Obtaining utility estimates of the health value of commonly prescribed treatments for asthma and depression.
Comparing the costs and health value associated with alternative quality improvement efforts is useful. This study employs expert panel methodology to elicit numerical estimates based on a 0 to 1 utility scale of the health benefit of usual treatment patterns for 2 medical conditions. The approach includes development of clinical profiles and derivation of treatment benefit estimates via the elicitation of utility ratings before and after treatment. Clinical profiles specified characteristics of patient groups, treatments to be rated, and their combinations. A panel of 13 asthma and depression experts made a series of utility ratings (before any new treatment, 1 or 3 mo later with no treatment, 1 or 3 mo after initiating various common treatments) for adult patient groups with depression or asthma. The panel convened to discuss discrepancies and subsequently made final ratings. Treatment benefit estimates were derived from the ratings made by the panelists after the panel meeting. The treatment benefit estimates had face validity and minimal variability, indicating considerable consensus among experts. Treatment benefit estimates ranged from -0.03 to 0.25 for depression and from -0.04 to 0.24 for asthma. There was minimal variation in the estimates for both conditions (the estimates' standard deviations ranged from 0.01 to 0.06). Comparisons of the treatment benefit estimates before and after the expert panel meeting indicated substantial convergence, and evidence suggests that the benefit estimates are comparable across the 2 health conditions. Comparable estimates of treatment benefit for distinct health conditions can be obtained from experts using the expert panel methodology.


Unique properties of dually innervated dendritic spines in pyramidal neurons of the somatosensory cortex uncovered by 3D correlative light and electron microscopy.
Pyramidal neurons (PNs) are covered by thousands of dendritic spines receiving excitatory synaptic inputs. The ultrastructure of dendritic spines shapes signal compartmentalization, but ultrastructural diversity is rarely taken into account in computational models of synaptic integration. Here, we developed a 3D correlative light-electron microscopy (3D-CLEM) approach allowing the analysis of specific populations of synapses in genetically defined neuronal types in intact brain circuits. We used it to reconstruct segments of basal dendrites of layer 2/3 PNs of adult mouse somatosensory cortex and quantify spine ultrastructural diversity. We found that 10% of spines were dually innervated and 38% of inhibitory synapses localized to spines. Using our morphometric data to constrain a model of synaptic signal compartmentalization, we assessed the impact of spinous versus dendritic shaft inhibition. Our results indicate that spinous inhibition is locally more efficient than shaft inhibition and that it can decouple voltage and calcium signaling, potentially impacting synaptic plasticity.


Paediatric dentists' knowledge of behavioural management principles in Tamil Nadu, India.
Behaviour management is one of the essential skills of paediatric dentists. Appropriate use of behavioural principles helps the child in developing the skills and behaviours necessary to willingly undergo dental care, not hindered by undue anxiety or fear. However, very little is known about the knowledge of principles regarding behaviour management among paediatric dentists. Contingency management which is based on the principles of behaviour analysis is a widely accepted behavioural management technique and it includes reinforcement and punishment. The aim and objective of this study was to assess the knowledge of paediatric dentists regarding behavioural management principles related to contingency management. A cross- sectional survey was conducted among paediatric dental professionals and post-graduate students pursuing masters in paediatric dentistry across Tamil Nadu, India using Knowledge of Behavioural Principles as Applied to Children (KBPAC) questionnaire modified for the dental setting. The data were obtained, tabulated and statistically analysed using SPSS. Responses were obtained from 130 participants, comprising 67 paediatric dental professionals and 63 post-graduate students. The overall average knowledge score was 40.72%. The mean knowledge level of paediatric dental professionals was (0.4378) versus (0.3597) among post-graduate students (p <0.05). Knowledge of behavioural management principles related to contingency management among paediatric dentists in Tamil Nadu, India is low.


[A method of increasing the effectiveness of anti-glaucoma operations].
The authors have proved the possibility to prevent cicatrization between scleral laminae after antiglaucoma surgery in 16 rat experiments. They analyze late and remote results of 341 surgeries for open-angle glaucoma, 52 of these traditional trabeculectomies and 289 trabeculectomies with placing hemostatic viscose under the scleral flap. The results evidence the efficacy of viscose application: the incidence of complications early after surgery and in the late periods was essentially reduced and a more stable hypotensive effect achieved. The method is simple and available.


High pre-chemoradiotherapy pan-immune-inflammation value levels predict worse outcomes in patients with stage IIIB/C non-small-cell lung cancer.
We explored the prognostic usefulness of the pan-immune-inflammation value (PIV) in patients with stage IIIB/C non-small-cell lung cancer (NSCLC) who underwent concurrent chemoradiotherapy (CCRT). For all patients, the PIV was calculated using platelet (P), monocyte (M), neutrophil (N), and lymphocyte (L) measures obtained on the first day of CCRT: PIV = P × M × N ÷ L. Using receiver operating characteristic (ROC) curve analysis, we searched for the existence of an ideal cutoff that may partition patients into two groups with unique progression-free- (PFS) and overall survival (OS) results. The primary endpoint of this retrospective cohort research was to determine whether there were any significant relationships between pretreatment PIV measures and post-CCRT OS outcomes. The present research included a total of 807 stage IIIB/C NSCLC patients. According to ROC curve analysis, the ideal PIV cutoff was 516 [area under the curve (AUC): 67.7%; sensitivity: 66.4%; specificity: 66.1%], which divided the whole cohort into two: low PIV (L-PIV: PIV < 516; N = 436) and high PIV (H-PIV: PIV ≥ 516; N = 371). The comparisons between the PIV groups indicated that either the median PFS (9.2 vs. 13.4 months; P < 0.001) or OS (16.7 vs. 32.7 months; P < 0.001) durations in the H-PIV group were substantially inferior to their L-PIV counterpart. Apart from the H-PIV (P < 0.001), the N3 nodal stage (P = 0.006), IIIC disease stage (P < 0.001), and receiving only one cycle of concurrent chemotherapy (P = 0.005) were also determined to be significant predictors of poor PFS (P < 0.05, for each) and OS (P < 0.05, for each) outcomes in univariate analysis. The multivariate analysis findings revealed that all four variables had independent negative impacts on PFS (P < 0.05, for each) and OS (P < 0.05, for each). The findings of this hypothesis-generating retrospective analysis claimed that the novel PIV was an independent and steadfast predictor of PFS and OS in stage IIIB/C NSCLC patients.


IL-15 expression on RA synovial fibroblasts promotes B cell survival.
The purpose of this study was to examine the role of RA Synovial Fibroblast (RASFib) IL-15 expression on B cell survival. Magnetically sorted peripheral blood memory B cells from 15 healthy subjects were cocultured with RASFib. RASFib constitutively expressed membrane IL-15. Survival of isolated B cells cultured for 6 days, below 5%, was extended in coculture with RASFib to 52+/-8% (p<0.001). IL-15 neutralizing agents but not isotype controls, reduced this rate to 31+/-6% (p<0.05). Interestingly, rhIL-15 had no effect on isolated B cells but significantly increased their survival in coculture with RASFib. In parallel, B cell IL-15R chains were upregulated in cocultures. BAFF and VCAM-1, that are expressed on RASFib, were tested as potential candidates involved in upregulating B cell IL-15R. Culture of B cells in the presence of rhBAFF or rhVCAM-1 resulted in significantly increased survival, together with upregulation of all three IL-15R chains; in parallel, rhIL-15 potentiated the anti-apoptotic effect of BAFF and VCAM-1. Both BAFF and VCAM-1 neutralizing agents downmodulated the effect of RASFib on B cell survival and IL-15R expression. In parallel, rhIL-15 had a lower effect on the survival of B cells cocultured with RASFib in the presence of BAFF or VCAM-1 neutralizing agents. Peripheral blood B cells from 15 early RA patients demonstrated an upregulated IL-15R and increased survival in cocultures. IL-15 expression on RASFib significantly contributes to the anti-apoptotic effect of RASFib on B cells. IL-15 action is facilitated by BAFF and VCAM-1 expressed on RASFib, through an upregulation of IL-15R chains.


Experiments and 3D simulations of flow structures in junctions and their influence on location of flowmeters.
Open-channel junctions are common occurrences in sewer networks and flow rate measurement often occurs near these singularities. Local flow structures are 3D, impact on the representativeness of the local flow measurements and thus lead to deviations in the flow rate estimation. The present study aims (i) to measure and simulate the flow pattern in a junction flow, (ii) to analyse the impact of the junction on the velocity distribution according to the distance from the junction and thus (iii) to evaluate the typical error derived from the computation of the flow rate close to the junction.


Recent Academic Research on Clinically Relevant Digital Measures: Systematic Review.
Digital clinical measures collected via various digital sensing technologies such as smartphones, smartwatches, wearables, ingestibles, and implantables are increasingly used by individuals and clinicians to capture health outcomes or behavioral and physiological characteristics of individuals. Although academia is taking an active role in evaluating digital sensing products, academic contributions to advancing the safe, effective, ethical, and equitable use of digital clinical measures are poorly characterized. We performed a systematic review to characterize the nature of academic research on digital clinical measures and to compare and contrast the types of sensors used and the sources of funding support for specific subareas of this research. We conducted a PubMed search using a range of search terms to retrieve peer-reviewed articles reporting US-led academic research on digital clinical measures between January 2019 and February 2021. We screened each publication against specific inclusion and exclusion criteria. We then identified and categorized research studies based on the types of academic research, sensors used, and funding sources. Finally, we compared and contrasted the funding support for these specific subareas of research and sensor types. The search retrieved 4240 articles of interest. Following the screening, 295 articles remained for data extraction and categorization. The top five research subareas included operations research (research analysis; n=225, 76%), analytical validation (n=173, 59%), usability and utility (data visualization; n=123, 42%), verification (n=93, 32%), and clinical validation (n=83, 28%). The three most underrepresented areas of research into digital clinical measures were ethics (n=0, 0%), security (n=1, 0.5%), and data rights and governance (n=1, 0.5%). Movement and activity trackers were the most commonly studied sensor type, and physiological (mechanical) sensors were the least frequently studied. We found that government agencies are providing the most funding for research on digital clinical measures (n=192, 65%), followed by independent foundations (n=109, 37%) and industries (n=56, 19%), with the remaining 12% (n=36) of these studies completely unfunded. Specific subareas of academic research related to digital clinical measures are not keeping pace with the rapid expansion and adoption of digital sensing products. An integrated and coordinated effort is required across academia, academic partners, and academic funders to establish the field of digital clinical measures as an evidence-based field worthy of our trust.


