PlantPAN 4.0: updated database for identifying conserved non-coding sequences and exploring dynamic transcriptional regulation in plant promoters.
PlantPAN 4.0 (http://PlantPAN.itps.ncku.edu.tw/) is an integrative resource for constructing transcriptional regulatory networks for diverse plant species. In this release, the gene annotation and promoter sequences were expanded to cover 115 species. PlantPAN 4.0 can help users characterize the evolutionary differences and similarities among cis-regulatory elements; furthermore, this system can now help in identification of conserved non-coding sequences among homologous genes. The updated transcription factor binding site repository contains 3428 nonredundant matrices for 18305 transcription factors; this expansion helps in exploration of combinational and nucleotide variants of cis-regulatory elements in conserved non-coding sequences. Additionally, the genomic landscapes of regulatory factors were manually updated, and ChIP-seq data sets derived from a single-cell green alga (Chlamydomonas reinhardtii) were added. Furthermore, the statistical review and graphical analysis components were improved to offer intelligible information through ChIP-seq data analysis. These improvements included easy-to-read experimental condition clusters, searchable gene-centered interfaces for the identification of promoter regions' binding preferences by considering experimental condition clusters and peak visualization for all regulatory factors, and the 20 most significantly enriched gene ontology functions for regulatory factors. Thus, PlantPAN 4.0 can effectively reconstruct gene regulatory networks and help compare genomic cis-regulatory elements across plant species and experiments.


Systematic literature review of efficacy, safety and tolerability outcomes of chemotherapy regimens in patients with metastatic Merkel cell carcinoma.
Merkel cell carcinoma (MCC) is a rare neuroendocrine, cutaneous malignancy with poor prognosis once metastasized. The aim of this study was to conduct a systematic literature review to assess clinical outcomes associated with chemotherapy regimens in metastatic MCC. Embase®, MEDLINE®, MEDLINE®-In-Process and CENTRAL were searched for studies published in January 2016. Overall, the literature on chemotherapy in patients with metastatic MCC is sparse, with most studies being case series/reports. Across all studies, response rates ranged from 20 to 61%, with higher response rates in first-line setting (53-61%) versus second-line setting (23-45%). Among responders, duration of response was short (≤8 months) in both first- and second-line settings. There is a need for novel agents that can induce durable responses in metastatic MCC.


Automatic Visual Acuity Loss Prediction in Children with Optic Pathway Gliomas using Magnetic Resonance Imaging.
Children with optic pathway gliomas (OPGs), a low-grade brain tumor associated with neurofibromatosis type 1 (NF1-OPG), are at risk for permanent vision loss. While OPG size has been associated with vision loss, it is unclear how changes in size, shape, and imaging features of OPGs are associated with the likelihood of vision loss. This paper presents a fully automatic framework for accurate prediction of visual acuity loss using multi-sequence magnetic resonance images (MRIs). Our proposed framework includes a transformer-based segmentation network using transfer learning, statistical analysis of radiomic features, and a machine learning method for predicting vision loss. Our segmentation network was evaluated on multi-sequence MRIs acquired from 75 pediatric subjects with NF1-OPG and obtained an average Dice similarity coefficient of 0.791. The ability to predict vision loss was evaluated on a subset of 25 subjects with ground truth using cross-validation and achieved an average accuracy of 0.8. Analyzing multiple MRI features appear to be good indicators of vision loss, potentially permitting early treatment decisions.Clinical relevance- Accurately determining which children with NF1-OPGs are at risk and hence require preventive treatment before vision loss remains challenging, towards this we present a fully automatic deep learning-based framework for vision outcome prediction, potentially permitting early treatment decisions.


Self-Complementary AAV9 Gene Delivery Partially Corrects Pathology Associated with Juvenile Neuronal Ceroid Lipofuscinosis (CLN3).
Juvenile neuronal ceroid lipofuscinosis (JNCL) is a fatal lysosomal storage disease caused by autosomal-recessive mutations in CLN3 for which no treatment exists. Symptoms appear between 5 and 10 years of age, beginning with blindness and seizures, followed by progressive cognitive and motor decline and premature death (late teens to 20s). We explored a gene delivery approach for JNCL by generating two self-complementary adeno-associated virus 9 (scAAV9) constructs to address CLN3 dosage effects using the methyl-CpG-binding protein 2 (MeCP2) and β-actin promoters to drive low versus high transgene expression, respectively. This approach was based on the expectation that low CLN3 levels are required for cellular homeostasis due to minimal CLN3 expression postnatally, although this had not yet been demonstrated in vivo One-month-old Cln3(Δex7/8) mice received one systemic (intravenous) injection of scAAV9/MeCP2-hCLN3 or scAAV9/β-actin-hCLN3, with green fluorescent protein (GFP)-expressing viruses as controls. A promoter-dosage effect was observed in all brain regions examined, in which hCLN3 levels were elevated 3- to 8-fold in Cln3(Δex7/8) mice receiving scAAV9/β-actin-hCLN3 versus scAAV9/MeCP2-hCLN3. However, a disconnect occurred between CLN3 levels and disease improvement, because only the scAAV9 construct driving low CLN3 expression (scAAV9/MeCP2-hCLN3) corrected motor deficits and attenuated microglial and astrocyte activation and lysosomal pathology. This may have resulted from preferential promoter usage because transgene expression after intravenous scAAV9/MeCP2-GFP injection was primarily detected in NeuN(+) neurons, whereas scAAV9/β-actin-GFP drove transgene expression in GFAP(+) astrocytes. This is the first demonstration of a systemic delivery route to restore CLN3 in vivo using scAAV9 and highlights the importance of promoter selection for disease modification in juvenile animals. Juvenile neuronal ceroid lipofuscinosis (JNCL) is a fatal lysosomal storage disease caused by CLN3 mutations. We explored a gene delivery approach using two self-complementary adeno-associated virus 9 (scAAV9) constructs to address CLN3 dosage effects using the methyl-CpG-binding protein 2 (MeCP2) and β-actin promoters. hCLN3 levels were elevated 3- to 8-fold in Cln3(Δex7/8) mice receiving scAAV9/β-actin-hCLN3 versus scAAV9/MeCP2-hCLN3 after a single systemic injection. However, only scAAV9/MeCP2-hCLN3 corrected motor deficits and attenuated glial activation and lysosomal pathology. This may reflect preferential promoter usage because transgene expression with scAAV9/MeCP2-green fluorescent protein (GFP) was primarily in neurons, whereas scAAV9/β-actin-GFP drove transgene expression in astrocytes. This is the first demonstration of systemic delivery for CLN3 using scAAV9 and highlights the importance of promoter selection for disease modification in juvenile animals.


Lower coronary plaque burden in patients with HIV presenting with acute coronary syndrome.
Treated HIV infection is associated with a higher incidence of coronary artery disease and myocardial infarction, although the mechanisms remain unclear. We sought to characterise the burden of coronary artery disease in men with HIV using retrospective data from invasive coronary angiograms in patients presenting with acute coronary syndrome (ACS). Demographic and coronary angiographic data were obtained from 160 men with ST elevation myocardial infarction, non-STEMI or high-risk chest pain; 73 HIV-infected cases and 87 age-matched controls. The burden of coronary disease was calculated using the Gensini Angiographic Scoring System by 2 independent cardiologists blinded to HIV status. The 2 groups were matched for age, sex and cardiac event subtype and there was no difference in rates of smoking or cholesterol levels. Compared with control participants, patients with HIV had higher usage of antihypertensives (46 (63%) vs 30 (35%), p<0.001) and statins (47 (64%) vs 29 (33%), p<0.001). There was no difference in plaque distribution between both groups; however, the Gensini score was 42% lower in cases with HIV than in controls (p<0.03). C reactive protein was higher in cases with HIV (13.4±15.4 vs 3.7±3.6). Men with HIV presenting with ACS paradoxically had a lower burden of coronary plaque than matched controls, despite more aggressive risk factor management, suggesting that plaque vulnerability, rather than total burden of atherosclerosis, may be important in the pathophysiology of coronary artery disease in men with HIV.


Profile. Preventing infections with today's tools.
With no vaccine in sight powerful enough to halt the spread of HIV, Africa is left with one strategy to combat the epidemic: prevention. The University of Manitoba's Frank Plummer, who oversees a large research collaboration in Nairobi, Kenya, says his group has identified a half-dozen effective interventions to lower HIV transmission rates, but "the scale at which they're implemented is tiny."


An increased ratio of dietary tryptophan to lysine improves feed efficiency and elevates plasma tryptophan and kynurenine in the absence of antimicrobials and regardless of infection with enterotoxigenic Escherichia coli in weaned pigs.
This experiment examined if a higher ratio of dietary Trp:Lys in the absence of antimicrobials improves production indices and modulates diarrhea in weaned pigs infected with enterotoxigenic Escherichia coli (ETEC). Effects of the Trp:Lys ratio on plasma levels of Trp and its metabolite kynurenine (Kyn) were also examined. Individually housed mixed-sex pigs (n = 72) weaned at 21 d of age (Landrace × Large White; initial BW of 6.3 ± 0.32 kg) were stratified into 1 of 6 treatments (n = 12) according to a 2 × 3 factorial arrangement of (i) infection or without infection with ETEC and (ii) 3 dietary standardized ileal digestible (SID) Trp:Lys ratios of 0.17, 0.21, or 0.26 in a randomized complete block design. Pigs were fed diets (10.4 MJ NE; 1.24% SID Lys; 19.5% CP) ad libitum for 3 wk after weaning. Pigs were infected with ETEC (O149:K98:K88) at 72, 96, and 120 h after weaning and then bled on day 11. A Trp:Lys ratio of 0.26 improved (P = 0.021) G:F over the study period compared to other ratios, without an infection effect (P > 0.05). Treatments did not affect ADG or ADFI (P > 0.05). Infection increased (P = 0.039) the diarrhea index and increased fecal consistency scores (P = 0.010). Plasma Trp and Kyn were lower (P < 0.001) in pigs fed 0.17 Trp:Lys than those fed ratios of 0.21 and 0.26 and were not affected (P > 0.05) by infection. In conclusion, in the absence of antimicrobials, increasing the dietary Trp:Lys ratio to 0.26 improved G:F after weaning and increased plasma levels of Trp and Kyn.


Fault tolerant quantum computation with very high threshold for loss errors.
Many proposals for fault tolerant quantum computation (FTQC) suffer detectable loss processes. Here we show that topological FTQC schemes, which are known to have high error thresholds, are also extremely robust against losses. We demonstrate that these schemes tolerate loss rates up to 24.9%, determined by bond percolation on a cubic lattice. Our numerical results show that these schemes retain good performance when loss and computational errors are simultaneously present.


