[Long-term memory, neurogenesis and novelty signal].
In accordance with the advanced hypothesis the long-term memory is a collection of "gnostic units" selectively tuned to experienced events. The long-term memory is continuously supplemented by new neurons differentiated from stem cells during neurogenesis (particularly, in adults). The transformation of neuronal progenitors into event-selective gnostic units is accomplished with participation of hippocampal "novelty neurons" emphasizing information inputs to be stored in the long-term memory. The formation of the gnostic units is preceded by informational processes occurring in the ventral ("what?") and dorsal ("where?") systems. The formation of a new gnostic unit selectively tuned to a particular event is a result of combination of feature-detector excitation and novelty signal generated by hippocampal novelty neurons.


Influence of Amino Acid Substitutions in ApoMb on Different Stages of Unfolding of Amyloids.
To date, most research on amyloid aggregation has focused on describing the structure of amyloids and the kinetics of their formation, while the conformational stability of fibrils remains insufficiently explored. The aim of this work was to investigate the effect of amino acid substitutions on the stability of apomyoglobin (ApoMb) amyloids. A study of the amyloid unfolding of ApoMb and its six mutant variants by urea has been carried out. Changes in the structural features of aggregates during unfolding were recorded by far-UV CD and native electrophoresis. It was shown that during the initial stage of denaturation, amyloids' secondary structure partially unfolds. Then, the fibrils undergo dissociation and form intermediate aggregates weighing approximately 1 MDa, which at the last stage of unfolding decompose into 18 kDa monomeric unfolded molecules. The results of unfolding transitions suggest that the stability of the studied amyloids relative to the intermediate aggregates and of the latter relative to unfolded monomers is higher for ApoMb variants with substitutions that increase the hydrophobicity of the residues. The results presented provide a new insight into the mechanism of stabilization of protein aggregates and can serve as a base for further investigations of the amyloids' stability.


Mucosal changes in gastric ulceration and their response to carbenoxolone sodium.
The epithelial differences between the normal stomach (six subjects) and 47 patients with gastric ulcers were compared. The concentrations of intraepithelial lymphocytes and polymorphonuclear leucocytes in lesser curve and prepyloric gastirc ulcers were compared, the effect of treatment with carbenoxolone sodium was studied. There is a statistically significant reduction in the total number of intraepithelial polymorphonuclear leucocytes before and after successful treatment with carbenoxolone sodium. There is also a statistically significant decrease in the quantity of intraepithelial lymphocytes in those patients with lesser curve gastric ulcers successfully treated with carbenoxolone sodium, whereas there is a significant increase in those patients with prepyloric gastric ulcers successfully treated and those patients in whom treatment failed. The value of counts of migrating white blood cells as a method of objectively assessing the effect of healing drugs upon the gastric mucosa is discussed. Pseudomonas aeruginosa was found in many specimens obtained, and evidence is presented that this was not a contaminant. Carbenoxolone appeared to increase the amount of mucus but had little effect upon the number of bacteria found. The possible contribution of Pseudomonas aeruginosa to gastric ulceration is discussed.


Combining Multiple Assays Improves Detection and Serotyping of Foot-and-Mouth Disease Virus. A Practical Example with Field Samples from East Africa.
Multiple serotypes and topotypes of foot-and-mouth disease virus (FMDV) circulate in endemic areas, posing considerable impacts locally. In addition, introductions into new areas are of great concern. Indeed, in recent years, multiple FMDV outbreaks, caused by topotypes that have escaped from their original areas, have been recorded in various parts of the world. In both cases, rapid and accurate diagnosis, including the identification of the serotype and topotype causing the given outbreaks, plays an important role in the implementation of the most effective and appropriate measures to control the spread of the disease. In the present study, we describe the performance of a range of diagnostic and typing tools for FMDV on a panel of vesicular samples collected in northern Tanzania (East Africa, EA) during 2012-2018. Specifically, we tested these samples with a real-time RT-PCR targeting 3D sequence for pan-FMDV detection; an FMDV monoclonal antibody-based antigen (Ag) detection and serotyping ELISA kit; virus isolation (VI) on LFBKαVβ6 cell line; and a panel of four topotype-specific real-time RT-PCRs, specifically tailored for circulating strains in EA. The 3D real-time RT-PCR showed the highest diagnostic sensitivity, but it lacked typing capacity. Ag-ELISA detected and typed FMDV in 71% of sample homogenates, while VI combined with Ag-ELISA for typing showed an efficiency of 82%. The panel of topotype-specific real-time RT-PCRs identified and typed FMDV in 93% of samples. However, the SAT1 real-time RT-PCR had the highest (20%) failure rate. Briefly, topotype-specific real-time RT-PCRs had the highest serotyping capacity for EA FMDVs, although four assays were required, while the Ag-ELISA, which was less sensitive, was the most user-friendly, hence suitable for any laboratory level. In conclusion, when the four compared tests were used in combination, both the diagnostic and serotyping performances approached 100%.


Spontaneous spatial navigation circuitry in schizophrenia spectrum disorders.
Spatial memory is core to wayfinding and everyday memory. Interestingly, individuals with schizophrenia using spatial navigation strategies (cognitive mapping) are impaired, whereas those using response-based (e.g., single-landmark) strategies show relatively intact memory performance. We observed abnormal brain communication in schizophrenia participants who used a spatial strategy during a virtual-reality navigation task, particularly between temporal and frontal brain regions. In contrast, schizophrenia participants using a response strategy recruited similar brain systems to healthy participants, but to a greater extent to support memory performance. These findings highlight that strategy use is an important consideration for understanding memory systems and navigation in schizophrenia.


Chlamydial genital infection in Ibadan, Nigeria. A seroepidemiological survey.
Sera from patients attending a sexually transmitted diseases (STD) clinic, a family planning clinic, and an antenatal clinic in Ibadan, Nigeria, as well as from male blood donors from the same area were tested for the presence of type specific antichlamydial antibodies using a modified micro-immunofluorescence test. Among men and women attending the STD clinic the exposure rates to Chlamydia trachomatis serotypes D to K (genital pathogens) were 18.7% and 26.7% respectively. Antibody titres suggesting active disease in these men and women were found in 11.8% and 22.7% respectively. The highest rate of exposure (35%) was among women attending the family planning clinic; of these women 25% had antibody suggesting active disease. Titres of IgG antibody in this study were similar to those found among men and women with chlamydial genital infections in the United Kingdom. Antibodies to serotypes D to K were also detected in 10.3% of women attending an antenatal clinic and in 9.9% of male blood donors. The prevalence of antibodies to C trachomatis serotypes A to C and lymphogranuloma venereum serotypes was low. These results suggest that the prevalence of chlamydial genital infections in Ibadan, both among STD patients and especially among those individuals not seeking treatment (family planning and antenatal clinic patients), is high. Since serious sequelae can follow chlamydial genital infections it is imperative to carry out further investigations in this area.


Seeking informed consent to cancer clinical trials: describing current practice.
Clinical trials have come to be regarded as the gold standard for treatment evaluation. However, many doctors and their patients experience difficulties when discussing trials, leading to poor accrual to trials and questionable quality of informed consent. We have previously developed a typology for ethical communication about Phase II and III clinical trials within four domains: (a) shared decision making, (b) sequencing information, (c) type and clarity of information, and (d) disclosure/coercion. The aim of this study was to compare current clinical practice when seeking informed consent with this typology. Fifty-nine consultations in which 10 participating oncologists sought informed consent were audiotaped. Verbatim transcripts were analysed using a coding system to (a) identify the presence or absence of aspects of the four domains and (b) rate the quality of aspects of two domains: (i) shared decision-making and (ii) type and clarity of information. Oncologists rarely addressed aspects of shared decision-making, other than offering to delay a treatment decision (78%). Moreover, many of these discussions scored poorly with respect to ideal content. The oncologists were rarely consistent with the sequence of information provision. A general rationale for randomising was only described in 46% of consultations. In almost one third of the consultations (28.8%) doctors made implicit statements favouring one option over another, either standard or clinical trial treatment. Doctors complied with some but not other aspects of a standard procedure for discussing clinical trials. This reflects the difficulty inherent in seeking ethical informed consent and the need for communication skills training for oncologists.


Estimating incidence and prevalence rates of chronic diseases using disease modeling.
Morbidity estimates between different GP registration networks show large, unexplained variations. This research explores the potential of modeling differences between networks in distinguishing new (incident) cases from existing (prevalent) cases in obtaining more reliable estimates. Data from five Dutch GP registration networks and data on four chronic diseases (chronic obstructive pulmonary disease [COPD], diabetes, heart failure, and osteoarthritis of the knee) were used. A joint model (DisMod model) was fitted using all information on morbidity (incidence and prevalence) and mortality in each network, including a factor for misclassification of prevalent cases as incident cases. The observed estimates vary considerably between networks. Using disease modeling including a misclassification term improved the consistency between prevalence and incidence rates, but did not systematically decrease the variation between networks. Osteoarthritis of the knee showed large modeled misclassifications, especially in episode of care-based registries. Registries that code episodes of care rather than disease generally provide lower estimates of the prevalence of chronic diseases requiring low levels of health care such as osteoarthritis. For other diseases, modeling misclassification rates does not systematically decrease the variation between registration networks. Using disease modeling provides insight in the reliability of estimates.


Molecular phylogeny of the Vomerifer and Pedroi Groups in the Spissipes Section of the subgenus Culex (Melanoconion).
Members of the New World mosquito subgenus Melanoconion of the genus Culex are important vectors of many alphaviruses including eastern and Venezuelan equine encephalitis viruses (VEEV). We investigated the phylogenetic relationships among nine putative species of the Vomerifer and Pedroi Groups of the Neotropical Spissipes Section by sequencing the internal transcribed spacer 2 (ITS-2) region of ribosomal DNA and using phylogenetic analyses. Results demonstrated that, within the Spissipes Section, the Vomerifer and Pedroi Groups are monophyletic sister groups. The clade comprised by Culex adamesi and Culex ribeirensis showed a sister group relationship to the group consisting of Culex pedroi sequences. The monophyly of the Vomerifer Group corroborated previous suggestions that it is a natural group. However, our topology showed that there are two well-supported, divergent groups within a major clade consisting of Cx. pedroi sequences, suggesting the possibility of a cryptic Cx. pedroi-like species. This finding could have important epidemiological implications for VEEV transmission in Central and South America.