Not All Academics Are Alike: First Validation of the Academics' Quality of Life at Work Scale (AQoLW).
Background: Relating to the macro-level changes and the increasing complexity of the academic system, a growing number of studies began to investigate the perceived working context impact on well-being and job satisfaction of academics. A unique duality characterizes this context: academics cannot be longer defined as stress-free, but at the same time they are still satisfied and engaged in their work. There is a need to evaluate the academic environment not only in terms of stressor and strain, but also in terms of which experiences are sources of fulfillment. The study aimed to explore psychometric properties of a new instrument (AQoLW) for assessing context-specific features of the academic work and environment that characterized academics' quality of life at work. Method: A 24 item scale was deployed to academics (full, associate, and assistant professors) in a public university in the north of Italy. Items were defined to represent the main academic activities in order to measure if respondents perceived each of it as a challenging or a hindrance demand. The scale was administered online to 1,012 academics, 443 females (48.7%), mean aged 51.1 years (SD = 8.2). In order to test three theoretical models underling AQoLW, a training sample was randomly extracted (242 participants) and analyzed using confirmatory factor analysis (CFA). A validation sample with the remaining 668 participants was used to test the measurement invariance by role of the best model emerging from the training sample. Results: Model fit demonstrate the goodness of a latent structure composed by five intercorrelated factors (CFI = 0.91, RMSEA = 0.08, SRMR = 0.07). Cronbach α of the five subscales was good, ranging from 0.76 to 0.88. The scale overtakes configural invariance, but not strong invariance by role. Conclusions: The scale is able to intercept the mainly dimensions of the academic work that contribute to the quality of life of academics' staff, namely: research and public engagement, didactic work and relationships with students, career development and competition, ordinary obligations, and fund raising. AQoLW is the first tool to evaluate the academic work and its environment, identifying which activities are stressful demands and which are engaging, and promote scholars' satisfaction.


Liposarcoma of the lower extremity.
Twenty patients with primary liposarcoma of the lower extremity were treated over a 25-year period. The adequacy of the initial surgical procedure and histological grade of malignancy both influenced survival rates. In addition local recurrence was noted only in patients who had undergone "inadequate" initial excision. Inguinal lymph nodes were uninvolved by tumor in all cases. In general, patients with liposarcomas of myxoid and/or round cell type survived for long periods of time. However, even patients with myxoid lesions occasionally exhibited evidence of early blood-borne metastases. This study suggests an important relationship between an inadequate primary resection, local recurrence, and eventual retroperitoneal spread. In the majority of cases, this may have resulted from failure to control the primary distal extremity tumor, with subsequent contiguous spread of metastases into the ipsilateral retroperitoneal space. If feasible, radical soft part resection should be performed as the primary surgical therapy of these neoplasms. Tumors contiguous to the knee or ankle joint should be treated by primary amputation. Failure to control local disease may result in blood-borne dissemination or local spread along musculoaponeurotic planes to involve proximal groin or retroperitoneal space.


Vitamin C and 6-amino-vitamin C conjugates of diclofenac: synthesis and evaluation.
Diclofenac (Diclo), its ascorbic acid (AA) or 6-amino-AA (AA-NH2) pro-drugs (AA-Diclo or AA-NH-Diclo) were prepared and evaluated on human retinal pigment epithelium (HRPE) cells to investigate their ability to interact with the vitamin C transporter SVCT2 and their cellular uptake. Furthermore, stabilities in physiological fluids of these compounds were investigated. For kinetic experiments, AA-Diclo was incubated in Tris-HCl buffer, human plasma or whole blood. The extracted samples were analysed by HPLC. AA-Diclo was hydrolysed following first order kinetics in buffer, plasma (t1/2 about 10 h) and whole blood (t1/2 about 3.5 h). Transport and inhibition assays were performed by adding [14C]AA and the above-mentioned unlabelled compounds to plated HRPE cells. Intracellular accumulation was measured incubating HRPE cells with increasing concentrations of unlabelled compounds, following by HPLC analysis. Diclo resulted as a non-competitive inhibitor of AA-transport, showing a Na+-dependent and ascorbate-independent uptake. AA-Diclo behaved as a competitive inhibitor, but it was not transported into cells, whereas its analogue AA-NH-Diclo showed a decreased inhibitory activity. Stability studies suggest AA-Diclo as a potential candidate to enhance the Diclo short half life in vivo. The discovery of a Na+-dependent transporter for Diclo on HRPE cells opens new perspectives for targeting diclofenac into the brain.


Parallel operation of Monte Carlo simulations on a diverse network of computers.
Monte Carlo simulation methods are frequently used to determine light propagation in tissue and x-ray propagation as well as for solving other non-medically related problems. Such techniques are computationally slow, with the signal to noise ratio improving only as the square root of computation time. We present a method for the design of a Monte Carlo program that is capable of running on up to 24 computers simultaneously, with there being very few restrictions on the computer types as long as they run on a common network. This parallel operation is useful when the run time is expected to be long. A mixture of PCs and Sun workstations have been successfully used. The program as described was designed for the simulation of light transport in tissue, but the technique of achieving simple simultaneous execution on a number of different computers could be used wherever Monte Carlo techniques are used.


2,5-Dimethylfuran from approximately 2.7 x 10-year-old Rupemba-Belingwe stromatolite, Rhodesia: Potential evidence for remnants of carbohydrates.
2,5-Dimethylfuran, 2-methylfuran, and C(9)-C(20)n-alkanes have been isolated from the kerogen of a Rupemba stromatolite. These furans could be the oldest known stable remnants of biological carbohydrates if it is possible to prove that their progenitors are as old as the rock. Experiments showed that it is improbable that these compounds are analytical artifacts or laboratory contaminations. Postdepositional contaminations caused by fluids flowing through the rocks seem doubtful because of minimal permeability, which is supported by petrographic observations. Contamination by diffusion also appears to be unlikely. Because the rock had a mild temperature history, these molecules could have survived since Archean time. Because of all the evidence, the furans and alkanes are quite likely biochemical fossils.


Purification and expression of the Tf190 adhesin in Tritrichomonas foetus.
Bovine trichomoniasis is a sexually transmitted disease caused by Tritrichomonas foetus and characterized by early embryo loss. The mechanism of this loss is not known, although the parasite is known to cause inflammation and to have the ability to kill host cells by a contact-dependent cytotoxic mechanism. Antibody specific for a 190,000-Da surface complex (Tf190) was previously shown to inhibit this adhesion. In this study we used immunoaffinity chromatography to purify Tf190 from T. foetus in order to analyze its composition and examine its expression. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of purified Tf190 followed by silver staining revealed three components of Tf190. Western blotting and antibody-binding experiments showed that the 140- and 60-kDa bands were immunogenic. By using a battery of monoclonal antibodies (MAbs) periodate-sensitive epitopes were identified on Tf190, suggesting that these epitopes contained carbohydrate structures. Analyses of affinity-purified Tf190 by high-performance liquid chromatography and gas-liquid chromatography demonstrated the presence of the monosaccharides and lipids known to be prominent constituents of the lipophosphoglycan (LPG) of T. foetus. Flow cytometry experiments on several isolates of T. foetus with Tf190-specific antibodies revealed that Tf190 was present on subpopulations of all isolates but that not all epitopes were present on every isolate. This pattern of reactivities on the different parasite isolates was confirmed by Western blots of whole-parasite extracts probed with MAbs and antiserum. These results suggest that although variation in the expression of epitopes of Tf190 occurs in different strains of T. foetus, the Tf190 adhesion complex is widespread in different populations of the parasite. The data further suggest that immunogenic structures, important in the adhesion of T. foetus to mammalian cells, are located in the LPG-like component of Tf190.


Blue-emitting and self-assembled thinner perovskite CsPbBr3 nanoplates: synthesis and formation mechanism.
Low dimensional semiconductor nanomaterials show great promise for a variety of applications due to their size-dependent and excellent optoelectronic properties. In this work, we developed a strategy to synthesize uniform and very thin CsPbBr3 perovskite nanoplates (NPls) by introducing additional metal bromides. The CsPbBr3 NPls, self-assembled into a face-to-face stacked state, had a thickness of 4.4 nm (equal to only 2 monolayers, 2 MLs) and showed a maximum emission at 437 nm and a narrow FWHM of 14 nm. The formation mechanism of the CsPbBr3 NPls by adding FeBr3 was ascribed to the constrained growth of CsPbBr3 nanocubes when the surface Cs+ ions were substituted by the protonated oleylammonium from the byproduct OLA-HBr.


Reducing long-term use of benzodiazepine receptor agonists: In-depth interview study with primary care stakeholders.
To increase our understanding of which factors contribute to long-term benzodiazepine receptor agonist (BZRA) use for insomnia in primary care, from a patients', general practitioners' (GP) and pharmacists' perspective. Qualitative research following a grounded theory approach. Primary care in Belgium. Twenty-four participants were interviewed, including nine patients, six GPs and nine pharmacists. In-depth, semistructured interviews with iterative cycles of data collection and analysis. Transcripts were analysed using the framework method. Thematic findings were interpreted in the context of the Theoretical Domains Framework. A reflexive relation was identified between views about hypnotic use at the level of society, healthcare and patients. Behaviour change appeared to depend strongly on context and social influence, including a need for supporting relationships by all stakeholders. Six key messages captured factors that contribute to long-term BZRA use for insomnia in primary care: societal beliefs as a game changer, the opportunity of nonpharmacological treatment, collaborative primary care, patient-centred goals, informed consent and self-management. Long-term BZRA use for insomnia is a complex and multifaceted public health problem that is not adequately addressed in primary care at this time. Although primary care professionals in this study found discontinuation of long-term BZRA use relevant to the patient's health, many organisational and personal barriers were reported. Moreover, the current social and healthcare context is not empowering patients and professionals to reduce long-term BZRA use for insomnia. Specifically, for primary care, all stakeholders reported the need for a nonmedicalised relationship between the patient and GP to lower prescribing rates. The Flemish Patient Platform, a patient representative organisation, assisted with recruitment by launching a call for participants in their newsletter and volunteered to disseminate the results. The call for recruitment was also published online in social media groups regarding insomnia and via posters in public pharmacies. Patients or public were not involved in designing or conducting the interview study.


