Facial nerve monitoring during parotidectomy: a systematic review and meta-analysis.
To determine the effectiveness of intraoperative facial nerve monitoring (FNM) in preventing immediate and permanent postoperative facial nerve weakness in patients undergoing primary parotidectomy. PubMed-NCBI database from 1970 to 2014. A systematic review and meta-analysis of the literature was conducted. Acceptable studies included controlled series that evaluated facial nerve function following primary parotidectomy with or without FNM (intraoperative nerve monitor vs control). Primary and secondary end points were defined as immediate postoperative and permanent facial nerve weakness (House-Brackmann score, ≥2), respectively. After a review of 1414 potential publications, 7 articles met inclusion criteria, with a total of 546 patients included in the final meta-analysis. The incidence of immediate postoperative weakness following parotidectomy was significantly lower in the FNM group compared to the unmonitored group (22.5% vs 34.9%; P = .001). The incidence of permanent weakness was not statistically different in the long term (3.9% vs 7.1%; P = .18). The number of monitored cases needed to prevent 1 incidence of immediate postoperative facial nerve weakness was 9, given an absolute risk reduction of 11.7% This corresponded to a 47% decrease in the incidence of immediate facial nerve dysfunction (odds ratio, 0.53; 95% CI, 0.35 to 0.79; P = .002). In primary cases of parotidectomy, intraoperative FNM decreases the risk of immediate postoperative facial nerve weakness but does not appear to influence the final outcome of permanent facial nerve weakness.


Requirements for medical modeling languages.
The development of tailor-made domain-specific modeling languages is sometimes desirable in medical informatics. Naturally, the development of such languages should be guided. The purpose of this article is to introduce a set of requirements for such languages and show their application in analyzing and comparing existing modeling languages. The requirements arise from the practical experience of the authors and others in the development of modeling languages in both general informatics and medical informatics. The requirements initially emerged from the analysis of information modeling techniques. The requirements are designed to be orthogonal, i.e., one requirement can be violated without violation of the others. The proposed requirements for any modeling language are that it be "formal" with regard to syntax and semantics, "conceptual," "expressive," "comprehensible," "suitable," and "executable." The requirements are illustrated using both the medical logic modules of the Arden Syntax as a running example and selected examples from other modeling languages. Activity diagrams of the Unified Modeling Language, task structures for work flows, and Petri nets are discussed with regard to the list of requirements, and various tradeoffs are thus made explicit. It is concluded that this set of requirements has the potential to play a vital role in both the evaluation of existing domain-specific languages and the development of new ones.


Dissociable effects of anterior and mediodorsal thalamic lesions on spatial goal-directed behavior.
Goal-directed behaviors are thought to be supported by a neural circuit encompassing the prefrontal cortex, the dorsomedial striatum, the amygdala, and, as more recently suggested, the limbic thalamus. Since evidence indicates that the various thalamic nuclei contribute to dissociable functions, we directly compared the functional contribution of the mediodorsal thalamus (MD) and of the anterior thalamic nuclei (ATN) in a new task assessing spatial goal-directed behavior in a cross-maze. Rats sustaining lesions of the mediodorsal or the anterior thalamus were trained to associate each of the two goal arms with a distinctive food reward. Unlike control rats, both lesioned groups failed to express a bias for the goal arm corresponding to the non-devalued outcome following devaluation by sensory-specific satiety. In addition, MD rats were slower than the other groups to complete the trials. When tested for spatial working memory using a standard non-matching-to-place procedure in the same apparatus, ATN rats were severely impaired but MD rats performed as well as controls, even when spatial or temporal challenges were introduced. Finally, all groups displayed comparable breaking points in a progressive ratio test, indicating that the slower choice performance of MD rats did not result from motivational factors. Thus, a spatial task requiring the integration of instrumental and Pavlovian contingencies reveals a fundamental deficit of MD rats in adapting their choice according to goal value. By contrast, the deficit associated with anterior thalamic lesions appears to simply reflect the inability to process spatial information.


Basic aspects of and recent developments in telepathology in Europe, with specific emphasis on quality assurance.
Telepathology is the diagnostic work of a pathologist from a distance and includes all specific fields of diagnostic pathology, such as frozen section services, expert consultation, cytometric and histometric measurement, and continuous education. For about 15 years experience has been collected at several universities in the United States and Europe based upon analog telephone lines (9.2 kbaud), digitized lines (ISDN, 64 kbaud), broad band connections (1.5 Mbaud) and the World Wide Web (28 kbaud). Potential use can be expected in the application of telepresentation, remote slide preparation, remote central diagnostics and telediscussion. The transfer of still images is well developed; that of live images is used in only a few institutions for frozen section services. The image quality and spatial resolution as well as the transfer speed are sufficient for expert consultations, morphometric measurements, quality assurance and education. All applications focus on discontinuous work flow. Although the European Community focuses on user needs and standardization aspects of telepathology by sponsoring a widespread telepathology project (Europath), implementation of telepathology into routine application in the continuous work flow has still to be developed. The technical equipment has still to be adjusted to the labor flow charts in routine pathologic diagnostic procedures. Telepathology seems to be the appropriate technique to offer both improvement in diagnostic quality and inclusion of the "control institution" into diagnostic responsibility.


Enhancement and regulation of extracellular protein production by Bacillus brevis 47 through manipulation of cell culture conditions.
Bacillus brevis 47 was cultivated in 2 liter fermentors in semidefined media containing polypeptone with or without glucose or fructose. Neither sugar was essential for growth or extracellular (S-layer) protein production, and 2.5 to 3.0 g/L protein was accumulated in the medium. When present, glucose was used very slowly, however, fructose was used much more quickly. Dramatic changes in metabolic indicators (dissolved oxygen and pH) were seen when fructose became depleted, and protease was produced, decreasing the amount of protein ultimatelv accumulated in the medium. Using the change in dissolved oxygen as a marker for the time of addition, polypeptone, fructose, or both were used to stimulate protein production. With the addition of polypeptone, on stimulation was achieved, but protease production was suppressed. Addition of fructose did result in a small stimulation of protein production (to 5 g/L) if added once. Further additions resulted in more growth, but no increase in protein production. Various combinations of polypeptone and fructose were also used, with the most effective combination (fructose added early, fructose and polypeptone added later) resulting in an accumulation of 15 g/L protein in the medium. This is comparable to that seen when B. brevis 47 is grown in a complex glucose medium and stimulated with polypeptone addition at 21 hours. These results are discussed with respect to the structure and function of S-layer proteins, as well as the use of this organism for the production of heterologous proteins.


Proteomic analysis of secreted proteins in early rheumatoid arthritis: anti-citrulline autoreactivity is associated with up regulation of proinflammatory cytokines.
To identify peripheral blood autoantibody and cytokine profiles that characterise clinically relevant subgroups of patients with early rheumatoid arthritis using arthritis antigen microarrays and a multiplex cytokine assay. Serum samples from 56 patients with a diagnosis of rheumatoid arthritis of <6 months' duration were tested. Cytokine profiles were also determined in samples from patients with psoriatic arthritis (PsA) and ankylosing spondylitis (n = 21), and from healthy individuals (n = 19). Data were analysed using Kruskal-Wallis test with Dunn's adjustment for multiple comparisons, linear correlation tests, significance analysis of microarrays (SAM) and hierarchical clustering software. Distinct antibody profiles were associated with subgroups of patients who exhibited high serum levels of tumour necrosis factor (TNF)alpha, interleukin (IL)1beta, IL6, IL13, IL15 and granulocyte macrophage colony-stimulating factor. Significantly increased autoantibody reactivity against citrullinated epitopes was observed in patients within the cytokine "high" subgroup. Increased levels of TNFalpha, IL1alpha, IL12p40 and IL13, and the chemokines eotaxin/CCL11, monocyte chemoattractant protein-1 and interferon-inducible protein 10, were present in early rheumatoid arthritis as compared with controls (p<0.001). Chemokines showed some of the most impressive differences. Only IL8/CXCL8 concentrations were higher in patients with PsA/ankylosing spondylitis (p = 0.02). Increased blood levels of proinflammatory cytokines are associated with autoantibody targeting of citrullinated antigens and surrogate markers of disease activity in patients with early rheumatoid arthritis. Proteomic analysis of serum autoantibodies, cytokines and chemokines enables stratification of patients with early rheumatoid arthritis into molecular subgroups.


Effects of levosimendan on respiratory muscle function in patients weaning from mechanical ventilation.
Respiratory muscle weakness frequently develops in critically ill patients and is associated with adverse outcome, including difficult weaning from mechanical ventilation. Today, no drug is approved to improve respiratory muscle function in these patients. Previously, we have shown that the calcium sensitizer levosimendan improves calcium sensitivity of human diaphragm muscle fibers in vitro and contractile efficiency of the diaphragm in healthy subjects. The main purpose of this study is to investigate the effects of levosimendan on diaphragm contractile efficiency in mechanically ventilated patients. In a double-blind randomized placebo-controlled trial, mechanically ventilated patients performed two 30-min continuous positive airway pressure (CPAP) trials with 5-h interval. After the first CPAP trial, study medication (levosimendan 0.2 µg/kg/min continuous infusion or placebo) was administered. During the CPAP trials, electrical activity of the diaphragm (EAdi), transdiaphragmatic pressure (Pdi), and flow were measured. Neuromechanical efficiency (primary outcome parameter) was calculated. Thirty-nine patients were included in the study. Neuromechanical efficiency was not different during the CPAP trial after levosimendan administration compared to the CPAP trial before study medication. Tidal volume and minute ventilation were higher after levosimendan administration (11 and 21%, respectively), whereas EAdi and Pdi were higher in both groups in the CPAP trial after study medication compared to the CPAP trial before study medication. Levosimendan does not improve diaphragm contractile efficiency.


Rosetta and the Design of Ligand Binding Sites.
Proteins that bind small molecules (ligands) can be used as biosensors, signal modulators, and sequestering agents. When naturally occurring proteins for a particular target ligand are not available, artificial proteins can be computationally designed. We present a protocol based on RosettaLigand to redesign an existing protein pocket to bind a target ligand. Starting with a protein structure and the structure of the ligand, Rosetta can optimize both the placement of the ligand in the pocket and the identity and conformation of the surrounding sidechains, yielding proteins that bind the target compound.


