Application of the two-dose-rate method for general recombination correction for liquid ionization chambers in continuous beams.
A method to correct for the general recombination losses for liquid ionization chambers in continuous beams has been developed. The proposed method has been derived from Greening's theory for continuous beams and is based on measuring the signal from a liquid ionization chamber and an air filled monitor ionization chamber at two different dose rates. The method has been tested with two plane parallel liquid ionization chambers in a continuous radiation x-ray beam with a tube voltage of 120 kV and with dose rates between 2 and 13 Gy min(-1). The liquids used as sensitive media in the chambers were isooctane (C(8)H(18)) and tetramethylsilane (Si(CH(3))(4)). The general recombination effect was studied using chamber polarizing voltages of 100, 300, 500, 700 and 900 V for both liquids. The relative standard deviation of the results for the collection efficiency with respect to general recombination was found to be a maximum of 0.7% for isooctane and 2.4% for tetramethylsilane. The results are in excellent agreement with Greening's theory for collection efficiencies over 90%. The measured and corrected signals from the liquid ionization chambers used in this work are in very good agreement with the air filled monitor chamber with respect to signal to dose linearity.


[Quantitative evaluation of aortic valve insufficiency in magnetic resonance tomography].
Flow-encoded magnetic resonance (MR) sequences allow the quantitative evaluation of blood flow in any plane of the heart and vessels. For the first time, ejection and regurgitation volumes of the left ventricle in the ascending aorta can be measured noninvasively. Thus, the regurgitation fraction as a reliable measure of aortic valve insufficiency can be determined. The quantitative evaluation of aortic valve insufficiency was done by MR in comparison to ultrasound-Doppler and, in some cases, in comparison to heart catheterization. A good correlation of grading aortic valve insufficiency by the new MR-technique in comparison to clinical graduation is shown. The development of a new noninvasive standard for quantification of aortic valve insufficiency seems possible.


Physics driven behavioural clustering of free-falling paper shapes.
Many complex physical systems exhibit a rich variety of discrete behavioural modes. Often, the system complexity limits the applicability of standard modelling tools. Hence, understanding the underlying physics of different behaviours and distinguishing between them is challenging. Although traditional machine learning techniques could predict and classify behaviour well, typically they do not provide any meaningful insight into the underlying physics of the system. In this paper we present a novel method for extracting physically meaningful clusters of discrete behaviour from limited experimental observations. This method obtains a set of physically plausible functions that both facilitate behavioural clustering and aid in system understanding. We demonstrate the approach on the V-shaped falling paper system, a new falling paper type system that exhibits four distinct behavioural modes depending on a few morphological parameters. Using just 49 experimental observations, the method discovered a set of candidate functions that distinguish behaviours with an error of 2.04%, while also aiding insight into the physical phenomena driving each behaviour.


Elevated plasma levels of neuropeptide proenkephalin a predict mortality and functional outcome in ischemic stroke.
The purpose of this study was to investigate neuropeptides in patients presenting with symptoms of acute cerebrovascular disease. The precursor neuropeptides proenkephalin A (PENK-A) and protachykinin (PTA) are markers of blood-brain barrier integrity and have been recently discussed in vascular dementia and neuroinflammatory disorders. In a prospective observational study, we measured plasma PENK-A and PTA concentrations in 189 consecutive patients who were admitted with symptoms of acute stroke. Plasma concentrations were determined by sandwich immunoassay; lower detection limits were 15.6 pmol/l (PENK-A) and 22 pmol/l (PTA). Clinical outcome was assessed at 3 months for mortality, major adverse cerebro/cardiovascular events, and functional outcome (modified Rankin scale). PENK-A was significantly elevated in patients with ischemic stroke (n = 124; 65.6%) compared to patients with transient ischemic attack (n = 16; 8.5%) and to patients with nonischemic events (n = 49; 25.9%): median (interquartile range), stroke 123.8 pmol/l (93 to 160.5); transient ischemic attack 114.5 pmol/l (85.3 to 138.8); and nonischemic event 102.8 pmol/l (76.4 to 137.6; both groups vs. stroke p < 0.05). High concentrations of PENK-A, but not PTA, were related to severity of stroke as assessed by National Institutes of Health Stroke Scale (NIHSS [r = 0.225; p = 0.002]) and to advanced functional disability (modified Rankin Scale score 3 to 6 vs. 0 to 2: 135.1 pmol/l [99.2 to 174.1] vs. 108.9 pmol/l [88.6 to 139.5]; p = 0.014). After adjusting for age, NIHSS, and brain lesion size (computed tomography), PENK-A predicted mortality (hazard ratio [HR] for log-10 PENK-A in pmol/l: 4.52; 95% confidence interval [CI]: 1.1 to 19.0; p < 0.05) and major adverse cerebro/cardiovascular events (HR: 6.65; 95% CI: 1.8 to 24.9; p < 0.05). Patients in the highest quartile of PENK-A (cutoff >153 pmol/l) had an increased risk of mortality (HR: 2.40; 95% CI: 1.02 to 5.40; p < 0.05) and of major adverse cerebro/cardiovascular events (HR: 2.23; 95% CI: 1.10 to 4.54; p < 0.05). PENK-A is a prognostic biomarker in the acute phase of ischemic stroke. Elevated PENK-A concentrations are associated with ischemic stroke, severity of cerebral injury, and may have prognostic value for fatal and nonfatal events.


Management by objectives.
Management by objectives, a system for stimulating growth and measuring performance in an organization, is explained, and its advantages for nursing management discussed. The author shows how to implement the system and how to make it succeed. Two examples of MBO in nursing are given: staff evaluation and patient care planning.


SUMOylation attenuates human β-arrestin 2 inhibition of IL-1R/TRAF6 signaling.
β-Arrestin 2 as an adaptor plays a role in the regulation of receptor desensitization, trafficking, and signaling. Bovine β-arrestin 2 has been shown to be SUMOylated on the lysine 400 residue, which links it to the endocytosis of the β2-adrenergic receptor. Here we identify a major SUMOylation site, lysine 295, on human β-arrestin 2. SUMOylation on this site attenuates β-arrestin 2 binding to TRAF6, then enhances TRAF6 oligomerization and autoubiquitination, and consequently leads to the increase of TRAF6-mediated NF-κB/AP-1 activation. We further determine SENP1 as a specific de-SUMOylation protease that can reverse the SUMOylation of β-arrestin 2-mediated processes. Our study reveals SUMOylation as a novel mechanism in the regulation of β-arrestin 2-mediated IL-1R/TRAF6 signaling.


Acute respiratory failure in goitre patients qualified for operative treatment.
To present a clinical picture and management of goitre patients with acute respiratory failure. A total of 7,356 patients were operated on between 2000 and 2011 for various goitres, including 1,214 (16.5%) retrosternal or mediastinal types. Eight (0.1%) patients (six women and two men aged 61-84, mean 76.9 years) presented with acute respiratory failure on admission. Seven patients were intubated on admission, and one showed severe dyspnoea at rest accompanied by symptoms of peripheral cyanosis. Giant retrosternal goitres were found in the eight operated patients. In two cases, the goitre was recurrent in character, and another two patients had previously suffered from hyperthyroidism (one treated pharmacologically, and one using J131). X-ray examination revealed tracheostenosis in all patients. No disorders in thyroid function was observed. Preoperative unilateral paralysis of laryngeal recurrent nerve was found in three patients. The operations were considered as most urgent. Four goitres were neoplastic: two were anaplastic carcinoma, one was follicular cell carcinoma and one was squamous cell carcinoma. These patients received partial resection to enable reduction of the goitre mass. In three patients, tracheostomy was necessary. On the other hand, four patients with non-malignant goitres underwent complete resection (one patient), nearly complete resection (two), and complete resection of one lobe and partial resection of the other (one). Three patients required mechanical ventilation postoperatively. Two of them, referred to the Intensive Therapy Unit, died from acute circulatory failure on day 6 and day 10 postoperatively. The rest were discharged in good general condition. 1. Acute respiratory failure caused by a giant goitre is a life-threatening condition that almost always requires an emergency intubation. 2. Due to a high risk of complications and high mortality, patients with acute respiratory failure caused by giant goitres should be operated in hospitals that are very experienced not only in thyroid but also in mediastinal surgery.


Identification and molecular diversity of T-superfamily conotoxins from Conus lividus and Conus litteratus.
The T-superfamily conotoxins comprise a large and diverse group of biologically active peptides and are widely distributed in venom ducts of all major feeding types of Conus. Six novel T-superfamily peptides from the two worm-hunting cone snail species of Conus lividus andConus. litteratus native to Hainan were identified and determined to share a common signal sequence as well as a conserved arrangement of cysteine residues (CC-CC). The predicted mature peptides consist of 11-15 amino acids only. Phylogenetic analyses of new conotoxins from C. lividus andC. litteratus in present study and published homologue T-superfamily sequences from the other Conus species was systematically performed. Phylogenetic trees, residue substitutions to view evolutionary relationships of the precursors' signal, propeptide, and mature toxin regions were explored, as well as residue frequency component and cystine codon usage. Percent divergence of the amino acid sequences of the signal-region exhibited high conservation, whereas the sequences of the mature peptides ranged from high similarity to high divergence between inter- and intro-species. Notably, diversity of pro-peptide region was also high with intermediate percent divergence between that observed in signal and toxin-regions. Consensus hydrophobic residues Leu, Val, Ala, Ile and Pro of signal regions were abundant, whereas among propeptides, basic residues Arg and Lys and acidic residue Asp, addition of hydrophilic residues Thr and Ser were abundant. Residue frequency components were hypervariable in mature toxin region except for highly conservative cystine frame residues. The T-superfamily conotoxins have been previously found mainly in piscivorous and molluscivorous cone snails. The newly identified six T-superfamily peptides described in this investigation exemplify the first to be found from vermivorousC. lividus andC. litteratus. The elucidated cDNAs of the six toxins will facilitate a better understanding of the relationship between structure and function as well as provide a framework for their further research and development.


Team structure, skill mix and clinical outcomes.
The majority of presentations to Australian EDs are for semi-urgent and non-urgent complaints in the older adult. For these patient's treatment and care is typically delivered by loosely organised teams of professionals. While substantial research has examined the clearly defined, hierarchical team structures used during resuscitation events, little is known about the composition and functioning of teams involved in non-urgent patient care in ED. Investigation of these team dynamics can identify personal and professional factors involved in the delivery of this care and enable the design of teams that enhance patient outcomes.