Severe viral respiratory infections in children with IFIH1 loss-of-function mutations.
Viral respiratory infections are usually mild and self-limiting; still they exceptionally result in life-threatening infections in previously healthy children. To investigate a potential genetic cause, we recruited 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Using exome and transcriptome sequencing, we identified and characterized three rare loss-of-function variants in IFIH1, which encodes an RIG-I-like receptor involved in the sensing of viral RNA. Functional testing of the variants IFIH1 alleles demonstrated that the resulting proteins are unable to induce IFN-β, are intrinsically less stable than wild-type IFIH1, and lack ATPase activity. In vitro assays showed that IFIH1 effectively restricts replication of human respiratory syncytial virus and rhinoviruses. We conclude that IFIH1 deficiency causes a primary immunodeficiency manifested in extreme susceptibility to common respiratory RNA viruses.


Evaluation of endocytosis of silica particles used in biodegradable implants in the brain.
Silica nanoparticles embedded in a biodegradable scaffold have been proposed to offer several advantages when used in laser-tissue-soldering of blood vessels in the brain. During degradation, these nanoparticles are likely to be released into the surrounding brain tissue. The aim of this study was to investigate possible cellular uptake mechanism(s) of the two silica nanoparticle types in microglial cells as well as their effect on autophagy and inflammatory cytokines. The nanoparticle uptake was analysed quantitatively using high-content analysis. Nanoparticle incubation did not modulate cytokine secretion and autophagy at any time point investigated. The nanoparticles were taken up by the microglia cells in a time- and particle-dependent manner. The maximal uptake was reached after 4hours and the nanoparticles were found in the endoplasmic reticulum and lysosomes. Macropinocytosis and phagocytosis were predominantly responsible for the uptake, whereas clathrin- and caveolin-independent endocytosis were involved to a minor extent.


[Expression of tumor suppressor gene PRDM1 in lung cancers].
To determine the expression of tumor suppressor gene PRDM1 in lung cancers. Forty-five cases were enrolled in this study, including squamous cell carcinoma (20 cases), adenocarcinoma (15 cases), and small cell cancer (10 cases). PRDM1 protein was detected in paraffin-embedded tissue by immunohistochemistry. Tumor cells in lung cancers were further selected by laser microdissection for RT-PCR analysis. PRDM1 protein in frozen tissue was also detected by Western blot. (1) PRDM1 protein was found in paraffin-embedded tissues in 90.0% (18/20) of squamous cell carcinoma, 13.3% (2/15) of adenocarcinoma, and 0 (0/10) small cell lung cancer. Squamous cell carcinoma predominantly expressed PRDM1 protein ( P < 0.01). (2) Gene product of PRDM1 DNA binding region was not found in microdissected tumor cells, but an abnormal PRDM1 protein about 70 KD was detected simultaneously in whole tumor tissue. PRDM1 may be considered as a specific biomarker in pulmonary squamous cell carcinoma. The abnormal PRDM1 expression both at transcriptional and protein levels indicated that this tumor suppressor gene lost its function, which may become a new target in the strategy of treatment for lung cancers.


Generation of the Brucella melitensis ORFeome version 1.1.
The bacteria of the Brucella genus are responsible for a worldwide zoonosis called brucellosis. They belong to the alpha-proteobacteria group, as many other bacteria that live in close association with a eukaryotic host. Importantly, the Brucellae are mainly intracellular pathogens, and the molecular mechanisms of their virulence are still poorly understood. Using the complete genome sequence of Brucella melitensis, we generated a database of protein-coding open reading frames (ORFs) and constructed an ORFeome library of 3091 Gateway Entry clones, each containing a defined ORF. This first version of the Brucella ORFeome (v1.1) provides the coding sequences in a user-friendly format amenable to high-throughput functional genomic and proteomic experiments, as the ORFs are conveniently transferable from the Entry clones to various Expression vectors by recombinational cloning. The cloning of the Brucella ORFeome v1.1 should help to provide a better understanding of the molecular mechanisms of virulence, including the identification of bacterial protein-protein interactions, but also interactions between bacterial effectors and their host's targets.


TRPV1 agonist monoacylglycerol increases UCP1 content in brown adipose tissue and suppresses accumulation of visceral fat in mice fed a high-fat and high-sucrose diet.
The administration of such a transient receptor potential vanilloid 1 (TRPV1) agonist as capsaicin, which is a pungent ingredient of red pepper, promotes energy metabolism and suppresses visceral fat accumulation. We have recently identified monoacylglycerols (MGs) having an unsaturated long-chain fatty acid as the novel TRPV1 agonist in foods. We investigated in this present study the effects of dietary MGs on uncoupling protein 1 (UCP1) expression in interscapular brown adipose tissue (IBAT) and on fat accumulation in mice fed with a high-fat, high-sucrose diet. The MG30 diet that substituted 30% of all lipids for MGs (a mixture of 1-oleoylglycerol, 1-linoleoylglycerol and 1-linolenoylglycerol) significantly increased the UCP1 content of IBAT and decreased the weight of epididymal white adipose tissue, and the serum glucose, total cholesterol and free fatty acid levels. The diet containing only 1-oleoylglycerol as MG also increased UCP1 expression in IBAT. MGs that activated TRPV1 also therefore induced the expression of UCP 1 and prevented visceral fat accumulation as well as capsaicin.


Viral Infection Drives the Regulation of Feeding Behavior Related Genes in Salmo salar.
The feeding behavior in fish is a complex activity that relies on the ability of the brain to integrate multiple signals to produce appropriate responses in terms of food intake, energy expenditure, and metabolic activity. Upon stress cues including viral infection or mediators such as the proinflammatory cytokines, prostaglandins, and cortisol, both Pomc and Npy/Agrp neurons from the hypothalamus are stimulated, thus triggering a response that controls both energy storage and expenditure. However, how appetite modulators or neuro-immune cues link pathogenesis and energy homeostasis in fish remains poorly understood. Here, we provide the first evidence of a molecular linkage between inflammation and food intake in Salmon salar. We show that in vivo viral challenge with infectious pancreatic necrosis virus (IPNV) impacts food consumption by activating anorexic genes such as mc4r, crf, and pomcb and 5-HT in the brain of S. salar. At the molecular level, viral infection induces an overall reduction in lipid content in the liver, favoring the production of AA and EPA associated with the increment of elovl2 gene. In addition, infection upregulates leptin signaling and inhibits insulin signaling. These changes are accompanied by a robust inflammatory response represented by the increment of Il-1b, Il-6, Tnfa, and Pge2 as well as an increased cortisol level in vivo. Thus, we propose a model in which hypothalamic neurons respond to inflammatory cytokines and stress-related molecules and interact with appetite induction/inhibition. These findings provide evidence of crosstalk between pathogenesis-driven inflammation and hypothalamic-pituitary-adrenocortical axes in stress-induced food intake behavior in fish.


Relevance of hot spots in the evolution and transmission of Tn1546 in glycopeptide-resistant Enterococcus faecium (GREF) from broiler origin.
Glycopeptide-resistant enterococci are still present within the broiler sector, despite the EU ban of avoparcin more than a decade ago. In the present study, we have developed a rapid method for screening the flanking regions at the integration point of Tn1546 in glycopeptide-resistant Enterococcus faecium isolated from broiler farms. Total DNA was digested, ligated and amplified using primers from inside Tn1546. The resulting amplicons were purified and sequenced. Two new primers were designed based on obtained sequences. Two main insertion points have been repeatedly found in isolates from the UK (n = 150). The first insertion point revealed that 25 isolates harboured Tn1546 positioned in a sequence with 96% homology to a streptomycin adenyltransferase gene (AY604739) from a Staphylococcus intermedius plasmid. At this insertion point, a direct repeat (GTCCT) was duplicated as previously described, indicating transposition at the target site. Furthermore, this 'hot spot' was also detected in isolates from Norway (2/8) and Denmark (17/20). The second insertion point detected in 45 isolates from the UK revealed integration into an Inc18-like plasmid, most likely by a process of target site recombination. The presence of a common insertion point for isolates from different geographical areas could suggest the insertion of Tn1546 by transposition in a plasmid-specific site, followed by genetic rearrangement both inside the transposon and in the flanking regions.


An inferolateral approach to nipple-sparing mastectomy: optimizing mastectomy and reconstruction.
An increasing number of women presenting with early stage breast cancer or a strong family history are choosing mastectomy as a therapeutic or prophylactic treatment option. In these selected patients, conservation of the nipple areolar complex is considered to improve cosmesis and body image. Incision placement is an important consideration in breast appearance after surgery. Functionally, the incision must allow adequate access for mastectomy and implant positioning. In addition, preservation of blood supply is critical to maintain a viable nipple. This article describes an inferolateral curvilinear incision on the breast mound, which can be designed de novo or as an extension of a preexisting lateral scar. The incision allows adequate access and hides the scar on anterior view, thus optimizing both the mastectomy and reconstruction. In patients with a preexisting lateral scar, this may be the incision of choice.


Maintenance and pharmacologic targeting of ROR1 protein levels via UHRF1 in t(1;19) pre-B-ALL.
Expression of the transmembrane pseudokinase ROR1 is required for survival of t(1;19)-pre-B-cell acute lymphoblastic leukemia (t(1;19) pre-B-ALL), chronic lymphocytic leukemia, and many solid tumors. However, targeting ROR1 with small-molecules has been challenging due to the absence of ROR1 kinase activity. To identify genes that regulate ROR1 expression and may, therefore, serve as surrogate drug targets, we employed an siRNA screening approach and determined that the epigenetic regulator and E3 ubiquitin ligase, UHRF1, is required for t(1;19) pre-B-ALL cell viability in a ROR1-dependent manner. Upon UHRF1 silencing, ROR1 protein is reduced without altering ROR1 mRNA, and ectopically expressed UHRF1 is sufficient to increase ROR1 levels. Additionally, proteasome inhibition rescues loss of ROR1 protein after UHRF1 silencing, suggesting a role for the proteasome in the UHRF1-ROR1 axis. Finally, we show that ROR1-positive cells are twice as sensitive to the UHRF1-targeting drug, naphthazarin, and undergo increased apoptosis compared to ROR1-negative cells. Naphthazarin elicits reduced expression of UHRF1 and ROR1, and combination of naphthazarin with inhibitors of pre-B cell receptor signaling results in further reduction of cell survival compared with either inhibitor alone. Therefore, our work reveals a mechanism by which UHRF1 stabilizes ROR1, suggesting a potential targeting strategy to inhibit ROR1 in t(1;19) pre-B-ALL and other malignancies.


