Clinical Potential of Statins in Prostate Cancer Radiation Therapy.
Statins are cholesterol- lowering drugs that have been shown to possess anti-tumour properties. Observational studies have shown that 3-hydroxy-3-methlyglutaryl coenzyme A reductase inhibitor (statin) use may be associated with reduced prostate cancer risk. Preclinical studies suggest that statins possess anticancer and radiosensitising properties. This review aims to determine the impact of statin use in the efficacy of radiation therapy and the therapeutic window in prostate cancer. The scientific databases PubMed, Science Direct, EMBASE, Cochrane Collaboration, and Google Scholar were searched for articles identifying statin use in histologically confirmed prostate cancer treated with external beam radiation therapy. Improvement was observed in freedom from biochemical failure (91% vs. 79%), relapse free survival (72% vs. 69%), distant metastasis free survival (96% vs. 94%), and prostate-specific antigen (PSA) relapse free survival (89% vs. 83%) with statin use, however this did not translate into an overall survival benefit for patients. Conflicting data concerning clinical outcomes reduce the integrity of these findings. The literature supports the radiosensitising properties of statins and their potential antitumor effects in prostate cancer. Statin use in prostate cancer presents many obstacles yet to be overcome, which warrant attention prior to the routine implementation of statins in treatment regimes. However, there is evidence to support their beneficial use.


Adverse drug reactions in neonates and infants: a population-tailored approach is needed.
Drug therapy is a powerful tool to improve outcome, but there is an urgent need to improve pharmacotherapy in neonates through tailored prevention and management of adverse drug reactions (ADRs). At present, infants commonly receive off-label drugs, at dosages extrapolated from those in children or adults. Besides the lack of labelling, inappropriate formulations, (poly)pharmacy, immature organ function and multiple illnesses further raise the risk for ADRs in neonates and infants. Pharmacovigilance to improve the prevention and management of ADRs needs to be tailored to neonates and infants. We illustrate this using prevention strategies for drug prescription and administration errors (e.g. formulation, bedside manipulation, access), detection through laboratory signalling or clinical outlier data (e.g. reference laboratory values, overall high morbidity), assessment through algorithm scoring (e.g. Naranjo or population specific), as well as understanding of the developmental toxicology (e.g. covariates, developmental pharmacology) to avoid re-occurrence and for development of guidelines. Such tailored strategies need collaborative initiatives to combine the knowledge and expertise of different disciplines, but hold promise to become a very effective tool to improve pharmacotherapy and reduce ADRs in infants.


Spindle cell carcinoma of the larynx: review of 26 cases including DNA content and immunohistochemistry.
Spindle cell carcinoma (SpCC) is uncommon, with a predilection for the upper aerodigestive tract. Its histogenesis has not been resolved, although most authors support the sarcomatoid carcinoma concept. Ploidy analysis and proliferation indices have not been reported for laryngeal SpCCs. The authors examined the pathological and clinical features of 26 patients (25 men, 1 woman; mean age, 64 years) with laryngeal SpCC treated at the Mayo Clinic from 1960 to 1990. Twenty-three tumors were examined with digital image analysis for DNA content of the spindle cell population (13 tumors had a sufficient squamous component to be analyzed separately). The glottis was involved most frequently (19 patients); 21 tumors were grossly polypoid. Twenty-three tumors were biphasic, and three were monophasic. Overall, 17 tumors (65%) showed keratin positivity in the spindle cell component. Polyclonal antikeratin (15 positive cases), 34betaE12 (15 positive), and AE1/AE3 (12 positive) were the most sensitive markers. Spindle cells were diploid in 5 tumors (22%) and nondiploid in 18 (78%); conventional squamous cell carcinoma was diploid in 4 cases and nondiploid in 9. DNA ploidy results were concordant between the two populations in 11 of 13 tumors (85%). Mean percent MIB-1 staining was 31% in the sarcomatoid component and 45% in the squamous component. In our primary treatment group of 22 patients (median follow-up, 6.4 years), 4 (18%) had local recurrence, 3 (14%) had distant metastasis, and 4 (18%) died of disease. Presence of a nondiploid spindle cell population in 78% of cases of laryngeal SpCC is interpreted as evidence of a neoplastic rather than reactive process. Keratin positivity in nearly two thirds of tumors supports the theory of epithelial origin of these tumors (sarcomatoid carcinoma).


Faster growth of the major prokaryotic versus eukaryotic CO2 fixers in the oligotrophic ocean.
Because maintenance of non-scalable cellular components--membranes and chromosomes--requires an increasing fraction of energy as cell size decreases, miniaturization comes at a considerable energetic cost for a phytoplanktonic cell. Consequently, if eukaryotes can use their superior energetic resources to acquire nutrients with more or even similar efficiency compared with prokaryotes, larger unicellular eukaryotes should be able to achieve higher growth rates than smaller cyanobacteria. Here, to test this hypothesis, we directly compare the intrinsic growth rates of phototrophic prokaryotes and eukaryotes from the equatorial to temperate South Atlantic using an original flow cytometric (14)CO2-tracer approach. At the ocean basin scale, cyanobacteria double their biomass twice as frequently as the picoeukaryotes indicating that the prokaryotes are faster growing CO2 fixers, better adapted to phototrophic living in the oligotrophic open ocean-the most extensive biome on Earth.


Heterologous expression of astaxanthin biosynthesis genes in Mucor circinelloides.
Most Mucor species accumulate beta-carotene as the main carotenoid. The crtW and crtZ astaxanthin biosynthesis genes from Agrobacterium aurantiacum were placed under the control of Mucor circinelloides expression signals. Expression vectors containing the bacterial genes were constructed, and PEG-mediated transformations were performed on a selected M. circinelloides strain. Transformants that exhibited altered carotene production were isolated and analyzed. Southern analysis showed that all plasmids behave as autoreplicative elements. Northern analysis detected the actual heterologous transcription products, whereas thin layer chromatography and high-performance liquid chromatography studies revealed the presence of new carotenoid compounds and intermediates among the transformants.


Potential adverse effects of replacing high volume hemofiltration exchanges on electrolyte balance and acid-base status using the current commercially available replacement solutions in patients with acute renal failure.
The original substitution and/or dialysates used for continuous hemofiltration and/or dialysis were either based on peritoneal dialysis fluids, or peritoneal dialysates themselves. Although these fluids have been refined over the years, by changing the anionic base from acetate or racemic d+ l-lactate, to bicarbonate or l-lactate, the fluids remain designed for low volume hourly exchanges. Even at relatively low volume exchanges, the composition of these fluids can affect systemic acidbase balance. Those fluids which contain a higher concentration of lactate with a corresponding lower chloride, predispose to a hypochloremic alkalosis, whereas those with a lower concentration of lactate with a corresponding higher chloride potentially lead to a hyperchloremic acidosis. In addition, cation balance, differs when using the same fluid as a replacement solution, compared to dialysate. In particular, sodium balance is greater for post-dilutional fluid replacement, due to the lower sieving coefficient. More recently, citrate has been introduced as an extracorporeal anticoagulant, and a variety of dialysates/replacement fluids have been developed, due to the difference in citrate clearance between dialysis and convection based extracorporeal circuits. Over the last decade, there has been a general increase in the standard hourly dialysate and exchange volumes used in the management of patients with acute kidney injury, from 1 to 2.5-3 l/h. Indeed, even larger volume exchanges, some 6-8 l/h have been advocated to improve patient outcomes. However, before embarking on such continuous high volume exchanges, a new generation of fluids may need to be developed to prevent acid-base and electrolyte imbalances.


[On the occurrence of the nematode Oswaldocruzia filiformis (Strongylida: Molineidae) in Karelia].
Contents of the intestines of the viper Vipera berus (L., 1758) from Kizhi archipelago (Lake Onego) was examined. Helminth fauna of the viper was found to include single nematode species, Oswaldocruzia filiformis Goeze, 1782 (Strongylida: Molineidae). Prevalence of the invasion was 60%, intensity of the invasion was 1-8 specimens per host, index of abundance was 1.92 specimens. Measurements and pictures of the parasite are given. Morphometric data on the nematode from viper are compared with those from other host species.


Possible health-protecting effects of feeling useful to others on symptoms of depression and sleep disturbance in the workplace.
The aim of this study was to examine the health-protecting effects of feeling useful to others on symptoms of depression and sleep disturbance in the workplace, as well as its buffering effects on associations between stressful work environments and symptoms of depression and sleep disturbance. The subjects of this cross-sectional survey were 773 Japanese workers (response rate: 64.8%) of five organizations. Feelings of being useful to others were assessed with one simple question used in a previous study. Psychosocial work environment, sleep disturbance, and depressive symptoms were assessed using the Japanese versions of the Effort-Reward Imbalance Questionnaire, the Pittsburgh Sleep Quality Index, and the 28-item General Health Questionnaire, respectively. We tested for linear and interactive effects with hierarchical regression analyses. Feeling useful to others was significantly (p<0.05) and negatively associated with scores of depression and sleep disturbance both in the univariate analyses and after adjusting for age in both genders. Significant (p<0.05) interactions showed that, in both genders, as the effort-reward balance worsened, symptoms of depression increased, but feeling useful to others buffered the associations. The results support the notion that feeling useful to others in both genders in the workplace has possible health-protecting effects.


High expression of HEF1 predicts a poorer prognosis of hepatocellular carcinoma: A retrospective study.
Human enhancer of filamentation 1 (HEF1), a scaffold protein, is highly expressed in a variety of cancer types and is involved cancer cell growth, migration and invasion. The prognostic value of HEF1 in hepatocellular carcinoma (HCC) remains to be elucidated. The aim of the present study was to assess the association between the expression of HEF1, the clinical/pathological parameters and survival in HCC. In the present study, immunohistochemistry was performed to investigate the protein expression of HEF1 in 123 hepatocellular carcinoma tissues and their adjacent normal liver tissues. Spearman's rank correlation, Kaplan-Meier plots and Cox regression model were used to analyze the data. Overexpression of HEF1 protein was observed in HCC tissue when compared with their adjacent non-malignant liver tissue. High expression of HEF1 correlated with higher advanced tumor, node, metastasis (TNM) stage and vascular invasion (P<0.05). In univariate and multivariate analysis, the expression of HEF1 was identified as an independent prognostic factor in the 123 patients with HCC. In subgroup analysis, high expression of HEF1 correlated with a poorer prognosis in advanced (TNM III+IV) stages (P<0.05). These findings demonstrated the potential value of detecting the expression of HEF1 by immunohistochemistry as a prognostic biomarker and therapeutic target for patients with HCC.