A multidimensional electrophoretic system of separation for the analysis of gene expression (MESSAGE).
Differential gene expression profiling has become of central importance for the analysis of cellular systems at the transcriptional level. By now, many platform technologies including DNA-microarrays, serial analysis of gene expression or RNA-seq have been established in order to facilitate transcriptional profiling. However, these technologies are all subjected to specific limitations, as they require a priori knowledge of annotated genome sequences or are based on substantial bioinformatic infrastructure, for example. As an unbiased alternative we describe here a multidimensional electrophoretic system of separation for the analysis of gene expression for the global transcriptional profiling in any eukaryotic organism. This approach is compatible with standard laboratory equipment comprising high-resolution separation of complex cDNA-probes using two-dimensional DNA-gel electrophoresis. In this context cDNA fragments are separated using non-denaturing PAGE in the first dimension with subsequent denaturing gradient gel electrophoresis in the second dimension. Two-dimensional spot patterns are quantified by well-established bioinformatic algorithms and selected spots are identified using DNA sequencing. Neither does this method necessarily depend on annotated genome sequences, nor does it require sophisticated instrumentation. Strikingly, quantitative data on differential gene expression derived from multidimensional electrophoretic system of separation for the analysis of gene expression highly correlate with corresponding data from quantitative RT-PCR even for transcriptional profiles of limited amounts of total RNA.


Near-Complete Genome Sequences of Streptomyces sp. Strains AC1-42T and AC1-42W, Isolated from Bat Guano from Cabalyorisa Cave, Mabini, Pangasinan, Philippines.
Streptomyces sp. strains AC1-42T and AC1-42W, isolated from bat guano from Cabalyorisa Cave, Mabini, Pangasinan, Philippines, are active against Bacillus subtilis subsp. subtilis KCTC 3135T. The near-complete genome sequences reported here represent a possible source of ribosomally synthesized, posttranslationally modified peptides, such as lantipeptides, bacteriocins, linaridin, and a lasso peptide.


A mechanistic pharmacokinetic model elucidating the disposition of trastuzumab emtansine (T-DM1), an antibody-drug conjugate (ADC) for treatment of metastatic breast cancer.
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) therapeutic for treatment of human epidermal growth factor receptor 2 (HER2)-positive cancers. The T-DM1 dose product contains a mixture of drug-to-antibody ratio (DAR) moieties whereby the small molecule DM1 is chemically conjugated to trastuzumab antibody. The pharmacokinetics (PK) underlying this system and other ADCs are complex and have not been elucidated. Accordingly, we have developed two PK modeling approaches from preclinical data to conceptualize and understand T-DM1 PK, to quantify rates of DM1 deconjugation, and to elucidate the link between trastuzumab, T-DM1, and DAR measurements. Preclinical data included PK studies in rats (n = 34) and cynomolgus monkeys (n = 18) at doses ranging from 0.3 to 30 mg/kg and in vitro plasma stability. T-DM1 and total trastuzumab (TT) plasma concentrations were measured by enzyme-linked immunosorbent assay. Individual DAR moieties were measured by affinity capture liquid chromatography-mass spectrophotometry. Two PK modeling approaches were developed for T-DM1 using NONMEM 7.2 software: a mechanistic model fit simultaneously to TT and DAR concentrations and a reduced model fit simultaneously to TT and T-DM1 concentrations. DAR moieties were well described with a three-compartmental model and DM1 deconjugation in the central compartment. DM1 deconjugated fastest from the more highly loaded trastuzumab molecules (i.e., DAR moieties that are ≥3 DM1 per trastuzumab). T-DM1 clearance (CL) was 2-fold faster than TT CL due to deconjugation. The two modeling approaches provide flexibility based on available analytical measurements for T-DM1 and a framework for designing ADC studies and PK-pharmacodynamic modeling of ADC efficacy- and toxicity-related endpoints.


[Multidimensional assessment of public health care services for adolescents in Chile].
Adolescents are an especially vulnerable age group in terms of behavioral issues and require skilled teams in health centers. To assess the quality of health services provided to teenage users in Primary Health Care. A study of multiple cases was carried out in two family health centers in Puente Alto, Chile. Health services delivered to adolescents were evaluated from the provider's perspective, through qualitative design of focus groups and interviews to the care teams at each centre. For technical quality, comparing electronic records of two tracer conditions (prenatal care and depression) with technical standards established by Delphi methodology and from teenage users perspective, through a survey of service satisfaction. In both centers, providers perceived a lack of training in adolescent care, a deficient preventive approach and a limited access to care. The technical evaluation showed an inappropriate recording of both tracer conditions. The instrument used to assess user satisfaction survey was reliable and showed that the best perceived issue was medical care and treatment, and the least perceived, was the access to the services. Professionals working in these health care facilities, feel unprepared to provide comprehensive approach to adolescents. The surveyed teenagers complained of limited access to care. Therefore this age group continues to be as a non-priority group for health care.


Ethanol upregulates glucocorticoid-induced leucine zipper expression and modulates cellular inflammatory responses in lung epithelial cells.
Alcohol abuse is associated with immunosuppressive and infectious sequelae. Particularly, alcoholics are more susceptible to pulmonary infections. In this report, gene transcriptional profiles of primary human airway epithelial cells exposed to varying doses of alcohol (0, 50, and 100 mM) were obtained. Comparison of gene transcription levels in 0 mM alcohol treatments with those in 50 mM alcohol treatments resulted in 2 genes being upregulated and 16 genes downregulated by at least 2-fold. Moreover, 0 mM and 100 mM alcohol exposure led to the upregulation of 14 genes and downregulation of 157 genes. Among the upregulated genes, glucocorticoid-induced leucine zipper (GILZ) responded to alcohol in a dose-dependent manner. Moreover, GILZ protein levels also correlated with this transcriptional pattern. Lentiviral expression of GILZ small interfering RNA in human airway epithelial cells diminished the alcohol-induced upregulation, confirming that GILZ is indeed an alcohol-responsive gene. Gene silencing of GILZ in A549 cells resulted in secretion of significantly higher amounts of inflammatory cytokines in response to IL-1beta stimulation. The GILZ-silenced cells were more resistant to alcohol-mediated suppression of cytokine secretion. Further data demonstrated that the glucocorticoid receptor is involved in the regulation of GILZ by alcohol. Because GILZ is a key glucocorticoid-responsive factor mediating the anti-inflammatory and immunosuppressive actions of steroids, we propose that similar signaling pathways may play a role in the anti-inflammatory and immunosuppressive effects of alcohol.


Increased risk of herpes zoster among 108 604 patients with inflammatory bowel disease.
Patients with inflammatory bowel disease (IBD) on certain immunosuppressants have increased herpes zoster (HZ) risk. To determine the risk of HZ in IBD and how antitumour necrosis factor-alpha (anti-TNF) agents affect this risk. We performed a retrospective cohort and nested case-control study using administrative data from IMS LifeLink(®) Information Assets-Health Plan Claims Database. In the cohort, we identified IBD patients <age 64 by diagnosis codes; matched to four individuals without IBD. HZ risk was evaluated by incidence rate ratio (IRR) and adjusted Cox proportional hazards models (HR). In the nested case-control analysis, 2659 IBD patients with HZ were each matched to four IBD patients without HZ. We determined associations between medications and HZ using conditional logistic regression. The cohort included 50 932 patients with Crohn's disease (CD), 56 403 patients with ulcerative colitis (UC) and 1269 with unspecified IBD, matched to 434 416 individuals without IBD. The IBD cohort had increased HZ risk compared with non-IBD (IRR: 1.68, 95% CI: 1.60-1.76). After adjustment, IBD patients had a higher risk of HZ than non-IBD (HR: 1.49, 95% CI: 1.42-1.57). In the nested case-control multivariate-adjusted analyses, anti-TNF medications (OR: 1.81, 95% CI: 1.48-2.21), corticosteroids (OR: 1.73, 95% CI: 1.51-1.99) and thiopurines (OR: 1.85, 95% CI: 1.61-2.13) were independently associated with HZ. Risk of HZ was highest with combination anti-TNF and thiopurine therapy (OR: 3.29, 95% CI: 2.33-4.65). Patients with inflammatory bowel disease are at increased risk for herpes zoster. Use of thiopurines, anti-TNF agents, combination therapy and corticosteroids increases herpes zoster risk.


Beyond DNA cross-linking: history and prospects of DNA-targeted cancer treatment--fifteenth Bruce F. Cain Memorial Award Lecture.
The origin of cancer chemotherapy can be traced to the wartime discovery of the lymphotoxic action of nitrogen mustards. These and other bifunctional agents were later found to produce various types of DNA cross-links, and some of these agents continue to be mainstays of current therapy. The cellular pharmacology of these drugs was studied extensively during the 1970s and 1980s by means of DNA filter elution methodology. In the course of these investigations, DNA topoisomerases were discovered to be targets of anthracyclines and several other classes of anticancer drugs. DNA cross-linkers and topoisomerase blockers have generally similar cytotoxic mechanisms, which depend on DNA damage detection, DNA repair, cell cycle arrest, and cell death by apoptosis. The molecular control of these processes, involving oncogenes and tumor suppressor genes, is being revealed by current research. Cancer cells often have defects within these control systems, and these defects may confer selective sensitivity to appropriately designed drug therapy. Panels of human tumor cell lines may serve to link the molecular defects with specific drug sensitivities. Such correlations could guide the selection of drugs for therapy based on molecular diagnosis of individual tumors.


Recurrent Type 1 Enterocutaneous Fistula and Granulomatous Gastritis: A Case Report.
BACKGROUND Enterocutaneous fistula is an abnormal communication between the gastrointestinal tract and skin. One-third of enterocutaneous fistulas disappear spontaneously, but the rest of them require surgical treatment. CASE REPORT We describe the case of a 34-year-old woman with enterocutaneous fistula that she had had for year. She had previously undergone 2 unsuccessful operations, and the fistula recurred twice. Distal subtotal gastrectomy and Billroth 2 reconstruction were performed. In the pathological examination, the distal gastrectomy specimen revealed foci of ulceration. Well-circumscribed non-necrotizing granulomas were occasionally encountered beneath the ulcers. CONCLUSIONS Failure of treatment in recurrent fistula management has a variety of reasons. Our clinical experience shows that granulomatous gastritis can be a complicating factor in treatment of recurrent enterocutaneous fistula.