Prediction of appropriate timing of palliative care for older adults with non-malignant life-threatening disease: a systematic review.
most people in contemporary western society die of the chronic diseases of old age. Whilst palliative care is appropriate for elderly patients with chronic, non-malignant disease, few of these patients access such care compared with cancer patients. Objective referral criteria based on accurate estimation of survival may facilitate more timely referral of non-cancer patients most appropriate for specialist palliative care. to identify tools and predictor variables that might aid clinicians estimate survival and assess palliative status in non-cancer patients aged 65 years and older. systematic review and quality assessment using criteria modified from the literature. 11 studies that evaluated prognoses in hospitalised and community-based older adults with non-malignant disease were identified. Key generic predictors of survival were increased dependency of activities of daily living, presence of comorbidities, poor nutritional status and weight loss, and abnormal vital signs and laboratory values. Disease-specific predictors of survival were identified for dementia, chronic obstructive pulmonary disorder and congestive heart failure. No study evaluated the relationship between survival and palliative status. prognostic models that attempt to estimate survival of < or = 6 months in non-cancer patients have generally poor discrimination, reflecting the unpredictable nature of most non-malignant disease. However, a number of generic and disease-specific predictor variables were identified that may help clinicians identify older, non-cancer patients with poor prognoses and palliative care needs. Simple, well-validated prognostic models that provide clinicians with objective measures of palliative status in non-cancer patients are needed. Additionally, research that evaluates the effect of general and specialist palliative care on psychosocial outcomes in non-cancer patients and their carers is needed.


Thiopental inhibits the activation of nuclear factor kappaB.
Thiopental is frequently used for the treatment of intracranial hypertension after severe head injury. Its long-term administration increases the incidence of nosocomial infections, which contributes to the high mortality rate of these patients. However, the mechanism of its immunosuppressing effect remains unknown. The effect of thiopental (200-1000 microg/ml) on the activation of the nuclear transcription factor kappaB (NF-kappaB; electrophoretic mobility shift assays), on NF-kappaB-driven reporter gene activity (transient transfection assays), on the expression of NF-kappaB target genes (enzyme-linked immunoassays), on T-cell activation (flow cytometric analyses of CD69 expression), and on the content of the NF-kappaB inhibitor IkappaB-alpha (Western blotting) was studied in human T lymphocytes in vitro. Thiopental inhibited the activation of the transcription factor NF-kappaB but did not alter the activity of the cyclic adenosine monophosphate response element binding protein. Other barbiturates (methohexital), anesthetics (etomidate, propofol, ketamine), or opioids (fentanyl, morphine) did not affect NF-kappaB activation. Thiopental-mediated suppression of NF-kappaB could be observed in Jurkat cells and in primary CD3+ lymphocytes from healthy volunteers, was time- and concentration-dependent, occurred at concentrations that are clinically achieved, and persisted for hours after the incubation. It was associated with an inhibition of NF-kappaB-driven reporter gene activity, of the expression of interleukin-2, -6, and -8, and interferon gamma, and of the activation of CD3+ lymphocytes. Suppression of NF-kappaB appeared to involve reduced degradation of IkappaB-alpha. The results demonstrate that thiopental inhibits the activation of NF-kappaB and may thus provide a molecular mechanism for some of the immunosuppressing effects associated with thiopental therapy.


Thermodynamic and structural basis of phosphorylation-induced disorder-to-order transition in the regulatory light chain of smooth muscle myosin.
We have performed molecular dynamics simulations of the phosphorylation domain (PD) of the regulatory light chain (RLC) of smooth muscle myosin, to gain insight into the thermodynamic principles governing the phosphorylation-induced disorder-to-order transition. Simulations were performed in explicit water under near-physiological conditions, starting with an ideal alpha-helix. In the absence of phosphorylation, the helical periodicity of the peptide was disrupted at residues T9-K11, while phosphorylation significantly favored the helical periodicity, in agreement with experimental data. Using the MM/PBSA approach, we calculated a relative free energy of -7.1 kcal/mol for the disorder-to-order transition. A large enthalpic decrease was compensated by a large loss of conformational entropy, despite the small helical increase (no more than three residues) upon phosphorylation. Phosphorylation decreased the conformational dynamics of K and R side chains, especially R16, which forms a salt bridge with pS19. Mutation of R16 to A or E prevented this phosphorylation-dependent ordering. We propose that phosphorylation balances the enthalpy-entropy compensation of the disorder-to-order transition of RLC via short and long-range electrostatic interactions with positively charged residues of the phosphorylation domain. We suggest that this balance is necessary to induce a disorder-to-order conformational change through a subtle energy switching.


Diet, physical inactivity and the prevalence of constipation throughout and after pregnancy.
Few studies appear to have investigated the prevalence of constipation for all three trimesters of the gestative period, or indeed after birth. Using a prospective 4- to 7-day weighed food diary, International Physical Activity Questionnaire and 7-day bowel habit diary, dietary factors, physical activity levels and bowel habit parameters were assessed and examined concurrently at weeks 13, 25, 35 of pregnancy and 6 weeks post-partum. Ninety-four primiparous pregnant women were initially recruited, and 72, 59, 62 and 55 completed the first, second, third trimester and post-partum study stages, respectively. Key dietary factors and physical activity levels were compared between the constipated and non-constipated groups from each of the three trimesters and after parturition. Compared with non-constipated mothers-to-be, constipated participants consumed statistically significantly less water in the first trimester (P = 0.04), more food in the second trimester (P = 0.04), and less iron (P = 0.02) and food (P = 0.04) in the third trimester and after birth, respectively. No statistically significant differences were identified between light, moderate and vigorous physical activity levels when groups were compared. This study demonstrates that dietary factors may play a role in terms of preventing, or alleviating, bowel habit perturbations both throughout and after pregnancy. Further research is required to investigate the interrelationship between physical activity and constipation during and after pregnancy.


Contributions of carotid bodies, retrotrapezoid nucleus neurons and preBötzinger complex astrocytes to the CO2 -sensitive drive for breathing.
Current models of respiratory CO2 chemosensitivity are centred around the function of a specific population of neurons residing in the medullary retrotrapezoid nucleus (RTN). However, there is significant evidence suggesting that chemosensitive neurons exist in other brainstem areas, including the rhythm-generating region of the medulla oblongata - the preBötzinger complex (preBötC). There is also evidence that astrocytes, non-neuronal brain cells, contribute to central CO2 chemosensitivity. In this study, we reevaluated the relative contributions of the RTN neurons, the preBötC astrocytes, and the carotid body chemoreceptors in mediating the respiratory responses to CO2 in experimental animals (adult laboratory rats). To block astroglial signalling via exocytotic release of transmitters, preBötC astrocytes were targeted to express the tetanus toxin light chain (TeLC). Bilateral expression of TeLC in preBötC astrocytes was associated with ∼20% and ∼30% reduction of the respiratory response to CO2 in conscious and anaesthetized animals, respectively. Carotid body denervation reduced the CO2 respiratory response by ∼25%. Bilateral inhibition of RTN neurons transduced to express Gi-coupled designer receptors exclusively activated by designer drug (DREADDGi ) by application of clozapine-N-oxide reduced the CO2 response by ∼20% and ∼40% in conscious and anaesthetized rats, respectively. Combined blockade of astroglial signalling in the preBötC, inhibition of RTN neurons and carotid body denervation reduced the CO2 -induced respiratory response by ∼70%. These data further support the hypothesis that the CO2 -sensitive drive to breathe requires inputs from the peripheral chemoreceptors and several central chemoreceptor sites. At the preBötC level, astrocytes modulate the activity of the respiratory network in response to CO2 , either by relaying chemosensory information (i.e. they act as CO2 sensors) or by enhancing the preBötC network excitability to chemosensory inputs. KEY POINTS: This study reevaluated the roles played by the carotid bodies, neurons of the retrotrapezoid nucleus (RTN) and astrocytes of the preBötC in mediating the CO2 -sensitive drive to breathe. The data obtained show that disruption of preBötC astroglial signalling, blockade of inputs from the peripheral chemoreceptors or inhibition of RTN neurons similarly reduce the respiratory response to hypercapnia. These data provide further support for the hypothesis that the CO2 -sensitive drive to breathe is mediated by the inputs from the peripheral chemoreceptors and several central chemoreceptor sites.


Escherichia coli urinary tract infections: Host age-related differences in bacterial virulence factors and antimicrobial susceptibility.
Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) are one of the most common outpatient bacterial infections. Although bacterial and host factors are reported to be associated with UTI pathogenesis, little is known about the host age-related differences in bacterial virulence factors and antimicrobial susceptibility. PCRs were carried out to detect K1 capsule antigen, 15 virulence factors, and phylogenetic groups in E. coli isolates. Antimicrobial susceptibility of selected agents was determined by the disk diffusion method. Isolates were divided into 6 groups based on their host age. The results showed that virulence factors PapGII, PapGIII, Cnf1, Aer, Usp, Iha, OmpT, HlyA, and Sat, had highest frequencies in the host age group 0-3. Phylogenetic group B2 dominated in our isolates (59.6%) followed by group D (20.7%). In addition, 77.4% of strains isolated from 0 to 3 age group belonged to phylogenetic group B2. Antimicrobial susceptibility tests showed that E. coli strains isolated were significantly more resistant to antimicrobial agents as host age increased. Phylogenetic group B2 isolates were more susceptible to antimicrobial agents, compared to A, B1, and D isolates. We found E. coli isolated from elders were more resistant to antimicrobial agents and had less virulence factors.


Surgical margins in oral cavity squamous cell carcinoma: Current practices and future directions.
To discuss the current available techniques for intraoperative margin assessment in the surgical treatment of oral squamous cell carcinoma (OSCC) through a review of the available literature. A systematic review was undertaken of the available English literature between 2008 through 2018 regarding surgical margins in OCSS. A total of 893 relevant articles were returned; 144 met criteria for review; and 64 articles were included. In this review, we discuss the data surrounding the use of frozen section in OCSS. Additionally, alternative techniques for margin assessment are discussed, including Mohs, molecular analysis, nonfluorescent dyes, fluorescent dyes, autofluorescent imaging, narrow-band imaging, optical coherence tomography, confocal microscopy, high-resolution microendoscopy, and spectroscopy. For each technique, particular emphasis is placed on the local recurrence, disease-free survival, and overall survival rates when available. This review provides support for the practice of specimen-driven margin assessment when using frozen section analysis to improve the utility of the results. Finally, several alternatives for intraoperative margin assessment currently under investigation, including pathologic, wide-field imaging and narrow-field imaging techniques, are presented. We aim to fuel further investigation into methods for margin assessment that will improve survival for patients with OSCC through a critical analysis of the available techniques. NA Laryngoscope, 130:128-138, 2020.