Toxins as biological weapons for terror-characteristics, challenges and medical countermeasures: a mini-review.
Toxins are hazardous biochemical compounds derived from bacteria, fungi, or plants. Some have mechanisms of action and physical properties that make them amenable for use as potential warfare agents. Currently, some toxins are classified as potential biological weapons, although they have several differences from classic living bio-terror pathogens and some similarities to manmade chemical warfare agents. This review focuses on category A and B bio-terror toxins recognized by the Centers for Disease Control and Prevention: Botulinum neurotoxin, staphylococcal enterotoxin B, Clostridium perfringens epsilon toxin, and ricin. Their derivation, pathogenesis, mechanism of action, associated clinical signs and symptoms, diagnosis, and treatment are discussed in detail. Given their expected covert use, the primary diagnostic challenge in toxin exposure is the early detection of morbidity clusters, apart from background morbidity, after a relatively short incubation period. For this reason, it is important that clinicians be familiar with the clinical manifestations of toxins and the appropriate methods of management and countermeasures.


Regional gray matter volume associated with exercise dependence: A voxel-based morphometry study.
Although regular physical exercise has multiple positive benefits for the general population, excessive exercise may lead to exercise dependence (EXD), which is harmful to one's physical and mental health. Increasing evidence suggests that stress is a potential risk factor for the onset and development of EXD. However, little is known about the neural substrates of EXD and the underlying neuropsychological mechanism by which stress affects EXD. Herein, we investigate these issues in 86 individuals who exercise regularly by estimating their cortical gray matter volume (GMV) utilizing a voxel-based morphometry method based on structural magnetic resonance imaging. Whole-brain correlation analyses and prediction analyses showed negative relationships between EXD and GMV of the right orbitofrontal cortex (OFC), left subgenual cingulate gyrus (sgCG), and left inferior parietal lobe (IPL). Furthermore, mediation analyses found that the GMV of the right OFC was an important mediator between stress and EXD. Importantly, these results remained significant even when adjusting for sex, age, body mass index, family socioeconomic status, general intelligence and total intracranial volume, as well as depression and anxiety. Collectively, the results of the present study provide crucial evidence of the neuroanatomical basis of EXD and reveal a potential neuropsychological pathway in predicting EXD in which GMV mediates the relationship between stress and EXD.


Serum and intraperitoneal pharmacokinetics of cisplatin within intraoperative intraperitoneal chemotherapy: influence of protein binding.
Intraperitoneal (i.p.) chemotherapy is a promising therapeutic method to improve the effectiveness of cisplatin in patients with ovarian cancer and peritoneum involvement. Intraperitoneal treatment can be intraoperatively performed just after a complete surgical resection of peritoneal tumor nodules. However, little is known regarding the pharmacokinetics of platinum during intraoperative i.p. chemotherapy (IIC). Serum and i.p. measurements of total and ultrafilterable platinum were performed to determined pharmacokinetic parameters in 11 consecutive patients who received a 2-h IIC with 50 mg/m cisplatin. Protein concentrations were determined in serum and peritoneal liquid at the same times. The cisplatin concentration required to kill OVCAR-3 human ovarian cancer cells and evaluation of cisplatin binding to proteins were determined in vitro. Platinum i.p. concentration decreased rapidly and quickly came under the cytotoxicity threshold (10 mg for 2 h). About 85% of i.p. and serum cisplatin was ultrafilterable during IIC. Platinum concentrations were closely related to protein concentrations. Due to the very low level of serum protein (almost 25 g/l), serum cisplatin binding during chemotherapy was very low (almost 25%), but increased with protein concentration recovery. These pharmacokinetic data show that a sufficient concentration to kill human ovarian cancer is not reached with a single i.p. bath containing 50 mg/m cisplatin for 2 h. A new protocol with a renewed bath and a higher cisplatin concentration is under investigation.


Mapping the spatiotemporal dynamics of processing task-relevant and task-irrelevant sound feature changes using concurrent EEG-fMRI.
The cortical processing of changes in auditory input involves auditory sensory regions as well as different frontoparietal brain networks. The spatiotemporal dynamics of the activation spread across these networks has, however, not been investigated in detail so far. We here approached this issue using concurrent functional magnetic resonance imaging (fMRI) and electroencephalography (EEG), providing us with simultaneous information on both the spatial and temporal patterns of change-related activity. We applied an auditory stimulus categorization task with switching categorization rules, allowing to analyze change-related responses as a function of the changing sound feature (pitch or duration) and the task relevance of the change. Our data show the successive progression of change-related activity from regions involved in early change detection to the ventral and dorsal attention networks, and finally the central executive network. While early change detection was found to recruit feature-specific networks involving auditory sensory but also frontal and parietal brain regions, the later spread of activity across the frontoparietal attention and executive networks was largely independent of the changing sound feature, suggesting the existence of a general feature-independent processing pathway of change-related information. Task relevance did not modulate early auditory sensory processing, but was mainly found to affect processing in frontal brain regions. Hum Brain Mapp 37:3400-3416, 2016. © 2016 Wiley Periodicals, Inc.


[Research advances in drug resistance mechanisms of bacterial biofilm and natural drug intervention].
Drug resistance resulting from bacterial biofilms can invalidate antibacterial agents. Therefore,eradicating bacterial biofilms to reverse drug resistance is a hotspot in the pharmaceutical research. In recent years,numerous studies have revealed the complicated mechanism of bacterial biofilm formation and strong drug resistance with multiple influential factors involved. This paper gives a comprehensive review on the process of biofilm formation and intervention by natural drugs,which can provide some reference and evidence for the following studies.


Selected contribution: ambient temperature for experiments in rats: a new method for determining the zone of thermal neutrality.
There is a misbelief that the same animal has the same thermoneutral zone (TNZ) in different experimental setups. In reality, TNZ strongly depends on the physical environment and varies widely across setups. Current methods for determining TNZ require elaborate equipment and can be applied only to a limited set of experimental conditions. A new, broadly applicable approach that rapidly determines whether given conditions are neutral for a given animal is needed. Consistent with the definition of TNZ [the range of ambient temperature (T(a)) at which body core temperature (T(c)) regulation is achieved only by control of sensible heat loss], we propose three criteria of thermoneutrality: 1) the presence of high-magnitude fluctuations in skin temperature (T(sk)) of body parts serving as specialized heat exchangers with the environment (e.g., rat tail), 2) the closeness of T(sk) to the median of its operational range, and 3) a strong negative correlation between T(sk) and T(c). Thermocouple thermometry and liquid crystal thermography were performed in five rat strains at 13 T(a). Under the conditions tested (no bedding or filter tops, no group thermoregulation), the T(a) range of 29.5-30.5 degrees C satisfied all three TNZ criteria in Wistar, BDIX, Long-Evans, and Zucker lean rats; Zucker fatty rats had a slightly lower TNZ (28.0-29.0 degrees C). Skin thermometry or thermography is a definition-based, simple, and inexpensive technique to determine whether experimental or housing conditions are neutral, subneutral, or supraneutral for a given animal.


Improving the Standards-Based Management-Recognition initiative to provide high-quality, equitable maternal health services in Malawi: an implementation research protocol.
The Government of Malawi is seeking evidence to improve implementation of its flagship quality of care improvement initiative-the Standards Based Management-Recognition for Reproductive Health (SBM-R(RH)). This implementation study will assess the quality of maternal healthcare in facilities where the SBM-R(RH) initiative has been employed, identify factors that support or undermine effectiveness of the initiative and develop strategies to further enhance its operation. Data will be collected in 4 interlinked modules using quantitative and qualitative research methods. Module 1 will develop the programme theory underlying the SBM-R(RH) initiative, using document review and in-depth interviews with policymakers and programme managers. Module 2 will quantitatively assess the quality and equity of maternal healthcare provided in facilities where the SBM-R(RH) initiative has been implemented, using the Malawi Integrated Performance Standards for Reproductive Health. Module 3 will conduct an organisational ethnography to explore the structures and processes through which SBM-R(RH) is currently operationalised. Barriers and facilitators will be identified. Module 4 will involve coordinated co-production of knowledge by researchers, policymakers and the public, to identify and test strategies to improve implementation of the initiative. The research outcomes will provide empirical evidence of strategies that will enhance the facilitators and address the barriers to effective implementation of the initiative. It will also contribute to the theoretical advances in the emerging science of implementation research.


A bite to fight: front-line innate immune defenses against malaria parasites.
Malaria infection caused by Plasmodium parasites remains a major health burden worldwide especially in the tropics and subtropics. Plasmodium exhibits a complex life cycle whereby it undergoes a series of developmental stages in the Anopheles mosquito vector and the vertebrate human host. Malaria severity is mainly attributed to the genetic complexity of the parasite which is reflected in the sophisticated mechanisms of invasion and evasion that allow it to overcome the immune responses of both its invertebrate and vertebrate hosts. In this review, we aim to provide an updated, clear and concise summary of the literature focusing on the interactions of the vertebrate innate immune system with Plasmodium parasites, namely sporozoites, merozoites, and trophozoites. The roles of innate immune factors, both humoral and cellular, in anti-Plasmodium defense are described with particular emphasis on the contribution of key innate players including neutrophils, macrophages, and natural killer cells to the clearance of liver and blood stage parasites. A comprehensive understanding of the innate immune responses to malaria parasites remains an important goal that would dramatically help improve the design of original treatment strategies and vaccines, both of which are urgently needed to relieve the burden of malaria especially in endemic countries.


Fine-needle aspiration biopsy with a vacuum test tube.
A simple, low-cost, automatic aspiration system that makes use of vacuum test tubes designed for the drawing of venous blood has been used for real-time ultrasound (US)-guided fine-needle aspiration biopsy of 13 cysts (breast), an abscess (liver), and five solid (breast, liver, thyroid) masses. Because it allows the operator to perform aspiration with one hand while holding the real-time US transducer with the other, and because creation of the suction is associated with no significant displacement of the needle, this approach has allowed sampling of lesions less than 1 cm in diameter. No complications have occurred.


Combinatorial synthesis, selection, and properties of esterase peptide dendrimers.
A 65,536-member combinatorial library of peptide dendrimers was prepared by split-and-mix synthesis and screened on solid support for esterolytic activity in aqueous buffer using 8-butyryloxypyrene-1,3,6-trisulfonate (2) as a fluorogenic substrate. Active sequences were identified by analysis of fluorescent beads. The corresponding dendrimers were resynthesized by solid-phase synthesis, cleaved from the resin, and purified by preparative reverse-phase HPLC. The dendrimers showed the expected catalytic activity in aqueous buffer. Catalysis was studied against a pannel of fluorogenic 8-acyloxypyrene-1,3,6-trisulfonate substrates. The catalytic peptide dendrimers display enzyme-like kinetics in aqueous buffer with substrate binding in the range K(M) approximately 0.1 mM, catalytic rate constants k(cat) approximately 0.1 min(-1), and specific rate accelerations over background up to k(cat)/k(uncat) = 10,000.