Challenges in the decomposition of 2D NMR spectra of mixtures of small molecules.
Analytical methods for mixtures of small molecules require specificity (is a certain molecule present in the mix?) and speciation capabilities. NMR spectroscopy has been a tool of choice for both of these issues since its early days, due to its quantitative (linear) response, sufficiently high resolving power and capabilities of inferring molecular structures from spectral features (even in the absence of a reference database). However, the analytical performances of NMR spectroscopy are being stretched by the increased complexity of the samples, the dynamic range of the components, and the need for a reasonable turnover time. One approach that has been actively pursued for disentangling the composition complexity is the use of 2D NMR spectroscopy. While any of the many experiments from this family will increase the spectral resolution, some are more apt for mixtures, as they are capable of unveiling signals belonging to whole molecules or fragments of it. Among the most popular ones, one can enumerate HSQC-TOCSY, DOSY and Maximum-Quantum (MaxQ) NMR spectroscopy. For multicomponent samples, the development of robust mathematical methods of signal decomposition would provide a clear edge towards identification. We have been pursuing, along these lines, Blind Source Separation (BSS). Here, the un-mixing of the spectra is achieved relying on correlations detected on a series of datasets. The series could be associated with samples of different relative composition or in a classically acquired 2D experiment by the mathematical laws underlying the construction of the indirect dimension, the one not recorded by the spectrometer. Many algorithms have been proposed for BSS in NMR spectroscopy since the seminal work of Nuzillard. In this paper, we use rather standard algorithms in BSS in order to disentangle NMR spectra. We show on simulated data (both 1D and 2D HSQC) that these approaches enable us to accurately disentangle multiple components, and provide good estimates for the concentrations of compounds. Furthermore, we show that after proper realignment of the signals, the same algorithms are able to disentangle real 1D NMR spectra. We obtain similar results on 2D HSQC spectra, where the BSS algorithms are able to successfully disentangle components, and provide even better estimates for concentrations.


[Optimization preparation of chansu-loaded solid lipid nanoparticles by central composite design and response surface method].
To optimize the formulation of chansu-loaded solid lipid nanoparticles (Cs-SLN). Cs-SLN was prepared by cold homogenization technique. The effects of influence factors such as the weight of compritol 888 ATO, soybean lecithin and poloxamer 188, on mean diameter, entrapment efficiency, drug loading and overall desirability were investigated by using central composite design and response surface method. The data were imitated using multi-linear equation and second-order polynomial equation. The latter was prior to the former considering from multiple correlation coefficients. Under the optimal conditions, the mean diameter, entrapment efficiency, drug loading of the Cs-SLN were 71.5 nm, 92.45% and 5.26%. The optimized preparation technique for Cs-SLN is stable, feasible and high inclusion rate. It can be used for production of Cs-SLN.


Pseudo-Wellens Syndrome in a Patient with Hypertension and Left Ventricular Hypertrophy.
BACKGROUND Wellens syndrome is a form of unstable angina that warrants a timely intervention to prevent extensive myocardial infarction. A few conditions can lead to electrocardiogram (EKG) changes mimicking Wellens syndrome. CASE REPORT A 61-year-old African American man with no significant medical history was admitted for chest pain and new biphasic EKG changes in leads V2 through V6 concerning for Wellens' syndrome. He was found to have hypertension during his hospitalization and had left ventricular hypertrophy by echocardiogram. He was urgently evaluated with a cardiac catheterization, which demonstrated a normal coronary artery anatomy. The patient was diagnosed with pseudo-Wellens syndrome. CONCLUSIONS LVH secondary to hypertension could mimic Wellens syndrome and should be considered when evaluating patients with anterior T wave abnormalities on electrocardiograms. In patients who do not have acute coronary syndrome and in whom the T wave abnormalities are not classic for Wellens-type changes, non-invasive imaging instead of cardiac catheterization may be indicated initially.


Biracial youth and families in therapy: issues and interventions.
Empirical research and clinical resources focusing specifically on minority youth and families have increased tremendously in the last 2 decades. Despite this trend, certain groups continue to be relatively neglected. In particular, very few resources exist for understanding the unique challenges that often face biracial youth and their families. In this article, we use a nationally representative database to compare functioning in biracial youth to white adolescents and other minority adolescents. Results suggest that biracial/biethnic youth are a particularly vulnerable group in terms of self-reported delinquency, school problems, internalizing symptoms, and self-regard. As a group, they are also more likely to receive some form of psychological intervention. Given these findings and the shortcoming of clinical resources for work with this population, we provide an in-depth discussion of why biracial youth may be particularly vulnerable from a social-constructionist framework and offer several strategies based on narrative family therapy for working with biracial youngsters and their families.


Identification of macrophage receptors for angiotensin: a potential role in antigen uptake for T lymphocyte responses?
To determine if macrophages express receptors for peptide antigens, guinea pig peritoneal exudate cells (PEC) were examined for their uptake of the octapeptide angiotensin II (AII). PEC were incubated with [3H]AII, with or without nonradioactive AII as a cold inhibitor, for varying lengths of time before harvesting to determine the cell-associated [3H]AII counts per minute. The PEC-associated [3H]AII increased from 90 to 120 min of incubation, then plateaued on additional incubation to 3.5 hr. Inclusion of nonradiolabeled AII into the culture decreased the cell-associated [3H]AII by 80 to 90% at all time points. The uptake of [3H]AII was temperature-sensitive, with maximum cell-associated [3H]-AII occurring at 37 degrees C and reduced uptake occurring at 4 degrees C. The association of [3H]AII with PEC was specific and saturable, and the inhibitory dose for reducing the cell-associated [3H]AII by 50% with nonradiolabeled AII was around 6 X 10(-6) M. Various AII analogs were also employed as inhibitors to determine the fine specificity of [3H]AII binding, and only those analogs with nonaromatic amino acid substitutions for the carboxyl terminal Phe8 showed reduced inhibitory activity, indicating that Phe8 is important for binding. Scatchard analysis of binding indicated that two classes of receptors interacted with AII: a low number of receptors with Ka approximately equal to 3.5 X 10(8) M-1, and a large number of relatively low affinity of binding showing a Ka approximately equal to 5 X 10(5) M-1. The cellular binding activity was associated with isolated PEC plasma membranes, and after density gradient fractionation of solubilized membranes, AII binding activity was primarily associated with molecules of m.w. of around 50,000. PEC were separated into macrophages and lymphocytes by adherence, and all of the [3H]AII binding activity was associated with the macrophage-enriched cells. These results show that macrophages express specific receptors for AII and related peptides that are responsible for most of the uptake of AII by macrophages. We discuss the relevance of this receptor for the immunologically important uptake of AII by macrophages, and a potential physiologic role in angiotensin-converting enzyme production.


Association of perioperative hypotension with subsequent greater healthcare resource utilization.
Determine if perioperative hypotension, a modifiable risk factor, is associated with increased postoperative healthcare resource utilization (HRU). Retrospective cohort study. Multicenter using the Optum® electronic health record database. Patients discharged to the ward after non-cardiac, non-obstetric surgeries between January 1, 2008 and December 31, 2017 with six months of data, before and after the surgical visit. Perioperative hypotension, a binary variable (presence/absence) at an absolute MAP of ≤65-mmHg, measured during surgery and within 48-h after, to dichotomize patients with greater versus lesser hypotensive exposures. Short-term HRU defined by postoperative length-of-stay (LOS), discharge to a care facility, and 30-day readmission following surgery discharge. Mid-term HRU (within 6 months post-discharge) quantified via number of outpatient and emergency department (ED) visits, and readmission LOS. 42,800 distinct patients met study criteria and 37.5% experienced perioperative hypotension. After adjusting for study covariates including patient demographics and comorbidities, patients with perioperative hypotension had: longer LOS (4.01 vs. 3.83 days; LOS ratio, 1.05; 95% CI, 1.04-1.06), higher odds of discharge to a care facility (OR, 1.18; 95% CI, 1.12-1.24; observed rate 22.1% vs. 18.1%) and of 30-day readmission (OR, 1.22; 95% CI, 1.11-1.33; observed rate 6.2% vs. 5.0%) as compared to the non-hypotensive population (all outcomes, p < 0.001). During 6-month follow-up, patients with perioperative hypotension showed significantly greater HRU regarding number of ED visits (0.34 vs. 0.31 visits; visit ratio, 1.10; 95% CI, 1.05-1.15) and readmission LOS (1.06 vs. 0.92 days; LOS ratio, 1.15; 95% CI, 1.07-1.24) but not outpatient visits (10.47 vs. 10.82; visit ratio, 0.97; 95% CI, 0.95-0.99) compared to those without hypotension. There was no difference in HRU during the 6-month period before qualifying surgery. We report a significant association of perioperative hypotension with an increase in HRU, including additional LOS and readmissions, both important contributors to overall medical costs.


Phylogeny Based on Whole Genome as inferred from Complete Information Set Analysis.
Previous molecular phylogeny algorithms mainly rely onmulti-sequence alignments of cautiously selected characteristic sequences,thus not directly appropriate for whole genome phylogeny where eventssuch as rearrangements make full-length alignments impossible. Weintroduce here the concept of Complete Information Set (CIS) and itsmeasurement implementation as evolution distance without reference tosizes. As method proof-test, the 16s rRNA sequences of 22 completelysequenced Bacteria and Archaea species are used to reconstruct aphylogenetic tree, which is generally consistent with the commonlyaccepted one. Based on whole genome, our further efforts yield a highlyrobust whole genome phylogenetic tree, supporting separate monophyleticcluster of species with similar phenotype as well as the early evolution ofthermophilic Bacteria and late diverging of Eukarya. The purpose of thiswork is not to contradict or confirm previous phylogeny standards butrather to bring a brand-new algorithm and tool to the phylogeny researchcommunity. The software to estimate the sequence distance and materialsused in this study are available upon request to corresponding author.