Flavonoids Synergistically Enhance the Anti-Glioblastoma Effects of Chemotherapeutic Drugs.
Flavonoids are polyphenolic plant secondary metabolites with pleiotropic biological properties, including anti-cancer activities. These natural compounds have potential utility in glioblastoma (GBM), a malignant central nervous system tumor derived from astrocytes. Conventional GBM treatment modalities such as chemotherapy, radiation therapy, and surgical tumor resection are beneficial but limited by extensive tumor invasion and drug/radiation resistance. Therefore, dietary flavonoids-with demonstrated anti-GBM properties in preclinical research-are potential alternative therapies. This review explores the synergistic enhancement of the anti-GBM effects of conventional chemotherapeutic drugs by flavonoids. Primary studies published between 2011 and 2021 on flavonoid-chemotherapeutic synergy in GBM were obtained from PubMed. These studies demonstrate that flavonoids such as chrysin, epigallocatechin-3-gallate (EGCG), formononetin, hispidulin, icariin, quercetin, rutin, and silibinin synergistically enhance the effects of canonical chemotherapeutics. These beneficial effects are mediated by the modulation of intracellular signaling mechanisms related to apoptosis, proliferation, autophagy, motility, and chemoresistance. In this light, flavonoids hold promise in improving current therapeutic strategies and ultimately overcoming GBM drug resistance. However, despite positive preclinical results, further investigations are necessary before the commencement of clinical trials. Key considerations include the bioavailability, blood-brain barrier (BBB) permeability, and safety of flavonoids; optimal dosages of flavonoids and chemotherapeutics; drug delivery platforms; and the potential for adverse interactions.


Patient-reported outcome measures in psoriasis: the good, the bad and the missing!
As a long-term condition, psoriasis demands significant personal and professional input for optimal self-management. Low levels of well-being and high levels of psychological distress in patients with psoriasis are associated with reduced resources for self-care. Patient-reported outcome (PRO) measures can be used to assess physical, social and psychological functioning in order to guide treatment. In this article, we systematically reviewed the development and validation of existing PRO measures. PubMed (Medline), PsycINFO and CINAHL were searched systematically using predefined search terms. The search was limited to articles in the English language relating to human subjects. Articles were selected for full review through explicit inclusion/exclusion criteria. PRO measures were critically reviewed in accordance with the published guidelines and theory on the development and validation of PROs. The search identified 967 abstracts; 71 of these articles met the criteria for full review. In these 71 articles, 45 PRO measures were found: 16 were specific to psoriasis, 21 assessed other dermatological conditions and eight were developed for generic nondermatological health conditions. The review revealed several limitations of the existing measures, including: (i) a composite structure assessing multiple, poorly-defined concepts; (ii) a lack of evidence for face and content validity; (iii) a failure to include both patient and clinician perspectives and requirements and (iv) a lack of evidence regarding the feasibility and acceptability for patients and physicians. No single PRO measure with adequate evidence of validity, reliability and sensitivity to change captures patient well-being in psoriasis. A valid, sensitive, specific and acceptable PRO that assesses the full impact of psoriasis on well-being is needed for the comprehensive clinical management of psoriasis.


[Participatory mapping as a tool for public health decision-making in nomadic settings. A case study among Dazagada pastoralists of the Bahr-el-Ghazal region in Chad].
Integrating the strategies of the point of view of nomadic breeders of cattle into a geographic information system (GIS) highlights the complexity of the temporospatial context associated with point of view of nding health care seeking by nomadic pastoralists. The method used in this study was based on a combination of participatory mapping with group discussions and semi-structured interviews. The resulting data allowed georeferencing of the pastoral environment in the inner Lake Chad Basin according to the representation of Dazagada pastoralists of the Bahr-el-Ghazal region (Kanem, Tchad). By providing better insight into the day-to-day life of nomadic people determining their capacities to make use of primary health care, this holistic approach provides a tool to assist public health decision-makers in optimizing the use of health care facilities by nomadic communities.


Incorporation of lipolysis in monolayer permeability studies of lipid-based oral drug delivery systems.
Lipid-based drug delivery systems, a well-tolerated class of formulations, have been evaluated extensively to enhance the bioavailability of poorly soluble drugs. However, it has been difficult to predict the in vivo performance of lipid dosage forms based on conventional in vitro techniques such as cell monolayer permeability studies because of the complexity of the gastrointestinal processing of lipid formulations. In the current study, we explored the feasibility of coupling Caco-2 and Madin-Darby canine kidney monolayer permeability studies with lipolysis, a promising in vitro technique to evaluate lipid systems. A self-emulsifying lipid delivery system was formulated using a blend of oil (castor oil), surfactant (Labrasol® or PL497), and co-surfactant (lecithin). Formulations demonstrating high drug solubility and rapid self-emulsification were selected to study the effect of lipolysis on in vitro cell permeability. Lipolysis of the formulations was carried out using pancreatin as the digestive enzyme. All the digested formulations compromised monolayer integrity as indicated by lowered trans-epithelial electrical resistance (TEER) and enhanced Lucifer yellow (LY) permeability. Further, the changes in TEER value and LY permeability were attributable to the digestion products of the formulation rather than the individual lipid excipients, drug, digestion enzyme, or the digestion buffer. The digested formulations were fractionated into pellet, oily phase, and aqueous phase, and the effect of each of these on cell viability was examined. Interestingly, the aqueous phase, which is considered important for in vivo drug absorption, was responsible for cytotoxicity. Because lipid digestion products lead to disruption of cell monolayer, it may not be appropriate to combine lipolysis with cell monolayer permeability studies. Additional in vivo studies are needed to determine any potential side effects of the lipolysis products on the intestinal permeability barrier, which could determine the suitability of lipid-based systems for oral drug delivery.


Computerization in industry causes problems for people with reading and writing difficulties (dyslexia).
For 10 years computerization in industry has advanced at a rapid pace. A problem which has not received attention is that of people with reading and writing difficulties who experience severe problems when they have to communicate with a computer monitor screen. These individuals are often embarrassed by their difficulties and conceal them from their fellow workers. A number of case studies are described which show the form the problems can take. In one case, an employee was compelled to move from department to department as each was computerized in turn. Computers transform a large number of manual tasks in industry into jobs which call for reading and writing skills. Better education at elementary school and at the workplace in connection with computerization are the most important means of overcoming this problem. Moreover, computer programs could be written in a more human way.


Inability to detect Chlamyodomonas microtubule assembly in vitro: possible implications to the in vivo regulation of microtubule assembly.
It has been demonstrated that the in vitro assembly of microtubules from Chlamydomonas preparations does not occur under a wide range of conditions, including those efficacious for mammalian brain tubulin. This incompetence of Chlamydomonas extracts to form microtubules is independent of the tubulin concentration, the presence of added nucleotides or an added seed, temperature, or the concentration of divalent cation. However, an amorphous aggregate was observed under certain conditions, who composition was mainly tubulin. The in vitro reassembly of microtubules in gerbil brain extracts is inhibited by Chlamydomonas preparations. Fractionation of the Chlamydomonas extracts by column chromatography suggests that the inhibitory component is Chlamydomonas tubulin itself. The mechanism of this inhibition is unknown, but reassembly experiments indicate that the 2 types of tubulins cannot copolymerize. We suggest that the Chlamydomonas tubulin, derived from a cytoplasmic pool, requires to be activated prior to its in vivo polymerization into microtubules.


Origins and structure of chloroplastic and mitochondrial plant protoporphyrinogen oxidases: implications for the evolution of herbicide resistance.
Protoporphyrinogen IX oxidase (PPO)-inhibiting herbicides are effective tools to control a broad spectrum of weeds, including those that have evolved resistance to glyphosate. Their utility is being threatened by the appearance of biotypes that are resistant to PPO inhibitors. While the chloroplastic PPO1 isoform is thought to be the primary target of PPO herbicides, evolved resistance mechanisms elucidated to date are associated with changes to the mitochondrial PPO2 isoform, suggesting that the importance of PPO2 has been underestimated. Our investigation of the evolutionary and structural biology of plant PPOs provides some insight into the potential reasons why PPO2 is the preferred target for evolution of resistance. The most common target-site mutation imparting resistance involved the deletion of a key glycine codon. The genetic environment that facilitates this deletion is apparently only present in the gene encoding PPO2 in a few species. Additionally, both species with this mutation (Amaranthus tuberculatus and Amaranthus palmeri) have dual targeting of PPO2 to both the chloroplast and the mitochondria, which might be a prerequisite to impart herbicide resistance. The most recent target-site mutations have substituted a key arginine residue involved in stabilizing the substrate in the catalytic domain of PPO2. This arginine is highly conserved across all plant PPOs, suggesting that its substitution could be equally likely on PPO1 and PPO2, yet it has only occurred on PPO2, underscoring the importance of this isoform for the evolution of herbicide resistance. © 2017 Society of Chemical Industry.


Emergence of Mixed Mode Oscillations in Random Networks of Diverse Excitable Neurons: The Role of Neighbors and Electrical Coupling.
In this paper, we focus on the emergence of diverse neuronal oscillations arising in a mixed population of neurons with different excitability properties. These properties produce mixed mode oscillations (MMOs) characterized by the combination of large amplitudes and alternate subthreshold or small amplitude oscillations. Considering the biophysically plausible, Izhikevich neuron model, we demonstrate that various MMOs, including MMBOs (mixed mode bursting oscillations) and synchronized tonic spiking appear in a randomly connected network of neurons, where a fraction of them is in a quiescent (silent) state and the rest in self-oscillatory (firing) states. We show that MMOs and other patterns of neural activity depend on the number of oscillatory neighbors of quiescent nodes and on electrical coupling strengths. Our results are verified by constructing a reduced-order network model and supported by systematic bifurcation diagrams as well as for a small-world network. Our results suggest that, for weak couplings, MMOs appear due to the de-synchronization of a large number of quiescent neurons in the networks. The quiescent neurons together with the firing neurons produce high frequency oscillations and bursting activity. The overarching goal is to uncover a favorable network architecture and suitable parameter spaces where Izhikevich model neurons generate diverse responses ranging from MMOs to tonic spiking.