Mechanistic studies of the palladium-catalyzed S,O-ligand promoted C-H olefination of aromatic compounds.
Pd-catalyzed C-H functionalization reactions of non-directed substrates have recently emerged as an attractive alternative to the use of directing groups. Key to the success of these transformations has been the discovery of new ligands capable of increasing both the reactivity of the inert C-H bond and the selectivity of the process. Among them, a new type of S,O-ligand has been shown to be highly efficient in promoting a variety of Pd-catalyzed C-H olefination reactions of non-directed arenes. Despite the success of this type of S,O-ligand, its role in the C-H functionalization processes is unknown. Herein, we describe a detailed mechanistic study focused on elucidating the role of the S,O-ligand in the Pd-catalyzed C-H olefination of non-directed arenes. For this purpose, several mechanistic tools, including isolation and characterization of reactive intermediates, NMR and kinetic studies, isotope effects and DFT calculations have been employed. The data from these experiments suggest that the C-H activation is the rate-determining step in both cases with and without the S,O-ligand. Furthermore, the results indicate that the S,O-ligand triggers the formation of more reactive Pd cationic species, which explains the observed acceleration of the reaction. Together, these studies shed light on the role of the S,O-ligand in promoting Pd-catalyzed C-H functionalization reactions.


A key role of microRNA-26a in the scar formation after glaucoma filtration surgery.
Glaucoma is one of the leading causes of blind worldwide. Post-operative scar formation of filtering tract was one of the main reasons for failure of glaucoma filtration surgery. In this study, we conducted several experiments to detect the expression of miR-26a in the scar tissue in filtering tract and then detect its potential biological effects as well as its target gene. In our present study, it was found that miR-26a was significantly down-regulated in filtering tract scar. Advanced study on the association between the miR-26a and connective tissue growth factor (CTGF) micro RNA (mRNA) showed that miR-26a was inversely correlated with CTGF mRNA level. Advanced biological studies showed that overexpression of miR-26a could decrease the cell viability and migration ability of human Tenon's fibroblasts (HTFs) fibrosis in vitro model. It was also found that miR-26a might up-regulate the apoptotic level of HTFs. Through protein expression detection and luciferase reporter assay, it was found that miR-26a could produce functions that directly target the CTGF. In conclusion, the key finding of the current study is that miR-26a can suppress the activation of HTFs by transforming growth factor (TGF)-β by targeting CTGF. This data indicates that miR-26a plays an essential role in the formation of filtering tract scar and function as a potential drug target.


Acute Hypotension After Moderate-Intensity Handgrip Exercise in Hypertensive Elderly People.
Souza, LR, Vicente, JB, Melo, GR, Moraes, VC, Olher, RR, Sousa, IC, Peruchi, LH, Neves, RV, Rosa, TS, Ferreira, AP, and Moraes, MR. Acute hypotension after moderate-intensity handgrip exercise in hypertensive elderly people. J Strength Cond Res 32(10): 2971-2977, 2018-Isometric handgrip (IHG) training is effective in reducing blood pressure (BP), but little is known about the occurrence of acute hypotension by postisometric exercise hypotension (PIEH) and the underlying mechanisms. Ten sedentary hypertensive elderly people (7 women and 3 men) individuals, with a mean age of 73.2 ± 2.2 years and systolic BP (SBP) of 135.1 ± 6.5, were included; they were hypertensive for 13.2 ± 3.1 years and were receiving medications. These patients underwent 2 experimental sessions of isometric exercise using a portable hydraulic handgrip dynamometer: (a) sham session with 3% of maximal voluntary isometric contraction (MVIC) and (b) experimental isometric session with 30% MVIC, completing a total of 8 sets of 1-minute contraction and 1-minute rest-pause (overload of work = 51.7 kgf·min). Blood pressure and heart rate were evaluated at rest and 1, 5, 10, 15, 30, 45, and 60 minutes postexercise. Blood lactate (Lac) and salivary nitric oxide (NO) were collected at rest, 0, 30, and 60 minutes postexercise. The SBP presented a reduction as of the tenth minute postexercise to session 30% MVIC (Δ = -14.4 at -18.7 mm Hg, p < 0.05). At 60-minute postexercise, the SBP was 30% lower vs. 3% MVIC (-20.2 mm Hg, p = 0.006). There were no differences for the other cardiovascular parameters and vasoactive substances for both sessions (p > 0.05). These results demonstrated that the IHG exercise with a higher overload of work induced PIEH in hypertensive elderly people, but there was no association with Lac and NO. Therefore, this IHG model with easy execution, quick adherence, short duration, and a portable equipment can be an excellent adjuvant strategy for the control and prevention of hypertension.


Epidemiology and treatment of congenital fibrinogen deficiency.
Congenital fibrinogen deficiency is a rare bleeding disorder, affecting either the quantity (afibrinogenemia, hypofibrinogenemia) or quality (dysfibrinogenemia) of circulating fibrinogen. There is a strong association between fibrinogen activity levels and clinical bleeding severity. Patients with afibrinogenemia experience frequent, often severe, spontaneous bleeds into the muscles and joints and are at significant risk of intracranial hemorrhage. Patients with hypofibrinogenemia are usually asymptomatic; however, they are vulnerable to bleeding after trauma. Dysfibrinogenemia is associated with both spontaneous bleeding and a relatively high risk of thrombosis. Fibrinogen replacement therapy is effective in treating bleeding episodes in congenital fibrinogen deficiency. Fibrinogen concentrates are the preferred treatment option and guidelines now exist for their on-demand use and to manage surgery. Prophylaxis may benefit patients with afibrinogenemia and others with a severe bleeding tendency. The dose and frequency of administration should be adjusted to maintain a fibrinogen activity level >0.5-1.0 g/L. Pregnant women with afibrinogenemia require prophylactic factor replacement as early as possible during pregnancy, continuing throughout pregnancy, and after the birth. Fibrinogen replacement should also be considered in pregnant women with other fibrinogen deficiencies. The risk of thrombosis presents an additional management challenge in these patients, often necessitating the concurrent use of anticoagulants and fibrinogen. Although basic guidelines have been developed, further studies are needed to help optimize treatment in different patient groups under different clinical circumstances and to improve our understanding of thrombotic events.


A multiplex immunoassay method for simultaneous quantification of iron, vitamin A and inflammation status markers.
Deficiencies of vitamin A and iron affect a significant portion of the world's population, and efforts to characterize patterns of these deficiencies are hampered by a lack of measurement tools appropriate for large-scale population-based surveys. Vitamin A and iron are not easily measured directly, so reliable proxy markers for deficiency status have been identified and adopted. Measurement of inflammatory markers is necessary to interpret vitamin A and iron status markers, because circulating levels are altered by inflammation. We developed a multiplex immunoassay method for simultaneous measurement of five markers relevant to assessing inflammation, vitamin A and iron status: α-1-acid glycoprotein, C-reactive protein, retinol binding protein 4, ferritin and soluble transferrin receptor. Serum and plasma specimens were used to optimize the assay protocol. To evaluate assay performance, plasma from 72 volunteers was assayed using the multiplex technique and compared to conventional immunoassay methods for each of the five markers. Results of the new and conventional assay methods were highly correlated (Pearson Correlations of 0.606 to 0.991, p<.0001). Inter-assay imprecision for the multiplex panel varied from 1% to 8%, and all samples fell within the limits of quantification for all assays at a single dilution. Absolute values given by the multiplex and conventional assays differed, indicating a need for further work to devise a new standard curve. This multiplexed micronutrient immunoassay technique has excellent potential as a cost effective tool for use in large-scale deficiency assessment efforts.


Myocardial Scar Detection by Standard CT Coronary Angiography.
We have described a myocardial infarct scar identified by a standard dual source CT coronary angiography (CTCA). We were able to detect the scar during the routine coronary assessment without contrast late enhancement and without additional radiation exposure. It is therefore feasible to assess chronic scar using a standard CTCA technique.


Detection of D2-40 monoclonal antibody-labeled lymphatic vessel invasion in esophageal squamous cell carcinoma and its clinicopathologic significance.
This study aims to investigate the clinicopathologic significance of lymphatic vessel invasion (LVI) labeled by D2-40 monoclonal antibody in esophageal squamous cell carcinoma (ESCC). Immunohistochemical assay was used to detect the expression of D2-40 and LVI in 107 ESCC patients. Then, the correlation between the clinicopathologic feature and the overall survival time of the patients was analyzed. The lymph node metastasis rates were 70% and 21% in the LVI-positive and LVI-negative groups, respectively. The nodal metastasis rate was higher in the LVI-positive group than in the LVI-negative group. Multivariate regression analysis showed that LVI was related to nodal metastasis (P<0.001). The median survival time of the patients was 26 and 43 months in the LVI-positive and LVI-negative groups, respectively. Although univariate regression analysis showed significant difference between the two groups (P=0.014), multivariate regression analysis revealed that LVI was not an independent prognostic factor for overall survival in the ESCC patients (P=0.062). Lymphatic node metastasis (P=0.031), clinical stage (P=0.019), and residual tumor (P=0.026) were the independent prognostic factors. LVI labeled by D2-40 monoclonal antibody is a risk factor predictive of lymph node metastasis in ESCC patients.


Self-fitting shape memory polymer foam inducing bone regeneration: A rabbit femoral defect study.
Although tissue engineering has been attracted greatly for healing of critical-sized bone defects, great efforts for improvement are still being made in scaffold design. In particular, bone regeneration would be enhanced if a scaffold precisely matches the contour of bone defects, especially if it could be implanted into the human body conveniently and safely. In this study, polyurethane/hydroxyapatite-based shape memory polymer (SMP) foam was fabricated as a scaffold substrate to facilitate bone regeneration. The minimally invasive delivery and the self-fitting behavior of the SMP foam were systematically evaluated to demonstrate its feasibility in the treatment of bone defects in vivo. Results showed that the SMP foam could be conveniently implanted into bone defects with a compact shape. Subsequently, it self-matched the boundary of bone defects upon shape-recovery activation in vivo. Micro-computed tomography determined that bone ingrowth initiated at the periphery of the SMP foam with a constant decrease towards the inside. Successful vascularization and bone remodeling were also demonstrated by histological analysis. Thus, our results indicate that the SMP foam demonstrated great potential for bone regeneration.


