A poly-herbal blend (Herbagut®) on adults presenting with gastrointestinal complaints: a randomised, double-blind, placebo-controlled study.
To evaluate the efficacy and tolerability of a poly-herbal formulation, Herbagut, for the treatment of gastrointestinal symptoms and its effect on quality of life parameters in patients presenting with self-reported, unsatisfactory bowel habits. This was a randomised, double-blind, placebo-controlled trial. Fifty adults with self-reported unsatisfactory bowel habits, primarily characterised by chronic constipation were randomly allocated to take Herbagut or a matching placebo for 28 days. Efficacy of gastrointestinal changes was measured by the completion of a patient daily diary evaluating changes in stool type (Bristol Stool Form Scale), ease of bowel movements, and feeling of complete evacuation; and the Gastrointestinal Symptom Rating Scale (GSRS). Changes in quality of life were also examined using the World Health Organization Quality of Life - abbreviated version (WHOQOL-BREF), and the Patient Assessment of Constipation-Quality of Life (PAC-QOL). All participants completed the 28-day trial with no adverse events reported. Compared to the placebo, weekly bowel movements increased over time (p < .001), as did self-reported, normal bowel motions (76% vs 4%; p < .001). Self-reported incomplete evacuation was also lower in the Herbagut group compared to placebo (24% vs 76%; p = <.001). GSRS domain ratings for abdominal pain, constipation, diarrhoea, indigestion, and reflux also decreased significantly in people taking Herbagut compared to placebo (p < .001, for all domains). Moreover, quality of life significantly improved in the Herbagut group compared to placebo as indicated by significantly greater improvement in WHOQOL-BREF domain ratings for overall quality of life, social relations, environmental health, psychological health, and physical health (p < .001, for all domains); and PAC-QOL domain ratings for physical discomfort, psychosocial discomfort, worries and concerns, and life satisfaction (p < .001, for all domains). The changes were considered clinically meaningful as evidenced by their large effect sizes. Herbagut ingestion over a 28-day period resulted in improvements in several gastrointestinal symptoms and overall quality of life. Further investigation utilising larger sample sizes and diverse clinical and cultural populations are needed. Clinical Trials Registry- India /2016/11/007479 . Registered 24 April 2015 (retrospectively registered).


[Colorectal cancer surgery. Analysis of risk factors in relation to incidence of morbidity and mortality].
The aim of the study was to investigate risk factors in relation to the incidence of morbidity and mortality in surgery for colorectal cancer. Between 1986-2005, 328 patients underwent colorectal cancer surgery, 308 of whom (93.9%) in elective and 20 (6.1%) in emergency surgery. Radical resection was performed in 276 (84.2%) and palliative surgery in 52 (15.8%) patients. Bivariate statistical analysis was used for morbidity and mortality factors and multivariate analysis was performed in order to find independent variables (age, gender, ASA grade, elective or emergency surgery, tumour excision, cancer stage according to Dukes) associated with dependent variable interactions. Differences were considered statistically significant for p values < 0.05. The incidences of mortality and morbidity were 0.91% and 20.1%, respectively. In our study we observed a leakage incidence of 2.74% (9/328). In emergency surgery we found morbidity and mortality rates of 20% and 10%, respectively. Age and advanced cancer stage influenced results but were not found to be statistically significant. 18.3% of patients (60/328) were ASA I, 32% (105/328) ASA II, 39.6% (130/328) ASA III and 10.1% (33/328) ASA IV. Among the independent variables observed in the multivariate analysis, ASA grade was found to be the only positive predictive factor correlated with morbidity. Logistic regression showed an exponential increase in operative risk: odds ratio (OR) 2.9 in ASA I vs ASA II, OR 4.2 in ASA I vs ASA Ill, OR 10.3 in ASA I vs ASA IV (95% confidence interval). As regards the mortality rate, none of the independent variables were found to be statistically significant risk factors (p < 0.05).


e-Delphi Study: Expert Consensus on the Needs and Resources Available to Family Caregivers of Individuals with Substance Use Disorder.
Family caregivers of individuals with substance use disorder (SUD) experience a significant burden and have few evidence-based resources available. To obtain a consensus of expert views on the needs, and resources available, to family caregivers of individuals with SUD given the COVID-19 pandemic and other sociopolitical factors. Quantitative design using the Classic e-Delphi method of multiple iterations of questioning to reach a consensus among expert panelists. Purposive sampling was used to recruit a multidisciplinary, nationwide panel of SUD experts from professional contacts, professional organization list servers, websites relevant to support groups for family caregivers, flyers, and word of mouth. In round 1 panelists (n = 96) responded to open-ended questions about the support provided to family caregivers, and the additional needs of family caregivers. In subsequent rounds, the panel rated collated responses in terms of agreement (n = 54) and importance (n = 48). Thematic content analysis identified ten needs in the resources available to family caregivers. Consensus was obtained across thematic categories and the remaining items were ranked according to importance. Participatory-based SUD research that includes the expertise of healthcare providers, support leaders, and family caregivers is necessary to develop evidence-based interventions to increase caregiver resilience and facilitate coping. Several clear conclusions that address social and structural determinants of health emerged, including the need for increased access to healthcare and community services, more self-care strategies for families, and focused public advocacy to reduce SUD-related stigma.


The survival-promoting peptide Y-P30 enhances binding of pleiotrophin to syndecan-2 and -3 and supports its neuritogenic activity.
Y-P30 is a polypeptide produced by peripheral blood mononuclear cells of the maternal immune system during pregnancy. The peptide passes the blood-placenta barrier and accumulates in neurons of the developing infant brain, where it enhances survival of thalamic neurons and displays neuritogenic activities. In this study, we identify pleiotrophin (PTN) and syndecan-2 and -3 as direct binding partners of Y-P30. PTN is known to promote neurite outgrowth of thalamic neurons due to its association with the proteoglycan syndecan-3. Via spontaneous oligomerization Y-P30 can capture large macromolecular complexes containing PTN and potentially syndecans. Accordingly, the neuritogenic activity of Y-P30 in thalamic primary cultures requires the presence of PTN in the media and binding to syndecans. Thus, we propose that the neurite outgrowth promoting actions of Y-P30 during brain development are essentially based on its association with the PTN/syndecan signaling complex. This identifies a new mechanism of communication between the nervous and the immune system that might directly affect the wiring of the brain during development.


Prognostic Significance of TWIST1, CD24, CD44, and ALDH1 Transcript Quantification in EpCAM-Positive Circulating Tumor Cells from Early Stage Breast Cancer Patients.
(1) Background: The aim of the study was to evaluate the prognostic significance of EMT-associated (TWIST1) and stem-cell (SC) transcript (CD24, CD44, ALDH1) quantification in EpCAM+ circulating tumor cells (CTCs) of early breast cancer patients. (2) Methods: 100 early stage breast cancer patients and 19 healthy donors were enrolled in the study. CD24, CD44, and ALDH1 transcripts of EpCAM+ cells were quantified using a novel highly sensitive and specific quadraplex RT-qPCR, while TWIST1 transcripts were quantified by single RT-qPCR. All patients were followed up for more than 5 years. (3) Results: A significant positive correlation between overexpression of TWIST1 and CD24-/low/CD44high profile was found. Kaplan-Meier analysis revealed that the ER/PR-negative (HR-) patients and those patients with more than 3 positive lymph nodes that overexpressed TWIST1 in EpCAM+ cells had a significant lower DFI (log rank test; p < 0.001, p < 0.001) and OS (log rank test; p = 0.006, p < 0.001). Univariate and multivariate analysis also revealed the prognostic value of TWIST1 overexpression and CD24-/low/CD44high and CD24-/low/ALDH1high profile for both DFI and OS. (4) Conclusions: Detection of TWIST1 overexpression and stem-cell (CD24, CD44, ALDH1) transcripts in EpCAM+ CTCs provides prognostic information in early stage breast cancer patients.


The effects of placental site on the arcuate artery flow velocity waveform.
Eighty-three consecutive patients were studied to determine the effect of placental site on the arcuate artery flow velocity waveform. The resistance indices derived from signals obtained from the placental side of the uterus were significantly lower than those derived from signals obtained from the nonplacental side. Doppler studies of the uteroplacental circulation should be performed preferably with knowledge of the placental site.


Detection of circular permutations within protein structures using CE-CP.
Circular permutation is an important type of protein rearrangement. Natural circular permutations have implications for protein function, stability and evolution. Artificial circular permutations have also been used for protein studies. However, such relationships are difficult to detect for many sequence and structure comparison algorithms and require special consideration. We developed a new algorithm, called Combinatorial Extension for Circular Permutations (CE-CP), which allows the structural comparison of circularly permuted proteins. CE-CP was designed to be user friendly and is integrated into the RCSB Protein Data Bank. It was tested on two collections of circularly permuted proteins. Pairwise alignments can be visualized both in a desktop application or on the web using Jmol and exported to other programs in a variety of formats. The CE-CP algorithm can be accessed through the RCSB website at http://www.rcsb.org/pdb/workbench/workbench.do. Source code is available under the LGPL 2.1 as part of BioJava 3 (http://biojava.org; http://github.com/biojava/biojava). email@example.com or email@example.com.


Adsorption and diffusion of mono, di, and trivalent ions on two-dimensional TiS2.
A comparative study of the monovalent (Li, Na, and K) and multivalent (Be, Mg, Ca, and Al) metal ion adsorption and diffusion on an electronically semi-metallic two-dimensional nanosheet of 1T structured TiS2 is presented here to contribute to the search for abundant, cheap, and nontoxic ingredients for efficient rechargeable metal ion batteries. The total formation energy of the metal ion adsorption and the Bader charge analysis show that the divalent Mg and Ca ions can have a charge storage density double that of the monovalent Li, Na, and K ions, while the Be and Al ions form metallic clusters even at a low adsorption density because of their high bulk energies. The adsorption of Mg ions shows the lowest averaged open circuit voltage (0.13 V). The activation energy barriers for the diffusion of metal ions on the surface of the monolayer successively decrease from Li to K and Be to Ca. Mg and Ca, being divalent, are capable of storing a higher power density than Li while K and Na have a higher rate capability than the Li ions. Therefore, rechargeable Li ion batteries can be totally or partially replaceable by Mg ion batteries, where high power density and high cell voltage are required, while the abundant, cheap, and fast Na ions can be used for green grid applications.