Theoretical study of liquid-immersed exposed-core microstructured optical fibers for sensing.
The absorption and fluorescence sensing properties of liquid-immersed exposed-core microstructured optical fibers are explored for the regime where these structures act as supported nanowires with direct access to the sensing environment. For absorption-based sensing we demonstrate that the amount of power propagating in the sensing region of the exposed-core fiber can compete with that of traditional MOFs. For fluorescence-based sensing, we see that in addition to the enhanced fluorescence capture efficiency already predicted for small-core, high refractive index contrast fibers, an improvement of up to 29% can be gained by using liquid-immersed exposed-core fibers. Additionally, calculation of the losses associated with interfaces between filled and unfilled sections predict significant benefit in using high refractive index substrate glasses for liquid-immersed exposed-core fiber sensing. This work demonstrates that, for fiber dimensions of interest, the exposed-core fiber is an attractive new sensor technology.


Reliability of an instrumental assessment of tardive dyskinesia: results from VA Cooperative Study #394.
Nine VA Medical Centers are participating in a 2-year double-blind placebo controlled study of antioxidant treatment for tardive dyskinesia (TD) conducted by the Department of Veteran Affairs Cooperative Studies Program. One of the principal outcome measures of this study is the score derived from the instrumental assessment of upper extremity dyskinesia. Dyskinetic hand movements are quantified by assessing the variability associated with steady-state isometric force generated by the patient. In the present report, we describe the training procedures and results of a multi-center reliability assessment of this procedure. Data from nine study centers comprising 45 individual patients with six trials each (three from left hand and three from right hand) were reanalyzed by an independent investigator and the results were subjected to reliability assessment. For the statistic of interest (average coefficient of variation over trials 2 and 3 for each hand, then take the larger of these two values), we found very high intraclass correlation coefficients for reliability over all patients across sites (ICC = 0.995). We also calculated the reliability of the measures across trials within patient for each combination of hand (right, left, dominant), rater group (site, control), and trials set (all three, trials 2 and 3). For a given hand and trial set, the reliability of the site raters was similar to that of the control. This study demonstrates that instrumental measures for the assessment of dyskinesia are reliable and can be implemented in multi-center studies with minimal training.


[Mobilization of alpha-glutathione S-transferase in the anesthetized patient].
To measure and assess changes in plasma concentrations of alpha glutathione S-transferase (alpha-GST) during and after anesthesia with isoflurane, desflurane and propofol. Study of 90 ASA I and II patients scheduled for lumbar back surgery under general anesthesia assigned randomly to one of three groups to receive anesthetic maintenance with isoflurane, desflurane or propofol. We measured plasma levels of alpha-GST, aspartate aminotransferase aspartate, alanine aminotransferase, alkaline phosphatase, pseudocholinesterase, gamma glutamyltransferase and total bilirubin at baseline and several times during and after surgery. Changes in plasma levels of alpha-GST were detected in all three groups, the tendency to increase reaching its peak with the sample taken at the end of anesthesia. The ranges considered normal were not exceeded in any of the patients studied. By measuring alpha-GST changes in plasma, we have detected signs of disturbance in hepatocellular integrity after anesthesia with all three maintenance agents used. However, the slight and transitory nature of the events confirms the scarce hepatotoxic potential of isoflurane, desflurane and propofol.


[Abscess of the prostate: intracavitary echography and echo-guided drainage].
We submit the present paper three cases of prostate abscess. The various aspects related to ethiopathogeny, clinic, and current diagnostic procedures are analyzed emphasixing the use of endocavitary echography, as well as the different therapeutic approaches that can be used, with particular attention to ecomonitored aspirative drainage.


Natural antisense transcripts with coding capacity in Arabidopsis may have a regulatory role that is not linked to double-stranded RNA degradation.
Overlapping transcripts in antisense orientation have the potential to form double-stranded RNA (dsRNA), a substrate for a number of different RNA-modification pathways. One prominent route for dsRNA is its breakdown by Dicer enzyme complexes into small RNAs, a pathway that is widely exploited by RNA interference technology to inactivate defined genes in transgenic lines. The significance of this pathway for endogenous gene regulation remains unclear. We have examined transcription data for overlapping gene pairs in Arabidopsis thaliana. On the basis of an analysis of transcripts with coding regions, we find the majority of overlapping gene pairs to be convergently overlapping pairs (COPs), with the potential for dsRNA formation. In all tissues, COP transcripts are present at a higher frequency compared to the overall gene pool. The probability that both the sense and antisense copy of a COP are co-transcribed matches the theoretical value for coexpression under the assumption that the expression of one partner does not affect the expression of the other. Among COPs, we observe an over-representation of spliced (intron-containing) genes (90%) and of genes with alternatively spliced transcripts. For loci where antisense transcripts overlap with sense transcript introns, we also find a significant bias in favor of alternative splicing and variation of polyadenylation. The results argue against a predominant RNA degradation effect induced by dsRNA formation. Instead, our data support alternative roles for dsRNAs. They suggest that at least for a subgroup of COPs, antisense expression may induce alternative splicing or polyadenylation.


Suppression of human immunodeficiency virus replication by ascorbate in chronically and acutely infected cells.
We have studied the action of ascorbate (vitamin C) on human immunodeficiency virus type 1 (HIV-1), the etiological agent clinically associated with AIDS. We report the suppression of virus production and cell fusion in HIV-infected T-lymphocytic cell lines grown in the presence of nontoxic concentrations of ascorbate. In chronically infected cells expressing HIV at peak levels, ascorbate reduced the levels of extracellular reverse transcriptase (RT) activity (by greater than 99%) and of p24 antigen (by 90%) in the culture supernatant. Under similar conditions, no detectable inhibitory effects on cell viability, host metabolic activity, and protein synthesis were observed. In freshly infected CD4+ cells, ascorbate inhibited the formation of giant-cell syncytia (by approximately 93%). Exposure of cell-free virus to ascorbate at 37 degrees C for 1 day had no effect on its RT activity or syncytium-forming ability. Prolonged exposure of virus (37 degrees C for 4 days) in the presence of ascorbate (100-150 micrograms/ml) resulted in the drop by a factor of 3-14 in RT activity as compared to a reduction by a factor of 25-172 in extracellular RT released from chronically infected cells. These results indicate that ascorbate mediates an anti-HIV effect by diminishing viral protein production in infected cells and RT stability in extracellular virions.


Quantitative Trait Locus and Brain Expression of HLA-DPA1 Offers Evidence of Shared Immune Alterations in Psychiatric Disorders.
Genome-wide association studies of schizophrenia encompassing the major histocompatibility locus (MHC) were highly significant following genome-wide correction. This broad region implicates many genes including the MHC complex class II. Within this interval we examined the expression of two MHC II genes (HLA-DPA1 and HLA-DRB1) in brain from individual subjects with schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and controls by differential gene expression methods. A third MHC II mRNA, CD74, was studied outside of the MHC II locus, as it interacts within the same immune complex. Exon microarrays were performed in anterior cingulate cortex (ACC) in BD compared to controls, and both HLA-DPA1 and CD74 were decreased in expression in BD. The expression of HLA-DPA1 and CD74 were both reduced in hippocampus, amygdala, and dorsolateral prefrontal cortex regions in SZ and BD compared to controls by specific qPCR assay. We found several novel HLA-DPA1 mRNA variants spanning HLA-DPA1 exons 2-3-4 as suggested by exon microarrays. The intronic rs9277341 SNP was a significant cis expression quantitative trait locus (eQTL) that was associated with the total expression of HLA-DPA1 in five brain regions. A biomarker study of MHC II mRNAs was conducted in SZ, BD, MDD, and control lymphoblastic cell lines (LCL) by qPCR assay of 87 subjects. There was significantly decreased expression of HLA-DPA1 and CD74 in BD, and trends for reductions in SZ in LCLs. The discovery of multiple splicing variants in brain for HLA-DPA1 is important as the HLA-DPA1 gene is highly conserved, there are no reported splicing variants, and the functions in brain are unknown. Future work on the function and localization of MHC Class II proteins in brain will help to understand the role of alterations in neuropsychiatric disorders. The HLA-DPA1 eQTL is located within a large linkage disequilibrium block that has an irrefutable association with schizophrenia. Future tests in a larger cohort are needed to determine the significance of this eQTL association with schizophrenia. Our findings support the long-held hypothesis that alterations in immune function are associated with the pathophysiology of psychiatric disorders.


Variations in Sedated Echocardiography and Association With Repeat Echocardiography in Nonrefractory Kawasaki Disease.
Echocardiography performed under sedation allows for better coronary artery visualization in children with Kawasaki disease. We sought to describe hospital-level variability in the percentage of sedated echocardiography (SE) among children with nonrefractory Kawasaki disease (NRKD) and then test its association with repeat echocardiography, length of stay (LOS), and costs. We identified children in the Pediatric Health Information System <36 months of age hospitalized with NRKD from March 2010 to February 2017. Hospital-level percentage of SE was the primary outcome. Secondary outcomes were repeat echocardiography during the same hospitalization, LOS, and costs. We used χ2 and Wilcoxon rank tests to compare differences in repeat echocardiography between SE and nonsedated echocardiography. Pearson correlation was used to test associations between SE and repeat echocardiography, LOS, and costs. There were 2887 NRKD hospitalizations from 40 children's hospitals. Initial SE varied from 0.0% to 87.0% (median 5.9%; interquartile range 1.4%-21.1%). Of initial echocardiographies, 22.4% were sedated and 10.1% of all hospitalizations had a repeat echocardiography. Use of SE at the hospital level was associated with a lower likelihood for repeat echocardiography (r = -0.32; 95% confidence interval -0.58 to -0.01; P = .042). Absolute risk reduction was 3.5% and the number needed to sedate was 29. Initial SE was not associated with LOS or hospital-level costs but was associated with increased patient-level costs. Significant variation exists in the use of SE for children <36 months of age with NRKD at children's hospitals. Our results suggest that determination of SE should not be driven by concern for repeat echocardiography or LOS considerations.