FBXW7-mutated colorectal cancer cells exhibit aberrant expression of phosphorylated-p53 at Serine-15.
FBXW7 mutations occur in a variety of human cancers including colorectal cancer (CRC). Elucidating its mechanism of action has become crucial for cancer therapy; however, it is also complicated by the fact that FBXW7 can influence many pathways due to its role as an E3-ubiquitin ligase in proteasome degradation. FBXW7 and TP53 are tumour suppressors intensively implicated in colorectal carcinogenesis. Deletion mutations in these two genes in animal models mark the progression from adenoma to carcinoma. Although still largely unknown, the last defense mechanism against CRC at the molecular level could be through a synergistic effect of the two genes. The underlying mechanism requires further investigation. In our laboratory, we have used a phospho-kinase profiler array to illustrate a potential molecular link between FBXW7 and p53 in CRC cells. In vitro and in vivo assessments demonstrated aberrant induction of phosphorylated p53 at Serine 15 [phospho-p53(Ser15)] in human FBXW7-deficient CRC cells as compared to their FBXW7-wild-type counterparts. FBXW7 loss in HCT116 cells promoted resistance to oxaliplatin. Immunoblotting data further confirmed that reduction of phospho-p53(Ser15) may contribute to the decreased efficacy of therapy in FBXW7-mutated CRC cells. The findings may suggest the applicability of phospho-p53(Ser15) as an indicative marker of FBXW7-mutations. Phospho-p53(Ser15) regulation by FBXW7 E3-ligase activity could provide important clues for understanding FBXW7 behavior in tumour progression and grounds for its clinical applicability thereafter.


Phase Behavior of Salt-Free Polyelectrolyte Gel-Surfactant Systems.
Ionic surfactants tend to collapse the outer parts of polyelectrolyte gels, forming shells that can be used to encapsulate other species including protein and peptide drugs. In this paper, the aqueous phase behavior of covalently cross-linked polyacrylate networks containing sodium ions and dodecyltrimethylammonium ions as counterions is investigated by means of swelling isotherms, dye staining, small-angle X-ray scattering, and confocal Raman spectroscopy. The equilibrium state is approached by letting the networks absorb pure water. With an increasing fraction of surfactant ions, the state of the water-saturated gels is found to change from being swollen and monophasic, via multiphasic states, to collapsed and monophasic. The multiphasic gels have a swollen, micelle-lean core surrounded by a collapsed, micelle-rich shell, or a collapsed phase forming a spheroidal inner shell separating two micelle-lean parts. It is shown that the transition between monophasic and core-shell states can be induced by variation of the osmotic pressure and variation of the charge of the micelles by forming mixed micelles with the nonionic surfactant octaethyleneglycol monododecylether. The experimental data are compared with theoretical predictions of a model derived earlier. In the calculations, the collapsed shell is assumed to be homogeneous, an approximation introduced here and shown to be excellent for a wide range of compositions. The theoretical results highlight the electrostatic and hydrophobic driving forces behind phase separation.


Structure and functional implications of the human rad9-hus1-rad1 cell cycle checkpoint complex.
Cellular DNA lesions are efficiently countered by DNA repair in conjunction with delays in cell cycle progression. Previous studies have demonstrated that Rad9, Hus1, and Rad1 can form a heterotrimeric complex (the 9-1-1 complex) that plays dual roles in cell cycle checkpoint activation and DNA repair in eukaryotic cells. Although the 9-1-1 complex has been proposed to form a toroidal structure similar to proliferating cell nuclear antigen (PCNA), which plays essential roles in DNA replication and repair, the structural basis by which it performs different functions has not been elucidated. Here we report the crystal structure of the human 9-1-1 complex at 3.2 A resolution. The crystal structure, together with biochemical assays, reveals that the interdomain connecting loops (IDC loop) of hRad9, hHus1, and hRad1 are largely divergent, and further cocrystallization study indicates that a PCNA-interacting box (PIP box)-containing peptide derived from hFen1 binds tightly to the interdomain connecting loop of hRad1, providing the molecular basis for the damage repair-specific activity of the 9-1-1 complex in contrast to PCNA. Furthermore, structural comparison with PCNA reveals other unique structural features of the 9-1-1 complex that are proposed to contribute to DNA damage recognition.


Simulating the effect of cerebral blood flow changes on regional quantification of [18F]flutemetamol and [18F]florbetaben studies.
Global and regional changes in cerebral blood flow (CBF) can result in biased quantitative estimates of amyloid load by PET imaging. Therefore, the current simulation study assessed effects of these changes on amyloid quantification using a reference tissue approach for [18F]flutemetamol and [18F]florbetaben. Previously validated pharmacokinetic rate constants were used to simulate time-activity curves (TACs) corresponding to full dynamic and dual-time-window acquisition protocols. CBF changes were simulated by varying the tracer delivery (K1) from +25 to -25%. The standardized uptake value ratio (SUVr) was computed and TACs were fitted using reference Logan (RLogan) and the simplified reference tissue model (SRTM) to obtain the relative delivery rate (R1) and volume of distribution ratio (DVR). RLogan was least affected by CBF changes (χ2 = 583 p < 0.001, χ2 = 81 p < 0.001, for [18F]flutemetamol and [18F]florbetaben, respectively) and the extent of CBF sensitivity generally increased for higher levels of amyloid. Further, SRTM-derived R1 changes correlated well with simulated CBF changes (R2 > 0.95) and SUVr's sensitivity to CBF changes improved for later uptake-times, with the exception of [18F]flutemetamol cortical changes. In conclusion, RLogan is the preferred method for amyloid quantification of [18F]flutemetamol and [18F]florbetaben studies and SRTM could be additionally used for obtaining a CBF proxy.


Central vs. peripheral metabolic control of estrous cycles in Syrian hamsters. I. Lipoprivation.
Metabolic energy availability has profound effects on reproduction in a wide variety of species. We have been studying the effects of fasting on estrous cycles in Syrian hamsters as a model system for metabolic control of reproduction. In previous experiments, a 48-h period of fasting inhibited estrous cycles in lean, but not fat, hamsters. In fat hamsters the effects of fasting may have been offset by the presence of high circulating levels of free fatty acids mobilized from lipids in adipose tissue. Consistent with this idea fat hamsters treated with the inhibitor of fatty acid oxidation methyl palmoxirate (MP) showed fasting-induced anestrus. Experiment 1 was designed to examine whether vagally transmitted signals are critical for the inhibitory effects of fasting and MP treatment. Lean or fat hamsters that had received bilateral subdiaphragmatic vagotomy or sham surgery were fasted and treated with MP or vehicle. In vagotomized and sham-operated hamsters, estrous cycles were inhibited in lean fasted hamsters and in fat fasted hamsters treated with MP, but not in fat fasted hamsters treated with vehicle. Thus the results of experiment 1 indicated that vagally transmitted signals about peripheral fatty acid availability are not critical for the effects of these particular metabolic challenges on estrous cycles in Syrian hamsters. In experiment 2, hamsters without food were allowed to ingest pure glucose or fructose solutions or vegetable shortening. One-half of each group was treated with an inhibitor of glucose utilization, 2-deoxy-D-glucose (2-DG), or vehicle. If ingestion of fructose or shortening, but not glucose, had protected hamsters from 2-DG-induced anestrus, this might have indicated that peripheral fuel availability is critical for anestrus. On the contrary, 2-DG treatment induced anestrus regardless of the type of fuel ingested. Neither experiment yielded results that implicated changes in peripheral fuel availability as a critical signal in metabolic control of estrous cycles.


A metal-free organic-inorganic aqueous flow battery.
As the fraction of electricity generation from intermittent renewable sources--such as solar or wind--grows, the ability to store large amounts of electrical energy is of increasing importance. Solid-electrode batteries maintain discharge at peak power for far too short a time to fully regulate wind or solar power output. In contrast, flow batteries can independently scale the power (electrode area) and energy (arbitrarily large storage volume) components of the system by maintaining all of the electro-active species in fluid form. Wide-scale utilization of flow batteries is, however, limited by the abundance and cost of these materials, particularly those using redox-active metals and precious-metal electrocatalysts. Here we describe a class of energy storage materials that exploits the favourable chemical and electrochemical properties of a family of molecules known as quinones. The example we demonstrate is a metal-free flow battery based on the redox chemistry of 9,10-anthraquinone-2,7-disulphonic acid (AQDS). AQDS undergoes extremely rapid and reversible two-electron two-proton reduction on a glassy carbon electrode in sulphuric acid. An aqueous flow battery with inexpensive carbon electrodes, combining the quinone/hydroquinone couple with the Br2/Br(-) redox couple, yields a peak galvanic power density exceeding 0.6 W cm(-2) at 1.3 A cm(-2). Cycling of this quinone-bromide flow battery showed >99 per cent storage capacity retention per cycle. The organic anthraquinone species can be synthesized from inexpensive commodity chemicals. This organic approach permits tuning of important properties such as the reduction potential and solubility by adding functional groups: for example, we demonstrate that the addition of two hydroxy groups to AQDS increases the open circuit potential of the cell by 11% and we describe a pathway for further increases in cell voltage. The use of π-aromatic redox-active organic molecules instead of redox-active metals represents a new and promising direction for realizing massive electrical energy storage at greatly reduced cost.


Choice of phantom material and test protocols to determine radiation exposure rates for fluoroscopy.
The image intensifier entrance exposure rate (IIEER)) and entrance skin exposure rate (ESER) are two characteristics that can be used to determine whether a fluoroscope is adjusted to operate at an optimal dose rate level. This article presents solutions to some of the practical problems that are encountered when measuring these parameters. Because the energy response of the ion chamber used to measure exposure rates is different from that of the image intensifier, a fluoroscope with a perfect automatic exposure rate control will have an IIEER that depends on the phantom composition, phantom thickness, and x-ray tube potential. The authors developed a simple mathematic model to investigate the relationship of ion chamber response to image intensifier response and to determine the effects of phantom composition and thickness. Results from this model were compared with measurements made with two C-arm fluoroscopes. Variations of 40% or more in the IIEER and ESER can be ascribed to these phenomena.


