[Features of cytogenetic changes in the human lymphoma U-937 cells after induction of apoptosis by tumor necrosis factor].
A comparative analysis of the frequency of cytogenetic abnormalities in cell population U-937 in control conditions and after exposure to tumor necrosis factor has been performed. We have found that in such treatment there is a maximum effect after 48 h, which is expressed in the stimulation of apoptosis and the accumulation of cells with micronuclei and binuclear cells. The induction of premature chromosome condensation is an early marker of the TNF influence. Changing the composition of the population by the number of chromosomes in the cell may lead to the emergence of a subline with new properties compared to the parental cell population.


The relation of early positive emotional memories to women's social safeness: The role of shame and fear of receiving compassion.
Early affiliative experiences play an important role in social and emotional development. Several authors have suggested that early positive experiences may be recorded as memories of warmth and soothing. However, the relationship between such memories and current feelings of social safeness and connectedness remains scarcely studied. The current study examined the association between recall of early positive affiliative experiences (with family and peers) and women's social safeness. External shame and fear of others' compassion were hypothesized to be mediators in these associations. The sample was recruited from October 2016 to February 2016 and included 400 women from the Portuguese population, aged between 18 and 55 years. The path model explained 52% of the variance of social safeness. Early positive affiliative memories (with family and peers) were associated with a lower tendency to fear receiving others' compassion and to feel ashamed, which seemed to be associated with an increased sense of social safeness. These findings offer pertinent insights for future studies in and interventions for women´s well-being and mental health by highlighting the importance of addressing shame and fears of compassion when working with women who tend to perceive their social world as unsafe and others' compassion as threatening.


[Treatment of HIV-1 infected pregnant women].
Since 1 January 2004, pregnant women in the Netherlands have been universally screened for HIV infection. Three HIV-infected, pregnant women aged 28, 24 and 33 years respectively, illustrate some of the problems that may be encountered in this situation, as well as the treatment options available to prevent the transmission of HIV from mother to child. The first patient had a positive antibody test early in pregnancy for which she did not need treatment, the second had a positive antibody test late in pregnancy and the third was seropositive and on medication, but had the wish to become pregnant. A vaginal delivery is possible when highly active antiretroviral therapy (HAART) of the mother is started in good time and the plasma HIV-RNA is < 400 copies/ml at the time of delivery. In this situation the risk of transmission is reduced to around 1%. However, if HIV infection is diagnosed late in pregnancy or, despite HAART, the plasma HIV-RNA is not expected to be < 400 copies/ml, an elective caesarean section is scheduled at 38 weeks of pregnancy. In all instances the neonate is treated for 28 days with antiretrovirals, as post-exposure prophylaxis. If a woman with a known HIV infection wants to become pregnant, the choice of antiretroviral regimen and when this is started is determined by her treatment history and the potential toxic effects of the medication on the foetus.


Studies on the lysosomal enzyme system of the liver in rats undergoing swimming training.
Lysosomal acid phosphatase, beta-glucuronidase, and cathepsin-D were studied in liver cell fractions of rats regularly exercised by swimming. On the 21st day of the training, enzyme activities in the extralysosomal fraction and in the lysosomal fraction were higher and lower, respectively, than in the untrained controls. On the 40th day an increased enzyme activity was found in both fractions. By the end of the training period (54th and 80th days), a slightly decreased activity was recorded in both fractions. Lysosomal membrane permeability for enzymes was higher during the first period of the training, in particular when estimated under hypotonic conditions. Regular swimming training or 12-day treatment by ACTH stabilized the membrane of the liver lysosomes. This stabilization was believed to be mediated by corticosteroids mobilized by exercise or by the administration of ACTH.


The engagement of new residents: a missing dimension in the evaluation of halfway houses for problem drinkers.
Residents (N = 29) and staff of a halfway house for problem drinkers in England were studied over 6 months to determine the cause of premature departure. Each new resident was interviewed in depth every week during his first 8 weeks in the house (or until he left if that occurred sooner), and the staff members were also interviewed weekly over the complete 6 months. The significant findings centered on two areas: staff's attitudes toward residents and residents' satisfaction with the house. The staff judged residents who subsequently left prematurely less positively overall, liked them less and spent less time with them. Residents who subsequently left prematurely were more dissatisfied with the lack of privacy, saw life as being better outside, judged the staff more negatively and felt generally that their expectations about the house had not been matched. The implications of these findings are discussed in terms of the notions of "sudden disappearances" from halfway houses, and of engagement of new residents. Conclusions about levels of staff training and support, and the "matching hypothesis are made.


ENTEROTOXIGENIC ESCHERICHIA COLI O169:HUT FROM A DIARRHEAL PATIENT: PHYLOGENETIC GROUP AND ANTIMICROBIAL SUSCEPTIBILITY.
Enterotoxigenic Escherichia coli (ETEC) is one of the most common pathogenic E. coli pathotypes causing diarrhea in children worldwide. Its enterotoxins, LT and ST, including colonization factors mainly are responsible for human pathogenesis. From 239 rectal swabs of diarrheal patients at Hat Yai and Pattani Hospitals during August 2013 and May 2014, five isolates from only a single E. coli sample demonstrated the possession of estA1, encoding porcine heat-stable enterotoxin (STp). These isolates all belonged to serotype 0169:H Untypeable (HUT) and carried astA, encoding enteroaggregative heat-stable enterotoxin 1. A PCR-based phylogenetic group investigation classified them as members of the virulent E. coli phylogenetic group D. The isolates were resistant to cephalothin, penicillin G, streptomycin, tetracycline and vancomycin. Confirmation of their clonality was conducted by enterobacterial repetitive intergenic consensus sequence PCR typing, which revealed that these ETEC were derived from the same clone. This is the first report of ETEC O169:HUT in southern Thailand.