Amniotic fluid cultures: post-cesarean section endomyometritis and neonatal infections.
Amniotic fluid cultures in 54 consecutive patients undergoing cesarean section were compared in regard to intrapartum and postpartum events. Neonatal outcome and cultures were also compared with amniotic fluid findings. Positive amniotic cultures were obtained in 57% and showed a multiplicity of organisms. Development of endomyometritis was correlated with a heavy growth of bacteria in culture. Positive cultures were significantly associated with duration of labor greater than eight hours and presence of ruptured membranes at the time of cesarean section. Thirty-three percent of the patients with positive cultures had intact membranes at the time of operation. Eighty-eight percent of cultures from infants and amniotic fluid grew organisms in common. Implications of the study for the pathogenesis of postcesarean endomyometritis and neonatal morbidity are discussed.


CD68 expression in the placenta of gestational diabetic mothers: A case-control study.
Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with the onset or first recognition during pregnancy and is the most common metabolic complication of pregnancy. Significant maternal and fetal complications can result from undiagnosed or inadequately treated GDM. To investigate the difference in the expression of the CD-68 marker in the Hofbauer cells (HCs) and their distribution within the villi in the placentas of diabetic and non-diabetic mothers. Sixty placentas were included in the study, 30 as controls and 30 from mothers with diagnosed GDM as cases. Full-thickness cross sections of placentas were obtained. Tissue processing was done, followed by haematoxylin and eosin (H&E). A study of CD68 markers (placental macrophages) was done using standard protocols of immunohistochemistry. Frequencies and percentages of Hofbauer cells (HCs) found in case and control placental tissue were calculated. Student's t-test was used to compare two groups using SPSS 13.0 software. When P is 0.0001, differences were considered statistically significant. We studied the distribution and number of fetal macrophages (CD68+) in diabetic and non-diabetic placentas. The immunostained CD68+ cell count was identified to be significantly higher in the GDM placenta. In relation to fetal blood vessels in the villus stroma of the GDM placenta in comparison to control, CD68+ cells were found more frequently. This study shows a significant increase in the number of Hofbauer cells in the placenta of mothers with GDM in comparison to control (P < 0.0001). An increase in macrophages in these placentae might be related to the protective mechanism against inflammation. Further studies are required to investigate the mechanism in detail.


Smoking and atherosclerosis: mechanisms of disease and new therapeutic approaches.
It has been clear that at least 1 billion adults worldwide are smokers and at least 700 million children are passive smokers at home. Smoking exerts a detrimental effect to many organ systems and is responsible for illnesses such as lung cancer, pneumonia, chronic obstructive pulmonary disease, cancer of head and neck, cancer of the urinary and gastrointestinal tract, periodontal disease, cataract and arthritis. Additionally, smoking is an important modifiable risk factor for the development of cardiovascular disease such as coronary artery disease, stable angina, acute coronary syndromes, sudden death, stroke, peripheral vascular disease, congestive heart failure, erectile dysfunction and aortic aneurysms via initiation and progression of atherosclerosis. A variety of studies has proved that cigarette smoking induces oxidative stress, vascular inflammation, platelet coagulation, vascular dysfunction and impairs serum lipid pro-file in both current and chronic smokers, active and passive smokers and results in detrimental effects on the cardiovascular system. The aim of this review is to depict the physical and biochemical properties of cigarette smoke and, furthermore, elucidate the main pathophysiological mechanisms of cigarette-induced atherosclerosis and overview the new therapeutic approaches for smoking cessation and augmentation of cardiovascular health.


Glucocorticoid metabolites in rabbit faeces--influence of environmental enrichment and cage size.
The concentration of glucocorticoid metabolites (GCM) in rabbit faeces has been suggested as a non-invasive indicator of stress. In the present study, GCM concentrations were measured in faeces of fattening rabbits kept in groups of eight, at seven different stocking densities (between 5 and 20 animals/m(2)), with or without environmental enrichment (a wooden structure used mainly for gnawing and resting). Transport (30 min) was used as an acute novel stressor to assess the glucocorticoid response to stress under the different housing conditions. GCM concentrations were elevated post-transport (P<0.001). Whilst cage size had no influence on GCM, enrichment reduced GCM concentrations before as well as after transport (P=0.007 in both cases). Effects of cage size and enrichment on growth characteristics were negligible, whilst enrichment decreased cage manipulation and social contact. The results indicate that even short transport durations may be stressful for rabbits, and that enrichment may decrease housing stress. They suggest that measuring baseline GCM concentrations in faeces is a useful tool to evaluate chronic stress in rabbits, whilst measuring the response to a novel stressor did not provide additional insight.


Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry.
Neural circuits of the basal ganglia are critical for motor planning and action selection. Two parallel basal ganglia pathways have been described, and have been proposed to exert opposing influences on motor function. According to this classical model, activation of the 'direct' pathway facilitates movement and activation of the 'indirect' pathway inhibits movement. However, more recent anatomical and functional evidence has called into question the validity of this hypothesis. Because this model has never been empirically tested, the specific function of these circuits in behaving animals remains unknown. Here we report direct activation of basal ganglia circuitry in vivo, using optogenetic control of direct- and indirect-pathway medium spiny projection neurons (MSNs), achieved through Cre-dependent viral expression of channelrhodopsin-2 in the striatum of bacterial artificial chromosome transgenic mice expressing Cre recombinase under control of regulatory elements for the dopamine D1 or D2 receptor. Bilateral excitation of indirect-pathway MSNs elicited a parkinsonian state, distinguished by increased freezing, bradykinesia and decreased locomotor initiations. In contrast, activation of direct-pathway MSNs reduced freezing and increased locomotion. In a mouse model of Parkinson's disease, direct-pathway activation completely rescued deficits in freezing, bradykinesia and locomotor initiation. Taken together, our findings establish a critical role for basal ganglia circuitry in the bidirectional regulation of motor behaviour and indicate that modulation of direct-pathway circuitry may represent an effective therapeutic strategy for ameliorating parkinsonian motor deficits.


Molecular diagnosis of infective endocarditis by real-time broad-range polymerase chain reaction (PCR) and sequencing directly from heart valve tissue.
Traditionally, infective endocarditis (IE) has been microbiologically diagnosed by blood cultures or serology. However, conventional microbiologic methods do not always provide an etiologic diagnosis. We conducted the current study to evaluate the usefulness of a universal real-time polymerase chain reaction (PCR) of the 16S rRNA gene followed by sequencing for the diagnosis of IE in explanted heart valve tissue (HV) as part of the routine of a clinical microbiology laboratory, and to compare it with conventional culture of blood or HV. We prospectively analyzed 177 HV samples by universal PCR and sequencing: 48 were from 35 patients with definite IE and 129 were from 120 patients without IE. Specific PCR tests were used when necessary to confirm broad-range PCR results. For the 35 patients with IE, all of the HV samples except for 2 from the same patient gave positive PCR results. The microorganisms identified matched those isolated by blood culture in 31 cases. The other 3 patients had negative blood culture IE, but PCR made possible the detection of Tropheryma whipplei, Bartonella quintana, and Streptococcus gallolyticus. For the negative control group, universal PCR was completely negative in 123 of the 129 samples. Sensitivity, specificity, and negative and positive predictive values of this real-time PCR method were 96%, 95.3%, 98.4%, and 88.5%, respectively, for the diagnosis of IE, using the Duke criteria to define IE and using blood culture results to identify etiologic microorganisms. Conventional HV culture correlated poorly with blood cultures and molecular techniques, and frequently represented tissue contamination resulting from valve handling. Our universal PCR method has proved to be more sensitive, specific, and rapid than conventional culture methods, and should therefore be included as a new major Duke criterion for the diagnosis of IE. According to the results of the current study, this technique should be used to supplement blood and HV culture. Conventional HV cultures are frequently responsible for false-positive and false-negative results, and are not always useful to establish the etiology of IE.


Breast density in polycystic ovarian syndrome patients: A case-control study.
Epidemiological studies suggested a positive relationship between breast density and risk of breast cancer. One of the common hormonal disorders in women's reproductive age is polycystic ovarian syndrome (PCOS) and the results from the studies about the risk of breast cancer among PCOS patients are equivocal. The objective was to evaluate the breast density in PCOS patients compared with the control group. In this case-control study, the PCOS patients who were older than 40 years and were referred to infertility or gynecology outpatient clinic of Arash women's hospital between 2015 and 2017 were selected as the case group. Control group was selected from healthy women who attended the same hospital and were older than 40 years. By digital mammography, breast density was classified according to the Breast Imaging Reporting and Data System (BIRADS) of the American College of Radiology and it was graded by one expert radiologist. Final analysis in 68 cases and controls showed statistically significant differences between breast densities in PCOS patients compared to the control (p░=░0.03), and when the analysis was conducted by considering the category of age, the control group who were younger than 45 years had higher breast density compared with PCOS patient. Multivariate logistic regression analyses manifested a statistically significant adverse association between body mass index (OR░=░0.87, 95% CI: 0.79-0.95), vitamin D intake (OR░=░0.35, 95% CI: 0.16-0.81), and breast density. Our data suggested that the PCOS patients had lower breast density compared with normal population. However, in multivariate analysis, considering other confounders, this association was not confirmed.


Signal Intensity of High B-value Diffusion-weighted Imaging for the Detection of Prostate Cancer.
Diffusion-weighted imaging (DWI) is a main component of multiparametric MRI for prostate cancer detection. Recently, high b value DWI has gained more attention because of its capability for tumor characterization. To assess based on histopathological findings of transrectal ultrasound (TRUS)-guided prostate biopsy as a reference, an increase in signal intensity of prostatic lesions in comparison with normal background tissue on high b-value diffusion-weighted images could be a sign of malignancy. Fifty-three consecutive patients retrospectively included in the study. All patients underwent routine TRUS-guided prostate biopsies involving 12 cores after the magnetic resonance imaging (MRI) examinations. In seventeen patients (n =35 lesions), the prostate cancer was histologically confirmed by TRUS-guided prostate biopsy. The biopsy results of other patients were negative. Signal intensities on the high b-value (1600 s/mm2) images of the peripheral zone, the central gland, and the defined lesions were evaluated using region of interest-based measurements. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for prostate cancer detection using signal intensity of high b value diffusion-weighted images were calculated. In the patients with confirmed prostate cancer, fourteen had visually increased SI on the high b-value images. The SI of lesions for these patients was higher than the SI of peripheral zone (22±18%) or central gland (31±20%). In patients with a negative biopsy, eight had visually increased SI on the high b-value images. The SI of lesions for these patients was 23±21% and 35±18% higher than the SI in the peripheral zone and the central gland, respectively. The sensitivity, specificity, PPV, and NPV for prostate cancer using SI of high b value DWI were 71, 87, 62, and 87 %, respectively. Visually increased SI on the high b-value images can be an indication of malignancy, although some benign lesions also show this increase in signal intensity.