[The influence of zinc on apoptosis and cell proliferation in palatal shelves during the fusion phaseand identification of a special protein family based on gene expression in cleft palate].
Objective: To investigate the effect of the trace element zinc (Zn) on apoptosis and cell proliferation in palate shelvesduring the fusion phase, and to screen candidate genes of the Zn-finger special protein (Sp) family that were differentially expressed between the cleft palate and the normal palate to explore the mechanism of Zn in the development of cleft palate. Methods: Zn-rich, normal-Zn, low-Zn, and Zn-deficient diets were fed to female mice and, for the resultant fetuses, paraffin slices of their heads were made at embryonicdays 14.5 and 16.5. Using terminaldeoxynucleotidyltransferase-mediated dUTP nick-end labeling, the number of apoptotic cells in the palatal shelves was counted, and cell proliferation activity was detected using proliferating cell nuclear antigen staining. Total RNA from the palatal shelves of fetal mice was extracted from the Zn-rich diet, normal Zn-diet, and Zn-deficient-diet groups. We used microarray analysis to examine the expression of genes to identify intergroup differential gene expression and polymerase chain reaction tests to validate the results. Results: At ED14.5, the incidence of cleft palate in the regular zinc group, zinc rich group, low zinc group, and zinc deficient group was 8% (3/36), 2% (1/39), 29% (12/41), and 39% (15/38), respectively. The HE staining results at ED14.5 showed that both the left and right palatal processes in the zinc group had been lifted up and were in contact and connected with each other; In the zinc deficiency group, the left and right palatine processes remained vertically downwards on both sides of the tongue, ultimately forming cleft palate; In the low zinc group, the left and right palatine processes were raised but not in contact, ultimately resulting in cleft palate; There is no significant difference between the zinc rich group and the regular zinc group. At ED14.5, the positive rates of proliferative cells in the palatal process of fetal mice in the regular zinc group (80.29% ± 7.39%) and the zinc rich group (87.69% ± 6.62%) were significantly higher than those in the zinc deficient group (56.05% ± 16.13%) and the low zinc group (56.22% ± 9.61%) (t=4.32, P<0.05); The apoptosis index of fetal rat palatal process cells in the zinc deficient group (38.80% ± 3.10%) and the low zinc group (28.80% ± 6.19%) were significantly higher than those in the regular zinc group (16.80% ± 1.82%) (t=19.35, P<0.001; t=5.81, P<0.001). There were 663 differentially expressed genes in the zinc rich group and the zinc deficient group, with 513 up-regulated genes and 150 down-regulated genes, among which Sp5 was found to be located. The real time PCR results showed that compared with the regular zinc group (2.22 ± 0.36), the expression level of Sp5mRNA in the palatal process tissue of the zinc deficient group (1.23 ± 0.38) significantly increased (P<0.05), while the zinc rich group (3.68 ± 0.90) significantly decreased (P<0.05). Conclusions: Trace element Zn content was found to be closely related to the occurrence of cleft palate in mice offspring, with a lack of Zn leading to cleft palate.


Kidney-on-a-Chip: A New Technology for Predicting Drug Efficacy, Interactions, and Drug-induced Nephrotoxicity.
Kidney dysfunction resulting from various drugs is an important issue during the drug development process. Traditional in vivo animal experiments are limited with respect to evaluating drug efficacy and nephrotoxicity due to discrepancies in drug pharmacokinetics and pharmacodynamics between humans and animals, and static cell culture experiments cannot fully reflect the actual microphysiological environment in humans. In this review article, authors collected manually relevant bibliographic databases including journal articles and textbooks related to microfluidics, kidney-on-a-chip, and drug screening and interaction. In this review, we discuss recent developments in microfluidic culturing technique and describe current and future kidney-on-a-chip applications. The pharmacodynamic and pathophysiological responses of cells are more realistic in microfluidic or 3D culture systems than in conventional 2D culture systems. Recently, several types of kidney-on-a-chip have been developed that reflect the microenvironment of the kidney tubule and have been shown to better reflect actual in-vivo results of drug nephrotoxicity. Using kidney-on-a-chip, investigators can measure various drug-induced biological responses. In the future, it is expected that a multi-organ chip will be utilized to examine the interaction between kidney and other organs, and kidney-on-a-chip can be used in disease modeling and the development of new renal replacement therapy. Using kidney-on-a-chip, researchers can create experimental environments resembling the physiological environments in human organs and obtain experimental results that better reflect human physiology. Kidney-ona- chip can be used to overcome the drawbacks of traditional animal models and to more effectively identify drug effects, interactions, and drug-induced nephrotoxicity.


Genes encoding alpha-heavy chains of rabbit IgA: characterization of cDNA encoding IgA-g subclass alpha-chains.
cDNA molecules encoding rabbit IgA alpha-heavy chains have been synthesized and six of these have been characterized. The complete nucleotide sequence of one cDNA, p 19 (942bp), showed that it encoded all but the N-terminal 57 amino acid residues of the constant region of alpha-chains. The cDNA molecules were subcloned into the expression vector pUC8 and E. coli were transformed. Radioimmunoassay of the molecules synthesized by these clones showed that all six cDNA molecules encoded alpha-chains of the IgA-g subclass. Comparison of the amino acids encoded by the alpha-cDNA with the amino acid sequence of mouse and human alpha-chains showed that although all of the intradomain disulfide bonds appear to be conserved, some positions, probably involved in interchain disulfide bonds, are not conserved. We propose that secretory component is covalently bound to cysteine 299 and/or cysteine 301 of the CH2 domain of mouse and human alpha-chains. The results from Southern blot analysis of genomic DNA with 32P-cDNA suggests that the rabbit genome has multiple C alpha genes.


From capturing nursing knowledge to retrieval of data from a data warehouse.
The purpose of the project was to capture nursing data and knowledge, represent it for use and re-use by retrieval from a data warehouse, which contains both clinical and financial hospital data. Today nurses at LUH use standardized nursing terminologies to document information related to patients and the nursing care in the EHR at all times. Pre-defined order sets for nursing care have been developed using best practice where available and tacit nursing knowledge has been captured and coded with standardized nursing terminologies and made explicit for dissemination in the EHR. All patient-nursing data is permanently stored in a data repository. Core nursing data elements have been selected for transfer and storage in the data warehouse and patient-nursing data are now captured, stored, can be related to other data elements from the warehouse and be retrieved for use and re-use.


BINOL as a Chiral Solvating Agent for Sulfiniminoboronic Acids.
1H NMR spectroscopic studies using BINOL as a chiral solvating agent (CSA) for a scalemic sulfiniminoboronic acid (SIBA) have revealed concentration- and enantiopurity-dependent variations in the chemical shifts of diagnostic imine protons used to determine enantiopurity levels. 11B/15N NMR spectroscopic studies and X-ray structural investigations revealed that unlike other iminoboronate species, BINOL-SIBA assemblies do not contain N-B coordination bonds, with 1H NMR NOESY experiments indicating that intermolecular H-bonding networks between BINOL and the SIBA analyte are responsible for these variations. These effects can lead to diastereomeric signal overlap at certain er values that could potentially lead to enantiopurity/configuration misassignments. Consequently, it is recommended that hydrogen-bonding-CSA-based 1H NMR protocols should be repeated using both CSA enantiomers to ensure that any concentration- and/or er-dependent variations in diagnostic chemical shifts are accounted for when determining the enantiopurity of a scalemic analyte.


Enhancing Light-Sheet Fluorescence Microscopy Illumination Beams through Deep Design Optimization.
Light sheet fluorescence microscopy (LSFM) provides the benefit of optical sectioning coupled with rapid acquisition times for imaging of tissue-cleared specimen. This allows for high-resolution 3D imaging of large tissue volumes. Inherently to LSFM, the quality of the imaging heavily relies on the characteristics of the illumination beam, with the notion that the illumination beam only illuminates a thin section that is being imaged. Therefore, substantial efforts are dedicated to identifying slender, non-diffracting beam profiles that can yield uniform and high-contrast images. An ongoing debate concerns the employment of the most optimal illumination beam; Gaussian, Bessel, Airy patterns and/or others. Comparisons among different beam profiles is challenging as their optimization objective is often different. Given that our large imaging datasets (∼0.5TB images per sample) is already analyzed using deep learning models, we envisioned a different approach to this problem by hypothesizing that we can tailor the illumination beam to boost the deep learning models performance. We achieve this by integrating the physical LSFM illumination model after passing through a variable phase mask into the training of a cell detection network. Here we report that the joint optimization continuously updates the phase mask, improving the image quality for better cell detection. Our method's efficacy is demonstrated through both simulations and experiments, revealing substantial enhancements in imaging quality compared to traditional Gaussian light sheet. We offer valuable insights for designing microscopy systems through a computational approach that exhibits significant potential for advancing optics design that relies on deep learning models for analysis of imaging datasets.


NF-kappaB inhibitors significantly attenuate the transcription of high affinity type-2 cationic amino acid transporter in LPS-stimulated rat kidney.
Sepsis-induced renal failure is closely related to inducible nitric oxide synthase (iNOS) upregulation and nitric oxide (NO) overproduction. Trans-membrane L-arginine transportation mediated by type-2 cationic amino acid transporter (CAT-2) isozymes, including CAT-2, CAT-2A, and CAT-2B, is one of the crucial mechanisms that regulate NO biosynthesis by iNOS. We previously had shown that endotoxemia significantly upregulated renal CAT-2 and CAT-2B but not CAT-2A expression. This study was, thus, conducted to further explore the role of nuclear factor-kappaB (NF-kappaB) in regulating the expression of CAT-2 isozymes in lipopolysaccharide (LPS)-treated rat kidney. Adult male Sprague-Dawley rats were randomly given intra-peritoneal injections of normal saline (N/S), LPS, LPS plus NF-kappaB inhibitor pre-treatment (PDTC, dexamethasone, or salicylate), or an NF-kappaB inhibitor alone. The rats were sacrificed at 6 hours after LPS injection and enzyme expression and renal injury were examined. Renal iNOS, CAT-2, and CAT-2B were significantly upregulated in LPS-stimulated rat kidney. NF-kappa B inhibitors significantly attenuated this upregulation induced by LPS and resultantly attenuated renal NO biosynthesis and renal injury induced by LPS. In contrast, renal CAT-2A expression was not affected by either LPS or NF-kappaB inhibitors. LPS co-induces iNOS, CAT-2 and CAT-2B expression in LPS-stimulated rat kidney. Furthermore, inhibition of NF-kappaB significantly attenuates NO biosynthesis through inhibition of iNOS, CAT-2, and CAT-2B, and, in turn, significantly reduces endotoxemia-induced renal injury.


