Alteration of Flt3-Ligand-dependent de novo generation of conventional dendritic cells during influenza infection contributes to respiratory bacterial superinfection.
Secondary bacterial infections contribute to the excess morbidity and mortality of influenza A virus (IAV) infection. Disruption of lung integrity and impaired antibacterial immunity during IAV infection participate in colonization and dissemination of the bacteria out of the lungs. One key feature of IAV infection is the profound alteration of lung myeloid cells, characterized by the recruitment of deleterious inflammatory monocytes. We herein report that IAV infection causes a transient decrease of lung conventional dendritic cells (cDCs) (both cDC1 and cDC2) peaking at day 7 post-infection. While triggering emergency monopoiesis, IAV transiently altered the differentiation of cDCs in the bone marrow, the cDC1-biaised pre-DCs being particularly affected. The impaired cDC differentiation during IAV infection was independent of type I interferons (IFNs), IFN-γ, TNFα and IL-6 and was not due to an intrinsic dysfunction of cDC precursors. The alteration of cDC differentiation was associated with a drop of local and systemic production of Fms-like tyrosine kinase 3 ligand (Flt3-L), a critical cDC differentiation factor. Overexpression of Flt3-L during IAV infection boosted the cDC progenitors' production in the BM, replenished cDCs in the lungs, decreased inflammatory monocytes' infiltration and lowered lung damages. This was associated with partial protection against secondary pneumococcal infection, as reflected by reduced bacterial dissemination and prolonged survival. These findings highlight the impact of distal viral infection on cDC genesis in the BM and suggest that Flt3-L may have potential applications in the control of secondary infections.


[Genetic counseling: should side issues become main issues?].
Three people applied for genetic counselling, but during the consultations the clinical geneticist discovered other problems for which advice could have been given but was not asked. This caused a serious dilemma. The first person was a woman who wanted to know the risks of epilepsy for her potential offspring, but then it became clear that she appeared to have Huntington's disease in the family. The second person was a man who wanted to know about the genetic risks for his offspring of a borderline psychiatric disorder, but the geneticist, seeing that the partner had severe limb defects, wondered whether these were caused by a genetic disorder. The third patient was a pregnant woman who came asking about the risks caused by mental retardation in one of her ancestors, but who appeared to be a heavy drinker and user of cocaine and ecstasy. In dealing with such 'secondary' problems, it should be kept in mind that persons seeking advice must decide for themselves whether or not they want to be informed regarding these problems or not.


On Mexican folk medicine.
In this paper traditional medical beliefs and practices in a Mexican village are described and interpreted. The analysis focuses on the notion that health is a balance of hot and cold within the body. Several lines of evidence are used to reveal the metaphorical meanings of hot and cold, and these meanings are then seen to be related to structural features of peasant society.


Tandemly repeated genes encode nucleoside triphosphate hydrolase isoforms secreted into the parasitophorous vacuole of Toxoplasma gondii.
The obligate intracellular parasite Toxoplasma gondii produces a nucleoside triphosphate hydrolase (NTPase) (nucleoside-triphosphatase, EC 220.127.116.11) activable by dithiol-containing compounds. We have isolated the genomic DNA for the NTPase from the RH strain of Toxoplasma and determined the nucleotide sequence of three tandemly arranged open reading frames termed NTP1, NTP2, and NTP3. We have also isolated and sequenced cDNAs for NTP1 and NTP3; no cDNA for NTP2 was obtained. The two cDNA clones encode proteins that are more than 97% identical at the amino acid level but significantly differ within two small domains, indicating the presence of NTPase isoforms. Both possess N-terminal signal sequences and two regions with partial homology to certain known ATP binding motifs: the glycine-rich loop common to many ATP binding proteins and the beta-phosphate binding domain found in the hexokinase-actin-hsp70 family. Antiserum against a NTP1-fusion protein immunoprecipitated NTPase activity from extracellular parasites that was increased in activity by treatment with dithiothreitol, confirming the identity of the cloned genes. By immunofluorescence, the NTPase is located in vesicular structures within the parasite, and in infected cells it is secreted into the vacuolar space and becomes partially associated with the parasitophorous vacuolar membrane. Since the vacuolar membrane is freely permeable to small molecules of < 1300 Da, host cell ATP may serve as a substrate for the NTPase and supply the energy for parasite-directed processes in the vacuolar space.


Effect of zinc and selenium supplementation on serum testosterone and plasma lactate in cyclist after an exhaustive exercise bout.
Zinc and selenium are essential minerals and have roles for more than 300 metabolic reactions in the body. The purpose of this study was to investigate how exhaustive exercise affects testosterone levels and plasma lactate in cyclists who were supplemented with oral zinc and selenium for 4 weeks. For this reason, 32 male road cyclists were selected equally to four groups: PL group, placebo; Zn group, zinc supplement (30 mg/day); Se group, selenium supplement (200 μg/day); and Zn-Se group, zinc-selenium supplement. After treatment, free, total testosterone, and lactate levels of subjects were determined before and after exhaustive exercise. Resting total, free testosterone, and lactate levels did not differ significantly between groups, and were increased by exercise (P > 0.05). Serum total testosterone levels in Zn group were higher than in Se group after exercise (P < 0.05). Serum-free testosterone levels in the Zn group were higher than the other groups (P < 0.05).There was an insignificant difference between levels of lactate in the four groups after exercise (P > 0.05). The results showed that 4-week simultaneous and separately zinc and selenium supplementation had no significant effect on resting testosterone and lactate levels of subjects who consume a zinc and selenium sufficient diet. It might be possible that the effect of zinc supplementation on free testosterone depends on exercise.


Rare Diseases and Orphan Drugs Accessibility in Bosnia and Herzegovina.
Rare diseases are becoming more and more important since awareness is increasing. There are a lot of initiatives to ensure access to orphan drugs intended to treat these diseases but due to high price patients have low access and policy makers and payers are struggling with costs and assuring patient access rights to the available medication. Objective of this study is to assess current situation regarding rare diseases in Bosnia and Herzegovina (BiH) and availability of orphan drugs. Four domains are examined: legislation and policy, diagnostics and research, patient organizations and reimbursement and availability of medicines for rare diseases. There are official programs and legislation ground for rare diseases in both entities of BiH: Republic of Srpska (RS) and Federation of BiH (FBiH). Diagnostic and genetic counseling are available but only for few rare diseases. Patient organizations are formed and active but still without engagement in some of international organizations. There are no special reimbursement criteria for orphan medicines. Number of reimbursed medicines is significantly lower than those on ORPHANET list, 67 and 26 in RS and FBiH respectively. Huge difference in number of reimbursed medicines within the country entities may be consequence of counting method. Even thou rare diseases in BiH are recognized in countries official programs and documents, with patients having their organizations, much more have to be done in availability of medicines and diagnostics in the rare disease field. Insufficient funds are huge obstacle toward this goal. New methods of medicine evaluation are need and recommended in order of better availability.


Comparative architectures of mammalian and chicken genomes reveal highly variable rates of genomic rearrangements across different lineages.
Molecular evolution studies are usually based on the analysis of individual genes and thus reflect only small-range variations in genomic sequences. A complementary approach is to study the evolutionary history of rearrangements in entire genomes based on the analysis of gene orders. The progress in whole genome sequencing provides an unprecedented level of detailed sequence data to infer genome rearrangements through comparative approaches. The comparative analysis of recently sequenced rodent genomes with the human genome revealed evidence for a larger number of rearrangements than previously thought and led to the reconstruction of the putative genomic architecture of the murid rodent ancestor, while the architecture of the ancestral mammalian genome and the rate of rearrangements in the human lineage remained unknown. Sequencing the chicken genome provides an opportunity to reconstruct the architecture of the ancestral mammalian genome by using chicken as an outgroup. Our analysis reveals a very low rate of rearrangements and, in particular, interchromosomal rearrangements in chicken, in the early mammalian ancestor, or in both. The suggested number of interchromosomal rearrangements between the mammalian ancestor and chicken, during an estimated 500 million years of evolution, only slightly exceeds the number of interchromosomal rearrangements that happened in the mouse lineage, over the course of about 87 million years.


Pattern of predictive features of continued cannabis use in patients with recent-onset psychosis and clinical high-risk for psychosis.
Continued cannabis use (CCu) is an important predictor for poor long-term outcomes in psychosis and clinically high-risk patients, but no generalizable model has hitherto been tested for its ability to predict CCu in these vulnerable patient groups. In the current study, we investigated how structured clinical and cognitive assessments and structural magnetic resonance imaging (sMRI) contributed to the prediction of CCu in a group of 109 patients with recent-onset psychosis (ROP). We tested the generalizability of our predictors in 73 patients at clinical high-risk for psychosis (CHR). Here, CCu was defined as any cannabis consumption between baseline and 9-month follow-up, as assessed in structured interviews. All patients reported lifetime cannabis use at baseline. Data from clinical assessment alone correctly classified 73% (p < 0.001) of ROP and 59 % of CHR patients. The classifications of CCu based on sMRI and cognition were non-significant (ps > 0.093), and their addition to the interview-based predictor via stacking did not improve prediction significantly, either in the ROP or CHR groups (ps > 0.065). Lower functioning, specific substance use patterns, urbanicity and a lack of other coping strategies contributed reliably to the prediction of CCu and might thus represent important factors for guiding preventative efforts. Our results suggest that it may be possible to identify by clinical measures those psychosis-spectrum patients at high risk for CCu, potentially allowing to improve clinical care through targeted interventions. However, our model needs further testing in larger samples including more diverse clinical populations before being transferred into clinical practice.


