs which, however, are treatable only in early stages. Conclusion. Although monitoring NF-1 patients for the development of MPNSTs is common practice, the index of clinical suspicion in patients without an established NF-1 diagnosis is low. Any atypical pain in young adults should raise the possibility of this malignancy, and this case illustrates the fact that MPNSTs can be the first manifestation of NF-1 in patients previously undiagnosed with the disease.


Phosphorus removal from SBR with controlled denitrification for weak sewage.
Most SBRs operating for weak sewage have a tendency of poor removal of phosphorus due to NO3N inhibition. To minimize this inhibition, NO3N storage was utilized in this study. With influent BOD 100 mg/L and VFA 30 mg/L, a total of the maximum removable nitrogen and phosphorus was about 25 mg/L with 8 hr cycle. With this storage, VFA utilized for phosphorus removal could be maximized. The effluent nitrogen and phosphorus levels were generally 11 and 1 mg/L, respectively.


The Helicobacter pylori urease B subunit binds to CD74 on gastric epithelial cells and induces NF-kappaB activation and interleukin-8 production.
The pathogenesis associated with Helicobacter pylori infection is the result of both bacterial factors and the host response. We have previously shown that H. pylori binds to CD74 on gastric epithelial cells. In this study, we sought to identify the bacterial protein responsible for this interaction. H. pylori urease from a pool of bacterial surface proteins was found to coprecipitate with CD74. To determine how urease binds to CD74, we used recombinant urease A and B subunits. Recombinant urease B was found to bind directly to CD74 in immunoprecipitation and flow cytometry studies. By utilizing both recombinant urease subunits and urease B knockout bacteria, the urease B-CD74 interaction was shown to induce NF-kappaB activation and interleukin-8 (IL-8) production. This response was decreased by blocking CD74 with monoclonal antibodies. Further confirmation of the interaction of urease B with CD74 was obtained using a fibroblast cell line transfected with CD74 that also responded with NF-kappaB activation and IL-8 production. The binding of the H. pylori urease B subunit to CD74 expressed on gastric epithelial cells presents a novel insight into a previously unrecognized H. pylori interaction that may contribute to the proinflammatory immune response seen during infection.


Arginine-conjugated albumin microspheres inhibits proliferation and migration in lung cancer cells.
Arginine is one of the essential amino acid involved in numerous biosynthetic pathways that significantly influence tumor growth. It has been demonstrated that arginine is effective to inhibit proliferation of cancer cells when an appropriate dose is applied. Generally, induction of cell death requires high concentration of arginine while low concentration of arginine facilitates cell proliferation. In addition to the apoptosis induced by metabolism of arginine, it has also been reported that in an ideal solution environment, arginine may assemble into arginine clusters to kill cancer cells. Therefore, to make the arginine an effective anticancer agent, arginine/albumin microspheres were designed and synthesized to provide a localized high concentration of arginine on tumor sites. In addition, the arginine/albumin mesospheres (AAMS) are also expected to provide an arginine-rich surface on microspheres, which is similar to the arginine cluster, to effectively inhibit tumor growth. In this study, the AAMS were synthesized through a water/organic solvent emulsion system and the surface properties were characterized. The in vitro effects of AAMS on A549, CRL-2081, MAK9 lung cancer cells (LCC) proliferation, migration, and tumor growth were determined. The expression of oncogenic protein EphA2 and transcription factor slug was also determined. AAMS significantly inhibited the cell proliferation, cell migration and tumor growth in all the three LCC, while same concentration of free arginine promoted the LCC tumor growth and migration. Our studies indicate that the synthesized AAMS has a more effective inhibiting effect on proliferation, migration and tumor growth of LCC than freely released arginine. The expression of EphA2 receptor mRNA was significantly decreased when compared to control cells. In addition the mRNA expression of transcription factor slug was also inhibited by AAMS suggesting that AAMS affects the expression of EphA2 and slug and may regulate LCC proliferation and migration. These data suggests that the AAMS can be an ideal delivery vehicle for therapeutic interventions against LCCs.


Steganography using reversible texture synthesis.
We propose a novel approach for steganography using a reversible texture synthesis. A texture synthesis process resamples a smaller texture image, which synthesizes a new texture image with a similar local appearance and an arbitrary size. We weave the texture synthesis process into steganography to conceal secret messages. In contrast to using an existing cover image to hide messages, our algorithm conceals the source texture image and embeds secret messages through the process of texture synthesis. This allows us to extract the secret messages and source texture from a stego synthetic texture. Our approach offers three distinct advantages. First, our scheme offers the embedding capacity that is proportional to the size of the stego texture image. Second, a steganalytic algorithm is not likely to defeat our steganographic approach. Third, the reversible capability inherited from our scheme provides functionality, which allows recovery of the source texture. Experimental results have verified that our proposed algorithm can provide various numbers of embedding capacities, produce a visually plausible texture images, and recover the source texture.


Transfer of proteins across membranes. I. Presence of proteolytically processed and unprocessed nascent immunoglobulin light chains on membrane-bound ribosomes of murine myeloma.
Fractionation of MOPC 41 DL-1 tumors revealed that the mRNA for the light chain of immunoglobulin is localized exclusively in membrane-bound ribosomes. It was shown that the translation product of isolated light chain mRNA in a heterologous protein-synthesizing system in vitro is larger than the authentic secreted light chain; this confirms similar results from several laboratories. The synthesis in vitro of a precursor protein of the light chain is not an artifact of translation in a heterologous system, because it was shown that detached polysomes, isolated from detergent-treated rough microsomes, not only contain nascent light chains which have already been proteolytically processed in vivo but also contain unprocessed nascent light chains. In vitro completion of these nascent light chains thus resulted in the synthesis of some chains having the same mol wt as the authentic secreted light chains, because of completion of in vivo proteolytically processed chains and of other chains which, due to the completion of unprocessed chains, have the same mol wt as the precursor of the light chain. In contrast, completion of the nascent light chains contained in rough microsomes resulted in the synthesis of only processed light chains. Taken together, these results indicate that the processing activity is present in isolated rough microsomes, that it is localized in the membrane moiety of rough microsomes, and, therefore, that it was most likely solubilized during detergent treatment used for the isolation of detached polysomes. Furthermore, these results established that processing in vivo takes place before completion of the nascent chain. The data also indicate that in vitro processing of nascent chains by rough microsomes is dependent on ribosome binding to the membrane. If the latter process is interfered with by aurintricarboxylic acid, rough microsomes also synthesize some unprocessed chains. The data presented in this paper have been interpreted in the light of a recently proposed hypothesis. This hypothesis, referred to as the signal hypothesis, is described in greater detail in the Discussion section.


Acute Cytomegalovirus Hepatitis in an Immunocompetent Host as a Reason for Upper Right Abdominal Pain.
Cytomegalovirus infections are widely distributed with a seroprevalence of up to 100%. The majority of the cases take a silent course or deal with unspecific clinical symptoms. Complications in immunocompetent patients are rare but may affect the liver and lead up to an acute organ failure. In this case report, we describe a 35-year-old immunocompetent female with an acute cytomegalovirus infection presenting as acute hepatitis with ongoing upper right abdominal pain after cholecystectomy. Upper right abdominal pain is a common symptom with a wide range of differential diagnoses. If common reasons can be excluded, we want to sensitize for cytomegalovirus infection as a minor differential diagnosis even in immunocompetent patients.