Detrimental effects of albuterol on airway responsiveness requires airway inflammation and is independent of β-receptor affinity in murine models of asthma.
Inhaled short acting β2-agonists (SABA), e.g. albuterol, are used for quick reversal of bronchoconstriction in asthmatics. While SABA are not recommended for maintenance therapy, it is not uncommon to find patients who frequently use SABA over a long period of time and there is a suspicion that long term exposure to SABA could be detrimental to lung function. To test this hypothesis we studied the effect of long-term inhaled albuterol stereoisomers on immediate allergic response (IAR) and airway hyperresponsiveness (AHR) in mouse models of asthma. Balb/C mice were sensitized and challenged with ovalbumin (OVA) and then we studied the IAR to inhaled allergen and the AHR to inhaled methacholine. The mice were pretreated with nebulizations of either racemic (RS)-albuterol or the single isomers (S)- and (R)-albuterol twice daily over 7 days prior to harvest. We found that all forms of albuterol produced a significant increase of IAR measured as respiratory elastance. Similarly, we found that AHR was elevated by albuterol. At the same time a mouse strain that is intrinsically hyperresponsive (A/J mouse) was not affected by the albuterol isomers nor was AHR induced by epithelial disruption with Poly-L-lysine affected by albuterol. We conclude that long term inhalation treatment with either isomer of albuterol is capable of precipitating IAR and AHR in allergically inflamed airways but not in intrinsically hyperresponsive mice or immunologically naïve mice. Because (S)-albuterol, which lacks affinity for the β2-receptor, did not differ from (R)-albuterol, we speculate that isomer-independent properties of the albuterol molecule, other than β2-agonism, are responsible for the effect on AHR.


Examining the time course of indexical specificity effects in spoken word recognition.
Variability in talker identity and speaking rate, commonly referred to as indexical variation, has demonstrable effects on the speed and accuracy of spoken word recognition. The present study examines the time course of indexical specificity effects to evaluate the hypothesis that such effects occur relatively late in the perceptual processing of spoken words. In 3 long-term repetition priming experiments, the authors examined reaction times to targets that were primed by stimuli that matched or mismatched on the indexical variable of interest (either talker identity or speaking rate). Each experiment was designed to manipulate the speed with which participants processed the stimuli. The results demonstrate that indexical variability affects participants' perception of spoken words only when processing is relatively slow and effortful.


Effect of soybean phytoestrogen intake on low density lipoprotein oxidation resistance.
The oxidation of low density lipoproteins (LDLs) is thought to take place in the arterial intima when the particles have become isolated from circulating water-soluble antioxidants. We hypothesized that isoflavonoid antioxidants derived from soy could be incorporated into lipoproteins and possibly could protect them against oxidation, which is regarded as atherogenic. Six healthy volunteers received 3 soy bars [containing the isoflavonoid antioxidants genistein (12 mg) and daidzein (7 mg)] daily for 2 weeks. LDLs were isolated from blood drawn at the the end of a 2-week dietary baseline period, after 2 weeks on soy, and after discontinuation of soy. Large increases in plasma isoflavonoid levels occurred during soy feeding, but only minute amounts were stably associated with lipoproteins (less than 1% of plasma isoflavonoids in the LDL fraction). The LDLs were subjected to copper-mediated oxidation in vitro. Compared with off soy values, lag phases of LDL oxidation curves were prolonged by a mean of 20 min (P < 0.02) during soy intake, indicating a reduced susceptibility to oxidation. The results suggest that intake of soy-derived antioxidants, such as genistein and daidzein, may provide protection against oxidative modification of LDL. As only very small amounts of these substances were detected in purified LDL, modified LDL particles may have been produced in vivo by circulating isoflavonoids promoting resistance to oxidation ex vivo.


Glycoprotein metabolism in human renal disease: serum glycoproteins and glycoprotein: glycosyl transferase levels in chronic renal failure.
Glycoprotein: galactosyl and glycoprotein: sialic acid transferase activity were measured in the serum of patients with renal insufficiency. Significant elevations in enzyme activity were found in all patients including those on regular hemodialysis. Galactosyl transferase activity was elevated in a group of renal transplant recipients with normal serum creatinine. Serum glycoproteins from renal failure serum have an altered carbohydrate composition, the major finding being a reduced galactose content. A smaller reduction in sialic acid content was also observed. The findings are discussed in terms of glycoprotein metabolism and the clinical setting of chronic renal failure.


A multi-channel device for high-density target-selective stimulation and long-term monitoring of cells and subcellular features in C. elegans.
Selective cell ablation can be used to identify neuronal functions in multicellular model organisms such as Caenorhabditis elegans. The optogenetic tool KillerRed facilitates selective ablation by enabling light-activated damage of cell or subcellular components in a temporally and spatially precise manner. However, the use of KillerRed requires stimulating (5 min-1 h), culturing (~24 h) and imaging (often repeatedly) a large number of individual animals. Current manual manipulation methods are limited by their time-consuming, labor-intensive nature, and their usage of anesthetics. To facilitate large-scale selective ablation, culturing, and repetitive imaging, we developed a densely-packed multi-channel device and used it to perform high-throughput neuronal ablation on KillerRed-expressing animals. The ability to load worms in identical locations with high loading efficiency allows us to ablate selected neurons in multiple worms simultaneously. Our device also enables continuous observation of animals for 24 h following KillerRed activation, and allows the animals to be recovered for behavioural assays. We expect this multi-channel device to facilitate a broad range of long-term imaging and selective illumination experiments in neuroscience.


Antimicrobial stewardship in wound care implementation and measuring outcomes: results of an e-survey.
Antimicrobial resistance (AMR) occurs (as a result of misuse, such as over-prescribing) when certain pathogens fail to respond to treatment with antimicrobials. Consequently, patients can become severely ill and possibly die. A strategy referred to as antimicrobial stewardship (AMS) has been introduced which reduces the impact of this antimicrobial misuse. To explore health professionals' (working in wound care, treating both acute and hard-to-heal wounds) position in terms of the following: awareness of AMS; if they are aware of AMS, if they implement procedures to support its practice; and if they implement AMS, do they measure its impact by and compare pre- and post-implementation? An e-survey designed to explore health professionals' awareness of AMS and its implications for wound care. There were 987 respondents to the survey. The majority were specialist wound care nurses, mainly based in the UK or the US and Canada. A high proportion of those surveyed were completely/partially aware (35.1/57.9%, respectively) of AMS, and almost all implemented strategies to reduce antimicrobial prescribing. Of those surveyed, 36% took steps to measure the impact of AMS, and as a result 35.2% reported positive impacts (for example, cost reductions, a reduction in the systemic use of antimicrobials, a reduction in the topical use of antimicrobials and a reduced level of antimicrobial-resistant microorganisms). Challenging aspects of AMS implementation were reported by 33.2% of respondents (for example, poorer clinical outcomes in terms of healing and increased costs). The data highlighted that 40.49% felt that AMS would be 'easy' or 'very easy' to implement while 21.73% felt that AMS would be 'difficult' or 'very difficult' to implement. Education strategies need to be devised to raise awareness and support health professionals, including wound care practitioners, to understand and implement effective AMS programmes. Development of clear metrics is required to evaluate the effect of AMS programmes in clinical practice.


Schlemm's canal: more than meets the eye, lymphatics in disguise.
Schlemm's canal (SC) is a unique vascular structure that functions to maintain fluid homeostasis by draining aqueous humor from the eye into the systemic circulation. The endothelium lining the inner wall of SC has both blood and lymphatic vascular characteristics, thus prompting exploration of the development and regulation of this unique channel. In this issue of the JCI, back-to-back papers by Aspelund et al. and Park et al. detail the mechanisms of SC development, which includes a lymphatic reprogramming that is necessary to maintain proper function. Furthermore, both groups exploit the lymph-like qualities of this canal: they identify VEGF-C as a potential therapeutic for glaucoma and suggest that expression of PROX1, a marker of lymphatic fate, could also serve as a biosensor for monitoring SC integrity. These studies provide substantial insight into the molecular and cellular pathways that govern SC development and reveal that ocular pathology is associated with deregulation of the lymph-like characteristics of SC.


[Integrated coronary artery bypass strategy prevents urgent pump conversion during off-pump coronary artery bypass grafting].
Urgent pump conversion during off-pump coronary artery bypass (OPCAB) results in high morbidity and mortality. We retrospectively evaluated if the peri-operative integrated strategy prevents this lethal event in our 400 consecutive OPCAB operations. The patients with preoperative cardiogenic shock and/or ventricular arrhythmias underwent on-pump coronary artery bypass grafting (CABG). All other patients (99% of total CABG) were scheduled to undergo OPCAB (n=400). Prophylactic intraaortic balloon pumping (IABP) was applied to the patients with critical (>95%) left main trunk stenosis or low (<0.35) left ventricular ejection fraction. All the patients received the deep pericardial suture, apex-traction device, suction-type stabilizer, test-clamp of target coronary arteries by micro bulldog clamp, and intra-coronary shunts. Intra-operative IABP was applied in the case of sustained ST-segment change and/or elevated pulmonary artery pressure. Pump conversion was indicated for the patients with ventricular fibrillation and/or cardiogenic shock. Two patients (0.5%) had pump conversion due to ventricular arrhythmia and sustained hypotension, respectively. These pump conversion did not result in hospital mortality. Three hospital deaths (0.7%) occurred due to non-cardiac causes. The integrated strategy using prophylactic or intra-operative IABP in OPCAB produce a low pump conversion rate even during an early period of surgeon's learning curve.