Activation of human polymorphonuclear neutrophils by environmental contaminants.
The toxicity of chemicals of environmental concern to the immune system has been primarily evaluated in animals and, to a lesser extent, in humans. In particular, the effects of various pollutants on B-cell, T-cell, natural killer cells, and monocyte-macrophage cells have been the focus of several reports, but polymorphonuclear neutrophils have largely been neglected. Recent data indicate that neutrophils are important targets for such chemicals, suggesting a potential role of these products in the development of the inflammatory process. The bulk of this review will focus on the role of certain environmental pollutants on human neutrophil cell physiology.


Cell kinetics in mouse epidermis studied by bivariate DNA/bromodeoxyuridine and DNA/keratin flow cytometry.
Hairless mice were injected intraperitoneally with bromodeoxyuridine (Brd-Urd). Basal cells were isolated from epidermis, fixed in 70% ethanol, and prepared for bivariate BrdUrd/DNA flow cytometric (FCM) analysis. Optimum detection of incorporated BrdUrd in DNA was obtained by combining pepsin digestion and acid denaturation. The cell loss was reduced to a minimum by using phosphate-buffered saline containing Ca2+ and Mg2+ to neutralize the acid. The percentage of cells in S phase and the average uptake of BrdUrd per labelled cell in eight consecutive windows throughout the S phase were measured after pulse labelling at intervals during a 24 h period. Furthermore, the cell cycle progression of a pulse-labelled cohort of cells was followed up to 96 h after BrdUrd injection. In general the results from both experiments were in good agreement with previous data from 3H-thymidine labelling studies. The percentage of cells in S phase was highest at night and lowest in the afternoon, whereas the average uptake of BrdUrd per labelled cell showed only minor circadian variations. There were no indications that BrdUrd significantly perturbed normal epidermal growth kinetics. A cell cycle time of about 36 h was observed for the labelled cohort. Indications of heterogeneity in traverse through G1 phase were found, and the existence of slowly cycling or temporarily resting cells in G2 phase was confirmed. There was, however, no evidence of a significant population of temporarily resting cells in the S phase. Bivariate DNA/keratin FCM analysis revealed a high purity of basal cells in the suspensions and indicated that the synthesis of the differentiation-keratin K10 was turned on only in G1 phase and after the last division.


Synthetic Genetic Interaction (CRISPR-SGI) Profiling in Caenorhabditis elegans.
Genetic interaction screens are a powerful methodology to establish novel roles for genes and elucidate functional connections between genes. Such studies have been performed to great effect in single-cell organisms such as yeast and E. coli (Schuldiner et al., 2005; Butland et al., 2008; Costanzo et al., 2010), but similar large-scale interaction studies using targeted reverse-genetic deletions in multi-cellular organisms have not been feasible. We developed a CRISPR/Cas9-based method for deleting genes in C. elegans and replacing them with a heterologous fluorescent reporter (Norris et al., 2015). Recently we took advantage of that system to perform a large-scale, reverse genetic screen using null alleles in animals for the first time, focusing on RNA binding protein genes (Norris et al., 2017). This type of approach should be similarly applicable to many other gene classes in C. elegans. Here we detail the protocols involved in generating a library of double mutants and performing medium-throughput competitive fitness assays to test for genetic interactions resulting in fitness changes.


Risk estimation for biliary tract cancer: Development and validation of a prognostic score.
Biliary tract cancer is a rare tumour entity characterized by a poor prognosis. We aimed to identify prognostic factors and create a prognostic score to estimate survival. Clinical data of the training set, consisting of 569 patients treated from 2000 to 2010 at Hannover Medical School, were analysed. A prognostic model defining three prognostic risk groups was derived from Cox regression analyses. The score was applied and validated in an independent cohort of 557 patients from four different German centres. Median overall survival (OS) was 14.5 months. If complete resection was performed, the patients had a significantly improved OS (23.9 months; n=242) as compared to patients with non-resectable tumours (9.1 months; n=329, P<.0001). Based on univariable and multivariable analyses of clinical data, a prognostic model was created using variables available before treatment. Those were age, metastasis, C-reactive protein (CRP), international normalized ratio (INR) and bilirubin. The prognostic score distinguished three groups with a median OS of 21.8, 8.6 and 2.6 months respectively. The validation cohort had a median OS of 20.2, 14.0 and 6.5 months respectively. The prognostic impact of the score was independent of the tumour site and of treatment procedures. Here, we identified prognostic factors and propose a prognostic score to estimate survival, which can be applied to all patients independent of tumour site and before initial treatment. Further validation in prospective trials is required.


A mechanistic investigation of morphology evolution in P3HT-PCBM films induced by liquid crystalline molecules under external electric field.
We demonstrate that the morphology of poly(3-hexyl thiophene) and [6,6]-phenyl-C61-butyric acid methyl ester (P3HT-PCBM) bulk heterojunctions (BHJ) could be tuned by the 4-cyano-4'-pentylterphenyl (5CT) liquid crystalline molecules under electric field assisted treatment for enhanced solar cell performance. The miscibility and interactions between the components were carefully studied, showing that 5CT could induce the crystallization of P3HT to form edge-on structures in ternary blends after electric field assisted treatment as revealed by grazing-incidence wide-angle X-ray diffraction (GIXRD). The PCBM and 5CT are supposed to form the rod-like complexes, and the nanorods could orient to the direction of electric field, accompanied by the homogeneous distribution of nanorods in diameters of about 30 nm at an electric field of 600 V mm(-1). The sizes of PCBM clusters and complexes are dependent on the 5CT doping ratios and intensity of electric field according to grazing-incidence small-angle X-ray scattering (GISAXS) analysis. When the active layers were processed under the atmospheric environment, the power conversion efficiency (PCE) could reach 3.5% at 5CT weight fraction of 6 wt% after treatment by an electric field of 600 V mm(-1), in contrast to the PCE value of 2.4% for a pristine P3HT-PCBM blend. This work provides an attractive strategy for manipulating the nanostructure of BHJ layers and also increases insight into morphology evolution when liquid crystalline molecules are incorporated into BHJs.


Low-Cost and Green Fabrication of Polymer Electronic Devices by Push-Coating of the Polymer Active Layers.
Because of both its easy processability and compatibility with roll-to-roll processes, polymer electronics is considered to be the most promising technology for the future generation of low-cost electronic devices such as light-emitting diodes and solar cells. However, the state-of-the-art deposition technique for polymer electronics (spin-coating) generates a high volume of chlorinated solution wastes during the active layer fabrication. Here, we demonstrate that devices with similar or higher performances can be manufactured using the push-coating technique in which a poly(dimethylsiloxane) (PDMS) layer is simply laid over a very small amount of solution (less than 1μL/covered cm2), which is then left for drying. Using mm thick PDMS provides a means to control the solvent diffusion kinetics (sorption/retention) and removes the necessity for additional applied pressure to generate the desired active layer thickness. Unlike spin-coating, push-coating is a slow drying process that induces a higher degree of crystallinity in the polymer thin film without the necessity for a post-annealing step. The polymer light-emitting diodes and solar cells prepared by push-coating exhibit slightly higher performances with respect to the reference spin-coated devices, whereas at the same time reduce the amounts of active layer materials and chlorinated solvents by 50 and 20 times, respectively. These increased performances can be correlated to the higher polymer crystallinities obtained without applying a post-annealing treatment. As push-coating is a roll-to-roll compatible method, the results presented here open the path to low-cost and eco-friendly fabrication of a wide range of emerging devices based on conjugated polymer materials.


Identification of a locus (DSP2) for disseminated superficial porokeratosis at chromosome 12q21.2-24.21.
Porokeratosis is a rare disorder of epidermal keratinization that is characterized by the presence of a border called the cornoid lamella. Disseminated superficial porokeratosis (DSP) is a subtype of porokeratosis, which is inherited as an autosomal trait. The first locus for DSP was localized to chromosome 18p11.3, but no causative gene has yet been identified. In this study, we recruited and analysed a large six-generation Chinese family with autosomal dominant DSP. The genome-wide screening identified a maximum two-point LOD score of 3.06 at θ = 0.00 with the microsatellite marker D12S78. Fine mapping and haplotype analysis defined a critical region of 38 Mb between D12S326 and D12S79 on chromosome 12q21.2-24.21, which is a probable second locus identified for DSP (DSP2). We sequenced 50 candidate genes in this region, but no causative mutation was found. This study provides a map location for isolation of a gene causing DSP.


Enalapril versus losartan for adults with chronic kidney disease: a systematic review and meta-analysis.
Both enalapril and losartan are effective and widely used in patients with chronic kidney disease (CKD). This review aimed to evaluate the benefits of enalapril and losartan in adults with CKD. PubMed, EMBASE, the Cochrane Library and ClinicalTrials.gov were searched, without language limitations, for randomized controlled trials (RCT), in which enalapril and losartan were compared in adults with CKD. Standard methods, consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, were used. Reviewer Manager software, ver. 5.2, was used for meta-analysis. Of 318 citations retrieved, 17 RCT (14 parallel-group and three cross-over) met our inclusion criteria. The pooled analysis for parallel RCT showed that the effects of enalapril and losartan on blood pressure, renal function and serum uric acid (UA) were similar. Meta-analysis indicated that patients taking enalapril had a higher risk of dry cough (risk ratio, 2.88; 95% CI, 1.11-7.48; P=0.03). Sensitivity analysis showed good robustness of these findings. Enalapril has similar effects to losartan on systemic blood pressure, renal function and serum UA in patients with CKD, but carries a higher risk of dry cough. Larger trials are required to evaluate the effects of these medications on clinical outcomes.


Cerebral revascularization in skull base tumors.
Skull base tumors involving the carotid artery pose a difficult surgical challenge. The potential for bypass grafting for cerebral revascularization carries inherent risks but may aid in tumor resection and control in those who warrant carotid sacrifice but have inappropriate natural cerebrovascular reserve. We include a review of the literature discussing the indications for carotid resection as part of skull base tumor surgery, indications for cerebral revascularization, balloon test occlusion, graft types and operative technique, complications, and results.