Effect of refractive error on temperament and character properties.
To determine the effect of refractive error on temperament and character properties using Cloninger's psychobiological model of personality. Using the Temperament and Character Inventory (TCI), the temperament and character profiles of 41 participants with refractive errors (17 with myopia, 12 with hyperopia, and 12 with myopic astigmatism) were compared to those of 30 healthy control participants. Here, temperament comprised the traits of novelty seeking, harm-avoidance, and reward dependence, while character comprised traits of self-directedness, cooperativeness, and self-transcendence. Participants with refractive error showed significantly lower scores on purposefulness, cooperativeness, empathy, helpfulness, and compassion (P<0.05, P<0.01, P<0.05, P<0.05, and P<0.01, respectively). Refractive error might have a negative influence on some character traits, and different types of refractive error might have different temperament and character properties. These personality traits may be implicated in the onset and/or perpetuation of refractive errors and may be a productive focus for psychotherapy.


Analysing linear multivariate pattern transformations in neuroimaging data.
Most connectivity metrics in neuroimaging research reduce multivariate activity patterns in regions-of-interests (ROIs) to one dimension, which leads to a loss of information. Importantly, it prevents us from investigating the transformations between patterns in different ROIs. Here, we applied linear estimation theory in order to robustly estimate the linear transformations between multivariate fMRI patterns with a cross-validated ridge regression approach. We used three functional connectivity metrics that describe different features of these voxel-by-voxel mappings: goodness-of-fit, sparsity and pattern deformation. The goodness-of-fit describes the degree to which the patterns in an input region can be described as a linear transformation of patterns in an output region. The sparsity metric, which relies on a Monte Carlo procedure, was introduced in order to test whether the transformation mostly consists of one-to-one mappings between voxels in different regions. Furthermore, we defined a metric for pattern deformation, i.e. the degree to which the transformation rotates or rescales the input patterns. As a proof of concept, we applied these metrics to an event-related fMRI data set consisting of four subjects that has been used in previous studies. We focused on the transformations from early visual cortex (EVC) to inferior temporal cortex (ITC), fusiform face area (FFA) and parahippocampal place area (PPA). Our results suggest that the estimated linear mappings explain a significant amount of response variance in the three output ROIs. The transformation from EVC to ITC shows the highest goodness-of-fit, and those from EVC to FFA and PPA show the expected preference for faces and places as well as animate and inanimate objects, respectively. The pattern transformations are sparse, but sparsity is lower than would have been expected for one-to-one mappings, thus suggesting the presence of one-to-few voxel mappings. The mappings are also characterised by different levels of pattern deformations, thus indicating that the transformations differentially amplify or dampen certain dimensions of the input patterns. While our results are only based on a small number of subjects, they show that our pattern transformation metrics can describe novel aspects of multivariate functional connectivity in neuroimaging data.


Effect of cardiotropic agents on the myocardial dysfunction of hyperdynamic sepsis.
We have previously shown that in vitro myocardial performance is impaired in rats during the hyperdynamic, hypermetabolic phase of sepsis. Although the heart in the resting animal generated an elevated cardiac output, the isolated, perfused heart showed a depressed ventricular function curve. In the present studies, interventions to improve contractile function (increased perfusate calcium concentration or perfusion with ouabain) or to decrease calcium availability to the myofibrils (verapamil and tetracaine) were investigated using the isolated perfused working heart. These studies showed that increasing or decreasing calcium concentration in the perfusion medium had little effect on ventricular performance in the septic group, whereas ouabain enhanced performance by approximately 25%. Addition of verapamil at a dose that caused a minimal decrease in myocardial work (cardiac output X peak systolic pressure) in control hearts showed a 20-25% increase in work in the experimental hearts. Increased levels of verapamil caused a greater depression in myocardial performance in the control hearts than in the hearts from septic rats. Thus, it appears that a multifaceted defect may be present in these hearts with a derangement that can be slightly improved with either ouabain or verapamil. Since neither intervention could completely reverse the myocardial dysfunction in hyperdynamic sepsis, it appears that the defect may be due to other factors in addition to calcium availability for contraction.


[Compartment syndrome of the forearm due to infusion and transfusion using a pressure pump].
Two cases are reported in whom infusions and transfusions by means of pressure pumps caused a compartment syndrome of the forearm. Subfascial tissue pressure measurement is a decisive device under general anaesthesia to confirm the diagnosis. The development of a compartment syndrome caused by extracorporal fluids, be it an arthroscopy or a transfusion, as well as the indication for a conservative or an invasive procedure are discussed.


Phosphoproteome analysis of formalin-fixed and paraffin-embedded tissue sections mounted on microscope slides.
Formalin-fixed and paraffin-embedded (FFPE) sections mounted on microscope slides are one of the largest available resources for retrospective research on various diseases, but quantitative phosphoproteome analysis of FFPE sections has never been achieved because of the extreme difficulty of procuring sufficient phosphopeptides from the limited amounts of proteins on the slides. Here, we present the first protocol for quantitative phosphoproteome analysis of FFPE sections by utilizing phase-transfer surfactant-aided extraction/tryptic digestion of FFPE proteins followed by high-recovery phosphopeptide enrichment via lactic acid-modified titania chromatography. We established that FFPE sections retain a similar phosphoproteome to fresh tissue specimens during storage for at least 9 months, confirming the utility of our method for evaluating phosphorylation profiles in various diseases. We also verified that chemical labeling based on reductive dimethylation of amino groups was feasible for quantitative phosphoproteome analysis of FFPE samples on slides. Furthermore, we improved the LC-MS sensitivity by miniaturizing nanoLC columns to 25 μm inner diameter. With this system, we could identify 1090 phosphopeptides from a single FFPE section obtained from a microscope slide, containing 25.2 ± 5.4 μg of proteins. This protocol should be useful for large-scale phosphoproteome analysis of archival FFPE slides, especially scarce samples from patients with rare diseases.


Building a Virtual Global Knowledge Network During the Coronavirus Disease 2019 Pandemic: The Infection Prevention and Control Global Webinar Series.
The coronavirus disease 2019 (COVID-19) pandemic has been an unprecedented global health challenge. Traditional modes of knowledge dissemination have not been feasible. A rapid solution was needed to share guidance and implementation examples within the global infection prevention and control (IPC) community. We designed the IPC Global Webinar Series to bring together subject matter experts and IPC professionals in the fight against COVID-19. The Extension for Community Healthcare Outcomes (ECHO) model was adapted to create an interactive global knowledge network. Speakers and panelists provided presentations and answers to questions. Webinars were simultaneously interpreted into 5 languages and recorded for later access. Thirteen webinar sessions were completed from 14 May through 6 August 2020. On average, 634 participants attended each session (range, 393-1181). Each session was represented by participants from, on average, more than 100 countries. Through the IPC Global Webinar Series, critical information was shared and peer-to-peer learning was promoted during the COVID-19 pandemic response. The webinar sessions reached a broader audience than many in-person events. The webinar series was rapidly scaled and can be rapidly reactivated as needed. Our lessons learned in designing and implementing the series can inform the design of other global health virtual knowledge networks. The continued and expanded use of adapted virtual communities of practice and other learning networks for the IPC community can serve as a valuable tool for addressing COVID-19 and other infectious disease threats.The infection prevention and control (IPC) Global Webinar Series convened subject matter experts and IPC professionals from more than 100 countries to establish a global learning community for COVID-19. We advocate for expanded use of virtual knowledge networks.


Whole genome sequence and genome annotation of Colletotrichum acutatum, causal agent of anthracnose in pepper plants in South Korea.
Colletotrichum acutatum is a destructive fungal pathogen which causes anthracnose in a wide range of crops. Here we report the whole genome sequence and annotation of C. acutatum strain KC05, isolated from an infected pepper in Kangwon, South Korea. Genomic DNA from the KC05 strain was used for the whole genome sequencing using a PacBio sequencer and the MiSeq system. The KC05 genome was determined to be 52,190,760 bp in size with a G + C content of 51.73% in 27 scaffolds and to contain 13,559 genes with an average length of 1516 bp. Gene prediction and annotation were performed by incorporating RNA-Seq data. The genome sequence of the KC05 was deposited at DDBJ/ENA/GenBank under the accession number LUXP00000000.


Transient AV Block as a Hemodynamic Complication of the Influenza A Virus: A Case Report.
Influenza virus causes annual epidemics of respiratory illness characterized by sudden onset of fever, malaise, myalgias, headache, cough, and other respiratory complains. Each year in the United States, it is estimated that this debilitating respiratory illness accounts for 294,000 excess hospitalizations and 36,000 attributable deaths. Epidemiological studies describe increased cardiovascular mortality during influenza seasons. Cardiovascular involvement in acute influenza infection can occur through direct effects of the virus on the myocardium or through exacerbation of existing cardiovascular disease. The purpose of this report is to document a transient atrioventricular (AV) block with hemodynamic compromise after infection with the influenza virus in a patient with underlying cardiac disease without myocarditis.


Management of Takayasu arteritis: a systematic review.
Assessment of the pattern and extent of arterial involvement and measurement of current disease activity are essential for the management of Takayasu arteritis (TA). Since there is no completed, placebo-controlled, randomized clinical trial, the level of evidence for management of TA is low, generally reflecting the results of open studies, case series and expert opinion. The most commonly used agents include corticosteroids and conventional immunosuppressive agents such as MTX, AZA, MMF and LEF. In patients who remain resistant and/or intolerant to these agents, biologic drugs including TNF inhibitors, rituximab and tocilizumab seem to be promising. Antiplatelet treatment may also lower the frequency of ischaemic events in TA. In the presence of short-segment, critical arterial stenosis, balloon angioplasty or stent graft replacement may be useful. On the other hand, long-segment stenosis with extensive periarterial fibrosis or occlusion requires surgical bypass of the affected segment, which is clearly associated with superior results compared with endovascular intervention. As a general rule, both endovascular intervention and surgical procedures should be avoided during the active phase of the disease. Earlier diagnosis, better assessment of disease activity and future clinical trials will obviously improve the management of TA.


Altered kinetics of Tap-1 gene expression in macrophages following stimulation with both IFN-gamma and LPS.
With recent studies suggesting a key role for professional antigen presenting cells in the induction of major histocompatibility class I cellular immune responses, we initiated studies on the regulation of Tap-1 and Tap-2 gene expression in macrophages. Stimulation of the human macrophage cell line THP-1 with interferon-gamma (IFN-gamma) resulted in maximal induction of both Tap-1 and Tap-2 mRNA within 24 hr. Nuclear run-on analyses showed that the increased expression of Tap-1 and Tap-2 was controlled at the level of transcription. Half-life studies demonstrated that mRNAs for both genes became destabilized after stimulation of THP-1 cells with IFN-gamma for 24 hr, suggesting that a posttranscriptional mechanism down-regulates TAP gene expression following activation. Treatment of cells with both IFN-gamma and lipopolysaccharide (LPS) altered the kinetics and amount of Tap-1 mRNA and protein expression, compared to those with stimulation with IFN-gamma alone. These data suggest that LPS enhances the ability of macrophages stimulated with IFN-gamma to initiate a cellular immune response by altering the kinetics of TAP gene expression.


