Relationship between activated clotting time and ischemic or hemorrhagic complications: analysis of 4 recent randomized clinical trials of percutaneous coronary intervention.
Unfractionated heparin (UFH) is the most widely used antithrombin during percutaneous coronary intervention (PCI). Despite significant pharmacological and mechanical advancements in PCI, uncertainty remains about the optimal activated clotting time (ACT) for prevention of ischemic or hemorrhagic complications. We analyzed the outcome of all UFH-treated patients enrolled in 4 large, contemporary PCI trials with independent adjudication of ischemic and bleeding events. Of 9974 eligible patients, maximum ACT was available in 8369 (84%). The median ACT was 297 seconds (interquartile range 256 to 348 seconds). The incidence of death, myocardial infarction, or revascularization at 48 hours, by ACT quartile, was 6.2%, 6.8%, 6.0%, and 5.7%, respectively (P=0.40 for trend). Covariate-adjusted rate of ischemic complications was not correlated with maximal procedural ACT (continuous value, P=0.29). Higher doses of UFH (>5000 U, or up to 90 U/kg) were independently associated with higher rates of events. The incidence of major or minor bleeding at 48 hours, by ACT quartile, was 2.9%, 3.5%, 3.8%, and 4.0%, respectively (P=0.04 for trend). In a multivariable logistic model with a spline transformation for ACT, there was a linear increase in risk of bleeding as the ACT approached 365 seconds (P=0.01), which leveled off beyond that value. Increasing UFH weight-indexed dose was independently associated with higher bleeding rates (OR 1.04 [1.02 to 1.07] for each 10 U/kg, P=0.001). In patients undergoing PCI with frequent stent and potent platelet inhibition use, ACT does not correlate with ischemic complications and has a modest association with bleeding complications, driven mainly by minor bleeding. Lower values do not appear to compromise efficacy while increasing safety.


Activating Natural Killer Cell Receptors, Selectins, and Inhibitory Siglecs Recognize Ebolavirus Glycoprotein.
Expression of the extensively glycosylated Ebolavirus glycoprotein (EBOV-GP) induces physical alterations of surface molecules and plays a crucial role in viral pathogenicity. Here we investigate the interactions of EBOV-GP with host surface molecules using purified EBOV-GP, EBOV-GP-transfected cell lines, and EBOV-GP-pseudotyped lentiviral particles. Subsequently, we wanted to examine which receptors are involved in this recognition by binding studies to cells transfected with the EBOV-GP as well as to recombinant soluble EBOV-GP. As the viral components can also bind to inhibitory receptors of immune cells (e.g., Siglecs, TIM-1), they can even suppress the activity of immune effector cells. Our data show that natural killer (NK) cell receptors NKp44 and NKp46, selectins (CD62E/P/L), the host factors DC-SIGNR/DC-SIGN, and inhibitory Siglecs function as receptors for EBOV-GP. Our results show also moderate to strong avidity of homing receptors (P-, L-, and E-selectin) and DC-SIGNR/DC-SIGN to purified EBOV-GP, to cells transfected with EBOV-GP, as well as to the envelope of a pseudotyped lentiviral vector carrying the EBOV-GP. The concomitant activation and inhibition of the immune system exemplifies the evolutionary antagonism between the immune system and pathogens. Altogether these interactions with activating and inhibitory receptors result in a reduced NK cell-mediated lysis of EBOV-GP-expressing cells. Modulation of these interactions may provide new strategies for treating infections caused by this virus.


AN 448 Sandoz (Mazindol) in the treatment of obesity.
The clinical value of a new anorectic agent, AN 448 Sandoz (mazindol) has been assessed in a double-blind trial against placebo in 50 obese patients. Over the 12 weeks of the trial, mazindol was shown to be an effective adjunct to carbohydrate restriction in weight reduction.


A Metacognitive Perspective of Visual Working Memory With Rich Complex Objects.
Visual working memory (VWM) has been extensively studied in the context of memory capacity. However, less research has been devoted to the metacognitive processes involved in VWM. Most metacognitive studies of VWM studies tested simple, impoverished stimuli, whereas outside of the laboratory setting, we typically interact with meaningful, complex objects. Thus, the present study aimed to explore the extent to which people are able to monitor VWM of real-world objects that are more ecologically valid and further afford less inter-trial interference. Specifically, in three experiments, participants viewed a set of either four or six memory items, consisting of images of unique real-world objects that were not repeated throughout the experiment. Following the memory array, participants were asked to indicate where the probe item appeared (Experiment 1) whether it appeared at all (Experiment 2) or whether it appeared and what was its temporal order (Experiment 3). VWM monitoring was assessed by subjective confidence judgments regarding participants' objective performance. Similar to common metacognitive findings in other domains, we found that subjective judgments overestimated performance and underestimated errors, even for real-world, complex items held in VWM. These biases seem not to be task-specific as they were found in temporal, spatial, and identity VWM tasks. Yet, the results further showed that meaningful, real-world objects were better remembered than distorted items, and this memory advantage also translated to metacognitive measures.


Neurobehavioral effects in HIV-positive individuals receiving highly active antiretroviral therapy (HAART) in Gaborone, Botswana.
To explore the prevalence and features of HIV-associated neurocognitive disorders (HANDS) in Botswana, a sub-Saharan country at the center of the HIV epidemic. A cross sectional study of 60 HIV-positive individuals, all receiving highly active antiretroviral therapy (HAART), and 80 demographically matched HIV-seronegative control subjects. We administered a comprehensive neuropsychological test battery and structured psychiatric interview. The lowest 10(th) percentile of results achieved by control subjects was used to define the lower limit of normal performance on cognitive measures. Subjects who scored abnormal on three or more measures were classified as cognitively impaired. To determine the clinical significance of any cognitive impairment, we assessed medication adherence, employment, and independence in activities of daily living (ADL). HIV+ subjects were impaired for all cognitive-motor ability areas compared with matched, uninfected control subjects. Thirty seven percent of HIV+ patients met criteria for cognitive impairment. These findings indicate that neurocognitive impairment is likely to be an important feature of HIV infection in resource-limited countries; underscoring the need to develop effective treatments for subjects with, or at risk of developing, cognitive impairment.


Assessment of malocclusion in pre-school children in Benin City using the incisor classification of malocclusion.
This study was aimed at analysing the incisors as a means of classifying malocclusion in pre-school children Incisal classification is not common but is a simple and reliable means of assessing malocclusion, especially in pre-school children. The classification is mainly used to describe the incisal relationship of cases in verbal and written communication between clinicians. Angle's classification holds when the first permanent molars are in place, but in the pre-school child, between the ages of 2-4 years, the first permanent molars may not have erupted. The methods of classifying malocclusion in pre-school children carried out by Foster and Hamilton (1969) and Baume (1950) took into consideration other parameters without the use of the incisors as a means of classifying malocclusion. The incisor classification would then be a more reliable means of analyzing the malocclusion and evaluating the need for early management. A sample of 505 pre-school children between the ages of 2-4 years of age were randomly selected from day care centres and pre-schools in three local government areas of Benin City, Edo State. The incisors were examined and classified using the British Standard Classification of Malocclusion. The results showed that the incisal Class I malocclusion was seen in 90.6% Class II in 2.4% (class II div 1 in 1.8% and class II div 2 in 0.6%) and the incisal class III in 7% of the total sample studied. The 4-year-old age group exhibited a higher frequency of malocclusion in the Class I, Class II div 1 and Class III groups, and showed no significant decrease with age (P > 0.05). Girls showed a higher frequency for a tendency to malocclusion than boys. Our findings show that the most common type of malocclusion seen in pre-school children is the incisal class I, followed by the incisal class III with the class II having the smallest number. The assessment of malocclusion using the incisal classification was fast and easy to use, and was able to detect those children that would require treatment later on. The importance of early detection of malocclusion as regards those that present a functional and aesthetic problem (class II and III) especially in pre-school children is suggested, in order to permit effective and long term planning, according to the child's individual requirements.


Protein Ontology: a controlled structured network of protein entities.
The Protein Ontology (PRO; http://proconsortium.org) formally defines protein entities and explicitly represents their major forms and interrelations. Protein entities represented in PRO corresponding to single amino acid chains are categorized by level of specificity into family, gene, sequence and modification metaclasses, and there is a separate metaclass for protein complexes. All metaclasses also have organism-specific derivatives. PRO complements established sequence databases such as UniProtKB, and interoperates with other biomedical and biological ontologies such as the Gene Ontology (GO). PRO relates to UniProtKB in that PRO's organism-specific classes of proteins encoded by a specific gene correspond to entities documented in UniProtKB entries. PRO relates to the GO in that PRO's representations of organism-specific protein complexes are subclasses of the organism-agnostic protein complex terms in the GO Cellular Component Ontology. The past few years have seen growth and changes to the PRO, as well as new points of access to the data and new applications of PRO in immunology and proteomics. Here we describe some of these developments.


Spleen neoangiogenesis in patients with myelofibrosis with myeloid metaplasia.
Neoangiogenesis is an integral component of bone marrow myeloproliferation in patients with myelofibrosis with myeloid metaplasia (MMM). As extramedullary haematopoiesis is a constitutive feature of MMM, we studied spleen neoangiogenesis by a computerized image analysis in MMM patients. Compared with five normal subjects, spleen CD34-staining capillary vascular density (CVD) was 2.1-3.03 times higher than the upper range of normal in six of the 15 (40%) MMM patients. CD8-staining sinusoidal vascular density (SVD) was constantly normal or lesser than normal and was inversely correlated with CVD (R = -0.53; P = 0.04). In MMM patients who did not receive cytoreductive or radiation therapy in the month before splenectomy (n = 9), the CVD was a significant determinant of spleen size (R = 0.88; P = 0.04). In MMM patients, the number of spleen CD34+ haematopoietic stem cells was increased from 1.2 to 98 times the upper limit of normal, and predicted the expansion of CVD (R = 0.57; P = 0.03). A population of cells expressing the CD34+/CD133+/VEGFR-2+ angiopoietic phenotype was present in the blood and spleen of five of seven patients. These results document that neoangiogenesis is an integral component of spleen re-localization of haematopoietic stem cells and suggest a cellular mechanism for spleen neoangiogenesis.