[Nuclear medicine in pneumonology in the light of 9 year's experience at the S. Luigi Gonzaga Hospital].
An attempt is made to draw a picture of the results obtained with nuclear medicine in the pneumological field in the light of 9 years experience. An attempt is also made to identify from among recently introduced techniques (T.A.C., echotomography) which ones might be substituted for radioisotopes and when, and on what occasion they can be used as complementary treatment. It is concluded that nuclear medicine is of absolute value for functional examinations of the respiratory apparatus (perfusors and ventilators) and for lung onconscannning with Ga67 citrate and Bleomycin-Co57 under present circumstances and that in other fields certain morphological scans (bone scans) are still useful by virtue of their cost-benefit ratio.


Ce-Doped La3Si6.5Al1.5N9.5O5.5, a Rare Highly Efficient Blue-Emitting Phosphor at Short Wavelength toward High Color Rendering White LED Application.
Phase pure nondoped and Ce doped La3Si6.5Al1.5N9.5O5.5 (Al containing La N-phase) samples have been obtained by solid-state reaction synthesis for the first time. 1% Ce-doped La3Si6.5Al1.5N9.5O5.5 phosphor displays a broad excitation band ranging from UV to 410 nm, with a maximum at 355 nm. UV light excitation results in a narrow Ce3+ 5d-4f emission band (fwhm = 68 nm) centered at 418 nm. The emission can be tuned from 417 nm at 0.5% Ce to 450 nm at 50% Ce. A high internal quantum efficiency up to 84% is achieved for a 1% Ce doped sample, which has CIE chromaticity coordinates of x = 0.157 and y = 0.069, close to the NTSC blue standard (x = 0.155; y = 0.070). Compared to La3Si8O4N11:Ce phosphor, the quantum efficiency and thermal stability have been enhanced for La3Si6.5Al1.5N9.5O5.5:Ce phosphor without shifting the emission peak wavelength. La3Si6.5Al1.5N9.5O5.5:Ce shows less thermal quenching than La3Si8O4N11:Ce and no shift or change in the shape of emission spectra with increasing the temperature from 4 to 573 K. These results show that La3Si6.5Al1.5N9.5O5.5:Ce is more efficient than any other (oxy-)nitride phosphor with an emission in the short wavelength blue region (400-450 nm). A white LED was fabricated using the La3Si6.5Al1.5N9.5O5.5:5%Ce as a blue phosphor. The high color rendering index (Ra = 93.2, R9 = 91.4, and R12 = 89.5) obtained shows that the phosphor is a very promising conversion phosphor for white LEDs.


Yellow nail syndrome following multiple orthopedic surgeries: a case report.
Yellow nail syndrome is a rare condition associated with a triad of symptoms: yellow nails, lung lesions, and lymphedema. We report a case of yellow nail syndrome caused by titanium exposure from multiple artificial joint replacements. A 78-year-old Asian woman presented to our outpatient department with chief complaints of cough, fever, and nausea. The patient was hospitalized for observation because of the presence of hypoxemia and bilateral pleural effusion. Her medical history included knee joint replacement and two spinal fusion surgeries. Her physical examination conducted following hospitalization revealed yellow nails on both hands and feet. This finding, combined with the observation of bilateral pleural effusion, raised suspicion for yellow nail syndrome. Blood analysis yielded negative results, as did the tests for sputum culture, interferon liberation, pleural effusion culture, and pleural effusion cytology. Pleural histopathological analysis and imaging yielded negative results. Considering the possibility of titanium exposure from artificial joints based on the patient's medical history, we examined a chest radiograph obtained before the second spinal fusion surgery; however, no pleural effusion was observed. Pleural effusion was observed, however, following the surgery. On the basis of these findings, the patient was diagnosed with yellow nail syndrome due to titanium exposure. Clinicians should examine the nails of patients with unexplained pleural effusion. Moreover, they should inquire about titanium exposure when obtaining the patient's medical history.


Robot-assisted nerve-sparing radical prostatectomy using near-infrared fluorescence technology and indocyanine green: initial experience.
Indocyanine green (ICG) is a fluorescent molecule that provokes detectable photon emission. The use of ICG with near-infrared (NIR) imaging system (Akorn, Lake Forest, IL) has been described during robotic partial nephrectomy (RAPN) as an adjunctive means of identifying renal artery and parenchymal perfusion. We propose the use of the ICG with NIR fluorescence during laparoscopic robot-assisted radical prostatectomy (RARP), to identify the benchmark artery improving the preservation of neurovascular bundle and to improve the visualization of the vascularization and then the hemostasis. From April 2015 to February 2016, 62 patients underwent to RARP in our Urology Unit. In 26 consecutive patients, in the attempt to have a better visualization of neurovascular bundles, we used to inject ICG during the procedure. We evaluated the percentage of identification of neurovascular bundles using NIR fluorescence. Then, we evaluated complications related to injection of ICG and operative time differences between RARP with and without ICG injection performed by the same surgeons. We identified prostatic arteries and neurovascular bundles using NIR fluorescence technology in all patients (100%). There was not any increase in the operative time compared with RARP without ICG injection performed by the same surgeons. Complications related to injection of ICG did not occurred. In our experience, even if on a limited number of patients, the application of ICG with NIR fluorescence during RARP is helpful to identify the benchmark artery of neurovascular bundle.


A new neurosurgical ventriculoscope--technical note.
A new, flexible fiberoptic ventriculoscope for observation of the ventricles and major cisterns is reported. This device has been safely used to examine patients with obstructive hydrocephalus due to lesions within the lateral and third ventricles or to congenital aqueductal stenosis. With this instrument, a pineal tumor protruding into the third ventricle was successfully observed and photographed in situ.


Mine safety assessment using gray relational analysis and bow tie model.
Mine safety assessment is a precondition for ensuring orderly and safety in production. The main purpose of this study was to prevent mine accidents more effectively by proposing a composite risk analysis model. First, the weights of the assessment indicators were determined by the revised integrated weight method, in which the objective weights were determined by a variation coefficient method and the subjective weights determined by the Delphi method. A new formula was then adopted to calculate the integrated weights based on the subjective and objective weights. Second, after the assessment indicator weights were determined, gray relational analysis was used to evaluate the safety of mine enterprises. Mine enterprise safety was ranked according to the gray relational degree, and weak links of mine safety practices identified based on gray relational analysis. Third, to validate the revised integrated weight method adopted in the process of gray relational analysis, the fuzzy evaluation method was used to the safety assessment of mine enterprises. Fourth, for first time, bow tie model was adopted to identify the causes and consequences of weak links and allow corresponding safety measures to be taken to guarantee the mine's safe production. A case study of mine safety assessment was presented to demonstrate the effectiveness and rationality of the proposed composite risk analysis model, which can be applied to other related industries for safety evaluation.


CALLING SONGS OF FIELD CRICKETS (TELEOGRYLLUS OCEANICUS) WITH AND WITHOUT PHONOTACTIC PARASITOID INFECTION.
The field cricket Teleogryllus oceanicus has been introduced to Hawaii, where it is parasitized by an acoustically orienting parasitoid fly, Ormia ochracea. Previous work showed that call parameters from parasitized populations differ from those in unparasitized populations in a direction expected if selection by flies is occurring. Here we examined songs of males collected in the field and compare calling song characters of crickets later found to harbor parasitoid larvae with those of males free of parasitoids. The two groups differ significantly in several song characteristics, particularly the trill-like long chirp given at the beginning of each song. Males with longer long chirps containing shorter interpulse intervals are more likely to be parasitized, suggesting that the flies find such males more attractive. Depending on the traits females prefer, sexual selection may oppose natural selection in altering T. oceanicus song in parasitized populations.


Stathmin 1 is a potential novel oncogene in melanoma.
In previous studies, we demonstrated that miR-193b expression is reduced in melanoma relative to benign nevi, and also that miR-193b represses cyclin D1 and Mcl-1 expression. We suggested that stathmin 1 (STMN1) might be a target of miR-193b. STMN1 normally regulates microtubule dynamics either by sequestering free tubulin heterodimers or by promoting microtubule catastrophe. Increased expression of STMN1 has been observed in a variety of human malignancies, but its association with melanoma is unknown. We now report that STMN1 is upregulated during the progression of melanoma relative to benign nevi, and that STMN1 is directly regulated by miR-193b. Using an experimental cell culture approach, overexpression of miR-193b using synthetic microRNAs repressed STMN1 expression, whereas inhibition of miR-193b with anti-miR oligos increased STMN1 expression in melanoma cells. The use of a luciferase reporter assay confirmed that miR-193b directly regulates STMN1 by targeting the 3'-untranslated region of STMN1 mRNA. We further demonstrated that STMN1 is overexpressed in malignant melanoma compared with nevi in two independent melanoma cohorts, and that its level is inversely correlated with miR-193b expression. However, STMN1 expression was not significantly associated with patient survival, Breslow depth, mitotic count or patient age. STMN1 knockdown by small-interfering RNA in melanoma cells drastically repressed cell proliferation and migration potential, whereas ectopic expression of STMN1 using lentivirus increased cell proliferation and migration rates. Subsequent gene expression analysis indicated that interconnected cytoskeletal networks are directly affected following STMN1 knockdown. In addition, we identified deregulated genes associated with proliferation and migration, and revealed that p21(Cip1/Waf1) and p27(Kip) could be downstream effectors of STMN1 signaling. Taken together, our study suggests that downregulation of miR-193b may contribute to increased STMN1 expression in melanoma, which consequently promotes migration and proliferation of tumor cells.


Atriopeptin does not augment the transvascular flux of macromolecules in the hamster cheek pouch.
Natriuretic peptides elaborated by atrial myocytes promote marked renal sodium and water excretion as a mechanism for fluid and electrolyte balance. Recent evidence suggests that atriopeptin (ANP) also targets the non-renal vasculature as a site for enhanced fluid exchange. It remains unclear whether ANP alters microvascular integrity to facilitate the efflux of both plasma and proteins across the endothelial barrier, or if fluid exchange is selectively enhanced. This study evaluated the influence of ANP on macromolecular transport through the direct observation of microvessels in the hamster cheek pouch using fluorescent intravital microscopy. Fluorescein isothiocyanate conjugated to either bovine serum albumin or dextran 150,000 Mw was utilized as a permeability probe. Macromolecular efflux was quantified as fluorochrome clearance. The clearance of fluorescein-conjugated bovine serum albumin (57.94 +/- 7.03) or fluorescein-conjugated dextran 150 (4.09 +/- 1.35) remained unaltered by intravascular injection of 1 microgram/kg ANP. Topical application of 40 ng to cheek pouch microvessels produced similar results. All pouches demonstrated positive leakage response to histamine 2.5 x 10(-6) M, increasing fluorochrome clearance approximately 2- to 11-fold. Bolus injection of 1 microgram/kg ANP reduced mean arterial pressure, increased urine flow from 6.63 +/- 2.59 microliters/min to 8.20 +/- 6.13 microliters/min, and elevated sodium excretion from 1.37 +/- 0.49 microEq/min to 2.54 +/- 0.99 microEq/min. These results suggest that ANP fails to significantly alter the integrity of the protein-transporting channels in the microvascular exchange barrier.