Toll-like receptor-2/6 and Toll-like receptor-9 agonists suppress viral replication but not airway hyperreactivity in guinea pigs.
Respiratory virus infections cause airway hyperreactivity (AHR). Preventative strategies for virus-induced AHR remain limited. Toll-like receptors (TLRs) have been suggested as a therapeutic target because of their central role in triggering antiviral immune responses. Previous studies showed that concurrent treatment with TLR2/6 and TLR9 agonists reduced lethality and the microbial burden in murine models of bacterial and viral pneumonia. This study investigated the effects of TLR2/6 and TLR9 agonist pretreatment on parainfluenza virus pneumonia and virus-induced AHR in guinea pigs in vivo. Synthetic TLR2/6 lipopeptide agonist Pam₂CSK₄ and Class C oligodeoxynucleotide TLR9 agonist ODN2395, administered in combination 24 hours before virus infection, significantly reduced viral replication in the lung. Despite a fivefold reduction in viral titers, concurrent TLR2/6 and TLR9 agonist pretreatment did not prevent virus-induced AHR or virus-induced inhibitory M2 muscarinic receptor dysfunction. Interestingly, the TLR agonists independently caused non-M2-dependent AHR. These data confirm the therapeutic antiviral potential of TLR agonists, while suggesting that virus inhibition may be insufficient to prevent virus-induced airway pathophysiology. Furthermore, TLR agonists independently cause AHR, albeit through a distinctly different mechanism from that of parainfluenza virus.


Abnormal incisor-tooth differentiation in transgenic mice expressing the muscle-specific desmin gene.
Immunocytochemistry and electron microscopic observations on the incisor-tooth organ of transgenic mice expressing the muscle-specific desmin gene under the direction of the vimentin promoter, reveal that the expression of the hybrid transgene occurs both in mesenchymal cells and differentiating odontoblasts. The muscle-specific desmin, as estimated by fluorescence intensity, is more expressed in immature mesenchymal cells than in postmitotic differentiated odontoblasts. The expression of the transgene generates alteration of the odontoblast-intermediate filament network and interferes with the secretory activity of both odontoblasts and ameloblasts. Our results are consistent with the hypothesis that odontoblasts have inductive properties on the differentiation of ameloblasts and that intermediate filaments among other factors play the role of cell and tissue organizer.


[Echocardiographic assessment of cardiac remodeling in the high-level football player].
The aim of this study is to assess the morphological and hemodynamic cardiovascular changes of 24 high-level football players, using Doppler-echocardiography, and compare them to a similar control group. Twenty-four elite football players were matched to 24 normal subjects according to age, sex, and body surface. All participants had a clinical examination, resting ECG, Doppler-echocardiography and a measurement of maximal oxygen uptake (VO2 max). The echocardiographic variables were compared between two groups by the Student's t-test and other statistical tests, using the SPSS 12 for Windows software. Compared to the control group, the wall thickness (10.49 + 1.04 vs. 7.5 + 2.04 mm, p < 0.05), the LV end-diastolic diameter (57.1 + 3.70 vs. 41.2 + 3.65 mm, p < 0.01) and left atrium surface (20.16 + 2.03 vs. 16.16 + 1.83 cm2, p < 0.01) were significantly more important in football players. The LV and RV ejection fractions were similar in both groups. The RV long-axis diastolic diameter (8 + 0.5 vs. 6.5 + 1.1 mm, p < 0.01) and S-wave using DTI (0.17 + 0.02 vs. 0.14 + 0.02, p < 0.05) were more important among football players. The hemodynamic and morphological changes result from an acquired cardiac adaptation in athletes with important endurance and resistive efforts. The majority of players presented an intermediate-type of remodeling, but the more offensive ones had an endurance-type heart, whereas the defense players had a resistance-type aspect. This study on the cardiac remodeling in high-level athletes permits to have a distinctive approach between physiological and pathological remodeling. This remodeling varies according to the player's post and exercise capacities. In a football player, a correlation between physical level and physical capacity is plausible.


Palladium(II) complexes of pyrazolated thio/selenoethers: syntheses, structures, single source precursors of Pd4Se and PdSe nano-particles and potential for catalyzing Suzuki-Miyaura coupling.
The reactions of 4-bromo-1-(2-chloroethyl)-1H-pyrazole prepared from 4-bromopyrazole with the in situ generated PhSNa, PhSeNa, Na(2)S and Na(2)Se have resulted in thio/selenoether ligands L1-L4 respectively. The complexes [PdL1/L2Cl(2)](1-2) and [PdL3/L4Cl]BF(4) (3-4) of these ligands have been synthesized by reacting them with [PdCl(2)(CH(3)CN)(2)] in CH(3)CN at 70 °C. The L1-L4 and their complexes (1-4) have been characterized with spectroscopic techniques viz.(1)H, (13)C{(1)H} and (77)Se{(1)H} NMR, IR and HR-MS. Single crystal structures of 1-4 determined by X-ray diffraction reveal nearly square planar geometry around Pd in each case. Thermally stable, moisture/air insensitive complexes 1-4 have been found to be efficient pre-catalysts for Suzuki-Miyaura coupling reactions (yield up to 96% in 2 h). Nano-particles (NPs) (size ~3-19 nm) were formed in the beginning of these reactions. They are composed of Pd and S or Se with more % of Pd. These NPs also catalyze Suzuki coupling and appear to play an important role in catalysis. Single source one pot synthesis of Pd(4)Se and PdSe NPs (size ranges ~8-26 nm), capped with trioctylphosphine (TOP), has been developed by thermolysis of 2 and 4 at 200-250 °C in TOP. HR-TEM, SEM, SEM-EDX and powder XRD have been used to authenticate these nano-particles. The NPs of PdP(2) are formed when attempts were made to prepare nano-sized phases of palladium-sulfide by thermolysis of 1 and 3 in TOP.


Mouse restin inhibits bovine aortic endothelial cell proliferation and causes cell apoptosis.
Restin, a homologous protein of endostatin, was found by Ramchandran et al. It was the C-terminal fragment of type XV collagen. To analysis the inhibition activity of mouse restin on the proliferation of endothelial cells, the cDNA of restin was amplified from the total RNA of the mouse muscle and cloned into the prokaryotic expression plasmid pQE32. The recombinant protein was expressed in inclusion body with a yield about 60%--70% of total protein. After refolding, the purified recombinant protein specifically inhibits bovine aortic endothelial (BAE) cell proliferation stimulated by basic fibroblast growth factor (bFGF) in a dose-dependent manner, but the activity of restin was weaker than that of endostatin. Treatment of BAE cell with recombinant restin caused G(1) arrest and apoptosis in BAE cells.


[Internal hernia of the abdomen. Apropos of 14 cases].
Internal abdominal hernias develop when one or more viscera extrude through an intraperitoneal orifice but remain within the peritoneal cavity. The orific may be normal (Winslow's foramen) or paranormal (peritoneal fossae: paraduodenal, ileocecal, inter- and mesosigmoidal, paracolic, supravesical, of the large ligament of uterus). All these hernias possess a sac and are true hernias. The orifice may also be abnormal: pathologic origin if formed in a mesentery or an omentum (trans-mesenteric, trans-mesocoloic, trans-omental, by colo-omental disinsertion) or in the form of an anomalous orific if it occurs in a congenital anomaly of a ligament (falciform ligament of liver) or a mesentery (mesentery of Meckel's diverticulum): all these hernias lack a sac and are "internal prolapses or procidentia". Of the 14 cases presently reported, 6 were hernias through a paranormal orifice: 2 left and 2 right paraduodenal, 1 intra-mesosigmoidal and 1 retrocecal; 6 were hernias through a pathologic orifice: 2 trans-mesenteric, 1 in the posterior cavity through a colo-omental dissinsertion hole and 3 trans-omental, and 2 were hernias through an anomalous orifice from absence of the falciform ligament of liver. Incidence of these hernias reported in the literature is between 0.2 and 0.9% of autopsies and 0.2 and 2% of parietal hernias, findings in our series being 0.098% (14 of 14,199 cases) of laparotomies and 0.32% (14 of 4,374 cases) of parietal hernias. Of 1,871 cases described in the occidental or near occidental literature (in French, English, Italian or German), 160 (8.55%) were hernias through Winslow's foramen, 1035 (55.31%) through a para-normal orifice and 676 (36.1) through an abnormal orifice (pathologic and anomalous). The sex ratio showed a male prevalence (3:2), age distribution demonstrating the onset of internal hernias at all ages with a preference for the 5th decade and a mean age of 46 years. Symptomatology was totally non specific, subacute to acute occlusive symptoms or even signs of already installed necrotizing-peritonitis being detected in 80 to 90% of cases. In 10 to 15% of patients the hernia was an unexpected finding during laparotomy for another affection, an almost typical feature of the largest para-normal hernias, the paraduodenal hernias. Preoperative diagnosis is practically impossible, and in many cases cannot be made because of time restriction, but it is sometimes possible with the largest hernias after a longer sub-occlusive period by radiologic, arteriographic and scan imaging. However, the primary task of the surgeon is not so much to establish the diagnosis as to assess the need for urgent operation. Hernias provoking large displacements of viscera can even make intraoperative diagnosis difficult with subsequent errors, and surgeons must recognize all possible types of these hernias, especially those passing through a para-normal orifice, and must be able to pinpoint the fixed guiding points. They must also work in as large an operative field as possible and should therefore always start by a median infra-supra-umbilical laparotomy to allow its maximum extension. Reduction of herniated viscera can be simple, by gentle traction, or difficult requiring dilatation of the hernial orifice and/or opening of the sac.(ABSTRACT TRUNCATED AT 400 WORDS)


Chemical approaches towards unravelling kinase-mediated signalling pathways.
Protein kinases control the function of about one third of cellular proteins by catalysing the transfer of the γ-phosphate group of ATP onto their substrate proteins. Protein phosphatases counter this action and also control the activation status of many kinases. Cellular responses to environmental changes, or signalling events, temporarily tilt the balance of protein phosphorylation and dephosphorylation to one side or the other. The identification of protein-kinase-substrate pairs and substrate-phosphatase pairs is critical to understanding cell function and how cells respond to environmental changes. Identification of these substrate-enzyme pairs is non-trivial, because of the structural and mechanistic conservation of the catalytic cores of protein kinases. In this tutorial review we review recent progress towards identifying protein-kinase-substrate pairs by emphasising the use of chemical genetics and purpose-designed ATP analogues that target one particular protein kinase. In addition, we discuss activity-based chemical profiling approaches, based on ATP analogues, for the detection of active kinases.


Acute post-streptococcal glomerulonephritis - immune-mediated acute kidney injury - case report and literature review.
Acute post-streptococcal glomerulonephritis (APSGN) is an immunological complication of infection with group A β-hemolytic streptococcus (GAS). The disease manifests as microscopic or gross hematuria, arterial hypertension, edema, and acute kidney injury and has most commonly a self-limiting course. We report a very severe case of APSGN in a 5-year-old girl with superimposed generalized infection. The girl presented significant overhydration, a very low glomerular filtration rate (GFR) (11.2 ml/min/1.73 m2), hyperuricemia (12.7 mg/dl), nephrotic proteinuria, and gross hematuria. Her immunological tests allowed for the diagnosis of APSGN (elevated antistreptolysin O [ASO] titer, low C3, and normal C4 complement factors). She also showed very high inflammatory indicators suggestive of sepsis. She received supportive treatment together with ceftriaxone and a single dose of rasburicase. Her renal function recovered, and urinalysis normalized. Gallbladder deposits complicated the treatment. This article summarizes the existing knowledge on APSGN with particular emphasis on the immunological mechanisms of the disease. The proposed immunological pathway leading to glomerular injury is discussed. In children, APSGN has an excellent prognosis, including in cases with severe renal impairment in the early stages of the disease.