Source apportionment of aerosol particles at a European air pollution hot spot using particle number size distributions and chemical composition.
Ostrava in the Moravian-Silesian region (Czech Republic) is a European air pollution hot spot for airborne particulate matter (PM), polycyclic aromatic hydrocarbons (PAHs), and ultrafine particles (UFPs). Air pollution source apportionment is essential for implementation of successful abatement strategies. UFPs or nanoparticles of diameter <100 nm exhibit the highest deposition efficiency in human lungs. To permit apportionment of PM sources at the hot-spot including nanoparticles, Positive Matrix Factorization (PMF) was applied to highly time resolved particle number size distributions (NSD, 14 nm-10 μm) and PM0.09-1.15 chemical composition. Diurnal patterns, meteorological variables, gaseous pollutants, organic markers, and associations between the NSD factors and chemical composition factors were used to identify the pollution sources. The PMF on the NSD reveals two factors in the ultrafine size range: industrial UFPs (28%, number mode diameter - NMD 45 nm), industrial/fresh road traffic nanoparticles (26%, NMD 26 nm); three factors in the accumulation size range: urban background (24%, NMD 93 nm), coal burning (14%, volume mode diameter - VMD 0.5 μm), regional pollution (3%, VMD 0.8 μm) and one factor in the coarse size range: industrial coarse particles/road dust (2%, VMD 5 μm). The PMF analysis of PM0.09-1.15 revealed four factors: SIA/CC/BB (52%), road dust (18%), sinter/steel (16%), iron production (16%). The factors in the ultrafine size range resolved with NSD have a positive correlation with sinter/steel production and iron production factors resolved with chemical composition. Coal combustion factor resolved with NSD has moderate correlation with SIA/CC/BB factor. The organic markers homohopanes correlate with coal combustion and the levoglucosan correlates with urban background. The PMF applications to NSD and chemical composition datasets are complementary. PAHs in PM1 were found to be associated with coal combustion factor.


Corticomotor and somatosensory evoked potential evaluation of acute spinal cord injury in the rat.
Somatosensory evoked potentials (SSEPs) and corticomotor evoked potentials (CMEPs) were utilized to study acute blunt spinal cord trauma. Rats, anesthetized with ketamine hydrochloride, were subjected to a parasagittal craniotomy and a midthoracic laminectomy. SSEPs were cortically recorded and CMEPs were transcortically produced using epidural ball and disc electrodes. SSEPs were elicited and CMEPs were recorded via hindlimb percutaneous needle electrodes. After control records were made, animals were subjected to a 25-, 50-, or 75-g/cm impact to the dorsal cord surface via a modified weight drop procedure. Evaluation of neurological injury was made by SSEP and CMEP analysis as well as by physical testing with noxious stimulation applied to the hindlimb. Neurohistopathological verification of each spinal cord lesion was performed. No significant change in SSEP configuration was identified in animals subjected to a 25-g/cm cord impact; however, a small decrement in CMEP amplitude was consistently observed. Although vocalization to noxious stimulation was present, flexion activity was less than normal. Animals subjected to a 50-g/cm cord impact also showed no change in SSEP wave forms. All components of the CMEP were greatly attenuated with this injury. Either very weak movement or no movement to noxious stimulation was present without vocalization. After a 75-g/cm cord impact, both SSEPs and CMEPs were abolished. There was no movement or vocalization in response to noxious stimulation. Serial sections of the spinal cords revealed incremental destruction with increasing severity of injury. These results support the hypothesis that CMEPs are a more sensitive indicator of residual spinal cord function after injury than are SSEPs.


Membrane potential changes during chemokinesis in Paramecium.
Intracellular recordings show that (i) paramecia hyperpolarize slightly in attractants and depolarize in repellents that depend on the avoiding reaction (an abrupt change of swimming direction), and (ii) paramecia more strongly hyperpolarize in repellents and more strongly depolarize in attractants that depend on changes of swimming velocity. These membrane potential changes are in agreement with a hypothesis of membrane potential control of chemokinesis in Paramecium.


Biomarkers for C9orf7-ALS in Symptomatic and Pre-symptomatic Patients: State-of-the-art in the New Era of Clinical Trials.
The development of new possible treatments for C9orf72-related ALS and the possibility of early identification of subjects genetically at risk of developing the disease is creating a critical need for biomarkers to track neurodegeneration that could be used as outcome measures in clinical trials. Current candidate biomarkers in C9orf72-ALS include neuropsychology tests, imaging, electrophysiology as well as different circulating biomarkers. Neuropsychology tests show early executive and verbal function involvement both in symptomatic and asymptomatic mutation carriers. At brain MRI, C9orf72-ALS patients present diffuse white and grey matter degeneration, which are already identified up to 20 years before symptom onset and that seem to be slowly progressive over time, while regions of altered connectivity at fMRI and of hypometabolism at [18F]FDG PET have been described as well. At the same time, spinal cord MRI has also shown progressive decrease of FA in the cortico-spinal tract over time. On the side of wet biomarkers, neurofilament proteins are increased both in the CSF and serum just before symptom onset and tend to slowly increase over time, while poly(GP) protein can be detected in the CSF and probably used as target engagement marker in clinical trials.


The pedunculopontine tegmental nucleus-A functional hypothesis from the comparative literature.
We present data from animal studies showing that the pedunculopontine tegmental nucleus-conserved through evolution, compartmentalized, and with a complex pattern of inputs and outputs-has functions that involve formation and updates of action-outcome associations, attention, and rapid decision making. This is in contrast to previous hypotheses about pedunculopontine function, which has served as a basis for clinical interest in the pedunculopontine in movement disorders. Current animal literature points to it being neither a specifically motor structure nor a master switch for sleep regulation. The pedunculopontine is connected to basal ganglia circuitry but also has primary sensory input across modalities and descending connections to pontomedullary, cerebellar, and spinal motor and autonomic control systems. Functional and anatomical studies in animals suggest strongly that, in addition to the pedunculopontine being an input and output station for the basal ganglia and key regulator of thalamic (and consequently cortical) activity, an additional major function is participation in the generation of actions on the basis of a first-pass analysis of incoming sensory data. Such a function-rapid decision making-has very high adaptive value for any vertebrate. We argue that in developing clinical strategies for treating basal ganglia disorders, it is necessary to take an account of the normal functions of the pedunculopontine. We believe that it is possible to use our hypothesis to explain why pedunculopontine deep brain stimulation used clinically has had variable outcomes in the treatment of parkinsonism motor symptoms and effects on cognitive processing. © 2016 International Parkinson and Movement Disorder Society.


Modification of tubuloglomerular feedback signal by dietary protein.
Compared with the effects of a 6% protein diet, feeding rats a 40% protein diet for 10 days increases glomerular filtration rate and decreases the activity of the tubuloglomerular (TG) feedback control system. The decrease in TG feedback activity results from an increase in the threshold at which the loop of Henle flow rate initiates feedback responses. To determine whether this protein-dependent shift in the TG feedback response curve is caused by changes in either the signal or the sensing mechanism in the feedback pathway, we used micropuncture and microperfusion techniques to study the TG feedback system of rats fed high- or low-protein (40 or 6% casein) diets for approximately 7-10 days. Compared with the rats fed the low-protein diet, in the high-protein group distally measured single nephron glomerular filtration rate was 17% higher, and Na and Cl concentrations in early distal tubule fluid were 30-50% lower. Early distal osmolality was not different in the two groups. TG feedback responses assessed by changes in stop-flow pressure during perfusion of the distal nephron with NaCl solutions did not differ between diet groups. We conclude that the sensing mechanism in the TG feedback system is not altered by this manipulation of dietary protein, whereas the signal eliciting the TG feedback response is affected. Because rats fed a high-protein diet have higher rates of Na and Cl absorption between the late proximal and early distal tubules than do rats fed a low-protein diet, early distal Na and Cl concentrations are reduced, and the signal for TG feedback is diminished in rats fed the high-protein diet.


Phase 1 cohort expansion study of LY3023414, a dual PI3K/mTOR inhibitor, in patients with advanced mesothelioma.
BACKGROUND LY3023414 is a selective, ATP competitive inhibitor of class I PI3K isoforms, mTORC1/2 and DNA-PK. A Phase 1 dose escalation, 200 mg twice daily (BID) of LY3023414 was the determined recommended phase 2 dose (RP2D). We report the antitumor activity and safety of LY3023414 monotherapy in patients with advanced mesothelioma.METHODS Patients enrolled had advanced malignant pleural or peritoneal mesothelioma with measurable disease, ECOG PS 0-1, were refractory or ineligible to receive standard therapies. Patients received LY3023414 200 mg BID. This dose expansion cohort is intended to evaluate preliminary antitumor activity of LY3023414 by overall response rate. Safety, tolerability and pharmacokinetics were assessed. Biomarkers associated with treatment response was an exploratory endpoint. RESULTS Forty-two patients received LY3023414 for a median duration of 11.2 weeks (range: 1.1-53.0). One patient had a confirmed partial response (PR) (ORR 2.4%). Three patients had an unconfirmed PR. Seventeen patients had stable disease (SD) (DCR 43%). Most common adverse events (AEs) included fatigue (43%), nausea (43%), decreased appetite (38%), vomiting (33%), and diarrhea (29%). AEs were mostly mild or moderate. Grade ≥ 3 AEs were reported for 21% of patients with fatigue as the most frequent event (10%). Alterations of BAP1 were identified in 11/19 patients as the most common molecular aberration, followed by SETD2 and NF2 alterations. No obvious pattern of genetic changes/mutations in single genes or pathways was associated with anti-tumor activity. CONCLUSION LY3023414 monotherapy (200 mg BID) demonstrated an acceptable and manageable safety profile with limited single-agent activity in patients with advanced mesothelioma. ClinicalTrials.gov identifier: NCT01655225; Date of registration: 19 July 2012.


Cadmium induces intracellular Ca2+- and H2O2-dependent apoptosis through JNK- and p53-mediated pathways in skin epidermal cell line.
Cadmium is a toxic heavy metal and has been widely used in industry. The skin is an important target for this metal. The mechanisms by which cadmium leads to damage to the skin are unclear at present. The aims of this study were to examine whether cadmium induces apoptosis in mouse skin epidermal cell line, JB6 Cl41 cells, and to investigate the cellular mechanisms by which cadmium causes cytotoxicity in the cells. The present study showed that cadmium induced cell death by apoptosis in a dose-dependent manner, as proven by the appearance of cell shrinkage, the increase of Annexin V positively stained cells, and the formation of nuclear DNA ladders. Cadmium-induced apoptosis involved a mitochondria-mediated mechanism but not caspase-dependent pathway in that the critical apoptotic events induced by cadmium, such as the decrease of Bcl-2/Bcl-xL, the increase of GADD45alpha, and the nuclear translocation of apoptosis inducing factor, were not affected by the inhibition of executive caspases. In contrast, blockage of p53 and JNK by pharmacological inhibitors or small interference RNA transfection suppressed the cadmium-induced apoptosis with the concomitant inhibition of antiapoptotic Bcl-2 family proteins and GADD45alpha, respectively. Furthermore, the activation of p53 and JNK and their downstream proteins in cadmium-exposed cells were inhibited by individual treatment with catalase and Bapta-acetoxymethyl. These results suggest that cadmium induces apoptosis via the activation of JNK- and p53-mediated signaling, where calcium ion and hydrogen peroxide act as the pivotal mediators of the apoptotic signaling.