Analysis of 3D gene expression patterns in plants using whole-mount RNA in situ hybridization.
In situ mRNA hybridization is one of the most powerful techniques for analyzing patterns of gene expression. However, its usefulness is limited in complex plant tissues by the need to fix, embed and section samples before localizing the desired mRNA. Here we present a robust whole-mount in situ hybridization method that allows easy access to patterns of gene expression in intact, complex tissues, such as the inflorescence apex of Arabidopsis thaliana. The tissue is first fixed and then permeabilized by treatment with a cocktail of cell wall-digesting enzymes that has been optimized to preserve the integrity of tissue structures, while also permitting the detection of expression patterns in deep tissues. In addition to colorimetric staining, fluorimetric staining that can be imaged by confocal microscopy can also be used with this protocol, thus providing full 3D resolution. The entire procedure can take <3 d from tissue preparation to image acquisition.


Features of Spleen Development in Newborn Rats Exposed to Endocrine Disrupter Dichlorodiphenyltrichloroethane during the Prenatal Period.
The development of the spleen in newborn male Wistar rats exposed to low-dose endocrine disruptor dichlorodiphenyltrichloroethane during the prenatal period was studied. Histological examination of the spleen revealed a more active development of periarterial lymphoid sheaths and lower granulocyte content in the organ. Cytofluorimetry showed a significantly lower content of B cells. Thus, low-dose exposure of the endocrine disruptor dichlorodiphenyltrichloroethane on the developing organism during the prenatal period induced changes in spleen morphogenesis resulting in extensive development of lymphoid formations and a lower intensity of lymphocyte and granulocyte differentiation.


Application of HUMF13A01 (AAAG)n STR polymorphism to the genetic diagnosis of coagulation factor XIII deficiency.
Deficiency of the A subunit of coagulation factor XIII causes a severe bleeding disorder requiring life long replacement therapy. The mutations causing A subunit deficiency appear to be very heterogeneous, and it is impractical to identify each mutation before genetic counselling or prenatal diagnosis can be attempted. In this study we have shown that a highly polymorphic short tandem repeat element, HUMF13A01 (AAAG)n that occurs in the 5' flanking sequence of the factor XIII A subunit gene, can be used to follow the segregation of deficiency causing mutations. We studied 6 families with factor XIII A subunit deficiency from 5 different ethnic groups. All parents were heterozygous for the repetitive element and therefore all the families were informative. The linked polymorphism was used to carry out the first prenatal diagnosis of factor XIII A subunit deficiency. The analysis of this polymorphism by the polymerase chain reaction is rapid, reliable, requires little DNA and is ideal for the genetic analysis of factor XIII A subunit deficiency.


Reflex sympathetic dystrophy. Traumatic and postoperative presentation and management in the lower extremity.
Reflex sympathetic dystrophy is a difficult diagnostic and therapeutic problem. Although it is not widespread in the podiatric community, when encountered, it is difficult to manage. It can result after even simple surgical procedures or seemingly insignificant trauma. Early diagnosis and staging is the key to treatment.


Biosynthesis of magnetosome-nanobody complex in Magnetospirillum gryphiswaldense MSR-1 and a magnetosome-nanobody-based enzyme-linked immunosorbent assay for the detection of tetrabromobisphenol A in water.
In this study, two mutant strains, TBC and TBC+, able to biosynthesize a novel functional magnetosome-nanobody (Nb), were derived from the magnetotactic bacteria Magnetospirillum gryphiswaldense MSR-1. The magnetosome-Nbs biosynthesized by TBC+ containing multi-copies of the Nb gene had a higher binding ability to an environmental pollutant, tetrabromobisphenol A (TBBPA), than those biosynthesized by TBC containing only one copy of the Nb gene. The magnetosome-Nbs from TBC+ can effectively bind to TBBPA in solutions with high capacity without being affected by a broad range of NaCl and methanol concentrations as well as pH. Therefore, a magnetosome-Nb-based enzyme-linked immunosorbent assay (ELISA) was developed and optimized for the detection of TBBPA, yielding a half-maximum signal inhibition concentration of 0.23 ng/mL and a limit of detection of 0.025 ng/mL. The assay was used to detect TBBPA in spiked river water samples, giving average recoveries between 90 and 120% and coefficients of variation of 2.5-6.3%. The magnetosome-Nb complex could be reused 4 times in ELISA without affecting the performance of the assay. Our results demonstrate the potential of magnetosome-Nbs produced by TBC+ as cost-effective and environment-friendly reagents for immunoassays to detect small molecules in environmental waters.


Calcification in major vessel beds relates to vascular brain disease.
Calcification in atherosclerotic plaques is a novel marker of atherosclerosis and is related to cardiovascular disease. However, its relationship with cerebrovascular disease has not been investigated extensively. We investigated the relationship between calcification in various vessel beds outside the brain and imaging markers of vascular brain disease. A total of 885 community-dwelling people (mean age, 66.7 years) underwent computed tomography of the coronary arteries, aortic arch, and extracranial and intracranial carotid arteries to assess arterial calcification. Brain magnetic resonance imaging scans were performed to assess cerebral infarcts, microbleeds, and white matter lesions (WMLs). Calcification in each vessel bed was associated with presence of cerebral infarcts and with larger WML volume. The most prominent associations were found between intracranial carotid calcification and WML volume and between extracranial carotid calcification and infarcts. Adjustment for cardiovascular risk factors or ultrasound carotid plaque scores did not change these results. No associations were found between calcification and cerebral microbleeds. Arterial calcification in major vessel beds is associated with vascular brain disease on magnetic resonance imaging. Most notably, larger intracranial carotid calcification load relates to larger WML volumes, and larger extracranial carotid calcification load relates to the presence of cerebral infarcts, independently of ultrasound carotid plaque score. This suggests that calcification of atherosclerotic plaque yields other information in addition to merely the presence of plaques, providing novel insights into the etiology of vascular brain disease.


Conformational Changes of a Surface-Tethered Polymer during Radical Growth Probed with Second-Harmonic Generation.
The surface-induced polymerization of a chromophore-functionalized monomer was probed in situ for the first time using a nonlinear optical technique, second-harmonic generation. During the first hours of the polymerization reaction, dramatic changes in the tilt angle of the chromophore-functionalized side groups were observed. Following evaluation of the nonlinear optical data with those obtained from atomic force microscopy and ultraviolet-visible, we conclude that second-harmonic generation efficiently probes the polymerization reaction and the conformational changes of the surface-grafted polymer. With polymerization time, the conformation of the surface-tethered polymer changes from a conformation with the polymer backbone and its side groups flat on the surface, i.e., a "pancake" conformation, to a conformation where the polymer backbone is stretched away combined with tilted side groups or an enlarged tilt angle distribution, i.e., a "brush-type" conformation.


The Neurogenome study: Comprehensive molecular profiling to optimize treatment for Danish glioblastoma patients.
Glioblastoma is an aggressive brain cancer with no possibility for cure. Treatment and survival have only improved slightly since 2005 when the current regime was implemented. The limited improvements in the treatment of glioblastoma may reflect our poor understanding of the disease. We hypothesize that systematically collected translational data will improve knowledge and hereby treatment. We have been performing whole exome sequencing in glioblastoma tumor tissue since 2016 and whole genome sequencing (WGS) since 2020 with the aim of offering experimental treatment. We have sequenced 400+ GBM patients and from these 100+ are paired tumor samples from relapse surgery. To develop genomic profiling and to increase the information on each patient´s contribution, we have initiated the Neurogenome study as of June 2022. The Neurogenome protocol is a national, comprehensive, translational, and omic protocol. It is a continuation of 2 previous protocols from 2016 and forth in our department, but with more substudies added, focusing on the translational and clinical utility. We collect and analyze data from an out-patient clinic in a systematic approach to a number of subprojects ranging from basic science to applied clinical science, including clinical trials. The protocol will act as a backbone for future projects in the national research center, Danish Comprehensive Cancer Center-Brain Tumor Center with the overall aim to select eligible patients for experimental treatment based upon genomic alterations. The article will present the Neurogenome setup and a presentation of selected projects that are based upon inclusion.


Human Enriched Serum Following Hydrolysed Collagen Absorption Modulates Bone Cell Activity: from Bedside to Bench and Vice Versa.
Collagen proteins are crucial components of the bone matrix. Since collagen-derived products are widely used in the food and supplement industry, one may raise the question whether collagen-enriched diets can provide benefits for the skeleton. In this study, we designed an innovative approach to investigate this question taking into account the metabolites that are formed by the digestive tract and appear in the circulation after ingestion of hydrolysed collagen. Blood samples collected in clinical and pre-clinical trials following ingestion and absorption of hydrolysed collagen were processed and applied on bone-related primary cell cultures. This original ex vivo methodology revealed that hydrolysed collagen-enriched serum had a direct impact on the behaviour of cells from both human and mouse origin that was not observed with controls (bovine serum albumin or hydrolysed casein-enriched serum). These ex vivo findings were fully in line with in vivo results obtained from a mouse model of post-menopausal osteoporosis. A significant reduction of bone loss was observed in mice supplemented with hydrolysed collagen compared to a control protein. Both the modulation of osteoblast and osteoclast activity observed upon incubation with human or mouse serum ex vivo and the attenuation of bone loss in vivo, clearly indicates that the benefits of hydrolysed collagen for osteoporosis prevention go beyond the effect of a simple protein supplementation.


Electricity generation from model organic wastewater in a cassette-electrode microbial fuel cell.
A new highly scalable microbial fuel cell (MFC) design, consisting of a series of cassette electrodes (CE), was examined for increasing power production from organic matter in wastewater. Each CE chamber was composed of a box-shaped flat cathode (two air cathodes on both sides) sandwiched in between two proton-exchange membranes and two graphite-felt anodes. Due to the simple design of the CE-MFC, multiple cassettes can be combined to form a single unit and inserted into a tank to treat wastewater. A 12-chamber CE-MFC was tested using a synthetic wastewater containing starch, peptone, and fish extract. Stable performance was obtained after 15 days of operation in fed-batch mode, with an organic removal efficiency of 95% at an organic loading rate of 2.9 kg chemical oxygen demand (COD) per cubic meter per day and an efficiency of 93% at 5.8 kg COD per cubic meter per day. Power production was stable during this period, reaching maximum power densities of 129 W m(-3) (anode volume) and 899 mW m(-2) (anode projected area). The internal resistance of CE-MFC decreased from 2.9 (day 4) to 0.64 Omega (day 25). These results demonstrate the usefulness of the CE-MFC design for energy production and organic wastewater treatment.