Segmenting skin lesions with partial-differential-equations-based image processing algorithms.
In this paper, a partial-differential equations (PDE)-based system for detecting the boundary of skin lesions in digital clinical skin images is presented. The image is first preprocessed via contrast-enhancement and anisotropic diffusion. If the lesion is covered by hairs, a PDE-based continuous morphological filter that removes them is used as an additional preprocessing step. Following these steps, the skin lesion is segmented either by the geodesic active contours model or the geodesic edge tracing approach. These techniques are based on computing, again via PDEs, a geodesic curve in a space defined by the image content. Examples showing the performance of the algorithm are given.


Both hand position and movement direction modulate visual attention.
The current study explored effects of continuous hand motion on the allocation of visual attention. A concurrent paradigm was used to combine visually concealed continuous hand movements with an attentionally demanding letter discrimination task. The letter probe appeared contingent upon the moving right hand passing through one of six positions. Discrimination responses were then collected via a keyboard press with the static left hand. Both the right hand's position and its movement direction systematically contributed to participants' visual sensitivity. Discrimination performance increased substantially when the right hand was distant from, but moving toward the visual probe location (replicating the far-hand effect, Festman et al., 2013). However, this effect disappeared when the probe appeared close to the static left hand, supporting the view that static and dynamic features of both hands combine in modulating pragmatic maps of attention.


Ferritin and increased vs upper reference interval tibc saturation to identify increased iron stores in African Americans.
Increased serum ferritin (SF) in combination with increased total iron binding capacity saturation (TS) in the upper reference internal was evaluated to identify African Americans with increased iron stores. Among 16,856 primary care-based African Americans screened at Howard University Field Center of the Hereditary Hemochromatosis and Iron Overload Screening (HEIRS) Study, 142 with SF >500 microg/l women or >700 microg/l men and increased TS (>45% women or >50% men; main study) and 146 with similar ferritin increases and upper reference interval TS (30-45% women or 35-50% men; ancillary study) were offered clinical evaluation to confirm increased SF and identify the cause. Repeat SF remained increased in 83% of 92 participants with increased TS initially (main study) vs 58% of 64 with upper reference interval TS initially (ancillary study) (P=0.0002). These persistent SF increases were associated with blood transfusions (treatment for sickle cell disease) in 20% of 76 main study and 11% of 37 ancillary study participants (P=0.4). Ninety percent of participants with persistent non-transfusional increased SF in the main study and 85% in the ancillary study had alanine-aminotransferase, aspartate-aminotransferase, C-reactive protein and/or hemoglobin values outside of the reference interval. Increased iron stores were documented by phlebotomy or liver biopsy in 4 of 7 main study and 2 of 2 ancillary study participants with persistent non-transfusional increase in SF. Increased iron stores occur in African Americans with increased SF in combination with either increased or upper reference interval TS. Limiting clinical evaluation to only those individuals with both increased SF and increased TS will miss individuals with increased iron stores.


Specific in situ hepatitis B viral double mutation (HBVDM) detection in urine with 60 copies ml(-1) analytical sensitivity in a background of 250-fold wild type without DNA isolation and amplification.
We have examined in situ detection of hepatitis B virus 1762T/1764A double mutation (HBVDM) in urine using a (Pb(Mg(1/3)Nb(2/3))O3)(0.65)(PbTiO3)(0.35) (PMN-PT) piezoelectric plate sensor (PEPS) coated with a 16-nucleotide (nt) probe DNA (pDNA) complementary to the HBVDM. The in situ mutation (MT) detection was carried out in a flow with the PEPS vertically situated at the center of the flow in a background of wild type (WT). For validation, this detection was followed by detection in the mixture of MT fluorescent reporter microspheres (FRMs) (MT FRMs) and WT FRMs that emitted different fluorescence colours and were designed to specifically bind to MT and WT, respectively. At 30 °C and 4 ml min(-1), a PEPS was shown to specifically detect HBVDM in situ with 60 copies ml(-1) analytical sensitivity in a background of clinically-relevant 250-fold more WT in 30 min without DNA isolation, amplification, or labelling as validated by the visualization of the captured MT FRMs and WT FRMs following FRM detection where the captured MT FRMs outnumbered the WT FRMs by a factor of 5 to 1.


The Copenhagen Hip and Groin Outcome Score (HAGOS): development and validation according to the COSMIN checklist.
Valid, reliable and responsive Patient-Reported Outcome (PRO) questionnaires for young to middle-aged, physically active individuals with hip and groin pain are lacking. To develop and validate a new PRO in accordance with the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) recommendations for use in young to middle-aged, physically active patients with long-standing hip and/or groin pain. Preliminary patient interviews (content validity) included 25 patients. Validity, reliability and responsiveness were evaluated in a clinical study including 101 physically active patients (50 women); mean age 36 years, range 18-63 years. The Copenhagen Hip and Groin Outcome Score (HAGOS) consists of six separate subscales assessing Pain, Symptoms, Physical function in daily living, Physical function in Sport and Recreation, Participation in Physical Activities and hip and/or groin-related Quality of Life (QOL). Test-retest reliability was substantial, with intraclass correlation coefficients ranging from 0.82 to 0.91 for the six subscales. The smallest detectable change ranged from 17.7 to 33.8 points at the individual level and from 2.7 to 5.2 points at the group level for the different subscales. Construct validity and responsiveness were confirmed with statistically significant correlation coefficients (0.37-0.73, p < 0.01) for convergent construct validity and for responsiveness from 0.56 to 0.69, p < 0.01. HAGOS has adequate measurement qualities for the assessment of symptoms, activity limitations, participation restrictions and QOL in physically active, young to middle-aged patients with long-standing hip and/or groin pain and is recommended for use in interventions where the patient's perspective and health-related QOL are of primary interest. Trial registration ClinicalTrials.gov NCT00716729.


Low dehydroepiandrosterone and ischemic heart disease in middle-aged men: prospective results from the Massachusetts Male Aging Study.
The adrenal steroid dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) have been characterized as "protective" against ischemic heart disease (IHD), especially in men, on the basis of sparse epidemiologic evidence. The authors used data from the Massachusetts Male Aging Study, a random sample prospective study of 1,709 men aged 40-70 years at baseline, to test whether serum levels of DHEA or DHEAS could predict incident IHD over a 9-year interval. At baseline (1987-1989) and follow-up (1995-1997), an interviewer-phlebotomist visited each subject in his home to obtain comprehensive health information, body measurements, and blood samples for hormone and lipid analysis. Incident IHD between baseline and follow-up was ascertained from hospital records and death registries, supplemented by self-report and evidence of medication. In the analysis sample of 1,167 men, those with serum DHEAS in the lowest quartile at baseline (<1.6 microg/ml) were significantly more likely to incur IHD by follow-up (adjusted odds ratio = 1.60, 95 percent confidence interval: 1.07, 2.39; p = 0.02), independently of a comprehensive set of known risk factors including age, obesity, diabetes, hypertension, smoking, serum lipids, alcohol intake, and physical activity. Low serum DHEA was similarly predictive. These results confirm prior evidence that low DHEA and DHEAS can predict IHD in men.