Functional inhibition of constitutive nitric oxide synthase in a rat model of sepsis.
Induction of inducible nitric oxide synthase (iNOS) expression is likely important in the pathogenesis of sepsis. However, the sepsis-mediated induction of iNOS is associated with a decrease in constitutive NO synthase (cNOS) activity (which is reversible following acute but not chronic sepsis). Whether this decreased cNOS activity is due to functional inhibition of cNOS by the high concentrations of NO produced by iNOS or to downregulation of cNOS expression is not clear. Thus, we tested the hypothesis that sepsis produces a reversible iNOS/NO-mediated inhibition of cNOS activity. Using a rat cecal ligation and perforation (CLP) model of sepsis, we examined the time course of the changes in iNOS and cNOS activities in lung and thoracic aortae. Reversibility of the sepsis-induced decrease in cNOS activity was assessed in vitro by enzyme activity determination following selective inhibition of iNOS. iNOS and endothelial cNOS protein concentrations were determined by Western blotting. In all septic tissues, cNOS activity was depressed at 6, 12, 24, and 48 hours post-CLP. Inhibition of the increased iNOS activity with aminoguanidine, in vitro, partially restored cNOS activity following acute (6-12 hours) but not chronic sepsis (24-48 hours post-CLP). Consistent with the irreversible depression of cNOS activities in tissues following chronic sepsis, endothelial NOS protein concentrations declined progressively during the time course of sepsis. We have demonstrated the restoration of cNOS activity following in vitro inhibition of iNOS, early, and the downregulation of endothelial NOS, later, in a rat CLP model of sepsis. This suggests that further study is required before iNOS-selective inhibition can be considered in human sepsis.


Serum thyroglobulin level measured after thyroxine withdrawal is useful to predict further recurrence in whole body scan-negative papillary thyroid cancer patients after reoperation.
The best treatment option for recurrent papillary thyroid carcinoma (PTC) is reoperation when the recurrent lesion is locoregional. The prognostic significance of serum thyroglobulin (Tg) levels before reoperation and the association between the outcome of reoperation and Tg level remain unclear. Our study aimed to determine the outcomes of patients who underwent reoperation and their association with serum Tg levels. We retrospectively studied 79 patients with PTC with locoregional recurrence whose whole-body scan results were negative for any recurrence but whose serum Tg levels were detectable after first-line treatment. All the patients underwent reoperation and follow-up examinations, which involved serial serum Tg measurements after thyroxine withdrawal (T4-off Tg), neck ultrasonography, chest computed tomography, and/or fluorodeoxyglucose-positron emission tomography, to detect further recurrence. During the median follow-up duration of 89 months (range, 38-332 months), 30 patients (38.0%) experienced a second recurrence even after the reoperation. Among all patients, only 12 whose Tg levels decreased postoperatively to undetectable levels showed no recurrence. Most recurrences were detected in the patients with high T4-off Tg levels after the reoperation (T4-off Tg level (ng/mL), number of patients with recurrence, %: <1, 0/12, 0%; 1-10, 9/31, 33.3%; >10, 16/22, 72.7%; P < 0.001). In conclusion, recurrence occurred in 38.0% of the patients even after the reoperation. The postoperative T4-off Tg level was a good indicator of recurrence after the reoperation. Therefore, patients who experience recurrence should undergo follow-up examinations that involve routine measurements of T4-off Tg levels, especially when postreoperative values exceed 10 ng/mL.


[Heterodimeric D1-D2 dopamine receptors: a review].
This review summarizes modern data on the structure and functions ofheteromersformed by D1 and D2 dopamine receptors focusing on their role in the mechanisms of drug dependence. This article discusses potential functional significance of heterodimeric D1-D2 dopamine receptorsdue to their localization in the brain as well as unique pharmacological propertiesversus constituent monomers. It is shown that heteromerization results in dramatic changes in activated signaling pathways compare to the corresponding monomers. These studies update our current knowledge of ligand-receptor interactions and provide better understanding of dopamine receptors pharmacology. Furthermore elucidation of significance of heterodimeric D1-D2 dopamine receptors as drug targets is important for the development of new effective drug addiction treatment.


Rapid endodontic management of type II dens invaginatus using an MTA plug: a case report.
Dens invaginatus is an anomaly characterized by an infolding of enamel and dentin that can lead to caries and pulpal death while the tooth is still immature, and present difficulties with diagnosis and treatment. Generally such open apices are managed by long term apexifaction procedures. This article demonstrated rapid management of a maxillary lateral incisor having a type 2 dens invaginatus, necrotic pulp, open apex and very large periradicular lesion using calcium hydroxide for one week prior to placement of a mineral trioxide aggregate (MTA) plug. After setting of the MTA, the remaining canal space was obturated using a warm vertical gutta percha technique. At 6 months follow-up the patient was asymptomatic, the lesion had almost entirely resolved, and, the root was already completely surrounded by bone.


Early detection of cutaneous melanoma by sequential digital dermatoscopy (SDD).
The early diagnosis and excision of cutaneous melanoma is essential for an improved prognosis of the disease. Besides the investigation of pigmented lesions with the unaided eye and conventional dermatoscopy, long-term sequential digital dermatoscopy has been shown to improve the sensitivity of melanoma detection, especially in high-risk patients. In addition to the static clinical and dermatoscopic assessment, the sequential digital dermatoscopy strategy helps to detect changes over time. This review summarizes the latest developments in the field of sequential digital dermatoscopy, describes current strategies for the selection of patients and lesions to monitor, and suggests objective criteria that should lead to an excisional biopsy.


Orientia tsutsugamushi: comprehensive analysis of the mobilome of a highly fragmented and repetitive genome reveals the capacity for ongoing lateral gene transfer in an obligate intracellular bacterium.
The rickettsial human pathogen Orientia tsutsugamushi (Ot) is an obligate intracellular Gram-negative bacterium with one of the most highly fragmented and repetitive genomes of any organism. Around 50% of its ~2.3-Mb genome is composed of repetitive DNA that is derived from the highly proliferated Rickettsiales amplified genetic element (RAGE). RAGE is an integrative and conjugative element (ICE) that is present in a single Ot genome in up to 93 copies, most of which are partially or heavily degraded. In this report, we analyzed RAGEs in eight fully sequenced Ot genomes and manually curated and re-annotated all RAGE-associated genes, including those encoding DNA mobilization proteins, P-type (vir), and F-type (tra) type IV secretion system (T4SS) components, ankyrin repeat- and tetratricopeptide repeat-containing effectors, and other piggybacking cargo. Originally, the heavily degraded Ot RAGEs have led to speculation that they are remnants of historical ICEs that are no longer active. Our analysis, however, identified two Ot genomes harboring one or more intact RAGEs with complete F-T4SS genes essential for mediating ICE DNA transfer. As similar ICEs have been identified in unrelated rickettsial species, we assert that RAGEs may play an ongoing role in lateral gene transfer within the Rickettsiales. We also identified a conserved set of gene transfer agent genes in all Ot genomes. Together these findings indicate that, despite their obligate intracellular lifestyle and host range restricted to mites, rodents, and humans, Ot genomes are highly dynamic and shaped through ongoing invasions by mobile genetic elements and virus-like elements. IMPORTANCE Obligate intracellular bacteria, or those only capable of growth inside other living cells, have limited opportunities for horizontal gene transfer with other microbes due to their isolated replicative niche. The human pathogen Ot, an obligate intracellular bacterium causing scrub typhus, encodes an unusually high copy number of a ~40 gene mobile genetic element that typically facilitates genetic transfer across microbes. This proliferated element is heavily degraded in Ot and previously assumed to be inactive. Here, we conducted a detailed analysis of this element in eight Ot strains and discovered two strains with at least one intact copy. This implies that the element is still capable of moving across Ot populations and suggests that the genome of this bacterium may be even more dynamic than previously appreciated. Our work raises questions about intracellular microbial evolution and sounds an alarm for gene-based efforts focused on diagnosing and combatting scrub typhus.


Ultrastructural effects of the high molecular weight cryoprotectants Dextran and polyvinyl pyrrolidone on liver and brown adipose tissue in vitro.
The ultrastructural changes caused by incubation of rat liver and brown fat in buffered solutions of high molecular weight cryoprotectives (Dextran and polyvinyl pyrrolidone) at high concentrations (up to 25% w/v) have been examined. Under appropriate conditions of incubation rather small qualitative changes were found. Hepatocytes showed some signs of plasmolysis. Evidence for the endocytosis of Dextran and polyvinyl pyrrolidone was obtained. Cryoultramicrotomy of unfixed, quench-frozen specimens after the same incubation procedures showed good cutting properties and only slight ice-crystal damage. Several of the larger tissue compartments were recognizable in such sections. Although high molecular weight cryoprotectants do penetrate cells by endocytosis (and these effects require further functional evaluation), the present observations provide further support for the idea that such compounds significantly improve the quench-freezing of biological specimens and offer a practical way forward for the preparation of material for X-ray microanalysis of diffusible elements.


[Coronary flow reserve in acute myocardial infarction in a patient treated with primary venous angioplasty. Case report].
Residual stenosis, dissection and/or microvascular damage have been proposed as mechanisms of impaired flow after primary angioplasty (PCI) for acute myocardial infarction (MI). In this report we present a patient who underwent PCI for acute anterior MI. Coronary flow reserve (CFR) assessment performed after balloon dilatation suggested possible improvement of coronary flow after stenting. However, we did not observe any improvement in CFR just after stent implantation. We conclude that in patients treated with primary PCI the use of additional pharmacological treatment to prevent microcirculation injury during reperfusion and slow-flow or no-reflow phenomenon should be considered.