Development and characterization of genic SSR markers in Medicago truncatula and their transferability in leguminous and non-leguminous species.
Expressed sequence tag (EST)-derived simple sequence repeat (eSSR) markers are important resources for gene discovery and comparative mapping aimed at crop improvement. In this study, we developed eSSR markers for Medicago truncatula and assessed their cross-species transferability. We detected 36,847 non-redundant sequences ("unigenes") from 198,642 M. truncatula EST sequences. Mining of microsatellites from the 36,847 unigene sequences (representing approximately 25.8 Mb) revealed 14,637 eSSRs in 11,750 SSR-containing ESTs, and primer pairs were successfully designed for 4,636 (39.5%). Of the 14 637 eSSRs, 82.6% were mononucleotide repeats and the rest (in descending order of abundance) were tri-, di-, penta-, and tetranucleotide repeats. When less stringent SSR detection criteria were used, the frequency of dinucleotide repeat motifs increased more than twofold, and the frequencies of di- (11%) and trinucleotide motifs (10.6%) were almost equal. This demonstrates that the eSSR frequency and distribution were related to the choice of search criteria. Forty-one randomly selected primer pairs were validated, and their transferability in three leguminous and three non-leguminous species was assessed. The markers showed a high level of transferability in the leguminous (53%-71%) and non-leguminous (33%-44%) species. The validation studies thus demonstrate the utility of the Medicago eSSRs in assessing genomic relationships in both leguminous and non-leguminous species.


Mortality of human epidermal keratinocytes in co-culture with oral squamous cell carcinoma cells.
Normal human epidermal keratinocytes (NHEK) died after 5 days of co-culture with an oral carcinoma cell line (HSC-4). However, the HSC-4 cells did not change in either mitotic character or shape. We analyzed the changes in the mitotic activity and DNA synthetic activity of NHEK in co-culture with the HSC-4 cells. The mitotic index of the NHEK decreased gradually with the presence of human beta-defensin-2 (HBD-2) in the media. However, the mitotic index (MI) of the HSC-4 cells did not change. The shape of the NHEK cells did not change during co-culture. The time changes of the labeling index (LI) measured by BrdU incorporation, and the LI decreased in neither NHEK nor in HSC-4 cells in the presence of HBD-2. Moreover, in co-culture with an anti-HBD-2 antibody, the MI of both NHEK and HSC-4 cells did not change. These results indicate that HBD-2 might not lead to apoptosis or necrosis, but rather to cellular reproductive death in NHEK cells. However, HSC-4 cells might be more tolerant of HBD-2, so that HBD-2 does not cause cellular reproductive death. HBD-2 does not diminish the DNA synthesis rate but decreases the mitotic activity in NHEK cells in vitro. HBD-2 diminishes neither the DNA synthesis rate nor the mitotic activity in HSC-4 cells.


Hemangioblast: an in vitro phantom.
The hemangioblast, a bipotent progenitor that generates both endothelial cells (EC) and blood cells (BC) in the blood islands (BI) of the yolk sac (YS) has been a core notion of developmental hematology since the early 20th century. However, its actual presence has not been directly addressed for long. At the very end of the 20th century, the hemangioblast was revisited as a result of the development of new technologies that enable detection of such bipotent precursors in vitro. Such studies provided evidence for the presence of bipotent precursors for EC and BC. On the other hand, subsequent studies analyzing the processes occurring within BI strongly argued against the notion of hemanigioblasts and suggest that the hemangioblast is an in vitro artefact. In this article, I overview the history of the study of the hemangioblast and try to explain why hemangioblast that can be defined in vitro cannot be detected in BI.


Regulation of Syntaxin3B-Mediated Membrane Fusion by T14, Munc18, and Complexin.
Retinal neurons that form ribbon-style synapses operate over a wide dynamic range, continuously relaying visual information to their downstream targets. The remarkable signaling abilities of these neurons are supported by specialized presynaptic machinery, one component of which is syntaxin3B. Syntaxin3B is an essential t-SNARE protein of photoreceptors and bipolar cells that is required for neurotransmitter release. It has a light-regulated phosphorylation site in its N-terminal domain at T14 that has been proposed to modulate membrane fusion. However, a direct test of the latter has been lacking. Using a well-controlled in vitro fusion assay, we found that a phosphomimetic T14 syntaxin3B mutation leads to a small but significant enhancement of SNARE-mediated membrane fusion following the formation of the t-SNARE complex. While the addition of Munc18a had only a minimal effect on membrane fusion mediated by SNARE complexes containing wild-type syntaxin3B, a more significant enhancement was observed in the presence of Munc18a when the SNARE complexes contained a syntaxin3B T14 phosphomimetic mutant. Finally, we showed that the retinal-specific complexins (Cpx III and Cpx IV) inhibited membrane fusion mediated by syntaxin3B-containing SNARE complexes in a dose-dependent manner. Collectively, our results establish that membrane fusion mediated by syntaxin3B-containing SNARE complexes is regulated by the T14 residue of syntaxin3B, Munc18a, and Cpxs III and IV.


The impact of parental psychological distress on child behavior issues in hospitalized children.
Child hospitalization has a negative impact on both children and parents' psychological well-being. Although prior studies in the general context demonstrated a favorable link between parental psychological distress and child behavior problems, research in the hospital situation was restricted. The purpose of this study was to see if parental psychological distress has an effect on child behavior problems in hospitalized children in Indonesia. This cross-sectional study included 156 parents who were recruited from four pediatric wards using a convenience sampling method between August 17 and December 25, 2020. The Hospital Anxiety and Depression Scale and the Child Behavior Checklist 1.5-5 and 6-18 were utilized. Parental anxiety was found to be a significant predictor of increased total behavior issue, internalizing behavior, externalizing behavior, anxious/ depressed, somatic complaints, and violent conduct in hospitalized children. Parental depression, on the other hand, was not related with any of the child behavior issue syndrome measures. The findings imply that identifying and treating parent anxiety early on is critical for preventing or reducing child behavior problems during hospitalization.


[Peculiarities of surgical tactics in complicated traumatic diaphragmal hernia].
Results of 18 patients with traumatic diaphragmal hernia treatment were generalized. Most of them were hospitalized at a date later than 1 year after injury for the other diseases, at 4--diagnosis was established during the operation. Operated in conditions of partial or complete strangulated hernia 16 patients. A critical analysis of diagnostic methods and options of surgical tactics in traumatic diaphragmatic hernia was lead. Based algorhythm for choosing the adequate surgical access.


The persistence of ancient settlements and urban sustainability.
We propose a dedicated research effort on the determinants of settlement persistence in the ancient world, with the potential to significantly advance the scientific understanding of urban sustainability today. Settlements (cities, towns, villages) are locations with two key attributes: They frame human interactions and activities in space, and they are where people dwell or live. Sustainability, in this case, focuses on the capacity of structures and functions of a settlement system (geography, demography, institutions) to provide for continuity of safe habitation. The 7,000-y-old experience of urbanism, as revealed by archaeology and history, includes many instances of settlements and settlement systems enduring, adapting to, or generating environmental, institutional, and technological changes. The field of urban sustainability lacks a firm scientific foundation for understanding the long durée, relying instead on narratives of collapse informed by limited case studies. We argue for the development of a new interdisciplinary research effort to establish scientific understanding of settlement and settlement system persistence. Such an effort would build upon the many fields that study human settlements to develop new theories and databases from the extensive documentation of ancient and premodern urban systems. A scientific foundation will generate novel insights to advance the field of urban sustainability.


The Great Organ System Debates.
Facilitating the learning of physiology by allied health majors who lack foundational coursework in biology and chemistry presents unique pedagogical challenges. By focusing on the strengths of this group of learners (team skills, interest in applied physiology), a new mechanism for conveying the primary interconnection and synergism of the body's organ systems was developed: the Great Organ Systems Debates. After learning sequentially about the primary organ systems, the Debates are a culminating, integrative experience, where students "debate" the relative importance of their system in different situations. Used and refined over several years, it is an engaging, interactive, and effective learning tool that could be adapted to almost any level of instruction.NEW & NOTEWORTHY Which organ system is "most important" when running a marathon? To answer this question, different groups of students were assigned different organ systems to see who could come up with the best argument.


Supercritical Carbon Dioxide Extraction of Coronene in the Presence of Perchlorate for In Situ Chemical Analysis of Martian Regolith.
The analysis of the organic compounds present in the martian regolith is essential for understanding the history and habitability of Mars, as well as studying the signs of possible extant or extinct life. To date, pyrolysis, the only technique that has been used to extract organic compounds from the martian regolith, has not enabled the detection of unaltered native martian organics. The elevated temperatures required for pyrolysis extraction can cause native martian organics to react with perchlorate salts in the regolith and possibly result in the chlorohydrocarbons that have been detected by in situ instruments. Supercritical carbon dioxide (SCCO2) extraction is an alternative to pyrolysis that may be capable of delivering unaltered native organic species to an in situ detector. In this study, we report the SCCO2 extraction of unaltered coronene, a representative polycyclic aromatic hydrocarbon (PAH), from martian regolith simulants, in the presence of 3 parts per thousand (ppth) sodium perchlorate. PAHs are a class of nonpolar molecules of astrobiological interest and are delivered to the martian surface by meteoritic infall. We also determined that the extraction efficiency of coronene was unaffected by the presence of perchlorate on the regolith simulant, and that no sodium perchlorate was extracted by SCCO2. This indicates that SCCO2 extraction can provide de-salted samples that could be directly delivered to a variety of in situ detectors. SCCO2 was also used to extract trace native fluorescent organic compounds from the martian regolith simulant JSC Mars-1, providing further evidence that SCCO2 extraction may provide an alternative to pyrolysis to enable the delivery of unaltered native organic compounds to an in situ detector on a future Mars rover. Biomarkers-Carbon dioxide-In situ measurement-Mars-Search for Mars' organics. Astrobiology 16, 703-714.