Refining the Short Version of the Leadership Scale for Sports: Factorial Validation and Measurement Invariance.
The purpose of this investigation was to examine the factorial validity and measurement invariance of the short version of the Leadership Scale for Sports (LSS; Chelladurai & Saleh, 1980): coaches' perceptions of their own behavior, athletes' preferences and athletes' perceptions of their coaches' behavior. This validation will allow researchers to minimize time demands on participants. Three independent samples of athletes (n1 = 373; n2 = 817; n3 = 246) and two samples of coaches (n1 = 115; n2 = 351) were studied to examine the factorial validity and measurement invariance of the 25-item version of the LSS (LSS-25; Chiu et al., 2016). Findings indicated that a 15-item version (LSS-15) fits the data better than the LSS-25. The LSS-15 showed factorial validity and proved to have adequate reliability, convergent validity and discriminant validity. Multiple-group confirmatory factor analysis showed that its factor structure was invariant across two independent samples and across gender for athletes' perceived and preferred versions. Significant relationships between the LSS-15 subscales and athlete satisfaction also demonstrate criterion validity. These findings support a valid and reliable alternative to the original LSS long-form, especially in applied settings when time constraints require a brief measure of leadership or when study designs include multiple variables.


A Biofeedback-Assisted Stress Management Program for Patients with Irritable Bowel Syndrome: a Randomised Controlled Trial.
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that affects the functionality and quality of life of the affected persons. There is a well-established detrimental reciprocal relationship between stress and IBS. In this randomised controlled trial, IBS patients were randomly assigned to an 8-week biofeedback-assisted stress management intervention group (n=24) or a control group (n=22). Psychometric measures were performed at baseline and following intervention to assess perceived stress, health locus of control and depressive symptoms. In patients of the intervention group, perceived stress and symptoms of depression were significantly decreased, while the sense of control over health was increased. The intervention program was beneficial to the health and quality of life of individuals with IBS. Future randomised controlled studies with larger samples and longer follow-up are required to establish the effectiveness of stress-management techniques in functional gastrointestinal disorders.


The novel application of Benford's second order analysis for monitoring radiation output in interventional radiology.
Benford's law is an empirical observation which predicts the expected frequency of digits in naturally occurring datasets spanning multiple orders of magnitude, with the law having been most successfully applied as an audit tool in accountancy. This study investigated the sensitivity of the technique in identifying system output changes using simulated changes in interventional radiology Dose-Area-Product (DAP) data, with any deviations from Benford's distribution identified using z-statistics. The radiation output for interventional radiology X-ray equipment is monitored annually during quality control testing; however, for a considerable portion of the year an increased output of the system, potentially caused by engineering adjustments or spontaneous system faults may go unnoticed, leading to a potential increase in the radiation dose to patients. In normal operation recorded examination radiation outputs vary over multiple orders of magnitude rendering the application of normal statistics ineffective for detecting systematic changes in the output. In this work, the annual DAP datasets complied with Benford's first order law for first, second and combinations of the first and second digits. Further, a continuous 'rolling' second order technique was devised for trending simulated changes over shorter timescales. This distribution analysis, the first employment of the method for radiation output trending, detected significant changes simulated on the original data, proving the technique useful in this case. The potential is demonstrated for implementation of this novel analysis for monitoring and identifying change in suitable datasets for the purpose of system process control.


Rapid identification of Candida species in blood cultures by a clinically useful PCR method.
Widespread use of fluconazole for the prophylaxis and treatment of candidiasis has led to a reduction in the number of cases of candidemia caused by Candida albicans but has also resulted in the emergence of candidemias caused by innately fluconazole-resistant, non-C. albicans Candida species. Given the fulminant and rapidly fatal outcome of acute disseminated candidiasis, rapid identification of newly emerging Candida species in blood culture is critical for the implementation of appropriately targeted antifungal drug therapy. Therefore, we used a PCR-based assay to rapidly identify Candida species from positive blood culture bottles. This assay used fungus-specific, universal primers for DNA amplification and species-specific probes to identify C. albicans, C. krusei, C. parapsilosis, C. tropicalis, or C. glabrata amplicons. It also used a simpler and more rapid (1.5-h) sample preparation technique than those described previously and used detergent, heat, and mechanical breakage to recover Candida species DNA from blood cultures. A simple and rapid (3.5-h) enzyme immunosorbent assay (EIA)-based format was then used for amplicon detection. One hundred fifty blood culture bottles, including 73 positive blood culture bottle sets (aerobic and anaerobic) from 31 patients with candidemia, were tested. The combined PCR and EIA methods (PCR-EIA) correctly identified all Candida species in 73 blood culture bottle sets, including bottles containing bacteria coisolated with yeasts and 3 cultures of samples from patients with mixed candidemias originally identified as single-species infections by routine phenotypic identification methods. Species identification time was reduced from a mean of 3.5 days by routine phenotypic methods to 7 h by the PCR-EIA method. No false-positive results were obtained for patients with bacteremias (n = 18), artificially produced non-Candida fungemias (n = 3), or bottles with no growth (n = 20). Analytical sensitivity was 1 cell per 2-microl sample. This method is simpler and more rapid than previously described molecular identification methods, can identify all five of the most medically important Candida species, and has the potential to be automated for use in the clinical microbiology laboratory.


Differences in histology between first and second primary lung cancer.
Data from the Surveillance, Epidemiology, and End Results (SEER) Program were used to compare the histological distribution of second lung cancer following an initial cancer of the lung, head and neck, and breast to primary lung carcinoma occurring as a first cancer. Following initial head and neck cancer or initial squamous cell carcinoma of the lung, the proportion of second primary lung cancer which was of squamous cell histology rose dramatically, while the proportion of pulmonary adenocarcinomas rose following initial adenocarcinoma of the lung. The histological distribution of lung cancer following an initial breast cancer in women was similar to the distribution of de novo lung cancer in women. These results persisted as the time interval between diagnosis of the two primaries was increased from 12 to 48 months. We conclude that the histology of a second primary lung cancer following an initial cancer of the lung or head and neck tends to repeat the histology of the initial cancer (field effect), and this observation is not likely to be due to misdiagnosis of a recurrence of the initial cancer.


Suprathreshold intrinsic dynamics of the human visual system.
Intrinsic high-frequency neural activities have been observed in the visual system of several species, but their functional significance for visual perception remains a fundamental puzzle in cognitive neuroscience. Spatiotemporal integration in the human visual system acts as a low-pass filter and makes the psychophysical observation of high-frequency activities very difficult. A computational model of retino-cortical dynamics (RECOD) is used to derive experimental paradigms that allow psychophysical studies of high-frequency neural activities. A reduced-parameter version of the model is used to quantitatively relate psychophysical data collected in two of these experimental paradigms. Statistical analysis shows that the model's account of the variance in the data is, in general, highly significant. We suggest that psychophysically measured oscillations reflect intrinsic neuronal oscillations observed in the visual cortex.