Sex-Specific Association Between Coronary Artery Disease Severity and Myocardial Ischemia Induced by Mental Stress.
It is unclear whether mental stress-induced myocardial ischemia (MSIMI) is related to obstructive coronary artery disease (CAD). We examined this question and contrasted results with ischemia induced by conventional stress testing (CSIMI). Because women are more susceptible to ischemia without coronary obstruction than men, we examined sex differences. We studied 276 patients 61 years and younger with recent myocardial infarction. CAD severity was quantified using the log-transformed Gensini Score (lnGS) and the Sullivan Stenosis Score. Patients underwent myocardial perfusion imaging with mental stress (public speaking) and conventional (exercise or pharmacological) stress testing. MSIMI and CSIMI were defined as a new or worsening perfusion defect. The prevalence of MSIMI was 15% in men and 20% in women. The median GS for patients with MSIMI was 65.0 in men and 28.5 in women. In logistic regression models adjusted for demographic and cardiovascular risk factors, CAD severity was associated with CSIMI in the full sample (odds ratio [OR] = 1.49, 95% [CI], 1.14-1.95, per 1-unit increase in lnGS), with no significant difference by sex. Although CAD severity was not associated with MSIMI in the entire sample, results differed by sex. CAD severity was associated with MSIMI among men (OR = 1.95, 95% CI, 1.13-3.36, per 1-unit increase in lnGS), but not among women (OR = 1.02, 95% CI, 0.74-1.42, p = .042 for interaction). Analysis using Sullivan Stenosis Score yielded similar results. Findings suggest that CAD severity is related to MSIMI in men but not women. MSIMI in women may therefore be driven by alternative mechanisms such as coronary microvascular disease.


High resolution magic angle spinning 1H NMR of childhood brain and nervous system tumours.
Brain and nervous system tumours are the most common solid cancers in children. Molecular characterisation of these tumours is important for providing novel biomarkers of disease and identifying molecular pathways which may provide putative targets for new therapies. 1H magic angle spinning NMR spectroscopy (1H HR-MAS) is a powerful tool for determining metabolite profiles from small pieces of intact tissue and could potentially provide important molecular information. Forty tissue samples from 29 children with glial and primitive neuro-ectodermal tumours were analysed using HR-MAS (600 MHz Varian gHX nanoprobe). Tumour spectra were fitted to a library of individual metabolite spectra to provide metabolite values. These values were then used in a two tailed t-test and multi-variate analysis employing a principal component analysis and a linear discriminant analysis. Classification accuracy was estimated using a leave-one-out analysis and B632+ bootstrapping. Glial tumours had significantly (two tailed t-test p < 0.05) higher creatine and glutamine and lower taurine, phosphoethanolamine, phosphorylcholine and choline compared with primitive neuro-ectodermal tumours. Classification accuracy was 90%. Medulloblastomas (n = 9) had significantly (two tailed t-test p < 0.05) higher creatine, glutamine, phosphorylcholine, glycine and scyllo-inositol than neuroblastomas (n = 7), classification accuracy was 94%. Supratentorial primitive neuro-ectodermal tumours had metabolite profiles in keeping with other primitive neuro-ectodermal tumours whilst ependymomas (n = 2) had metabolite profiles intermediate between pilocytic astrocytomas (n = 10) and primitive neuro-ectodermal tumours. HR-MAS identified key differences in the metabolite profiles of childhood brain and nervous system improving the molecular characterisation of these tumours. Further investigation of the underlying molecular pathways is required to assess their potential as targets for new agents.


Targeting the pathophysiology of type 2 diabetes: rationale for combination therapy with pioglitazone and exenatide.
The objectives of this article are to review the pathophysiology of type 2 diabetes mellitus (T2DM), present the rationale for a pathophysiologically based treatment approach for patients with T2DM and discuss the role of the therapeutic combination of pioglitazone and exenatide in the management of T2DM. References were identified from searches of the PubMed database that were conducted in May 2007, October 2007 and March 2008 and updates to product labeling that occurred between May 2007 and December 2007. Information was selected for inclusion on the basis of its relevance to the pathophysiology of T2DM or the clinical use of thiazolidinediones or exenatide. Discussion of other anti-diabetic treatment strategies is not included. T2DM results from a combination of insulin resistance and beta-cell dysfunction. The combination of a thiazolidinedione and an incretin mimetic offers a combination of characteristics (e.g., glycemic control, reduced insulin resistance, decreased weight, potential cardiovascular benefits, beta-cell preservation) that addresses many of the pathophysiologic underpinnings of T2DM. A recent small placebo-controlled study assessed the effects of exenatide used with a thiazolidinedione (TZD; pioglitazone or rosiglitazone) with or without metformin. Exenatide demonstrated a greater incidence of glycosylated hemoglobin (HbA(1c)) < 7%; greater reductions in fasting blood glucose, postprandial plasma glucose and body weight; and improved beta-cell function versus the TZD/placebo group. However, exenatide was associated with a high dropout rate, and the 16-week duration of treatment in this study precluded evaluation of the long-term effects of the exenatide/pioglitazone combination. Furthermore, exenatide/pioglitazone has not been compared with any other anti-diabetic combination in a head-to-head clinical study. Dual effects on insulin sensitivity (TZD) and insulin secretion (exenatide) make the TZD/exenatide combination a rational treatment option for patients who do not attain glycemic control with a single agent. Studies undertaken to evaluate the effects on cardiovascular outcomes and the potential for prevention of T2DM with impaired glucose tolerance may reveal additional advantages of this combination approach.


Emergence of a Higher Energy Structure in Strong Field Ionization with Inhomogeneous Electric Fields.
Studies of strong field ionization have historically relied on the strong field approximation, which neglects all spatial dependence in the forces experienced by the electron after ionization. More recently, the small spatial inhomogeneity introduced by the long-range Coulomb potential has been linked to a number of important features in the photoelectron spectrum, such as Coulomb asymmetry, Coulomb focusing, and the low energy structure. Here, we demonstrate using midinfrared laser wavelength that a time-varying spatial dependence in the laser electric field, such as that produced in the vicinity of a nanostructure, creates a prominent higher energy peak. This higher energy structure (HES) originates from direct electrons ionized near the peak of a single half-cycle of the laser pulse. The HES is separated from all other ionization events, with its location and width highly dependent on the strength of spatial inhomogeneity. Hence, the HES can be used as a sensitive tool for near-field characterization in the "intermediate regime," where the electron's quiver amplitude is comparable to the field decay length. Moreover, the large accumulation of electrons with tuneable energy suggests a promising method for creating a localized source of electron pulses of attosecond duration using tabletop laser technology.


Are Iranian patients with von Willebrand disease type 2N properly differentiated from hemophilia A and do they receive appropriate treatment?
: The defect function of the von Willebrand factor (VWF) in carrying factor VIII (FVIII) leads to von Willebrand disease type 2N (VWD 2N) which could be easily misdiagnosed as hemophilia A. Differentiating of VWD 2N from hemophilia A is crucial for patient treatment and genetic counseling. As a retrospective study, we aimed to evaluate the current diagnostic work-up of Iranian patients with mild/moderate deficiency of FVIII levels and the possibility of misdiagnosis of VWD 2N as hemophilia A. All patients who referred to the reference coagulation laboratory at the Iranian Blood Transfusion Organization in a 10-months period for bleeding diathesis work-up with the request of FVIII activity level were included. Clinical and laboratory phenotypes including International Society on Thrombosis and Hemostasis - Bleeding Assessment Tool, FVIII activity, VWF antigen, VWF ristocetin cofactor, and FVIII binding capacity of VWF were assessed on suspected cases for VWD 2N. In total, the results of 896 patients for investigation of VWD 2N were evaluated and five new patients were identified within unrelated families with abnormal VWF:FVIIIB levels. Four were heterozygous for VWD 2N and one homozygous whom all were misdiagnosed as hemophilia A and underwent inappropriate treatments. The median bleeding score of the VWD 2N population was nine (4-13). In Iran, probably a significant number of VWD 2N patients are misdiagnosed as hemophilia A due to insufficient test panel for subtyping of von Willebrand disease. This study also emphasized the need for inclusion of the VWF:FVIIIB in suspected hemophilia A to achieve an optimal treatment strategy.


Asbestos Exposures, Mesothelioma Incidence and Mortality, and Awareness by General Practitioners in the Molise Region, Central Italy.
The aim of this study was to evaluate environmental asbestos sources, mesothelioma incidence and mortality, and awareness on asbestos-related diseases (ARDs) by general practitioners (GPs) in Molise Region. The contaminated sites in three towns were identified by census; mesothelioma incidence (2000 to 2012) and mortality (2003 to 2013) was achieved from local registries; GPs were interviewed on practiced population's exposures and ARDs diagnosis. About 54.3% of visited sites were contaminated (71.2% by friable asbestos) and 38.8% was extremely damaged. Over above time-periods, 32 mesothelioma cases (62.5% males, 25% in people aged 70 to 75 years) and 27 deaths (90% males, 69 ± 10 years, 70.4% pleural mesothelioma) have been reported. A total of 122 GPs were interviewed who had diagnosed 40 mesothelioma and 28 asbestosis cases. There is the need of remediation/removal interventions for contaminated sites and of strategies to increase GPs awareness on asbestos risks for better patients' management.


Methyl antcinate A from Antrodia camphorata induces apoptosis in human liver cancer cells through oxidant-mediated cofilin- and Bax-triggered mitochondrial pathway.
We investigated the effects of antcin A, antcin C, and methyl antcinate A (MAA) isolated from Antrodia camphorata on the proliferation of human liver cancer cell lines Huh7, HepG2, and Hep3B and the normal cell rat hepatocytes. The three compounds selectively inhibit the proliferation of tumor cells rather than normal cells, with IC(50) values ranging from 30.2 to 286.4 microM. The compound MAA was a more potent cytotoxic agent than antcins A and C with IC(50) values of 52.2, 78.0, and 30.2 microM against HepG2, Hep3B, and Huh7 cells, respectively. To elucidate the molecular mechanism, treatment of Huh7 cells with 100 microM MAA induced an apoptotic cell death, which was characterized by the appearance of sub-G1 population, DNA fragmentation, TUNEL positive cells, and caspase activation. MAA triggered the mitochondrial apoptotic pathway, as indicated by an increase in the protein expression of Bax, Bak, and PUMA, as well as a decrease in Bcl-(XL) and Bcl-2 and disruption of mitochondrial membrane potential and promotion of mitochondrial cytochrome c release, as well as activation of caspases-2, -3, and -9. We also found that pretreatment with inhibitors of caspases-2, -3, and -9 noticeably blocked MAA-triggered apoptosis. Furthermore, intracellular reactive oxygen species (ROS) generation and NADPH oxidase activation were observed in MAA-stimulated Huh7 cells. Mechanistic studies showed that MAA induces mitochondrial translocation of cofilin. When Huh7 cells were treated with cyclosporine A and bongkrekic acid, an inhibitor of the mitochondria permeability transition pore, the levels of cell death induced by MAA were significantly attenuated. Additionally, pretreatment of Huh7 cells with antioxidants ascorbic acid and N-acetyl cysteine markedly attenuated the MAA-induced apoptosis by upregulation of Bax, Bak, and PUMA, mitochondrial translocation of cofilin, activation of caspase-3, and cell death. Taken together, our results provide the first evidence of the activation of the ROS-dependent cofilin- and Bax-triggered mitochondrial pathway as a critical mechanism of MAA-induced cell death in liver cancer cells.