Robotic simple prostatectomy: a consideration for large prostate adenomas.
The management of benign prostatic hyperplasia (BPH) has changed considerably over the last several decades. First line treatment of BPH and lower urinary tract symptoms (LUTS) with medical therapy has created a population of men with much larger prostate glands, many of whom require surgical intervention. Patients with prostate glands greater than 80 to 100 grams may be better managed surgically with a retropubic prostatectomy. We explore our experience with robotic assisted simple prostatectomy and review the relevant literature. The database reviewed includes our experience with seven patients undergoing robotic simple prostatectomy, and a comprehensive review of the previously published series of this procedure. In addition, the literature pertaining to a pure laparoscopic approach to simple prostatectomy is reviewed. Robotic experience and training has become a standard in resident training programs; while classic transurethral resection is being performed less for large prostate glands. The robotic approach to simple prostatectomy provides an excellent option for surgical treatment of very large prostate glands, providing patients acceptable results in terms of operative time, estimated blood loss, hospital stay and duration of Foley catheter.


Immunostaining for DNA Modifications: Computational Analysis of Confocal Images.
For several decades, 5-methylcytosine (5mC) has been thought to be the only DNA modification with a functional significance in metazoans. The discovery of enzymatic oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) as well as detection of N6-methyladenine (6mA) in the DNA of multicellular organisms provided additional degrees of complexity to the epigenetic research. According to a growing body of experimental evidence, these novel DNA modifications may play specific roles in different cellular and developmental processes. Importantly, as some of these marks (e. g. 5hmC, 5fC and 5caC) exhibit tissue- and developmental stage-specific occurrence in vertebrates, immunochemistry represents an important tool allowing assessment of spatial distribution of DNA modifications in different biological contexts. Here the methods for computational analysis of DNA modifications visualized by immunostaining followed by confocal microscopy are described. Specifically, the generation of 2.5 dimension (2.5D) signal intensity plots, signal intensity profiles, quantification of staining intensity in multiple cells and determination of signal colocalization coefficients are shown. Collectively, these techniques may be operational in evaluating the levels and localization of these DNA modifications in the nucleus, contributing to elucidating their biological roles in metazoans.


Potential HIV transmission risk among spouses: marriage intention and expected extramarital male-to-male sex among single men who have sex with men in Hunan, China.
The HIV epidemic in China is shifting from the high-risk groups of men who have sex with men (MSM), injection drug users and sex workers to the general population, and sexual contact among spouses is assumed to be one route of transmission. Our objective was to determine the intention to marry and the expected extramarital male-to-male sex among single Chinese MSM, in order to estimate the potential HIV transmission risk among MSM living with HIV and their female spouses. We conducted a web-based, cross-sectional survey between May 2016 and May 2017. A questionnaire covering sociodemographic characteristics, sexual behaviours, HIV-related and homosexuality-related stigma, marriage intention, and expected extramarital sexual behaviours was completed by 556 single MSM in Hunan, China. Descriptive statistics, χ2 test, two-sample t-test and multivariate logistic regression analysis were performed. Currently 48.9% of the participants intended to marry a woman in their lifetime, and 91% of them reported that they would continue to have sex with men after getting married. Those who were living with parents (OR=2.26), self-identified as bisexual (OR=2.57), had at least one heterosexual partner in the previous 6 months (OR=0.33) and perceived a higher level of self-homosexual stigma (OR=1.78) had greater intention to marry a woman. Nearly half of Chinese MSM intend to marry women, which has significantly dropped from the estimated percentage more than 10 years ago for Chinese MSM. However, the expectation of extramarital homosexual behaviours was common in these men. Sexual and gender minority stresses especially from family members, homosexual identity assertiveness and related stigma were the main factors for marriage intention, which should be addressed in future studies and practices.


Biochemical properties of ricin in immature castor seed.
The biochemical properties of ricin at different stages of seed i.e. from immature to mature seed were studied. Hemagglutination, SDS-PAGE and UV-spectrometry studies showed total absence of RCA protein in the immature seed. Interestingly, ricin extract on SDS-PAGE showed only one protein band with a molecular weight of 29,000 dalton corresponding to the molecular weight of A chain of ricin. Our results have shown that at immature seed level only the toxic moiety of ricin (A chain) is being synthesized first and gradually the RCA and B chain of ricin.


The Nicolas Andry Award-1995. Fracture healing. Radiation induced alterations.
This study investigated the effects of radiation on fractures in a rat femur model. Two different radiation dosage fractionation schemes (1100 rads given in one dose and 2500 rads given in 10 divided doses over 12 days) and three different times of initiation of radiation (1 day before fracture, 3 or 10 days after fracture) were studied. Fractures exposed to these levels of radiation all appeared to heal during the course of this experiment, although with varying degrees of delay, with the exception of those exposed to a single dose of 1100 rads 3 days after fracture. These animals remained at a more immature level of repair histologically compared with the control group, throughout the entire time evaluated. The strength of the final repair remained less than the control for all the groups receiving treatment. These results may offer some explanation for the clinical observations of an increased incidence of delayed union and nonunion of fractures, an increased incidence of fracture and refracture in irradiated bone, and an increased incidence of fracture and nonunion in constructs using radiation in conjunction with allogeneic bone. Furthermore, the observed effects were generally no different in the animals treated with the two clinically relevant dose fractionation schemes chosen for this study.


WSES/GAIS/WSIS/SIS-E/AAST global clinical pathways for patients with skin and soft tissue infections.
Skin and soft-tissue infections (SSTIs) encompass a variety of pathological conditions that involve the skin and underlying subcutaneous tissue, fascia, or muscle, ranging from simple superficial infections to severe necrotizing infections.Together, the World Society of Emergency Surgery, the Global Alliance for Infections in Surgery, the Surgical Infection Society-Europe, The World Surgical Infection Society, and the American Association for the Surgery of Trauma have jointly completed an international multi-society document to promote global standards of care in SSTIs guiding clinicians by describing reasonable approaches to the management of SSTIs.An extensive non-systematic review was conducted using the PubMed and MEDLINE databases, limited to the English language. The resulting evidence was shared by an international task force with different clinical backgrounds.


Aberrations of a cell adhesion molecule CADM4 in renal clear cell carcinoma.
Renal clear cell carcinoma (RCCC) is the most frequent subpopulation of renal cell carcinoma and is derived from the proximal uriniferous tubules. We have previously reported that an actin-binding protein, 4.1B/DAL-1, is expressed in renal proximal tubules, whereas it is inactivated in 45% of RCCC by promoter methylation. In the lung and several epithelial tissues, 4.1B is shown to associate with a tumor suppressor protein, CADM1, belonging to the immunoglobulin-superfamily cell adhesion molecules. Here, we demonstrate by immunohistochemistry that another member of the CADM-family protein, CADM4, as well as 4.1B is expressed specifically in human proximal tubules, while CADM1 and 4.1N, another member of the 4.1 proteins, are expressed in the distal tubules. Immunoprecipitation analysis coupled with Western blotting revealed that CADM4 associated with 4.1B, while CADM1 associated with 4.1N in the lysate from normal human kidney, implicating that a cascade of CADM4 and 4.1B plays an important role in normal cell adhesion of the proximal tubules. On the other hand, CADM4 expression was lost or markedly reduced in 7 of 10 (70%) RCC cell lines and 28 of 40 (70%) surgically resected RCCC, including 10 of 16 (63%) tumors with T1a. CADM4 expression was more preferentially lost in RCCC with vascular infiltration (p = 0.04), suggesting that loss of CADM4 is involved in tumor invasion. Finally, introduction of CADM4 into an RCC cell line, 786-O, dramatically suppressed tumor formation in nude mice. These findings suggest that CADM4 is a novel tumor suppressor candidate in RCCC acting with its binding partner 4.1B.


Outcome of super-responders to cardiac resynchronization therapy defined by endpoint-derived parameters of left ventricular remodeling: a two-center retrospective study.
Various studies have attempted to identify super-responders to cardiac resynchronization therapy (CRT) by echocardiographic parameters of reverse remodeling. However, scientific evidence regarding those parameters is scarce. This study aimed at validating the definition of super-response to CRT based on the following frequently employed echocardiographic parameters: left ventricular ejection fraction (LVEF), end-diastolic volume index (EDVI), and end-systolic volume index (ESVI). We retrospectively investigated echocardiographic data and outcomes of 542 patients after CRT implantation. The primary endpoint comprised all-cause mortality, heart transplantation, ventricular assist device implantation (VAD), and hospitalization for heart failure. Secondary endpoints were hospitalization for heart failure, and the combination of all-cause mortality, heart transplantation and VAD. Two approaches were employed defining super-response based on improvement of echocardiographic parameters: one derived from the negative predictive value (NPV) for clinical endpoints, and second from best quartiles of improvement. Using the NPV method, an absolute 25 % increase in LVEF, a relative 38 % reduction in EDVI, and 46 % in ESVI were calculated as optimal cut-offs identifying 4.9, 18.5, and 21.3 % as super-responders. The best quartiles method resulted in lower cut-off values, i.e. 14 % increase in LVEF, 26 % reduction in EDVI, and 36 % in ESVI. All cut-offs except LVEF ≥ 25% were significantly associated with improved outcomes after 5 years (median follow-up 35.7 months). NPV- and best quartile-based cut-offs validate previously applied empirical echocardiographic cut-offs to define super-response to CRT. These data provide evidence for using these empirical cut-offs in daily practice and facilitate inter-study comparability.