Preventing tick attachment to dogs using essential oils.
Preventing tick bites using repellents could make a valuable contribution to an integrated tick management programme for dogs. Here, the ability of a range of essential oils or active ingredients of commercially available repellents, to abolish the orientation and taxis of the tick Ixodes ricinus towards sebum extracted from dog hair was examined in laboratory bioassays. Substantial differences between oils were observed, but turmeric oil was both able to prevent a climbing response by ticks and had a longer residual activity than other oils. A blanket-drag field assay was then used to compare the attachment of ticks to blankets impregnated with one of: turmeric oil, DEET (positive control), orange-oil or excipient only (negative controls). In total, 899 ticks were counted, with an average of 23.3 (SD ± 21.3) ticks per blanket drag for excipient-only (n = 16), 26.9 (SD ± 28.6) for orange oil (n = 16), 2.6 (SD ± 2.0) for turmeric oil (n = 16) and 3.4 (SD ± 3.7) for DEET (n = 16). Finally, in a participatory in vivo trial, tick acquisition by 15 untreated control dogs was compared with 24 dogs sprayed with turmeric-oil and 16 dogs sprayed with orange oil (both 2.5% v/v diluted in water with a 1% coco glucoside excipient) before each walk in known tick infested areas. The percentage of dogs with ticks attached to the legs or belly of dogs sprayed with turmeric oil suspension (15% ± 19.4%) was significantly lower than that of ticks attached to the same areas of dogs sprayed with orange oil suspension (85% ± 19.4%) and unsprayed dogs (73% ± 26.2%) (P < 0.05). The data indicate that turmeric-oil may form a valuable component of a tick management programme for domestic dogs.


Parallel synthesis of poly(amino ether)-templated plasmonic nanoparticles for transgene delivery.
Plasmonic nanoparticles have been increasingly investigated for numerous applications in medicine, sensing, and catalysis. In particular, gold nanoparticles have been investigated for separations, sensing, drug/nucleic acid delivery, and bioimaging. In addition, silver nanoparticles demonstrate antibacterial activity, resulting in potential application in treatments against microbial infections, burns, diabetic skin ulcers, and medical devices. Here, we describe the facile, parallel synthesis of both gold and silver nanoparticles using a small set of poly(amino ethers), or PAEs, derived from linear polyamines, under ambient conditions and in absence of additional reagents. The kinetics of nanoparticle formation were dependent on PAE concentration and chemical composition. In addition, yields were significantly greater in case of PAEs when compared to 25 kDa poly(ethylene imine), which was used as a standard catonic polymer. Ultraviolet radiation enhanced the kinetics and the yield of both gold and silver nanoparticles, likely by means of a coreduction effect. PAE-templated gold nanoparticles demonstrated the ability to deliver plasmid DNA, resulting in transgene expression, in 22Rv1 human prostate cancer and MB49 murine bladder cancer cell lines. Taken together, our results indicate that chemically diverse poly(amino ethers) can be employed for rapidly templating the formation of metal nanoparticles under ambient conditions. The simplicity of synthesis and chemical diversity make PAE-templated nanoparticles useful tools for several applications in biotechnology, including nucleic acid delivery.


Design and Validation of a Semi-Active Variable Stiffness Foot Prosthesis.
This paper presents the design and validation of a novel lower limb prosthesis called the variable stiffness foot (VSF), designed to vary its forefoot stiffness in response to user activity. The VSF is designed as a semi-active device that adjusts its stiffness once per stride during swing phases, in order to minimize size, mass, and power consumption. The forefoot keel is designed as an overhung composite beam, whose stiffness is varied by moving a support fulcrum to change the length of the overhang. Stiffness modulation is programmed in response to the gait characteristics detected through foot trajectory reconstruction based on an embedded inertial sensor. The prototype VSF has a mass of only 649 g including the battery, and a build height of 87 mm. Mechanical testing demonstrated a forefoot stiffness range of 10-32 N/mm for the prototype, a threefold range of stiffness variation. The stiffness range can be altered by changing the keel material or geometry. Actuation testing showed that the VSF can make a full-scale stiffness adjustment within three strides, and tracks moderate speed-driven variations within one swing phase. Human subjects testing demonstrated greater energy storage and return with lower stiffness settings. This capability may be useful for the modulating prosthesis energy return to better mimic human ankle function. Subjective feedback indicated clear perception by the subjects of contrasts among the stiffness settings, including interpretation of scenarios for which different settings may be beneficial. Future applications of the VSF include adapting stiffness to optimize stairs, ramps, turns, and standing.


Phosphomannosyl receptors may participate in the adhesive interaction between lymphocytes and high endothelial venules.
Normal and malignant lymphocytes can migrate from the bloodstream into lymph nodes and Peyer's patches. This process helps distribute normal lymphocytes throughout the lymphoid system and may provide a portal of entry for circulating malignant cells. An adhesive interaction between lymphocytes and the endothelium of postcapillary venules is the first step in the migratory process. We have recently shown that the simple sugars L-fucose and D-mannose, and an L-fucose-rich polysaccharide (fucoidin), can inhibit this adhesive interaction in vitro. We now report that mannose-6-phosphate, the structurally related sugar fructose-1-phosphate, and a phosphomannan, core polysaccharide from the yeast Hansenula holstii (PPME) are also potent inhibitors. Inhibitory activity was assessed by incubating freshly prepared suspensions of lymphocytes, containing the various additives, over air-dried, frozen sections of syngeneic lymph nodes at 7-10 degrees C. Sections were then evaluated in the light microscope for the binding of lymphocytes to postcapillary venules. Mannose-6-phosphate and fructose-1-phosphate were potent inhibitors of lymphocyte attachment (one-half maximal inhibition at 2-3 mM). Mannose-1-phosphate and fructose-6-phosphate had slight inhibitory activity, while glucose-1-phosphate, glucose-6-phosphate, galactose-1-phosphate, and galactose-6-phosphate had no significant activity (at 10 mM). In addition, the phosphomannan core polysaccharide was a potent inhibitor (one-half maximal inhibition at 10-20 micrograms/ml); dephosphorylation with alkaline phosphatase resulted in loss of its inhibitory activity. Preincubation of the lymphocytes, but not the lymph node frozen sections, with PPME resulted in persistent inhibition of binding. Neither the monosaccharides nor the polysaccharide suppressed protein synthesis nor decreased the viability of the lymphocytes. Furthermore, inhibitory activity did not correlate with an increase in negative charge on the lymphocyte surface (as measured by cellular electrophoresis). These data suggest that a carbohydrate-binding molecule on the lymphocyte surface, with specificity for mannose-phosphates and structurally related carbohydrates, may be involved in the adhesive interaction mediating lymphocyte recirculation.


Virologic Failure Among People Living With HIV Initiating Dolutegravir-Based Versus Other Recommended Regimens in Real-World Clinical Care Settings.
Guidelines for initial antiretroviral treatment (ART) regimens have evolved, with integrase strand transfer inhibitors (INSTIs) increasingly prominent. Research on virologic failure (VF) with INSTI therapy is predominantly from clinical trials not care settings, especially for recently approved medications including dolutegravir. We compared outcomes among people living with HIV (PLWH) who initiated recommended regimens in clinical care across the United States. We examined 2 groups of PLWH at 8 clinics who initiated ART regimens (August 1, 2013-March 31, 2017): those ART treatment-naive at initiation, and those treatment-experienced. The outcome in this longitudinal cohort study was VF, defined as a viral load of ≥400 copies/mL ≥6 months after ART initiation. We examined the proportion of individuals who remained on, switched, or discontinued the regimen. Associations between regimens and outcomes were examined with adjusted Cox proportional hazards models. Among 5177 PLWH, a lower proportion experienced VF on dolutegravir- versus other INSTI- or darunavir-based regimens for previously treatment-naive (7% vs. 12% vs. 28%) and treatment-experienced PLWH (6% vs. 10% vs. 21%). In adjusted analyses, hazard ratios were similar across regimens for the combined outcome of regimen discontinuation or treatment switch. The hazard ratios for VF comparing dolutegravir- to darunavir-based regimens was 0.30 (95% CI: 0.2 to 0.6) among previously treatment-naive PLWH and was 0.60 (95% CI: 0.4 to 0.8) among treatment-experienced PLWH. The proportion of previously treatment-naive PLWH remaining on recommended ART regimens did not differ by regimen. The likelihood of VF was lower with dolutegravir- than darunavir-based regimens for previously treatment-naive and treatment-experienced PLWH.