Electronic and infrared absorption spectra of linear and cyclic C6+ in a neon matrix.
Electronic and infrared absorption spectra of mass-selected C6+, generated by dissociative electron impact ionization of C6Cl6 and C6Br6, have been recorded in 6 K neon matrices. Linear and cyclic forms of C6+ have been observed. The 2Pig<--Chi2Piu electronic transition of linear C6+ has its origin band at 646 nm whereas for the (2) 2B2<--Chi2A1 system of the cyclic isomer it lies at 570 nm. An infrared active fundamental mode in the ground electronic state of C6+ is observed at 2092 and 1972 cm(-1) for the linear and cyclic isomer, respectively.


Variability of glucose-lowering effect as a limiting factor in optimizing basal insulin therapy: a review.
Lowering blood glucose with insulin therapy towards beneficial target levels while also avoiding hypoglycaemia is a challenging task. An important confounding factor, which might be under-appreciated in this scenario, is that of variable glucose readings causing difficulties with dose adjustment. Furthermore, this glucose variability is, to some extent, a reflection of variability in the glucose-lowering action of the insulin therapy itself. Not only is glucose variability a major confounding factor in disease management but it is possibly also of direct prognostic consequence and is increasingly recognized as an informative measurement in diabetes management. The scope for insulin-induced glucose variability is particularly great with basal insulins because of their prolonged absorption from high-dose depots. Pharmacodynamic (PD) variability manifests as both fluctuations in the level of glucose-lowering effect over time, and as inconsistencies in the response from one injection to another. Well-controlled pharmacokinetic (PK)/PD studies using repeated isoglycaemic clamp methodology clearly how that many injected basal insulin products have high variable absorption with correspondingly variable action. Incomplete resuspension and precipitation appear to be important issues with regard to unpredictability in this action, while an inadequate duration of action relative to the dosing interval results in a fluctuating action profile. There are some ultra-long-acting basal insulins with novel protraction mechanisms currently in clinical development for which clamp studies show markedly improved PK/PD profiles.


The impact of Continuing Professional Development on nurses' wellbeing and satisfaction.
The European Centre of Excellence for Research in Continuing Professional Development (CPD) aims to develop a pan-European network of researchers, clinicians, regulators, and professional bodies to advance the science of CPD through research and foster knowledge exchange to promote best practices in CPD that can be translated across Europe. Currently, the Centre has members from 22 European countries. Three research-working groups have been established to develop key activities into CPD: 1) Evaluating the impact of CPD; 2) Digital Pedagogies for CPD; 3) The economics of CPD. One of its research activities focuses on exploring CPD needs of newly qualified nurses and midwives (NQNMs) and the impact on their "Intention to leave" and "Job satisfaction". However, information about the range and extent of CPD activities NQNMs participate in during the first 24 months following graduation is limited. It is also not well known how NQNMs' participation in CPD activities is associated with job satisfaction and intention to leave the organisation or the profession. To develop a better understanding of the CPD needs of NQNMs and explore the impact on NQNMs' job satisfaction and intention to leave. A cross-sectional study using an online survey in four European countries: Ireland, UK, Italy, and Croatia. 2254 NQNMs. The questionnaire was developed using three validated sources: 1. The Q-PDN measures "motives", "conditions" and "importance" given to CPD and "CPD activities undertaken" by nurses. 2. The McCloskey/Mueller Satisfaction Scale (MMSS) assesses nurses' job satisfaction. 3. Four questions on Intention to leave current workplace (e.g., ward), organisation, or the nursing profession, adapted from Heinen et al. (2013). The last open-ended question, developed by the RCSI research team, asks the main motivation for leaving the profession. Data collection will start by the end of September 2021. Expected outcomes are: 1) Create a database to inform a further pan-European wide survey of NQNMs and their CPD needs and 2) Provide recommendations to regulators, healthcare providers and policy makers about the CPD needs of NQNMs and factors associated with job satisfaction and Intention to Leave. Previous research into CPD demonstrates its potential to improve job satisfaction and retention. Likewise, there is evidence that it is important to support NQNMs through appropriately designed CPD programs. The present European study intends to contribute to the scientific knowledge base on CPD needs and its impact on job satisfaction and retention in NQNMs.


Bridging the Transient Intraluminal Stroke Preclinical Model to Clinical Practice: From Improved Surgical Procedures to a Workflow of Functional Tests.
Acute ischemic stroke (AIS) remains a leading cause of mortality, despite significant advances in therapy (endovascular thrombectomy). Failure in developing novel effective therapies is associated with unsuccessful translation from preclinical studies to clinical practice, associated to inconsistent and highly variable infarct areas and lack of relevant post-stroke functional evaluation in preclinical research. To outreach these limitations, we optimized the intraluminal transient middle cerebral occlusion, a widely used mouse stroke model, in two key parameters, selection of appropriate occlusion filaments and time of occlusion, which show a significant variation in the literature. We demonstrate that commercially available filaments with short coating length (1-2 mm), together with 45-min occlusion, results in a consistent affected brain region, similar to what is observed in most patients with AIS. Importantly, a dedicated post-stroke care protocol, based on clinical practice applied to patients who had stroke, resulted in lower mortality and improved mice welfare. Finally, a battery of tests covering relevant fine motor skills, sensory functions, and learning/memory behaviors revealed a significant effect of tMCAO brain infarction, which is parallel to patient symptomatology as measured by relevant clinical scales (NIH Stroke Scale, NIHSS and modified Rankin Scale, mRS). Thus, in order to enhance translation to clinical practice, future preclinical stroke research must consider the methodology described in this study, which includes improved reproducible surgical procedure, postoperative care, and the battery of functional tests. This will be a major step s closing the gap from bench to bedside, rendering the development of novel effective therapeutic approaches.


Elucidating the Mechanism of Excited-State Bond Homolysis in Nickel-Bipyridine Photoredox Catalysts.
Ni 2,2'-bipyridine (bpy) complexes are commonly employed photoredox catalysts of bond-forming reactions in organic chemistry. However, the mechanisms by which they operate are still under investigation. One potential mode of catalysis is via entry into Ni(I)/Ni(III) cycles, which can be made possible by light-induced, excited-state Ni(II)-C bond homolysis. Here, we report experimental and computational analyses of a library of Ni(II)-bpy aryl halide complexes, Ni(Rbpy)(R'Ph)Cl (R = MeO, t-Bu, H, MeOOC; R' = CH3, H, OMe, F, CF3), to illuminate the mechanism of excited-state bond homolysis. At given excitation wavelengths, photochemical homolysis rate constants span 2 orders of magnitude across these structures and correlate linearly with Hammett parameters of both bpy and aryl ligands, reflecting structural control over key metal-to-ligand charge-transfer (MLCT) and ligand-to-metal charge-transfer (LMCT) excited-state potential energy surfaces (PESs). Temperature- and wavelength-dependent investigations reveal moderate excited-state barriers (ΔH‡ ∼ 4 kcal mol-1) and a minimum energy excitation threshold (∼55 kcal mol-1, 525 nm), respectively. Correlations to electronic structure calculations further support a mechanism in which repulsive triplet excited-state PESs featuring a critical aryl-to-Ni LMCT lead to bond rupture. Structural control over excited-state PESs provides a rational approach to utilize photonic energy and leverage excited-state bond homolysis processes in synthetic chemistry.


Immigration and acculturation-related factors and asthma morbidity in Latino children.
This article presents a summary of findings from asthma studies focusing on immigration and acculturation-related factors. A study examining associations between these processes, family cohesion and social support networks, and asthma morbidity in a sample of Dominican and Puerto Rican caregivers residing in the mainland U.S., is also described. Latino children with asthma (n = 232), ages 7-16 (49% female) and their caregivers completed interview-based questionnaires on immigration and acculturation-related processes, family characteristics, and asthma morbidity. The frequency of ED use due to asthma may be higher for children of caregivers born in Puerto Rico. Acculturative stress levels were higher for Puerto Rican born caregivers residing in the mainland U.S. Asthma-related educational and intervention programs for Latino children and families should be tailored to consider the effects that the immigration and acculturation experience can have on asthma management. Specific family-based supports focused on decreasing stress related to the acculturation process, and increasing social and family support around the asthma treatment process may help to reduce asthma morbidity in Latino children.


Round Form-Stable Breast Implants: Diagnosis and Management of Complications.
Silicone gel breast implants have been used for breast augmentation and reconstruction since 1962. Since then, multiple generations of implants have been created in an effort to improve safety and efficacy. Before 1990, silicone gel implants were characterized as having thin shells and non-cohesive gel; however, since then devices are created with cohesive silicone gel and a variety of surfaces. Despite improvements, no implant will last forever; however, these devices are safe and effective based on numerous clinical and epidemiologic studies. As with all medical devices, complications using round form-stable implants for breast reconstruction can occur and will be reviewed in this article.


Comparative study of matrix-assisted laser desorption/ionization and gas chromatography for quantitative determination of cocoa butter and cocoa butter equivalent triacylglycerol composition.
The triacylglycerol (TAG) composition study of cocoa butter (CB) and cocoa butter equivalents (CBEs) has been performed by gas chromatography (GC) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS). These two techniques provided comparable results. The advantage of the MALDI technique was the detection of each compound comprising the triacylglycerol classes (Cn). Moreover, comparison of the data obtained by these two techniques indicated that TAG relative percentages could be obtained quantitatively with the MALDI technique. These techniques have been applied for the composition determination of CB + CBE mixtures. Encouraging results showed that it is possible to quantify an admixture containing as little as 4% of CBE.