Apical ballooning syndrome following exercise treadmill testing.
Transient left ventricular apical ballooning syndrome is an increasingly recognized cause of acute coronary syndrome, particularly in postmenopausal women, and is the subject of increasing interest to both clinicians and researchers. Emotional and physical stressors are often implicated in its development and, while excess sympathetic drive appears to act as a primary trigger, the exact mechanism remains controversial.The clinical presentation is characterized by transient, often severe, left ventricular dysfunction affecting the mid and apical myocardium. By definition, no significant coronary artery lesions are present, although this may not be recognized at initial presentation. While recovery of function with evidence of limited myocardial necrosis is common, significant complications may manifest in the acute phase.A case involving an elderly patient who developed classical features of the syndrome following an exercise treadmill test is presented. To the authors' knowledge, the present case is the only such report that meets the recently proposed diagnostic criteria. The present case serves to highlight a rare but important complication of exercise testing in an elderly patient. Recent large systematic reviews have provided valuable insights into the clinical features of this condition. The current article examines the data from these studies and others to provide a comprehensive clinical overview.


Application of novel targeting nanoparticles contrast agent combined with contrast-enhanced computed tomography during screening for early-phase gastric carcinoma.
Gastric cancer is one of the most common human tumors worldwide. The biggest bottleneck is a lack of advanced and sensitive protocols for the diagnosis of patients with early-stage gastric cancer. Therefore, more sensitive methods of diagnosing gastric cancer are urgently required to improve survival rates. In this clinical study, contrast-enhanced computed tomography (CECT) with targeting nanoparticles contrast agent (CECT-TNCA) was used to diagnose early-stage gastric cancer. The specific-targeted tyrosine kinase inhibitors of gastric cancer, including platelet-derived growth factor receptor-β, Ret and Kit, were used as TNCAs. A total of 484 patients with suspected gastric cancer were voluntarily recruited to investigate the efficacy of CECT-TNCA in the diagnosis of patients with early-stage gastric cancer. Patients with suspected gastric cancer were subjected CT and CECT-TNCA to detect whether gastric tumors existed. TNCA was orally administered before CT and CECT-TNCA (20 min). Our diagnostic data revealed that CECT-TNCA improved sensitivity and provided a new protocol to diagnose tumors in patients with suspected gastric cancer at the early stage. In addition, imaging using CECT-TNCA enabled the visualization of tiny nodules in the gastric area. CECT-TNCA diagnosed 182 patients with suspected gastric cancer as tumor-free. CECT-TNCA confirmed gastric cancer in 302 patients. Our novel diagnosis indicated significantly (P<0.01) differential signal enhancement in the gastric nodules via CECT-TNCA compared with CT, suggesting higher accuracy and the accumulation of TNCA in tumor nodules in the stomach. Furthermore, survival rates of patients detected by early-diagnosis of CECT-TNCA were significantly higher than the mean five-year survival (P<0.01). In conclusion, our investigations demonstrate that the sensibility and accuracy of CT is improved through combination with liposome-encapsulated nanoparticle contrast agent for the diagnosis of early stage gastric cancer when compared with single CT detection. CECT-TNCA improves the accuracy of CT and diagnostic confidence in assessing mural enhancement in patients with suspected gastric cancer.


Phase II study of tacrolimus and methotrexate for prophylaxis of acute graft-versus-host disease after HLA-A, B, and DRB1 genotypically mismatched unrelated bone marrow transplantation among Japanese patients.
Bone marrow transplantation from unrelated donors (UR-BMT) has been considered to be effective for patients with hematological malignancies who have no suitable related donor. However, disparities of HLA between a recipient and a donor increase the risk of severe acute graft-versus-host disease (GVHD). We evaluated GVHD prophylaxis using tacrolimus and methotrexate for HLA-A, B, or DRB1 genotypically mismatched UR-BMT. Fifty-five patients were enrolled in this study. The incidence of grade III to IV acute GVHD was 23.6% for all patients. No significant difference in the incidence of grade III to IV acute GVHD was observed between HLA-A or B 1 locus mismatch transplantation (18.8%) and HLA-DRB1 1 locus mismatch transplantation (16.7%) (P = 0.96). The incidence of chronic GVHD was 71.7%. Disease-free survival at 5 years was 53.2% for patients with standard risk disease and 24.5% for patients with high-risk disease. Patients with chronic GVHD exhibited better disease-free survival than those without chronic GVHD (53.2 vs. 30.9%, P = 0.011). Twenty patients (36.4%) had a relapse of leukemia and 14 of them died of recurrent leukemia. This study indicates tacrolimus and methotrexate can lower the risk of severe acute GVHD after HLA-A, B, or DRB1 genotypically 1 locus mismatched UR-BMT.


Out-of-bed extubation: a feasibility study.
In clinical intensive care practice, weaning from mechanical ventilation is accompanied by concurrent early patient mobilization. The aim of this study was to compare the success of extubation performed with patients seated in an armchair compared to extubation with patients in a supine position. A retrospective study, observational and non-randomized was conducted in a mixed-gender, 23-bed intensive care unit. The primary study outcome was success of extubation, which was defined as the patient tolerating the removal of the endotracheal tube for at least 48 hours. The differences between the study groups were assessed using Student's t-test and chi-squared analysis. Ninety-one patients were included from December 2010 and June 2011. The study population had a mean age of 71 years ± 12 months, a mean APACHE II score of 21±7.6, and a mean length of mechanical ventilation of 2.6±2 days. Extubation was performed in 33 patients who were seated in an armchair (36%) and in 58 patients in a supine position (64%). There were no significant differences in age, mean APACHE II score or length of mechanical ventilation between the two groups, and a similar extubation success rate was observed (82%, seated group versus 85%, supine group, p>0.05). Furthermore, no significant differences were found between the two groups in terms of post-extubation distress, need for tracheostomy, duration of mechanical ventilation weaning, or intensive care unit stay. Our results suggest that the clinical outcomes of patients extubated in a seated position are similar to those of patients extubated in a supine position. This new practice of seated extubation was not associated with adverse events and allowed extubation to occur simultaneously with early mobilization.


Unmodified and pyroglutamylated amyloid β peptides form hypertoxic hetero-oligomers of unique secondary structure.
Amyloid β (Aβ) peptide plays a major role in Alzheimer's disease (AD) and occurs in multiple forms, including pyroglutamylated Aβ (AβpE). Identification and characterization of the most cytotoxic Aβ species is necessary for advancement in AD diagnostics and therapeutics. While in brain tissue multiple Aβ species act in combination, structure/toxicity studies and immunotherapy trials have been focused on individual forms of Aβ. As a result, the molecular composition and the structural features of "toxic Aβ oligomers" have remained unresolved. Here, we have used a novel approach, hydration from gas phase coupled with isotope-edited Fourier transform infrared (FTIR) spectroscopy, to identify the prefibrillar assemblies formed by Aβ and AβpE and to resolve the structures of both peptides in combination. The peptides form unusual β-sheet oligomers stabilized by intramolecular H-bonding as opposed to intermolecular H-bonding in the fibrils. Time-dependent morphological changes in peptide assemblies have been visualized by atomic force microscopy. Aβ/AβpE hetero-oligomers exert unsurpassed cytotoxic effect on PC12 cells as compared to oligomers of individual peptides or fibrils. These findings lead to a novel concept that Aβ/AβpE hetero-oligomers, not just Aβ or AβpE oligomers, constitute the main neurotoxic conformation. The hetero-oligomers thus present a new biomarker that may be targeted for development of more efficient diagnostic and immunotherapeutic strategies to combat AD.


[The influence of volume expansion with induced hypertension on vessel reactivities, blood-brain-barrier, cerebral edema and infarction].
Eighteen anesthetized cats were randomly divided into 3 groups. One group was treated with 10 ml/kg of 6% hydroxyethyl starch (HES). Another group was treated with 15 ml/kg, and there was a control group. There were six cats in each group. Cerebral pial arterial reactivities were measured by means of intravital microscopic observation through a cranial window. Middle cerebral artery (MCA) was clipped for 70 minutes using a transorbital approach. Five hours later, Evans blue dye was injected intravenously and then the animals were killed. Administration of HES or Ringer's solution (control) was started 15 minutes before clipping of MCA. Systemic arterial pressure was elevated by using dopamine at the same time as the MCA occlusion was carried out. Pial arteries dilated soon after the clipping of MCA in all three groups, but showed different patterns in each group after recirculation of MCA. In the control group, they returned to 20% of their dilated state first, but, after about 4 hours, they redilated by 45% at the end of experiment periods. In the group treated with 10 ml/kg of 6% HES, they remained in an almost resting state after MCA recirculation, but in the group with 15 ml/kg, they constricted by 10% at the end of the experiment periods. Regarding the Evans blue dye extravasation, cerebral edema and infarction, they were largest in the control group. But animals treated with 15 ml/kg of 6% HES showed significantly larger Evans blue dye extravasation and cerebral edema than that of animals with 10 ml/kg. However cerebral infarctions were almost the same sizes in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)


Sequential alteration of the pancreas during carcinogenesis in Syrian hamsters by N-nitrosobis(2-oxopropyl)amine.
A systematic histological-pancreatographic study indicated that, during pancreatic carcinogenesis by N-nitrosobis(2-oxopropyl)amine, the ductular cells (cells of intercalated or intralobular ductules and especially those of peri-and intrainsular ductules) are most responsive. The initial proliferation (multiplication) and distension of ductules seemed due to primary hyperplasia of ductular cells, followed by metaplasia, atypia, and malignant alteration. Among 75 induced adenocarcinomas, most were of ductular origin, whereas only a few seemed to arise from ductal epithelium (interlobular, secondary, and main ducts). There was no preferential segment for tumor development. However, about one-third of the adenocarcinomas in the head of the pancreas had a periampullary location, while most neoplasms in other pancreatic lobes arose along the main pancreatic ducts. There was evidence of "leaking" of pancreatic juice through altered epithelium of main ducts, and this may have caused a marked periductal chronic inflammatory reaction.