Symbiont physiology and population dynamics before and during symbiont shifts in a flexible algal-cnidarian symbiosis.
For cnidarians that can undergo shifts in algal symbiont relative abundance, the underlying algal physiological changes that accompany these shifts are not well known. The sea anemone Anthopleura elegantissima associates with the dinoflagellate Symbiodinium muscatinei and the chlorophyte Elliptochloris marina, symbionts with very different tolerances to light and temperature. We compared the performance of these symbionts in anemones maintained in an 8-11.5 month outdoor common garden experiment with simulated intertidal conditions and three levels of shading (2, 43, and 85% ambient irradiance). Symbiont densities, mitotic indices, photophysiology and pigments were assessed at three time points during the summer, a period of high irradiance and solar heating during aerial exposure. Whereas S. muscatinei was either neutrally or positively affected by higher irradiance treatments, E. marina responded mostly negatively to high irradiance. E. marina in the 85% irradiance treatment exhibited significantly reduced Pmax and chlorophyll early in the summer, but it was not until nearly 3 months later that a shift in symbiont relative abundance toward S. muscatinei occurred, coincident with bleaching. Symbiont densities and proportions remained largely stable in all other treatments over time, and displacement of S. muscatinei by E. marina was not observed in the 2% irradiance treatment despite the potentially better performance of E. marina. While our results support the view that rapid changes in symbiont relative abundance are typically associated with symbiont physiological dysfunction and bleaching, they also show that significant temporal lags may occur between the onset of symbiont stress and shifts in symbiont relative abundances.


The utility of transition zone index in predicting acute urinary morbidity after 125I prostate brachytherapy.
Acute urinary morbidity after prostate brachytherapy is common and, although usually self-limited, can be distressing to the patient, especially if acute urinary retention (AUR) develops. We undertook to determine whether prospective measurement of the transition zone index would be predictive of either urinary retention or the severity of urinary symptoms after brachytherapy. One hundred men undergoing transperineal interstitial permanent prostate brachytherapy (TIPPB) with 125I underwent transrectal ultrasound before the procedure to measure prostate and transition zone (TZ) volumes. TZ index was calculated as TZ volume divided by total prostate volume. TIPPB was performed between July 2000 and January 2002. Patients were observed for 1, 3, or 6 months with an International Prostate Symptom Score (IPSS) at each visit. alpha-Blockers were prescribed prophylactically in all patients. Postimplant dosimetry was performed at 1 month by using CT/MRI fusion for all patients. The mean patient age was 65.1 years (range, 46-77 years). There were 59 T1c tumors and 41 T2a tumors. The Gleason score was 6 in 86% of patients, with 3% being Gleason 4 or 5 and 11% Gleason 7. The mean baseline IPSS was 7.4, with the mean at 1 month being 17.3; at 3 months, 14.4; and at 6 months, 11.3. Baseline IPSS was the only factor predictive of IPSS at 1 and 3 months after TIPPB. Neoadjuvant androgen deprivation was used for 26% of men for 2-6 months to reduce prostate size before the procedure. AUR developed in 17%. In univariate analysis, prior hormone therapy (p = 0.002), duration of hormone therapy (p = 0.005), TZ index (p = 0.014), number of seeds implanted (p = 0.016), T stage (p = 0.035), percentage of the prostate volume receiving at least the full prescribed dose (V100, p = 0.036), percentage of the prostate volume receiving > 200% of the prescribed dose (V200, p = 0.037), and prostate volume (p = 0.038) were all predictive of AUR. When the TZ index was divided into quartiles, the risk of AUR was 4%, 16%, 20%, and 28% (p = 0.032). However, in multivariate analysis, TZ index was no longer predictive of AUR. Baseline urinary function is the only factor predictive of symptom scores at 1 and 3 months after brachytherapy. TZ index, initial prostate volume, and use of neoadjuvant hormones are interrelated and are all predictive of AUR in univariate analysis, but in multivariate analysis, TZ index is not an independent prognostic factor.


miR‑203 contributes to IL‑17‑induced VEGF secretion by targeting SOCS3 in keratinocytes.
Interleukin (IL)-17 signaling serves an important role in the development and pathogenesis of psoriasis; a chronic skin disease characterized by increased dermal vascularity and the hyperproliferation of keratinocytes. microRNA (miR)‑203 is preferentially expressed in the skin and is an important regulator of keratinocyte differentiation. miR‑203 has been implicated in a number of skin diseases, including psoriasis. However, the role of miR‑203 in IL‑17‑induced vascular endothelial growth factor (VEGF) secretion has yet to be elucidated. The present study demonstrated that miR‑203 expression was upregulated in the ears of IL‑17‑stimulated mice and IL‑17‑treated HaCaT cells. In addition, the IL‑17‑induced increase in miR‑203 expression activated the Janus kinase/signal transducer and activator of transcription signaling pathway and promoted VEGF secretion in HaCaT cells. Furthermore, miR‑203 was observed to bind to the 3'‑untranslated region of suppressor of cytokine signaling 3 (SOCS3) and inhibited SOCS3 expression. The results suggest that miR‑203 expression may be upregulated by IL‑17 stimulation, and miR‑203 is a positive regulator of IL‑17‑induced VEGF secretion. The present study may support potential therapeutic strategies for the treatment of psoriasis.


Microcircuit failure in STXBP1 encephalopathy leads to hyperexcitability.
De novo mutations in STXBP1 are among the most prevalent causes of neurodevelopmental disorders and lead to haploinsufficiency, cortical hyperexcitability, epilepsy, and other symptoms in people with mutations. Given that Munc18-1, the protein encoded by STXBP1, is essential for excitatory and inhibitory synaptic transmission, it is currently not understood why mutations cause hyperexcitability. We find that overall inhibition in canonical feedforward microcircuits is defective in a P15-22 mouse model for Stxbp1 haploinsufficiency. Unexpectedly, we find that inhibitory synapses formed by parvalbumin-positive interneurons were largely unaffected. Instead, excitatory synapses fail to recruit inhibitory interneurons. Modeling confirms that defects in the recruitment of inhibitory neurons cause hyperexcitation. CX516, an ampakine that enhances excitatory synapses, restores interneuron recruitment and prevents hyperexcitability. These findings establish deficits in excitatory synapses in microcircuits as a key underlying mechanism for cortical hyperexcitability in a mouse model of Stxbp1 disorder and identify compounds enhancing excitation as a direction for therapy.


Transgenic tobacco (Nicotiana tabacum L.) plants with increased expression levels of mitochondrial NADP+-dependent isocitrate dehydrogenase: evidence implicating this enzyme in the redox activation of the alternative oxidase.
Many metabolic reactions are coupled to NADPH in the mitochondrial matrix, including those involved in thiol group reduction. One enzyme linked to such processes is mitochondrial NADP+-dependent isocitrate dehydrogenase (mtICDH; EC 184.108.40.206), although the precise role of this enzyme is not yet known. Previous work has implicated mtICDH as part of a biochemical mechanism to reductively activate the alternative oxidase (AOX). We have partially purified mtICDH from tobacco (Nicotiana tabacum L. cv. Petit Havana SR1) cell suspension cultures and localized this to a 46-kDa protein on SDS-PAGE, which was verified by peptide sequencing. In the inflorescence of the aroid Sauromatum guttatum Schott (voodoo lily), mtICDH appears to be developmentally regulated, presenting maximal specific activity during the thermogenic period of anthesis when the capacity for AOX respiration is also at its peak. Transgenic tobacco plants were generated that overexpress mtICDH and lines were obtained that demonstrated up to a 7-fold increase in mtICDH activity. In isolated mitochondria, this resulted in a measurable increase in the reductive activation of AOX in comparison with wild type. When examined in planta in response to citrate feeding, a strong conversion of AOX from its oxidized to its reduced form was observed in the transgenic line. These data support the hypothesis that mtICDH may be a regulatory switch involved in tricarboxylic acid cycle flux and the reductive modulation of AOX.


The Ascidia Ciona robusta Provides Novel Insights on the Evolution of the AP-1 Transcriptional Complex.
The Activator Protein-1 transcription factor family (AP-1) transcriptional complex is historically defined as an early response group of transcription factors formed by dimeric complexes of the Jun, Fos, Atf, and Maf bZIP proteins that control cell proliferation and differentiation by regulating gene expression. It has been greatly investigated in many model organisms across metazoan evolution. Nevertheless, its complexity and variability of action made its multiple functions difficult to be defined. Here, we place the foundations for understanding the complexity of AP-1 transcriptional members in tunicates. We investigated the gene members of this family in the ascidian Ciona robusta and identified single copies of Jun, Fos, Atf3, Atf2/7, and Maf bZIP-related factors that could have a role in the formation of the AP-1 complex. We highlight that mesenchyme is a common cellular population where all these factors are expressed during embryonic development, and that, moreover, Fos shows a wider pattern of expression including also notochord and neural cells. By ectopic expression in transgenic embryos of Jun and Fos genes alone or in combination, we investigated the phenotypic alterations induced by these factors and highlighted a degree of functional conservation of the AP-1 complex between Ciona and vertebrates. The lack of gene redundancy and the first pieces of evidence of conserved functions in the control of cell movements and structural organization exerted by these factors open the way for using Ciona as a helpful model system to uncover the multiple potentialities of this highly complex family of bZIP transcription factors.


Brain Connectivity Reflected in Electroencephalogram Coherence in Individuals With Autism: A Meta-Analysis.
Many theories have been proposed about the etiology of autism. One is related to brain connectivity in patients with autism. Several studies have reported brain connectivity changes in autism disease. This study was performed on Electroencephalogram (EEG) studies that evaluated patients with autism, using functional brain connectivity, and compared them with typically-developing individuals. Three scientific databases of ScienceDirect, Medline (PubMed), and BioMed Central were systematically searched through their online search engines. Comprehensive Meta-analysis software analyzed the obtained data. The systematic search led to 10 papers, in which EEG coherence was used to obtain the brain connectivity of people with autism. To determine the effect size, Cohen's d parameter was used. In the first meta-analysis, the study of the maximum effect size was considered, and all significant effect sizes were evaluated in the second meta-analysis. The effect size was assessed using a random-effects model in both meta-analyses. The results of the first meta-analysis indicated that heterogeneity was not present among the studies (Q=13.345, P>0.1). The evaluation of all effect sizes in the second meta-analysis showed a significant lack of homogeneity among the studies (Q=56.984, P=0.0001). On the whole, autism was found to be related to neural connectivity, and the present research showed the difference in the EEG coherence of people with autism and healthy people. These conclusions require further studies with more extensive data, considering different brain regions, and novel analysis techniques for assessing brain connectivity.