Quantitative testing of pain perception in subjects with PTSD--implications for the mechanism of the coexistence between PTSD and chronic pain.
Post-traumatic stress disorder (PTSD) often co-occurs with chronic pain. Neither the underlying mechanism of this comorbidity nor the nature of pain perception among subjects with PTSD is well defined. This study is the first systematic and quantitative evaluation of pain perception and chronic pain in subjects with PTSD. The study group consisted of 32 outpatients with combat- and terror-related PTSD, 29 outpatients with anxiety disorder and 20 healthy controls. Quantitative somatosensory testing included the measurement of warm, cold, light touch and heat-pain thresholds and responses to acute suprathreshold heat and mechanical stimuli. Chronic pain was characterized, and levels of PTSD and anxiety symptomatology were assessed by self-report questionnaires. Subjects with PTSD exhibited higher rates of chronic pain, more intense chronic pain and more painful body regions compared with the other two groups. PTSD severity correlated with chronic pain severity. Thresholds of subjects with PTSD were significantly higher than those of subjects with anxiety and healthy controls, but they perceived suprathreshold stimuli as being much more intense than the other two groups. These results suggest that subjects with PTSD exhibit an intense and widespread chronic pain and a unique sensory profile of hyposensitivity to pain accompanied by hyper-reactivity to suprathreshold noxious stimuli. These features may be attributed to the manner with which PTSD subjects emotionally interpret and respond to painful stimuli. Alternatively, but not mutually exclusive, the findings may reflect altered sensory processing among these subjects.


High levels of serum platelet-derived growth factor-AA and human epidermal growth factor receptor-2 are predictors of colorectal cancer liver metastasis.
To develop predictive markers in blood for colorectal cancer liver metastasis. Twenty colorectal cancer patients were selected and divided into two groups. Group A consisted of 10 patients whose pathological TNM stage was IIIC (T3-4N2M0), while another 10 patients with synchronous liver metastasis (TNM stage IV) were recruited for group B. During the surgical procedure, a 10-mL drainage vein (DV) blood sample was obtained from the DV of the tumor-bearing segment prior to the ligation of the DV. At the same time, a 10-mL peripheral vein (PV) blood sample was collected via peripheral venipuncture. The serum levels of 24 molecules that are potentially involved in the mechanism of liver metastasis in both DV blood and PV blood were analyzed by using high-throughput enzyme-linked immunosorbent assay technology. Univariate analysis revealed that platelet-derived growth factor AA (PDGFAA) in DV blood (dPDGFAA) (P = 0.001), PDGFAA in PV blood (pPDGFAA) (P = 0.007), and human epidermal growth factor receptor-2 in PV blood (pHER2) (P = 0.001), pMMP7 (P = 0.028), pRANTES (P = 0.013), and pEGF (P = 0.007) were significantly correlated with synchronous liver metastasis. Multivariate analysis identified dPDGFAA (HR = 1.001, P = 0.033) and pHER2 (HR = 1.003, P = 0.019) as independent predictive factors for synchronous liver metastasis. Besides, high peripheral HER2 level may also be a risk factor for metachronous liver metastasis, although the difference did not reach statistical significance (P = 0.06). Significant correlations were found between paired DV and PV blood levels for PDGFAA (r = 0.794, P < 0.001), but not for HER2 (r = 0.189, P = 0.424). PDGFAA in tumor drainage and HER2 in PV blood may be useful predictive factors for synchronous liver metastasis of colorectal cancer.


[Protection of HOE642 against cardiomyocyte injury caused by anoxia and reoxygenation].
To investigate the protective effect of calcium antagonists (A/R) injury of cardiomyocytes. Primary-cultured cardiomyocytes were divided A/R, A/R+nicardipine(Nic), A/R+HOE642, A/R+H7, A/R+PD98059 and control parameters were measured in all groups, intracellular calcium concentration ([Ca2+]i), content, lactate dehydrogenase (LDH) and creative phosphokinase(CK) activity in the activity. The calpain (u-calpain and m-calpain) protein expression levels were measured In comparison with A/R group, A/R + nicardipine (Nic) and A/R + Nic groups showed [Ca2+]i, m-calpain protein expression, LDH and CK content in the medium, a higher activity of PKC and MAPK (P < 0.01). On the contrary, A/R+H7 and A/R+PD98059 LDH and CK content in the medium, and lower ATP content and cell viability as compared 0. 05). The A/R mediated Ca2+ overload resulting from cardiomyocyte injury blocking Ca2+ entry and H+/Na+ exchange, and very likely PKC and MAPK are involved protection against the A/R injury of cardiomyocytes.


Echocardiographic features of primary cardiac sarcoma.
Primary cardiac sarcoma is extremely rare and seldom causes symptoms until late in its course. Discomfort may occur only when the mass causes obstruction to the intracardiac flow. Early diagnosis is vital because it allows prompt and relevant management. We describe the history and echocardiographic features in four patients with primary cardiac sarcoma and review the current literature.


A biogenic amine and a neuropeptide act identically: tyramine signals through calcium in Drosophila tubule stellate cells.
Insect osmoregulation is subject to highly sophisticated endocrine control. In Drosophila, both Drosophila kinin and tyramine act on the Malpighian (renal) tubule stellate cell to activate chloride shunt conductance, and so increase the fluid production rate. Drosophila kinin is known to act through intracellular calcium, but the mode of action of tyramine is not known. Here, we used a transgenically encoded GFP::apoaequorin translational fusion, targeted to either principal or stellate cells under GAL4/UAS control, to demonstrate that tyramine indeed acts to raise calcium in stellate, but not principal cells. Furthermore, the EC(50) tyramine concentration for half-maximal activation of the intracellular calcium signal is the same as that calculated from previously published data on tyramine-induced increase in chloride flux. In addition, tyramine signalling to calcium is markedly reduced in mutants of NorpA (a phospholipase C) and itpr, the inositol trisphosphate receptor gene, which we have previously shown to be necessary for Drosophila kinin signalling. Therefore, tyramine and Drosophila kinin signals converge on phospholipase C, and thence on intracellular calcium; and both act to increase chloride shunt conductance by signalling through itpr. To test this model, we co-applied tyramine and Drosophila kinin, and showed that the calcium signals were neither additive nor synergistic. The two signalling pathways thus represent parallel, independent mechanisms for distinct tissues (nervous and epithelial) to control the same aspect of renal function.


A trial of levofloxacin 750 mg once daily for 5 days versus ciprofloxacin 400 mg and/or 500 mg twice daily for 10 days in the treatment of acute pyelonephritis.
A double-blind, noninferiority trial was conducted to establish the safety and efficacy of a once-daily, 5-day course of levofloxacin 750 mg compared to a twice-daily, 10-day course of ciprofloxacin in complicated urinary tract infections (cUTI) and acute pyelonephritis (AP). This report focuses on subjects with AP. Adult male and female subjects with clinical signs and symptoms of AP and laboratory confirmation of their diagnosis were randomized to receive one dose of levofloxacin 750 mg once daily intravenously (i.v.) or orally and one dose of placebo for 5 days, followed by placebo; or ciprofloxacin 400 mg i.v. and/or 500 mg orally twice daily for 10 days. The primary, prospectively defined end point was microbiologic eradication at post-therapy (study days 15-22). Secondary outcomes included clinical response and safety and tolerability. In the modified intent-to-treat (mITT) population (levofloxacin 94, ciprofloxacin 98), 83% of levofloxacin-treated and 79.6% of ciprofloxacin-treated subjects achieved microbiological eradication (difference -3.4, 95% CI -14.4%, 7.6%). In the microbiologically evaluable (ME) population (levofloxacin 80, ciprofloxacin 76), 92.5% of levofloxacin-treated vs. 93.4% of ciprofloxacin-treated subjects (difference -0.9, 95% CI -7.1%, 8.9%) achieved microbiologic eradication. Clinical success was achieved in 86.2% vs. 80.6% (mITT) and in 92.5% vs. 89.5% (ME) of levofloxacin-treated and ciprofloxacin-treated subjects, respectively. Escherichia coli was the most commonly isolated uropathogen. Few (2.1%) of the pathogens were fluoroquinolone-resistant. Adverse events (AEs) were similar to those seen previously with both agents. Potential limitations are that this analysis is based on a subset of subjects from a larger study and, because of different durations of therapy, the results may be biased against levofloxacin. High-dose, short-course therapy with levofloxacin in subjects with AP is at least as effective as standard 10-day therapy with ciprofloxacin.


A novel association of an uncommon pigmentation pattern: coexistence of cutis tricolor with intracranial teratoma and holoprosencephaly.
Cutis tricolor was first described in a 17-year-old male patient by Happle et al. as a rare coexistence of circumscribed hyperpigmentation and hypopigmentation close to each other on a background of normally pigmented skin. Cutis tricolor has been reported as an isolated cutaneous finding or in various associations. To the best of our knowledge, cutis tricolor in association with teratoma and holoprosencephaly has not been reported in the literature. Herein, we report a male patient who presented with a teratoma and a combination of whorl-like hypopigmentation together with hyperpigmented patches adjacent to each other on intermediately pigmented skin. This case report supports the view that cutis tricolor may be a marker of an underlying neurological abnormality.


Shared abstract representation of linguistic structure in bilingual sentence comprehension.
Although there is strong evidence for shared abstract grammatical structure in bilingual speakers from studies of sentence production, comparable evidence from studies of comprehension is lacking. Twenty-seven (N = 27) English-German bilingual adults participated in a structural priming study where unambiguous English subject and object relative clause (RC) structures were used to prime corresponding subject and object RC interpretations of structurally ambiguous German RCs. The results showed that English object RCs primed significantly greater object RC interpretations in German in comparison to baseline and subject RC prime conditions, but that English subject RC primes did not change the participants' baseline preferences. This is the first study to report abstract crosslinguistic priming in comprehension. The results specifically suggest that word order overlap supports the integration of syntactic structures from different languages in bilingual speakers, and that these shared representations are used in comprehension as well as production.


Systematic identification of cell size regulators in budding yeast.
Cell size is determined by a complex interplay between growth and division, involving multiple cellular pathways. To identify systematically processes affecting size control in G1 in budding yeast, we imaged and analyzed the cell cycle of millions of individual cells representing 591 mutants implicated in size control. Quantitative metric distinguished mutants affecting the mechanism of size control from the majority of mutants that have a perturbed size due to indirect effects modulating cell growth. Overall, we identified 17 negative and dozens positive size control regulators, with the negative regulators forming a small network centered on elements of mitotic exit network. Some elements of the translation machinery affected size control with a notable distinction between the deletions of parts of small and large ribosomal subunit: parts of small ribosomal subunit tended to regulate size control, while parts of the large subunit affected cell growth. Analysis of small cells revealed additional size control mechanism that functions in G2/M, complementing the primary size control in G1. Our study provides new insights about size control mechanisms in budding yeast.