Systems biology visualization tools for drug target discovery.
Post-genome drug development has been driven by the need to study biological perturbations at the molecular system level. Systems biology visualization tools can help researchers extract hidden patterns from complex and large Omics data sets, model disease molecular mechanisms, and identify drug targets and drugs with good pharmacological and toxicological profiles. This review covers basic concepts in developing and applying information visualization tools to systems biology. We describe a framework and basic data representation schemes for visual data analysis in systems biology. We review major application areas of these visualization tools within drug discovery by focusing on early-stage drug discovery tasks such as disease biology modeling, target identifications and lead identification. We also show case studies and summarize our experience using visualization tools as lessons to our readers. The reader will understand what visualization tools are available for diverse types of systems biology studies in drug discovery and understand how these tools can help advance drug development. In spite of the complexity inherent in systems biology, proper use of information visualization tools may reveal emerging properties hidden in the data and enhance chances of success for drug discovery.


[Animal mediation and social bond: a psychosocial study in Ehpad].
Ehpad are French establishments intended to elderly people in a situation of physical and/or psychological loss of autonomy. Institutionalization in Ehpad is often synonymous with the disruption of social ties. In this context, different group activities are likely to favour the residents' relationships. Among these activities, animal mediation is an emerging approach that is gradually being introduced in these establishments. The aim of this research is to study the benefits of animal mediation on the social bond of Ehpad residents, according to animal mediation practitioners and professionals working in these establishments. Semi-directive interviews were carried out with nine professionals working in Ehpad in daily contact with the residents and who had attended collective sessions. These professionals were invited to give their views on the interactions between residents and on the benefits of the sessions. At the same time, fifty animal mediation practitioners responded to a questionnaire aimed at determining the place given to the development of social links in their practices. The professionals working in Ehpad described animal mediation as a practice that facilitates interactions during the sessions but also outside. For residents for whom verbalization is difficult or even impossible, animal mediation is presented as facilitating non-verbal communication. These comments converge with the discourse of animal mediation practitioners who place the creation of social links and the development of social skills at the heart of their practices. They highlight the central role of the animal which facilitates interactions and provides an emotional exchange.


Diagnosis Prevalence and Comorbidity in a Population of Mobile Integrated Community Health Care Patients.
Frequent calls to 911 and requests for emergency services by individuals place a costly burden on emergency response systems and emergency departments (EDs) in the United States. Many of the calls by these individuals are non-emergent exacerbations of chronic conditions and could be treated more effectively and cost efficiently through another health care service. Mobile integrated community health (MICH) programs present a possible partial solution to the over-utilization of emergency services by addressing factors which contribute to a patient's likelihood of frequent Emergency Medical Services (EMS) use. To provide effective care to eligible individuals, MICH providers must have a working understanding of the common conditions they will encounter. The purpose of this descriptive study was to evaluate the diagnosis prevalence and comorbidity among participants in the Queen Anne's County (Maryland USA) MICH Program. This fundamental knowledge of the most common medical conditions within the MICH Program will inform future mobile integrated health programs and providers. This study examined preliminary data from the MICH Program, as well as 2017 Maryland census data. It involved secondary analysis of de-identified patient records and descriptive statistical analysis of the disease prevalence, degree of comorbidity, insurance coverage, and demographic characteristics among 97 program participants. Diagnoses were grouped by their ICD-9 classification codes to determine the most common categories of medical conditions. Multiple linear regression models and chi-squared tests were used to assess the association between age, sex, race, ICD-9 diagnosis groups, and comorbidity among program enrollees. Results indicated the most prevalent diagnoses included hypertension, high cholesterol, esophageal reflux, and diabetes mellitus. Additionally, 94.85% of MICH patients were comorbid; the number of comorbidities per patient ranged from one to 13 conditions, with a mean of 5.88 diagnoses per patient (SD=2.74). Overall, patients in the MICH Program are decidedly medically complex and may be well-suited to additional community intervention to better manage their many conditions. The potential for MICH programs to simultaneously improve patient outcomes and reduce health care costs by expanding into larger public health and addressing the needs of the most vulnerable citizens warrants further study.ScharfBM, BissellRA, TrevittJL, JenkinsJL.Diagnosis prevalence and comorbidity in a population of mobile integrated community health care patients.Prehosp Disaster Med. 2019;34(1):46-55.


Denver meteorite: a new fall.
A meteorite, a single stone weighing 230 grams, was discovered in the roof of a warehouse on 17 July 1967; evidently it fell during the preceding week. The warehouse is on the northeast edge of Denver, Colorado; coordinates, 39 degrees 46'57''N, 104 degrees 55'50''W. This is the first recovered fresh fall in the United States since the Bells (Texas) meteorite of 9 September 1961. The composition and structure are those of an olivine-hypersthene chondrite.


Qualitative Assessment of Collagen and Elastic Fibers in Oral Submucous Fibrosis (OSMF), OSMF with Dysplasia and Oral Squamous Cell Carcinoma Arising from OSMF: A Histochemical Study.
Oral submucous fibrosis (OSMF) is a habit related potentially malignant disorder seen mainly in South Asian people. The malignancy arising from OSMF has been regarded as low grade with better outcome. The present study was orchestrated to histochemically analyze collagen and elastic fibres in OSMF without dysplasia, OSMF with dysplasia and OSMF turning malignant. 100 cases (80 cases and 20 healthy controls) were included after obtaining clearance from ethical committee. All cases were subjected to Van Gieson staining for collagen and a novel simple method for elastic fibres (Orcein staining). Data were analyzed using SPSS software. Controls showed haphazard arrangement of collagen and elastic fibres. The collagen bundles were parallelly arranged in OSMF without dysplasia and OSMF with dysplasia; the collagen was however haphazard in cases of OSMF turning malignant. As with collagen, elastic fibres were also haphazardly arranged in the control group; in contrast, the elastic fibres were predominantly arranged in a criss-cross pattern in the other study groups. The difference in orientation and density among the groups was statistically significant. With advancement of stage there is increased collagenization of OSMF, as the condition acquires dysplastic changes and turns malignant, microenvironment alters resulting in increased activity of collagenases. However, the arrangement of more resistant elastic fibres depicts the better outcome, once OSMF shows malignant transformation, limiting locoregional and distant spread.


[Modern technologies for the management of atopic dermatitis in children].
Pathogenetic mechanisms of atopic dermatitis in children, its clinical features, medicamentous treatment, and modern technologies for external therapy are considered based on the results of original studies and literature data. The analysis is focused on the available experience with the use of modern dermocosmetic preparations. A strategy of stage-by-stage therapy of atopic dermatitis in children using these preparations is proposed.


False aneurysm of the superficial femoral artery after total hip arthroplasty: a case report.
Vascular lesions in hip prosthetic replacement are rare events; it is mandatory to be aware of the risk, though, in order of the vascular bundle's proximity to the surgical field. A 74-year-old patient was admitted to our department for primary hip arthroplasty for osteoarthritis. The patient was healthy but had mild hypertension. A cemented total hip prosthesis was implanted. The patient complained of growing groin pain and swelling from the third postoperative day. The suspicion of a vascular injury arose with worsening pain and low haemoglobin at blood tests. Then ultrasonography scans and digital angiography were performed, showing a superficial femoral artery pseudo-aneurysm. The patient had further surgery to repair the lesion. In the described case, the pseudo-aneurysm might have been caused by the pulling of a Hohmann retractor on arterial vessels possibly affected by atherosclerosis. The final output was favourable, but the authors point out that knowledge of neurovascular anatomy is necessary as well as postoperative surveillance of the clinical presentation of the patient if groin pain or swelling should arise. In the case of suspicion of vascular lesions, ultrasound and angiography will allow diagnosis and confirm the indication for surgical repair.


Combination therapy of mesenchymal stromal cells and sulfasalazine attenuates trinitrobenzene sulfonic acid induced colitis in the rat: The S1P pathway.
Adipose derived mesenchymal stem cells (ASCs) transplantation is a novel immunomodulatory therapeutic tool to ameliorate the symptom of inflammatory bowel disease (IBD). The objective of this study was to investigate the therapeutic effects of combined sufasalazine and ASCs therapy in a rat model of IBD. After induction of colitis in rats, ASCs were cultured and intraperitoneally injected (3 × 106 cells/kg) into the rats on Days 1 and 5 after inducing colitis, in conjunction with daily oral administration of low dose of sulfasalazine (30 mg/kg). The regenerative effects of combination of ASCs and sulfasalazine on ulcerative colitis were assessed by measuring body weight, colonic weight/length ratio, disease activity index, macroscopic scores, histopathological examinations, cytokine, and inflammation markers profiles. In addition, western blot analysis was used to assess the levels of nuclear factor-kappa B (NF-κB) and apoptosis related proteins in colitis tissues. Simultaneous treatment with ASCs and sulfasalazine was associated with significant amelioration of disease activity index, macroscopic and microscopic colitis scores, as well as inhibition of the proinflammatory cytokines in trinitrobenzene sulfonic acid (TNBS)-induced colitis. Moreover, combined ASCs and sulfasalazine therapy effectively inhibited the NF-κB signaling pathway, reduced the expression of Bax and prevented the loss of Bcl-2 proteins in colon tissue of the rats with TNBS-induced colitis. Furthermore, combined treatment with ASCs and sulfasalazine shifted inflammatory M1 to anti-inflammatory M2 macrophages by decreasing the levels of MCP1, CXCL9 and increasing IL-10, Arg-1 levels. In conclusion, combination of ASCs with conventional IBD therapy is potentially a much more powerful strategy to slow the progression of colitis via reducing inflammatory and apoptotic markers than either therapy alone.


The mixed management of patients' medical records: responsibility sharing between the patient and the physician.
Through this article, we propose a mixed management of patients' medical records, so as to share responsibilities between the patient and the Medical Practitioner by making Patients responsible for the validation of their administrative information, and MPs responsible for the validation of their Patients' medical information. Our proposal can be considered a solution to the main problem faced by patients, health practitioners and the authorities, namely the gathering and updating of administrative and medical data belonging to the patient in order to accurately reconstitute a patient's medical history. This method is based on two processes. The aim of the first process is to provide a patient's administrative data, in order to know where and when the patient received care (name of the health structure or health practitioner, type of care: out patient or inpatient). The aim of the second process is to provide a patient's medical information and to validate it under the accountability of the Medical Practitioner with the help of the patient if needed. During these two processes, the patient's privacy will be ensured through cryptographic hash functions like the Secure Hash Algorithm, which allows pseudonymisation of a patient's identity. The proposed Medical Record Search Engines will be able to retrieve and to provide upon a request formulated by the Medical Practitioner all the available information concerning a patient who has received care in different health structures without divulging the patient's identity. Our method can lead to improved efficiency of personal medical record management under the mixed responsibilities of the patient and the MP.