High resolution mapping of the cardiac transmural proteome using reverse phase protein microarrays.
The expression level of proteins governing the electrical excitability of and conduction within ventricular myocardium are known to vary as a function of distance through the heart wall. The expression patterns of a subset of these proteins are altered in disease. Precise measurement of such patterns is therefore essential to understanding structure-function relationships within the heart in health and disease. Here, we report a new experimental approach using reverse-phase protein microarrays to map the left ventricular transmural proteome. This approach can yield submillimeter spatial resolution, and when coupled with the method of array microenvironment normalization, reduces nonbiological components of variability to ∼10% of overall study variability. In addition, the experimental design provides sufficient statistical power to detect small, yet potentially biologically significant expression changes on the order of 1.1-fold. The usefulness of this technique is demonstrated by mapping the transmural expression of Serca2a in the left ventricle of 12 canine hearts, each in one of three states: normal, dyssynchronous heart failure, and dyssynchronous heart failure followed by cardiac resynchronization therapy. We confirm the existence of a 40% transmural gradient (epi>endo) of Serca2a, and demonstrate the ability of this technique to yield highly significant transmural expression differences within each individual heart.


[Bias in time delay in ICU admission as a mortality risk factor or "lead time bias"].
To assess if delay in admission to the Intensive Care Unit (ICU), measured according to the prognostic estimation of survival in critical patients (EPEC) system, influences the final outcome of patients admitted to our ICU. Retrospective and systematic analysis of data collected during six months in 2003. Nineteen-bed ICU (15 from Standard intensive care and 4 from intermediate care) in a referral teaching hospital. Four hundred and eighty one patients consecutively admitted to our ICU and followedup to hospital discharge. MAIN INTEREST VARIABLES: Risk of death was estimated with the EPEC, SAPS II and MPM II 0. Variables collected were gender, age, origin of admission, risk of death by means of the 3 methods mentioned, admission time delay (lead time bias) as measured by EPEC and life status on ICU and hospital discharge (alive or dead). A total of 44 out of 481 patients died during the hospital stay, overall admission delay being 0.7 +/- 1.98 hours (2.96 +/- 3.28, range 0.25-20 hours, for those with delay > 0). No differences were found when comparing delay in admission among those surviving and the deceased, and there was very bad correlation between the prognosis made considering delay time for admission and that established without considering it (SAPS II or MPM II 0). Our study does not make it possible to relate lead time bias with patient survival. Due to the EPEC design, it is possible to differentiate "physiopathological delay" (inappropriate detection of the critical situation) and "logistic delay" (conditioned by factors such as lack of available beds). Our study as well as the EPEC only considers the latter. It cannot be ruled out that the increase in mortality regarding prognosis is directly related with first type of delay and not with the overall lead time bias.


Human circadian pacemaker is sensitive to light throughout subjective day without evidence of transients.
Fifty-six resetting trials were conducted across the subjective day in 43 young men using a three-cycle bright-light (approximately 10,000 lx). The phase-response curve (PRC) to these trials was assessed for the presence of a "dead zone" of photic insensitivity and was compared with another three-cycle PRC that had used a background of approximately 150 lx. To assess possible transients after the light stimulus, the trials were divided into 43 steady-state trials, which occurred after several baseline days, and 13 consecutive trials, which occurred immediately after a previous resetting trial. We found that 1) bright light induces phase shifts throughout subjective day with no apparent dead zone; 2) there is no evidence of transients in constant routine assessments of the fitted temperature minimum 1-2 days after completion of the resetting stimulus; and 3) the timing of background room light modulates the resetting response to bright light. These data indicate that the human circadian pacemaker is sensitive to light at virtually all circadian phases, implying that the entire 24-h pattern of light exposure contributes to entrainment.


Simulation educators in clinical work: the manager's perspective.
Information is scarce on healthcare managers' understanding of simulation educators' impact on clinical work. Therefore, the aim of this study was to explore healthcare managers' perceptions of the significance of clinically active simulation educators for the organisation. Healthcare managers were invited to be interviewed in a semi-structured manner. Inductive thematic analysis was used to identify and analyse patterns of notions describing the managers' perceptions of simulation educators' impact as co-workers on their healthcare organisations. The identified relevant themes for the healthcare unit were: (1) value for the manager, (2) value for the community and (3) boundaries. Simulation educators were perceived to be valuable gatekeepers of evidence-based knowledge and partners in leadership for educational issues. Their most prominent value for the community was establishing a reflective climate, facilitating open communication and thereby improving the efficacy of teamwork. Local tradition, economy, logistics and staffing of the unit during simulation training were suggested to have possible negative impacts on simulation educators' work. The findings might have implications for the implementation and support of simulation training programs. Healthcare managers appreciated both the personal value of simulation educators and the effect of their work for their own unit. Local values were prioritised versus global. Simulation training was valued as an educational tool for continual professional development, although during the interviews, the managers did not indicate the importance of employment of pedagogically competent and experienced staff. The study provided new insights about how simulation educators as team members affect clinical practice.


NABS: non-local automatic brain hemisphere segmentation.
In this paper, we propose an automatic method to segment the five main brain sub-regions (i.e. left/right hemispheres, left/right cerebellum and brainstem) from magnetic resonance images. The proposed method uses a library of pre-labeled brain images in a stereotactic space in combination with a non-local label fusion scheme for segmentation. The main novelty of the proposed method is the use of a multi-label block-wise label fusion strategy specifically designed to deal with the classification of main brain sub-volumes that process only specific parts of the brain images significantly reducing the computational burden. The proposed method has been quantitatively evaluated against manual segmentations. The evaluation showed that the proposed method was faster while producing more accurate segmentations than a current state-of-the-art method. We also present evidences suggesting that the proposed method was more robust against brain pathologies than the compared method. Finally, we demonstrate the clinical value of our method compared to the state-of-the-art approach in terms of the asymmetry quantification in Alzheimer's disease.


Strategies for antiviral drug discovery.
The need for antiviral drugs is growing rapidly as more viral diseases are recognized. The methods used to discover antiviral drugs have evolved considerably over the past 40 years and the overall process of discovery can be broken down into subprocesses which include lead generation, lead optimization and lead development. Various methods are now employed to ensure these processes are carried out efficiently. For lead generation, screening methodologies have developed to the extent where hundreds of thousands of compounds can be screened against a particular target. An alternative approach is to use the structures of enzyme substrates as a starting point for drug discovery. Much use is now made of X-ray crystallographic data of target-inhibitor complexes for the optimization of lead structures, and methods for preparing libraries of compounds to assist both generation and optimization of leads are well-developed. The methods used to predict and improve the pharmacokinetic properties of compounds are also changing rapidly. Finally, novel approaches to antiviral therapy using oligonucleotide-based compounds or by modulating the host immune response are also being explored. This review discusses these approaches, provides examples of where their application has been successful and sets them against a historical background.


Protein free microcapsules obtained from plant spores as a model for drug delivery: ibuprofen encapsulation, release and taste masking.
Sporopollenin exine capsules (SEC) extracted from Lycopodium clavatum spores were shown to encapsulate ibuprofen as a drug model, with 97 ± 1% efficiency as measured by recovery of the loaded drug and absence of the drug on the SEC surface by scanning electron microscopy (SEM). The encapsulated ibuprofen was shown to be unchanged from its bulk crystalline form by solid state NMR, FTIR and XRD. Essential for drug delivery applications, SEC were shown to be non-toxic to human endothelial cells and free of allergenic protein epitopes by MALDI-TOF-MS and ESI-QqToF-MS. Potential application for targeted release into the intestinal region of the gastrointestinal tract (GIT) was demonstrated by 88 ± 1% of the drug being retained in simulated gastric fluid (SGF) after 45 minutes and 85 ± 2% being released after 5 min in buffer (PBS; pH 7.4). The SEC were shown to provide significant taste masking of encapsulated ibuprofen in a double blind trial with 10 human volunteers.


Effect of respiratory alkalosis on renal phosphate excretion.
Respiratory alkalosis induced hypophosphatemia and hypophosphaturia in intact animals. The present studies evaluated the effect of respiratory alkalosis on tissue phosphate distribution and renal phosphate transport in the presence and absence of parathyroid hormone (PTH). Respiratory alkalosis decreased plasma phosphate concentration and increased phosphate concentrations in muscle and liver. It decreased fractional phosphate excretion (FEPi) from 6.1 +/- 1.4 to 0.6 +/- 0.2%. In thyroparathyroidectomized (TPTX) rats infused with 20 mM phosphate, respiratory alkalosis decreased FEPi from 15.0 +/- 0.9 to 5.5 +/- 0.1%. PTH or dibutyryl cAMP administration produced a phosphaturia that was blunted by respiratory alkalosis. The phosphaturic response to PTH was also blunted in hypocapnic rats in which alkalosis was prevented by infusion of HCl. We conclude that respiratory alkalosis increases phosphate uptake by muscle, which largely accounts for the hypophosphatemia. The kidney response with increased phosphate reabsorption independent of plasma and kidney phosphate concentrations and with refractoriness to the phosphaturic effect of PTH. This refractoriness to the phosphaturic effect of PTH is due to decreased PCO2 rather than to the concomitant extracellular alkalosis.


Factors that influence patient preferences for prostate cancer management options: A systematic review.
We performed a systematic review to evaluate evidence regarding factors that influence patient preferences for management options for localized prostate cancer. We followed a prespecified search protocol (PROSPERO identifier CRD42014009173) to identify studies that evaluated patient preferences for prostate cancer management options for localized prostate cancer. We queried PubMed, the Cochrane Database of Systematic Reviews, Embase, Cumulative Index to Nursing & Allied Health Literature (CINAHL) Plus, and Econ-Lit databases. Two separate reviewers completed the article selection process and review, including coding of study characteristics. Study quality was scored according to the PREFS checklist, which consists of five criteria: Purpose, Respondents, Explanation, Findings, and Significance. Reviewers summarized the primary findings of each article included in the analysis. Of the 606 citations identified in the literature search, there were a total of 21 articles that met all selection criteria, reporting results for a total of 4,131 subjects. Themes identified in the studies included: the importance of patient perceptions of treatment efficacy and side effects; the influence of physician recommendations on patient decision-making; and the prioritization of concerns regarding treatment side effects among those men who prefer radiation therapy or active surveillance. The articles had an average PREFS score of 3.4 (standard deviation [SD] 1.0), which is similar to a recent study for breast cancer treatment preferences. This systematic review of factors that influence patient preferences for prostate cancer management options identified a small, but high quality, group of articles that satisfied the selection criteria. The available evidence suggests that interventions aimed at informing patients regarding the comparative effectiveness of prostate cancer management alternatives should include the influence of physician recommendations and family members' desires on patient decision-making.