Enhanced functional connectivity in the reward circuitry in healthy adults with weekend catch-up sleep.
We aimed to identify structural and functional changes in healthy adults with catch-up sleep (CUS), we applied seed-based functional connectivity (FC) analysis using resting-state functional magnetic resonance imaging (MRI). We hypothesized that deficits in reward processing could be a fundamental mechanism underlying the motivation of taking CUS. Then, 55 healthy adults voluntarily (34 with CUS and 21 without CUS) participated in this study. Voxel-based morphometry was performed to explore region of gray matter volume (GMV) difference between CUS and non-CUS groups. Between-group comparison of FC was then carried out using resting-state functional MRI analysis seeding at the region of volume difference. Moreover, the region of volume difference and the strength of FC were correlated with scores of questionnaires for reward-seeking behavior and clinical variables. CUS group had a higher reward-seeking tendency, and increased GMV in the bilateral nucleus accumbens and right superior frontal gyrus relative to non-CUS group. FC analysis seeding at the bilateral accumbens revealed increases of FC in the bilateral medial prefrontal cortex in CUS group compared to non-CUS group. The questionnaire scores reflecting the reward-seeking tendency were correlated with the FC strength between bilateral accumbens and medial prefrontal cortex. Our results indicate that CUS is associated with reward-seeking tendency and increased GMV and FC in regions responsible for reward network. Our findings suggest that enhanced reward network could be the crucial mechanism underlying taking CUS and might be implicated in the detrimental effects of circadian misalignment.


A quarter century of hospice care: the southern california kaiser permanente experience.
Kaiser Permanente (KP) has been a pioneer in the development of hospice services in the United States. Since 1978, when hospice services were introduced in the KP Southern California Region, they have been gradually expanded to benefit thousands of patients and their families. However, important barriers to timely, appropriate utilization of hospice care remain. A pilot project conducted in our TriCentral Service Area has shown that palliative care-a newer development in end-of-life care-can be cost-effective in addition to being beneficial for patients and their families. Efforts are underway to emulate this model of care at other KP facilities. Availability of both home-based and inpatient palliative care services can expand the number and type of patients who, as they near the end of life, can benefit from effective symptom control and other support.


Brain-specific tryptophan hydroxylase, TPH2, and 5-HTTLPR are associated with frontal lobe symptoms in Alzheimer's disease.
A prospective, longitudinal study was set up to investigate possible genetic associations of behavioral and psychological signs and symptoms of dementia (BPSD) in Alzheimer's disease (AD) with two candidate genes in the serotonergic neurotransmitter pathway: serotonin transporter (SLC6A4) and brain-specific tryptophan hydroxylase (TPH2). Patients with probable AD (n = 249) were diagnosed according to NINCDS/ADRDA criteria. During follow-up, autopsy-confirmation of clinical diagnosis was obtained in 32 AD patients. Taking into account follow-up behavioral assessments by means of validated behavioral assessment scales (Middelheim Frontality Score and Behave-AD), behavioral ratings reflecting the highest scores on any behavioral item ever observed since dementia onset were calculated and applied for statistical analyses. A functional insertion/deletion polymorphism in the promoter region of SLC6A4 (5-HTTLPR) and 10 selected SNPs within TPH2 were genotyped. Single-marker allelic association analyses (TPH2, 5-HTTLPR) were performed. TPH2 allelic analyses revealed significant associations with frontal lobe symptoms, as well as with diurnal rhythm disturbances. 5-HTTLPR S allele carriers had an increased risk to display loss of insight and judgment, another frontal lobe symptom. The present prospective, longitudinal study showed that mainly frontal lobe symptoms were significantly associated with TPH2 and 5-HTTLPR polymorphisms, pointing toward a role of the serotonergic neurotransmitter system in the pathophysiology of frontal lobe symptoms in AD.


Idiopathic hypertrophic pyloric stenosis in an adult, a potential mimic of gastric carcinoma.
Primary or idiopathic hypertrophy of the pyloric muscle (IHPM) is a rare entity with uncertain pathogenesis which both clinically and pathologically mimics gastric cancer. We present a rare late-occurring case of IHPM in a 71-year-old Caucasian man with no apparent predisposing factor. Imaging studies demonstrated gastric distension with air fluid levels and no evidence of extrinsic compression. At upper endoscopy, massive gastric distension and no evidence of any ulcer or other mucosal defects were observed. Microscopically, marked hypertrophy of muscularis mucosa with smooth muscle cells arranged in whorls and fascicles was present which gradually transitioned to normal areas. The muscle fibers stained with smooth muscle actin and trichrome stain highlighted fibrosis between the muscle fibers. Although uncommon, IHPM can clinically and histologically mimic other proliferations in the gastric wall, such as gastrointestinal stromal tumor or a spindle cell neoplasm. The recent advances in understanding the pathogenesis of IHPM are discussed.


Accuracy of digital palpation for size assessment of the prostate evaluated by transrectal sonography.
In order to clarify how precisely digital palpation gives information on prostatic size, evaluation of the size measurement of the prostate by means of transrectal sonography was performed on 1,543 subjects with various prostatic disorders. There was little agreement between the assessment of prostatic size by digital palpation and the ultrasonic measurement. The larger the prostate the less accurate was digital palpation. The prostatic size assessed by digital palpation was particularly dispersed widely in the prostate of 'hen's egg' size. It was proved that the size assessment by digital palpation was only effective statistically in a two-step differentiation, 'hen's egg' size and smaller. More complicated size classification was of little clinical value in digital palpation.


A perforated anodised aluminium slide for improved specimen clearing and imaging for confocal laser scanning microscopy.
The bleaching, clearing and handling of tiny specimens with soft tissue and cuticular components for confocal laser scanning microscopy is difficult, because after cuticle bleaching and tissue clearing the specimens are virtually invisible. We have adjusted the design of the specimen container described by Smolla et al. (Arthropod Struct Dev 43:175-81, 2014) to handle tiny specimens. We describe a perforated and anodised aluminium slide that was designed to hold the distal tips of the pedipalp appendages of the spider Parasteatoda tepidariorum during clearing, and that can then be used directly for confocal laser scanning microscopy. We believe that this slide design will be helpful for others who want to visualise specimens between 500 and 800 µm with confocal laser scanning microscopy.


Effects of mucin ophthalmic solution on epithelial wound healing in rabbit cornea.
To test the hypothesis that a mucin ophthalmic solution could accelerate the healing of corneal epithelium, we conducted a study in rabbits using an ophthalmic solution containing mucin extracted from bovine submaxillary gland. The corneas of rabbits were abraded with a razor blade in the central portion over an area demarcated with a 7-mm trephine. Mucin-containing eye drops were instilled into the right eye 4 times a day for 3 days, and the vehicle was instilled into the left eye. After enucleation, the eyes were observed by scanning and transmission electron microscopy as well as light microscopy. Mucin-containing eye drops were shown to reduce the epithelial defect area more rapidly than the vehicle. Thus, the eye drops accelerated corneal epithelial wound healing.


A review on mechanisms of resistance to PARP inhibitors.
Standard therapy for advanced ovarian cancer (OC) consists of radical debulking cytoreductive surgery followed by adjuvant chemotherapy. An important risk factor for OC is genetic predisposition, with BRCA1 or BRCA2 mutations accounting for the majority of hereditary OC. Mutation in BRCA ultimately causes accumulation of genetic alterations because of the failure of cells to arrest and repair DNA damage or to undergo apoptosis, resulting in tumorigenesis. Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as a promising approach for managing BRCA-associated cancers, especially high-grade OC and breast cancers. They lead to synthetic lethality in BRCA-mutated cells by stalling the replication forks in homologous recombination-deficient (HR) cells. Four PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) are currently approved by the Food and Drug Administration for OC, breast, and pancreatic cancer indications and are being evaluated for other BRCA-associated cancers. Despite their clinical efficacy, cancer cells generally develop resistance to them through several mechanisms. Understanding these mechanisms is crucial for developing strategies to counter resistance and identify the basic mechanisms of DNA damage response. This review focuses on the mechanism of action of PARP inhibitors, understanding various causes of resistance, and building strategies to overcome PARP inhibitor resistance.


Improved HYDROPS: Imaging of Endolymphatic Hydrops after Intravenous Administration of Gadolinium.
To improve the imaging protocol for the evaluation of endolymphatic hydrops after intravenous administration of a gadolinium-based contrast agent, we modified our previously reported hybrid of reversed image of positive endolymph signal and native image of positive perilymph signal (HYDROPS) method. Although the scan time of the new protocol was half that of the previous one, there were no significant differences between two protocols in the mean contrast noise ratio between the endolymph and perilymph and the area ratio of the endolymph size values in nine patients.


Peer-engagement and its role in reducing the risky behavior among crack and methamphetamine smokers of the Downtown Eastside community of Vancouver, Canada.
The role of peers (former or current drug users) in reducing risky behavior within methamphetamine and crack smokers has not been well described or researched. The current study not only explores the role of peers in reducing risk factors for morbidity within the illicit drug smoking population in the Downtown Eastside (DTES) community of Vancouver but it also investigates the changes in the nature of drug use after the closure of an unsanctioned smoking facility. The data pertain to qualitative interviews with 10 peers and 10 illicit drug smokers. The semi-structured interviews were conducted through community-based research, and the digital transcripts were analyzed via NVivo 10 software. The results indicate that peers (former and current drug users who are employed as educators) are instrumental in transferring risk reduction knowledge within crack and methamphetamine smokers. For example, these peers have been able to teach users about the risk of sharing pipes, using brillo, and using public drug. Furthermore, the Vancouver Area Network of Drug Users provides employment for crack and methamphetamine users in Vancouver who tend to have scarce sources of employment. However, since the closure of the unsanctioned inhalation facility, there has been significantly more public drug use and pipe sharing in the vicinity of the facility, placing drug smokers at significant risk of arrest, violence, and blood-borne infections. The current study recommends expanding the harm reduction peer network for people who smoke illicit drugs in the DTES community of Vancouver who have historically been underserved.


Tertiary syphilis mimicking metastatic rectal cancer.
Syphilis is a sexually transmitted infection caused by the bacterium Treponema pallidum. Tertiary syphilis, a late-stage multi-visceral complication of the disease is characterized by its diversity of clinical manifestations. Here, we present the first documented case of tertiary syphilis that clinically and radiologically mimicked primary rectal cancer with hepatic metastasis.