Dorsomedial hypothalamic lesions counteract decreases in locomotor activity in male Syrian hamsters transferred from long to short day lengths.
The dorsomedial nucleus (DMN) of the hypothalamus has been implicated in seasonal control of reproduction. Syrian hamsters with DMN lesions, unlike control hamsters, do not undergo testicular regression after transfer from a long day length (14 h of light per day; LD) to a short day length (8 h of light per day; SD). SDs also markedly reduce hamster locomotor activity (LMA). To assess whether the DMN is a component of the neural circuitry that mediates seasonal variation in LMA, neurologically intact males (controls) and hamsters that had sustained lesions of the DMN (DMNx) were housed in an LD or SD photoperiod for 26 weeks. DMNx that prevented testicular regression counteracted decreases in LMA during 8 to10 weeks of SD treatment; steroid-independent effects of SDs did not override high levels of LMA in DMNx males. As in previous studies, testosterone (T) restoration increased LMA in LD but not SD castrated control males. In the present study, T also failed to increase LMA in SD-DMNx hamsters. The DMN is not necessary to maintain decreased responsiveness of locomotor activity systems to T in SDs, which presumably is mediated by other central nervous system androgen target tissues. Finally, DMNx did not interfere with the spontaneous increase in LMA exhibited by photorefractory hamsters after 26 weeks of SD treatment. We propose that DMN is an essential part of the substrate that mediates seasonal decreases in LMA as day length decreases but is not required to sustain decreased SD responsiveness to T or for development of refractoriness to SDs.


[Epidemiology of rheumatic diseases in the German Federal Republic-- current state and perspectives].
During the last few years epidemiologic research on rheumatic diseases in the Federal Republic of Germany has been sponsored, primarily, by the Ministry of Research and Technology. The projects, either completed, ongoing or planned, concentrate on health services research, population studies of the prevalence of specific diseases or complaints (rheumatoid arthritis, back pain, juvenile chronic arthritis, osteoarthritis) and clinical epidemiology, especially concerning early arthritis. As a result of the general shortage of public funds, less projects could be sponsored than expected. The aim of the Ministry to establish research organizations that will continue to exist even if public funding is curtailed seems to be jeopardized. Therefore, not only the federal government, but also the federal states and institutions like the Deutsche Forschungsgemeinschaft should be engaged in this field. More groups should have the opportunity to work in epidemiology of rheumatic diseases, and groups which are able to work in close connection with basic scientists and rheumatological clinicians should be institutionally affiliated on a permanent basis. This is critical for the further development of this discipline which is important for health services research, quality assurance, as well as for analytical research and prevention.


In vivo frequency domain optoacoustic tomography.
Optoacoustic imaging has been primarily implemented in the time domain, i.e., using ultrashort nanosecond laser pulses for illumination. Alternatively, frequency domain optoacoustic imaging can be performed when employing amplitude modulated light sources. We present herein a tomographic implementation of optoacoustic imaging using a linear frequency modulated laser source. The method developed demonstrated the ability to produce tomographic images of optical absorbing phantoms and in vivo images, by enabling visualization of the mouse tail following ICG injection.


Hemodynamic changes during aortic valve surgery among patients with aortic stenosis.
Introduction. Patients with severe aortic stenosis (AS) undergoing surgery are at increased risk of hypotension and hypoperfusion. Although treatable with inotropic agents or fluid, little is known about how these therapies affect central hemodynamics in AS patients under general anesthesia. We measured changes in central hemodynamics after dobutamine infusion and fluid bolus among patients with severe AS and associated these changes with preoperative echocardiography. Methods. We included 33 patients with severe AS undergoing surgical AVR. After induction of general anesthesia, hemodynamic measurements were obtained with a pulmonary artery catheter, including Cardiac index (CI), stroke volume index (SVi) and pulmonary capillary wedge pressure (PCWP). Measurements were repeated during dobutamine infusion, after fluid bolus and lastly after sternotomy. Results. General anesthesia resulted in a decrease in CI and SVi compared to preoperative values. During dobutamine infusion CI increased but mean SVi did not (38 ± 12 vs 37 ± 13 ml/m2, p = .90). Higher EF and SVi before surgery and a larger decrease in SVi after induction of general anesthesia were associated with an increase in SVi during dobutamine infusion. After fluid bolus both CI, SVi (48 ± 12 vs 37 ± 13 ml/min/m2, p < .0001) and PCWP increased. PCWP increased mostly among patients with a larger LA volume index. Conclusion. In patients with AS, CI can be increased with both dobutamine and fluid during surgery. Dobutamine's effect on SVI was highly variable and associated with baseline LVEF, and an increase in CI was mostly driven by an increase in heart rate. Fluid increased SVi at the cost of an increase in PCWP.


A class frequency mixture model that adjusts for site-specific amino acid frequencies and improves inference of protein phylogeny.
Widely used substitution models for proteins, such as the Jones-Taylor-Thornton (JTT) or Whelan and Goldman (WAG) models, are based on empirical amino acid interchange matrices estimated from databases of protein alignments that incorporate the average amino acid frequencies of the data set under examination (e.g JTT + F). Variation in the evolutionary process between sites is typically modelled by a rates-across-sites distribution such as the gamma (Gamma) distribution. However, sites in proteins also vary in the kinds of amino acid interchanges that are favoured, a feature that is ignored by standard empirical substitution matrices. Here we examine the degree to which the pattern of evolution at sites differs from that expected based on empirical amino acid substitution models and evaluate the impact of these deviations on phylogenetic estimation. We analyzed 21 large protein alignments with two statistical tests designed to detect deviation of site-specific amino acid distributions from data simulated under the standard empirical substitution model: JTT+ F + Gamma. We found that the number of states at a given site is, on average, smaller and the frequencies of these states are less uniform than expected based on a JTT + F + Gamma substitution model. With a four-taxon example, we show that phylogenetic estimation under the JTT + F + Gamma model is seriously biased by a long-branch attraction artefact if the data are simulated under a model utilizing the observed site-specific amino acid frequencies from an alignment. Principal components analyses indicate the existence of at least four major site-specific frequency classes in these 21 protein alignments. Using a mixture model with these four separate classes of site-specific state frequencies plus a fifth class of global frequencies (the JTT + cF + Gamma model), significant improvements in model fit for real data sets can be achieved. This simple mixture model also reduces the long-branch attraction problem, as shown by simulations and analyses of a real phylogenomic data set. Protein families display site-specific evolutionary dynamics that are ignored by standard protein phylogenetic models. Accurate estimation of protein phylogenies requires models that accommodate the heterogeneity in the evolutionary process across sites. To this end, we have implemented a class frequency mixture model (cF) in a freely available program called QmmRAxML for phylogenetic estimation.


The Hybrid Approach to Chronic Total Occlusion Percutaneous Coronary Intervention: Update From the PROGRESS CTO Registry.
The aim of this study was to determine the techniques and outcomes of hybrid chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in a diverse group of patients and operators on 2 continents. CTO PCI has been evolving with constant improvement of equipment and techniques. Contemporary outcomes of CTO PCI were examined by analyzing the clinical, angiographic, and procedural characteristics of 3,122 CTO interventions performed in 3,055 patients at 20 centers in the United States, Europe, and Russia. The mean age was 65 ± 10 years, and 85% of the patients were men, with high prevalence of diabetes (43%), prior myocardial infarction (46%), prior coronary artery bypass graft surgery (33%), and prior PCI (65%). The CTO target vessels were the right coronary artery (55%), left anterior descending coronary artery (24%), and left circumflex coronary artery (20%). The mean J-CTO (Multicenter Chronic Total Occlusion Registry of Japan) and PROGRESS CTO (Prospective Global Registry for the Study of Chronic Total Occlusion Intervention) scores were 2.4 ± 1.3 and 1.3 ± 1.0, respectively. The overall technical and procedural success rate was 87% and 85%, respectively, and the rate of in-hospital major complications was 3.0%. The final successful crossing strategy was antegrade wire escalation in 52.0%, retrograde in 27.1%, and antegrade dissection re-entry in 20.9%; >1 crossing strategy was required in 40.9%. Median contrast volume, air kerma radiation dose, and procedure and fluoroscopy time were 270 ml (interquartile range: 200 to 360 ml), 2.9 Gy (interquartile range: 1.7 to 4.7 Gy), 123 min (interquartile range: 81 to 188 min) and 47 min (interquartile range: 29 to 77 min), respectively. CTO PCI is currently being performed with high success and acceptable complication rates among various experienced centers in the United States, Europe, and Russia. (Prospective Global Registry for the Study of Chronic Total Occlusion Intervention [PROGRESS CTO]; NCT02061436).


Psychometric properties of the eating disorder inventory in clinical and nonclinical populations in Taiwan.
To examine psychometric properties and investigate factor structures of the Mandarin Chinese version of the Eating Disorder Inventory (C-EDI). The Mandarin C-EDI and other self-administered questionnaires were completed by a group of female eating disorder (ED) patients (n = 551) and a group of female nursing students (n = 751). Internal consistency, and convergent and discriminant validities were evaluated. Exploratory and confirmatory factor analyses were conducted to examine the construct validity of the Mandarin C-EDI. The Mandarin C-EDI had good internal consistency and convergent and discriminant validities. With a few exceptions, the original clinically derived eight EDI subscales were clearly identified and the factorial validity of the first-order eight-factor structure and the second-order two-factor structure showed an acceptable degree of fit to our empirical data in clinical patients. The findings suggest that the Mandarin C-EDI is a valid tool for clinical use in Taiwan.


Clinical efforts to reduce myocardial infarct size--the next step.
Prompt myocardial reperfusion reduces infarct size in patients experiencing coronary occlusion. However, its clinical value is limited because reperfusion also causes ischemic myocardial reperfusion injury (IMRI). Considerable research to reduce IMRI has been conducted. Three interventions appear to be promising: 1) myocardial conditioning, which consists of repetitive occlusions of coronary or other arteries prior to or at the time of myocardial reperfusion; 2) the administration of cyclosporine A; and 3) the administration of adenosine. A plan for the testing of these interventions in patients with acute myocardial infarction is described.