Construction of multiple modes using gold nanoparticles as probes for the rapid detection of fenpyroximate.
Herein, three patterns for the detection of fenpyroximate based on the response signal of gold nanoparticles are described. The strong interaction between the guanidine group of arginine-modified gold nanoparticles and the ester group of fenpyroximate led to the aggregation of the nanoparticles and to a variation of ultraviolet-visible light spectrum and color of the solution. Sensors were constructed based on the correlation of the concentration of fenpyroximate with the absorbance ratio (A650/A525) and the R value was obtained by extracting the color of the test solution by using a smartphone to take a photo of the solution, which was then analyzed by colorimeter software. The absorbance ratio increased linearly in the range of 0.225-0.375 mg L-1 and the limit of detection was 0.215 mg L-1, while the R value declined linearly in the range of 0.20-0.40 mg L-1 and the limit of detection was 0.21 mg L-1. Further, the gold nanoparticles could cause a fluorescence quenching of fluorescent dyes, such as rhodamine B, and it was found that the fluorescence could be quenched and then restored after aggregation; therefore, a fluorescence method based on fluorescence "off-on" was constructed, and the fluorescence quenching was found to increase linearly in the range of 0.0-1.0 mg L-1 and the limit of detection was 0.013 mg L-1. These three patterns indicated highly selective and sensitive response signals for fenpyroximate, and all were applied to the detection of fenpyroximate in apple juice, pear juice, and environmental water samples, with the results showing that the three methods could be mutually verified, with the recoveries ranging from 94.15% to 110.65%.


Serum phosphate is associated with increased risk of bone fragility fractures in hemodialysis patients.
Bone fragility fractures are associated with high morbidity and mortality. This study analysed the association between the current biochemical parameters of CKD-MBD and bone fragility fractures in the COSMOS project. COSMOS is a 3-year, multicentre, open cohort, prospective, observational study carried out in 6797 hemodialysis patients (227 centres from 20 European countries). The association of bone fragility fractures (outcome) with serum calcium, phosphate and PTH (exposure), was assessed using Standard Cox proportional hazards regression and Cox proportional hazards regression for recurrent events. Additional analyses were performed considering all-cause mortality as a competitive event for bone fragility fracture occurrence. Multivariable models were used in all strategies, with the fully adjusted model including a total of 24 variables. During a median follow-up of 24 months 252 (4%) patients experienced at least one bone fragility fracture (incident bone fragility fracture rate 28.5 per 1000 patient-years). In the fractured and non-fractured patients, the percentage of men was 43.7% and 61.4%, mean age 68.1 and 63.8 years and a haemodialysis vintage of 55.9 and 38.3 months respectively. Baseline serum phosphate > 6.1 mg/dL (reference value 4.3-6.1 mg/dL) was significantly associated with a higher bone fragility fracture risk in both regression models (HR: 1.53[95%CI: 1.10-2.13] and HR: 1.44[95%CI: 1.02-2.05]. The significant association persisted after competitive risk analysis (subHR: 1.42[95%CI: 1.02-1.98]) but the finding was not confirmed when serum phosphate was considered as a continuous variable. Baseline serum calcium showed no association with bone fragility fracture risk in any regression model. Baseline serum PTH > 800 pg/mL was significantly associated with a higher bone fragility fracture risk in both regression models, but the association disappeared after a competitive risk analysis. Hyperphosphatemia was independently and consistently associated with an increased bone fracture risk, suggesting serum phosphate could be a novel risk factor for bone fractures in hemodialysis patients.


Management of relative polycythaemia: studies of cerebral blood flow and viscosity.
Cerebral blood flow has been shown to be reduced in a group of patients with high packed cell volume due to a reduced plasma volume (relative polycythaemia). 500 ml of intravenous Dextran 40 resulted in a significant fall in PCV and whole blood viscosity with a concomitant rise in cerebral blood flow (CBF). This effect, however, lasted less than 24 h. Oral fludrocortisone therapy (0.2 mg daily) resulted in no definite change in either PCV, viscosity or CBF. Venesection brought about a significant fall in PCV and whole blood viscosity with a significant rise in CBF. Of the methods used, venesection was the only practical long-term method of lowering PCV in this group of patients.


Skills not pills: learning to cope with anxiety symptoms.
A pilot project to assess the benefit of a psychology service in general practice for patients with anxiety is described. A course of lessons in ;anxiety management skills' was provided at two practices. At a follow-up appointment one year later two thirds of the 35 patients studied had stopped taking anxiolytic medication and two thirds reported an elimination of their anxiety symptoms. It is proposed that a psychology service be provided for general practitioners, in health centres and health clinics, as a possible alternative to repeat prescribing of anxiolytic medication.


Single-step PCR using (GACA)4 primer: utility for rapid identification of dermatophyte species and strains.
Dermatophytes are fungi that belong to three genera: Epidermophyton, Microsporum, and Trichophyton. Identification of dermatophyte species is essential for appropriate diagnosis and treatment of dermatophytosis. Routine identification depends on macroscopic and microscopic morphology, which is time-consuming and does not identify dermatophyte strains. In this study, two PCR-based methods were compared for their abilities to identify 21 dermatophyte isolates obtained from Egyptian patients to the species and strain levels. The first method employed a two-step method: PCR amplification, using ITS1 and ITS4 as primers, followed by restriction enzyme digestion using the endonuclease MvaI. The second method employed a one-step approach employing the repetitive oligonucleotide (GACA)(4) as a primer. Dermatophyte strains were also identified using a conventional culture method. Our results showed that the conventional culture method identified four species: Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum, and Trichophyton violaceum. Moreover, both PCR methods agreed with the diagnosis made using the conventional approach. Furthermore, ITS1/ITS4-based PCR provided no strain differentiation, while (GACA)(4)-based PCR identified different varieties among the T. mentagrophytes isolates. Taken together, our results suggest that (GACA)(4)-based PCR has utility as a simple and rapid method for identification of dermatophyte species as well as utility for differentiation of T. mentagrophytes variants.


An in situ stretching instrument combined with low field nuclear magnetic resonance (NMR): Rheo-Spin NMR.
An in situ stretching instrument combined with low field nuclear magnetic resonance (LF-NMR) was designed and developed, namely, Rheo-Spin NMR. The time resolved stress-strain curve together with the corresponding NMR signal can be simultaneously obtained. The Rheo-Spin NMR contains the functional modules, including (1) the in situ stretching module, (2) the NMR signal acquisition module, and (3) the cavity of the NMR positioning module. The unique ring-like shape of the sample is used to replace the traditional dumbbell sample due to limited space in the NMR probe, and the whole ring-like sample will be deformed during the uniaxial stretching process, which avoids the generation of interference signals from the undeformed sample. The designed stretching assembly made by zirconia ceramics is manufactured to match and stretch the ring-like samples. The strain rate can be tuned within the range of 10-5-10-2 s-1 with the maximum stretching ratio λmax of ∼3.8. The in situ stretching experiments combined with LF-NMR were carried out successfully with natural rubber of different fractions of carbon black. The time-resolved T2 relaxometry was adopted to evaluate segmental relaxation during uniaxial deformation which, for the first time, provides the direct and in situ molecular dynamics information. The Rheo-Spin NMR is promising to provide more in-depth insights into the structure and dynamics evolution of polymer products under real service conditions.


Effects of glycaemic management on diabetic kidney disease.
Hyperglycaemia contributes to the onset and progression of diabetic kidney disease (DKD). Observational studies have not consistently demonstrated a glucose threshold, in terms of HbA1c levels, for the onset of DKD. Tight glucose control has clearly been shown to reduce the incidence of micro- or macroalbuminuria. However, evidence is now also emerging to suggest that intensive glucose control can slow glomerular filtration rate loss and possibly progression to end stage kidney disease. Achieving tight glucose control needs to be balanced against the increasing appreciation that glucose targets for the prevention of diabetes related complications need be individualised for each patient. Recently, empagliflozin which is an oral glucose lowering agent of the sodium glucose cotransporter-2 inhibitor class has been shown to have renal protective effects. However, the magnitude of empagliflozin's reno-protective properties are over and above that expected from its glucose lowering effects and most likely largely result from mechanisms involving alterations in intra-renal haemodynamics. Liraglutide and semaglutide, both injectable glucose lowering agents which are analogues of human glucagon like peptide-1 have also been shown to reduce progression to macroalbuminuria through mechanisms that remain to be fully elucidated. Here we review the evidence from observational and interventional studies that link good glucose control with improved renal outcomes. We also briefly review the potential reno-protective effects of newer glucose lowering agents.


Testing the Derjaguin approximation for colloidal mixtures of spheres and disks.
The depletion potential between two large hard spheres due to the presence of hard disks has been derived up to first order in the number density of disks by Piech and Walz [J. Colloid Interface Sci. 232, 86 (2000)] using the Derjaguin approximation. Using the generalized Gibbs equation, we compare this depletion potential to the exact solution up to first order in density. The Derjaguin approximation turns out to be surprisingly accurate; for aspect ratios smaller than 0.25 the error is less than 1%.


A novel pipeline for computerized mouse spermatogenesis staging.
Differentiating 12 stages of the mouse seminiferous epithelial cycle is vital towards understanding the dynamic spermatogenesis process. However, it is challenging since two adjacent spermatogenic stages are morphologically similar. Distinguishing Stages I-III from Stages IV-V is important for histologists to understand sperm development in wildtype mice and spermatogenic defects in infertile mice. To achieve this, we propose a novel pipeline for computerized spermatogenesis staging (CSS). The CSS pipeline comprises four parts: (i) A seminiferous tubule segmentation model is developed to extract every single tubule; (ii) A multi-scale learning (MSL) model is developed to integrate local and global information of a seminiferous tubule to distinguish Stages I-V from Stages VI-XII; (iii) a multi-task learning (MTL) model is developed to segment the multiple testicular cells for Stages I-V without an exhaustive requirement for manual annotation; (iv) A set of 204D image-derived features is developed to discriminate Stages I-III from Stages IV-V by capturing cell-level and image-level representation. Experimental results suggest that the proposed MSL and MTL models outperform classic single-scale and single-task models when manual annotation is limited. In addition, the proposed image-derived features are discriminative between Stages I-III and Stages IV-V. In conclusion, the CSS pipeline can not only provide histologists with a solution to facilitate quantitative analysis for spermatogenesis stage identification but also help them to uncover novel computerized image-derived biomarkers. https://github.com/jydada/CSS. Supplementary data are available at Bioinformatics online.