The painful scrotum: torsion vs epididymo-orchitis.
In summary, an acute disorder of the scrotum in a child without previous urologic history must be viewed as torsion until proved otherwise by surgical exploration. No deleterious effects have been reported from such an approach, which requires a minimal period of hospitalization and little discomfort to the child. The shorter the interval between the onset of symptoms and surgical exploration, the greater the likelihood that the testicle will be viable later. The diagnosis of epididymo-orchitis in a healthy child without a history of urologic abnormality or evidence of lower urinary tract infection has no place in the differential diagnosis of the child with the painful scrotum.


Freeze-fracture autoradiography: feasibility.
We have shown that the combination of freeze-fracture with electron microscope autoradiography can be developed into a technique for correlating the molecular structure of the biological membrane with its chemical and functional characteristics. Within the limits of electron microscope autoradiographic resolution, FARG has the potential to detect the relative distribution of molecules in each half of the membrane and within the plane of the membrane. The use of radioisotopic labels in combination with freezing techniques requires minimal perturbation of the system being studied and may be suitable for the examination of substances which would be extracted or would diffuse during the normal fixation and embedding procedures used in standard electron microscope autoradiography.


[Retrospective study on the mortality of children under 5 in a rural district of the region of Brazzaville (People's Republic of Congo). I. Rate and causes of mortality].
A retrospective study of 1,003 children permits us to identify precisely rates and causes of mortality in children under 5 years old in a rural holoendemic malaria area of the People's Republic of the Congo. The mortality rates are distinctly lower than those generally observed in tropical Africa. Infant mortality (0-1 year) was found to be 71%, mortality 13%, early neonatal mortality (0-7 days) 41% and mortality between 1-5 years, 49%. Main causes of mortality are those related to pregnancy (prematurity, obstetrical pathology) and with infectious diseases particularly measles. On the other hand, no death seems to be attributable directly to malaria in this study.


Image-guided laparoscopic surgery. Review and current status.
The main drawback with laparoscopic surgery is that the surgeon is unable to palpate vessels, tumours and organs during surgery. Further-more, the laparoscope only provides a surface view of organs. There is a need for more advanced visualizations techniques that can enhance the display presented to the surgeon so that important information below the surface of the organs is included when planning the procedure as well as for guidance and control during treatment. In this paper, we present a review of the literature and the state of art within image-guided laparoscopic surgery. We describe our own experience using a prototype navigation system for advanced visualizations and guidance during laparoscopic procedures in the retroperitoneum. Furthermore, we show sample images from the Future Operating Room for laparoscopic surgery in Trondheim, where this technology is being further developed and tested in clinical studies. Our system is based on three-dimensional navigation technology, i.e. preoperatively acquired magnetic resonance or computed tomography data used in combination with tracked instruments, allowing the surgeon to interactively control the display of images prior to and during surgery with normal use of the instruments. In summary, we believe that abdominal image navigation using tracked instruments and advanced visualizations has a large potential for improving future laparoscopic surgery, especially in cases where vessels and anatomical relations beyond surfaces is difficult to identify using only a laparoscope. The technology helps the surgeon to better understand the anatomy and locate blood vessels. Accordingly, we believe that this new technology could increase safety and make it easier for the surgeon to perform successful laparoscopic surgery.


In vivo full-field functional optical hemocytometer.
We present an in vivo lab-free full-field functional optical hemocytometer (FFOH) for application to the capillaries of a live biological specimen, based on the absorption intensity fluctuation modulation (AIFM) effect. Because of the absorption difference between the red blood cells (RBCs) and background tissue under low-coherence light illumination, an endogenous instantaneous intensity fluctuation is generated by the AIFM effect when RBCs discontinuously traverse the capillary. The AIFM effect is used to highlight the RBC signal relative to the background tissue by computing the real-time modulation depth. FFOH can simultaneously provide a flow video, the flow velocity and the RBC count. Ourexperimental results can potentially be applied to study the physiological mechanisms of the blood circulation systems of near-transparent live biological samples.


Peptide-Appended Permethylated β-Cyclodextrins with Hydrophilic and Hydrophobic Spacers.
A novel synthetic methodology, employing a combination of the strain-promoted azide-alkyne cycloaddition and maleimide-thiol reactions, for the preparation of permethylated β-cyclodextrin-linker-peptidyl conjugates is reported. Two different bifunctional maleimide cross-linking probes, the polyethylene glycol containing hydrophilic linker bicyclo[6.1.0] nonyne-maleimide and the hydrophobic 5'-dibenzoazacyclooctyne-maleimide, were attached to azide-appended permethylated β-cyclodextrin. The successfully introduced maleimide function was exploited to covalently graft a cysteine-containing peptide (Ac-Tyr-Arg-Cys-Amide) to produce the target conjugates. The final target compounds were isolated in high purity after purification by isocratic preparative reverse-phase high-performance liquid chromatography. This novel synthetic approach is expected to give access to many different cyclodextrin-linker peptides.


A randomized controlled trial of the effect of exercise on sleep.
We tested the hypothesis that exercise would improve subjective sleep quality and activity in depressed elders. A 10-week randomized controlled trial was utilized. Participants consisted of a volunteer sample, aged > 60 with a diagnosis of major or minor depression or dysthymia. A total of 32 subjects aged 60-84 years with a mean age of 71.3 +/- 1.2 years was used. Intervention consisted of a supervised weight-training program three times a week or an attention-control group. Main outcome measures were Pittsburgh Subjective Sleep Quality Index (PSQI), Likert Scale of Subjective Sleep Quality and Quantity. Paffenbarger Activity Index. Geriatric Depression Scale (GDS). Beck Depression Inventory (BDI), Hamilton Rating Scale of Depression (HRSD), and the Medical Outcomes Survey Short Form 36 (SF-36). Results showed that exercise significantly improved all subjective sleep-quality and depression measures. Depression measures were reduced by approximately twice that of controls. Habitual activity was not significantly increased by exercise. Quality of life subscales significantly improved. In a forward stepwise multiple regression, percent improvement in GDS and percent increase in strength remained significant predictors of the improvement in total PSQI score (r = 0.71, p = 0.0002). In conclusion, weight lifting exercise was effective in improving subjective sleep quality, depression, strength, and quality of life without significantly changing habitual activity.


Interaction of natural and synthetic albumin polymers with hepatocytes.
The hepatitis B virus binds avidly to albumin polymers which in turn may mediate the initial binding of viral particles to the liver cell. However, the interaction of albumin polymers with the liver remains poorly characterized, and the possibility that hepatic binding reflects an artifact of polymerization with glutaraldehyde has not been excluded. We therefore characterized the binding of 125I-labeled natural and synthetic albumin polymers to suspensions of rat hepatocytes. Saturable binding was demonstrated for all preparations of monomeric and polymeric albumin studied. Glutaraldehyde-polymerized albumin (mean polymerization number = 15) bound much more avidly than naturally occurring albumin polymers (mostly dimers and trimers) or monomeric albumin. Competition between monomer and synthetic polymer was not observed. Reduction of free aldehyde groups on the synthetic polymer decreased nonsaturable binding without affecting saturable binding. Autoradiography confirmed binding of polyalbumin to hepatic parenchymal cells. Glutaraldehyde-polymerized ovalbumin, a protein unrelated to serum albumin, also bound hepatocytes saturably. We conclude that hepatic binding of synthetic albumin polymers is not due to residual aldehyde groups on the polymer and is much more avid than for natural polymer. This difference may reflect the higher degree of polymerization or chemical modification of the synthetic polymer. The hepatic binding sites for synthetic polymer appear distinct from those previously described for monomeric albumin and may not be specific for albumin.


Mental health concerns precede quits: shifts in the work discourse during the Covid-19 pandemic and great resignation.
To study the causes of the 2021 Great Resignation, we use text analysis and investigate the changes in work- and quit-related posts between 2018 and 2021 on Reddit. We find that the Reddit discourse evolution resembles the dynamics of the U.S. quit and layoff rates. Furthermore, when the COVID-19 pandemic started, conversations related to working from home, switching jobs, work-related distress, and mental health increased, while discussions on commuting or moving for a job decreased. We distinguish between general work-related and specific quit-related discourse changes using a difference-in-differences method. Our main finding is that mental health and work-related distress topics disproportionally increased among quit-related posts since the onset of the pandemic, likely contributing to the quits of the Great Resignation. Along with better labor market conditions, some relief came beginning-to-mid-2021 when these concerns decreased. Our study underscores the importance of having access to data from online forums, such as Reddit, to study emerging economic phenomena in real time, providing a valuable supplement to traditional labor market surveys and administrative data. The online version contains supplementary material available at 10.1140/epjds/s13688-023-00417-2.


mRNA decay is rapidly induced after spore germination of Saccharomyces cerevisiae.
Spores from the yeast Saccharomyces cerevisiae can germinate and resume their vegetative growth when placed in favorable conditions. Biochemical studies on germination have been limited by the difficulty of obtaining a pure population of spores germinating synchronously. Here, we report that spores can be purified and sorted according to their size by centrifugal elutriation and that these spores are able to germinate synchronously. Synchronizing their development has allowed reevaluating certain parameters of germination, and we demonstrate that both transcription and translation are induced very rapidly after germination induction. Spores contain mRNAs that are stable for several months in spores kept at 4 degrees C. Germination induction leads to very rapid degradation of these mRNAs, thus providing a simple model to study induction of mRNA decay in eukaryotes. mRNAs from the spore are polyadenylated, capped, and cosediment on sucrose gradients with ribosomes and polysomes and with components of the mRNA degradation machinery. The presence of polysomes in the spores led us to evaluate the activity of the translation apparatus in these cells. We present evidence that there is ongoing transcription and translation in nongerminating yeast spores incubated in water at 30 degrees C, suggesting that these activities could play a role in spore long term survival.


Development of patient-centred standards of care for osteoarthritis in Europe: the eumusc.net-project.
The eumusc.net project is an initiative founded by the European Community and the European League Against Rheumatism. One aim of the project was to facilitate equal standards for musculoskeletal health across Europe. The aim of this work-package was to develop patient-centred and consensus based standards of care (SOC) for osteoarthritis (OA), which should be available in a professional and a patient version. A systematic review concerning guidelines dealing with OA was conducted. Furthermore, experts in musculoskeletal diseases were contacted to ensure that 'grey' literature was not excluded. Documents that fulfilled predefined inclusion/exclusion criteria were included and all interventions for OA were extracted and categorised. Based on this list of interventions, a three round Delphi exercise with an international and multidisciplinary expert panel, including patient research partners, was performed to achieve expert consensus. Six documents were included and used for further analysis. Out of them, 46 interventions have been extracted and 10 consensus based SOC were formulated. In addition, a patient version, written in a lay-understandable wording and in the format of checklist questions was developed. An example is SOC 5: "People with OA should achieve optimal pain control using pharmacological and non-pharmacological means." The matching patient-centred checklist question reads: "Do I know how to control pain associated with OA?" The SOC for OA will be available in the 23 languages of the European Union to enhance unified information to patients and professionals and to further harmonise the treatment/care of OA within Europe.