Proteinase-activated receptor-2 activating peptides: distinct canine coronary artery receptor systems.
In canine coronary artery preparations, the proteinase-activated receptor-2 (PAR(2)) activating peptides (PAR(2)-APs) SLIGRL-NH(2) and 2-furoyl-LIGRLO-NH(2) caused both an endothelium-dependent relaxation and an endothelium-independent contraction. Relaxation was caused at peptide concentrations 10-fold lower than those causing a contractile response. Although trans-cinnamoyl-LIGRLO-NH(2), like other PAR(2)-APs, caused relaxation, it was inactive as a contractile agonist and instead antagonized the contractile response to SLIGRL-NH(2). RT-PCR-based sequencing of canine PAR(2) revealed a cleavage/activation (indicated by underlines) sequence (SKGR/SLIGKTDSSLQITGKG) that is very similar to the human PAR(2) sequence (R/SLIGKV). As a synthetic peptide, the canine PAR-AP (SLIGKT-NH(2)) was a much less potent agonist than either SLIGRL-NH(2) or 2-furoyl-LIGRLO-NH(2), either in the coronary contractile assay or in a Madin-Darby canine kidney (MDCK) cell PAR(2) calcium signaling assay. In the MDCK signaling assay, the order of potencies was as follows: 2-furoyl-LIGRLO-NH(2) >> SLIGRL-NH(2) = trans-cinnamoyl-LIGRLO-NH(2) >> SLIGKT-NH(2), as expected for PAR(2) responses. In the coronary contractile assay, however, the order of potencies was very different: SLIGRL-NH(2) >> 2-furoyl-LIGRLO-NH(2) >> SLIGKT-NH(2), trans-cinnamoyl-LIGRLO-NH(2) = antagonist. Because of 1) the distinct agonist (relaxant) and antagonist (contractile) activity of trans-cinnamoyl-LIGRLO-NH(2) in the canine coronary contractile assays, 2) the different concentration ranges over which the peptides caused either relaxation or contraction in the same coronary preparation, and 3) the markedly distinct structure-activity profiles for the PAR-APs in the coronary contractile assay, compared with those for PAR(2)-mediated MDCK cell calcium signaling, we suggest that the canine coronary tissue possesses a receptor system for the PAR-APs that is distinct from PAR(2) itself.


Reproductive Genetic Medicine in a Post-Dobbs World: Will it Make Life Harder for People with Genetic Disease?
Post-Dobbs abortion restrictions impact access and choice in the context of reproductive genetic medicine, raising serious reproductive justice concerns. The consequences of these restrictions are particularly acute and far-reaching for individuals with genetic conditions and their families.


Immunological and spectroscopic studies of poly(dG-dC).poly(dG-dC) modified by cis-diamminedichloroplatinum(II).
The conformational changes induced by the binding of cis-diamminedichloroplatinum(II) to poly(dG-dC).poly(dG-dC) have been studied by reaction with specific antibodies, by circular dichroism and 31P nuclear magnetic resonance. Polyclonal and monoclonal antibodies to Z-DNA bind to platinated poly(dG-dC).poly(dG-dC) at low and high ionic strength. Antibodies elicited in rabbits immunized with the platinated polynucleotide bind to double stranded polynucleotides known to adopt the Z-conformation. At low and high ionic strength the circular dichroism spectrum of platinated poly(dG-dC).poly(dG- dC) does not resemble that of poly(dG-dC).poly(dG-dC) (B or Z conformation). At low ionic strength, the characteristic 31P nuclear magnetic resonance spectrum of the Z-form is not detected. It appears only at high ionic strength, as a component of a more complex spectrum.


A Mixed Methods Analysis of Southern HIV Service Organizations' Implementation of Harm Reduction to Address the HIV and Opioid Syndemic.
Southern HIV Service Organizations (SHSOs) are promising sites for the adoption and implementation of harm reduction as a means for addressing the HIV and opioid syndemic. However, little research to date has examined exactly how harm reduction is operationalized within and among SHSOs. Using program evaluation data (i.e., organizational assessment data and semi-structured qualitative group interview data with SHSO staff), this study aimed to characterize organizational implementation of harm reduction among SHSOs that sought harm reduction capacity-building assistance (i.e., training, coaching, funding) from the SUSTAIN Center. Authors utilized a convergent mixed methods design in which quantitative and qualitative approaches were employed in parallel to gain simultaneous insights into how harm reduction was operationalized in SHSOs and how the local context influenced implementation. Means and proportions of each organizational assessment domain were compared. Thematic analysis of group interview transcripts examined SHSO staff perceptions of harm reduction implementation in their respective communities. Quantitative results revealed that SHSOs most commonly operationalize harm reduction in the Outreach, Advocacy, and Principles domains but struggle to do so in terms of Services and Organizational Infrastructure. Qualitative results revealed that various factors in SHSOs' local context, such as the community's lack of knowledge and understanding of harm reduction, limited harm reduction services, and a challenging socio-political context, influence SHSOs implementation of harm reduction. Taken together, analyses reveal that (1) SHSOs expend significant effort conducting outreach activities because Southern communities are generally unaware of harm reduction, (2) SHSOs continually advocate for harm reduction in the midst of a challenging socio-political context, and (3) SHSOs offer fewer harm reduction services and integrate harm reduction into their organizational infrastructure to a lesser extent due to external, contextual factors. The combination of organizational-level data and SHSO staff insights provided by this mixed methods study have implications for policy advocacy, funding initiatives, and capacity-building efforts.


Geometric and energetic data from quantum chemical calculations of halobenzenes and xylenes.
This article presents theoretical data on geometric and energetic features of halobenzenes and xylenes. Data were obtained from ab initio geometry optimization and frequency calculations at HF, B3LYP, MP2 and CCSD levels of theory on 6-311++G(d,p) basis set. In total, 1504 structures of halobenzenes, three structures of xylenes and one structure of benzene were generated and processed by custom-made codes in Mathematica. The quantum chemical calculation was completed in Q-Chem software package. Geometric and energetic data of the compounds are presented in this paper as supplementary tables. Raw output files as well as codes and scripts associated with production and extraction of data are also provided.


P130Cas-associated protein (p140Cap) as a new tyrosine-phosphorylated protein involved in cell spreading.
Integrin-mediated cell adhesion stimulates a cascade of signaling pathways that control cell proliferation, migration, and survival, mostly through tyrosine phosphorylation of signaling molecules. p130Cas, originally identified as a major substrate of v-Src, is a scaffold molecule that interacts with several proteins and mediates multiple cellular events after cell adhesion and mitogen treatment. Here, we describe a novel p130Cas-associated protein named p140Cap (Cas-associated protein) as a new tyrosine phosphorylated molecule involved in integrin- and epidermal growth factor (EGF)-dependent signaling. By affinity chromatography of human ECV304 cell extracts on a MBP-p130Cas column followed by mass spectrometry matrix-assisted laser desorption ionization/time of flight analysis, we identified p140Cap as a protein migrating at 140 kDa. We detected its expression in human, mouse, and rat cells and in different mouse tissues. Endogenous and transfected p140Cap proteins coimmunoprecipitate with p130Cas in ECV304 and in human embryonic kidney 293 cells and associate with p130Cas through their carboxy-terminal region. By immunofluorescence analysis, we demonstrated that in ECV304 cells plated on fibronectin, the endogenous p140Cap colocalizes with p130Cas in the perinuclear region as well as in lamellipodia. In addition p140Cap codistributes with cortical actin and actin stress fibers but not with focal adhesions. We also show that p140Cap is tyrosine phosphorylated within 15 min of cell adhesion to integrin ligands. p140Cap tyrosine phosphorylation is also induced in response to EGF through an EGF receptor dependent-mechanism. Interestingly expression of p140Cap in NIH3T3 and in ECV304 cells delays the onset of cell spreading in the early phases of cell adhesion to fibronectin. Therefore, p140Cap is a novel protein associated with p130Cas and actin cytoskeletal structures. Its tyrosine phosphorylation by integrin-mediated adhesion and EGF stimulation and its involvement in cell spreading on matrix proteins suggest that p140Cap plays a role in controlling actin cytoskeleton organization in response to adhesive and growth factor signaling.


Lactoferrin prevents dendritic cell-mediated human immunodeficiency virus type 1 transmission by blocking the DC-SIGN--gp120 interaction.
One of the cell types first encountered by human immunodeficiency virus type 1 (HIV-1) following sexual transmission are dendritic cells (DC). DC capture HIV-1 through C-type lectin receptors, of which the best studied example is DC-SIGN, which mediates HIV-1 internalization. DC can keep the virus infectious for several days and are able to transmit HIV-1 to CD4(+) T cells. We tested proteins from milk and serum for their ability to block DC-mediated HIV-1 transmission, of which bovine lactoferrin (bLF) is the most potent inhibitor. bLF binds strongly to DC-SIGN, thus preventing virus capture and subsequent transmission. Interestingly, bLF is a much more efficient inhibitor of transmission than human lactoferrin. Since bLF is nontoxic and easy to purify in large quantities, it is an interesting candidate microbicide against HIV-1. Another advantage of bLF is its ability to block HIV-1 replication in T cells. DC-mediated capture of a bLF-resistant HIV-1 variant that was selected during long-term culturing in T cells could still be blocked by bLF. This underscores the usefulness of bLF as a microbicide drug to prevent HIV-1 transmission.


Non-heme High-Spin {FeNO}6-8 Complexes: One Ligand Platform Can Do It All.
Heme and non-heme iron-nitrosyl complexes are important intermediates in biology. While there are numerous examples of low-spin heme iron-nitrosyl complexes in different oxidation states, much less is known about high-spin (hs) non-heme iron-nitrosyls in oxidation states other than the formally ferrous NO adducts ({FeNO}7 in the Enemark-Feltham notation). In this study, we present a complete series of hs-{FeNO}6-8 complexes using the TMG3tren coligand. Redox transformations from the hs-{FeNO}7 complex [Fe(TMG3tren)(NO)]2+ to its {FeNO}6 and {FeNO}8 analogs do not alter the coordination environment of the iron center, allowing for detailed comparisons between these species. Here, we present new MCD, NRVS, XANES/EXAFS, and Mössbauer data, demonstrating that these redox transformations are metal based, which allows us to access hs-Fe(II)-NO-, Fe(III)-NO-, and Fe(IV)-NO- complexes. Vibrational data, analyzed by NCA, directly quantify changes in Fe-NO bonding along this series. Optical data allow for the identification of a "spectator" charge-transfer transition that, together with Mössbauer and XAS data, directly monitors the electronic changes of the Fe center. Using EXAFS, we are also able to provide structural data for all complexes. The magnetic properties of the complexes are further analyzed (from magnetic Mössbauer). The properties of our hs-{FeNO}6-8 complexes are then contrasted to corresponding, low-spin iron-nitrosyl complexes where redox transformations are generally NO centered. The hs-{FeNO}8 complex can further be protonated by weak acids, and the product of this reaction is characterized. Taken together, these results provide unprecedented insight into the properties of biologically relevant non-heme iron-nitrosyl complexes in three relevant oxidation states.