"I'm So Tired": Fatigue as a Persistent Physical Symptom among Working People Experiencing Exhaustion Disorder.
Fatigue is widespread in the population, particularly among working people. Exhaustion disorder (ED), a clinical manifestation of burnout, is common, but, after treatment, about one-third still experience fatigue and other physical symptoms. We propose that in some instances, fatigue as a persistent physical symptom (PPS) might be a more appropriate formulation of ED patients' fatigue problems, and we suggest that ED patients who meet fatigue PPS criteria will differ from other ED patients in terms of psychological distress, non-fatigue PPSs and functional impairment. Questionnaires were sent to 10,956 members of a trade union of which 2479 (22.6%) responded. Of 1090 participants who met criteria for ED, 106 (9.7%) met criteria for fatigue as a PPS. Participants who met fatigue PPS criteria scored on average higher on measures of depression, anxiety and functional impairment and were more likely to have clinically significant scores. Moreover, they had 27 times higher odds of meeting other PPS subtypes and reported more non-fatigue PPS subtypes, suggesting a more complex health problem. Specific evidence-based interventions are available for both ED and PPSs, and therefore, it is crucial to accurately formulate the fatigue problem reported by patients to provide appropriate treatment.


Intrahepatic chemotherapy with floxuridine, leucovorin and dexamethasone in continuous infusion and mitomycin-C bolus in unresectable hepatic metastases from colorectal cancer: a phase II study.
Intrahepatic continuous infusion FUDR induces a 50% response rate in patients with hepatic metastases from colorectal cancer. Lower rates have been observed in pretreated patients. The combination of floxuridine plus leucovorin has obtained over 70% responses, with high hepatic toxicity. The use of dexamethasone can decrease hepatic toxicity. A randomized study reported an increase in response rate and a decrease in hepatic toxicity in a group of patients treated with floxuridine plus dexamethasone compared to a group receiving only floxuridine. Moreover, the combination of mitomycin C, carmustine and floxuridine is also effective in pretreated patients. On such premises, since July 1993 we have treated 39 patients affected by unresectable hepatic metastases from colon carcinoma (26 patients) and rectal carcinoma (13 patients) with the combination continuous infusion of floxuridine (0.20 mg/kg per day) + leucovorin (7.5 mg/m2/day) + dexamethasone (20 mg on days 1 to 14) and bolus mitomycin C (10 mg/m2 on day 1) via the hepatic artery. Cycles were administered every four weeks. There were as 28 males and 11 females, with a median age of 64 years (range, 39-75) and a median PS = 0. Twenty-two patients were pretreated with systemic chemotherapy including 5-fluorouracil plus leucovorin. Total number of cycles was 189, with a median of 6 cycles per patient (range, 1-12). Of 39 patients 37 were assessable for response (2 patients were not assessable because they stopped chemotherapy for occlusion of the catheter after the first cycle). There were 3 complete responses (1 in a naive patient and 2 in pretreated patients), 16 partial responses (11 in pretreated patients and 5 in chemonaive patients), 4 minor responses, 4 stable disease and 10 progressive disease. The overall response rate was 51.3% (95 Cl, 51.3-86.7%). Median time to progression was 6 months (range, 1-34+). Overall survival was 18 months (range, 1-34+). Of 39 patients, 36 were assessable for toxicity (WHO) (3 patients died after the first cycle for progression of disease): diarrhea and nausea-vomiting grade 3-4 occurred respectively in 15 (41%) and 3 patients (8%); hepatic toxicity was mild. The treatment we used showed an elevated activity in liver metastases from colorectal cancer even in patients pretreated and resistant to systemic chemotherapy, although toxicity grade 3-4 diarrhea occurred in approximately 40% of the patients.


COMPARING THE EFFECTS OF LITHIUM HEPARIN AND DIPOTASSIUM ETHYLENEDIAMINETETRAACETIC ACID ON HEMATOLOGIC VALUES IN EASTERN BOX TURTLES (TERRAPENE CAROLINA CAROLINA).
Anticoagulants are employed to prevent clotting and preserve cellular morphology for clinical pathology tests. Lithium heparin (LH) is the most frequently used anticoagulant in chelonians; however, dipotassium ethylenediaminetetraacetic acid (EDTA) may be superior in some species. Although eastern box turtles' (Terrapene carolina carolina) hematologic parameters are well studied, the effects of different anticoagulants on hematology in this species are unknown. This study evaluated the effects of LH and EDTA on hematologic values in free-living eastern box turtles (N = 59). Blood samples were collected from eastern box turtles in Illinois and immediately divided between LH and EDTA microtainers, and complete blood counts were performed on each sample. Grossly, plasma from EDTA blood samples was frequently and significantly hemolyzed. Blood mixed with LH had higher packed cell volume (PCV) (P = 0.04), white blood cell count (WBC) determined by Leukopet (P < 0.0001), WBC determined by blood film estimate (P < 0.0001), absolute heterophils (P = 0.007), absolute lymphocytes (P < 0.0001), and lower total solids (P < 0.0001) and absolute monocytes (P = 0.0001) than blood mixed with EDTA. All relative leukocyte counts were significantly different between the anticoagulants (P < 0.0001). EDTA apparently lysed turtle erythrocytes in this study, making it difficult to accurately count white blood cells and artificially lowering PCV. These findings demonstrate that EDTA should not be used in eastern box turtles.


The roles of different CLE domains in Arabidopsis CLE polypeptide activity and functional specificity.
The CLE (CLVATA3/ESR-related) family of plant polypeptide signaling molecules shares a conserved 14-amino-acid (aa) motif, designated the CLE motif, which recent studies suggest is sufficient for CLE function in vitro. In this study, we report that Arabidopsis CLE proteins can function in a tissue-specific manner and confirm some CLE factors can act through different receptors. Using domain swapping, we show for the first time that the CLE motif likely determines much of the functional tissue-specificity of the proteins in planta. However, we also provide evidence in support of the new view that sequences outside the CLE motif (14 aa) contribute to CLE function and functional specificity in vivo. Additionally, we report that deletion of the putative signal peptide from different CLE proteins completely inactivates CLE function in vivo, whereas exchanging the CLE signal peptides with a conventional signal peptide from a rice glycine-rich cell wall protein also influences CLE function. We thus propose that the CLE motif itself determines its functional tissue-specificity by dictating the direct recognition and interaction of each CLE peptide with its optimal receptor(s), whereas the receptor(s) may be available in a tissue-specific manner. On the other hand, the sequences outside the CLE motif may influence CLE function by affecting the processing of CLE peptides, resulting in a change in the availability and/or abundance of CLE peptides in specific tissues and/or cells.


Childhood lead exposure in France: benefit estimation and partial cost-benefit analysis of lead hazard control.
Lead exposure remains a public health concern due to its serious adverse effects, such as cognitive and behavioral impairment: children younger than six years of age being the most vulnerable population. In Europe, the lead-related economic impacts have not been examined in detail. We estimate the annual costs in France due to childhood exposure and, through a cost benefit analysis (CBA), aim to assess the expected social and economic benefits of exposure abatement. Monetary benefits were assessed in terms of avoided national costs. We used results from a 2008 survey on blood-lead (B-Pb) concentrations in French children aged one to six years old. Given the absence of a threshold concentration being established, we performed a sensitivity analysis assuming different hypothetical threshold values for toxicity above 15 μg/L, 24 μg/L and 100 μg/L. Adverse health outcomes of lead exposure were translated into social burden and economic costs based on literature data from literature. Direct health benefits, social benefits and intangible avoided costs were included. Costs of pollutant exposure control were partially estimated in regard to homes lead-based paint decontamination, investments aiming at reducing industrial lead emissions and removal of all lead drinking water pipes. The following overall annual benefits for the three hypothetical thresholds values in 2008 are: €22.72 billion, €10.72 billion and €0.44 billion, respectively. Costs from abatement ranged from €0.9 billion to 2.95 billion/year. Finally, from a partial CBA of lead control in soils and dust the estimates of total net benefits were € 3.78 billion, € 1.88 billion and €0.25 billion respectively for the three hypothesized B-Pb effect values. Prevention of childhood lead exposure has a high social benefit, due to reduction of B-Pb concentrations to levels below 15 μg/L or 24 μg/L, respectively. Reducing only exposures above 100 μg/L B-Pb has little economic impact due to the small number of children who now exhibit such high exposure levels. Prudent public policies would help avoiding future medical interventions, limit the need for special education and increase future productivity, and hence lifetime income for children exposed to lead.


Particle manipulations in non-Newtonian microfluidics: A review.
Microfluidic devices have been widely used since 1990s for diverse manipulations of particles (a general term of beads, cells, vesicles, drops, etc.) in a variety of applications. Compared to the active manipulation via an externally imposed force field, the passive manipulation of particles exploits the flow-induced intrinsic lift and/or drag to control particle motion with several advantages. Along this direction, inertial microfluidics has received tremendous interest in the past decade due to its capability to handle a large volume of samples at a high throughput. This inertial lift-based approach in Newtonian fluids, however, becomes ineffective and even fails for small particles and/or at low flow rates. Recent studies have demonstrated the potential of elastic lift in non-Newtonian fluids for manipulating particles with a much smaller size and over a much wider range of flow rates. The aim of this article is to provide an overview of the various passive manipulations, including focusing, separation, washing and stretching, of particles that have thus far been demonstrated in non-Newtonian microfluidics.


Optical biosensors based on refractometric sensing schemes: A review.
Biosensor technology is an active field of research and development presenting rapid progress in recent decades, and the subfield of optical biosensors based on refractometric sensing schemes has developed dramatically during this time. This review focuses on advances in the refractometric sensing-based guided-wave optical biosensors particularly in the last two decades. It starts with a concise discussion on the underlying principles of label-free refractometric biosensor. Subsequently, advances in biosensor design, especially the transducer configuration and the integration of the sensing device are reviewed, highlighting the challenges and efforts dedicated to improving this technology. Various surface functionalization strategies designed to produce well-defined and reproducible surface properties are introduced for evaluation. Refractometric sensing scheme-based optical biosensors have found versatile applications varying from environmental monitoring and food safety to clinical diagnostics, together with advances in these applications and others are described. This paper concludes with a brief discussion on the outlook for integrating biosensors with emerging technologies.