Lamina 3D display: projection-type depth-fused display using polarization-encoded depth information.
In order to realize three-dimensional (3D) displays, various multiplexing methods have been proposed to add the depth dimension to two-dimensional scenes. However, most of these methods have faced challenges such as the degradation of viewing qualities, the requirement of complicated equipment, and large amounts of data. In this paper, we further developed our previous concept, polarization distributed depth map, to propose the Lamina 3D display as a method for encoding and reconstructing depth information using the polarization status. By adopting projection optics to the depth encoding system, reconstructed 3D images can be scaled like images of 2D projection displays. 3D reconstruction characteristics of the polarization-encoded images are analyzed with simulation and experiment. The experimental system is also demonstrated to show feasibility of the proposed method.


Vitamin D3 alters macrophage phenotype and endosomal trafficking markers in dairy cattle naturally infected with Mycobacterium avium subsp. paratuberculosis.
Macrophages are important host defense cells in ruminant paratuberculosis (Johne's Disease; JD), a chronic enteritis caused by Mycobacterium avium subsp. paratuberculosis (MAP). Classical macrophage functions of pathogen trafficking, degradation, and antigen presentation are interrupted in mycobacterial infection. Immunologic stimulation by 25-hydroxyvitamin D3 (25(OH)D3) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) enhances bovine macrophage function. The present study aimed to investigate the role of vitamin D3 on macrophage phenotype and endosomal trafficking of MAP in monocyte-derived macrophages (MDMs) cultured from JD-, JD+ subclinical, and JD+ clinically infected cattle. MDMs were pre-treated 100 ng/ml 25(OH)D3 or 4 ng/ml 1,25(OH)2D3 and incubated 24 hrs with MAP at 10:1 multiplicity of infection (MOI). In vitro MAP infection upregulated pro-inflammatory (M1) CD80 and downregulated resolution/repair (M2) CD163. Vitamin D3 generally decreased CD80 and increased CD163 expression. Furthermore, early endosomal marker Rab5 was upregulated 140× across all stages of paratuberculosis infection following in vitro MAP infection; however, Rab5 was reduced in MAP-activated MDMs from JD+ subclinical and JD+ clinical cows compared to healthy controls. Rab7 expression decreased in control and clinical cows following MDM infection with MAP. Both forms of vitamin D3 reduced Rab5 expression in infected MDMs from JD- control cows, while 1,25(OH)2D3 decreased Rab7 expression in JD- and JD+ subclinical animals regardless of MAP infection in vitro. Vitamin D3 promoted phagocytosis in MDMs from JD- and JD+ clinical cows treated with either vitamin D3 analog. Results from this study show exogenous vitamin D3 influences macrophage M1/M2 polarization and Rab GTPase expression within MDM culture.


Strongly coupled versus uncoupled spin response to radio frequency interference effects: application to glutamate and glutamine in spectroscopic imaging.
It is well known that comparable radio frequency (RF) wavelengths and human head dimensions at high fields can lead to an inhomogeneous RF field when using standard RF transmission. However, the impact of RF inhomogeneity on potential differences in quantification between coupled and uncoupled spins at longer echo times has not been investigated thoroughly. The consequence of this RF interference on metabolite quantification in spectroscopic imaging at 4.7 T was investigated for the strongly coupled spin systems of glutamate and glutamine at an echo time of 120 ms, and compared with the singlet response of choline. These effects were studied using a single-voxel PRESS sequence (alpha-2alpha-2alpha) with varying flip angle (alpha) from 90 degrees to 65 degrees in simulation, phantom, and in vivo experiments. Phantom metabolite yield decreased to 57% for choline and 27% for glutamate/glutamine in agreement with the simulations. Even a minor reduction from alpha = 85 degrees to 80 degrees produced a large difference between coupled and uncoupled yields, with a reduction of 7% for choline and 17% for glutamate/glutamine. Anecdotal in vivo spectroscopic imaging studies show similar trends, with large differences between choline and glutamate/glutamine yield over a small, 2.2 cm, region. These results demonstrate severe effects on metabolite yield due to RF variation between strongly coupled and uncoupled spin systems at long echo time, which complicates metabolite quantification.


Deriving and Analyzing Analytical Structures of a Class of Typical Interval Type-2 TS Fuzzy Controllers.
A conventional controller's explicit input-output mathematical relationship, also known as its analytical structure, is always available for analysis and design of a control system. In contrast, virtually all type-2 (T2) fuzzy controllers are treated as black-box controllers in the literature in that their analytical structures are unknown, which inhibits precise and comprehensive understanding and analysis. In this regard, a long-standing fundamental issue remains unresolved: how a T2 fuzzy set's footprint of uncertainty, a key element differentiating a T2 controller from a type-1 (T1) controller, affects a controller's analytical structure. In this paper, we describe an innovative technique for deriving analytical structures of a class of typical interval T2 (IT2) TS fuzzy controllers. This technique makes it possible to analyze the analytical structures of the controllers to reveal the role of footprints of uncertainty in shaping the structures. Specifically, we have mathematically proven that under certain conditions, the larger the footprints, the more the IT2 controllers resemble linear or piecewise linear controllers. When the footprints are at their maximum, the IT2 controllers actually become linear or piecewise linear controllers. That is to say the smaller the footprints, the more nonlinear the controllers. The most nonlinear IT2 controllers are attained at zero footprints, at which point they become T1 controllers. This finding implies that sometimes if strong nonlinearity is most important and desired, one should consider using a smaller footprint or even just a T1 fuzzy controller. This paper exemplifies the importance and value of the analytical structure approach for comprehensive analysis of T2 fuzzy controllers.


Association between bystander cardiopulmonary resuscitation and redeemed prescriptions for antidepressants and anxiolytics in out-of-hospital cardiac arrest survivors.
This study aimed to examine rates of redeemed prescriptions of antidepressants and anxiolytics, used as markers for cerebral dysfunction in out-of-hospital cardiac arrest (OHCA) survivors, and examine the association between bystander CPR and these psychoactive drugs. We included all 30-day survivors of OHCA in Denmark between 2001 and 2011, who had not redeemed prescriptions for antidepressants or anxiolytics in the last six months prior to OHCA. Main outcome measures were redeemed prescriptions of antidepressants and anxiolytics within one year after OHCA. Among 2,001 30-day survivors, 174 (8.6% died and 12.0% redeemed a first prescription for an antidepressant and 8.2% for an anxiolytic drug within one year after arrest. The corresponding frequencies for redeemed prescribed drugs among age- and sex-matched population controls were 7.5% and 5.2%, respectively. Among survivors who received bystander CPR, prescriptions for antidepressants and anxiolytics were redeemed in 11.1% [95% CI 9.2-13.3%] and 6.3% [95% CI 4.9-8.0%] of the cases, respectively, versus 17.2% [95% CI 13.9-21.1%] and 13.4% [95% CI 10.5-17.0%], respectively, among patients who had not received bystander CPR. Adjusted for age, sex, year of arrest, comorbidity, witnessed status and socioeconomic status, bystander CPR was associated with significant reductions in redeemed prescriptions for antidepressants, Hazard Ratio (HR) 0.71 [95% CI 0.52-0.98], P=0.031; and anxiolytics, HR 0.55 [95% CI 0.38-0.81], P=0.002. Relative to no bystander CPR, redeemed prescriptions for antidepressants and anxiolytics were significantly lower among 30-day survivors of OHCA who received bystander CPR, suggesting a cerebral dysfunction-lowering potential of bystander CPR.


Multiple segmental and selective isotope labeling of large RNA for NMR structural studies.
Multiple segmental and selective isotope labeling of RNA with three segments has been demonstrated by introducing an RNA segment, selectively labeled with (13)C(9)/(15)N(2)/(2)H((1', 3', 4', 5', 5''))-labeled uridine residues, into the central position of the 20 kDa epsilon-RNA of Duck Hepatitis B Virus. The RNA molecules were produced via two efficient protocols: a two-step protocol, which uses T4 DNA ligase and T4 RNA ligase 1, and a one-pot protocol, which uses T4 RNA ligase 1 alone. With T4 RNA ligase 1 all not-to-be-ligated termini are usually protected to prevent formation of side products. We show that such labor-intensive protection of termini is not required, provided segmentation sites can be chosen such that the segments fold into the target structure or target-like structures and thus are not trapped into stable alternate structures. These sites can be reliably predicted via DINAMelt. The simplified NMR spectrum provided evidence for the presence of a U28 H(3)-imino resonance, previously obscured in the fully labeled sample, and thus of the non-canonical base pair U28:C37. The demonstrated multiple segmental labeling protocols are generally applicable to large RNA molecules and can be extended to more than three segments.


Mobility and the spread of human immunodeficiency virus into rural areas of West Africa.
In eastern and southern Africa, the human immunodeficiency virus (HIV) epidemic appeared first in urban centres and then spread to rural areas. Its overall prevalence is lower in West Africa, with the highest levels still found in cities. Rural areas are also threatened, however, because of the population's high mobility. We conducted a study in three different communities with contrasting infection levels to understand the epidemiology of HIV infection in rural West Africa. A comparative cross-sectional study using a standardized questionnaire and biological tests was conducted among samples in two rural communities of Senegal (Niakhar and Bandafassi, 866 and 952 adults, respectively) and a rural community of Guinea-Bissau (Caio, 1416 adults). We compared the distribution of population characteristics and analysed risk factors for HIV infection in Caio at the individual level. The level of HIV infection was very low in Niakhar (0.3%) and Bandafassi (0.0%), but 10.5% of the adults in Caio were infected, mostly with HIV type 2 (HIV-2). Mobility was very prevalent in all sites. Short-term mobility was found to be a risk factor for HIV infection among men in Caio (adjusted odds ratio (aOR) = 2.06; 95% CI: 1.06-3.99). Women from Caio who reported casual sex in a city during the past 12 months were much more likely to be infected with HIV (aOR = 5.61 95% CI: 1.56-20.15). Short-term mobility was associated with risk behaviours at all sites. Mobility appears to be a key factor for HIV spread in rural areas of West Africa, because population movement enables the virus to disseminate and also because of the particularly risky behaviours of those who are mobile. More prevention efforts should be directed at migrants from rural areas who travel to cities with substantial levels of HIV infection.