Mutagenesis by 4-nitrobenzofurazans and furoxans.
15 nitrobenzofurazans and 10 nitrobenzofuroxans synthesized primarily for testing as potential anti-rheumatic drugs were also tested for mutagenicity in Salmonella typhimurium strains TA98 and TA100. The method used involved placing each compound in a "well" cut out of a plate of selective medium previously seeded with the appropriate tester strain, and then adding a rat liver microsome/cofactor mixture to one of the two wells on each plate. This method is considerably cheaper and more convenient than the conventional agar overlay technique, but in the present series of experiments failed to detect 4 compounds which could be detected by the overlay technique. Using a combination of the two techniques, 21 of the 25 compounds tested were found to be mutagenic. All 10 benzofuroxans and 9 of the 15 benzofurazans were detected as direct-acting mutagens with at least one of the two tester strains. Two of the benzofurazans gave positive results only in the presence of rat liver microsomes, and hence are pro-mutagens. One of the 4 benzofurazans which gave negative results for mutagenicity in these tests was found to be an efficient inhibitor of a neutral protease activity found in rheumatic synovial fluid, and may therefore have some potential as an anti-rheumatic drug.


Sequence analysis of clonal immunoglobulin and T-cell receptor gene rearrangements in children with acute lymphoblastic leukemia at diagnosis and at relapse: implications for pathogenesis and for the clinical utility of PCR-based methods of minimal residual disease detection.
Immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements provide clonal markers useful for diagnosis and measurement of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL). We analyzed the sequences of Ig and TCR gene rearrangements obtained at presentation and relapse in 41 children with ALL to study clonal stability, which has important implications for monitoring MRD, during the course of the disease. In 42%, all original Ig and/or TCR sequences were conserved. In 24%, one original sequence was preserved but the other lost, and in 14% the original sequences were conserved with new sequences identified at relapse. In 20% only new sequences were found at relapse. Using primers designed from the novel relapse sequences, the relapse clone could be identified as subdominant clones in the diagnostic sample in 8 of 14 patients. Alteration of these clonal gene rearrangements is a common feature in childhood ALL. MRD detection should include multiple gene targets to minimize false-negative samples or include also multicolor flow cytometry. In some cases the leukemic progenitor cell might arise earlier in lineage before DHJH recombination but retain the capacity to further differentiate into cells capable of altering the pattern of Ig and/or TCR rearrangements.


Cerenkov luminescence imaging of medical isotopes.
The development of novel multimodality imaging agents and techniques represents the current frontier of research in the field of medical imaging science. However, the combination of nuclear tomography with optical techniques has yet to be established. Here, we report the use of the inherent optical emissions from the decay of radiopharmaceuticals for Cerenkov luminescence imaging (CLI) of tumors in vivo and correlate the results with those obtained from concordant immuno-PET studies. In vitro phantom studies were used to validate the visible light emission observed from a range of radionuclides including the positron emitters (18)F, (64)Cu, (89)Zr, and (124)I; beta-emitter (131)I; and alpha-particle emitter (225)Ac for potential use in CLI. The novel radiolabeled monoclonal antibody (89)Zr-desferrioxamine B [DFO]-J591 for immuno-PET of prostate-specific membrane antigen (PSMA) expression was used to coregister and correlate the CLI signal observed with the immuno-PET images and biodistribution studies. Phantom studies confirmed that Cerenkov radiation can be observed from a range of positron-, beta-, and alpha-emitting radionuclides using standard optical imaging devices. The change in light emission intensity versus time was concordant with radionuclide decay and was also found to correlate linearly with both the activity concentration and the measured PET signal (percentage injected dose per gram). In vivo studies conducted in male severe combined immune deficient mice bearing PSMA-positive, subcutaneous LNCaP tumors demonstrated that tumor-specific uptake of (89)Zr-DFO-J591 could be visualized by both immuno-PET and CLI. Optical and immuno-PET signal intensities were found to increase over time from 24 to 96 h, and biodistribution studies were found to correlate well with both imaging modalities. These studies represent the first, to our knowledge, quantitative assessment of CLI for measuring radiotracer uptake in vivo. Many radionuclides common to both nuclear tomographic imaging and radiotherapy have the potential to be used in CLI. The value of CLI lies in its ability to image radionuclides that do not emit either positrons or gamma-rays and are, thus, unsuitable for use with current nuclear imaging modalities. Optical imaging of Cerenkov radiation emission shows excellent promise as a potential new imaging modality for the rapid, high-throughput screening of radiopharmaceuticals.


Prolonged urocortin 2 administration in experimental heart failure: sustained hemodynamic, endocrine, and renal effects.
Although acute administration of urocortin 2 has beneficial actions in heart failure, the integrated hemodynamic, hormonal, and renal effects of sustained urocortin 2 treatment in this disease have not been investigated. In the current study, we administered a 4-day infusion of a vehicle control (0.9% saline; n=6) or urocortin 2 (0.75 μg/kg per hour; n=6) to sheep with pacing-induced heart failure. Compared with time-matched controls, infusion of urocortin 2 produced rapid (30-minute) and persistent (4-day) improvements in cardiac contractility (day 4: control 905±73 versus urocortin 2 1424±158 mm Hg/s; P<0.001) and output (2.6±0.1 versus 3.8±0.3 L/min; P<0.001), together with reductions in left atrial pressure (28±1 versus 12±1 mm Hg; P<0.001) and peripheral resistance (30±2 versus 20±2 mm Hg/L per min; P<0.001). In contrast, urocortin 2-induced falls in mean arterial pressure were not established until the second day (day 4: 74±2 versus 72±2 mm Hg; P<0.05). Prolonged urocortin 2 administration was associated with sustained (days 0 to 4) declines in plasma renin activity (day 4: 1.33±0.27 versus 0.73±0.20 nmol/L per hour; P<0.001), aldosterone (970±383 versus 396±96 pmol/L; P<0.05), vasopressin (2.4±0.8 versus 1.3±0.1 pmol/L; P<0.05), endothelin 1 (7.2±0.7 versus 4.5±0.4 pmol/L; P<0.01), and atrial (269±27 versus 150±19 pmol/L; P<0.001) and B-type (65±9 versus 29±6 pmol/L; P<0.001) natriuretic peptides, as well as an acute transient rise in plasma cortisol (day 1: P<0.001). Chronic urocortin 2 also persistently augmented urinary sodium (day 4: 4-fold increase; P<0.001) and creatinine (1.4-fold; P<0.001) excretion and creatinine clearance (1.5-fold; P<0.01) compared with control. Food consumption was temporarily suppressed (P<0.05). In conclusion, 4-day urocortin 2 administration induces sustained improvements in hemodynamics and renal function, in association with inhibition of multiple vasoconstrictor/volume-retaining systems. These findings support the therapeutic potential for urocortin 2 in heart failure.


Seroprevalence and genotype of hepatitis C virus among immigrant workers from Cambodia and Myanmar in Thailand.
There is a large number of immigrant workers from Cambodia and Myanmar in Thailand. The aim of our study was to determine seroprevalence and genotypes of hepatitis C virus (HCV) in this group. Immigrants aged between 15 and 60 years (1,431 Cambodians and 1,594 Myanmarese) were recruited into this study. Each sample was screened for anti-HCV by ELISA. RNA was extracted from seropositive samples and RT-PCR was performed in order to amplify the HCV core region. Each sample was subsequently sequenced, and the genotype was determined by phylogenetic analysis. The prevalence of HCV infection in immigrant workers from Cambodia and Myanmar was 33 (2.3%) and 27 (1.69%) samples, respectively. Of the anti-HCV-positive individuals, 25 (75.8%) from Cambodia and 15 (55.6%) from Myanmar harbored viral RNA. Phylogenetic analysis showed that the predominant HCV genotypes in this group were 1a, 1b, 3a, 3b and 6 (6e, 6f, 6m, 6p and 6r). Most HCV isolates can be found in Thailand, though some subtypes of HCV-6 are uncommon. This study shows the HCV seroprevalence and genotypes among immigrant Cambodians and Myanmarese which may reflect the prevalence in each country and closely relate to the prevalence in the guest country.


Endogenous glucocorticoids: role in the etiopathogenesis of Alzheimer's disease.
Endogenous glucocorticoids (eGCs) are steroid hormones with a wide spectrum of physiological effects. However, enhanced basal eGCs levels have been observed in patients affected by Alzheimer's disease (AD) and they have been correlated with dysregulation of the hypothalamic-pituitary-adrenocortical axis, hippocampal degeneration and reduced cognitive/memory performance. Therefore, it has been proposed that elevated concentration of eGCs might have a role in AD pathogenesis. AD is the most common form of dementia, characterized by the pathological accumulation of two proteins: the Amyloid Beta (Aβ) and the microtubule-associated protein tau in the neurons of the hippocampus and prefrontal cortex. In particular, the hippocampus, the cerebral area involved in learning and memory, is the brain region more vulnerable to chronic eGCs exposure. Although clinical studies have failed to establish a direct causative link between eGCs e and AD pathogenesis, evidences from pre-clinical studies have shown that increased eGCs levels accelerate the formation of Aβ in AD animal models by promoting the amyloidogenic pathway, and in parallel by reducing Aβ clearance, through transcriptional mechanisms involving the Glucocorticoid receptors. Instead, the effects of stress on tau phosphorylation seem to be mainly mediated bv the corticotropin-releasing factor receptor (CRFR1) and independent from stress-induced eGCs elevation.


Disparities in registration and use of an online patient portal among older adults: findings from the LitCog cohort.
To document disparities in registration and use of an online patient portal among older adults. Data from 534 older adults were linked with information from the Northwestern Medicine Electronic Data Warehouse on patient portal registration and use of functions (secure messaging, prescription reauthorizations, checking test results, and monitoring vital statistics). Age, gender, race, education, self-reported chronic conditions, and the Newest Vital Sign health literacy measure were available from cohort data. Most patients (93.4%) had a patient portal access code generated for them, and among these 57.5% registered their accounts. In multivariable analyses, White patients (P < .001) and college graduates were more likely to have registered their patient portal (P = .015). Patients with marginal (P = .034) or adequate (P < .001) health literacy were also more likely to have registered their patient portal. Among those registering their accounts, most had messaged their physician (90%), checked a test result (96%), and ordered a reauthorization (55%), but few monitored their vital statistics (11%). Adequate health literacy patients were more likely to have used the messaging function (P = .003) and White patients were more likely to have accessed test results (P = .004). Higher education was consistently associated with prescription reauthorization requests (all P < .05). Among older American adults, there are stark health literacy, educational, and racial disparities in the registration, and subsequent use of an online patient portal. These population sub-group differences may exacerbate existing health disparities. If patient portals are implemented, intervention strategies are needed to monitor and reduce disparities in their use.