Right ventricular sensitivity to metabolic injury during cardiopulmonary bypass.
To determine intrinsic right ventricular susceptibility to metabolic injury, we examined the effect of ischemia and reperfusion during cardiopulmonary bypass on right and left ventricular myocardial adenine nucleotide metabolism in the absence of ventricular work load as a determinant of energy production and utilization. Dogs were subjected either to 30 minutes of normothermic or hypothermic myocardial ischemia and reperfusion or to 60 minutes of potassium-arrested normothermic ischemia; serial ventricular biopsy specimens were assayed for adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, nucleoside, and base content. In each group the depletion rates of right and left ventricular nucleotides with ischemia did not differ. Mitochondrial ability to rephosphorylate the nucleotide pool during and after ischemia also did not differ in the two ventricles, and there were no detectable differences in the catabolism of nucleotide precursors and loss of total purine content with reperfusion. These observations indicate that right ventricular myocardium is as equally sensitive to ischemic and reperfusion injury as left ventricular myocardium, and metabolic recovery from injury is equally prolonged.


Functional neuroanatomical investigation of vision-related acupuncture point specificity--a multisession fMRI study.
The concept that specific acupuncture points have salubrious effects on distant target organ systems is a salient feature of Traditional Chinese Medicine (TCM). In this study, we used a multiple-session experiment to test whether electroacupuncture stimulation at two TCM vision-related acupoints, UB 60 and GB 37, located on the leg, could produce fMRI signal changes in the occipital regions of the brain, and the specificity of this effect when compared with stimulation at an adjacent non-acupoint (NAP). Six normal, acupuncture naive subjects completed the study. Each subject participated in six identical scanning sessions. Voxelwise group analysis showed that electroacupuncture stimulation at both vision-related acupoints and the NAP produced modest, comparable fMRI signal decreases in the occipital cortex, including the bilateral cuneus, calcarine fissure and surrounding areas, lingual gyrus, and lateral occipital gyrus. Further analysis of fMRI signal changes in occipital cortex showed no significant difference among the three points, UB 60, GB 37, and NAP. Our results thus do not support the view that acupuncture stimulation at vision-related acupoints induces specific fMRI blood oxygen level dependent (BOLD) signal changes in the occipital cortex. We speculate that cross modal inhibition, produced by needling-evoked somatosensory stimulation, may account for our finding of BOLD signal decreases in the occipital cortex. Given the complexity of acupuncture systems and brain activity, additional work is required to determine whether functional neuroanatomical correlates of acupoint specificity can be validated by means of brain imaging tools.


Conducting rehabilitation groups for people suffering from chronic pain.
The aim of this study was to offer guidelines for counsellors who work with rehabilitation groups of patients with chronic pain. The sample involved nine counsellors engaged in a multidisciplinary pain management programme. Two focus group interviews were conducted. Data were analysed using qualitative content analysis. These indicate that main challenges facing counsellors were related to maintaining constructive group processes and being mentally prepared. The counsellors reported that knowledge concerning self-awareness, theoretical frameworks and counselling techniques was important. Personal learning included: group leadership, teamwork, grasping the inside story and obtaining supervision. The results show how important it is to have trained counsellors that are well prepared to prevent and deal with challenging group processes. Counsellors need to understand the concept of pain and be acquainted with cognitive behavioural framework and group processes. The results indicate that counsellors perceive regular supervision as supportive and is likely to promote good team functioning.


Thermal Sensations during a Partial-Body Cryostimulation Exposure in Elite Basketball Players.
Partial-body cryostimulation is used to improve recovery after exercise, especially during competitions or heavy training; however, a limited number of studies have been conducted with international-level athletes in situ during competitions. This study was undertaken to assess the thermal sensation ratings during 3 min of cold exposure (at -130°C) in 24 international-level athletes during the European Basketball Championship. The mean thermal sensation score, measured using a perceptive scale, increased significantly (p < 0.05) during partial-body cryostimulation exposure in athletes from 3.0 ± 1.7 at 30 s to 5.7 ± 2.3 at 3 min (maximal observed value = 10.0). The mean value of 5.7 is considered a "cold" sensation on the scale (ranging from 0 = neutral sensation to 10 = very cold). However, we observed a large inter-individual variation in the perceived thermal sensations. The body mass index was significantly and negatively correlated with the thermal sensation value after 2 min 30 s and 3 min of exposure in females (r = -0.61, n = 13, p < 0.05; r = -0.56, n = 13, p = 0.054, respectively). Three participants reported high perceived thermal sensation after 30 s of exposure and their cold-induced discomfort worsened as the exposure continued. In conclusion, a 3-min exposure is globally well tolerated by athletes and can be used during a heavy competition period and/or during a training period. However, special attention should be given to female athletes with a low body mass index as they seem to be much more sensitive to cold.


Osteogenic lithium-doped brushite cements for bone regeneration.
This study investigated the osteogenic performance of new brushite cements obtained from Li+-doped β-tricalcium phosphate as a promising strategy for bone regeneration. Lithium (Li+) is a promising trace element to encourage the migration and proliferation of adipose-derived stem cells (hASCs) and the osteogenic differentiation-related gene expression, essential for osteogenesis. In-situ X-ray diffraction (XRD) and in-situ 1H nuclear magnetic resonance (1H NMR) measurements proved the precipitation of brushite, as main phase, and monetite, indicating that Li+ favored the formation of monetite under certain conditions. Li+ was detected in the remaining pore solution in significant amounts after the completion of hydration. Isothermal calorimetry results showed an accelerating effect of Li+, especially for low concentration of the setting retarder (phytic acid). A decrease of initial and final setting times with increasing amount of Li+ was detected and setting times could be well adjusted by varying the setting retarder concentration. The cements presented compressive mechanical strength within the ranges reported for cancellous bone. In vitro assays using hASCs showed normal metabolic and proliferative levels. The immunodetection and gene expression profile of osteogenic-related markers highlight the incorporation of Li+ for increasing the in vivo bone density. The osteogenic potential of Li-doped brushite cements may be recommended for further research on bone defect repair strategies.


Maspin controls mammary tumor cell migration through inhibiting Rac1 and Cdc42, but not the RhoA GTPase.
Rac1 and Cdc42 are members of the Rho family of small GTPases that play essential roles in diverse cellular functions, including cell migration. The activities of these Rho family proteins are controlled by growth factor receptor activation and cell-ECM interactions. Here, we show that maspin, a well-documented tumor suppressor gene, also controls cell motility through inhibiting Rac1/Cdc42 activity. Using the GST-PAK and GST-Rho binding protein pull-down assays for GTP-bound Rac1, Cdc42, and RhoA, we showed that treatment of MDA-MB-231 tumor cells with recombinant maspin for a short time period significantly inhibited the activity of Rac1 and Cdc42, but not RhoA. The reactive site loop (RSL) within maspin protein is the functional domain involved in the inhibition. Maspin mutants with the RSL deleted or a point mutation in the RSL region lost their inhibitory activity. We further examined the ability of maspin to inhibit Rac1- and Cdc42-mediated signaling pathways and transcription factors. Treatment of MDA-MB-231 cells with maspin led to the inhibition of JNK kinase activity as assayed by immuno-kinase assays. In addition, the AP-1 transcription activity downstream of JNK kinase pathway was also reduced. Together, we have identified Rac1 and Cdc42 as the downstream targets that mediate the inhibition of mammary tumor cell migration by maspin.


Design and synthesis of sirtinol analogs as human neutrophil elastase inhibitors.
Human neutrophil elastase (HNE) overexpression has a crucial role in most acute inflammation and alpha1-antitrypsin deficiency syndromes observed in humans, triggering neutrophil invasion and activation of macrophage inflammatory and proteolytic effects, leading to tissue damage. Manipulating HNE level homeostasis could potentially help treat neutrophilic inflammation. Previous studies have shown that sirtinol (1) has a specific influence on HNE and potently attenuates acute lung injury and hepatic injury mediated by lipopolysaccharide or trauma hemorrhage. Therefore, 1 was chosen as the model structure to obtain more potent anti-HNE agents. In the present study, we synthesized a series of sirtinol analogues and determined their inhibitory effects on HNE. Structure-activity relationship (SAR) studies showed that swapping the imine and methyl groups of the sirtinol scaffold with diazene and carboxyl groups, respectively, enhances the HNE inhibiting potency. Compound 29 exhibited the highest potency in the SAR study and showed dual inhibitory effects on HNE and proteinase 3 with IC50 values of 4.91 and 20.69 µM, respectively. Furthermore, 29 was confirmed to have dual impacts on inhibiting O2•- generation and elastase release in cell-based assays with IC50 values of 0.90 and 1.86 µM, respectively. These findings suggest that 29 is a promising candidate for developing HNE inhibitors in the treatment of neutrophilic inflammatory diseases.


[Hemorheology and blood thrombotic potential in pulmonary thromboembolism].
Examination of 138 patients with acute venous thrombosis of the lower limbs, which was complicated by thromboembolism of the pulmonary artery in 49 of them, showed the rheologic status to be disturbed to a greater extent in patients with pulmonary embolism than in those with acute venous thrombosis. An interrelationship between the rheologic properties and the coagulation system of the blood in various conditions of the hemostasis system was revealed. It is pointed out that pathogenetically grounded correction of the disorders of the blood coagulation and rheologic systems is necessary in choosing the method for treatment and prevention of acute venous thrombosis and pulmonary embolism.


A single nucleotide polymorphism in fibronectin 1 determines tumor shape in colorectal cancer.
Depressed and flat surface lesions are not easy to identify with routine colonoscopies during screening for colorectal cancer (CRC). Identifying clinically relevant genes that influence tumor shape could be useful when screening for the presence of depressed lesions. Total RNA was extracted from tumor cells collected by laser microdissection from the primary lesions of 146 CRC cases. Microarray analysis was performed to identify genes that were differentially expressed between depressed and elevated tumors. Single nucleotide polymorphism (SNP) analysis of genomic DNA from the peripheral blood of 67 CRC patients was then used to associate polymorphisms with the occurrence of depressed tumors. Microarray analysis revealed significantly higher expression of the fibronectin 1 (FN1) gene in 129 depressed-type tumors and lesions compared to 17 elevated-type tumors. FN1-abundant CRC tumors were large with a significantly higher incidence of lymphatic permeation. SNP analysis indicated that 44 tumors with a GG genotype at SNP rs6707530 showed significantly higher FN1 expression than did 23 tumors with GT/TT genotypes (p<0.05). The product of the FN1 gene (located at 2q34) is involved in cell adhesion, migration and metastasis in mesenchymal tumors. Abundant expression of FN1 may allow cancer cells to invade deeper layers, which would eventually define tumor shape. Identification of this SNP in blood samples may facilitate disease diagnosis and allow prediction of the presence of depressed tumors in the colorectal epithelium before a colon fiberscope examination.