Ultrasonic contrast studies for the detection of cardiac shunts.
Contrast echocardiography has achieved importance in the diagnosis of cardiac shunt lesions. The technique provides information about flow patterns and serves as an adjunct to identifying communications that may be too small to image, even with high resolution real time scanning. This report reviews clinical applications and experiences in the use of standard, peripherally injected echocardiographic contrast agents for the detection of atrial septal defect, ventricular septal defect and patent ductus arteriosus. The importance and development of transpulmonary contrast agents capable of crossing the pulmonary capillary bed to opacify the left ventricle are reviewed and experience with a variety of experimental echocardiographic contrast agents is presented. Agents opacifying the left ventricle after intravenous injection are capable of providing direct ultrasonic contrast imaging of congenital left to right shunts. Further, recent experience with an experimental standardized, gas-producing contrast agent in an open chest animal model with an experimentally produced ventricular septal defect suggests that a combination of an experimental right heart agent that produces a measurable and reproducible amount of contrast effect, with a videodensitometric system capable of quantifying both positive and negative contrast effects, may provide an ultrasonic method for evaluating the magnitude of cardiac shunts.


The Low-Dose (7.5 mg/day) Pioglitazone Therapy.
Pioglitazone is one of thiazolidinedione derivatives, which stimulates nuclear peroxisome proliferator-activated receptor gamma and improves glucose and lipid metabolism and insulin sensitivity. A recent systematic review and meta-analysis showed that pioglitazone therapy was associated with a lower risk of major adverse cardiovascular events in patients with pre-diabetes and diabetes. Further, in a cohort study of patients with type 2 diabetes, pioglitazone therapy was associated with a statistically significant decrease in the risk of all-cause mortality. Despite these beneficial effects, the meta-analysis showed that pioglitazone therapy had higher risks of heart failure, bone fractures, edema and weight gain. To find out the efficacy and safety of the low-dose (7.5 mg/day) pioglitazone therapy, we reviewed the dose-response of pioglitazone on favorable effects and adverse effects due to pioglitazone, by searching the reports on effects of daily dose of 7.5 mg and/or 15 mg and/or 30 mg of pioglitazone. The low-dose pioglitazone therapy may show the same degree of improvements in glucose and lipid metabolism, fatty liver, insulin resistance, and adiponectin as the standard- and high-dose pioglitazone therapy. Furthermore, the low-dose pioglitazone therapy may also show less adverse effects on weight gain, edema and heart failure as compared with the standard- and high-dose pioglitazone therapy.


Accuracy of mandibular cross-sectional imaging with tuned- aperture computed tomography (TACT), iteratively reconstructed TACT, and multidirectional, linear, and transverse panoramic tomography.
This study was designed to compare 5 modalities with respect to accuracy in mandibular cross-sectional imaging. The modalities tested were tuned-aperture computed tomography (TACT), iteratively reconstructed TACT, multidirectional tomography, linear tomography, and transverse panoramic tomography. Twenty sites were selected from 3 dry human mandibles, and cross-sectional views were imaged through use of each of the 5 modalities. A quantitative analysis included measurements of 2 linear distances; a qualitative study included image evaluation by 6 observers. A nested mixed analysis of variance model was used to control for mandibles and locations within mandibles for the quantitative analysis; the Cochran-Mantel-Haenszel test was used for the qualitative analysis. There was a significant difference in measurement error for maximum height but not for width. There was also a significant difference in qualitative image evaluation results. Of the 5 modalities tested, the narrow-layer multidirectional tomographic technique produced the greatest diagnostic accuracy and quality in cross-sectional imaging. The transverse panoramic tomographic technique produced the least diagnostic accuracy and quality. Linear tomography, TACT, and iteratively reconstructed TACT were intermediate in accuracy and quality.


Brain derived neurotrophic factor in the retina of the teleost N. furzeri.
BDNF plays an important role in the development and maintenance of visual circuitries in the retina and brain visual centers. In adulthood, BDNF signaling is involved in neural protection and regeneration of retina. In this survey, we investigated the expression of BDNF in the retina of adult Nothobranchius furzeri, a teleost fish employed for age research. After describing the retina of N. furzeri and confirming that the structure is organized in layers as in all vertebrates, we have studied the localization of BDNF mRNA and protein throughout the retinal layers. BDNF mRNA is detectable in all layers, whereas the protein is lacking in the photoreceptors. The occurrence of BDNF provides new insights on its role in the retina, particularly in view of age-related disease of retina.


TIM29 is a subunit of the human carrier translocase required for protein transport.
Hydrophobic inner mitochondrial membrane proteins with internal targeting signals, such as the metabolite carriers, use the carrier translocase (TIM22 complex) for transport into the inner membrane. Defects in this transport pathway have been associated with neurodegenerative disorders. While the TIM22 complex is well studied in baker's yeast, very little is known about the mammalian TIM22 complex. Using immunoprecipitation, we purified the human carrier translocase and identified a mitochondrial inner membrane protein TIM29 as a novel component, specific to metazoa. We show that TIM29 is a constituent of the 440 kDa TIM22 complex and interacts with oxidized TIM22. Our analyses demonstrate that TIM29 is required for the structural integrity of the TIM22 complex and for import of substrate proteins by the carrier translocase.


Performing Isometric Force Control in Combination with a Cognitive Task: A Multidimensional Assessment.
We used a multidimensional approach to study isometric force control in single and dual-task conditions. Multiple measures of performance, efficiency, variability, and structural interference were calculated at low and higher force levels under single (force maintenance) and dual-task (force maintenance and reaction time) conditions. Reaction time and signal-to-noise ratio were larger in the dual-task conditions. They were also greater for the higher force condition, while sample entropy was lower. Perturbation analyses revealed smaller relative amplitude of downward perturbations for the higher force level. Attentional effort and efficiency are positively related when force level increases, and inversely related to entropy. These relations were presumably mediated by attentional investment. Behavioral perturbations show that attentional resources and structural interference models are not mutually exclusive to account for dual-task situation. Overall, the present study highlights the interest of a multidimensional assessment of force control.