Multiplication of certain soil micro-organisms under simulated Martian conditions.
According to earlier observations, severe UV irradiation kills all micro-organisms in a chamber with simulated Martian conditions. However, even a thin soil layer protects buried micro-organisms from UV irradiation. The chief limiting factor for microbial multiplication under simulated Martian conditions seems to be soil humidity. Several micro-organisms were isolated from harsh environments (e.g., from Arctic, Antarctic desert and high-mountain soil samples). A strain of an oligonitrophilic mycococcus, isolated from Dixon Island, proved to be most resistant to low humidity. It multiplied in a mixture of limonite (maximal hygroscopical humidity 3.8%) + 2% (w/w) garden soil kept in a chamber simulating Martian conditions. Total cell count increased 7.6-fold and, in some experiments, 26-fold in 14 days. The oligonitrophilic mycococcus was able to grow even at a humidity level of 2.5%, that is less than maximal hygroscopical (3.8%). Under these conditions cell count increased 10-fold in 36 days. Thus, it was shown that even in Earth soils there are xerophytic micro-organisms which are able to multiply in limonite of low humidity. These data might correct our current concepts concerning microbial water requirements. One might speculate that Martian micro-organisms belong to xerophytic species.


Cortical progression patterns in individual ALS patients across multiple timepoints: a mosaic-based approach for clinical use.
The majority of imaging studies in ALS infer group-level imaging signatures from group comparisons, as opposed to estimating disease burden in individual patients. In a condition with considerable clinical heterogeneity, the characterisation of individual patterns of pathology is hugely relevant. In this study, we evaluate a strategy to track progressive cortical involvement in single patients by using subject-specific reference cohorts. We have interrogated a multi-timepoint longitudinal dataset of 61 ALS patients to demonstrate the utility of estimating cortical disease burden and the expansion of cerebral atrophy over time. We contrast our strategy to the gold-standard approach to gauge the advantages and drawbacks of our method. We modelled the evolution of cortical integrity in a conditional growth model, in which we accounted for age, gender, disability, symptom duration, education and handedness. We hypothesised that the variance associated with demographic variables will be successfully eliminated in our approach. In our model, the only covariate which modulated the expansion of atrophy was motor disability as measured by the ALSFRS-r (t(153) = - 2.533, p = 0.0123). Using the standard approach, age also significantly influenced progression of CT change (t(153) = - 2.151, p = 0.033) demonstrating the validity and potential clinical utility of our approach. Our strategy of estimating the extent of cortical atrophy in individual patients with ALS successfully corrects for demographic factors and captures relevant cortical changes associated with clinical disability. Our approach provides a framework to interpret single T1-weighted images in ALS and offers an opportunity to track cortical propagation patterns both at individual subject level and at cohort level.


Life on the outside: role of biofilms in environmental persistence of Shiga-toxin producing Escherichia coli.
Escherichia coli is a heterogeneous species that can be part of the normal flora of humans but also include strains of medical importance. Among pathogenic members, Shiga-toxin producing E. coli (STEC) are some of the more prominent pathogenic E. coli within the public sphere. STEC disease outbreaks are typically associated with contaminated beef, contaminated drinking water, and contaminated fresh produce. These water- and food-borne pathogens usually colonize cattle asymptomatically; cows will shed STEC in their feces and the subsequent fecal contamination of the environment and processing plants is a major concern for food and public safety. This is especially important because STEC can survive for prolonged periods of time outside its host in environments such as water, produce, and farm soil. Biofilms are hypothesized to be important for survival in the environment especially on produce, in rivers, and in processing plants. Several factors involved in biofilm formation such as curli, cellulose, poly-N-acetyl glucosamine, and colanic acid are involved in plant colonization and adherence to different surfaces often found in meat processing plants. In food processing plants, contamination of beef carcasses occurs at different stages of processing and this is often caused by the formation of STEC biofilms on the surface of several pieces of equipment associated with slaughtering and processing. Biofilms protect bacteria against several challenges, including biocides used in industrial processes. STEC biofilms are less sensitive than planktonic cells to several chemical sanitizers such as quaternary ammonium compounds, peroxyacetic acid, and chlorine compounds. Increased resistance to sanitizers by STEC growing in a biofilm is likely to be a source of contamination in the processing plant. This review focuses on the role of biofilm formation by STEC as a means of persistence outside their animal host and factors associated with biofilm formation.


Prenatal bupropion exposure enhances the cocaine reward and stress susceptibility in adult mice.
Although a growing body of evidence supports the notion that certain antidepressant treatments in pregnancy produce earlier delivery and minor behavioral teratogenesis in infants, the long-term effects of such treatments in adulthood remain ill-defined. Recently, postnatal exposure to psychotropic drugs was found to affect the emotional development and susceptibility to abused drugs. Thus, this study aimed to examine whether prenatal exposure of four frequently-used antidepressants, bupropion, fluvoxamine, citalopram, and trazodone, altered the responsiveness to stress and cocaine in the adulthood. Dams received daily injection of bupropion (25 or 12.5 mg/kg), citalopram (5 mg/kg), fluvoxamine (10 mg/kg), trazodone (20 mg/kg) or saline throughout their third trimester of gestation, and several birth outcome indices were then examined. Locomotor activity, naive anxiety levels, and the sensitivity to the cocaine reinforcing effects were observed in pups at their day 56-60 post partum. We found that trazodone treatment produced a high mortality rate in pups after weaning. Mice, prenatally treated with bupropion at 25 mg/kg, exhibited lower rearing numbers and ambulatory activity as compared to the saline-treated mice. More importantly, such treatment enhanced the mouse sensitivity to the reinforcing effects of cocaine. Taken together, these results suggest that use of bupropion in the late pregnancy may run a risk of enhancing the offspring's susceptibility to stress and cocaine reward in adulthood.


First-line boosted protease inhibitor-based regimens in treatment-naive HIV-1-infected patients--making a good thing better.
Lopinavir/ritonavir has been the recommended boosted protease inhibitor for treatment-naive individuals in all guidelines since its approval in the year 2000. More recently, the rest of ritonavir-boosted protease inhibitors (namely lopinavir once-daily, fosamprenavir, saquinavir, atazanavir, and darunavir) have demonstrated non-inferior antiviral efficacy at 48 weeks than lopinavir twice-daily. Overall, all ritonavir-boosted protease inhibitors display a high genetic and pharmacological barrier to resistance development and protect the rest of the drugs on board in the regimen, achieving similar CD4 count gains among them. During the last year, studies conducted with atazanavir and darunavir have demonstrated superior virologic efficacy against lopinavir at 96 weeks in their pivotal trials. These two protease inhibitors provide significant improvements in triglycerides and gastrointestinal toxicity, together with simpler once-daily formulations, compared to lopinavir. In the case of atazanavir, this is mainly driven by a lower rate of discontinuations due to drug-related side effects, as pure antiviral efficacy is essentially similar to lopinavir. Furthermore, the gastrointestinal intolerance of lopinavir is actually compensated by an increased risk of hyperbilirubinemia and jaundice with atazanavir, but this is more a cosmetic problem and rarely a cause of drug withdrawal. Darunavir has been licensed to be taken once-daily in treatment-naive patients, and shows significantly better lipid and gastrointestinal tolerance than lopinavir. Robust sensitivity analysis with darunavir prove superior antiviral efficacy than lopinavir at 96 weeks also when non-virologic failures (toxicity and discontinuations) are censored, or when only patients receiving lopinavir twice-daily are included in the estimation. Moreover, darunavir has shown superior antiviral efficacy than lopinavir, particularly in three situations of particular clinical concern: high baseline viral load, low baseline CD4 counts, and suboptimal drug adherence. Over the last years, the treatment landscape with ritonavir-boosted protease inhibitors as initial HIV therapy has accomplished significant advances, with improved degrees of efficacy, tolerability, and convenience, that should be used to guide treatment choice in first-line antiretroviral therapy.


Assisted PD throughout Europe: advantages, inequities, and solution proposals.
Peritoneal dialysis provides several benefits for patients and should be offered as first line kidney replacement therapy, particularly for fragile patients. Limitation to self-care drove assisted peritoneal dialysis to evolve from family-based care to institutional programs, with specialized care givers. Some European countries have mastered this, while others are still bound by the availability of a volunteer to become responsible for treatment. A group of leading nephrologists from 13 European countries integrated real-life application of such therapy, highlighting barriers, lessons learned and practical solutions. The objective of this work is to share and summarize several different approaches, with their intrinsic difficulties and solutions, which might helpperitoneal dialysis units to develop and offer assisted peritoneal dialysis. Assisted peritoneal dialysis does not mean 4 continuous ambulatory peritoneal dialysis exchanges, 7 days/week, nor does it exclude cycler. Many different prescriptions might work for our patients. Tailoring PD prescription to residual kidney function, thereby maintaining small solute clearance, reduces dialysis burden and is associated with higher technique survival. Assisted peritoneal dialysis does not mean assistance will be needed permanently, it can be a transitional stage towards individual or caregiver autonomy. Private care agencies can be used to provide assistance; other options may involve implementing PD training programs for the staff of nursing homes or convalescence units. Social partners may be interested in participating in smaller initiatives or for limited time periods. Assisted peritoneal dialysis is a valid technique, which should be expanded. In countries without structural models of assisted peritoneal dialysis, active involvement by the nephrologist is needed in order for it to become a reality.