Awareness With Paralysis in Mechanically Ventilated Patients in the Emergency Department and ICU: A Systematic Review and Meta-Analysis.
Awareness with paralysis is a devastating complication for mechanically ventilated patients and can carry long-term psychologic sequelae. Hundreds of thousands of patients require mechanical ventilation in the emergency department and ICU annually, yet awareness has only been rigorously examined in the operating room (incidence ~0.1%). This report collates the global literature regarding the incidence of awareness with paralysis outside of the operating room. We searched OvidMedline, Embase, Scopus, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, conference proceedings, and reference lists. Randomized or nonrandomized studies (except single case studies) reporting on awareness with paralysis in the emergency department or ICU were eligible. Two independent reviewers screened abstracts for eligibility. The search identified 4,454 potentially eligible studies. Seven studies (n = 941 patients) were included for analysis. A random effects meta-analysis of proportions along with multiple subgroup analyses was performed. Significant between-study heterogeneity in reporting of awareness with paralysis was noted, and the quality of the evidence was low. Analyses stratified by: 1) good-quality studies and 2) use of the modified Brice questionnaire to detect awareness revealed estimates of 3.4% (95% CI, 0-10.2%) and 1.9% (95% CI, 1.0-3.0%), respectively. The incidence of awareness with paralysis in mechanically ventilated patients in the emergency department and ICU, as evaluated in a small number of qualifying studies from this comprehensive systematic review, appears much higher than that reported from the operating room. Given the clinical and statistical heterogeneity, caution is warranted in the interpretation of these findings. Further high-quality studies are needed to both define the true incidence and to target the prevention of awareness with paralysis in this vulnerable patient cohort.


Laterally projecting cerebrospinal fluid-contacting cells in the lamprey spinal cord are of two distinct types.
Cerebrospinal fluid-contacting (CSF-c) cells are found in all vertebrates, but their function remains elusive. In the lamprey spinal cord, they surround the central canal and some have processes passing the gray matter to the lateral edge of the flattened spinal cord. Stimulation of CSF-c cells at the central canal elicits GABAergic inhibitory postsynaptic potentials (IPSPs) in intraspinal stretch receptor neurons (edge cells). Here, we characterize laterally projecting CSF-c cells according to their morphology, phenotype, and neuronal properties by using immunohistochemistry, retrograde tracing, calcium imaging, and whole-cell recordings. We identify two types of CSF-c cells. Type 1 cells have a bulb-like ending that protrudes into the central canal and a lateral process that ramifies ventrolaterally and laterally with a dense plexus surrounding the mechanosensitive dendrites of the edge cells. Most type 1 cells fire spontaneous action potentials that are abolished by tetrodotoxin, and all display spontaneous excitatory postsynaptic potentials and IPSPs that remain in the presence of tetrodotoxin. GABA and somatostatin are colocalized in type 1 cells, and they express both GABA and glutamate receptors. Type 2 cells, on the other hand, have a flat ending protruding into the central canal and a laterally projecting process that ramifies only at the lateral edge. These cells show immunoreactivity to taurine, but they do not express GABA or somatostatin, nor do they have any active neuronal properties. Type 2 cells might be a form of glia. Type 1 CSF-c cells are neurons and may play a modulatory role by influencing edge cells and thus the locomotor-related sensory feedback.


Genetic aberrations in multiple myeloma characterized by cIg-FISH: a Brazilian context.
Genetic abnormalities are critical prognostic factors for patients diagnosed with multiple myeloma (MM). This retrospective, multicenter study aimed to contribute with the genetic and clinical characterization of MM patients in a country with continental dimensions such as Brazil. Genetic abnormalities were assessed by cIg-fluorescent in situ hybridization (cIg-FISH) in a series of 152 MM patients (median age 55 years, 58.5% men). Overall, genetic abnormalities were detected in 52.7% (80/152) of patients. A 14q32 rearrangement was detected in 33.5% (n=51), including t(11;14), t(4;14) and t(14;16) in 18.4, 14.1, and 1% of cases, respectively. del(13q) was identified in 42.7% (n=65) of patients, of whom 49.2% (32/65) presented a concomitant 14q32 rearrangement. del(17p) had a frequency of 5.2% (n=8). del(13q) was associated with high plasma cell burden (≥50%, P=0.02), and del(17p) with advanced ISS stages (P=0.05) and extramedullary disease (P=0.03). t(4;14) was associated with advanced Durie-Salmon stages (P=0.008), renal insufficiency (P=0.01) and was more common in patients over 60 years old. This study reports similar frequencies of genetic abnormalities to most series worldwide, whereas the t(14;16) and del(17p), two high risk factors for newly diagnosed patients, exhibited lower frequencies. Our results expand the knowledge on the molecular features of MM in Brazil, a country where innovative therapies that could overcome a poor prognosis for some genetic abnormalities are not always available.


GroupRegNet: a groupwise one-shot deep learning-based 4D image registration method.
Accurate deformable four-dimensional (4D) (three-dimensional in space and time) medical images registration is essential in a variety of medical applications. Deep learning-based methods have recently gained popularity in this area for the significantly lower inference time. However, they suffer from drawbacks of non-optimal accuracy and the requirement of a large amount of training data. A new method named GroupRegNet is proposed to address both limitations. The deformation fields to warp all images in the group into a common template is obtained through one-shot learning. The use of the implicit template reduces bias and accumulated error associated with the specified reference image. The one-shot learning strategy is similar to the conventional iterative optimization method but the motion model and parameters are replaced with a convolutional neural network and the weights of the network. GroupRegNet also features a simpler network design and a more straightforward registration process, which eliminates the need to break up the input image into patches. The proposed method was quantitatively evaluated on two public respiratory-binned 4D-computed tomography datasets. The results suggest that GroupRegNet outperforms the latest published deep learning-based methods and is comparable to the top conventional method pTVreg. To facilitate future research, the source code is available at https://github.com/vincentme/GroupRegNet.


A rights-based approach to sexuality education: conceptualization, clarification and challenges.
Although a rights-based approach to sexuality education has been increasingly discussed in the past decade, documented consensus regarding the goals, concepts and underlying assumptions of this approach is lacking. Differences in the assumed meaning of a rights-based approach can limit discussions of its implementation and evaluation, and impede opportunities to explore and critique a new model for sexuality education. In-depth interviews were conducted in 2012 with 21 U.S. and international sexuality education experts. Data were thematically coded and analyzed using an iterative approach. Responses were compared according to respondents' professional discipline and geographic focus. A rights-based approach can be defined as the intersection of four elements: an underlying principle that youth have sexual rights; an expansion of programmatic goals beyond reducing unintended pregnancy and STDs; a broadening of curricula content to include such issues as gender norms, sexual orientation, sexual expression and pleasure, violence, and individual rights and responsibilities in relationships; and a participatory teaching strategy that engages youth in critical thinking about their sexuality and sexual choices. These elements were consistently identified by respondents across professional disciplines and geographic foci. In addition, all respondents raised questions about the feasibility of implementing a rights-based approach, particularly in the United States. While questions remain to be answered regarding the implementation and impact of rights-based sexuality education, the proposed conceptual definition suggests multiple avenues for advocates, researchers, program developers and funders to enhance adolescent sexual health.


[Immunity in children with acquired scarred stenosis of the larynx and cervical trachea].
Humoral immunity was studied in 63 children with acquired laryngotracheal stenosis 1 year 9 months to 14 years 8 months of age. The study discovered humoral immunity dysfunction which was most pronounced in patients who developed scary stenosis after critical care for acute stenotic laryngotracheobronchitis. It was found that if a child has allergy (atopy) in conduction of critical care requiring long-term nasotracheal intubation, he/she is at risk to develop scary stenosis.


Replacement of the positively charged Walker A lysine residue with a hydrophobic leucine residue and conformational alterations caused by this mutation in MRP1 impair ATP binding and hydrolysis.
MRP1 (multidrug resistance protein 1) couples ATP binding/hydrolysis at its two non-equivalent NBDs (nucleotide-binding domains) with solute transport. Some of the NBD1 mutants, such as W653C, decreased affinity for ATP at the mutated site, but increased the rate of ATP-dependent solute transport. In contrast, other NBD1 mutants, such as K684L, had decreased ATP binding and rate of solute transport. We now report that mutations of the Walker A lysine residue, K684L and K1333L, significantly alter the tertiary structure of the protein. Due to elimination of the positively charged group and conformational alterations, the K684L mutation greatly decreases the affinity for ATP at the mutated NBD1 and affects ATP binding at the unmutated NBD2. Although K684L-mutated NBD1 can bind ATP at higher concentrations, the bound nucleotide at that site is not efficiently hydrolysed. All these alterations result in decreased ATP-dependent solute transport to approx. 40% of the wild-type. In contrast, the K1333L mutation affects ATP binding and hydrolysis at the mutated NBD2 only, leading to decreased ATP-dependent solute transport to approx. 11% of the wild-type. Consistent with their relative transport activities, the amount of vincristine accumulated in cells is in the order of K1333L> or =CFTR (cystic fibrosis transmembrane conductance regulator)>K684L>>>wild-type MRP1. Although these mutants retain partial solute transport activities, the cells expressing them are not multidrug-resistant owing to inefficient export of the anticancer drugs by these mutants. This indicates that even partial inhibition of transport activity of MRP1 can reverse the multidrug resistance caused by this drug transporter.