Can secondary osteoporosis be identified when screening for osteoporosis with digital X-ray radiogrammetry? Initial results from the Stockholm Osteoporosis Project (STOP).
To identify causes of low age-adjusted bone mass at digital X-ray radiogrammetry (DXR) in individuals attending an osteoporosis screening program. In a descriptive observational cohort study, women aged 40-75 years who attended a general mammography screening program had their bone mass investigated with DXR and answered a questionnaire regarding several clinical risk factors for osteoporosis. Each month the 2% with the lowest Z-scores were selected for further clinical examination with DXA of the hip and lumbar spine and pre-defined blood tests. Causes of secondary osteoporosis determined by clinical and laboratory evaluation. 14,783 women attended mammography screening and had their bone mass evaluated. In total, 327 women had a low DXR BMD and 281 accepted further DXA examination. Of these, 93 (33.1%) had osteoporosis. The diagnosis was new in 79 cases (84.9%) and in 32 (34.4%) a potential underlying cause was identified. Primary hyperparathyroidism was found in 8.6% and secondary hyperparathyroidism in 13.5%. Several self-reported risk factors for osteoporosis, including rheumatic disease, insulin-treated diabetes, cortisone treatment, smoking, reduced mobility, hyperparathyroidism, and malabsorption, were significantly more common among those selected for DXA referral than in the total cohort. For example, rheumatic disease and insulin-treated diabetes were reported 3.4 and 2.3 times as often, respectively. The prevailing potential cause of secondary osteoporosis according to DXR was primary and secondary hyperparathyroidism. Most of the women with these conditions were previously undiagnosed, indicating that further follow-up of patients with low age-adjusted DXR BMD is justified.


[STAT5B deficiency: a new growth hormone insensitivity syndrome associated to immunological dysfunction].
A new presentation of growth hormone insensitivity (GHI) caused by homozygous mutations in STAT5B (signal transducer and activator of transcription 5B) gene has been characterized in the last years. Its particularity is the association with severe immune dysfunction, especially with lymphocytic interstitial pneumonitis. This may mislead physicians into considering short stature as secondary to chronic immunological disease and consequently into underdiagnosing this form of GHI. The objective of this review is to propagate current knowledge about this rare pathology, facilitating the diagnosis of patients with GHI due to STAT5B mutations in endocrinology and other specialties clinics.


Fibromyxoma masquerading as dacryocystitis.
Primary tumors of the lacrimal sac are extremely rare and predominantly epithelial in origin. We report a unique case of fibromyxoma of the lacrimal sac in an 86-year-old Caucasian woman who presented with 3 months of lower eyelid edema and 1 week of purulent discharge, epiphora, and acute pain. Examination revealed right lower eyelid erythema/edema and a tender, firm, palpable mass of the right lacrimal sac, which self-expressed a yellow, purulent discharge. On surgical exploration, a firm, rubbery, yellow mass was encountered and excised. Histopathologic analysis identified a nonencapsulated mass composed of loose interlacing fascicles and bundles of spindle-shaped cells with prominent myxoid changes; immunostaining was strongly positive for vimentin, weakly for smooth muscle actin, and negative for S-100 and muscle-specific actin. These findings were consistent with the diagnosis of a fibromyxoma of the lacrimal drainage system. After excision, the patient did well, with resolution of dacryocystitis.


MUCOPOLYSACCHARIDOSIS II (MPS II) IN A FREE-LIVING KAKA (NESTOR MERIDIONALIS) IN NEW ZEALAND.
A lysosomal storage disease, identified as a mucopolysaccharidosis (MPS), was diagnosed in a free-living Kaka (Nestor meridionalis), an endemic New Zealand parrot, which exhibited weakness, incoordination, and seizures. Histopathology showed typical colloid-like cytoplasmic inclusions in Purkinje cells and many other neurons throughout the brain. Electron microscopy revealed that storage bodies contained a variety of linear, curved, or circular membranous profiles and electron-dense bodies. Because the bird came from a small isolated population of Kaka in the northern South Island, a genetic cause was deemed likely. Tandem mass spectrometry revealed increased levels of heparan sulfate-derived disaccharides in the brain and liver compared with tissues from controls. Enzymatic assays documented low levels of iduronate-2-sulfatase activity, which causes a lysosomal storage disorder called MPS type II or Hunter syndrome. A captive breeding program is currently in progress, and the possibility of detecting carriers of this disorder warrants further investigation.


Dinucleotide and stop codon frequencies in single-stranded RNA viruses.
To identify potential selection pressures which lead to RNA sequence conservation, we examined the occurrence rates of dinucleotides in 64 single-stranded RNA virus genomes. These viruses may offer a particular insight into these pressures since their RNA-dependent RNA polymerases lack proofreading capability. This potentiates introduction of mutations into their genomes, yet unidentified selection processes conserve the genomes to a large degree. We report a strong inverse correlation between the C+G content and the occurrence of the CpG dinucleotide (r=0.71) in the RNA virus genomes, in contrast to earlier reports (Karlin et al., 1994, Journal of Virology 68, 2889-2897). We also detected significant suppression of UpA, correlating inversely with genomic U+A content. These suppressions are coupled with over-representation of the complementary pair of dinucleotides, CpA and UpG. In addition, we highlight the fact that odds ratios for dinucleotides are not independent variables, a situation apparently not widely appreciated in the literature. This led us to view the over-representation of CpA and UpG as a consequential outcome of UpA and CpG suppression in the virus genomes. Potential factors influencing these disturbances are discussed. In addition, higher than random incidence was observed for 'out-of-frame' stop codons in the viral RNA genomes, with some preferences for individual codons being exhibited by certain virus groups. The UAG codon appeared more common in the +1 frame, the UGA in the -1 frame.


CD antigens 2001.
The most recent Human Leucocyte Differentiation Antigen Workshop ("HLDA7") took place in 2000 in Harrogate, UK and the proceedings are about to be published (Leucocyte Typing VII). New Sections were introduced in this Workship (Dendritic cells, Stem/progenitor cells, Erythroid cells and Carbohydrate Structures) and monoclonal antibodies were selected for which at least some molecular data were already available (to avoid "blind" screening of reagents against known specificities). A total of more than 80 new CD specificities were established (previously the average was less than 30 new CD specificities per Workshop) and these are listed in this article. There is already evidence for the existence of many new leucocyte surface molecules for study at the next HLDA Workshop (in Adelaide in 2004), and we have listed in this article a number of such potential CD candidates (identified following the production of monoclonal antibodies or via gene cloning). There are also today an increasing number of lineage- and/or stage-restricted leucocyte-associated molecules localised within the cell cytoplasm (or nucleus): they will certainly prove of intense in the future for many laboratories studying human haematopoietic cells (regardless of whether a new "intracellular CD" categorisation scheme is devised for such molecules).


Early Events in the Molecular Pathogenesis of Lung Cancer.
The majority of cancer-related deaths in the United States and worldwide are attributed to lung cancer. There are more than 90 million smokers in the United States who represent a significant population at elevated risk for lung malignancy. In other epithelial tumors, it has been shown that if neoplastic lesions can be detected and treated at their intraepithelial stage, patient prognosis is significantly improved. Thus, new strategies to detect and treat lung preinvasive lesions are urgently needed in order to decrease the overwhelming public health burden of lung cancer. Limiting these advances is a poor knowledge of the earliest events that underlie lung cancer development and that would constitute markers and targets for early detection and prevention. This review summarizes the state of knowledge of human lung cancer pathogenesis and the molecular pathology of premalignant lung lesions, with a focus on the molecular premalignant field that associates with lung cancer development. Lastly, we highlight new approaches and models to study genome-wide alterations in human lung premalignancy in order to facilitate the discovery of new markers for early detection and prevention of this fatal disease. Cancer Prev Res; 9(7); 518-27. ©2016 AACR.


Creating speech-synchronized animation.
We present a facial model designed primarily to support animated speech. Our facial model takes facial geometry as input and transforms it into a parametric deformable model. The facial model uses a muscle-based parameterization, allowing for easier integration between speech synchrony and facial expressions. Our facial model has a highly deformable lip model that is grafted onto the input facial geometry to provide the necessary geometric complexity needed for creating lip shapes and high-quality renderings. Our facial model also includes a highly deformable tongue model that can represent the shapes the tongue undergoes during speech. We add teeth, gums, and upper palate geometry to complete the inner mouth. To decrease the processing time, we hierarchically deform the facial surface. We also present a method to animate the facial model over time to create animated speech using a model of coarticulation that blends visemes together using dominance functions. We treat visemes as a dynamic shaping of the vocal tract by describing visemes as curves instead of keyframes. We show the utility of the techniques described in this paper by implementing them in a text-to-audiovisual-speech system that creates animation of speech from unrestricted text. The facial and coarticulation models must first be interactively initialized. The system then automatically creates accurate real-time animated speech from the input text. It is capable of cheaply producing tremendous amounts of animated speech with very low resource requirements.


Effect of acupuncture at neck-Jiaji (EX-B 2) and tuina on the cognitive function in the patients with subjective cognitive decline.
To observe the effects on cognitive function, sleep quality and hemodynamics in the patients with subjective cognitive decline (SCD) after treated with acupuncture at neck-Jiaji (EX-B 2) and tuina on the base of healthy lifestyle education and meta-memory training. Sixty SCD patients were randomly divided into an observation group (30 cases, 1 case dropped out) and a control group (30 cases, 3 cases dropped out). In the control group, the healthy lifestyle education and meta-memory training was performed, twice daily, 15 min each time; the 5-day intervention was delivered a week, lasting consecutively 4 weeks. On the base of the intervention as the control group, in the observation group, acupuncture at neck-Jiaji (EX-B 2) and tuina was conducted. First, one-finger pushing and plucking method of tuina was exerted on the neck region along the running courses of the bladder meridian of foot-taiyang and the governor vessel, for 10 min to 15 min; afterwards, acupuncture was delivered at bilateral neck-Jiaji (EX-B 2), from C1 to C7; and the needles were retained for 30 min. This intervention was given once daily, 5 times a week, for consecutive 4 weeks. Before and after treatment, the score of the mini-mental state examination (MMSE), the score of full scale memory quotient (FSMQ) were assessed by Wechsler memory scale-fourth edition (WMS-Ⅳ) and the score of the Pittsburgh sleep quality index (PSQI) was compared between the two groups. Using transcranial Doppler ultrasound, the hemodynamic indexes (the mean velocity [Vm] and pulsatility index [PI] of the left vertebral artery [LVA], the right vertebral artery [RVA] and the basilar artery [BA]) were determined in the two groups. After treatment, the scores of MMSE and FSMQ increased compared with those before treatment in the two groups (P<0.05, P<0.001), PSQI score was lower (P<0.05) and Vm of BA was higher (P<0.001) in the observation group when compared with those before treatment. The scores of MMSE and FSMQ, as well as Vm of BA were higher (P<0.05, P<0.001), and PSQI score was decreased (P<0.05) in the observation group when compared with the control group. The combined therapy of acupuncture at neck-Jiaji (EX-B 2) and tuina is more advantageous to improving cognitive function, relieving chronic emotional stress and ameliorating sleeping quality in the patients with subjective cognitive decline, which may be achieved by improving the blood supply of the basilar artery.