Novel males' capacity to disrupt early pregnancy in mice (Mus musculus) is attenuated via a chronic reduction of males' urinary 17beta-estradiol.
Mature male mice of proven fertility were administered chronic oral doses of anastrozole, a potent aromatase inhibitor, and also given a low-phytoestrogen diet. Urine was taken non-invasively from such males and from untreated control males and assayed for 17beta-estradiol and testosterone via ELISA procedures. After 8 weeks of drug or vehicle administration, urinary 17beta-estradiol declined to significantly lower levels in anastrozole-treated males than in non-treated males, whereas testosterone levels were comparable in the two groups. Inseminated females were exposed to drug-treated, vehicle-treated, or no males during days 1-6 of gestation, around intrauterine implantation of fertilized ova. Females exposed to vehicle-treated males produced fewer litters than did those kept in isolation. Females exposed to anastrozole-treated males produced significantly more litters than did those exposed to vehicle-treated males. These data support the notion that male excretions of estrogens may in part mediate novel-male-induced pregnancy disruptions, although other influences of aromatization on behaviour and metabolism remain possibilities.


High voltage pulsed current stimulation of the sciatic nerve in rats: analysis by the SFI.
To analyze the efficiency of high voltage pulsed current (HVPC) with early application in three different sites, in the regeneration of the sciatic nerve in rats submitted to crush injury, the sciatic functional index (SFI) was used to assess the functional recovery. After crushing of the nerve, 57 animals were submitted to cathodal HVPC at frequency of 50Hz and voltage of 100V, 20 minutes per day, 5 days per week. The rats were divided into five groups: control group; ganglion group; ganglion + muscle group; muscle group; and sham group. The SFI was determined weekly for seven weeks, from the preoperative period to the 6(th) postoperative week. Compared with the control group, the results showed a significantly better performance of group 2 for the first 3 weeks; group 3 showed significantly better performance in the third week; and group 4 showed a significantly negative performance during the 4(th) and 6(th) weeks. Early application of HVPC had a positive effect in the treatment of the spinal cord region and the sciatic nerve root ganglion with a dispersive electrode on the contralateral lumbar region or on the gastrocnemius. However, HVPC had a negative effect in the treatment with an active electrode on the gastrocnemius and a dispersive electrode on the contralateral thigh. Level of evidence II, Prospective comparative study.


Glycation free adduct accumulation in renal disease: the new AGE.
Glycation adducts formed in the later stages of protein glycation reactions, advanced glycation endproducts (AGEs), are a class of uraemic toxin. Protein glycation was viewed originally as a post-translational modification that accumulated mostly on extracellular proteins. We now know that AGE residues are also formed on short-lived cellular and extracellular proteins. Cellular proteolysis forms AGE free adducts from these proteins, which are released into plasma for urinary excretion. AGE free adducts are also absorbed from food. AGE free adducts are the major molecular form by which AGEs are excreted in urine. They normally have high renal clearance, but this declines markedly in chronic renal failure patients, leading to profound increases in plasma AGE free adducts. Accumulation of plasma AGE free adducts is increased further in end stage renal disease patients on peritoneal dialysis and haemodialysis by increased AGE formation. The impact of AGEs absorbed from food is probably most marked for undialysed patients with mild uraemia. The toxicity of AGEs has been associated with resistance of the extracellular matrix to proteolysis and AGE receptor-mediated responses. AGE free adducts may also contribute to vascular disease in uraemia. They represent an important new age for glycation research in nephrology.


Young children's food brand knowledge. Early development and associations with television viewing and parent's diet.
Brand knowledge is a prerequisite of children's requests and choices for branded foods. We explored the development of young children's brand knowledge of foods highly advertised on television - both healthy and less healthy. Participants were 172 children aged 3-5 years in diverse socio-economic settings, from two jurisdictions on the island of Ireland with different regulatory environments. Results indicated that food brand knowledge (i) did not differ across jurisdictions; (ii) increased significantly between 3 and 4 years; and (iii) children had significantly greater knowledge of unhealthy food brands, compared with similarly advertised healthy brands. In addition, (iv) children's healthy food brand knowledge was not related to their television viewing, their mother's education, or parent or child eating. However, (v) unhealthy brand knowledge was significantly related to all these factors, although only parent eating and children's age were independent predictors. Findings indicate that effects of food marketing for unhealthy foods take place through routes other than television advertising alone, and are present before pre-schoolers develop the concept of healthy eating. Implications are that marketing restrictions of unhealthy foods should extend beyond television advertising; and that family-focused obesity prevention programmes should begin before children are 3 years of age.


[The current concepts of the effect of cardiac glycosides on sinus node function and atrioventricular conductivity].
The clinical aspects of the influence of cardiac glycosides on the sinus node and atrioventricular junction in health and dysfunction are reviewed. It has been shown that digitalis drugs do not produce any effect on sinus node automatism including that in dysfunction. Cardiac glycosides suppress enhanced atrioventricular conduction and do not affect it provided it remains within normal. The mechanisms by which cardiac glycosides may act are discussed: extracardiac, cholinomimetic (in the acute test and direct one) and influencing heart conduction components (when used continuously).


Improving the survival of human CNS precursor-derived neurons after transplantation.
We have examined the effects of predifferentiation and energy substrate deprivation on long-term expanded human neural precursor cells (HNPCs). The pre-differentiation of HNPC cultures produced large numbers of neurons (>60%) and mature glial cells capable of generating glycogen stores that protected the neuronal population from experimental metabolic stress. When predifferentiated HNPCs were transplanted into intact adult rat hippocampus, fewer cells survived compared to undifferentiated HNPC transplants. This cell death was completely attenuated, however, when predifferentiated HNPC cultures were pretreated to boost glial energy stores and resulted in greatly increased neuronal survival in vivo. The transplanted cells primarily engrafted within the granular layer of the dentate gyrus, where a large proportion of the predifferentiated HNPCs co-expressed neuronal markers whereas most HNPCs outside of the neuronal layer did not, indicating that the predifferentiated cells remained capable of responding to local cues in the adult brain. Undifferentiated HNPCs migrated more widely in the brain after grafting than did the predifferentiated cells, which generally remained within the hippocampus.


A Small-Molecule Inhibitor of Lin28.
New discoveries in RNA biology underscore a need for chemical tools to clarify their roles in pathophysiological mechanisms. In certain cancers, synthesis of the let-7 microRNA tumor suppressor is blocked by an RNA binding protein (RBP) Lin28, which docks onto a conserved sequence in let-7 precursor RNA molecules and prevents their maturation. Thus, the Lin28/let-7 interaction might be an attractive drug target, if not for the well-known difficulty in targeting RNA-protein interactions with drugs. Here, we describe a protein/RNA FRET assay using a GFP-Lin28 donor and a black-hole quencher (BHQ)-labeled let-7 acceptor, a fluorescent protein/quencher combination which is rarely used in screening despite favorable spectral properties. We tested 16 000 molecules and identified N-methyl-N-[3-(3-methyl[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide, which blocked the Lin28/let-7 interaction, rescued let-7 processing and function in Lin28-expressing cancer cells, induced differentiation of mouse embryonic stem cells, and reduced tumor-sphere formation by 22Rv1 and Huh7 cells. A biotinylated derivative captured Lin28 from cell lysates consistent with an on-target mechanism in cells, though the compound also showed some activity against bromodomains in selectivity assays. The Lin28/let-7 axis is presently of high interest not only for its role as a bistable switch in stem-cell biology but also because of its prominent roles in numerous diseases. We anticipate that much can be learned from the use of this first reported small molecule antagonist of Lin28, including the potential of the Lin28/let-7 interaction as a new drug target for selected cancers. Furthermore, this approach to assay development may be used to identify antagonists of other RBP/RNA interactions suspected to be operative in pathophysiological mechanisms.


The Shepard-Risset glissando: music that moves you.
Sounds are thought to contribute to the perceptions of self-motion, often via higher-level, cognitive mechanisms. This study examined whether illusory self-motion (i.e. vection) could be induced by auditory metaphorical motion stimulation (without providing any spatialized or low-level sensory information consistent with self-motion). Five different types of auditory stimuli were presented in mono to our 20 blindfolded, stationary participants (via a loud speaker array): (1) an ascending Shepard-Risset glissando; (2) a descending Shepard-Risset glissando; (3) a combined Shepard-Risset glissando; (4) a combined-adjusted (loudness-controlled) Shepard-Risset glissando; and (5) a white-noise control stimulus. We found that auditory vection was consistently induced by all four Shepard-Risset glissandi compared to the white-noise control. This metaphorical auditory vection appeared similar in strength to the vection induced by the visual reference stimulus simulating vertical self-motion. Replicating past visual vection findings, we also found that individual differences in postural instability appeared to significantly predict auditory vection strength ratings. These findings are consistent with the notion that auditory contributions to self-motion perception may be predominantly due to higher-level cognitive factors.


Sources of DPOAEs revealed by suppression experiments, inverse fast Fourier transforms, and SFOAEs in impaired ears.
DPOAE sources are modeled by intermodulation distortion generated near the f2 place and a reflection of this distortion near the DP place. In a previous paper, inverse fast Fourier transforms (IFFTs) of DPOAE filter functions in normal ears were consistent with this model [Konrad-Martin et al., J. Acoust. Soc. Am. 109, 2862-2879 (2001)]. In the present article, similar measurements were made in ears with specific hearing-loss configurations. It was hypothesized that hearing loss at f2 or DP frequencies would influence the relative contributions to the DPOAE from the corresponding basilar membrane places, and would affect the relative magnitudes of SFOAEs at frequencies equal to f2 and fDP. DPOAEs were measured with f2 = 4 kHz, f1 varied, and a suppressor near fDP. L2 was 25-55 dB SPL (L1 = L2 + 10 dB). SFOAEs were measured at f2 and at 2.7 kHz (the average fDP produced by the f1 sweep) for stimulus levels of 20-60 dB SPL. SFOAE results supported predictions of the pattern of amplitude differences between SFOAEs at 4 and 2.7 kHz for sloping losses, but did not support predictions for the rising- and flat-loss categories. Unsuppressed IFFTs for rising losses typically had one peak. IFFTs for flat or sloping losses typically have two or more peaks; later peaks were more prominent in ears with sloping losses compared to normal ears. Specific predictions were unambiguously supported by the results for only four of ten cases, and were generally supported in two additional cases. Therefore, the relative contributions of the two DPOAE sources often were abnormal in impaired ears, but not always in the predicted manner.