[Glycine dependence of Staphylococcus aureus strains].
Glycine dependent Staphylococcus aureus var. bovis strains (TSCHAPE and RISCHE 1971) were tested for their ability to grow on glycine containing and glycine deprived media. We observed glycine dependence only in minimal media. In complete media the strains grew in absence of glycine. Testing the ability of some glycine precursors we found that in minimal media glycine could be replaced by threonine and in some cases by serine. One mutant (Gly 100 Glyox.r.) was able to metabolize glyoxylate instead of glycine. Aspartic acid was metabolized in presence of glycine. Using 14C-aspartic acid we detected 14C-glycine and 14C-threonine. Presumably the bacteria metabolize aspartic acid to glycine via threonine.


Anti-inflammatory activity of Motherwort (Leonurus sibiricus L.).
Motherwort (MW), a Korean folk medicine, has been applied to treat inflammatory disease. However, its effect on inflammatory cytokine release from mast cells is not well known. We investigated the anti- inflammatory effect of MW on the secretion of inflammatory cytokine such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 and IL-8 in human mast cell line (HMC-1). MW was treated in vitro before activation of HMC-1 cells with phorbol 12-myristate 13-acetate (PMA) plus calcium ionophore A23187. MW had no cytotoxic effects on HMC-1 cell viability. MW (1 mg/ml) inhibited PMA plus A23187-stimulated gene expression and production of TNF-alpha, IL-6, and IL-8. Stimulation with PMA plus A23187 induced NF-kappaB activation in HMC-1 cells, which was inhibited by MW (1 mg/ml). MW inhibited secretion of TNF-alpha, IL-6, and IL-8 possibly by inhibiting NF-kappaB activation. These results indicate that MW may be helpful in regulating inflammatory diseases.


Novel insight into MALAT-1 in cancer: Therapeutic targets and clinical applications.
Long non-protein-coding RNAs (lncRNAs) are emerging as important gene expression regulators that are linked to various biological processes at the post-transcriptional and transcriptional levels. lncRNAs are known to be important in cell proliferation, cell differentiation, apoptosis and metastasis. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1), a novel lncRNA, is highly conserved amongst mammals. In addition, it has been considered to act as an oncogene, depending on the tumor system. An increasing number of studies have indicated that MALAT-1 may be detected in certain types of human tumors, including lung and bladder cancer and hepatocellular carcinoma. MALAT-1 silencing may be an effective therapeutic approach against tumors. The present study reviews the current knowledge on the functional role of MALAT-1 in the control of various cancers.


Rapid detection of group A streptococcal antigen for the clinician and the epidemiologist: accurate? cost-effective? useful?
Reviewing the literature describing rapid antigen detection for the diagnosis of group A streptococcal upper respiratory tract infections, one can conclude that the rapid aspect of these tests is clearly advantageous. To be able to have an answer in 5-20 minutes has distinct advantages with regard to therapy for patients. The specificity of most of these tests is acceptable for group A streptococci, although one must recognise that group C and group G streptococci can cause upper respiratory tract infection, and would not be detected by any group A antigen test. A remaining problem appears to be that of sensitivity. Although the range of sensitivity with various techniques and in the hands of different investigators may vary, it is difficult to ignore the fact that the sensitivity for many tests does not appear to be optimal. Furthermore, appropriate technical skill is required before these tests can be recommended for use in the hands of inadequately trained individuals, either in an office laboratory or in peripheral health care stations. There is also the concern that the cost for these diagnostic tests, unless purchased in large quantities, generally is greater than for the throat culture. This could have significant implications in some health care situations. One potential alternative for the office practitioner to consider is that if a rapid antigen test is negative, he or she should also perform a throat culture. This is the routine carried out in many practising clinicians' offices.(ABSTRACT TRUNCATED AT 250 WORDS)


The radiographic union scale in tibial fractures: reliability and validity.
Radiographic assessment of tibial fracture healing continues to pose significant challenges to both routine fracture care and clinical research. Orthopaedic surgeons fail to achieve sufficient agreement on fracture healing when using conventional radiographic measures such as their general impression or the number of cortices bridged by callus. Moreover, the extent to which radiographic assessment of healing corresponds to patient-important outcomes is largely unknown. In an attempt to improve the former (ie, reliability) and inform the latter (ie, validity), recent studies have explored a novel radiographic assessment for tibial shaft fractures, the Radiographic Union Scale for Tibial fractures (RUST). The RUST score assesses the presence of bridging callus and that of a fracture line on each of 4 cortices seen on 2 orthogonal radiographic views. A recent study has found that RUST scores have greater inter-rater reliability when compared with surgeon's general impression or the number of cortices bridged by callus. This may increase the utility of radiographs as a standardized measure of treatment efficacy in the follow-up of tibial fractures.


Practical science communication strategies for graduate students.
Development of skills in science communication is a well-acknowledged gap in graduate training, but the constraints that accompany research (limited time, resources, and knowledge of opportunities) make it challenging to acquire these proficiencies. Furthermore, advisors and institutions may find it difficult to support graduate students adequately in these efforts. The result is fewer career and societal benefits because students have not learned to communicate research effectively beyond their scientific peers. To help overcome these hurdles, we developed a practical approach to incorporating broad science communication into any graduate-school time line. The approach consists of a portfolio approach that organizes outreach activities along a time line of planned graduate studies. To help design the portfolio, we mapped available science communication tools according to 5 core skills essential to most scientific careers: writing, public speaking, leadership, project management, and teaching. This helps graduate students consider the diversity of communication tools based on their desired skills, time constraints, barriers to entry, target audiences, and personal and societal communication goals. By designing a portfolio with an advisor's input, guidance, and approval, graduate students can gauge how much outreach is appropriate given their other commitments to teaching, research, and classes. The student benefits from the advisors' experience and mentorship, promotes the group's research, and establishes a track record of engagement. When graduate student participation in science communication is discussed, it is often recommended that institutions offer or require more training in communication, project management, and leadership. We suggest that graduate students can also adopt a do-it-yourself approach that includes determining students' own outreach objectives and time constraints and communicating these with their advisor. By doing so we hope students will help create a new culture of science communication in graduate student education.


Public health inspectors in restaurants: what they do and why.
This report identifies strategies used by public health inspectors in the Central West Region of Ontario during restaurant inspections, based on and comparing the perceptions of inspectors, their managers, and restaurant operators. Factors influencing the choice of strategies are reviewed, putting into perspective the importance of manager and policy expectations relative to other influences experienced by inspectors in the field. The need to set pragmatic and reality-tested criteria and objectives for a HACCP-based inspection protocol is discussed.


Variations in mortality of the coloured, white and Asian population groups in the RSA, 1978-1982. Part VI. Ischaemic heart disease.
An analysis of ischaemic heart disease (IHD) mortality for the period 1978-1982 showed markedly different rates for the Asian, white and coloured population groups in the RSA. Age-specific and age-standardised rates for Asians were in general considerably higher than those for whites, and did not show the marked decline with time observed in rates for whites. Although coloureds were seen to have considerably lower age-standardized rates than Asians or whites of the same sex, an increase in the age-standardised rates for coloured males over a 10-year period and a slight decrease among females suggested that rates for coloureds may be in the process of approaching those for the other groups. The observed decline in IHD rates among whites of both sexes suggests that preventable major risk factors may be coming under control, apparently to a greater extent in this group than among Asians or coloureds.


Molecular mechanisms of lymphocyte homing to peripheral lymph nodes.
To characterize the adhesion cascade that directs lymphocyte homing to peripheral lymph nodes (PLNs), we investigated the molecular mechanisms of lymphocyte interactions with the microvasculature of subiliac lymph nodes. We found that endogenous white blood cells and adoptively transferred lymph node lymphocytes (LNCs) tethered and rolled in postcapillary high endothelial venules (HEVs) and to a lesser extent in collecting venules. Similarly, firm arrest occurred nearly exclusively in the paracortical HEVs. Endogenous polymorphonuclear (PMNs) and mononuclear leukocytes (MNLs) attached and rolled in HEVs at similar frequencies, but only MNLs arrested suggesting that the events downstream of primary rolling interactions critically determine the specificity of lymphocyte recruitment. Antibody inhibition studies revealed that L-selectin was responsible for attachment and rolling of LNCs, and that LFA-1 was essential for sticking. LFA-1-dependent arrest was also abolished by pertussis toxin, implicating a requirement for G alpha i--protein-linked signaling. alpha 4 integrins, which play a critical role in lymphocyte homing to Peyer's Patches, made no significant contribution to attachment, rolling, or sticking in resting PLNs. Velocity analysis of interacting LNCs revealed no detectable contribution by LFA-1 to rolling. Taken together, our results suggest that lymphocyte- HEV interactions within PLNs are almost exclusively initiated by L-selectin followed by a G protein-coupled lymphocyte-specific activation event and activation-induced engagement of LFA-1. These events constitute a unique adhesion cascade that dictates the specificity of lymphocyte homing to PLNs.


[Multiple cartilaginous exostoses with polyposis of stomach and colon: a new, hereditary combination different from Gardner's syndrome (author's transl)].
Multiple cartilaginous exostoses were found in a 41-year-old man and his two sons, aged 11 and 15 years. The older boy had extensive polyposis of the sigmoid colon and gastric antrum, his brother had radiological changes suspicious of sigmoid polyposis, while there was no radiological evidence of polyposis in the father. None of them had any symptoms of polyposis. The described combination of findings suggests a separate entity from Gardner's syndrome, perhaps on the basis of a combined dominant gene inheritance. In case of multiple exostoses radiological and endoscopic examination of the gastro-intestinal tract for polyposis are indicated.