Prenatal diagnosis of vein of Galen malformation: a multidisciplinary challenge.
Vein of Galen aneurysmal malformation (VGAM) is a rare congenital arteriovenous malformation of the choroid plexus situated within the roof of the third ventricle. If large, it leads to an extracardiac left-to-right shunt featuring as a high output heart failure in the neonate. In our case of VGAM, hypoxic-ischemic brain lesions due to the steal phenomenon could be demonstrated prenatally. In a multidisciplinary clinical setting, withdrawal of active care and initiation of good end-of-life care was decided on and carried through.


Biological activity of the G-quadruplex ligand RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate) is associated with telomere capping alteration.
This study had two goals: 1) to evaluate the biological effect of the novel pentacyclic acridine 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4) on human melanoma lines possessing long telomeres, and 2) to elucidate the relationship between G-quadruplex-based telomerase inhibitor-induced cellular effects and telomere length/dysfunction. The cellular pharmacological effects of RHPS4 have been evaluated by treating melanoma lines with increasing concentrations of RHPS4. A dose-dependent inhibition of cell proliferation was observed in all the lines during short-term treatment. Flow cytometric analysis demonstrated that RHPS4 induced a dose-dependent accumulation of cells in the S-G(2)/M phase of cell cycle. The RHPS4-induced cell cycle alteration was irreversible even at low doses, and the cells died from apoptosis. At high RHPS4 concentration, apoptosis was accompanied by the induction of a senescence phenotype: large cell size, vacuolated cytoplasm, and beta-galactosidase activity. The short-term biological activity of RHPS4 was not caused by telomere shortening, but it was associated with telomere dysfunction, in terms of presence of telomeric fusions, polynucleated cells, and typical images of telophase bridge. In conclusion, our results demonstrate that the G-quadruplex ligand RHPS4 can function in a telomere length-independent manner through its ability to cause telomere-capping alteration.


Sphingosine-1-Phosphate Receptor-1 Promotes Environment-Mediated and Acquired Chemoresistance.
Drug resistance is a major barrier for the development of effective and durable cancer therapies. Overcoming this challenge requires further defining the cellular and molecular mechanisms underlying drug resistance, both acquired and environment-mediated drug resistance (EMDR). Here, using neuroblastoma (NB), a childhood cancer with high incidence of recurrence due to resistance to chemotherapy, as a model we show that human bone marrow-mesenchymal stromal cells induce tumor expression of sphingosine-1-phosphate receptor-1 (S1PR1), leading to their resistance to chemotherapy. Targeting S1PR1 by shRNA markedly enhances etoposide-induced apoptosis in NB cells and abrogates EMDR, while overexpression of S1PR1 significantly protects NB cells from multidrug-induced apoptosis via activating JAK-STAT3 signaling. Elevated S1PR1 expression and STAT3 activation are also observed in human NB cells with acquired resistance to etoposide. We show in vitro and in human NB xenograft models that treatment with FTY720, an FDA-approved drug and antagonist of S1PR1, dramatically sensitizes drug-resistant cells to etoposide. In summary, we identify S1PR1 as a critical target for reducing both EMDR and acquired chemoresistance in NB. Mol Cancer Ther; 16(11); 2516-27. ©2017 AACR.


In vitro fermentation potential of the residue of Korean red ginseng root in a mixed culture of swine faecal bacteria.
Agricultural by-products such as the ginseng residue contain dietary fibre. This study was aimed at investigating the intestinal fermentation potential of the residue of Korean red ginseng root using an in vitro simulator of the colon using swine fecal bacteria. pH-Controlled glass fermentors were used to conduct a small scale in vitro batch fermentation under anaerobic conditions for 48 h. One of the following substrates was included in each fermentor: commercial cellulose (CEL), xylooligosaccharide (XOS), and crude ginseng-insoluble fibre (CGF). The pH was lower (p < 0.05) and the production of total short chain fatty acid was increased (p < 0.05) in the XOS and CGF groups compared with the CEL group after 6 h of incubation. The α-diversity analysis of the microbial community at 48 h showed that the number of bacterial species was (p < 0.05) reduced in the XOS and CGF groups compared with that in the CEL group. β-Diversity of the microbial population at 48 h showed that all groups were clustered differently. The relative abundance of Bifidobacterium and Prevotella in the CGF group were significantly (p < 0.05) higher than those in the CEL and XOS groups. Ammonia nitrogen production in the XOS and CGF groups was (p < 0.05) lower after 6 h of incubation, and skatole production in the CGF group was (p < 0.05) lower at 48 h than that in the CEL group. These results suggested that the ginseng residue might be fermentable in the large intestine and thus would promote the maintenance of a healthy colonic environment in the host.


[Catalytic properties and stability of catalase in reversed micelles of aerosol OT in octane].
The catalytic function of catalase and its peroxidatic activity during tetramethylbenzidine (TMB) oxidation by cumene hydroperoxide were studied in reversed micelles of Aerosol OT (AOT) in octane relative to the [H2O]/[AOT] ratio and the initial catalase concentration. The optimum conditions permitting to retain the catalytic activity of the enzyme and its ability to induce peroxidation of TMB, were found. The catalytic function of the enzyme was shown to be dependent on its concentration in AOT micelles. The catalase stability monitored by the catalytic reaction and the decrease of the Soret band were analyzed. Both processes have two phases differing by the rate constants of the pseudo-first order. The catalase inserted into AOT micelles is characterized by the high stability as compared to other hemoproteins (cytochrome P-450, myoglobin, hemoglobin, peroxidase) under identical conditions.


Studies on the cytosolic estrogen receptor from rat thymus.
The estrogen receptor present in rat thymus cytosol was characterized by its association constant, KA, the number of binding sites present, Bmax, and by the effect of added estradiol on the binding parameters. The binding parameters were determined by fitting the raw binding data directly to the hyperbolic binding function, and the Lineweaver-Burk, Scatchard, and Woolf linear transforms of the hyperbolic function. The binding parameters were also determined using the direct linear plot method of Eisenthal and Cornish-Bowden. The Woolf plot and the direct linear plot gave results that indicated that added estradiol caused both competitive and noncompetitive inhibition of the receptor. The Scatchard and Lineweaver-Burk methods were not capable of showing a systematic trend. The parameters derived from the hyperbolic binding equation were in agreement with the Woolf and direct linear plot methods. The results of this study show that the cytosolic estrogen receptor from rat thymus is both competitively and noncompetitive inhibited by estradiol.


The inter- and intraexaminer reliability of a paraspinal skin temperature differential instrument.
An experiment was undertaken to determine the intra- and interexaminer reliability of a paraspinal skin temperature differential instrument. Nineteen pain-free female chiropractic college students participated as subjects for the investigation. Three separate areas of the spine (C4-T2, T4-T8 and L2-L5) were examined for concordance between two examiners. Additionally, intraexaminer reliability was tested by having each examiner repeat the scanning procedure. Concordance for whether a temperature differential existed in a particular area was evaluated with the Kappa statistic. Kappas ranged from 0.034 to 0.6591 and were all statistically significant (p less than 0.05). This represented slight to moderate reliability in the area C4-T2 and substantial agreement in the region T4-T8. The lumbar region could not be evaluated with the Kappa statistic due to limited variation. Following agreement for a positive finding in a given area, the numerical ratings were evaluated for agreement with the intraclass correlation coefficient (ICC). The first observation between examiners indicated fair agreement (ICC = 0.2756, p = 0.0478). The second observation between examiners had substantial agreement (ICC = 0.6402, p = 0.042). Intraexaminer agreement was moderate for one examiner (ICC = 0.5078, p = 0.0016). The other examiner showed an excellent level of agreement (ICC = 0.8588, p less than 0.001) between observations.


Genome-wide analysis of the rice and Arabidopsis non-specific lipid transfer protein (nsLtp) gene families and identification of wheat nsLtp genes by EST data mining.
Plant non-specific lipid transfer proteins (nsLTPs) are encoded by multigene families and possess physiological functions that remain unclear. Our objective was to characterize the complete nsLtp gene family in rice and arabidopsis and to perform wheat EST database mining for nsLtp gene discovery. In this study, we carried out a genome-wide analysis of nsLtp gene families in Oryza sativa and Arabidopsis thaliana and identified 52 rice nsLtp genes and 49 arabidopsis nsLtp genes. Here we present a complete overview of the genes and deduced protein features. Tandem duplication repeats, which represent 26 out of the 52 rice nsLtp genes and 18 out of the 49 arabidopsis nsLtp genes identified, support the complexity of the nsLtp gene families in these species. Phylogenetic analysis revealed that rice and arabidopsis nsLTPs are clustered in nine different clades. In addition, we performed comparative analysis of rice nsLtp genes and wheat (Triticum aestivum) EST sequences indexed in the UniGene database. We identified 156 putative wheat nsLtp genes, among which 91 were found in the 'Chinese Spring' cultivar. The 122 wheat non-redundant nsLTPs were organized in eight types and 33 subfamilies. Based on the observation that seven of these clades were present in arabidopsis, rice and wheat, we conclude that the major functional diversification within the nsLTP family predated the monocot/dicot divergence. In contrast, there is no type VII nsLTPs in arabidopsis and type IX nsLTPs were only identified in arabidopsis. The reason for the larger number of nsLtp genes in wheat may simply be due to the hexaploid state of wheat but may also reflect extensive duplication of gene clusters as observed on rice chromosomes 11 and 12 and arabidopsis chromosome 5. Our current study provides fundamental information on the organization of the rice, arabidopsis and wheat nsLtp gene families. The multiplicity of nsLTP types provide new insights on arabidopsis, rice and wheat nsLtp gene families and will strongly support further transcript profiling or functional analyses of nsLtp genes. Until such time as specific physiological functions are defined, it seems relevant to categorize plant nsLTPs on the basis of sequence similarity and/or phylogenetic clustering.