Rewritable Polymer Brush Micropatterns Grafted by Triazolinedione Click Chemistry.
Triazolinedione (TAD) click reactions were combined with microcontact chemistry to print, erase, and reprint polymer brushes on surfaces. By patterning substrates with a TAD-tagged atom-transfer radical polymerization initiator (ATRP-TAD) and subsequent surface initiated ATRP, it was possible to graft micropatterned polymer brushes from both alkene- and indole-functionalized substrates. As a result of the dynamic nature of the Alder-ene adduct of TAD and indole at elevated temperatures, the polymer pattern could be erased while the regenerated indole substrate could be reused to print new patterns. To demonstrate the robustness of the methodology, the write-erase cycle was repeated four times.


Molecular features and clinical phenotypes in androgen insensitivity syndrome in the absence and presence of androgen receptor gene mutations.
Androgen insensitivity syndrome (AIS) is characterized by deficient or absent virilization in 46,XY individuals despite normal or even elevated androgen levels. AIS is usually caused by mutations in the androgen receptor (AR) gene. We aimed at contrasting clinical, biochemical, and molecular genetic characteristics of three patients (P1-P3) with clinically evident partial (P1) and complete (P2, P3) AIS with and without AR gene mutations. AR expression was studied in cultured genital skin fibroblasts (GSF) by Western immunoblotting, ligand binding analyses, Northern blotting, semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), and RT-PCR spanning exons 1-8. AR gene DNA sequence was analyzed by single-strand conformation analysis (SSCA), and DNA sequencing. GSF revealed reduced (P1) or absent (P2, P3) ligand binding. Northern blots showed either slightly reduced hybridization of the 10.5-kb AR transcript (P3) or no hybridization (P1, P2), as confirmed by semiquantitative RT-PCR. RT-PCR spanning exons 1-8 detected single AR mRNA bands in P1-P3 excluding splicing errors. Western analyses showed either low (P1) or no (P2, P3) AR protein. While SSCA initially did not reveal any molecular abnormality, sequencing showed a novel CAG (Gln) to TAG (stop) mutation at codon 59 (P3) and a previously described 2-bp deletion at codon 472, leading to a frameshift and premature stop in codon 499 (P2). Intriguingly, P1 showed an unaltered DNA sequence of the coding region of the AR gene including all intron-exon boundaries. In conclusion, patients with clinically evident complete AIS are likely to harbor an AR gene mutation, demanding that the two polymorphic regions must always be included in molecular analyses of the AR gene. Moreover, our data support the concept that in a subset of AIS patients, particularly those with partial AIS, molecular alterations outside the coding region of the AR gene must be presumed.


Clonal integration and expression of human T-cell lymphotropic virus type I in carriers detected by polymerase chain reaction and inverse PCR.
Adult T-cell leukemia (ATL) is a neoplasm of mature helper (CD4) T lymphocytes, and human T-cell lymphotropic virus type-I (HTLV-I) has been suggested to be the causative virus of ATL. HTLV-I integrates its proviruses into random sites in host chromosomal DNA. Clonal integration has been observed in patients with ATL, including smoldering, chronic, and acute states. However, random and/or polyclonal integration has only been reported in a few asymptomatic HTLV-I carriers. To clarify the clonality of HTLV-I-infected cells in carriers, we used an inverse polymerase chain reaction (IPCR), which is more sensitive than Southern blot analysis. We used the peripheral blood momonuclear cells (PBMC) from 16 asymptomatic carriers and the separated CD4-positive cells. No cases showed either a monoclonal or polyclonal integration of the HTLV-I provirus by Southern blot. But, using IPCR, 7 of 16 cases showed either mono- or oligoclonal integration. In addition, the populations of clonal provirus in the total PBMC were frequently different from those in the CD4-positive cells. Three cases showed expression of HTLV-I tax/rex mRNA in the total PBMC, but no such expression was found in CD4-positive cells. In this study, an unexpected frequency of clonal HTLV-I provirus DNA was observed in HTLV-I carriers. These findings indicate that the clonal but nonmalignant proliferation of HTLV-I-infected cells already occurs even in HTLV-I carriers, and therefore that some other step is necessary to induce malignant proliferation.


[Roentgeno-morphological comparisons in rheumatoid arthritis based on data of a long-term prospective study].
During a prospective observation lasting 6 years 68 patients with rheumatic arthritis (RA) were repeatedly examined (up to 8 times) roentgenologically with parallel puncture biopsy of the synovial fluid of the knee joint made with an atraumatic needle, and numerical evaluation of markedness of 25 morphological signs of synovitis. A comparative analysis of the markedness of morphological signs of synovitis in relation to the degree and dynamics of destructive changes in the knee joint was made on the basis of the findings of 254 puncture biopsies and the same amount of roentgenograms. There is a close relationship between the activity of synovitis and the progress of destructive arthritis except for the morphological signs characterizing the reaction of hypersensitivity of an immediate type that may serve the purpose of prognostication of further articular destruction and of the choice of an early adequate therapy.


Stressful life events' effects on rheumatoid arthritis disease activity.
A 53-year-old female rheumatoid arthritis (RA) patient endured 2 unexpected family deaths during a 12-week study investigating the prospective relationships between stressful small life events, negative affect, and disease activity. Her disease went into temporary remission the same week as the deaths. She was identified as a case study participant, and weekly data collection was extended to 1 year. Clinical exams verified a large decrease in disease status immediately after the major losses. In addition to major events, negative affect and small events were found to serve as independent arthritis symptom predictors within this patient. Major events were associated with decreased symptoms. Negative affect and small events related to symptom increases. Subsequent between-subjects analyses conducted on 25 participants from the parent project probed for generalizability. The substantive findings from the case study were supported: Major life events and small life events functioned as opposing predictors of RA disease states.


Linking phylogenetic and functional diversity to nutrient spiraling in microbial mats from Lower Kane Cave (USA).
Microbial mats in sulfidic cave streams offer unique opportunities to study redox-based biogeochemical nutrient cycles. Previous work from Lower Kane Cave, Wyoming, USA, focused on the aerobic portion of microbial mats, dominated by putative chemolithoautotrophic, sulfur-oxidizing groups within the Epsilonproteobacteria and Gammaproteobacteria. To evaluate nutrient cycling and turnover within the whole mat system, a multidisciplinary strategy was used to characterize the anaerobic portion of the mats, including application of the full-cycle rRNA approach, the most probable number method, and geochemical and isotopic analyses. Seventeen major taxonomic bacterial groups and one archaeal group were retrieved from the anaerobic portions of the mats, dominated by Deltaproteobacteria and uncultured members of the Chloroflexi phylum. A nutrient spiraling model was applied to evaluate upstream to downstream changes in microbial diversity based on carbon and sulfur nutrient concentrations. Variability in dissolved sulfide concentrations was attributed to changes in the abundance of sulfide-oxidizing microbial groups and shifts in the occurrence and abundance of sulfate-reducing microbes. Gradients in carbon and sulfur isotopic composition indicated that released and recycled byproduct compounds from upstream microbial activities were incorporated by downstream communities. On the basis of the type of available chemical energy, the variability of nutrient species in a spiraling model may explain observed differences in microbial taxonomic affiliations and metabolic functions, thereby spatially linking microbial diversity to nutrient spiraling in the cave stream ecosystem.


[Oxygen consumption during photodynamic therapy in vitro].
The consumption of dissolved molecular oxygen was measured during photodynamic therapy in vitro. Aqueous solutions of hematoporphyrin derivative (HpD) containing different concentrations of serum or numbers of cells were prepared. Decrease in oxygen in the solution and cell suspensions was monitored during light-irradiation (at a wavelength of 610 to 640 nm). The rate of oxygen consumption increased with increasing concentrations of HpD, serum levels or numbers of cells. Upon repeated irradiation of the same solutions (after restitution of the initial pO2 of 100 mm Hg), the rate of oxygen consumption decreased indicating a disaggregation process of HpD. The rate of oxygen content of the solutions decreased independently of the actual oxygen partial pressure. Even at a low pO2 below 10 mm Hg, oxygen consumption was unimpeded until the solutions were free of oxygen. No O2-consumption was noted in aqueous solutions of HpD (up to 40 g/ml) without serum or cells during irradiation.


An unexpectedly large and loosely packed mitochondrial genome in the charophycean green alga Chlorokybus atmophyticus.
The Streptophyta comprises all land plants and six groups of charophycean green algae. The scaly biflagellate Mesostigma viride (Mesostigmatales) and the sarcinoid Chlorokybus atmophyticus (Chlorokybales) represent the earliest diverging lineages of this phylum. In trees based on chloroplast genome data, these two charophycean green algae are nested in the same clade. To validate this relationship and gain insight into the ancestral state of the mitochondrial genome in the Charophyceae, we sequenced the mitochondrial DNA (mtDNA) of Chlorokybus and compared this genome sequence with those of three other charophycean green algae and the bryophytes Marchantia polymorpha and Physcomitrella patens. The Chlorokybus genome differs radically from its 42,424-bp Mesostigma counterpart in size, gene order, intron content and density of repeated elements. At 201,763-bp, it is the largest mtDNA yet reported for a green alga. The 70 conserved genes represent 41.4% of the genome sequence and include nad10 and trnL(gag), two genes reported for the first time in a streptophyte mtDNA. At the gene order level, the Chlorokybus genome shares with its Chara, Chaetosphaeridium and bryophyte homologues eight to ten gene clusters including about 20 genes. Notably, some of these clusters exhibit gene linkages not previously found outside the Streptophyta, suggesting that they originated early during streptophyte evolution. In addition to six group I and 14 group II introns, short repeated sequences accounting for 7.5% of the genome were identified. Mitochondrial trees were unable to resolve the correct position of Mesostigma, due to analytical problems arising from accelerated sequence evolution in this lineage. The Chlorokybus and Mesostigma mtDNAs exemplify the marked fluidity of the mitochondrial genome in charophycean green algae. The notion that the mitochondrial genome was constrained to remain compact during charophycean evolution is no longer tenable. Our data raise the possibility that the emergence of land plants was not associated with a substantial gain of intergenic sequences by the mitochondrial genome.


Primer on medical decision analysis: Part 1--Getting started.
This paper is Part 1 of a five-part series covering practical issues in the performance of decision analysis. The intended audience is individuals who are learning how to perform decision analyses, not just read them. The series assumes familiarity with the basic concepts of decision analysis. It imparts many of the recommendations the authors have learned in teaching a one-semester course in decision analysis to graduate students. Part 1 introduces the topic and covers questions such as choosing an appropriate question, determining the tradeoff between accuracy and simplicity, and deciding on a time frame.