Visual awareness negativity is an early neural correlate of awareness: A preregistered study with two Gabor sizes.
Electrophysiological recordings are commonly used to study the neural correlates of consciousness in humans. Previous research is inconsistent as to whether awareness can be indexed with visual awareness negativity (VAN) at about 200 ms or if it occurs later. The present study was preregistered with two main aims: First, to provide independent evidence for or against the presence of VAN, and second, to study whether stimulus size may account for the inconsistent findings. Subjects were shown low-contrast Gaussian filtered gratings (Gabor patches) in the four visual quadrants. Gabor size (large and small) was varied in different sessions and calibrated to each subject's threshold of visual awareness. Event-related potentials were derived from trials in which subjects localized the Gabors correctly to capture the difference between trials in which they reported awareness versus no awareness. Bayesian analyses revealed very strong evidence for the presence of VAN for both Gabor sizes. However, there was no evidence for or against an effect of stimulus size. The present findings provide evidence for VAN as an early neural correlate of awareness.


Early detection of metachronous bile duct cancer in Lynch syndrome: report of a case.
Lynch syndrome is an autosomal dominant disease associated with a high incidence of colorectal, endometrial, stomach, ovarian, pancreatic, ureter and renal pelvis, bile duct and brain tumors. The syndrome can also include sebaceous gland adenomas and keratoacanthomas, and carcinoma of the small bowel. The lifetime risk for bile duct cancer in patients with Lynch syndrome is approximately 2 %. The present report describes a case of Lynch syndrome with metachronous bile duct cancer diagnosed at an early stage. The patient was a 73-year-old Japanese male who underwent a successful left lobectomy of the liver, and there was no sign of recurrence for 2 years postoperative. However, this patient harbored a germline mutation in MLH1, which prompted diagnostic examinations for noncolorectal tumors when a periodic surveillance blood examination showed abnormal values of hepatobiliary enzymes. Although most patients with bile duct cancer are diagnosed at an advanced stage, the bile duct cancer was diagnosed at an early stage in the present patient due to the observation of the gene mutation and the preceding liver tumor. This case illustrates the importance of continuous surveillance for extracolonic tumors, including bile duct cancer, in patients with Lynch syndrome.


Antibacterial activity of bark extracts of Moringa oleifera Lam. against some selected bacteria.
The methanol, chloroform, ethyl acetate and aqueous bark extracts of Moringa oleifera were evaluated for their antibacterial activity against four bacteria viz. Staphylococcus aureus, Citrobacter freundii, Bacillus megaterium and Pseudomonas fluorescens using erythromycin as positive control. The activity was analyzed using paper disc diffusion method at different concentration of the extract. The study revealed that all the bark extracts irrespective of their types, in different concentrations inhibited growth of the test pathogens to varying degrees. Ethyl acetate extract showed maximum activity against all the bacterial strains followed in descending order by chloroform, methanol and aqueous extracts. The activity decreased with decrease in concentration of the extract. Staphylococcus aureus was found to be the most sensitive test organism to different extracts of Moringa oleifera. Looking to these results it may be concluded that M. oleifera may be a potential source for the treatment of different infections caused by the resistant microbes.


The sources of phosphorus in the waters of Great Britain.
Total phosphorus (TP) and soluble reactive phosphorus (SRP) loads to watercourses of the River Basin Districts (RBDs) of Great Britain (GB) were estimated using inventories of industrial P loads and estimates of P loads from sewage treatment works and diffuse P loads calculated using region-specific export coefficients for particular land cover classes combined with census data for agricultural stocking densities and human populations. The TP load to GB waters was estimated to be 60 kt yr(-1), of which households contributed 73%, agriculture contributed 20%, industry contributed 3%, and 4% came from background sources. The SRP load to GB waters was estimated to be 47 kt yr(-1), of which households contributed 78%, agriculture contributed 13%, industry contributed 4%, and 6% came from background sources. The 'average' area-normalized TP and SRP loads to GB waters approximated 2.4 kg ha(-1) yr(-1) and 1.8 kg ha(-1) yr(-1), respectively. A consideration of uncertainties in the data contributing to these estimates suggested that the TP load to GB waters might lie between 33 and 68 kt yr(-1), with agriculture contributing between 10 and 28% of the TP load. These estimates are consistent with recent appraisals of annual TP and SRP loads to GB coastal waters and area-normalized TP loads from their catchments. Estimates of the contributions of RBDs to these P loads were consistent with the geographical distribution of P concentrations in GB rivers and recent assessments of surface waters at risk from P pollution.


Plasmodesmata of maize root tips: structure and composition.
A procedure is described for obtaining clean maize cell wall preparations that contain embedded plasmodesmata. Negative staining and rotary shadowing have been used with transmission electron microscopy to visualise the plasmodesmata in these isolated walls, and to assess the effects of simple biochemical treatments on plasmodesmal components. Light protease treatment removes material from the exposed ends of plasmodesmata but does not extract the plasmodesmal core, which lies within the cell wall. However, heavy proteolysis occasionally removes the complete plasmodesma, including its enclosing collar structure, from the wall. Extraction with urea has a similar effect. The collar itself appears not to be proteinaceous in composition, although protein may bind it into the wall. Callose is localised in the wall around plasmodesmata, but does not appear to be a constituent of the collar. The membrane components of the plasmodesma (plasma membrane and desmotubule) can be extracted with membrane-solubilising detergents. This treatment releases from the wall a small number of proteins that are regarded as being potentially of plasmodesmal origin. These results show that plasmodesmata from maize can be dissected biochemically and suggest a strategy for the characterisation of individual molecular components.


2018 AMI Lifetime Achievement Award.
This JBC Showcase features the award winning medical illustration of William Andrews. Bill was the 2018 recipient of the Association of Medical Illustrators' Lifetime Achievement Award. His award was presented at the Awards Ceremony during the AMI's annual meeting held in Newton, Massachusetts.


Small Molecule Anti-biofilm Agents Developed on the Basis of Mechanistic Understanding of Biofilm Formation.
Microbial biofilms are the cause of persistent infections associated with various medical implants and distinct body sites such as the urinary tract, lungs, and wounds. Compared with their free living counterparts, bacteria in biofilms display a highly increased resistance to immune system activities and antibiotic treatment. Therefore, biofilm infections are difficult or impossible to treat with our current armory of antibiotics. The challenges associated with biofilm infections have urged researchers to pursue a better understanding of the molecular mechanisms that are involved in the formation and dispersal of biofilms, and this has led to the identification of several steps that could be targeted in order to eradicate these challenging infections. Here we describe mechanisms that are involved in the regulation of biofilm development in Pseudomonas aeruginosa, Escherichia coli, and Acinetobacter baumannii, and provide examples of chemical compounds that have been developed to specifically inhibit these processes. These compounds include (i) pilicides and curlicides which inhibit the initial steps of biofilm formation by E. coli; (ii) compounds that interfere with c-di-GMP signaling in P. aeruginosa and E. coli; and (iii) compounds that inhibit quorum-sensing in P. aeruginosa and A. baumannii. In cases where compound series have a defined molecular target, we focus on elucidating structure activity relationship (SAR) trends within the particular compound series.


Intrinsic Motivation and Achievement in Mathematics in Elementary School: A Longitudinal Investigation of Their Association.
This study examined the associations between intrinsic motivation and achievement in mathematics in a sample of 1,478 Canadian school-age children followed from Grades 1 to 4 (ages 7-10). Children self-reported their intrinsic motivation toward mathematics, whereas achievement was measured through direct assessment of mathematics abilities. Cross-lagged models showed that achievement predicted intrinsic motivation from Grades 1 to 2, and from Grades 2 to 4. However, intrinsic motivation did not predict achievement at any time. This developmental pattern of association was gender invariant. Contrary to the hypothesis that motivation and achievement are reciprocally associated over time, our results point to a directional association from prior achievement to subsequent intrinsic motivation. Results are discussed in light of their theoretical and practical implications.