[Delayed hypersensitivity and nonspecific cellular immunity. The role of mono- and polynuclear phagocytes].
Differences in the influence produced by sensitization with BCG vaccine and Staphylococcus aureus and by the reaction of delayed hypersensitivity (DH) induced, respectively, by the injection of old tuberculin and staphylococcal phagolysate on the phagocytic activity of peritoneal macrophages and blood leukocytes in different animals were experimentally demonstrated. A considerable activation of the bactericidal and ingesting functions of macrophages was observed in animals showing a pronounced DH reaction (rabbits, guinea pigs and mice), while in Wistar rats no such activation was noted. The latter showed no DH reaction after sensitization with BCG vaccine and the injection of the specific antigen. Among different strains of mice, the activation of macrophages occurred in the animals with the most pronounced DH reaction. Sensitization with BCG vaccine led to an insignificant sensitization of macrophages, and sensitization with S. aureus even suppressed the phagocytic activity of macrophages. The treatment of mice with antimacrophagal preparations (carrageenan, silica and trypan blue, but T-lymphocyte antiserum) before and after the injection of the specific antigen into the sensitized animals abolished the stimulation of anti-infection immunity.


Evolutionary patterns and processes in the radiation of phyllostomid bats.
The phyllostomid bats present the most extensive ecological and phenotypic radiation known among mammal families. This group is an important model system for studies of cranial ecomorphology and functional optimisation because of the constraints imposed by the requirements of flight. A number of studies supporting phyllostomid adaptation have focused on qualitative descriptions or correlating functional variables and diet, but explicit tests of possible evolutionary mechanisms and scenarios for phenotypic diversification have not been performed. We used a combination of morphometric and comparative methods to test hypotheses regarding the evolutionary processes behind the diversification of phenotype (mandible shape and size) and diet during the phyllostomid radiation. The different phyllostomid lineages radiate in mandible shape space, with each feeding specialisation evolving towards different axes. Size and shape evolve quite independently, as the main directions of shape variation are associated with mandible elongation (nectarivores) or the relative size of tooth rows and mandibular processes (sanguivores and frugivores), which are not associated with size changes in the mandible. The early period of phyllostomid diversification is marked by a burst of shape, size, and diet disparity (before 20 Mya), larger than expected by neutral evolution models, settling later to a period of relative phenotypic and ecological stasis. The best fitting evolutionary model for both mandible shape and size divergence was an Ornstein-Uhlenbeck process with five adaptive peaks (insectivory, carnivory, sanguivory, nectarivory and frugivory). The radiation of phyllostomid bats presented adaptive and non-adaptive components nested together through the time frame of the family's evolution. The first 10 My of the radiation were marked by strong phenotypic and ecological divergence among ancestors of modern lineages, whereas the remaining 20 My were marked by stasis around a number of probable adaptive peaks. A considerable amount of cladogenesis and speciation in this period is likely to be the result of non-adaptive allopatric divergence or adaptations to peaks within major dietary categories.


Influence of resistance to streptogramin A type antibiotics on the activity of quinupristin-dalfopristin in vitro and in experimental endocarditis due to Staphylococcus aureus.
We evaluated the activity of quinupristin-dalfopristin (Q-D) against three clinical strains of Staphylococcus aureus susceptible to Q (MIC, 8 microg/ml) and Q-D (MICs, 0.5 to 1 microg/ml) but displaying various levels of susceptibility to D. D was active against S. aureus HM 1054 (MIC, 4 microg/ml) and had reduced activity against S. aureus RP 13 and S. aureus N 95 (MICs, 32 and 64 microg/ml, respectively). In vitro, Q-D at a concentration two times the MIC (2xMIC) produced reductions of 4.3, 3.9, and 5.8 log(10) CFU/ml after 24 h of incubation for HM 1054, RP 13, and N 95, respectively. Comparable killing was obtained at 8xMIC. Q-D-resistant mutants were selected in vitro at a frequency of 2 x 10(-8) to 2 x 10(-7) for the three strains on agar containing 2xMIC of Q-D; no resistant bacteria were detected at 4xMIC. Rabbits with aortic endocarditis were treated for 4 days with Q-D at 30 mg/kg of body weight intramuscularly (i.m.) three times a day (t.i.d.) or vancomycin at 50 mg/kg i.m. t.i.d. In vivo, Q-D and vancomycin were similarly active and bactericidal against the three tested strains compared to the results for control animals (P < 0.01). Among animals infected with RP 13 and treated with Q-D, one rabbit retained Q-D-resistant mutants that were resistant to Q and to high levels of D (MICs, 64, >256, and 8 microg/ml for Q, D, and Q-D, respectively). We conclude that the bactericidal activity of Q-D against strains with reduced susceptibility to D and susceptible to Q-D is retained and is comparable to that of vancomycin. Acquisition of resistance to both Q and D is necessary to select resistance to Q-D.


The Cochrane review of assistive technology for rheumatoid arthritis.
The aim of this systematic review is to summarise the available evidence on the effectiveness of assistive technology for adults with rheumatoid arthritis in terms of improving functional ability and reducing pain, and to assess potential adverse effects related to device use. In this review, randomised controlled trials, clinical controlled trials, controlled before and after studies and interrupted time series available through systematic searches (electronic databases, grey literature, contact with authors, reference lists) up to October 2008 were included. Two reviewers independently selected trials for inclusion, assessed the validity of included trials, and extracted data. Investigators were contacted to obtain missing information. Out of 7177 hits, 13 articles were reviewed in full text and only one trial was finally included (N.=29). The study was a randomised crossover trial, in which the use of an eye drop device was compared to a standard bottle in people with rheumatoid arthritis suffering from persistent dry eyes. The results show that the eye drop device improved application of eye drops and prevented adverse effects in terms of touching the eye with the bottle tip. The study was considered to have low quality of evidence. Since only one trial met the inclusion criteria for this review, there is very limited evidence for the effect of assistive technology for adults with rheumatoid arthritis. There is an urgent need for high-quality research in this field, in order to reach sufficient evidence on the effectiveness of this commonly used intervention.


A conformational switch driven by phosphorylation regulates the activity of the evolutionarily conserved SNARE Ykt6.
Ykt6 is a soluble N-ethylmaleimide sensitive factor activating protein receptor (SNARE) critically involved in diverse vesicular fusion pathways. While most SNAREs rely on transmembrane domains for their activity, Ykt6 dynamically cycles between the cytosol and membrane-bound compartments where it is active. The mechanism that regulates these transitions and allows Ykt6 to achieve specificity toward vesicular pathways is unknown. Using a Parkinson's disease (PD) model, we found that Ykt6 is phosphorylated at an evolutionarily conserved site which is regulated by Ca2+ signaling. Through a multidisciplinary approach, we show that phosphorylation triggers a conformational change that allows Ykt6 to switch from a closed cytosolic to an open membrane-bound form. In the phosphorylated open form, the spectrum of protein interactions changes, leading to defects in both the secretory and autophagy pathways, enhancing toxicity in PD models. Our studies reveal a mechanism by which Ykt6 conformation and activity are regulated with potential implications for PD.


Open radical prostatectomy reproducing robot-assisted radical prostatectomy: Involving antegrade nerve sparing and continuous anastomosis.
To present modified RRP using the same method as RALP and compare its surgical outcomes with RALP. Demographics, perioperative and functional outcomes of the 322 patients that underwent RRP (N=99) or RALP (N=223) at our institution from January 2011 through June 2013 were evaluated retrospectively. Postoperative incontinence and erectile dysfunction are involved functional outcomes. During the modified procedure, the bladder neck was dissected first as for RALP. After dissection of vas deference and seminal vesicle, the prostate was dissected in an antegrade fashion with bilateral nerve saving. Finally, the urethra was cut at the prostate apex. After a Rocco suture was applied, and then urethrovesical anastomosis was performed with continuous suture as for RALP. Perioperative characteristics and complication rates were similar in the RRP and RALP groups except for mean estimated blood loss (p<0.001) and operative time (p<0.001). Incontinence rates at 3 and 12 months after RRP decreased from 67.6% to 10.1 and after RALP decreased from 53.4% to 5.4%. Positive surgical margin rates were non-significantly different in the RRP and RALP groups (30.3% and 37.2%, respectively). Overall postoperative potency rate at 12 months was not significant different in RRP and RALP groups (34.3% and 43.0%). RRP reproducing RALP was found to have surgical outcomes comparable to RALP. This technique might be adopted by experienced urologic surgeons as a standard procedure.


Upper gastrointestinal haemorrhage in portal hypertension. Is an emergency endoscopy necessarily required?
Early fibre-optic oesophago-gastroduodenoscopy was performed in 23 portal hypertensive patients with acute upper gastrointestinal haemorrhage to evaluate the source of bleeding. Oesophageal varices grade II or more were documented in all patients. None of the patients showed a source of bleeding other than the ruptured oesophageal varices, probably because, unlike western countries, the alcoholic cirrhosis as a source of portal hypertension is rather uncommon in India. Hence, we could presume that most of the emergency endoscopies are unnecessary in bleeding patients with portal hypertension.


Comparative study on presentation of biliary ascariasis with dead and living worms.
Ascariasis is a common parasitic infestation in Asia and Latin America. The most serious presentation is biliary and pancreatic ascariasis (BPA). The aim of the present study was to compare the clinical presentation of BPA with dead worms with that with living worms. We included 138 consecutive cases of BPA that occured during the period January 2005 to July 2009. All the patients had endoscopically proven BPA consisting of living or dead worms. Comparison was done by chi-square and independent t tests. The age (mean +/- SD) of the patients was 36.8 +/- 16.1 years. Prevalence ratio between male and female patients was 1:5. Ninety eight patients contained living worms and 40 had dead worms. Males were more prone to develop dead worm BPA. The commonest presentation was biliary colic (131; 94.9%); others were acute cholangitis (30; 21.7%), obstructive jaundice (19; 13.8%), choledocholithiasis (20; 14.5%), acute pancreatitis (10; 7.2%), acute cholecystitis (6; 4.3%), liver abscess (2; 1.4%), hepatolithiasis (3; 2.2%), stricture of common bile duct (2; 1.4%), pancreatic abscess (1; 0.7%) and cirrhosis of liver (1; 0.7%). Choledocholithiasis, hepatolithiasis, liver abscess and cirrhosis were associated only with dead worms. We could successfully remove all the worms with endoscopic interventions, but 5 patients required surgical intervention as there were strictures and stones within the biliary tree or Ascaris were in gallbladder. Recurrences of stone and cholangitis occurred only in those with dead worms. Biliary ascariasis with dead worms is more dangerous than that with living worms. Endoscopic or surgical intervention may be required repeatedly in those with dead worms.