LEAPS therapeutic vaccines as antigen specific suppressors of inflammation in infectious and autoimmune diseases.
The L.E.A.P.S.(™) (Ligand Epitope Antigen Presentation System) technology platform has been used to develop immunoprotective and immunomodulating small peptide vaccines for infectious and autoimmune diseases. Several products are currently in various stages of development, at the pre-clinical stage (in animal challenge efficacy studies). Vaccine peptides can elicit protection of animals from lethal viral (herpes simplex virus [HSV-1] and influenza A) infection or can block the progression of autoimmune diseases (e.g. rheumatoid arthritis as in the collagen induced arthritis (CIA] or experimental autoimmune myocarditis (EAM) models). L.E.A.P.S. technology is a novel T-cell immunization technology that enables the design and synthesis of non-recombinant, proprietary peptide immunogens. Combination of a small peptide that activates the immune system with another small peptide from a disease-related protein, thus a conjugate containing both an Immune Cell Binding Ligand (ICBL) and a disease specific epitope, which allows the L.E.A.P.S. vaccines to activate precursors to differentiate and become more mature cells that can initiate and direct appropriate T cell responses. As such, readily synthesized, defined immunogens can be prepared to different diseases and are likely to elicit protection or therapy as applicable in humans as they are in mice. L.E.A.P.S. vaccines have promise for the treatment of rheumatoid arthritis and other inflammatory diseases and for infections, such as influenza and HSV1. The protective responses are characterized as Th1 immune and immunomodulatory responses with increased IL-12p70 and IFN-γ (Th1 cytokines) but reduced inflammatory cytokines TNF-α, IL-1 and IL-17 (Th2 and Th17 cytokines) and concomitant changes in antibody subtypes. LEAPS immunogens have been used directly in vivo or as ex vivo activators of DC which are then administered to the host.


Relevance of weak flavin binding in human D-amino acid oxidase.
In the brain, the human flavoprotein D-amino acid oxidase (hDAAO) is involved in the degradation of the gliotransmitter D-serine, an important modulator of NMDA-receptor-mediated neurotransmission; an increase in hDAAO activity (that yields a decrease in D-serine concentration) was recently proposed to be among the molecular mechanisms leading to the onset of schizophrenia susceptibility. This human flavoenzyme is a stable homodimer (even in the apoprotein form) that distinguishes from known D-amino acid oxidases because it shows the weakest interaction with the flavin cofactor in the free form. Instead, cofactor binding is significantly tighter in the presence of an active site ligand. In order to understand how hDAAO activity is modulated, we investigated the FAD binding process to the apoprotein moiety and compared the folding and stability properties of the holoenzyme and the apoprotein forms. The apoprotein of hDAAO can be distinguished from the holoenzyme form by the more "open" tertiary structure, higher protein fluorescence, larger exposure of hydrophobic surfaces, and higher sensitivity to proteolysis. Interestingly, the FAD binding only slightly increases the stability of hDAAO to denaturation by urea or temperature. Taken together, these results indicate that the weak cofactor binding is not related to protein (de)stabilization or oligomerization (as instead observed for the homologous enzyme from yeast) but rather should represent a means of modulating the activity of hDAAO. We propose that the absence in vivo of an active site ligand/substrate weakens the cofactor binding, yielding the inactive apoprotein form and thus avoiding excessive D-serine degradation.


A report of heat stroke in two Nigerian siblings.
Infants and children are at higher risk of heat stroke for several reasons. We report these cases to highlight the danger of leaving children unsupervised in vehicles, aid prompt diagnosis, and management of heat stroke. Two Nigerian siblings aged ranges 5 and 3 years old, were trapped inside an unlocked vehicle and subsequently developed heat stroke. Both children presented with hyperthermia, severe dehydration, convulsions, and loss of consciousness. One of them also had hematuria. They were treated by spraying water onto their bodies to bring down the temperature, intravenous fluid resuscitation, oxygen therapy, and anticonvulsants. Both eventually recovered and were discharged with no obvious neurologic sequalae, but are being followed-up.


General practitioners' views on the over-the-counter availability of H2-antagonists.
In recent years there has been a trend towards increasing the number of drugs that are available over the counter (OTC) without prescription. Simultaneously, community pharmacists have been encouraged to develop and extend their role. General practitioners (GPs) have been shown to have some reservations about these developments. A group of drugs widely used in general practice, the H2-antagonists, have recently become available OTC. To examine GPs' attitudes towards community pharmacists dispensing H2-antagonists over the counter (OTC) without prescription. Postal questionnaire to a sample of GPs from inner and outer London, Surrey, Kent, Hampshire, Northumberland, Newcastle upon Tyne and Leicestershire. Of 850 questionnaires sent, 515 were returned, an overall response rate of 60.5%. Fifty four per cent of respondents agreed that cimetidine should be available over the counter for dyspepsia in adults under 45 years not responsive to antacids. Ninety per cent of respondents were aware that H2-antagonists had been deregulated. Most general practitioners learned about the deregulation from professional journals. Very few GPs stated they had changed their prescribing practice since H2-antagonists became available OTC. The high cost to the patient of the OTC product was the most frequently mentioned reason why respondents did not encourage their patients to switch from prescription to OTC H2-antagonists. Worries and concerns regarding the OTC availability of H2-antagonists included masking serious conditions, missed diagnosis, loss of control by the GP and the potential for inappropriate use by patients. Since 1990, there has been a large increase in GPs support for the OTC availability of cimetidine. However, according to their stated behaviour, the reclassification of H2-antagonists does not seem to have changed GPs' prescribing practice, and few appear to be recommending that their patients buy them over the counter.


Factors Associated with Sustained Remission among Chronic Opioid Users.
Chronic opioid use is a major public health problem with significant morbidity. The aim of this study was to investigate factors associated with sustained remission among a sample of Iranian chronic opioid users in Shiraz, Iran. This was a cross-sectional study to evaluate sustained remission among chronic opiate users aged 20-60 years. Participants included two groups: 365 people who have been in sustained remission for the past year, and 187 persons who did not achieve remission for the past one year. Then, demographic and factors related to drug use pattern and previous treatments were compared between two groups. Pearson chi-square test was used for univariate analysis and backward stepwise logistic regression was used to estimate adjusted odds ratios (AORs). Our findings showed that sustained remission was associated with Narcotic Anonymous (NA) participation [AOR = 3.28, 95% confidence interval (CI): 2.19-4.89, P < 0.001], male gender (AOR = 2.53, 95% CI: 1.45-4.43, P = 0.001), younger age of onset (AOR = 1.63, 95% CI: 1.03-2.58, P = 0.037), higher total years of opioid use (AOR = 2.13, 95% CI: 1.42-3.19, P < 0.001), no history of imprisonment (AOR = 2.11, 95% CI: 1.16-3.85, P = 0.015), and family support (AOR = 2.58, 95% CI: 1.33-5.01, P = 0.005). Participation in self-help groups can be a suitable alternative in predicting sustained remission among chronic opiate users. Chronic opioid users should be encouraged by the physicians who are involved in the treatment of drug addiction to participate in NA programs.


The relationship between anogenital distance and the androgen receptor CAG repeat length.
Anogenital distance (AGD) is used to define degree of virilization of genital development, with shorter length being associated with feminization and male infertility. The first exon of the androgen receptor (AR) consists of a polymorphic sequence of cytosine-adenine-guanine (CAG) repeats, with longer CAG repeat lengths being associated with decreased receptor function. We sought to determine if there is an association between AGD and AR CAG repeat length. A cross-sectional, prospective cohort of men evaluated at a urology clinic at a single institution was recruited. AGD (the distance from the posterior scrotum to the anal verge) and penile length (PL) were measured. Sanger DNA sequence analysis was used to define CAG repeat length. AGD and CAG repeat lengths in 195 men were determined. On unadjusted analysis, there was no linear relationship between CAG repeat length and PL (P=0.17) or AGD (P=0.31). However, on sub-population analyses, those men with longer CAG repeat lengths (>26) had significantly shorter AGDs compared to men with shorter CAG repeat lengths. For example, the mean AGD was 41.9 vs. 32.4 mm with a CAG repeat length ≤26 vs. >26 (P=0.01). In addition, when stratifying the cohort based on AGD, those with AGD less than the median (i.e. 40 mm) had a longer CAG repeat length compared to men with an AGD >40 mm (P=0.02). In summary, no linear relationship was found between AGD and AR CAG repeat length overall.


Nanoscale evolution of interface morphology during electrodeposition.
Control of interfacial morphology in electrochemical processes is essential for applications ranging from nanomanufacturing to batteries. Here, we quantify the evolution of an electrochemical growth front, using liquid cell electron microscopy to access unexplored length and time scales. During galvanostatic deposition of copper from an acidic electrolyte, we find that the growth front initially evolves consistent with kinetic roughening theory. Subsequently, it roughens more rapidly, consistent with diffusion-limited growth physics. However, the onset of roughening is strongly delayed compared to expectations, suggesting the importance of lateral diffusion of ions. Based on these growth regimes, we discuss morphological control and demonstrate the effects of two strategies, pulse plating and the use of electrolyte additives.


Minimally invasive surgery in emergency surgery: a WSES survey.
The diffusion of minimally invasive surgery in emergency surgery still represents a developing challenge. Evidence about the use of minimally invasive surgery shows its feasibility and safety; however, the diffusion of these techniques is still poor. The aims of the present survey were to explore the diffusion and variations in the use of minimally invasive surgery among surgeons in the emergency setting. This is a web-based survey administered to all the WSES members investigating the diffusion of minimally invasive surgery in emergency. The survey investigated personal characteristics of participants, hospital characteristics, personal confidence in the use of minimally invasive surgery in emergency, limitations in the use of it and limitations to prosecute minimally invasive surgery in emergency surgery. Characteristics related to the use of minimally invasive surgery were studied with a multivariate ordinal regression. The survey collected a total of 415 answers; 42.2% of participants declared a working experience > 15 years and 69.4% of responders worked in tertiary level center or academic hospital. In primary emergencies, only 28,7% of participants declared the use of laparoscopy in more than 50% of times. Personal confidence with minimally invasive techniques was the highest for appendectomy and cholecystectomy. At multivariate ordinal regression, a longer professional experience, the use of laparoscopy in major elective surgery and bariatric surgery expertise were related to a higher use of laparoscopy in emergency surgery. The survey shows that minimally invasive techniques in emergency surgery are still underutilized. Greater focus should be placed on the development of dedicated training in laparoscopy among emergency surgeons.