Chaperone Use in Plastic and Reconstructive Surgery Outpatient Clinics: The Patient Perspective.
Patient perspectives on chaperone use during examinations, especially in surgical subspecialties, are understudied. We aimed to identify specific patient cohorts that desire the presence of chaperones and compare patient and surgeon perspectives, all in an effort to improve quality of care. We prospectively administered a 15-question survey to all patients visiting 2 plastic surgery outpatient clinics between January 2015 and April 2016. Data on demographics, types of procedures (cosmetic or reconstructive), area of examination (sensitive or nonsensitive), views on chaperone use, type of chaperone, and instances of inappropriate behavior by surgeons were collected. Univariate analysis was performed after stratifying patients on their individual desire to have a chaperone. Subsequently, multivariate regression models were constructed to identify individual patient cohorts independently more likely to require a chaperone. A total of 398 participants were surveyed. There were 58.3% female and 41.7% male respondents; of whom 41.8% were 55 years or older and 8.1% were younger than 24 years. Ninety percent of all patients were receiving care for a reconstructive procedure. Most (77%) were being examined over a nonsensitive area. Overall, 82.1% preferred not to have a chaperone present during examinations. Most (72.6%) felt the sex of the examining physician was inconsequential to their need for a chaperone. Most (54.8%) preferred either a family member or a friend to be the chaperone. Only 1.8% (n = 7) experienced inappropriate behavior, of whom 77% (n = 5) noted the absence of a chaperone while being examined. On multivariate analysis, younger patients and examination over a sensitive area were independently associated with a higher odd of requiring a chaperone (odds ratios, 3.4 [95% confidence interval, 1.3-8.9; P = 0.016] and 3.9 [95% confidence interval, 1.9-6.7; P < 0.001], respectively). Most patients did not want a chaperone during examinations. Younger patients and those having a sensitive area examined were independently more likely to desire a chaperone. Patients preferred having their family member or friend as their chaperone. Given the major differences in perceptions, plastic surgeons should consider selectively using chaperones rather than the carte blanche use of chaperones with every patient.


Influence of smoking and smoking cessation on levels of urinary 11-dehydro thromboxane B2.
Thromboxane is a key clinical risk endpoint of smoking-induced inflammation which has been associated in the pathogenesis of cardiovascular disease. The goal of this review is to quantify the effect of smoking and smoking cessation on one of its urinary metabolites, 11-dehydrothromboxaneB2. PubMed and SCOPUS were searched to identify publications which report urinary 11-dehydrothromboxaneB2 levels in smokers and non-smokers, as well as articles reporting the effect of smoking cessation on urinary 11-dehydrothromboxaneB2 excretion. We found ten studies assessing urinary 11-dehydrothroboxaneB2 levels in smokers and non-smokers. Four papers reported the amount of urinary 11-dehydrothromboxaneB2 excreted in 24 h while six reported the amount excreted adjusted for creatinine. The meta-analyses comparing the excretion of urinary 11-dehydrothromboxane in current smokers to non-smokers report increased levels in current smokers (mean difference = 0.31 μg/24-h [95%CI: 0.27-0.34] and 166.45 pg/mg creatinine [95%CI: 120.51-212.40]). There were not enough publications to perform meta-analyses on the effects of smoking cessation on urinary 11-dehydrothromboxaneB2 excretion. Urinary 11-dehydrothromboxaneB2 levels are increased in cigarette smokers, however, more data are needed to elucidate the effects of smoking cessation on urinary 11-dehydrothromboxaneB2 excretion.


Novel method of gene transfer in birds: intracytoplasmic sperm injection for green fluorescent protein expression in quail blastoderms.
This study was conducted to establish a new method of avian transgenesis by intracytoplasmic sperm injection (ICSI). First, we evaluated the fertilization ability of quail oocytes after microinjection of Triton X-100 (TX-100)-treated quail sperm with PLCZ cRNA. The quail oocytes were cultured for 24 h, and blastoderm development was examined by histological observation. The TX-100 treatment induced damage to the quail sperm membrane and interfered with fertilization of oocytes injected with sperm. On the other hand, when quail oocytes were injected with TX-100-treated sperm and PLCZ cRNA simultaneously, 43.5% (10/23) of the oocytes developed into blastoderms. This rate of development was comparable to that for oocytes injected with sperm without TX-100 treatment but with PLCZ cRNA (6 [42.9%] of 14). Second, we evaluated the rate of transduction of the enhanced green fluorescent protein (EGFP) gene in quail oocytes injected with TX-100-treated sperm and PLCZ cRNA. The EGFP expression was assessed by histological observation of fluorescence emission in the embryos. The intracytoplasmic injection of sperm without TX-100 treatment but with PLCZ cRNA and EGFP vector induced blastoderm development in 40% (4/10) of the oocytes, but those oocytes showed no fluorescence emission. In contrast, the intracytoplasmic injection of TX-100-treated sperm and PLCZ cRNA induced blastoderm development in 43.8% (7/16) of the oocytes, and, importantly, 85.7% (6/7) of oocytes showed fluorescence emission. In addition, PCR analysis detected GFP fragments in 50% (3/6) of GFP-expressing blastoderms. These results indicate that this ICSI method with additional treatments described herein may be the first step toward the production of transgenic birds.


Linking Sensory Factors to Participation: Establishing Intervention Goals With Parents for Children With Autism Spectrum Disorder.
Parents often focus on independence in activities of daily living and social participation when setting goals for their children with autism spectrum disorders. Occupational therapy practitioners use clinical reasoning to translate these goals to define occupation-based outcomes. This article describes an exploratory analysis of 160 parent-identified goals for children with autism. We identified sensory integrative factors hypothesized to influence each goal and then categorized the goals using the Occupational Therapy Practice Framework: Domain and Process and the International Classification of Functioning, Disability and Health (ICF). Most goals were at the ICF participation and activity levels. Activities of daily living were the most common area of occupation identified, followed by social participation and play. Sensory reactivity and somatopraxis were the most frequently occurring sensory integrative factors. The value of addressing parent goals using a systematic reasoning process to identify factors affecting participation and the importance of measuring participation outcomes are discussed.