Tumour origin, diagnostic accuracy and histopathological evaluation in patients with periampullary cancer: nationwide cohort study.
The prevalence of different periampullary cancers (pancreatic ductal adenocarcinoma, distal cholangiocarcinoma, ampullary cancer and duodenal cancer) is heterogeneous in the literature. During the 2010s, a standardized histopathological protocol for pancreatoduodenectomy specimens based on axial slicing was adopted in Sweden. The present study sought to provide information about periampullary cancers with regard to tumour types in curative and noncurative settings, preoperative diagnostic accuracy and the impact of a standardized evaluation of the surgical specimen on diagnosis, R status and lymph node assessment. Data from patients diagnosed with periampullary cancer from 2010 to 2019 were retrieved from the Swedish National Registry for Pancreatic and Periampullary Cancer. Among non-curative patients, 3704 (83.6 per cent) were diagnosed with pancreatic ductal adenocarcinoma. Among patients treated with pancreatoduodenectomy, diagnosis was pancreatic ductal adenocarcinoma in 1380 (50.0 per cent), distal cholangiocarcinoma in 284 (10.3 per cent), ampullary cancer in 376 (13.6 per cent), duodenal cancer in 160 (5.8 per cent) and other diagnoses in 560 (20.3 per cent) patients. The preoperative diagnosis corresponded to the postoperative in 1177 (67.5 per cent) patients for pancreatic ductal adenocarcinoma, 162 (37.4 per cent) patients for distal cholangiocarcinoma, 220 (61.3 per cent) patients for ampullary cancer and 120 (53.6 per cent) patients for duodenal cancer. A higher rate of pancreatic ductal adenocarcinoma was seen in surgical specimens who underwent standardized evaluation, from 56.8 per cent to 64.3 per cent (P = 0.003). After standardization, higher rates of R1 resection (31.7 per cent versus 44.6 per cent, P < 0.001) and N1 stage (62.1 per cent versus 77.0 per cent, P < 0.001) were found. The proportion of pancreatic ductal adenocarcinoma was higher in patients in a non-curative setting compared with patients who underwent surgery. The rate of misdiagnosis for periampullary cancers was confirmed to be high. Thus, it should be taken into account when preoperative oncological treatment is considered. Standardized evaluation of the surgical specimen has increased pancreatic ductal adenocarcinoma, R1 and N1 rates.


Fingerprinting of neurotoxic compounds using a mouse embryonic stem cell dual luminescence reporter assay.
Identification of neurotoxic drugs and environmental chemicals is an important challenge. However, only few tools to address this topic are available. The aim of this study was to develop a neurotoxicity/developmental neurotoxicity (DNT) test system, using the pluripotent mouse embryonic stem cell line CGR8 (ESCs). The test system uses ESCs at two differentiation stages: undifferentiated ESCs and ESC-derived neurons. Under each condition, concentration-response curves were obtained for three parameters: activity of the tubulin alpha 1 promoter (typically activated in early neurons), activity of the elongation factor 1 alpha promoter (active in all cells), and total DNA content (proportional to the number of surviving cells). We tested 37 compounds from the ESNATS test battery, which includes polypeptide hormones, environmental pollutants (including methylmercury), and clinically used drugs (including valproic acid and tyrosine kinase inhibitors). Different classes of compounds showed distinct concentration-response profiles. Plotting of the lowest observed adverse effect concentrations (LOAEL) of the neuronal promoter activity against the general promoter activity or against cytotoxicity, allowed the differentiation between neurotoxic/DNT substances and non-neurotoxic controls. Reporter activity responses in neurons were more susceptible to neurotoxic compounds than the reporter activities in ESCs from which they were derived. To relate the effective/toxic concentrations found in our study to relevant in vivo concentrations, we used a reverse pharmacokinetic modeling approach for three exemplary compounds (teriflunomide, geldanamycin, abiraterone). The dual luminescence reporter assay described in this study allows high-throughput, and should be particularly useful for the prioritization of the neurotoxic potential of a large number of compounds.


Evaluation of diabetes patient-education programs.
Patient education is generally regarded as an essential component of the clinical management of diabetes. However, analysis of the role of patient education in diabetes control has been limited. Formal patient teaching programs at several medical centers range in operation from merely providing knowledge about diabetes to integrating patient education into the chronic health care system. Improvements in knowledge about diabetes have been demonstrated with patients who have been given questionnaires before and after instruction, but changes in diabetes control and other clinical parameters have not necessarily followed. In those cases in which patient education has been a part of a comprehensive improvement in the entire clinical management of diabetes, significant decreases in rates of hospitalization and acute complications have occurred. Guidelines for future evaluations are discussed.


Online teaching in physiotherapy education during COVID-19 pandemic in Italy: a retrospective case-control study on students' satisfaction and performance.
During COVID-19 pandemic, physiotherapy lecturers faced the challenge of rapidly shifting from face-to-face to online education. This retrospective case-control study aims to compare students' satisfaction and performances shown in an online course to a control group of students who underwent the same course delivered face-to-face in the previous five years. Between March and April 2020, a class (n = 46) of entry-level physiotherapy students (University of Verona - Italy), trained by an experienced physiotherapist, had 24-hours online lessons. Students exposed to the same course in the previous five academic years (n = 112), delivered with face-to-face conventional lessons, served as a historical control. The course was organized in 3 sequential phases: (1) PowerPoint presentations were uploaded to the University online platform, (2) asynchronous video recorded lectures were provided on the same platform, and (3) between online lectures, the lecturer and students could communicate through an email chat to promote understanding, dispel any doubts and collect requests for supplementary material (e.g., scientific articles, videos, webinars, podcasts). Outcomes were: (1) satisfaction as routinely measured by University with a national instrument and populated in a database; (2) performance as measured with an oral examination. We compared satisfaction with the course, expressed on a 5-point Likert scale, resulting in no differences between online and face-to-face teaching (Kruskal-Wallis 2 = 0.24, df = 1, p = 0.62). We weighted up students' results by comparing their mean performances with the mean performances of the same course delivered face-to-face in the previous five years, founding a statistical significance in favour of online teaching (Wilcoxon rank sum test W = 1665, p < 0.001). Online teaching in entry-level Physiotherapy seems to be a feasible option to face COVID-19 pandemic, as satisfies students as well as face-to-face courses and leading to a similar performance. Entry-level Bachelors in Physiotherapy may consider moving to eLearning to facilitate access to higher education. Universities will have to train lecturers to help them develop appropriate pedagogical skills, and supply suitable support in terms of economic, organizational, and technological issues, aimed at guaranteeing a high level of education to their students. Retrospectively registered.


The novel inosine analogue, INO-2002, protects against diabetes development in multiple low-dose streptozotocin and non-obese diabetic mouse models of type I diabetes.
Endogenous purines including inosine have been shown to exert immunomodulatory and anti-inflammatory effects in a variety of disease models. The dosage of inosine required for protection is very high because of the rapid metabolism of inosine in vivo. The aim of this study was to determine whether a metabolic-resistant purine analogue, INO-2002, exerts anti-inflammatory effects in two animal models of type I diabetes. Type I diabetes was induced chemically with streptozotocin or genetically using the non-obese diabetic (NOD) female mouse model. Mice were treated with INO-2002 or inosine as required at 30, 100, or 200 mg/kg per day, while blood glucose and diabetes incidence were monitored. The effect of INO-2002 on the pancreatic cytokine profile was also determined. INO-2002 reduced both the hyperglycaemia and incidence of diabetes in both streptozotocin-induced and spontaneous diabetes in NOD mice. INO-2002 proved to be more effective in protecting against diabetes than the naturally occurring purine, inosine, when administered at the same dose. INO-2002 treatment decreased pancreatic levels of interleukin (IL)-12 and tumour necrosis factor-alpha, while increasing levels of IL-4 and IL-10. INO-2002 also reduced pancreatic levels of the chemokine MIP-1 alpha. The inosine analogue, INO-2002, was protected more effectively than the naturally occurring purine, inosine, against development of diabetes in two separate animal models. INO-2002 exerts protective effects by changing the pancreatic cytokine expression from a destructive Th1 to a protective Th2 profile. The use of analogues of inosine such as INO-2002 should be considered as a potential preventative therapy in individuals susceptible to developing type I diabetes.


Socioeconomic inequalities in the prevalence of nine established cardiovascular risk factors in a southern European population.
The evaluation of the gender-specific prevalence of cardiovascular risk factors across socioeconomic position (SEP) categories may unravel mechanisms involved in the development of coronary heart disease. Using a sample of 1704 community dwellers of a Portuguese urban center aged 40 years or older, assessed in 1999-2003, we quantified the age-standardized prevalence of nine established cardiovascular risk factors (diabetes mellitus, hypertension, hypercholesterolemia, smoking, sedentariness, abdominal obesity, poor diet, excessive alcohol intake and depression) across SEP and gender categories. Data on individual education and occupation were collected by questionnaire and used to characterize SEP. The prevalence of seven out of nine well-established risk factors was higher in men. Among women, the prevalence of most of the studied risk factors was higher in lower SEP groups. The main exception was smoking, which increased with education and occupation levels. Among men, socioeconomic gradients were less clear, but lower SEP was associated with a higher prevalence of diabetes, excessive alcohol intake and depression in a graded mode. The historical cultural beliefs and practices captured throughout the lifecourse frame the wide socioeconomic gradients discernible in our study conducted in an unequal European developed population. While men were more exposed to most risk factors, the clearer associations between SEP and risk factors among women support that their adoption of particular healthy behaviors is more dependent on material and symbolic conditions. To fully address the issue of health inequalities, interventions within the health systems should be complemented with population-based policies specifically designed to reduce socioeconomic gradients.