Set-based corral control in stochastic dynamical systems: making almost invariant sets more invariant.
We consider the problem of stochastic prediction and control in a time-dependent stochastic environment, such as the ocean, where escape from an almost invariant region occurs due to random fluctuations. We determine high-probability control-actuation sets by computing regions of uncertainty, almost invariant sets, and Lagrangian coherent structures. The combination of geometric and probabilistic methods allows us to design regions of control, which provide an increase in loitering time while minimizing the amount of control actuation. We show how the loitering time in almost invariant sets scales exponentially with respect to the control actuation, causing an exponential increase in loitering times with only small changes in actuation force. The result is that the control actuation makes almost invariant sets more invariant.


Expression of the immunoregulatory molecule FcRH4 defines a distinctive tissue-based population of memory B cells.
The FcRH4 transmembrane molecule, a member of the Fc receptor homologue family, can potently inhibit B cell receptor (BCR) signaling. We show that cell surface expression of this immunoregulatory molecule is restricted to a subpopulation of memory B cells, most of which lack the classical CD27 marker for memory B cells in humans. The FcRH4+ and FcRH4- memory B cells have undergone comparable levels of immunoglobulin isotype switching and somatic hypermutation, while neither subpopulation expresses the transcription factors involved in plasma cell differentiation. The FcRH4+ memory cells are morphologically distinctive large lymphocytes that express the CD69, CD80, and CD86 cell activation markers. They are also shown to be poised to secrete high levels of immunoglobulins in response to stimulation with T cell cytokines, but they fail to proliferate in response either to BCR ligation or Staphylococcus aureus stimulation. A heightened expression of the CCR1 and CCR5 chemokine receptors may facilitate their preferential localization in lymphoid tissues near epithelial surfaces. Cell surface FcRH4 expression thus marks a unique population of memory B cells with distinctive morphology, functional capabilities, and tissue localization.


Combination of PURE-DNA extraction and LAMP-DNA amplification methods for accurate malaria diagnosis on dried blood spots.
Malaria is one of the most important parasitic infectious diseases for which almost half of the world's population is at risk. Although several diagnostic methods are now available to detect the infection, more sensitive and applicable tests are still required in the field. The loop-mediated isothermal amplification (LAMP) method is a DNA amplification tool in which the DNA amplification can be achieved by incubation at a stable temperature. A malaria detection kit based on this methodology has already been commercialized and is being used in some countries. The kit includes two reaction tubes: one targeting the common Plasmodium genus (Pan tube) and the other specifically targeting Plasmodium falciparum (Pf tube). In parallel, a simple DNA extraction method, the procedure for ultra rapid extraction (PURE), which can produce a DNA solution suitable for the LAMP reaction without the use of a centrifuge, has also become available. In this study, the sensitivity of the combination of the PURE and LAMP methods (PURE-LAMP) was evaluated with archived dried clinical blood samples of imported malaria cases, including P. falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae. Using a nested PCR as the reference, 117 samples including 46 P. falciparum, 7 P. vivax, 9 P. ovale, 4 P. malariae, and 51 negative cases were tested. The PURE-LAMP Pan correctly identified 64 of the 66 positives and the 51 negatives. Among the Pan-positive samples 45 P. falciparum were also detected with the PURE-LAMP Pf. The PURE-LAMP Pan and PURE-LAMP Pf had respective sensitivities of 96.96% (95% CI 89.47-99.63) and 97.82% (95% CI 88.47-99.94) and common specificity of 1. The PURE-LAMP system is accurate when used with dried blood spots and extendable to the field.


COVID-19 vaccination program in Cambodia: Achievements and remaining challenges.
Since Cambodia has been recognized as one of the low- and middle-income countries with a successful COVID-19 vaccine program, its program approaches were reviewed based mainly on press articles and announcements from the Ministry of Health. From the beginning, the government's proactive approach to securing vaccines and its flexibility prior to WHO Emergency Use Listing (EUL) contributed greatly to the success of the program. Vaccines were provided by COVAX and other countries, but more than half of the vaccines secured were Chinese vaccines purchased with government funds. The rollout of the vaccine has also been flexible, moving from a strategy of prioritizing risk groups and essential workers to one of expanding the campaign from population centers to rural areas, as well as gradually expanding the target age group, eventually targeting the population age 3 and older. As a result of this high level of commitment by the government and its flexible response, Cambodia has achieved 95% primary series coverage of the entire population, including those not eligible for vaccination. Although the sixth booster is now being administered in Cambodia and vaccination every six months was recommended, several challenges might be anticipated in continuing this program, including the lack of clear global guidance on how to sustain and modify the COVID-19 immunization program and vaccine fatigue after COVID-19 outbreaks have been controlled. How these challenges are overcome and how the COVID-19 vaccine program remains need to be carefully observed into the future.


Baia soyae gen. nov., sp. nov., a mesophilic representative of the family Thermoactinomycetaceae, isolated from soybean root [Glycine max (L.) Merr].
A mesophilic, endophytic, filamentous bacterium, designated strain NEAU-gxj18T, was isolated from soybean root [Glycine max (L.) Merr.] collected from Harbin, Heilongjiang Province, China and characterized using a polyphasic approach. Growth was observed at 20–40 °C (optimum 37 °C). Aerial mycelium was absent on all the media tested. Substrate mycelia were well-developed and formed abundant single endospores with smooth surfaces. The only menaquinone was MK-7.The diagnostic diamino acid was meso-diaminopimelic acid. The whole-cell sugars were ribose, glucose and galactose. The major fatty acids were iso-C15 : 0, C13 : 0 and iso-C17 : 0. The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylethanolamine, phosphatidylglycerol, one unidentified aminophospholipid and one undientified phospholipid. The DNA G+C content was 49.9 mol%. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain NEAU-gxj18T was phylogenetically related to members of the family Thermoactinomycetaceae, with the highest sequence similarity to Geothermomicrobium terrae YIM 77562T (93.35 %). On the basis of morphological and chemotaxonomic characteristics, phylogenetic analysis and characteristic patterns of 16S rRNA gene signature nucleotides, strain NEAU-gxj18T represents a novel species of a new genus within the family Thermoactinomycetaceae, for which the name Baia soyae gen. nov., sp. nov. is proposed. The type strain of the type species is NEAU-gxj18T ( = CGMCC 4.7223T = DSM 46831T).


Avian LHRH during embryonic development: measurement by competitive ELISA with a monoclonal antibody.
A mouse monoclonal antibody directed against chicken Gln8-luteinizing hormone-releasing hormone (cLHRH-I) was developed and characterized. This antibody was used for the development of a competitive microtiter plate enzyme-linked immunosorbent assay for avian LHRH. The assay was validated for use with tissue and was used at a working range between 5 pg and 10 ng per sample. Using this procedure, cLHRH-I and II were assayed in whole brain extracts of Japanese Quail embryos. Samples were taken at regular intervals between Day 6 of incubation through Day 1 posthatch. There were 10 samples taken at each age with 2 replicates of the entire sampling regime. Data from males and females were pooled. LHRH concentrations were low, then rose to higher levels (15 pg/mg tissue) between Days 10 through 13 and decreased thereafter. These changes are likely to be correlated with the activation of the hypothalamic-pituitary-gonadal axis. This is particularly apparent in later embryonic development.


Health care practitioners' perceptions of psychogenic nonepileptic seizures: A systematic review of qualitative and quantitative studies.
A recent systematic synthesis of qualitative research demonstrated that patients with psychogenic nonepileptic seizures (PNES) often experience unsatisfactory encounters with health care practitioners (HCPs). It is important to understand such interactions from the perspective of those responsible for delivering care. This systematic review aimed to examine the attitudes and perceptions of HCPs toward PNES. A systematic search of 3 databases (Web of Science, PubMed, and CINAHL) was conducted in November 2017. Studies from around the world published after 1997 using qualitative or quantitative methodologies were reviewed. An interpretative stance was taken to analyze the data utilizing a grounded theory approach. The quality of studies included was assessed using the Mixed Methods Appraisal Tool. Overall, 30 separate studies capturing the views of at least 3900 professionals were included. Five concepts emerged from the analysis: (1) HCPs' responses demonstrated uncertainty about many aspects of PNES, including diagnosis and treatment; (2) HCPs understood PNES in dualistic terms, perceiving the condition as largely associated with psychological factors; (3) Patients with PNES were considered challenging and frustrating; (4) HCPs held mixed or contested views about who is responsible for treating patients with PNES; and (5) PNES was viewed as less severe or disabling than epilepsy and associated with a greater degree of volition. Although some HCPs have an excellent understanding of PNES, the views of many give rise to concern. The number of qualitative studies that directly ask HCPs about their perceptions of PNES is limited. Moreover, some professional groups (ie, mental health specialists) are underrepresented in current research. This study reveals a demand for additional training. However, effort is needed also to change the attitudes of some practitioners toward PNES.


Malacoplakia of the pelvis. Report of a case with cytologic and ultrastructural findings obtained by fine needle aspiration.
Malacoplakia is a rare granulomatous, inflammatory disease usually diagnosed on a biopsy specimen. Only five cases have been diagnosed by FNA, most of them in the prostate. We report the cytologic and ultrastructural findings in fine needle aspirates of pelvic malacoplakia. The main characteristic of the smears was a richly inflammatory background with abundant, foamy histiocytes containing Michaelis-Gutmann bodies. The results indicate that fine needle aspiration is useful in diagnosing this disease, excluding a neoplastic process and performing follow-up.


Lipid droplet and milk lipid globule membrane associated placental protein 17b (PP17b) is involved in apoptotic and differentiation processes of human epithelial cervical carcinoma cells.
The intracellular role of placental protein 17b (PP17b)/TIP47 has been controversial, because it is considered to be a protein required for mannose 6-phosphate receptor transport from endosome to trans-Golgi as well as a neutral lipid droplet-associated protein. The similarity between the amino acid sequences of PP17 variants, adipophilin and perilipins, and between their gene structures indicate that PP17b as well as other alternatively spliced PP17 variants belong to the lipid storage droplet protein family, containing also some differentiation factors. Using a specific antibody, PP17b was detected in lipid droplet fractions and co-localized with neutral lipid droplets stained by Nile red, and fluorescently labelled PP17 antibody in HeLa cells with confocal microscopy. PP17b was also detected in milk, associated to milk lipid globule membranes. Cytostatic agents induced apoptosis and PP17b synthesis in HeLa cells, which was significantly inhibited by protein kinase C (PKC) inhibitor, indicating the involvement of NF-kappa B and AP-1 transcription factors in this process, while protein kinase A (PKA) inhibitor had only a modest inhibitory effect. Cell differentiation induced by dibutyryl cyclic AMP or phorbol myristate acetate also increased PP17b synthesis, demonstrating its strong involvement in cell differentiation. PP17b synthesis was higher in M than in G0/G1 phases in control, apoptotic and differentiated cells. This data shows that PP17b is a neutral lipid droplet-associated protein, and its expression is regulated by PKC- and PKA-dependent pathways.