Play context, commitment, and dating violence: a structural equation model.
This study develops a structural equation model to describe the effect of two groups of factors (type of commitment and play context) on the violence experienced during intimate partner conflict. After contrasting the model in adolescents and university students, we have confirmed that aggressive play and the simulation of jealousy and anger increase the risk of dating victimization during conflicts through the negative reactions that they cause. Where commitment is concerned, the results are different according to whether commitment is personal or constraining. The former provides protection against dating victimization, reducing risk in the play context, whereas the latter has no effect on the violence experienced but facilitates a more dangerous play dynamic. The model can be applied in the design of programs to prevent dating violence.


Impaired skeletal muscle mitochondrial function in morbidly obese patients is normalized one year after bariatric surgery.
Obesity and type 2 diabetes are associated with impaired skeletal muscle mitochondrial metabolism. As an intrinsic characteristic of an individual, skeletal muscle mitochondrial dysfunction could be a risk factor for weight gain and obesity-associated co-morbidities, such as type 2 diabetes. On the other hand, impaired skeletal muscle metabolism could be a consequence of obesity. We hypothesize that marked weight loss after bariatric surgery recovers skeletal muscle mitochondrial function. Skeletal muscle mitochondrial function as assessed by high-resolution respirometry was measured in 8 morbidly obese patients (body mass index [BMI], 41.3±4.7 kg/m(2); body fat, 48.3%±5.2%) before and 1 year after bariatric surgery (mean weight loss: 35.0±8.6 kg). The results were compared with a lean (BMI 22.8±1.1 kg/m(2); body fat, 15.6%±4.7%) and obese (BMI 33.5±4.2 kg/m(2); body fat, 34.1%±6.3%) control group. Before surgery, adenosine diphosphate (ADP)-stimulated (state 3) respiration on glutamate/succinate was decreased compared with lean patients (9.5±2.4 versus 15.6±4.4 O2 flux/mtDNA; P<.05). One year after surgery, mitochondrial function was comparable to that of lean controls (after weight loss, 12.3±5.5; lean, 15.6±4.4 O2 flux/mtDNA). In addition, we observed an increased state 3 respiration on a lipid substrate after weight loss (10.0±3.2 versus 14.0±6.6 O2 flux/mtDNA; P< .05). We conclude that impaired skeletal muscle mitochondrial function is a consequence of obesity that recovers after marked weight loss.


The energy landscapes of bidisperse particle assemblies on a sphere.
The interplay between crystalline ordering, curvature, and size dispersity make the packing of bidisperse mixtures of particles on a sphere a varied and complex phenomenon. These structures have functional significance in a broad range of systems, such as cellular organisation in spherical epithelia, catalytic activity in binary colloidosomes, and chemical activity in heterofullerenes. In this contribution, we elucidate the potential energy landscapes for systems of repulsive, bidisperse particles confined to the surface of a sphere. It is commonly asserted that particle size dispersity destroys ordered arrangements, leading to glassy landscapes. Surprisingly, across a range of compositions, we find highly ordered global minima. Moreover, a minority of small particles is able to passivate defects, stabilising bidisperse global minima relative to monodisperse systems. However, our landscape analysis also reveals that bidispersity introduces numerous defective, low-lying states that are expected to cause broken ergodicity in corresponding experimental and computational systems. Probing the global minimum structures further, particle segregation is energetically preferred at intermediate compositions, contrasting with the approximate icosahedral global packing at either end of the composition range. Finally, changing the composition has a dramatic effect on the heat capacity: systems with low-symmetry global minima have melting temperatures an order of magnitude lower than monodisperse or high-symmetry systems. This observation may provide a further example of the principle of maximum symmetry: higher symmetry global minima exhibit a larger energy separation from the minima that define the high-entropy phase-like region of configuration space, raising the transition temperature.


High-power, broadly tunable, and low-quantum-defect KGd(1-x)Lu(x)(WO(4))(2):Yb(3+) channel waveguide lasers.
In KGd(1-x)Lu(x)(WO(4))(2):Yb(3+) channel waveguides grown onto KY(WO(4))(2) substrates by liquid phase epitaxy and microstructured by Ar+ beam etching, we produced 418 mW of continuous-wave output power at 1023 nm with a slope efficiency of 71% and a threshold of 40 mW of launched pump power at 981 nm. The degree of output coupling was 70%. By grating tuning in an extended cavity and pumping at 930 nm, we demonstrated laser operation from 980 nm to 1045 nm. When pumping at 973 nm, lasing at 980 nm with a record-low quantum defect of 0.7% was achieved.


Phase II trial design with Bayesian adaptive randomization and predictive probability.
We propose a randomized phase II clinical trial design based on Bayesian adaptive randomization and predictive probability monitoring. Adaptive randomization assigns more patients to a more efficacious treatment arm by comparing the posterior probabilities of efficacy between different arms. We continuously monitor the trial by using the predictive probability. The trial is terminated early when it is shown that one treatment is overwhelmingly superior to others or that all the treatments are equivalent. We develop two methods to compute the predictive probability by considering the uncertainty of the sample size of the future data. We illustrate the proposed Bayesian adaptive randomization and predictive probability design by using a phase II lung cancer clinical trial, and we conduct extensive simulation studies to examine the operating characteristics of the design. By coupling adaptive randomization and predictive probability approaches, the trial can treat more patients with a more efficacious treatment and allow for early stopping whenever sufficient information is obtained to conclude treatment superiority or equivalence. The design proposed also controls both the type I and the type II errors and offers an alternative Bayesian approach to the frequentist group sequential design.


Towards Better Understanding of KSHV Life Cycle: from Transcription and Posttranscriptional Regulations to Pathogenesis.
Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8 (HHV-8), is etiologically linked to the development of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. These malignancies often occur in immunosuppressed individuals, making KSHV infection-associated diseases an increasing global health concern with persistence of the AIDS epidemic. KSHV exhibits biphasic life cycles between latent and lytic infection and extensive transcriptional and posttranscriptional regulation of gene expression. As a member of the herpesvirus family, KSHV has evolved many strategies to evade the host immune response, which help the virus establish a successful lifelong infection. In this review, we summarize the current research status on the biology of latent and lytic viral infection, the regulation of viral life cycles and the related pathogenesis.


Spasticity and its contribution to hypertonia in cerebral palsy.
Spasticity is considered an important neural contributor to muscle hypertonia in children with cerebral palsy (CP). It is most often treated with antispasticity medication, such as Botulinum Toxin-A. However, treatment response is highly variable. Part of this variability may be due to the inability of clinical tests to differentiate between the neural (e.g., spasticity) and nonneural (e.g., soft tissue properties) contributions to hypertonia, leading to the terms "spasticity" and "hypertonia" often being used interchangeably. Recent advancements in instrumented spasticity assessments offer objective measurement methods for distinction and quantification of hypertonia components. These methods can be applied in clinical settings and their results used to fine-tune and improve treatment. We reviewed current advancements and new insights with respect to quantifying spasticity and its contribution to muscle hypertonia in children with CP. First, we revisit what is known about spasticity in children with CP, including the various definitions and its pathophysiology. Second, we summarize the state of the art on instrumented spasticity assessment in CP and review the parameters developed to quantify the neural and nonneural components of hypertonia. Lastly, the impact these quantitative parameters have on clinical decision-making is considered and recommendations for future clinical and research investigations are discussed.


Targeting TNF-Alpha in HIV-1 Infection.
Highly active antiretroviral therapy (HAART) has dramatically extended the lifespan and quality of life of individuals infected with human immunodeficiency virus type 1 (HIV-1). HAART comprises of a cocktail of various pharmacological inhibitors which interfere with almost every stages of HIV-1 life cycle. However, constant application of drugs often results in the evolution of hostpathogen relationship resulting in the emergence of drug resistant viral strains. Drug resistant HIV-1 is a potent threat for the humankind. Therefore, there is a constant need to search for novel therapeutic molecules. HIV-1 infection results in the depletion of CD4+/CD8+T cells and alters the cytokine network in the infected individuals. Tumor necrosis factor alpha (TNF-alpha), a proinflammatory cytokine, plays a critical role in HIV-1 pathogenesis. HIV-1 utilizes the TNF-alpha signaling pathway for expanding its reservoir. Several HIV-1 proteins mimic and regulate the TNF-alpha signaling pathway. TNF-alpha inhibitors have been used in several inflammatory pathologies with success to some extent. In the present mini review we will discuss the role of TNF-alpha in HIV-1 pathogenesis. Furthermore we will evaluate the TNF-alpha inhibitors as an additional therapeutic option for HIV-1 infection.


Educating Pediatric Residents About Parenting: A Survey of Residency Program Leaders.
The American Academic of Pediatrics guides pediatricians to counsel parents about how to promote their children's cognitive, emotional, and self-regulatory development, but the extent to which pediatricians receive the training needed to do so is unknown. An online survey was distributed to members of the Association of Pediatric Program Directors. Although most respondents agreed that it was "very important" to educate residents about parenting skills, only 11% rated their program as doing so "very well." The most frequently reported reason for not doing very well was lack of a curriculum. Residents currently learn about parenting most commonly in continuity clinic talks, are educated via lectures, and are taught most frequently by clinic preceptors. Nearly half of the respondents reported that their residents relied on self-learning about parenting behaviors. When asked which topics respondents would like covered by an evidence-based parenting curriculum, the most commonly endorsed topic was positive discipline.


Canvas SPW: calling de novo copy number variants in pedigrees.
Whole genome sequencing is becoming a diagnostics of choice for the identification of rare inherited and de novo copy number variants in families with various pediatric and late-onset genetic diseases. However, joint variant calling in pedigrees is hampered by the complexity of consensus breakpoint alignment across samples within an arbitrary pedigree structure. We have developed a new tool, Canvas SPW, for the identification of inherited and de novo copy number variants from pedigree sequencing data. Canvas SPW supports a number of family structures and provides a wide range of scoring and filtering options to automate and streamline identification of de novo variants. Canvas SPW is available for download from https://github.com/Illumina/canvas. email@example.com. Supplementary data are available at Bioinformatics online.