Exome and genome sequencing in adults with undiagnosed disease: a prospective cohort study.
Exome and genome sequencing have been demonstrated to increase diagnostic yield in paediatric populations, improving treatment options and providing risk information for relatives. There are limited studies examining the clinical utility of these tests in adults, who currently have limited access to this technology. Patients from adult and cancer genetics clinics across Toronto, Ontario, Canada were recruited into a prospective cohort study evaluating the diagnostic utility of exome and genome sequencing in adults. Eligible patients were ≥18 years of age and suspected of having a hereditary disorder but had received previous uninformative genetic test results. In total, we examined the diagnostic utility of exome and genome sequencing in 47 probands and 34 of their relatives who consented to participate and underwent exome or genome sequencing. Overall, 17% (8/47) of probands had a pathogenic or likely pathogenic variant identified in a gene associated with their primary indication for testing. The diagnostic yield for patients with a cancer history was similar to the yield for patients with a non-cancer history (4/18 (22%) vs 4/29 (14%)). An additional 24 probands (51%) had an inconclusive result. Secondary findings were identified in 10 patients (21%); three had medically actionable results. This study lends evidence to the diagnostic utility of exome or genome sequencing in an undiagnosed adult population. The significant increase in diagnostic yield warrants the use of this technology. The identification and communication of secondary findings may provide added value when using this testing modality as a first-line test.


Near-IR luminescence and field-induced single molecule magnet of four salen-type ytterbium complexes.
A series of rigid hexadentate salen-type (H2L) ytterbium complexes, namely, [Yb2L3(CH3OH)]·3CH3CN (1), [Yb2LL'L″(CH3OH)(H2O)2](ClO4)2·CH3OH·H2O (2), [Yb2L(OAc)4(CH3OH)2]·2CH3OH (3), and {[Yb2L(OAc)4]·3H2O}n (4) (H2L = N,N'-bis(2-oxy-3-methoxybenzylidene)-1,2-phenylenediamine, HL' = 2-(2'-hydroxy-3'-methyloxy-phenyl)benzimidazole and HL" = 3-methoxysalicylaldehyde) have been synthesized by reactions of H2L with multifarious Yb(3+) salts. X-ray crystallographic analyses demonstrate that complex 1 is of a triple-decker sandwich-type Yb2L3 structure with a ratio of H2L/Yb = 3:2, 2 and 3 possess the unique Yb2 core with a ratio of H2L/Yb = 2:2 and 1:2, respectively, 4 exhibits one dimensional coordination polymers in which the polymeric structures are formed by acetate (OAc(-)) groups. All complexes 1-4 exhibit near-IR luminescence, which can be rationalized on the basis of the disparate structural effects. The magnetic analysis unveils that all complexes 1-4 are of field-induced single-molecule magnet behavior with the energy barriers (Ueff/kB) of 14.5, 2.0, 9.5, and 2.4 K at 3 kOe direct current fields, respectively.


Determining complete electron flow in the cofactor photoreduction of oxidized photolyase.
The flavin cofactor in photoenzyme photolyase and photoreceptor cryptochrome may exist in an oxidized state and should be converted into reduced state(s) for biological functions. Such redox changes can be efficiently achieved by photoinduced electron transfer (ET) through a series of aromatic residues in the enzyme. Here, we report our complete characterization of photoreduction dynamics of photolyase with femtosecond resolution. With various site-directed mutations, we identified all possible electron donors in the enzyme and determined their ET timescales. The excited cofactor behaves as an electron sink to draw electron flow from a series of encircling aromatic molecules in three distinct layers from the active site in the center to the protein surface. The dominant electron flow follows the conserved tryptophan triad in a hopping pathway across the layers with multiple tunneling steps. These ET dynamics occur ultrafast in less than 150 ps and are strongly coupled with local protein and solvent relaxations. The reverse electron flow from the flavin is slow and in the nanosecond range to ensure high reduction efficiency. With 12 experimentally determined elementary ET steps and 6 ET reaction pairs, the enzyme exhibits a distinct reduction-potential gradient along the same aromatic residues with favorable reorganization energies to drive a highly unidirectional electron flow toward the active-site center from the protein surface.


Mortality in siblings of patients coinfected with HIV and hepatitis C virus.
Coinfection with hepatitis C virus (HCV) is a poor prognostic factor for human immunodeficiency virus (HIV)-infected patients. We examined whether the increased mortality in these patients is partly explained by a familial excess risk of death. Danish HIV-infected patients who had had at least 1 HCV test were included (n=3531). In addition, 336,652 population control subjects matched for sex, age, and residency were identified from the Danish Civil Registration System. For both HIV-infected patients and population control subjects, we identified all siblings born after 1951, with dates of death or emigration. Siblings of HIV-infected patients were classified according to the patients' HCV serostatus. Survival after age 20 years was compared among the groups of siblings. We identified 437 siblings of HIV/HCV-coinfected patients, 1856 siblings of HIV-monoinfected patients, and 285,509 siblings of population control subjects. Mortality was substantially higher in siblings of HIV/HCV-coinfected patients than in either siblings of HIV-monoinfected patients (mortality rate ratio [MRR], 2.97 [95% confidence interval {CI}, 1.98-4.45]) or siblings of control subjects (MRR, 4.23 [95% CI, 3.09-5.79]). Siblings of HIV-monoinfected patients had slightly higher mortality (MRR, 1.43 [95% CI, 1.10-1.85]) than siblings of control subjects. HCV infection is a marker of familial factors that affect the survival of HIV-infected patients independently of the pathogenicity of HCV.


The Efficacy of a Dietary Supplement with Carnosine and Hibiscus Sabdariffa L. (AqualiefTM) in Patients with Xerostomia: a Randomized, Placebo-Controlled, Double-Blind Trial.
The purpose of this study was to test the safety and efficacy of AqualiefTM in patients affected by xerostomia. The main ingredients of AqualiefTM are carnosine and dried calyces of Hibiscus sabdariffa L. (karkadè) for their buffering effect at pH 7 as well as for their antioxidant, antimicrobial and lenitive properties. In a Randomized, Placebo-Controlled, Double-Blind Trial, sixty patients with xerostomia (RTOG/EORTC grade 1-2) were randomly assigned to receive either placebo, or AqualiefTM tablets (three times/day after meals) for 6 consecutive days. A questionnaire was used to evaluate dry mouth symptoms before and after 6 days of AqualiefTM or placebo application. Unstimulated and stimulated salivary flow rates and pH were measured before and after application. Treatment with AqualiefTM for 6 days induced a significant increase in saliva pH from 6.2 ± 0.5 to 6.4 ± 0.6 (P < 0.05) while placebo was ineffective (from 6.2 ± 0.5 to 6.3 ± 0.5). AqualiefTM also induced a significant increase in the pH of stimulated saliva from 6.3 ± 0.5 to 6.6 ± 0.5 (P < 0.01). Placebo was ineffective also in this setting (from 6.2 ± 0.5 to 6.3 ± 0.5). Besides an expected normalization of the saliva pH value, AqualiefTM treatment for 6 days greatly increased (56%, P < 0.0001) saliva production. Placebo induced a 19% increase (P < 0.05), which was likely due to mechanical stimulation. AqualiefTM also increased stimulated saliva production (27% increase with respect to day 0, P < 0.05), while placebo was ineffective. AqualiefTM was effective in regulating the saliva pH, in increasing saliva production and improving dry mouth symptoms in xerostomic patients.


Asthma education in a subsidized preschool setting.
The Inspire education program, with nine modules, was developed to improve medical management of asthma and was piloted among parents of preschool children in an economically disadvantaged community of color with high asthma prevalence. Program flexibility, individualized educational modules, a case management approach, and institutional involvement were key elements.


Sequence variations in 185/333 messages from the purple sea urchin suggest posttranscriptional modifications to increase immune diversity.
The 185/333 gene family is highly expressed in two subsets of immune cells in the purple sea urchin in response to immune challenges. The genes encode a surprisingly diverse set of transcripts, which is a function of the variable presence or absence of blocks of shared sequences, known as elements that generate element patterns. Diversity is also the result of a significant level of point mutations. Together, variable element patterns and single nucleotide polymorphisms result in many unique transcripts. The 185/333 genes only have two exons, with the variable element patterns encoded entirely within the second exon. The diversity of the gene family may be the result of frequent recombination among the 185/333 genes that generates a mosaic distribution of element sequences among the genes. A comparative analysis of the sequences for the genes and messages from individual sea urchins indicates that these two sequence sets have largely different nucleotide sequences and appear to use different element patterns. Furthermore, the nucleotide substitution patterns between genes and messages reveal a strong bias toward transitions, particularly cytidine to uridine conversions. These data are consistent with cytidine deaminase activity and may represent a novel form of immunological diversification in an invertebrate immune response system.


Aggregation-induced emission (AIE) of pyridyl-enamido-based organoboron luminophores.
A new family of pyridyl-enamido-based organoboron complexes (Borepy1–4) with aggregation-induced emission (AIE) properties were developed. They show very weak fluorescence in low-viscosity organic solvents and exhibit intense fluorescence in high-viscosity solvents or in their aggregate/solid states. X-ray crystallographic analysis shows that the weak intermolecular interactions by fixing the molecular conformations of Borepy1–4 are responsible for intense fluorescence in the solid state. TD-DFT calculations show that the maximum absorption bands for Borepy1–4 can be easily tuned.


Clinical characteristics and treatment outcomes of patients with major depressive disorder and comorbid anxiety disorders - results from a European multicenter study.
This naturalistic European multicenter study aimed to elucidate the association between major depressive disorder (MDD) and comorbid anxiety disorders. Demographic and clinical information of 1346 MDD patients were compared between those with and without concurrent anxiety disorders. The association between explanatory variables and the presence of comorbid anxiety disorders was examined using binary logistic regression analyses. 286 (21.2%) of the participants exhibited comorbid anxiety disorders, 10.8% generalized anxiety disorder (GAD), 8.3% panic disorder, 8.1% agoraphobia, and 3.3% social phobia. MDD patients with comorbid anxiety disorders were characterized by younger age (social phobia), outpatient status (agoraphobia), suicide risk (any anxiety disorder, panic disorder, agoraphobia, social phobia), higher depressive symptom severity (GAD), polypsychopharmacy (panic disorder, agoraphobia), and a higher proportion receiving augmentation treatment with benzodiazepines (any anxiety disorder, GAD, panic disorder, agoraphobia, social phobia) and pregabalin (any anxiety disorder, GAD, panic disorder). The results in terms of treatment response were conflicting (better response for panic disorder and poorer for GAD). The logistic regression analyses revealed younger age (any anxiety disorder, social phobia), outpatient status (agoraphobia), suicide risk (agoraphobia), severe depressive symptoms (any anxiety disorder, GAD, social phobia), poorer treatment response (GAD), and increased administration of benzodiazepines (any anxiety disorder, agoraphobia, social phobia) and pregabalin (any anxiety disorder, GAD, panic disorder) to be associated with comorbid anxiety disorders. Our findings suggest that the various anxiety disorders subtypes display divergent clinical characteristics and are associated with different variables. Especially comorbid GAD appears to be characterized by high symptom severity and poor treatment response.