Frequency, determinants and outcome of elevated troponin in acute ischemic stroke patients.
Myocardial injury indicated by elevation of cardiac troponins (cTnT) can be observed in acute ischemic stroke patients. Frequency, determinants and prognostic value are still unsettled. We performed a retrospective analysis including all consecutive ischemic stroke patients admitted to our stroke unit within 72 h after symptom onset in a one-year period. Multivariable logistic regression analyses were conducted to identify determinants of cTnT elevation and to detect factors independently associated with unfavorable short-term outcome (modified Rankin scale >2), major neurologic improvement (improvement of NIHSS> =8 or NIHSS 0-1) and in-hospital mortality. Admission cTnT levels were measured in 715 ischemic stroke patients. Frequency of cTnT elevation was 14% (n=103). Factors independently associated with increased cTnT were higher stroke severity (p=0.04), renal insufficiency (p<0.001), pre-existing coronary artery disease (p=0.03), hypercholesterolemia (p=0.02) and insular cortex involvement (p<0.001). After exclusion of patients with renal insufficiency and coronary artery disease frequency of cTnT elevation was 10% (n=44) and only insular cortex involvement remained significantly associated. Increased cTnT on admission was an independent predictor of unfavorable outcome (adjusted odds ratio 2.65 [95% confidence interval 1.29-5.46]) and in-hospital mortality (4.51 [1.93-10.57]). There was a trend towards a negative association of cTnT elevation with major neurologic improvement (0.54 [0.27-1.07]). Elevation of cTnT occurs in every seventh patient with acute ischemic stroke and is independently associated with poor short-term outcome and mortality. Patients with strokes affecting the insular cortex are particularly prone to myocardial injury justifying intensive cardiac monitoring.


Divergent dispersion behavior of ssDNA fragments during microchip electrophoresis in pDMA and LPA entangled polymer networks.
Resolution of DNA fragments separated by electrophoresis in polymer solutions ("matrices") is determined by both the spacing between peaks and the width of the peaks. Prior research on the development of high-performance separation matrices has been focused primarily on optimizing DNA mobility and matrix selectivity, and gave less attention to peak broadening. Quantitative data are rare for peak broadening in systems in which high electric field strengths are used (>150 V/cm), which is surprising since capillary and microchip-based systems commonly run at these field strengths. Here, we report results for a study of band broadening behavior for ssDNA fragments on a glass microfluidic chip, for electric field strengths up to 320 V/cm. We compare dispersion coefficients obtained in a poly(N,N-dimethylacrylamide) (pDMA) separation matrix that was developed for chip-based DNA sequencing with a commercially available linear polyacrylamide (LPA) matrix commonly used in capillaries. Much larger DNA dispersion coefficients were measured in the LPA matrix as compared to the pDMA matrix, and the dependence of dispersion coefficient on DNA size and electric field strength were found to differ quite starkly in the two matrices. These observations lead us to propose that DNA migration mechanisms differ substantially in our custom pDMA matrix compared to the commercially available LPA matrix. We discuss the implications of these results in terms of developing optimal matrices for specific separation (microchip or capillary) platforms.


Quantifying Information via Shannon Entropy in Spatially Structured Optical Beams.
While information is ubiquitously generated, shared, and analyzed in a modern-day life, there is still some controversy around the ways to assess the amount and quality of information inside a noisy optical channel. A number of theoretical approaches based on, e.g., conditional Shannon entropy and Fisher information have been developed, along with some experimental validations. Some of these approaches are limited to a certain alphabet, while others tend to fall short when considering optical beams with a nontrivial structure, such as Hermite-Gauss, Laguerre-Gauss, and other modes with a nontrivial structure. Here, we propose a new definition of the classical Shannon information via the Wigner distribution function, while respecting the Heisenberg inequality. Following this definition, we calculate the amount of information in Gaussian, Hermite-Gaussian, and Laguerre-Gaussian laser modes in juxtaposition and experimentally validate it by reconstruction of the Wigner distribution function from the intensity distribution of structured laser beams. We experimentally demonstrate the technique that allows to infer field structure of the laser beams in singular optics to assess the amount of contained information. Given the generality, this approach of defining information via analyzing the beam complexity is applicable to laser modes of any topology that can be described by well-behaved functions. Classical Shannon information, defined in this way, is detached from a particular alphabet, i.e., communication scheme, and scales with the structural complexity of the system. Such a synergy between the Wigner distribution function encompassing the information in both real and reciprocal space and information being a measure of disorder can contribute into future coherent detection algorithms and remote sensing.


Readability of Online Health Information: A Meta-Narrative Systematic Review.
Online health information should meet the reading level for the general public (set at sixth-grade level). Readability is a key requirement for information to be helpful and improve quality of care. The authors conducted a systematic review to evaluate the readability of online health information in the United States and Canada. Out of 3743 references, the authors included 157 cross-sectional studies evaluating 7891 websites using 13 readability scales. The mean readability grade level across websites ranged from grade 10 to 15 based on the different scales. Stratification by specialty, health condition, and type of organization producing information revealed the same findings. In conclusion, online health information in the United States and Canada has a readability level that is inappropriate for general public use. Poor readability can lead to misinformation and may have a detrimental effect on health. Efforts are needed to improve readability and the content of online health information.


HIC1 promoter methylation and 17p13.3 allelic loss in invasive ductal carcinoma of the breast.
The HIC1 gene is a transcriptional regulator commonly methylated in a variety of human cancer. Thirty-three invasive ductal carcinomas of the breast and 21 matched normal breast tissues were analysed for HIC1 promoter methylation, and allelic loss of a 700 kb region spanning the gene locus. At least one genetic or epigenetic abnormality was found in 27 of the carcinomas tested (82%). Promoter methylation was demonstrated in 21 carcinomas (64%), and nine normal tissues (43%), whereas 18 malignant tumors (54%) showed allelic loss. Concomitant loss of heterozigosity and promoter hypermethylation in the region spanning HIC1 was detected in eight carcinomas (24%) suggesting that in this subset of tumors both copies of the gene are functionally lost. These observations support a role for the HIC1 gene in the pathogenesis of breast ductal carcinomas.


Controllable red, green, blue (RGB) and bright white upconversion luminescence of Lu2O3:Yb3+/Er3+/Tm3+ nanocrystals through single laser excitation at 980 nm.
Light fantastic! Lu(2)O(3):Yb(3+)/Er(3+)/Tm(3+) nanocrystals with controllable red, green, blue (RGB) and bright white upconversion luminescence by a single laser excitation of 980 nm have been successfully synthesized (see picture). Due to abundant UC PL colors, it can potentially be used as fluorophores in the field of color displays, back light, UC lasers, photonics, and biomedicine.Lu(2)O(3):Yb(3+)/Er(3+)/Tm(3+) nanocrystals have been successfully synthesized by a solvothermal process followed by a subsequent heat treatment at 800 degrees C. Powder X-ray diffraction, transmission electron microscopy, upconversion photoluminescence spectra, and kinetic decay were used to characterize the samples. Under single-wavelength diode laser excitation of 980 nm, the bright blue emissions of Lu(2)O(3):Yb(3+), Tm(3+) nanocrystals near 477 and 490 nm were observed due to the (1)G(4)-->(3)H(6) transition of Tm(3+). The bright green UC emissions of Lu(2)O(3):Er(3+) nanocrystals appeared near 540 and 565 nm were observed and assigned to the (2)H(11/2)-->(4)I(15/2) and (4)S(3/2)-->(4)I(15/2) transitions, respectively, of Er(3+). The ratio of the intensity of green luminescence to that of red luminescence decreases with an increase of concentration of Yb(3+) in Lu(2)O(3):Er(3+) nanocrystals. In sufficient quantities of Yb(3+) with resprct to Er(3+), the bright red UC emission of Lu(2)O(3):Yb(3+)/Er(3+) centered at 662 nm was predominant, due to the (4)F(9/2)-->(4)I(15/2) transition of Er(3+). Based on the generation of red, green, and blue emissions in the different doped Lu(2)O(3):RE(3+) nanocrystals, it is possible to produce the luminescence with a wide spectrum of colors, including white, by the appropriate doping of Yb(3+), Tm(3+), and Er(3+) in the present Lu(2)O(3) nanocrystals. Namely, Lu(2)O(3):3 %Yb(3+)/0.2 %Tm(3+)/0.4 %Er(3+) nanocrystals show suitable intensities of blue, green, and red (RGB) emission, resulting in the production of perfect and bright white light with CIE-x=0.3456 and CIE-y=0.3179, which is very close to the standard equal energy white light illuminate (x=0.33, y=0.33). Because of abundant luminescent colors from RGB to white in Lu(2)O(3):Yb(3+)/Er(3+)/Tm(3+) nanocrystals under 980 nm laser diode (LD) excitation, they can potentially be used as fluorophores in the field of color displays, back light, UC lasers, photonics, and biomedicine.


Lipopolysaccharide-Defective Mutants of the Wilt Pathogen Pseudomonas solanacearum.
Lipopolysaccharide (LPS)-defective mutants of Pseudomonas solanacearum were used to test the hypothesis that differences in LPS structure are associated with the ability or inability of different strains to induce a hypersensitive response (HR) in tobacco. To obtain these mutants, LPS-specific bacteriophage of P. solanacearum were isolated and used to select phage-resistant mutants of the virulent, non-HR-inducing strain K60. The LPS of 24 of these mutants was purified and compared with that of K60 and its HR-inducing variant, B1. Upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis, LPS from K60 and other smooth strains separated into many evenly spaced bands that migrated slowly, whereas LPS from B1 and most phage-resistant strains separated into one to three bands that migrated rapidly. Carbohydrate analysis showed that the LPS of the phage-resistant strains lacked O-antigen sugars (rhamnose, xylose, and N-acetylglucosamine) and could be grouped into (i) those that had all core sugars (rhamnose, glucose, heptose, and 2-keto-3-deoxyoctonate), (ii) those that had no core rhamnose, and (iii) those that lacked all core sugars except for 2-keto-3-deoxyoctonate. The LPS composition of 10 of the rough, phage-resistant mutants was similar to that of the HR-inducing strain, B1, yet none of them induced the HR. Only 2 of 13 mutant strains tested caused wilting of tobacco, and these had rough LPS but produced large amounts of extracellular polysaccharide, unlike most LPS-defective mutants. The evidence did not support the hypothesis that the initial interaction between rough LPS and tobacco cell walls is the determining factor in HR initiation.