Exploring the role of cyclodextrins as a cholesterol scavenger: a molecular dynamics investigation of conformational changes and thermodynamics.
This study presents a comprehensive analysis of the cholesterol binding mechanism and conformational changes in cyclodextrin (CD) carriers, namely βCD, 2HPβCD, and MβCD. The results revealed that the binding of cholesterol to CDs was spontaneous and thermodynamically favorable, with van der Waals interactions playing a dominant role, while Coulombic interactions have a negligible contribution. The solubility of cholesterol/βCD and cholesterol/MβCD complexes was lower compared to cholesterol/2HPβCD complex due to stronger vdW and Coulombic repulsion between water and CDs. Hydrogen bonding was found to have a minor role in the binding process. The investigation of mechanisms and kinetics of binding demonstrated that cholesterol permeates into the CD cavities completely. Replicas consideration indicated that while the binding to 2HPβCD occurred perpendicularly and solely through positioning cholesterol's oxygen toward the primary hydroxyl rim (PHR), the mechanism of cholesterol binding to βCD and MβCD could take place with the orientation of oxygen towards both rims. Functionalization resulted in decreased cavity polarity, increased constriction tendency, and altered solubility and configuration of the carrier. Upon cholesterol binding, the CDs expanded, increasing the cavity volume in cholesterol-containing systems. The effects of cholesterol on the relative shape anisotropy (κ2) and asphericity parameter (b) in cyclodextrins were investigated. βCD exhibited a spherical structure regardless of cholesterol presence, while 2HPβCD and MβCD displayed more pronounced non-sphericity in the absence of cholesterol. Loading cholesterol transformed 2HPβCD and MβCD into more spherical shapes, with increased probabilities of higher κ2. MβCD showed a higher maximum peak of κ2 compared to 2HPβCD after cholesterol loading, while 2HPβCD maintained a significant maximum peak at 0.2 for b.


[Image distortions occurring on intraoral dental x-rays and the ways to overcome them].
Typical errors occurring in roentgenography of the teeth were simulated in a series of experiments. The results evidence that erroneous centering and angle of the x-ray tube inclination, incorrect centering of the film lead to disproportionate distortion of the shape, size, and position of all anatomical elements, that make the results of x-ray examination unreliable. Standardization of methods of intraoral roentgenography implies strict adherence to the rules of roentgenogram recording and treatment; this will permit obtaining high-quality roentgenograms and reduce the x-ray load of the patients.


Social and emotional adjustment following early pregnancy in young Australian women: a comparison of those who terminate, miscarry, or complete pregnancy.
To compare social and emotional adjustment including educational attainment and substance use in women who had a child, pregnancy termination, or miscarriage by young adulthood. Data were from a population-based longitudinal study of the health and well-being of 1,943 young Australians (Victorian Adolescent Health Cohort Study) followed from 15 to 24 years of age. The sample was restricted to female participants and based on pregnancies reported by age 24 years. Analyses were adjusted for early teenage depressive symptoms, cigarette smoking, alcohol use, cannabis use, and parent socioeconomic context. A total of 208 pregnancies (in 170 women) were reported from a sample of 824 young women by 24 years of age. Compared with those who had never been pregnant, those who had a child had lower tertiary education completion and a higher risk of nicotine dependence; those who terminated a pregnancy were more commonly single and had a higher risk of smoking and alcohol use as well as nicotine and alcohol dependence; and those who had a miscarriage had a higher risk of depressive symptomatology and binge drinking as well as nicotine and cannabis dependence. Young women who have been pregnant by their mid-twenties report a range of difficulties in social and emotional adjustment that vary across the different pregnancy outcomes. Broad-based psychosocial health care is essential not only for young women whose pregnancies proceed to live birth, but also for those whose pregnancies end with miscarriage or induced abortion.


[Current epidemiological evidence regarding the health effects of low-dose ionizing radiation. Implications for radiation protection, public health and forensic medicine].
The health effects of low-dose ionizing radiation have been widely studied, but remain uncertain. Up-to-date knowledge about epidemiologic evidence for potential human health effects of low dose ionizing radiation is important for revising national radiation protection legislation. This review, conducted by a multidisciplinary research team of the Italian Institute of Social Medicine, evaluates epidemiologic studies published since July 2003. After careful selection, a total of 302 studies were reviewed. Greater emphasis was given to papers that analyzed data using standardized incidence and mortality ratios and to studies regarding occupational exposures in all workers, healthcare workers and aircrew members. Nevertheless, studies regarding A-bomb survivors of Hiroshima/Nagasaki, Chernobyl cleanup workers, patients exposed for medical reasons, and workers in nuclear plants were also included. Given the limitations of epidemiological studies and excluding the cosmic rays context, which requires further research, the authors conclude that harmful effects from exposures to ionizing radiation at doses lower than 100 mSv cannot be ruled out. Nevertheless, if any harmful health effects do exist, they are certainly very small. The implications for radiation protection, public health and forensic medicine are discussed.


Transcript profiles in cortical cells of maize primary root during ethylene-induced lysigenous aerenchyma formation under aerobic conditions.
Internal aeration is important for plants to survive during periods of waterlogging, and the ability to form aerenchyma contributes by creating a continuous gas space between the shoots and the roots. Roots of maize (Zea mays) react to prolonged waterlogging by forming aerenchyma in root cortical cells by programmed cell death (PCD) in response to ethylene. The aim of this study was to understand the molecular mechanisms of ethylene-induced aerenchyma formation by identifying genes that are either up- or downregulated by ethylene treatment in maize root cortical cells. Three-day-old maize seedlings were treated with ethylene for several hours under aerobic conditions. Cortical cells were isolated from the primary roots using laser microdissection (LM), and transcript profiles with and without ethylene treatment were compared by microarray. In addition, the effect on ethylene-induced aerenchyma formation of diphenyleneiodonium (DPI), an inhibitor of NADPH oxidases, was examined in order to assess the involvement of reactive oxygen species (ROS). A total of 223 genes were identified whose transcript levels were significantly increased or decreased by ethylene treatment in root cortical cells under aerobic conditions. Subsequent tissue-specific quantitative reverse-transcription PCR analyses revealed that ethylene increased the transcript levels of genes related to ethylene signalling in all of the root tissues examined (stelar cells, cortical cells and outer cell layers), whereas it increased the transcript levels of genes related to cell wall modification and proteolysis specifically in the cortical cells. DPI treatment inhibited the ethylene-induced aerenchyma formation and suppressed expression of some cell wall modification-related genes. Several genes related to cell wall modification and proteolysis are specifically up- or downregulated in cortical cells during lysigenous aerenchyma formation under aerobic conditions with ethylene treatment. The results suggest that ethylene is perceived in stelar cells, cortical cells and outer cell layers in the maize primary root, and that the cortical cell-specific PCD is controlled downstream of ethylene perception through subsequent gene expression, which is partly regulated by ROS, in the cortical cells.


How does the past of a soccer match influence its future? Concepts and statistical analysis.
Scoring goals in a soccer match can be interpreted as a stochastic process. In the most simple description of a soccer match one assumes that scoring goals follows from independent rate processes of both teams. This would imply simple Poissonian and Markovian behavior. Deviations from this behavior would imply that the previous course of the match has an impact on the present match behavior. Here a general framework for the identification of deviations from this behavior is presented. For this endeavor it is essential to formulate an a priori estimate of the expected number of goals per team in a specific match. This can be done based on our previous work on the estimation of team strengths. Furthermore, the well-known general increase of the number of the goals in the course of a soccer match has to be removed by appropriate normalization. In general, three different types of deviations from a simple rate process can exist. First, the goal rate may depend on the exact time of the previous goals. Second, it may be influenced by the time passed since the previous goal and, third, it may reflect the present score. We show that the Poissonian scenario is fulfilled quite well for the German Bundesliga. However, a detailed analysis reveals significant deviations for the second and third aspect. Dramatic effects are observed if the away team leads by one or two goals in the final part of the match. This analysis allows one to identify generic features about soccer matches and to learn about the hidden complexities behind scoring goals. Among others the reason for the fact that the number of draws is larger than statistically expected can be identified.


The effect of black coffee on fasting metabolic markers and an abbreviated fat tolerance test.
Coffee is typically prohibited prior to metabolic assessment in clinical and research settings. However, whether coffee meaningfully alters fasted metabolic testing or the results of a fat tolerance test is unclear. We investigated whether allowing black coffee intake within a fast prior to blood work affected fasting triglycerides (TG) and glucose, as well as the postprandial lipemic and glycemic response following an abbreviated fat tolerance test (AFTT). Participants completed two randomized AFTTs separated by at least 1 week. For each AFTT, participants arrived into the laboratory following a 10 h overnight fast and consumed either 8 oz of water or black coffee. Thirty minutes later, a baseline blood draw was collected. Immediately following, participants consumed a standardized high-fat shake (70% fat; 9 kcal/kg body mass), vacated the laboratory, and returned 4 h later for a follow-up blood draw. Ten healthy individuals (5M, 5F; age: 22.9 ± 3.8 years; BMI: 24.3 ± 2.6 kg/m2) completed the study. There was no difference between trials with regard to baseline TG (MD = 1.7 mg/dL; p = 0.74), 4 h TG (MD = 2.7 mg/dL; p = 0.75), Δ TG (MD = 4.4 mg/dL; p = 0.52), or % change TG (MD = 7.7%; p = 0.99). Similarly, following coffee consumption, baseline glucose was unchanged relative to water (MD = 0.4 mg/dL; p = 0.84) and there were no differences in postprandial glucose measures, including 4 h (MD = 0.9 mg/dL; p = 0.58), Δ (MD = 1.3 mg/dL; p = 0.31), and % change in glucose (MD = 1.6%; p = 0.29). In our small study sample, coffee intake prior to an AFTT did not affect baseline or postprandial TG and glucose. Therefore, coffee intake prior to an AFTT may not affect its validity.


Role of phosphodiesterase 5 in synaptic plasticity and memory.
Phosphodiesterases (PDEs) are enzymes that break down the phosphodiesteric bond of the cyclic nucleotides, cAMP and cGMP, second messengers that regulate many biological processes. PDEs participate in the regulation of signal transduction by means of a fine regulation of cyclic nucleotides so that the response to cell stimuli is both specific and activates the correct third messengers. Several PDE inhibitors have been developed and used as therapeutic agents because they increase cyclic nucleotide levels by blocking the PDE function. In particular, sildenafil, an inhibitor of PDE5, has been mainly used in the treatment of erectile dysfunction but is now also utilized against pulmonary hypertension. This review examines the physiological role of PDE5 in synaptic plasticity and memory and the use of PDE5 inhibitors as possible therapeutic agents against disorders of the central nervous system (CNS).