Expression map of the human exome in CD34+ cells and blood cells: increased alternative splicing in cell motility and immune response genes.
Hematopoietic cells are endowed with very specific biological functions, including cell motility and immune response. These specific functions are dramatically altered during hematopoietic cell differentiation, whereby undifferentiated hematopoietic stem and progenitor cells (HSPC) residing in bone marrow differentiate into platelets, red blood cells and immune cells that exit into the blood stream and eventually move into lymphoid organs or inflamed tissues. The contribution of alternative splicing (AS) to these functions has long been minimized due to incomplete knowledge on AS events in hematopoietic cells. Using Human Exon ST 1.0 microarrays, the entire exome expression profile of immature CD34+ HSPC and mature whole blood cells was mapped, compared to a collection of solid tissues and made freely available as an online exome expression atlas (Amazonia Exon! : http://amazonia.transcriptome.eu/exon.php). At a whole transcript level, HSPC strongly expressed EREG and the pluripotency marker DPPA4. Using a differential splicing index scheme (dsi), a list of 849 transcripts differentially expressed between hematopoietic cells and solid tissues was computed, that included NEDD9 and CD74. Some of these genes also underwent alternative splicing events during hematopoietic differentiation, such as INPP4B, PTPLA or COMMD6, with varied contribution of CD3+ T cells, CD19+ B cells, CD14+ or CD15+ myelomonocytic populations. Strikingly, these genes were significantly enriched for genes involved in cell motility, cell adhesion, response to wounding and immune processes. The relevance and the precision provided by this exon expression map highlights the contribution of alternative splicing to key feature of blood cells differentiation and function.


Gradual cessation of milking reduces milk leakage and motivation to be milked in dairy cows at dry-off.
The effects of gradual versus abrupt cessation of milking at dry-off in dairy cows are not well understood, but gradually reducing milk production in human mothers is known to reduce discomfort and milk leakage. This study compared the effects of abrupt versus gradual cessation of milking on milk leakage and dairy cow behavior. Holstein dairy cows were housed in groups of 6 and randomly assigned to either abrupt milk cessation (i.e., dry-off on d 0) or gradual milk cessation (i.e., skipped milkings beginning on d 0; dry-off on d 5). Four replicates were performed over time, for a total of 24 cows (mean ± SD; parity=2.3±1.2; milk production the day before d 0=24±5 kg/d). Intramammary antibiotic, internal teat sealer, and external teat sealant were administered at dry-off. Measurements were taken from d -3 to 8 relative to dry-off. Three periods were identified for behavior data: baseline (d -3 to 1), period 1 (abrupt cows dry, gradual cows milking; d 0-4), and period 2 (all cows dry; d 5-8). Lying time was recorded with data loggers. Video scan samples (5-min intervals) were used to measure feeding time and motivation to be milked (i.e., standing at the pen's exit gate). Milk leakage was monitored every 20 min during the 2-h period following the milking times of 0500 and 1500 h after complete cessation of milking (period 1 for abrupt vs. period 2 for gradual). Composite milk samples were taken before dry-off (d -1, 0, and 5) and at the start of the next lactation (colostrum, 24h and 7-10 d postcalving) to determine somatic cell score (SCS) and conduct bacteriological examinations in clinical mastitis cases. Regardless of treatment, dry-off resulted in reduced lying time [14.1 vs. 13.2h/d; standard error of the difference (SED)=0.2], reduced lying bouts (10.7 vs. 8.3 bouts/d; SED=0.2), increased lying bout duration (1.4 vs. 1.7h/bout; SED=0.03) and increased feeding time (5.0 vs. 5.9h/d; SED=0.2). Compared with baseline, the odds of standing at the gate increased for abrupt cows (period 1: odds ratio=6.2; 95% CI: 2.7-14.4; and period 2: odds ratio=5.2; 95% CI: 1.8-14.6). No increase in time spent standing at the gate was noted in gradual cows. Frequency of leakage was greater in abrupt versus gradual cows (75 vs. 27%). Although the gradual treatment showed an increase in SCS over the 5 d of reduced milking frequency, both treatments showed an increase in SCS at calving and both returned to pre-experiment levels within 7 to 10 d after calving. This work demonstrates that gradually reducing milking frequency in high-producing cows results in reduced time spent anticipating milking and reduced milk leakage after dry-off.


Microwave-activated carbons from tucumã (Astrocaryum aculeatum) seed for efficient removal of 2-nitrophenol from aqueous solutions.
Activated carbons (ACs) prepared from tucumã seed (Astrocaryum aculeatum) were used for 2-nitrophenol removal from aqueous solutions. The ACs were characterized by elemental analysis, FTIR, N2 adsorption/desorption isotherms, TGA, hydrophobicity/hydrophilicity balance, and total of acidic and basic groups. The ACs showed to have hydrophilic surfaces and they presented high specific surface areas (up to 1318 m2 g-1). In batch optimization studies, maximum removal was obtained at pH 7, contact time of 30 min, adsorbent dosage 1.5 gL-1 and temperature of 50°C. The general-order kinetic model and Liu isotherm model best fit the kinetic and equilibrium adsorption data with a maximum adsorption capacity of 1382 mg g-1 at 50°C. Effect of temperature and thermodynamic studies revealed that the adsorption processes of 2-nitrophenol onto ACs are dependent on temperature and are exothermic and spontaneous, respectively. About the applicability of the ACs for treating simulated effluents, the tucumã seed-activated carbon showed an excellent outcome in the treatment of simulated effluents, evidencing its high efficiency for phenolic compound adsorption. Tucumã seed-ACs showed to be cost effective and highly efficient adsorbents for efficient removal of 2-nitrophenol from aqueous solutions.


A Meta-Analysis of the Metabolic Syndrome Prevalence in the Global HIV-Infected Population.
Cardio-metabolic risk factors are of increasing concern in HIV-infected individuals, particularly with the advent of antiretroviral therapy (ART) and the subsequent rise in longevity. However, the prevalence of cardio-metabolic abnormalities in this population and the differential contribution, if any, of HIV specific factors to their distribution, are poorly understood. Therefore, we conducted a systematic review and meta-analysis to estimate the global prevalence of metabolic syndrome (MS) in HIV-infected populations, its variation by the different diagnostic criteria, severity of HIV infection, ART used and other major predictive characteristics. We performed a comprehensive search on major databases for original research articles published between 1998 and 2015. The pooled overall prevalence as well as by specific groups and subgroups were computed using random effects models. A total of 65 studies across five continents comprising 55094 HIV-infected participants aged 17-73 years (median age 41 years) were included in the final meta-analysis. The overall prevalence of MS according to the following criteria were: ATPIII-2001:16.7% (95%CI: 14.6-18.8), IDF-2005: 18% (95%CI: 14.0-22.4), ATPIII-2004-2005: 24.6% (95%CI: 20.6-28.8), Modified ATPIII-2005: 27.9% (95%CI: 6.7-56.5), JIS-2009: 29.6% (95%CI: 22.9-36.8), and EGIR: 31.3% (95%CI: 26.8-36.0). By some MS criteria, the prevalence was significantly higher in women than in men (IDF-2005: 23.2% vs. 13.4, p = 0.030), in ART compared to non-ART users (ATPIII-2001: 18.4% vs. 11.8%, p = 0.001), and varied significantly by participant age, duration of HIV diagnosis, severity of infection, non-nucleoside reverse transcriptase inhibitors (NNRTIs) use and date of study publication. Across criteria, there were significant differences in MS prevalence by sub-groups such as in men, the Americas, older publications, regional studies, younger adults, smokers, ART-naïve participants, NNRTIs users, participants with shorter duration of diagnosed infection and across the spectrum of HIV severity. Substantial heterogeneities across and within criteria were not fully explained by major study characteristics, while evidence of publication bias was marginal. The similar range of MS prevalence in the HIV-infected and general populations highlights the common drivers of this condition. Thus, cardio-metabolic assessments need to be routinely included in the holistic management of the HIV-infected individual. Management strategies recommended for MS in the general population will likely provide similar benefits in the HIV-infected.


Pulsed field ablation for atrial fibrillation - Lessons from magnetic resonance imaging.
Pulsed field ablation (PFA) is a promising technology for the treatment of atrial fibrillation (AF). Due to its unique tissue selectivity, PFA potentially bears superior characteristics as compared to established thermal energy sources in AF ablation procedures. Cardiovascular magnetic resonance imaging (CMR) using late gadolinium enhancement (LGE) is an established tool in the analysis of myocardial fibrosis representing atrial cardiomyopathy as well as ablation-induced atrial scar formation following catheter ablation with thermal energy. Mechanisms of atrial lesion formation differ between thermal ablation and electroporation and its impact on results of CMR imaging are not fully understood until now. In this review article, the potential of CMR imaging for PFA lesion assessment and available data are discussed. Further, additional needs to adopt imaging approaches to the cellular mechanisms of electroporation are considered.


Nesiritide (Natrecor): a new treatment for acutely decompensated congestive heart failure.
The care of the patient experiencing acutely decompensated congestive heart failure requires therapies that promote vasodilation and increase cardiac output while decreasing symptomatic hypotension and dysrhythmias. Nesiritide (Natrecor) is a new type of drug, recombinant human B-type natriuretic peptide (hBNP), approved for use in acutely decompensated congestive heart failure. The neurohormonal effects of endogenous BNP are reproduced by nesiritide. Indications, dosing, administration, and review of clinical trials are presented in this article.


Energy response of GR-200A thermoluminescence dosemeters to 60Co and to monoenergetic synchrotron radiation in the energy range 28-40 keV.
The response of LiF:Mg,Cu,P thermoluminescence dosemeters (type GR-200A) to monoenergetic radiation of energy 28, 35, 38 and 40 keV was evaluated with respect to irradiation with a calibrated (60)Co gamma-ray source. High-precision measurements of the relative air kerma response performed at the SYRMEP beamline of the ELETTRA synchrotron radiation facility (Trieste, Italy) showed a significant deviation of the average response to low-energy X-rays from that to (60)Co, with an over-response from 6 % (at 28 keV) to 22 % (at 40 keV). These data are not consistent with literature data for these dosemeters, where model predictions gave deviation from unity of the relative air kerma response of about 10 %. The authors conclude for the need of additional determinations of the low-energy relative response of GR-200A dosemeters, covering a wider range of monoenergetic energies sampled at a fine energy step, as planned in future experiments by their group at the ELETTRA facility.