Beneficial effects of atorvastatin on myocardial regions with initially low vasodilatory capacity at various stages of coronary artery disease.
The aim of this study was to analyse non-invasively the regional effect of therapy with an HMG-CoA reductase inhibitor on myocardial blood flow in patients with coronary artery disease (CAD) with special reference to segments with initially substantially impaired vasodilation. The study included 26 patients with untreated hypercholesterolaemia. Coronary angiography revealed CAD in nine patients with stenosis >50% and wall irregularities or minimal stenosis <30% in 17 patients. Before and 4.6+/-1.8 months after atorvastatin therapy, ( 13)N-ammonia positron emission tomography (PET) studies were performed at rest and under pharmacological stress. Minimum coronary vascular resistance (MCR) and coronary flow reserve (CFR) were determined. Segments were divided into those with normal or near-normal (MBF during adenosine > or =2.0 ml/min/g) and those with abnormal (MBF<2.0 ml/min/g) vasodilator flow response. In CAD patients, 156 segments were analysed, 85 of which had abnormal MBF; in the non-obstructive group, 59 of 297 segments had abnormal MBF. LDL cholesterol decreased after atorvastatin therapy from 186+/-43 mg/dl to 101+/-26 mg/dl (p<0.001). In normal segments no significant changes in MBF, CFR and MCR were found. However, initially abnormal segments showed significant improvements in MCR (15%, p<0.0001) and MBF during adenosine (30%, p<0.0001) after therapy. The improvement in regional coronary vasodilator function after atorvastatin in patients with coronary atherosclerosis may be caused, at least in part, by increased flow-mediated (endothelium-dependent) dilation of the total arteriolar and arterial vascular system. These data further support the concept of non-invasive management of stable CAD by statin therapy and life-style modification guided by PET.


A Literature Review of the Potential Impact of Medication on Vitamin D Status.
In recent years, there has been a significant increase in media coverage of the putative actions of vitamin D as well as the possible health benefits that supplementation might deliver. However, the potential effect that medications may have on the vitamin D status is rarely taken into consideration. This literature review was undertaken to assess the degree to which vitamin D status may be affected by medication. Electronic databases were searched to identify literature relating to this subject, and study characteristics and conclusions were scrutinized for evidence of potential associations. The following groups of drugs were identified in one or more studies to affect vitamin D status in some way: anti-epileptics, laxatives, metformin, loop diuretics, angiotensin-converting enzyme inhibitors, thiazide diuretics, statins, calcium channel blockers, antagonists of vitamin K, platelet aggregation inhibitors, digoxin, potassium-sparing diuretics, benzodiazepines, antidepressants, proton pump inhibitors, histamine H2-receptor antagonists, bile acid sequestrants, corticosteroids, antimicrobials, sulphonamides and urea derivatives, lipase inhibitors, hydroxychloroquine, highly active antiretroviral agents, and certain chemotherapeutic agents. Given that the quality of the data is heterogeneous, newer, more robustly designed studies are required to better define likely interactions between vitamin D and medications. This is especially so for cytochrome P450 3A4 enzyme (CYP3A4)-metabolized medications. Nevertheless, this review suggests that providers of health care ought to be alert to the potential of vitamin D depletions induced by medications, especially in elderly people exposed to multiple-drug therapy, and to provide supplementation if required.


Primary leiomyosarcoma of the kidney.
Primary leiomyosarcoma of the kidney is a rare tumor with an aggressive behaviour. A 55-year-old woman presented with a left sided abdominal mass in our outpatient department. Radiologic investigations revealed the mass to be renal in origin with colonic adhesions for which radical nephrectomy and hemicolectomy were done. The tumor completely appeared to replace the left kidney and had a whorled character focally on cut section. Microscopically, spindle cells having malignant features with cigar shaped nuclei were seen. The smooth muscle origin of the cells was confirmed by immunohistochemical positivity for smooth muscle actin. Sarcomatoid variant of the renal cell carcinoma was ruled out as the tumor was negative for cytokeratin. Tumors with spindle cell morphology in the kidney should not always be taken for a sarcomatoid variant of renal cell carcinoma and should be investigated thoroughly.


Cancer patients' experiences with medicinal cannabis-related care.
Little is known about medical cannabis (MC)-related care for patients with cancer using MC. Semistructured telephone interviews were conducted in a convenience sample of individuals (n = 24) with physician-confirmed oncologic diagnoses and state/district authorization to use MC (Arizona, California, Florida, Illinois, Massachusetts, Oregon, New York, and Washington, DC) from April 2017 to March 2019. Standard qualitative techniques were used to assess the degree of MC-related health care oversight, MC practices, and key information sources. Among 24 participants (median age, 57 years; range, 30-71 years; 16 women [67%]), MC certifications were typically issued by a professional new to a patient's care after a brief, perfunctory consultation. Patients disclosed MCuse to their established medical teams but received little medical advice about whether and how to use MC. Patients with cancer used MC products as multipurpose symptom management and as cancer-directed therapy, sometimes in lieu of standard-of-care treatments. Personal experimentation, including methodical self-monitoring, was an important source of MC know-how. Absent formal advice from medical professionals, patients relied on nonmedical sources for MC information. Patients with cancer used MC with minimal medical oversight. Most received MC certifications through brief meetings with unfamiliar professionals. Participants desired but were often unable to access high-quality clinical information about MC from their established medical teams. Because many patients are committed to using MC, a product sustained by a growing industry, medical providers should familiarize themselves with the existing data for MM and its limitations to address a poorly met clinical need.


Correlation of helical and incremental high-resolution thin-section computed tomographic imaging with histomorphometric quantitative evaluation of lungs in dogs.
To develop protocols for helical computed tomography (CT) and axial high-resolution CT (HRCT) of lungs and correlate densitometric CT values with morphometric and histologic data for normal pulmonary tissue in dogs. 8 healthy adult dogs. 2 dogs were used to establish a protocol for helical CT and HRCT of lungs. Six dogs were used to acquire densitometric CT data regarding normal lungs. After the dogs were euthanatized, their lungs were fixed and sampled for morphometric and histologic evaluation. Four CT acquisitions were compared by means of paired t tests. For normal lung tissue of dogs, mean densitometric CT value obtained during helical CT scans reconstructed in a sharp algorithm was -846 Hounsfield units. Values obtained via helical CT or HRCT acquisitions and reconstructed with sharp or standard algorithms did not differ significantly. Morphometric analysis was used to determine the proportion of lung parenchymal (82%) and non-parenchymal tissue (18%). Alveolar size, estimated by mean linear intercept, was approximately 172 microm, and alveolar surface area-to-volume ratio was 0.024 to 0.026 microm(-1). Histologic evaluation confirmed the presence of normal lung tissue. Correlation of densitometric CT data with morphometric and histologic findings and the establishment of helical CT and HRCT protocols were attained; clinical use of this information may facilitate investigation of pulmonary disease in dogs. Sharp helical CT acquisitions were preferred because of better lung parenchyma detail and rapid image acquisitions, compared with HRCT.


A solution method for predictive simulations in a stochastic environment.
Predictive gait simulations currently do not account for environmental or internal noise. We describe a method to solve predictive simulations of human movements in a stochastic environment using a collocation method. The optimization is performed over multiple noisy episodes of the trajectory, instead of a single episode in a deterministic environment. Each episode used the same control parameters. The method was verified on a torque-driven pendulum swing-up problem. A different optimal trajectory was found in a stochastic environment than in the deterministic environment. Next, it was applied to gait to show its application in predictive simulation of human movement. We show that, unlike in a deterministic model, a nonzero minimum foot clearance during swing is predicted by a minimum-effort criterion in a stochastic environment. The predicted amount of foot clearance increased with the noise amplitude.


Modelling Graft-Versus-Host Disease in Mice Using Human Peripheral Blood Mononuclear Cells.
Graft-versus-host disease (GvHD) is a significant complication of allogeneic hematopoietic stem cell transplantation. In order to develop new therapeutic approaches, there is a need to recapitulate GvHD effects in pre-clinical, in vivo systems, such as mouse and humanized mouse models. In humanized mouse models of GvHD, mice are reconstituted with human immune cells, which become activated by xenogeneic (xeno) stimuli, causing a multi-system disorder known as xenoGvHD. Testing the ability of new therapies to prevent or delay the development of xenoGvHD is often used as pre-clinical, proof-of-concept data, creating the need for standardized methodology to induce, monitor, and report xenoGvHD. Here, we describe detailed methods for how to induce xenoGvHD by injecting human peripheral blood mononuclear cells into immunodeficient NOD SCID gamma mice. We provide comprehensive details on methods for human T cell preparation and injection, mouse monitoring, data collection, interpretation, and reporting. Additionally, we provide an example of the potential utility of the xenoGvHD model to assess the biological activity of a regulatory T-cell therapy. Use of this protocol will allow better standardization of this model and comparison of datasets across different studies. Graft-versus-host disease (GvHD) is a significant complication of allogeneic hematopoietic stem cell transplantation. In order to develop new therapeutic approaches, there is a need to recapitulate GvHD effects in pre-clinical, in vivo systems, such as mouse and humanized mouse models. In humanized mouse models of GvHD, mice are reconstituted with human immune cells, which become activated by xenogeneic (xeno) stimuli, causing a multi-system disorder known as xenoGvHD. Testing the ability of new therapies to prevent or delay the development of xenoGvHD is often used as pre-clinical, proof-of-concept data, creating the need for standardized methodology to induce, monitor, and report xenoGvHD. Here, we describe detailed methods for how to induce xenoGvHD by injecting human peripheral blood mononuclear cells into immunodeficient NOD SCID gamma mice. We provide comprehensive details on methods for human T cell preparation and injection, mouse monitoring, data collection, interpretation, and reporting. Additionally, we provide an example of the potential utility of the xenoGvHD model to assess the biological activity of a regulatory T-cell therapy. Use of this protocol will allow better standardization of this model and comparison of datasets across different studies. This protocol was validated in: Sci Transl Med (2020), DOI: 10.1126/scitranslmed.aaz3866 Graphical abstract.


ACTH-secreting medullary carcinoma of the thyroid: monitoring of clinical course with calcitonin and cortisol assays and immunohistochemical studies.
The clinical course of a patient with Cushing's syndrome secondary to metastatic medullary carcinoma of the thyroid was documented with serial calcitonin and cortisol assays and tumor immunohistochemistry studies. Cortisol levels were originally markedly elevated but returned to normal after total thyroidectomy. These levels rose again when the patient developed liver metastases but normalized during chemotherapy, never to rise again despite the appearance of cervical lymph node metastasis. Calcitonin levels remained elevated throughout the course. The original tumor was composed of two cell lines: one containing both calcitonin and ACTH and another containing only calcitonin-reacting cells. However, the cervical metastasis showed a marked decrease in both cell lines with fever than 1% of cells reacting to ACTH, and only 25% to calcitonin. The almost total disappearance of ACTH-reacting cells may have been therapeutically induced or may represent a consequence of tumor progression.