Eruption disturbances: an aetiological-cum-management perspective.
Failure of permanent teeth to erupt without any known cause is a rare incident. We report a case of multiple unerupted permanent teeth and make an effort to predict all possible causes of non-eruption of permanent teeth clinically and radiographically. It is essential to diagnose and treat eruption disturbances as early as possible because treatment at a later stage is usually more complicated due to the tendency of malocclusion to increase with time and reduced ability of remaining dentition to adjust.


Canadian educational approaches for the advancement of pharmacy practice.
Canadian faculties (schools) of pharmacy are actively engaged in the advancement and restructuring of their programs in response to the shift in pharmacy to pharmacists having/assuming an advanced practitioner role. Unfortunately, there is a paucity of evidence outlining optimal strategies for accomplishing this task. This review explores several educational changes proposed in the literature to aid in the advancement of pharmacy education such as program admission requirements, critical-thinking assessment and teaching methods, improvement of course content delivery, value of interprofessional education, advancement of practical experiential education, and mentorship strategies. Collectively, implementation of these improvements to pharmacy education will be crucial in determining the direction the profession will take.


Vascularization of melanoma by mobilization and remodeling of preexisting latent vessels to patency.
Tumors must manipulate the host vasculature to provide a blood supply adequate for their proliferation. Although tumors may arise as avascular masses, there is increasing evidence that some tumors begin to proliferate by first co-opting preexisting host blood vessels. By fluorescent vascular imaging, we provide evidence that the vasculature in orthotopically implanted melanoma arises from a preexisting red cell-deficient vascular network that remodels to patency to accommodate the requirements of the expanding tumor mass. Topical application of vascular endothelial growth factor to vascular beds generated immediate and robust vascular transitions that were morphologically similar to tumor-induced transitions. N(phi)-nitro-L-arginine, a nitric oxide inhibitor, significantly inhibited the growth of a syngeneic K1735M2 melanoma by reducing blood supply to the tumor by a mechanism independent of endothelial cell proliferation. These findings suggest that tumor-induced remodeling of red cell-deficient vessels to patency contributes to tumor vascularization and growth.


Rationale and design of the REgistry of Fast Myocardial Perfusion Imaging with NExt generation SPECT (REFINE SPECT).
We aim to establish a multicenter registry collecting clinical, imaging, and follow-up data for patients who undergo myocardial perfusion imaging (MPI) with the latest generation SPECT scanners. REFINE SPECT (REgistry of Fast Myocardial Perfusion Imaging with NExt generation SPECT) uses a collaborative design with multicenter contribution of clinical data and images into a comprehensive clinical-imaging database. All images are processed by quantitative software. Over 290 individual imaging variables are automatically extracted from each image dataset and merged with clinical variables. In the prognostic cohort, patient follow-up is performed for major adverse cardiac events. In the diagnostic cohort (patients with correlating invasive angiography), angiography and revascularization results within 6 months are obtained. To date, collected prognostic data include scans from 20,418 patients in 5 centers (57% male, 64.0 ± 12.1 years) who underwent exercise (48%) or pharmacologic stress (52%). Diagnostic data include 2079 patients in 9 centers (67% male, 64.7 ± 11.2 years) who underwent exercise (39%) or pharmacologic stress (61%). The REFINE SPECT registry will provide a resource for collaborative projects related to the latest generation SPECT-MPI. It will aid in the development of new artificial intelligence tools for automated diagnosis and prediction of prognostic outcomes.


Solution structure of the single-domain prolyl cis/trans isomerase PIN1At from Arabidopsis thaliana.
The 119-amino acid residue prolyl cis/trans isomerase from Arabidopsis thaliana (PIN1At) is similar to the catalytic domain of the human hPIN1. However, PIN1At lacks the N-terminal WW domain that appears to be essential for the hPIN1 function. Here, the solution structure of PIN1At was determined by three-dimensional nuclear magnetic resonance spectroscopy. The PIN1At fold could be superimposed on that of the catalytic domain of hPIN1 and had a 19 residue flexible loop located between strand beta1 and helix alpha1. The dynamical features of this beta1/alpha1-loop, which are characteristic for a region involved in protein-protein interactions, led to exchange broadening in the NMR spectra. When sodium sulfate salt was added to the protein sample, the beta1/alpha1 loop was stabilized and, hence, a complete backbone resonance assignment was obtained. Previously, with a phospho-Cdc25 peptide as substrate, PIN1At had been shown to catalyze the phosphoserine/phosphothreonine prolyl cis/trans isomerization specifically. To map the catalytic site of PIN1At, the phospho-Cdc25 peptide or sodium sulfate salt was added in excess to the protein and chemical shift changes in the backbone amide protons were monitored in the (1)H(N)-(15)N heteronuclear single quantum coherence spectrum. The peptide caused perturbations in the loops between helix alpha4 and strand beta3, between strands beta3 and beta4, in the alpha3 helix, and in the beta1/alpha1 loop. The amide groups of the residues Arg21 and Arg22 showed large chemical shift perturbations upon phospho-Cdc25 peptide or sulfate addition. We conclude that this basic cluster formed by Arg21 and Arg22, both located in the beta1/alpha1 loop, is homologous to that found in the hPIN1 crystal structure (Arg68 and Arg69), which also is involved in sulfate ion binding. We showed that the sulfate group competed for the interaction between PIN1At and the phospho-Cdc25 peptide. In the absence of the WW domain, three hydrophobic residues (Ile33, Ile34, and Leu35) located in the long flexible loop and specific for the plant PIN-type peptidyl prolyl cis/trans isomerases (PPIases) could be an additional interaction site in PIN1At. However, phospho-peptide addition did not affect the resonances of these residues significantly. Electrostatic potential calculations revealed a negatively charged area not found in hPIN1 on the PIN1At molecular surface, which corresponds to the surface shielded by the WW domain in hPIN1. Based on our experimental results and the molecular specificities of the PIN1At enzyme, functional implications of the lack of WW domains in this plant PIN-type PPIase will be discussed.


The biting performance of Homo sapiens and Homo heidelbergensis.
Modern humans have smaller faces relative to Middle and Late Pleistocene members of the genus Homo. While facial reduction and differences in shape have been shown to increase biting efficiency in Homo sapiens relative to these hominins, facial size reduction has also been said to decrease our ability to resist masticatory loads. This study compares crania of Homo heidelbergensis and H. sapiens with respect to mechanical advantages of masticatory muscles, force production efficiency, strains experienced by the cranium and modes of deformation during simulated biting. Analyses utilize X-ray computed tomography (CT) scan-based 3D models of a recent modern human and two H. heidelbergensis. While having muscles of similar cross-sectional area to H. heidelbergensis, our results confirm that the modern human masticatory system is more efficient at converting muscle forces into bite forces. Thus, it can produce higher bite forces than Broken Hill for equal muscle input forces. This difference is the result of alterations in relative in and out-lever arm lengths associated with well-known differences in midfacial prognathism. Apparently at odds with this increased efficiency is the finding that the modern human cranium deforms more, resulting in greater strain magnitudes than Broken Hill when biting at the equivalent tooth. Hence, the facial reduction that characterizes modern humans may not have evolved as a result of selection for force production efficiency. These findings provide further evidence for a degree of uncoupling between form and function in the masticatory system of modern humans. This may reflect the impact of food preparation technologies. These data also support previous suggestions that differences in bite force production efficiency can be considered a spandrel, primarily driven by the midfacial reduction in H. sapiens that occurred for other reasons. Midfacial reduction plausibly resulted in a number of other significant changes in morphology, such as the development of a chin, which has itself been the subject of debate as to whether or not it represents a mechanical adaptation or a spandrel.


Innovative screening tests for COVID-19 in South Korea.
Recently, the number of Corona Virus Disease 2019 (COVID-19) cases has increased remarkably in South Korea, so the triage clinics and emergency departments (ED) are expected to be overcrowded with patients with presumed infection. As of March 21st, there was a total of 8,799 confirmed cases of COVID-19 and 102 related deaths in South Korea that was one of the top countries with high incidence rates [1]. This sharp increase in infection is associated with 1) outbreaks in individual provinces, 2) deployment of rapid and aggressive screening tests, 3) dedicated healthcare staffs for virus screening tests, 4) quarantine inspection data transparency and accurate data reporting, and 5) public health lessons from previous Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) outbreaks. This commentary introduces innovative screening tests that are currently used in South Korea for COVID-19, e.g., Drive-Through and Walk-Through tests, and compare the advantages and disadvantages of both methods.


Cytodiagnosis of lesions of the pancreas and related areas.
Our experience of six and one-half years with cyto-diagnosis of pancreatic and related lesions is presented. We studied 22 cases of direct (perioperative and endoscopic) aspiration (group A) and 14 cases of percutaneous aspiration using ultrasound guidance (group B). Cytohistologic correlation in the direct aspiration cases and cytoclinical correlation in the percutaneous aspiration cases showed a specificity of 90% in group A and 100% in group B. Sensitivity was 100% in group A and 72.7% in group B. Predictive value of positive results was 92% in group A and 100% in group B. Eight of ten positive cancer cases in group A were confirmed by initial endoscopic tissue biopsies. One periampullary duodenal aspiration and one bile aspirate were cytologically positive, with negative endoscopic biopsy; final clinical evaluation with laparotomy confirmed these two cases as cancer. Thus, cytodiagnosis was more sensitive than tissue biopsy.


Comparative lipid and lipoprotein metabolism.
This review summarizes a number of recent reports in several areas of lipid and lipoprotein metabolism. Absorption of dietary lipids, cholesterol synthesis, and biliary cholesterol metabolism are mentioned only briefly to be complete. Comparative aspects of lipoprotein metabolism, however, are detailed in an effort to integrate the myriad metabolic events which characterize these important lipid transport particles. Where comparative information is known, those aspects of lipoprotein metabolism that may be protective against atherogenesis in certain mammalian species are also described. Efforts to understand atherogenic resistance comparatively in animals lends a better understanding of the metabolic events leading to coronary artery disease in humans. They also provide an important basis for understanding lipid metabolism in numerous veterinary species.