Audiovisual spatial ventriloquism is reduced in musicians.
There is great scientific and public interest in claims that musical training improves general cognitive and perceptual abilities. While this is controversial, recent and rather convincing evidence suggests that musical training refines the temporal integration of auditory and visual stimuli at a general level. We investigated whether musical training also affects integration in the spatial domain, via an auditory localisation experiment that measured ventriloquism (where localisation is biased towards visual stimuli on audiovisual trials) and recalibration (a unimodal localisation aftereffect). While musicians (n = 22) and non-musicians (n = 22) did not have significantly different unimodal precision or accuracy, musicians were significantly less susceptible than non-musicians to ventriloquism, with large effect sizes. We replicated these results in another experiment with an independent sample of 24 musicians and 21 non-musicians. Across both experiments, spatial recalibration did not significantly differ between the groups even though musicians resisted ventriloquism. Our results suggest that the multisensory expertise afforded by musical training refines spatial integration, a process that underpins multisensory perception.


Key players of singlet oxygen-induced cell death in plants.
The production of reactive oxygen species (ROS) is an unavoidable consequence of oxygenic photosynthesis. Singlet oxygen ((1)O2) is a highly reactive species to which has been attributed a major destructive role during the execution of ROS-induced cell death in photosynthetic tissues exposed to excess light. The study of the specific biological activity of (1)O2 in plants has been hindered by its high reactivity and short lifetime, the concurrent production of other ROS under photooxidative stress, and limited in vivo detection methods. However, during the last 15 years, the isolation and characterization of two (1)O2-overproducing mutants in Arabidopsis thaliana, flu and ch1, has allowed the identification of genetically controlled (1)O2 cell death pathways and a (1)O2 acclimation pathway that are triggered at sub-cytotoxic concentrations of (1)O2. The study of flu has revealed the control of cell death by the plastid proteins EXECUTER (EX)1 and EX2. In ch1, oxidized derivatives of β-carotene, such as β-cyclocitral and dihydroactinidiolide, have been identified as important upstream messengers in the (1)O2 signaling pathway that leads to stress acclimation. In both the flu and ch1 mutants, phytohormones act as important promoters or inhibitors of cell death. In particular, jasmonate has emerged as a key player in the decision between acclimation and cell death in response to (1)O2. Although the flu and ch1 mutants show many similarities, especially regarding their gene expression profiles, key differences, such as EXECUTER-independent cell death in ch1, have also been observed and will need further investigation to be fully understood.


Deformity correction in thoracic adolescent idiopathic scoliosis.
To compare the rates of sagittal and coronal correction for all-pedicle screw instrumentation and hybrid instrumentation using sublaminar bands in the treatment of thoracic adolescent idiopathic scoliosis (AIS). We retrospectively reviewed the medical records of 124 patients who had undergone surgery in two centres for the correction of Lenke 1 or 2 AIS. Radiological evaluation was carried out preoperatively, in the early postoperative phase, and at two-year follow-up. Parameters measured included coronal Cobb angles and thoracic kyphosis. Postoperative alignment was compared after matching the cohorts by preoperative coronal Cobb angle, thoracic kyphosis, lumbar lordosis, and pelvic incidence. A total of 179 patients were available for analysis. After matching, 124 patients remained (62 in each cohort). Restoration of thoracic kyphosis was significantly better in the sublaminar band group than in the pedicle screw group (from 23.7° to 27.5° to 34.0° versus 23.9° to 18.7° to 21.5°; all p < 0.001). When the preoperative thoracic kyphosis was less than 20°, sublaminar bands achieved a normal postoperative thoracic kyphosis, whereas pedicle screws did not. In the coronal plane, pedicle screws resulted in a significantly better correction than sublaminar bands at final follow-up (73.0% versus 59.7%; p < 0.001). This is the first study to compare sublaminar bands and pedicle screws for the correction of a thoracic AIS. We have shown that pedicle screws give a good coronal correction which is maintained at two-year follow-up. Conversely, sublaminar bands restore the thoracic kyphosis better while pedicle screws are associated with a flattening of the thoracic spine. In patients with preoperative hypokyphosis, sublaminar bands should be used to restore a proper sagittal profile. Cite this article: Bone Joint J 2020;102-B(3):376-382.


Muscle tenderness score in temporomandibular disorders patients: A case-control study.
The total tenderness score (TTS) is commonly used in headache practice and contributes valuable information. To assess muscle tenderness scores in patients diagnosed with Temporomandibular disorders (TMD) and analyse their associations with various demographic and clinical parameters. Masticatory (MTS), cervical (CTS) and TTSs were analysed in this case-control study among 192 TMD patients and 99 controls. The study included a questionnaire and a clinical examination following RDC/TMD guidelines. Data were analysed using: Pearson's chi-square, analysis of variance, t test and Bonferroni post hoc. To examine the factors associated with MTS score in a multivariate manner, a conceptual hierarchical multiple regression model was adopted. Masticatory and TTS differed between TMD sub-groups and controls. Muscle tenderness was positively associated with: female sex, whiplash history, parafunction, co-morbid pains such as headaches and body pain, pain intensity, onset, frequency and duration. In the conceptual hierarchical multiple regression model, pain onset, frequency and duration, co-morbid pains were mediators in the relationship between TMD diagnosis and MTS. Muscle tenderness scores were positively associated with TMD disease characteristics and co-morbid pain conditions, which may reflect associations with disease severity. MTS differed between TMD populations and may be used in routine patient workup, to assess MMD severity and changes over time as well as treatments response and as a research tool. MTS can be used as a common methodology to describe both headaches and masticatory muscle disorders and to facilitate interprofessional research and crosstalk between a headache and oro-facial pain practitioners.


Temporal variations in the hepatitis C virus intrahost population during chronic infection.
The intrahost evolution of hepatitis C virus (HCV) holds keys to understanding mechanisms responsible for the establishment of chronic infections and to development of a vaccine and therapeutics. In this study, intrahost variants of two variable HCV genomic regions, HVR1 and NS5A, were sequenced from four treatment-naïve chronically infected patients who were followed up from the acute stage of infection for 9 to 18 years. Median-joining network analysis indicated that the majority of the HCV intrahost variants were observed only at certain time points, but some variants were detectable at more than one time point. In all patients, these variants were found organized into communities or subpopulations. We hypothesize that HCV intrahost evolution is defined by two processes: incremental changes within communities through random mutation and alternations between coexisting communities. The HCV population was observed to incrementally evolve within a single community during approximately the first 3 years of infection, followed by dispersion into several subpopulations. Two patients demonstrated this pattern of dispersion for the rest of the observation period, while HCV variants in the other two patients converged into another single subpopulation after ∼9 to 12 years of dispersion. The final subpopulation in these two patients was under purifying selection. Intrahost HCV evolution in all four patients was characterized by a consistent increase in negative selection over time, suggesting the increasing HCV adaptation to the host late in infection. The data suggest specific staging of HCV intrahost evolution.


Context and significance of emergency department visits and readmissions after pediatric appendectomy.
The readmission rate after pediatric appendectomy is frequently reported in clinical outcomes studies and quality improvement initiatives without proper description. Our aim was to delineate the context and significance of these encounters. Patients (<18 years old) who underwent appendectomy for acute appendicitis at a tertiary children's hospital from January 2007 through June 2010 were reviewed. Emergency department (ED) visits and inpatient readmissions within 90 days were identified and classified as unrelated, related surgical complications, or potentially avoidable visits for minor related concerns. Of 629 patients, 119 (18.9%) had 141 ED visits or readmissions within 90 days after discharge. Eighty-three (58.9%) encounters were limited to the ED, and 58 (41.1%) required inpatient hospitalization. Eighty-seven percent of encounters within the first 30 days after discharge, but only 26% of those occurring beyond 30 days, were related to the operation (P < .001). Overall, 45 (31.9%) ED visits or readmissions were totally unrelated to the appendectomy, 36 (25.5%) represented true surgical complications requiring inpatient hospitalization, and 60 (42.6%) were minor, potentially avoidable visits related to the appendectomy. Potentially avoidable encounters were more common in Spanish-speaking patients (P < .01). Emergency department visits and inpatient readmissions after pediatric appendectomy are frequent but not uniformly indicative of surgical complications or suboptimal care. Opportunities exist to reduce avoidable ED visits related to minor postoperative concerns.


[Inhibitory effect of pyrrolidine dithiocarbamate combined with matrine on the growth of human hepatocellular carcinoma xenografts].
To investigate the relationship between activation of nuclear factor-K-gene binding (NF-κB) and apoptosis induced by matrine(MT) in transplanted tumor of human hepatocellular carcinoma in nude mouse. Tumors were established by injection of hepatocellular carcinoma cell line HepG2 into the back of nude mice. The mice were divided randomly into four groups: Control group, MT group (35 mg/kg), PDTC group (120 mg/kg) and Combination group: PDTC + MT group (120 mg/kg + 35 mg/kg), the reagents were injected peritoneally. The tumor growth curve of nude mice bearing transplanted tumor were observed and the inhibition ratios were evaluated. Apoptosis of carcinoma cells was analyzed by TUNEL. The DNA-binding activity of NF-κB was determined by electrophoretic mobility shift assay (EMSA). Expression of bcl-2 and bax in carcinoma tissue were detected by immunohistochemical method. NF-κB mRNA, bcl-2 mRNA and bax mRNA in carcinoma tissue were detected by RT-PCR. Pyrrolidine dithiocarbamate (PDTC) could enhance the inhibition of matrine on carcinoma proliferation (P < 0.05). The apoptosis and activation of NF-κB in carcinoma cells could be induced by matrine. PDTC significantly suppressed NF-κB activation induced by matrine in carcinoma cells from 93.64 ± 2.95 to 65.78 ± 5.65 (F = 124.754, P < 0.01). Meanwhile, PDTC increased the apoptosis induced by matrine from 55.9% ± 2.8% to 74.3% ± 4.8% (P < 0.05).A positive correlation observed between the expressions of NF-κB and of bcl-2 (Pearson correlation coefficient = 0.983, P < 0.01). Matrine could induce apoptosis and activation of NF-κB in transplanted tumor. PDTC could increase apoptosis in hepatocellular carcinoma cells might be due to the suppression of NF-κB activation and the enhancement of bcl-2 expression.