Ganoderma lucidum: a potent pharmacological macrofungus.
Ganoderma lucidum (Ling Zhi) is a basidiomycete white rot macrofungus which has been used extensively as "the mushroom of immortality" in China, Japan, Korea and other Asian countries for 2000 years. A great deal of work has been carried out on therapeutic potential of Ganoderma lucidum. The basidiocarp, mycelia and spores of Ganoderma lucidum contain approximately 400 different bioactive compounds, which mainly include triterpenoids, polysaccharides, nucleotides, sterols, steroids, fatty acids, proteins/peptides and trace elements which has been reported to have a number of pharmacological effects including immunomodulation, anti-atherosclerotic, anti-inflammatory, analgesic, chemo-preventive, antitumor, chemo and radio protective, sleep promoting, antibacterial, antiviral (including anti-HIV), hypolipidemic, anti-fibrotic, hepatoprotective, anti-diabetic, anti-androgenic, anti-angiogenic, anti-herpetic, antioxidative and radical-scavenging, anti-aging, hypoglycemic, estrogenic activity and anti-ulcer properties. Ganoderma lucidum has now become recognized as an alternative adjuvant in the treatment of leukemia, carcinoma, hepatitis and diabetes. The macrofungus is very rare in nature rather not sufficient for commercial exploitation for vital therapeutic emergencies, therefore, the cultivation on solid substrates, stationary liquid medium or by submerged cultivation has become an essential aspect to meet the driving force towards the increasing demands in the international market. Present review focuses on the pharmacological aspects, cultivation methods and bioactive metabolites playing a significant role in various therapeutic applications.


DDX3 Activates CBC-eIF3-Mediated Translation of uORF-Containing Oncogenic mRNAs to Promote Metastasis in HNSCC.
Mutated or dysregulated DDX3 participates in the progression and metastasis of cancer via its multiple roles in regulating gene expression and cellular signaling. Here, we show that the high expression levels of DDX3 in head and neck squamous cell carcinoma (HNSCC) correlate with lymph node metastasis and poor prognosis and demonstrate that DDX3 is essential for the proliferation, invasion, and metastasis of oral squamous cell carcinoma (OSCC) cells. Microarray analyses revealed that DDX3 is required for the expression of a set of pro-metastatic genes, including ATF4-modulated genes in an aggressive OSCC cell line. DDX3 activated translation of ATF4 and a set of its downstream targets, all of which contain upstream open reading frames (uORF). DDX3 promoted translation of these targets, likely by skipping the inhibitory uORF. DDX3 specifically enhanced the association of the cap-binding complex (CBC) with uORF-containing mRNAs and facilitated recruitment of the eukaryotic initiation factor 3 (eIF3). CBC and certain eIF3 subunits contributed to the expression of metastatic-related gene expression. Taken together, our results indicate a role for the novel DDX3-CBC-eIF3 translational complex in promoting metastasis.Significance: The discovery of DDX3-mediated expression of oncogenic uORF-containing genes expands knowledge on translational control mechanisms and provides potential targets for cancer therapy.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4512/F1.large.jpg Cancer Res; 78(16); 4512-23. ©2018 AACR.


[The conditioned avoidance reflex and intersignal movements: the correlation of the cardiac and motor components].
In five dogs correlation was studied of heart rate (HR) and motor component of conditioned avoidance reflex (CAR), elaborated by Petropavlovskiĭ method. Stable CAR was expressed in lifting and long (not less than 5-10 sec) holding of the paw on definite height (5-10 cm) for the avoidance of painful electrocutaneous paw stimulation in response to conditioned acoustic stimulus. The level of defensive excitation, evaluated by heart rate change was maximum before the beginning of the conditioned motor reaction. Immediately after lifting and placing the paw in the zone of security a sharp decrease of defensive excitation level ("drive" reduction) took place. Intertrial motor reactions of two types were revealed. The first type imitated the conditioned motor reaction, the second one the usual phasic bending of the paw. Against the background of intertrial movement of the first, operant type a decrease of defensive motivation took similarity as it occurred against the background of CAR during the performance response.


Benefits and Costs of Happy Entrepreneurs: The Dual Effect of Entrepreneurial Identity on Entrepreneurs' Subjective Well-Being.
Entrepreneurship research generally focuses more on the entrepreneurial outcomes of entrepreneurs and less on their entrepreneurial process. To a certain extent, well-being reflects how tired entrepreneurs are during entrepreneurship. Based on conservation of resources theory, this study proposes a double-edged sword model of the effect of entrepreneurial identity on subjective well-being, using the two-dimensional structure of work rumination as a mediator. This study also concentrates on the moderating role of entrepreneurial mindfulness. Multiple hierarchical regression methods are used to analyze and test 882 valid samples. Results suggest that the effect of entrepreneurial identity produces distinctly different outcomes. On the one hand, entrepreneurial identity induces entrepreneurs' work-related affective rumination to reduce their subjective well-being through the path of resource depletion. On the other hand, entrepreneurial identity stimulates entrepreneurs' contemplation on work-related problem-solving pondering to enhance their subjective well-being through the path of resource acquisition. In the path of resource depletion, work-related affective rumination produces a "suppressing effect" between an entrepreneur's identity and entrepreneurial subjective well-being. In addition, entrepreneurial mindfulness weakens the resource depletion path. Entrepreneurial mindfulness negatively moderates the relationship between entrepreneurial identity and work-related affective rumination. Entrepreneurial mindfulness also does not strengthen the resource acquisition path. Mindfulness does not positively moderate the relationship between entrepreneurial identity and work-related problem-solving pondering. The findings further extend the research on the influence of entrepreneurial identity on subjective well-being. They also reveal the mechanisms and boundary conditions of the effect of entrepreneurial identity on subjective well-being.


Anaphylactic shock during elimination diets for severe atopic eczema.
Eighty patients with atopic eczema were treated with various elimination diets. Some or all foods were withdrawn then later reintroduced singly to the diet. In four patients reintroduction of a single food (soya, chicken, corn, cows' milk) caused anaphylactic shock. In two patients spontaneous recovery occurred but in two resuscitation and intensive care were required. Anaphylaxis is a definite hazard of these elimination diets. Other than warning the parents, practical precautions are difficult because of the unpredictability of violent reactions and uncertainty about the life saving efficacy of injected adrenaline.


Optical disk technology and information.
The optical video disk, spawned by the home entertainment industry, and its counterpart, the optical digital disk, both hold great promise for information storage and retrieval and the scientific enterprise. Optical digital disks for computer mass storage are currently under development by many firms. In addition, efforts are under way to allow encoding of digital information on video disks. This is desirable as an inexpensive publication medium for machine-readable data as well as a means of obtaining both video and digital information on one disk. Potential applications of this technology include inexpensive on-line storage, random access graphics to complement on-line information systems, hybrid network architectures, office automation systems, and archival storage.


Neurophysiological Response Based on Auditory Sense for Brain Modulation Using Monaural Beat.
Brain modulation is a modification process of brain activity through external stimulations. However, which condition can induce the activation is still unclear. Therefore, we aimed to identify brain activation conditions using 40 Hz monaural beat (MB). Under this stimulation, auditory sense status which is determined by frequency and power range is the condition to consider. Hence, we designed five sessions to compare; no stimulation, audible (AB), inaudible in frequency, inaudible in power, and inaudible in frequency and power. Ten healthy participants underwent each stimulation session for ten minutes with electroencephalogram (EEG) recording. For analysis, we calculated the power spectral density (PSD) of EEG for each session and compared them in frequency, time, and five brain regions. As a result, we observed the prominent power peak at 40 Hz in only AB. The induced EEG amplitude increase started at one minute and increased until the end of the session. These results of AB had significant differences in frontal, central, temporal, parietal, and occipital regions compared to other stimulations. From the statistical analysis, the PSD of the right temporal region was significantly higher than the left. We figure out the role that the auditory sense is important to lead brain activation. These findings help to understand the neurophysiological principle and effects of auditory stimulation.


Analysis of differential survival of syngeneic islets transplanted into hyperglycemic C57BL/6J versus C57BL/KsJ mice.
C57BL/KsJ (BKs) male mice were more sensitive to diabetes induction by administration of multiple low-doses of streptozotocin (Sz) than were C57BL/6J (B6) male mice. Analysis of islet size and insulin content of the two parental strains did not indicate that differences in drug sensitivity could be attributed to an effect of genetic background on islet size or insulin content. 50 BKs islets implanted into the spleens of BKs male mice made diabetic by Sz were eliminated within 12 days posttransplantation, whereas an equal number of B6 islets implanted into the spleens of diabetic B6 recipients were retained, even though the numbers of islets implanted were insufficient to effect remission from hyperglycemia. In contrast to the rapid loss of islets implanted into spleens of hyperglycemic BKs recipients, BKs islets implanted into spleens of normoglycemic recipients were not eliminated, thus suggesting that the basis for the differential survival between the B6 and BKs strains reflected their ability to survive hyperglycemic stress rather than a differential ability to replicate. Since BKs beta cells have been shown to respond to hyperglycemia by expression of an endogenous retroviral gene that cannot be expressed by B6 beta cells, the possibility that this differential survival represents a strain difference in autoreactivity against islet cells is raised.


Impaired vitreous composition and retinal pigment epithelium function in the FoxG1::LRP2 myopic mice.
High myopia (HM) is one of the main causes of visual impairment and blindness all over the world and an unsolved medical problem. Persons with HM are predisposed to other eye pathologies such as retinal detachment, myopic retinopathy or glaucomatous optic neuropathy, complications that may at least partly result from the extensive liquefaction of the myopic vitreous gel. To identify the involvement of the liquid vitreous in the pathogenesis of HM we here analyzed the vitreous of the recently described highly myopic low density lipoprotein receptor-related protein 2 (Lrp2)-deficient eyes. Whereas the gel-like fraction was not apparently modified, the volume of the liquid vitreous fraction (LVF) was much higher in the myopic eyes. Biochemical and proteome analysis of the LVF revealed several modifications including a marked decrease of potassium, sodium and chloride, of proteins involved in ocular tissue homeostasis and repair as well as of ADP-ribosylation factor 4 (ARF4), a protein possibly involved in LRP2 trafficking. A small number of proteins, mainly comprising known LRP2 ligands or proteins of the inflammatory response, were over expressed in the mutants. Moreover the morphology of the LRP2-deficient retinal pigment epithelium (RPE) cells was affected and the expression of ARF4 as well as of proteins involved in degradative endocytosis was strongly reduced. Our results support the idea that impairment of the RPE structure and most likely endocytic function may contribute to the vitreal modifications and pathogenesis of HM.