Sensitization profiles of Malaysian and Singaporean subjects to allergens from Dermatophagoides pteronyssinus and Blomia tropicalis.
The house dust mites Dermatophagoides pteronyssinus (Der p) and Blomia tropicalis (Blo t) are the most common house dust mite species in Southeast Asia. To date, there have only been a few studies on the sensitization profile of the general populations in Southeast Asia to house dust mites. The aim of this study was to determine the profiles of Der p and Blo t sensitization among Singaporean and Malaysian subjects. Enzyme-linked immunosorbent assay was used to detect specific IgE to Der p and Blo t mite crude extracts as well as purified Der p 1, Der p 2 and Blo t 5 allergens. Sera used were from 229 Singaporean subjects (124 with rhinitis, 105 without rhinitis) and 143 Malaysian subjects (94 adults and 49 children with asthma). The sensitization profile of rhinitis subjects to the dust mite allergens used in this study was as follows: Blo t extract positive: 91/124 (73%); Blo t 5 positive: 62/124 (50%); Der p extract positive: 61/124 (49%); Der p 1 positive: 53/124 (43%); Der p 2 positive: 45/124 (36%). The nonrhinitis subjects' sensitization profile was as follows: Blo t extract positive: 60/105 (57%); Blo t 5 positive: 24/105 (23%); Der p extract positive: 38/105 (36%); Der p 1 positive: 14/105 (13%); Der p 2 positive: 17/105 (16%). The study of Malaysian asthmatic adults showed that 39% of them were sensitized to Der p 1, 32% to Der p 2 and 37% to Blo t 5. Among the asthmatic children, sensitization to Blo t 5, Der p 1 and Der p 2 was 90, 57 and 39%, respectively. This study clearly revealed that dual sensitization to B. tropicalis and D. pteronyssinus is common in the general populations of Singapore and Malaysia. Sensitization to Blo t 5 is more prevalent than to Der p 1 and Der p 2.


Cytokine regulation of tumor necrosis factor-alpha and -beta (lymphotoxin)-messenger RNA expression in human peripheral blood mononuclear cells.
The immune response at the molecular level is characterized by a carefully coordinated interplay of both cytokine production and receptor induction. The regulation of these molecules including the closely related tumor necrosis factors alpha (TNF) and beta (lymphotoxin, LT) is still incompletely understood. We have examined the effects of various cytokines on the expression of TNF and LT mRNA in human peripheral blood mononuclear cells (PBMC). Northern blot analysis with total cellular RNA from mixed populations of PBMC revealed that genes coding for TNF and LT were not spontaneously expressed. Treatment of PBMC with recombinant interleukin (IL)-2 resulted in a high level expression of TNF and LT mRNA. Whereas IL-1 beta was equally effective as IL-2 in inducing both TNF and LT mRNA, granulocyte-macrophage colony-stimulating factor selectively induced only TNF mRNA. Both TNF and LT mRNA were minimally induced by IL-1 alpha, IL-3, interferon (IFN)-alpha, or IFN-gamma. Similarly TNF alone had little effect on induction of TNF and LT mRNA. In conjunction with IL-2, cytokines such as IFN-alpha, IFN-gamma, or TNF did not interfere with IL-2 induction of TNF and LT mRNA. Interestingly, IL-4 in combination with IL-2 inhibited the IL-2-driven induction of TNF and LT mRNA. This inhibitory effect of IL-4 was also observed at the level of TNF and LT protein secretion. Furthermore, IL-4 was also inhibitory of IL-2-mediated induction of Tac mRNA in PBMC. These results extend the interrelationship of cytokine regulation of TNF and LT expression. In particular, they reveal the previously unrecognized function of IL-4 in antagonizing the IL-2 induction of TNF, LT, and Tac mRNA in PBMC.


Views of the chairs of Scottish health boards on engagement with quality management and comparisons with English trusts.
To describe the views of the chairs of Scottish health boards on the engagement of their boards with healthcare quality and to compare them with the views of the chairs of boards of English acute trusts. The focus of the Scottish Health Boards is on providing and commissioning care, while in England the acute trusts only provide care. We mailed a questionnaire, based on one used in England, to the 14 health board chairs in NHS Scotland in January 2011. The results were compared with the results of a similar questionnaire given to English acute trust chairs in 2009. Most chairs in Scotland (67%) prioritised oversight of quality. Quality is considered at most Board meetings (92%), taking over 20% of time for 69% of chairs. Most boards have local quality targets and feedback quality data to staff. Compared with England, boards in Scotland meet less frequently and focus less on quality (shorter discussions, less frequent data review, fewer local targets) but they are more optimistic about their board's performance. Although most chairs of Scottish boards view quality as a priority, they pay less attention to it than chairs in England, possibly due to their additional role in commissioning care.


Retinal and Choroidal Vascular Changes in Eyes with Pseudoexfoliation Syndrome: A Comparative Study Using Optical Coherence Tomography Angiography
Optical coherence tomography angiography allows a detailed evaluation of retinal and choroidal microvascular structures without the need for a contrast agent. Pseudoexfoliation syndrome is a condition that leads to anatomical and functional losses due to accumulation of degraded abnormal fibrillar material in the intraocular and extraocular tissues. Histopathological studies have shown that the accumulation of Pseudoexfoliation syndrome material in the vascular structures may play a role in different ocular pathologies such as retinal vein occlusion, iris hypoperfusion, anterior segment hypoxia, retinal arterial occlusion, and neovascular glaucoma. To evaluate and compare flow and vascular density in the retina and choroid in eyes with Pseudoexfoliation syndrome, fellow eyes without Pseudoexfoliation syndrome, and healthy eyes using optical coherence tomography angiography. Case control study. The study included 35 eyes with Pseudoexfoliation syndrome of 35 Pseudoexfoliation syndrome patients, 32 fellow eyes without Pseudoexfoliation syndrome of 32 unilateral Pseudoexfoliation syndrome patients, and 35 eyes of healthy control subjects. Flow area and vascular density in the superficial capillary plexus and deep capillary plexus were measured by optical coherence tomography angiography as three separate parameters: total, parafoveal, and foveal. Choroidal thickness and foveal avascular zone area were measured for each patient. There were significant differences between the Pseudoexfoliation syndrome eyes and control eyes in total, parafoveal, and foveal flow and vascular density in the superficial capillary plexus (p<0.05 for all), while there were no significant differences between these groups in any of the flow or vascular density values in the deep capillary plexus (p>0.05). None of the superficial capillary plexus and deep capillary plexus flow and vascular density values showed significant differences between Pseudoexfoliation syndrome eyes and non-Pseudoexfoliation syndrome fellow eyes or between the non-Pseudoexfoliation syndrome fellow eyes and control eyes (p>0.05). Choroidal thickness was significantly lower in Pseudoexfoliation syndrome eyes compared to control eyes. Foveal avascular zone area was significantly enlarged in Pseudoexfoliation syndrome eyes compared to control eyes in both the superficial and deep layers (p<0.05). Pseudoexfoliation syndrome eyes exhibit significant damage to the retinal and choroidal vascular structures.


Evolution of the human brain: changing brain size and the fossil record.
Although the study of the human brain is a rapidly developing and expanding science, we must take pause to examine the historical and evolutionary events that helped shape the brain of Homo sapiens. From an examination of the human lineage to a discussion of evolutionary principles, we describe the basic principles and theories behind the evolution of the human brain. Specifically, we examine several theories concerning changes in overall brain size during hominid evolution and relate them to the fossil record. This overview is intended to provide a broad understanding of some of the controversial issues that are currently being debated in the multidisciplinary field of brain evolution research.


Measuring empathy in a group of South African undergraduate medical students using the student version of the Jefferson Scale of Empathy.
Patient-centred care is a model of care that demands healthcare providers change their focus from the disease to the patient and his or her perceived physical and psycho-social needs. This model requires healthcare workers to listen actively and to have effective communication skills and well-developed levels of empathy. The aim of this study was to determine the suitability of the Jefferson Scale for Empathy (JSE-S) as a valid test for empathy in third-year medical students at a South African university and also to determine the baseline level of empathy in this same group of students. The study took place at a medical school in the Western Cape, South Africa. This medical degree (MB ChB) is a 6-year programme. Students are first exposed to patients within their second year of training, but it is during their third-year that they start their clinical rotations. We wanted to test whether our empathy training would give students the necessary skills and enable them to establish good empathic communication habits in order to prevent a fall in empathy during this vulnerable period. This article explores the suitability of the student version of the JSE-S as a valid test for empathy, within the South African medical school context. We briefly discuss the psychometrics and the scores against what is already known in countries like ours, specifically, developing nations where cultural and language differences exist in the student populations. Furthermore, we explore whether the JSE-S is a valid scale for pre- and post-intervention measurement of medical student empathy within our context and discuss the limitations of self-assessment. We also report on baseline levels of empathy in third-year medical students. Two hundred and six third-year medical students (69% females) completed the JSE-S prior to the intervention. Females and students aged 25 years and older had significantly higher scores than males and those 22 years old or less. The mean JSE was 109.98 (SD = 12.54), which is lower than most internationally reported scores. The Cronbach's alpha coefficient was 0.81, indicating scale reliability and consistency, but graded item response testing highlighted variance in three reverse-scored questions. The JSE-S is an appropriate and valid scale for measuring levels of empathy in undergraduate medical students in South Africa. However, language may need to be clarified in the negatively phrased items.


Recurrence rate of ABO hemolytic disease of the newborn.
ABO hemolytic disease of the newborn is a common and potentially severe disease. It can cause hyperbilirubinemia and anemia in the infant. A review of 230 primigravid mothers of affected offspring is presented. Evaluation of their subsequent pregnancies showed a recurrence rate of 88% in those infants at risk for the disease (of same blood type as their index sibling), with 62% of the affected infants requiring therapy. Guidelines for antenatal counseling are presented.


Targeting the Orexin System for Prescription Opioid Use Disorder.
Prescription opioids are potent analgesics that are used for clinical pain management. However, the nonmedical use of these medications has emerged as a major concern because of dramatic increases in abuse and overdose. Therefore, effective strategies to prevent prescription opioid use disorder are urgently needed. The orexin system has been implicated in the regulation of motivation, arousal, and stress, making this system a promising target for the treatment of substance use disorder. This review discusses recent preclinical studies that suggest that orexin receptor blockade could be beneficial for the treatment of prescription opioid use disorder.