Economic evaluation of the fentanyl transdermal system for the treatment of chronic moderate to severe pain.
The fentanyl transdermal system (Duragesic) is an opioid analgesic indicated for the management of chronic moderate to severe pain. The purpose of this analysis is to estimate its economic value compared to two long-acting oral opioids. A cost-utility analysis was performed using a three-phased decision analytic model. The transdermal system had the highest expected cost during the first year of therapy ($2,491), moderately higher than the cost of a year of therapy with controlled-release morphine ($2,037) or controlled-release oxycodone ($2,307). The system also had the highest expected number of quality-adjusted life-days (QALDs) (244 compared to 236 for morphine and 231 for oxycodone), despite conservative assumptions. The fentanyl transdermal system achieved incremental cost-utility ratios of $20,709 (vs. morphine) and $5,273 (vs. oxycodone) per quality-adjusted life year (QALY) gained. In a conservative modeled analysis, the fentanyl transdermal system led to increased QALDs at a nominal increased cost. In the absence of head-to-head clinical trials, models help clarify cost and outcome trade-offs and provide a consistent theoretical framework for use by individual decisionmakers.


Canadian Cardiovascular Society Consensus Conference guidelines on heart failure, update 2009: diagnosis and management of right-sided heart failure, myocarditis, device therapy and recent important clinical trials.
The Canadian Cardiovascular Society published a comprehensive set of recommendations on the diagnosis and management of heart failure in January 2006. Based on feedback obtained through a national program of heart failure workshops and through active solicitation of stakeholders, several topics were identified because of their importance to the practicing clinician. Topics chosen for the present update include best practices for the diagnosis and management of right-sided heart failure, myocarditis and device therapy, and a review of recent important or landmark clinical trials. These recommendations were developed using the structured approach for the review and assessment of evidence adopted and previously described by the Society. The present update has been written from a clinical perspective to provide a user-friendly and practical approach. Specific clinical questions that are addressed include: What is right-sided heart failure and how should one approach the diagnostic work-up? What other clinical entities may masquerade as this nebulous condition and how can we tell them apart? When should we be concerned about the presence of myocarditis and how quickly should patients with this condition be referred to an experienced centre? Among the myriad of recently published landmark clinical trials, which ones will impact our standards of clinical care? The goals are to aid physicians and other health care providers to optimally treat heart failure patients, resulting in a measurable impact on patient health and clinical outcomes in Canada.


Quisinostat is a brain-penetrant radiosensitizer in glioblastoma.
Histone deacetylase (HDAC) inhibitors have garnered considerable interest for the treatment of adult and pediatric malignant brain tumors. However, owing to their broad-spectrum nature and inability to effectively penetrate the blood-brain barrier, HDAC inhibitors have failed to provide substantial clinical benefit to patients with glioblastoma (GBM) to date. Moreover, global inhibition of HDACs results in widespread toxicity, highlighting the need for selective isoform targeting. Although no isoform-specific HDAC inhibitors are currently available, the second-generation hydroxamic acid-based HDAC inhibitor quisinostat possesses subnanomolar specificity for class I HDAC isoforms, particularly HDAC1 and HDAC2. It has been shown that HDAC1 is the essential HDAC in GBM. This study analyzed the neuropharmacokinetic, pharmacodynamic, and radiation-sensitizing properties of quisinostat in preclinical models of GBM. It was found that quisinostat is a well-tolerated and brain-penetrant molecule that extended survival when administered in combination with radiation in vivo. The pharmacokinetic-pharmacodynamic-efficacy relationship was established by correlating free drug concentrations and evidence of target modulation in the brain with survival benefit. Together, these data provide a strong rationale for clinical development of quisinostat as a radiosensitizer for the treatment of GBM.


Efficacy and Safety of an mRNA-Based RSV PreF Vaccine in Older Adults.
Respiratory syncytial virus (RSV) can cause substantial morbidity and mortality among older adults. An mRNA-based RSV vaccine, mRNA-1345, encoding the stabilized RSV prefusion F glycoprotein, is under clinical investigation. In this ongoing, randomized, double-blind, placebo-controlled, phase 2-3 trial, we randomly assigned, in a 1:1 ratio, adults 60 years of age or older to receive one dose of mRNA-1345 (50 μg) or placebo. The two primary efficacy end points were the prevention of RSV-associated lower respiratory tract disease with at least two signs or symptoms and with at least three signs or symptoms. A key secondary efficacy end point was the prevention of RSV-associated acute respiratory disease. Safety was also assessed. Overall, 35,541 participants were assigned to receive the mRNA-1345 vaccine (17,793 participants) or placebo (17,748). The median follow-up was 112 days (range, 1 to 379). The primary analyses were conducted when at least 50% of the anticipated cases of RSV-associated lower respiratory tract disease had occurred. Vaccine efficacy was 83.7% (95.88% confidence interval [CI], 66.0 to 92.2) against RSV-associated lower respiratory tract disease with at least two signs or symptoms and 82.4% (96.36% CI, 34.8 to 95.3) against the disease with at least three signs or symptoms. Vaccine efficacy was 68.4% (95% CI, 50.9 to 79.7) against RSV-associated acute respiratory disease. Protection was observed against both RSV subtypes (A and B) and was generally consistent across subgroups defined according to age and coexisting conditions. Participants in the mRNA-1345 group had a higher incidence than those in the placebo group of solicited local adverse reactions (58.7% vs. 16.2%) and of systemic adverse reactions (47.7% vs. 32.9%); most reactions were mild to moderate in severity and were transient. Serious adverse events occurred in 2.8% of the participants in each trial group. A single dose of the mRNA-1345 vaccine resulted in no evident safety concerns and led to a lower incidence of RSV-associated lower respiratory tract disease and of RSV-associated acute respiratory disease than placebo among adults 60 years of age or older. (Funded by Moderna; ConquerRSV ClinicalTrials.gov number, NCT05127434.).


Anti-Human VEGF Repebody Effectively Suppresses Choroidal Neovascularization and Vascular Leakage.
Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness among people over the age of 60. Vascular endothelial growth factor (VEGF) plays a major role in pathological angiogenesis in AMD. Herein, we present the development of an anti- human VEGF repebody, which is a small-sized protein binder consisting of leucine-rich repeat (LRR) modules. The anti-VEGF repebody selected through a phage-display was shown to have a high affinity and specificity for human VEGF. We demonstrate that this repebody effectively inhibits in vitro angiogenic cellular processes, such as proliferation and migration, by blocking the VEGF-mediated signaling pathway. The repebody was also shown to have a strong suppression effect on choroidal neovascularization (CNV) and vascular leakage in vivo. Our results indicate that the anti-VEGF repebody has a therapeutic potential for treating neovascular AMD as well as other VEGF-involved diseases including diabetic retinopathy and metastatic cancers.


Structural and genetic characterization of glycosylation of type a flagellin in Pseudomonas aeruginosa.
Type a flagellins from two strains of Pseudomonas aeruginosa, strains PAK and JJ692, were found to be glycosylated with unique glycan structures. In both cases, two sites of O-linked glycosylation were identified on each monomer, and these sites were localized to the central, surface-exposed domain of the monomer in the assembled filament. The PAK flagellin was modified with a heterogeneous glycan comprising up to 11 monosaccharide units that were O linked through a rhamnose residue to the protein backbone. The flagellin of JJ692 was less complex and had a single rhamnose substitution at each site. The role of the glycosylation island gene cluster in the production of each of these glycosyl moieties was investigated. These studies revealed that the orfA and orfN genes were required for attachment of the heterologous glycan and the proximal rhamnose residue, respectively.


Adverse effects of antiglaucoma medications.
Most patients with relatively early glaucomatous damage can be satisfactorily managed with topically or orally administered medications. These drugs, however, can sometimes cause adverse ocular or systemic effects. In this paper the fundamental pharmacologic activity of antiglaucoma medications is reviewed, and appropriate strategies to prevent or manage drug-induced side effects are considered.


Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance.
The unique ability to adapt and thrive in inhospitable, stressful tumor microenvironments (TME) also renders cancer cells resistant to traditional chemotherapeutic treatments and/or novel pharmaceuticals. Cancer cells exhibit extensive metabolic alterations involving hypoxia, accelerated glycolysis, oxidative stress, and increased extracellular ATP that may activate ancient, conserved prion adaptive response strategies that exacerbate multidrug resistance (MDR) by exploiting cellular stress to increase cancer metastatic potential and stemness, balance proliferation and differentiation, and amplify resistance to apoptosis. The regulation of prions in MDR is further complicated by important, putative physiological functions of ligand-binding and signal transduction. Melatonin is capable of both enhancing physiological functions and inhibiting oncogenic properties of prion proteins. Through regulation of phase separation of the prion N-terminal domain which targets and interacts with lipid rafts, melatonin may prevent conformational changes that can result in aggregation and/or conversion to pathological, infectious isoforms. As a cancer therapy adjuvant, melatonin could modulate TME oxidative stress levels and hypoxia, reverse pH gradient changes, reduce lipid peroxidation, and protect lipid raft compositions to suppress prion-mediated, non-Mendelian, heritable, but often reversible epigenetic adaptations that facilitate cancer heterogeneity, stemness, metastasis, and drug resistance. This review examines some of the mechanisms that may balance physiological and pathological effects of prions and prion-like proteins achieved through the synergistic use of melatonin to ameliorate MDR, which remains a challenge in cancer treatment.


The Role of Human Papillomavirus in Oropharyngeal Squamous Cell Carcinoma.
- Human papillomavirus (HPV) is implicated in the development of oropharyngeal squamous cell carcinomas (OPC), particularly those cancers developing in tonsillar tissue. - To review the prevalence, subtypes, and methods of detecting HPV in OPC and to review the epidemiology, histology, staging, management, and prevention of these cancers. - The study comprised a review of the literature. - The incidence of HPV-OPC is rising globally and in the United States, but rates of HPV-positivity vary with the anatomic site(s) and the population studied, as well as the method of detecting HPV infection. These tumors are more common in men. In contrast to HPV- OPC, the rates of smoking and alcohol abuse are lower. The HPV 16 subtype is predominant, and immunohistochemistry staining for p16 and in situ hybridization are the most widely used methods clinically to detect transcriptionally active HPV. Moreover, HPV-OPC has a unique tumor phenotype with predominantly nonkeratinizing morphology and a variety of patterns. These cancers often present with cystic lymph node metastases. The prognosis for HPV-OPC is significantly better than HPV- OPC and has led to differences in grading, staging, and management. Although there are similarities to cervical cancer, there are challenges in preventing such cancers.