Quality of guidelines for cognitive rehabilitation following traumatic brain injury.
Cognitive rehabilitation following traumatic brain injury can aid in optimizing function, independence, and quality of life by addressing impairments in attention, executive function, cognitive communication, and memory. This study aimed to identify and evaluate the methodological quality of clinical practice guidelines for cognitive rehabilitation following traumatic brain injury. Systematic searching of databases and Web sites was undertaken between January and March 2012 to identify freely available, English language clinical practice guidelines from 2002 onward. Eligible guidelines were evaluated using the validated Appraisal of Guidelines for Research and Evaluation II instrument. The 11 guidelines that met inclusion criteria were independently rated by 4 raters. Results of quality appraisal indicated that guidelines generally employed systematic search and appraisal methods and produced unambiguous, clearly identifiable recommendations. Conversely, only 1 guideline incorporated implementation and audit information, and there was poor reporting of processes for formulating, reviewing, and ensuring currency of recommendations and incorporating patient preferences. Intraclass correlation coefficients for agreement between raters showed high agreement (intraclass correlation coefficient > 0.80) for all guidelines except for 1 (moderate agreement; intraclass correlation coefficient = 0.76). Future guidelines should address identified limitations by providing implementation information and audit criteria, along with better reporting of guideline development processes and stakeholder engagement.


p53R245W Mutation Fuels Cancer Initiation and Metastases in NASH-driven Liver Tumorigenesis.
Obesity is a significant global health concern. Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) are common risk factors for hepatocellular carcinoma (HCC) and are closely associated with metabolic comorbidities, including obesity and diabetes. The TP53 tumor suppressor is the most frequently mutated gene in liver cancers, with half of these alterations being missense mutations. These mutations produce highly abundant proteins in cancer cells which have both inhibitory effects on wildtype (WT) p53, and gain-of-function (GOF) activities that contribute to tumor progression. A Western diet increases p53 activity in the liver. To elucidate the functional consequences of Trp53 mutations in a NASH-driven liver tumorigenesis model, we generated somatic mouse models with Trp53 deletion or the missense hotspot mutant p53R245W only in hepatocytes and placed mice on a high-fat, choline-deficient diet. p53R245W in the presence of diet increased fatty liver, compensatory proliferation in the liver parenchyma, and enriched genes of tumor-promoting pathways such as KRAS signaling, MYC, and epithelial-mesenchymal transition when compared with controls in the premalignant liver. Moreover, p53R245W suppressed transcriptional activity of WT p53 in the liver in vivo under metabolic challenges, and shortened survival and doubling of HCC incidence as compared with control heterozygous mice. Complete loss of Trp53 also significantly accelerated liver tumor incidence and lowered time-to-tumor development compared with WT controls. p53R245W GOF properties increased carcinoma initiation, fueled mixed hepatocholangial carcinoma incidence, and tripled metastatic disease. Collectively, our in vivo studies indicate that p53R245W has stronger tumor promoting activities than Trp53 loss in the context of NASH. Using somatic NASH-driven mouse models with p53 deletion or mutant p53R245W only in hepatocytes, we discovered that p53R245W increased carcinoma initiation, fueled hepatocholangial carcinoma incidence, and tripled metastases.


Spatial relations of dorsal anastomoses and lesion border after middle cerebral artery occlusion.
Occlusion of the middle cerebral artery invariably results in infarction of tissue in stroke-prone spontaneously hypertensive rats (SHRSP). To determine if the lesion border extends beyond the territory of the occluded middle cerebral artery or if the lesion enlarges with time after the occlusion, spatial relations of the lesion and the primary anastomosing collateral branches were investigated. Measurements were made 1 day (n = 8) or 21 days (n = 8) after occlusion in 5-8-week-old SHRSP brains marked by triphenyltetrazolium chloride (TTC) or tissue atrophy. After 1 day of occlusion, the border between TTC-marked and -unmarked tissue was parallel to, and without spatial displacement from, the medial border of infarcted tissue measured 21 days after the occlusion. Thus, the TTC border accurately localizes the medial border of ischemic tissue that progresses to atrophy. The lesion border was 1.16 +/- 0.04 mm downstream from the anastomoses, and the mean distance was not significantly different in frontal, parietal, or rostral occipital regions or between the 2 groups of rats. Thus, a small but significant amount of tissue between the anastomoses and the lesion border was protected against infarction after middle cerebral artery occlusion in SHRSP. After 21 days of occlusion, the dorsal anastomoses were enlarged, bilaterally symmetric in position but not size, and without displacement from the anastomoses in 1-Day rats. Large-diameter anastomoses were further from the lesion than small-diameter anastomoses in both groups of rats, thus indicating that protection is greater near large anastomoses than near small ones.(ABSTRACT TRUNCATED AT 250 WORDS)


Recombination dynamics of charge pairs in a push-pull polyfluorene-derivative.
We investigate the properties of long-lived species in F8BT films through time-resolved photoluminescence (PL) measurements at room temperature and 10 K. The kinetics consist of an initial exponential decay (τ = 2.26 ns) followed by a weak power-law decay (I(t) [proportionality] t(-1)) up to at least 1 ms, both of which depend weakly on temperature. From fluence-dependent PL and ultrafast transient absorption (TA) measurements, we confirm that this emission arises from the recombination of geminate charge-pairs generated through singlet-singlet annihilation. This behavior is a consequence of the donor-acceptor nature of this polymer, which enhances singlet-singlet annihilation and facilitates the formation of long-lived geminate-pairs from energetic singlet states.


Lipoprotein metabolism differs between Marek's disease susceptible and resistant chickens.
Marek's disease (MD) is a lymphoproliferative disease of chickens caused by MD virus and has an important impact on the poultry industry worldwide. There have been reports showing different physiological characteristics between MD susceptible and resistant chickens. However, little is known about whether there are differences in lipid metabolism between MD susceptible and resistant lines of chickens. In this study, we examined the BW and the weight of tissues (abdominal fat, breast muscle with bone, leg muscle with bone, liver, and heart), the lipoprotein-cholesterol concentrations and distributions, and the plasma and tissue levels of adiponectin and its receptors in the highly resistant and susceptible lines during chicken growth. Our data showed that the increase in total cholesterol during growth was mainly due to the elevation of cholesterol in the low-density/very low-density lipoprotein fraction in MD susceptible chickens, whereas the increase of total cholesterol was mainly attributable to the increase in high-density lipoprotein-cholesterol in MD resistant chickens. Meanwhile, the MD resistant line appeared to have increased plasma adiponectin levels compared with MD susceptible chickens during growth. Taken together, our data suggested that lipoprotein-cholesterol and adiponectin metabolism are different between MD susceptible and resistant chickens.


Ascertaining the impact of public rapid transit system on spread of dengue in urban settings.
Urbanization is an important factor contributing to the global spread of dengue in recent decades, especially in tropical regions. However, the impact of public transportation system on local spread of dengue in urban settings remains poorly understood, due to the difficulty in collecting relevant locality, transportation and disease incidence data with sufficient detail, and in suitably quantifying the combined effect of proximity and passenger flow. We quantify proximity and passenger traffic data relating to 2014-2015 dengue outbreaks in Kaohsiung, Taiwan by introducing a "Risk Associated with Metro Passengers Presence" (RAMPP), which considers the passenger traffic of stations located within a fixed radius, giving more weight to the busier and/or closer stations. In order to analyze the contagion risk associated with nearby presence of one or more Kaohsiung Rapid Transit (KRT) stations, we cluster the Li's (the fourth level administrative subdivision in Taiwan) of Kaohsiung based on their RAMPP value using the K-means algorithm. We then perform analysis of variance on distinct clusterings and detect significant differences for both years. The subsequent post hoc tests (Dunn) show that yearly incidence rate observed in the areas with highest RAMPP values is always significantly greater than that recorded with smaller RAMPP values. RAMPP takes into account of population mobility in urban settings via the use of passenger traffic information of urban transportation system, that captures the simple but important idea that large amount of passenger flow in and out of a station can dramatically increase the contagion risk of dengue in the neighborhood. Our study provides a new perspective in identifying high-risk areas for transmissions and thus enhances our understanding of how public rapid transit system contributes to disease spread in densely populated urban areas, which could be useful in the design of more effective and timely intervention and control measures for future outbreaks.