Expression of Nectin-4 in Bladder Urothelial Carcinoma, in Morphologic Variants, and Nonurothelial Histotypes.
The antibody-drug conjugate enfortumab-vedotin acts by targeting nectin-4, a protein that is nearly ubiquitously expressed in conventional urothelial cancer. However, expression of nectin-4 in morphologic variants of urothelial carcinoma and nonurothelial histotypes was unknown. Immunohistochemistry for nectin-4 using was performed on 169 patients including 83 with nonmuscle invasive bladder cancer and 86 patients with muscle invasive bladder cancer. Staining was scored for intensity (0 to 3) and extent (% positive cells) using the histological score system, where >15 was considered positive. Overall, 72/83 (87%) samples of nonmuscle invasive urothelial carcinoma were positive, including 29/30 (97%) noninvasive papillary urothelial carcinomas, 7/8 (87.5%) carcinomas in situ, 36/45 (80%) papillary urothelial carcinomas invading the lamina propria. Overall, 50/86 muscle invasive tumors were positive, including 15/22 (68.2%) urothelial carcinomas, 7/10 (70%) squamous cell carcinomas, 3/11 (28%) micropapillary tumors, 4/6 (66%) adenocarcinomas, 2/4 (50%) nested carcinomas, 5/8 (63%) plasmacytoid, 1/10 (10%) sarcomatoid carcinomas, and 0/15 (0%) small cell carcinomas. Whole transcriptome RNA sequencing revealed that compared with conventional urothelial carcinomas, most sarcomatoid carcinomas and all but 2 small cell carcinomas expressed very low levels of nectin-4 mRNA but expressed significant levels of either trop2 or ERBB2, which are the molecular targets of 2 other antibody-drug conjugates-sacituzumab gavitecan (trop2) or trastuzumab deruxtecan (ERBB2/HER2). In summary, our study demonstrates that there is heterogeneity of expression of nectin-4 in morphologic variants of urothelial cancer and nonurothelial histotypes, and suggests that testing expression of nectin-4 should be considered in morphologic variants or nonurothelial histotypes found to have lower expression.


[Study of the antiradiation properties of contrykal in experiments on mice].
From experiments in mice exposed to gamma-rays (LD95 and LD91) it is shown that single intraperitoneal administration of contrykal (30-50 units per animal) elicits a slight (20-30%) radioprotective and therapeutic effect. An insignificant therapeutic effect is also registered after repeated injections of the drug at the height of radiation sickness (on the 5th-20th days).


Graphene-based in-plane micro-supercapacitors with high power and energy densities.
Micro-supercapacitors are important on-chip micro-power sources for miniaturized electronic devices. Although the performance of micro-supercapacitors has been significantly advanced by fabricating nanostructured materials, developing thin-film manufacture technologies and device architectures, their power or energy densities remain far from those of electrolytic capacitors or lithium thin-film batteries. Here we demonstrate graphene-based in-plane interdigital micro-supercapacitors on arbitrary substrates. The resulting micro-supercapacitors deliver an area capacitance of 80.7 μF cm⁻² and a stack capacitance of 17.9 F cm⁻³. Further, they show a power density of 495 W cm⁻³ that is higher than electrolytic capacitors, and an energy density of 2.5 mWh cm⁻³ that is comparable to lithium thin-film batteries, in association with superior cycling stability. Such microdevices allow for operations at ultrahigh rate up to 1,000 V s⁻¹, three orders of magnitude higher than that of conventional supercapacitors. Micro-supercapacitors with an in-plane geometry have great promise for numerous miniaturized or flexible electronic applications.


Low-temperature Electronic Paramagnetic Resonance Measurements of TEMPO and 4-Hydroxy-TEMPO Benzoate for Purity Analyses by the Effective Magnetic-moment Method.
The purities of two high-purity organic compounds with a nitroxyl radical moiety were quantified based on their free-radical content using the effective magnetic-moment method. Magnetic moments were measured and X-band electron paramagnetic resonance (EPR) spectra were obtained using a superconducting quantum interference device and X-band EPR spectrometer, respectively, over a wide temperature range of near-room temperature to near-liquid-helium temperature. Concerning measurements of effective g-values using an EPR spectrometer, both the sweep direction and sweep speed were taken into account to obtain accurate g-values. The purities of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) and 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl benzoate (4-hydroxy-TEMPO benzoate) were close to 1 kg kg-1 with relative uncertainties of 1%, which represented improved values compared to those obtained by us previously. These results show a possibility for both compounds to act as reference materials in providing reliable quantification of free radicals per unit mass using this analytical method.


Challenges of Data Dissemination Efforts Within a Community-Based Participatory Project About Persistent Racial Disparities in Excess Weight.
Despite universal environmental and policy-focused initiatives that resulted in declines in obesity among children in Cambridge, Massachusetts, disparities persist among racial/ethnic groups. In response, a community coalition formed the Healthy Eating and Living Project (HELP), to investigate and disseminate findings regarding disparities in excess weight among Cambridge Black youth (ages 6-14), with the aim of facilitating reciprocal learning and community mobilization to ultimately increase community engagement and inform prevention efforts. This paper details the theoretical framework, methods, and results of disseminating HELP findings to various sectors of the Cambridge Black/African American (Black) community. First, using a community-based participatory research (CBPR) approach, the HELP coalition analyzed existing data and conducted qualitative studies with Cambridge Black families to better understand the sociocultural and familial determinants of excess weight. We then developed presentation and print materials and used different dissemination approaches. We solicited feedback to inform the dissemination process and mobilization of obesity prevention efforts. We disseminated information through six community groups (parents, students, pastors, men's health group, community leaders, and a health coalition), email lists, and websites. Reciprocal learning among and between HELP and community members yielded data presentation challenges, as well as prevention effort ideas and barriers. Dissemination of local health data should be considered both as a strategy to increase community engagement and as an intervention to promote collective efficacy and community change. Careful attention should be dedicated to the language used when communicating racial disparities in excess weight to various community groups.


In Vitro Evaluation of Bond Strength between Zirconia Core and CAD/CAM-Produced Veneers.
To evaluate the shear bond strength between various CAD/CAM veneer materials and the zirconia ceramic core. Ninety square prism zirconia specimens (10 specimens per each group, n = 10) in dimensions of 10 × 5 × 5 mm were prepared. Eighty square prism veneering specimens (40 feldspathic ceramic [Cerec Bloc] and 40 lithium disilicate [IPS e.max CAD]) in dimensions of 3 × 3 × 1 mm were connected to zirconia specimens. Conventional layering was applied to the remaining zirconia specimens as control group (n = 10). CAD/CAM-produced veneers were connected to the zirconia specimens using fusion porcelain or resin cement. One of following treatments were applied to the cemented specimens: no surface treatment, HF etching of the veneering material, or HF acid etching of the veneer in combination with the application of a glaze layer to the zirconia surface. Following the veneering procedures, a shear bond strength test was performed at a speed of 1 mm/min using a universal testing machine. Univariate ANOVA (α = 0.05) was performed for statistical analyses of the obtained data. Statistically significant differences were not found among the materials (F = 0.176, p = 0.656), while statistically significant differences were found amongst the veneering procedures (F = 57.921, p < 0.001). Statistical differences were observed between the groups (F = 13.766, p < 0.001). The highest shear bond strength values were observed in IPS e.max CAD specimens connected to zirconia with low fusion porcelain (27.11 ± 7.7 MPa), and the lowest values were observed in IPS e.max CAD specimens connected to zirconia with resin cement without surface treatment (9.82 ± 2.8 MPa). The application of fusion porcelain with IPS e.max CAD (p = 0.967) and Cerec Blocs (p = 1.00) showed statistically similar results to those with conventional layering. The application of fusion porcelain to bond zirconia and digitally produced veneering material can serve as an alternative veneering method to the conventional layering method by accelerating and facilitating clinical and laboratory stages.


The optic nerve head vasoreactive response to systemic hyperoxia and visual field defect progression in open-angle glaucoma, a pilot study.
To investigate the effect of optic nerve head (ONH) tissue vasoreactivity on glaucoma visual field defect progression. This prospective, longitudinal study comprised 28 eyes of 16 patients with open-angle glaucoma. Baseline data were obtained from oxygen inhalation testing, including laser speckle flowgraphy measurements of tissue-area mean blur rate (MT), which represents ONH tissue blood flow, and the mean percentage change in MT (MT-change). Follow-up data were collected for at least 2 years, including at least 5 reliable visual field tests. The average total deviation (TD) was calculated in each sector of the Garway-Heath map; in this study, superior, central and inferior TD corresponded to inferior, temporal and superior MT or MT-change, respectively. MT and MT-change in three sectors per eye were included as explanatory variables in a multivariable linear mixed-effects model, with TD slope set as the response variable. At baseline, lower MT and higher diastolic blood pressure were associated with lower MT-change (p < 0.05). Additionally, MT-change significantly contributed to TD slope in the corresponding sectors (β = 0.41, p = 0.01). Weaker ONH tissue vasoreactivity to systemic hyperoxia, assessed with laser speckle flowgraphy, was associated with lower baseline ONH tissue blood flow, higher diastolic blood pressure and rapid visual field defect progression. Laser speckle flowgraphy variables during oxygen provocation testing may represent potentially useful predictive biomarkers of glaucoma progression.


Nostril capsaicin application as a model of trigeminal primary sensory neuronal activation.
Capsaicin was applied unilaterally to the nostril mucosa of 18 episodic cluster headache sufferers in remission. Plasma and saliva levels of substance P (SP), calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) were measured by radioimmunoassay. Increase of salivary SP-LI and CGRP-LI as well as of plasma CGRP-LI occurred after capsaicin stimulation. Capsaicin-induced neurochemical changes in saliva and in plasma were compared to the changes observed during cluster headache attacks measured in a separate study. The comparative changes in SP, CGRP and VIP characterizing these two conditions suggest that trigeminal capsaicin-sensitive sensory neurones are unlikely to play any fundamental role in the mechanics of cluster headache.