Transcriptional and functional analyses of SLC12A3 mutations: new clues for the pathogenesis of Gitelman syndrome.
Gitelman syndrome (GS) is a recessive salt-losing tubulopathy that is caused by mutations in the SLC12A3 gene that encodes the sodium-chloride co-transporter (NCC). GS is characterized by significant inter- and intrafamilial phenotype variability, with early onset and/or severe clinical manifestations in some patients. No correlations between the disease variability and the position/nature of SLC12A3 mutations have been investigated thus far. In this study, extensive mutational analyses of SLC12A3 were performed in 27 patients with GS, including genomic DNA sequencing, multiplex ligation-dependent probe amplification, cDNA analysis, and quantification of allele-specific transcripts, in parallel with functional analyses in Xenopus laevis oocytes and detailed phenotyping. Twenty-six SLC12A3 mutations were identified in 25 patients with GS, including eight novel (detection rate 80%). Transcript analysis demonstrated that splicing mutations of SLC12A3 lead to frameshifted mRNA subject to degradation by nonsense-mediated decay. Heterologous expression documented a novel class of NCC mutants with defective intrinsic transport activity. A subgroup of patients presented with early onset, growth retardation, and/or detrimental manifestations, confirming the potential severity of GS. The mutations that were associated with a severe presentation were the combination at least for one allele of a missplicing resulting in a truncated transcript that was downregulated by nonsense-mediated decay or a nonfunctional, cell surface-absent mutant. The most recurrent mutation on the second allele was a newly described NCC mutant that affected the functional properties of the co-transporter. These data suggest that the nature/position of SLC12A3 mutation, combined with male gender, is a determinant factor in the severity of GS and provide new insights in the underlying pathogenic mechanisms of the disease.


Effect of uranium(VI) speciation on simultaneous microbial reduction of uranium(VI) and iron(III).
Uranium is a pollutant of concern to both human and ecosystem health. Uranium's redox state often dictates whether it will reside in the aqueous or solid phase and thus plays an integral role in the mobility of uranium within the environment. In anaerobic environments, the more oxidized and mobile form of uranium (UO2(2+) and associated species) may be reduced, directly or indirectly, by microorganisms to U(IV) with subsequent precipitation of UO. However, various factors within soils and sediments, such as U(VI) speciation and the presence of competitive electron acceptors, may limit biological reduction of U(VI). Here we examine simultaneous dissimilatory reduction of Fe(III) and U(VI) in batch systems containing dissolved uranyl acetate and ferrihydrite-coated sand. Varying amounts of calcium were added to induce changes in aqueous U(VI) speciation. The amount of uranium removed from solution during 100 h of incubation with S. putrefaciens was 77% in absence of Ca or ferrihydrite, but only 24% (with ferrihydrite) and 14% (without ferrihydrite) were removed for systems with 0.8 mM Ca. Dissimilatory reduction of Fe(III) and U(VI) proceed through different enzyme pathways within one type of organism. We quantified the rate coefficients for simultaneous dissimilatory reduction of Fe(III) and U(VI) in systems varying in Ca concecentration (0-0.8 mM). The mathematical construct, implemented with the reactive transport code MIN3P, reveals predominant factors controlling rates and extent of uranium reduction in complex geochemical systems.


Safety Aspects, Tolerability and Modeling of Retinofugal Alternating Current Stimulation.
While alternating current stimulation (ACS) is gaining relevance as a tool in research and approaching clinical applications, its mechanisms of action remain unclear. A review by Schutter and colleagues argues for a retinal origin of transcranial ACS' neuromodulatory effects. Interestingly, there is an alternative application form of ACS specifically targeting α-oscillations in the visual cortex via periorbital electrodes (retinofugal alternating current stimulation, rACS). To further compare these two methods and investigate retinal effects of ACS, we first aim to establish the safety and tolerability of rACS. The goal of our research was to evaluate the safety of rACS via finite-element modeling, theoretical safety limits and subjective report. 20 healthy subjects were stimulated with rACS as well as photic stimulation and reported adverse events following stimulation. We analyzed stimulation parameters at electrode level as well as distributed metric estimates from an ultra-high spatial resolution magnetic resonance imaging (MRI)-derived finite element human head model and compared them to existing safety limits. Topographical modeling revealed the highest current densities in the anterior visual pathway, particularly retina and optic nerve. Stimulation parameters and finite element modeling estimates of rACS were found to be well below existing safety limits. No serious adverse events occurred. Our findings are in line with existing safety guidelines for retinal and neural damage and establish the tolerability and feasibility of rACS. In comparison to tACS, retinofugal stimulation of the visual cortex provides an anatomically circumscribed model to systematically study the mechanisms of action of ACS.


NMR Metabolomics Show Evidence for Mitochondrial Oxidative Stress in a Mouse Model of Polycystic Ovary Syndrome.
Polycystic ovary syndrome (PCOS) is associated with metabolic and endocrine disorders in women of reproductive age. The etiology of PCOS is still unknown. Mice prenatally treated with glucocorticoids exhibit metabolic disturbances that are similar to those seen in women with PCOS. We used an untargeted nuclear magnetic resonance (NMR)-based metabolomics approach to understand the metabolic changes occurring in the plasma and kidney over time in female glucocorticoid-treated (GC-treated) mice. There are significant changes in plasma amino acid levels (valine, tyrosine, and proline) and their intermediates (2-hydroxybutyrate, 4-aminobutyrate, and taurine), whereas in kidneys, the TCA cycle metabolism (citrate, fumarate, and succinate) and the pentose phosphate (PP) pathway products (inosine and uracil) are significantly altered (p < 0.05) from 8 to 16 weeks of age. Levels of NADH, NAD(+), NAD(+)/NADH, and NADH redox in kidneys indicate increased mitochondrial oxidative stress from 8 to 16 weeks in GC-treated mice. These results indicate that altered metabolic substrates in the plasma and kidneys of treated mice are associated with altered amino acid metabolism, increased cytoplasmic PP, and increased mitochondrial activity, leading to a more oxidized state. This study identifies biomarkers associated with metabolic dysfunction in kidney mitochondria of a prenatal gluococorticoid-treated mouse model of PCOS that may be used as early predictive biomarkers of oxidative stress in the PCOS metabolic disorder in women.


Peripheral and central sites of action for anti-allodynic activity induced by the bifunctional opioid/NPFF receptors agonist BN-9 in inflammatory pain model.
The activation of opioid and neuropeptide FF (NPFF) receptors plays important roles to modulate nociceptive signal in inflammatory pain states. Recently, BN-9 (Tyr-D. Ala-Gly-Phe-Gln-Pro-Gln-Arg-Phe-NH2) was pharmacologically characterized as a novel bifunctional agonist at both opioid and NPFF receptors. In the present study, the anti-allodynic activity and site(s) of action of BN-9 were assessed in a mouse model of carrageenan-induced inflammatory pain. In mice, BN-9 induced a dose-dependent anti-allodinic effect through opioid receptor at supraspinal or spinal level, and this effect was augmented by pretreatment with the NPFF receptor antagonist at the same level. In contrast, peripheral administration of BN-9 produced opioid receptor-mediated anti-allodynia, which was insensitive of the NPFF receptor antagonist. In addition, systemic BN-9 produced anti-allodynic effect via opioid receptors, independent of NPFF system. Therefore, these data indicate that central, peripheral or systemic administrations of BN-9 exert potent analgesic activities in inflammatory pain model via opioid receptor, and central effects of BN-9 are associated with NPFF system. Interestingly, systemic anti-allodynia of BN-9 was blocked by intraperitoneal administration of the opioid receptor antagonists, naloxone and naloxone methiodide, but not by intracerebroventricular injection of the peripherally acting opioid antagonist naloxone methiodide. Furthermore, BN-9-induced systemic anti-allodynia was reversed by intraplantar administration of naloxone, but not by peripheral administration of the NPFF receptor antagonist. Taken together, our data further suggest that systemic BN-9-induced anti-allodynic effect is mainly mediated by peripheral opioid receptors, independent of NPFF receptors.


Requirements for guinea pig cytomegalovirus tropism and antibody neutralization on placental amniotic sac cells.
Congenital cytomegalovirus (cCMV) is a leading cause of birth defects. The guinea pig is the only small cCMV animal model. Guinea pig cytomegalovirus (GPCMV) encodes similar glycoprotein complexes to human CMV (HCMV) including gB and the gH-based pentamer complex (PC). In HCMV, both gB and PC are neutralizing antibody antigens. The relevance of GPCMV PC for virus tropism and vaccine target remains controversial. A novel guinea pig placental amniotic sac epithelial (GPASE) cell-line did not express viral cell receptor platelet derived growth factor receptor alpha (PDGFRA) and resulted in requirement for the PC for GPCMV infection unless PDGFRA was ectopically expressed. High titer anti-gB sera from a GPCMV gB vaccine study was evaluated for GPCMV neutralizing capability on GPASE cells in comparison to convalescent sera from GPCMV(PC+) or GPCMV(PC-) infected animals. Anti-gB sera neutralized fibroblast infection but was less effective compared to anti-GPCMV(PC-), which had antibodies to gH/gL. However, both anti-GPCMV(PC-) and anti-gB sera similarly had reduced neutralizing capability on GPASE and renal epithelial cells in comparison to anti-GPCMV(PC+) sera, which had additional antibodies to PC. Overall, results demonstrate the importance of the PC for GPCMV tropism to various cell types that lack PDGFRA expression and the limited ability of anti-gB sera to neutralize GPCMV on non-fibroblast cells despite the essential nature of gB glycoprotein.


The effect of routine hoof trimming on locomotion score, ruminating time, activity, and milk yield of dairy cows.
The objective of this study was to quantify the effect of hoof trimming on cow behavior (ruminating time, activity, and locomotion score) and performance (milk yield) over time. Data were gathered from a commercial dairy farm in Israel where routine hoof trimming is done by a trained hoof trimmer twice per year on the entire herd. In total, 288 cows spread over 6 groups with varying production levels were used for the analysis. Cow behavior was measured continuously with a commercial neck activity logger and a ruminating time logger (HR-Tag, SCR Engineers Ltd., Netanya, Israel). Milk yield was recorded during each milking session with a commercial milk flow sensor (Free Flow, SCR Engineers Ltd.). A trained observer assigned on the spot 5-point locomotion scores during 19 nighttime milking occasions between 22 October 2012 and 4 February 2013. Behavioral and performance data were gathered from 1wk before hoof trimming until 1wk after hoof trimming. A generalized linear mixed model was used to statistically test all main and interactive effects of hoof trimming, parity, lactation stage, and hoof lesion presence on ruminating time, neck activity, milk yield, and locomotion score. The results on locomotion scores show that the proportional distribution of cows in the different locomotion score classes changes significantly after trimming. The proportion of cows with a locomotion score ≥3 increases from 14% before to 34% directly after the hoof trimming. Two months after the trimming, the number of cows with a locomotion score ≥3 reduced to 20%, which was still higher than the baseline values 2wk before the trimming. The neck activity level was significantly reduced 1d after trimming (380±6 bits/d) compared with before trimming (389±6 bits/d). Each one-unit increase in locomotion score reduced cow activity level by 4.488 bits/d. The effect of hoof trimming on ruminating time was affected by an interaction effect with parity. The effect of hoof trimming on locomotion scores was affected by an interaction effect with lactation stage and tended to be affected by interaction effects with hoof lesion presence, indicating that cows with a lesion reacted different to the trimming than cows without a lesion did. The results show that the routine hoof trimming affected dairy cow behavior and performance in this farm.


The most distant known galaxies.
Ever since the proposal of the idea of an expanding universe more than 50 years ago, each generation of investigators has found that some current theory could be (marginally) tested by the properties of the most distant known galaxies. There has consequently been a continuing effort to identify very remote objects, especially to confront theories of the evolution of galaxies (since galaxies are seen as they were at prior epochs) and to confront cosmological theories (which make predictions about the overall dynamics of the expansion of the universe). These theories have yet to be definitively tested, but a new generation of optical telescopes and detectors provides hope for significant progress during this decade.


Visual perception of multilocular radiolucent mandibular lesions quantified by morphometric analysis.
The aim of this study was to analyse the visual perceptions of different experts with respect to multilocular radiolucent lesions in circumstances when the diagnosis is either known or unknown. 6 radiographs of ameloblastomas (AMELs), keratocystic odontogenic tumours (KOTs), central giant cell lesions (CGCLs) and myxomas (MIXs) were analysed by 16 dental experts [stomatologists/oral surgeons (SS) and dental radiologists (R)]. They delimited the lesions prior to having knowledge of the diagnosis (T1) and after 30 days, when they were aware of the histopathological results (T2). For each image, the following morphometric parameters were calculated: area (A), perimeter (P) and shape factor (SF); after image subtraction procedures (T1 - T2), the exclusive area (EA) of the non-overlapping delimited region was also calculated. For both groups, the T2 area was larger than the T1, although the EA of the SS group was higher than that of the R group independently of the type of lesion. The SF from the SS group was greater than that from the R group, and at T2 the SF values were higher for both groups. AMELs and MIXs showed larger SF and A values; the SS group tended to have the greatest changes in the delimitations of the lesions at T2. The methodology allowed us to quantify differences in the spatial perceptions of professionals. The knowledge of the diagnosis and the expertise of examiners influenced the examiner's perception of the limits of the lesions independently of the actual biological behaviour of the lesion.


Prognostic implications of dipyridamole cardiac MR imaging: a prospective multicenter registry.
To evaluate dipyridamole cardiac magnetic resonance (MR) imaging in the prediction of major events (MEs) in patients with ischemic chest pain in a large multicenter registry. Institutional ethics committee approval and written informed consent were obtained. A total of 1722 patients who were undergoing cardiac MR imaging for chest pain were included. Wall motion abnormalities (WMAs) at rest, hyperemia perfusion defect (PD), late gadolinium enhancement (LGE), and inducible WMA were analyzed (abnormal if more than one abnormal segment was seen) with the 17-segment model. A cardiac MR categorization was created: category 1, no PD, LGE, or inducible WMA; category 2, PD without LGE and inducible WMA; category 3, LGE without inducible WMA; and category 4, inducible WMA. The association with ME was analyzed by using Cox proportional hazard regression multivariate models. During a median follow-up period of 308 days, 61 MEs (4%) occurred (36 cardiac deaths, 25 nonfatal myocardial infarctions). MEs were associated with a greater extent of WMA, PD, LGE, and inducible WMA (P ≤ .001 for all analyses). In multivariable analyses, PD (P = .002) and inducible WMA (P = .0001) were the only cardiac MR predictors. ME rate in categories 1, 2, 3, and 4 was 2% (14 of 901 patients), 3% (six of 219 patients), 4% (15 of 409 patients), and 14% (26 of 193 patients), respectively (category 4 vs category 1, adjusted P < .001). Cardiac MR-directed revascularization was performed in 242 patients (14%) and reduced the risk of ME in only category 4 (7% [six of 92 patients] vs 26% [26 of 101 patients], P = .0004). Dipyridamole cardiac MR imaging can be used to predict MEs in patients with ischemic chest pain. Patients with inducible WMA are at the highest risk for MEs and benefit the most from revascularization.


Additive CAD/CAM process for dental prostheses.
This article describes the evolution of a computer-aided design/computer-aided manufacturing (CAD/CAM) process where ceramic paste is deposited in a layer-by-layer sequence using a computer numerical control machine to build up core and fixed partial denture (FPD) structures (robocasting). Al(2)O(3) (alumina) or ZrO(2) (Y-TZP) are blended into a 0.8% aqueous solution of ammonium polyacrylate in a ratio of approximately 1:1 solid:liquid. A viscosifying agent, hydroxypropyl methylcellulose, is added to a concentration of 1% in the liquid phase, and then a counter polyelectrolyte is added to gel the slurry. There are two methods for robocasting crown structures (cores or FPD framework). One is for the core to be printed using zirconia ink without support materials, in which the stereolithography (STL) file is inverted (occlusal surface resting on a flat substrate) and built. The second method uses a fugitive material composed of carbon black codeposited with the ceramic material. During the sintering process, the carbon black is removed. There are two key challenges to successful printing of ceramic crowns by the robocasting technique. First is the development of suitable materials for printing, and second is the design of printing patterns for assembly of the complex geometry required for a dental restoration. Robocasting has room for improvement. Current development involves enhancing the automation of nozzle alignment for accurate support material deposition and better fidelity of the occlusal surface. An accompanying effort involves calculation of optimal support structures to yield the best geometric results and minimal material usage.


α-Fe2O3 Nanodisk/Bacterial Cellulose Hybrid Membranes as High-Performance Sulfate-Radical-Based Visible Light Photocatalysts under Stirring/Flowing States.
High activity and long-term stability are particularly important for peroxymonosulfate (PMS)-based degradation processes in wastewater treatment, especially under a flowing state. However, if the highly active nanomaterials are in a powder form, they could disperse well in water but would not be convenient for application under varied flow rates. A metal oxide/bacterial cellulose hybrid membrane fixed in a flowing bed is expected to solve these problems. Herein, α-Fe2O3 nanodisk/bacterial cellulose hybrid membranes as high-performance sulfate-radical-based visible light photocatalysts are synthesized for the first time. The bacterial cellulose with excellent mechanical stability and film-forming feature not only benefits the formation of a stable membrane to avoid the separation and recycling problems but also helps disperse and accommodate α-Fe2O3 nanodisks and thus enhances the visible light absorption performances, leading to an excellent PMS-based visible light degradation efficiency under both stirring and flowing states. Particularly, the optimized hybrid membrane photocatalyzes both cationic and anionic organic dyes under a flowing bed state for at least 84 h with the catalytic efficiency up to 100% and can be easily separated after the reaction, confirming its remarkable catalytic performance and long-term stability. Even under varied flow rates during the continuous process, it efficiently degrades rhodamine B and orange II from 3 to 16 mL h-1. When the flow rate goes back from high to low, the hybrid membrane quickly recovers its original performance, demonstrating the high activity and stability of the α-Fe2O3/bacterial cellulose membrane.


[Reproduction of Ichthyophthirius multifiliis (Ciliata, Ophryoglenidae)].
A case of reproduction of Ichthyophthirius multifiliis in the superficial tissues of larvae and fry of Amur wild carp is described. At a temperature of water from 28 to 29 degrees trophonts of Ichthyophthirius encysted on fishes. Inside cysts repeated cell division occurred but this process did not result in swarm spores formation. Later on with the increase of temperature to 29.5--31.5 degrees cysts degenerated.


Should a regurgitant mitral valve be replaced simulataneously with a stenotic aortic valve?
Mitral valve regurgitation frequently accompanies aortic valve stenosis. It has been suggested that mitral regurgitation improves after aortic valve replacement alone and that the mitral valve need not be replaced simultaneously Furthermore, mitral regurgitation associated with coronary artery disease, particularly in patients with poor left ventricular function, shows immediate improvement after coronary artery bypass grafting. We studied 60 consecutive patients with aortic stenosis and mitral regurgitation to determine the degree of improvement in mitral regurgitation after aortic valve replacement alone versus aortic valve replacement combined with coronary artery bypass grafting. Thirty-six of the patients had normal coronary arteries (Group 1); the other 24 had symptomatic coronary artery disease requiring bypass surgery (Group 2). Echocardiography was performed preoperatively, 1 week postoperatively, and at follow-up. In Group 1, left ventricular ejection fraction did not improve early or at 2.5 months postoperatively, but mitral regurgitation improved gradually during follow-up. In Group 2, mitral regurgitation showed improvement 1 week postoperatively (p < 0.001), and left ventricular ejection fraction was improved at 2.5 months. We conclude that patients with aortic valve stenosis and mild-to-severe mitral regurgitation, without echocardiographic signs of chordal or papillary muscle rupture and without coronary artery disease, should undergo aortic valve replacement alone. The mitral regurgitation will remain the same or improve. For patients with coexisting coronary artery disease, simultaneous aortic valve replacement and coronary artery bypass grafting are imperative; however, the mitral valve again requires no intervention, since mitral regurgitation improves significantly after the other 2 procedures.