Chronic inhalation of rotenone or paraquat does not induce Parkinson's disease symptoms in mice or rats.
Epidemiological studies suggest that some pesticides might constitute a risk factor for Parkinson's disease (PD). However, risk assessment cannot be performed in the current experimental animal models because they use non-natural pathways of pesticide exposure, such as intraperitoneal or intravenous injection, that might bypass body defences. A new model based on daily inoculation of neurotoxins in the nasal cavity of C57BL/6 mice for 30 days was used to evaluate risk of three complex I inhibitors, 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP), rotenone and paraquat. These compounds displayed very different effects on motor activity, striatal dopamine and dihydroxyphenylacetic acid (DOPAC) levels and loss of dopaminergic neurons. MPTP-treated mice developed motor deficits that correlated with a severe depletion of striatal dopamine levels, and loss of tyrosine hydroxylase staining in substantia nigra and striatum. By contrast, rotenone-treated mice or rats were asymptomatic. Paraquat induced severe hypokinesia and vestibular damage but did not alter the nigrostriatal system. The new animal model described here, based on chronic intranasal inoculation of neurotoxicants, provides a new tool to assess the potential danger of environmental toxins as risk factors for development of PD.


[Mnemonics are useful memory tools in modern medicine].
Mnemonics are useful memory tools in medical school and during clinical work. They serve to learn, consolidate or recall information. Different types of mnemonics exist. The most commonly used are acronyms or alphabetical types (e.g. RICE in case of soft tissue injury or ABC in acute situations), though other types such as visual mnemonics or the method of loci are possibly more effective. Memory techniques work because they apply other routes to remembering than traditional learning. They often link information to well-known knowledge and sometimes they appeal to humour or feelings.


Network meta-analysis of diagnostic test accuracy studies identifies and ranks the optimal diagnostic tests and thresholds for health care policy and decision-making.
Network meta-analyses (NMA) have extensively been used to compare the effectiveness of multiple interventions for health care policy and decision-making. However, methods for evaluating the performance of multiple diagnostic tests are less established. In a decision-making context, we are often interested in comparing and ranking the performance of multiple diagnostic tests, at varying levels of test thresholds, in one simultaneous analysis. Motivated by an example of cognitive impairment diagnosis following stroke, we synthesized data from 13 studies assessing the efficiency of two diagnostic tests: Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA), at two test thresholds: MMSE <25/30 and <27/30, and MoCA <22/30 and <26/30. Using Markov chain Monte Carlo (MCMC) methods, we fitted a bivariate network meta-analysis model incorporating constraints on increasing test threshold, and accounting for the correlations between multiple test accuracy measures from the same study. We developed and successfully fitted a model comparing multiple tests/threshold combinations while imposing threshold constraints. Using this model, we found that MoCA at threshold <26/30 appeared to have the best true positive rate, whereas MMSE at threshold <25/30 appeared to have the best true negative rate. The combined analysis of multiple tests at multiple thresholds allowed for more rigorous comparisons between competing diagnostics tests for decision making.


Induction of Rev-ErbA alpha, an orphan receptor encoded on the opposite strand of the alpha-thyroid hormone receptor gene, during adipocyte differentiation.
Rev-ErbA alpha (Rev-Erb) is a nuclear hormone receptor-related transcriptional activator that is encoded on the noncoding strand of the alpha-thyroid hormone receptor (TR) gene. The similarities between Rev-Erb and receptors for differentiating agents, as well as the abundance of Rev-Erb mRNA in fat, led us to study Rev-Erb gene expression during adipogenesis. Remarkably, Rev-Erb mRNA levels increased dramatically during the differentiation of 3T3-L1 cells into adipocytes. Rev-Erb was similarly induced in the related 3T3-F442A cell line but not in nondifferentiating 3T3-C2 cells. The time course of Rev-Erb induction was similar to that of C/EBP alpha, an important transcriptional regulator in adipocytes, and Rev-Erb mRNA was superinduced by cycloheximide. Nuclear run-on assays indicated that an increased rate of Rev-Erb mRNA synthesis accounted for the increased steady state mRNA levels; the half-life of Rev-Erb mRNA was indistinguishable in preadipocytes and adipocytes. Treatment of preadipocytes with retinoic acid inhibited adipocyte differentiation and also prevented Rev-Erb induction. Thus, there is a correlation between Rev-Erb gene expression and differentiation, and transcriptional regulation by Rev-Erb could play an important role in the generation and/or maintenance of the adipocyte phenotype. Interestingly, and possibly related to the overlap between the Rev-Erb gene and the exon specific for TR alpha 2, the induction of Rev-Erb was also associated with a 3-fold increase in the ratio of TR alpha 1 to TR alpha 2 mRNA levels, indicating that Rev-Erb expression has the potential to modulate adipocyte gene expression by multiple mechanisms.


Characterization of recombinant skeletal muscle (Ser-2843) and cardiac muscle (Ser-2809) ryanodine receptor phosphorylation mutants.
Phosphorylation of the skeletal muscle (RyR1) and cardiac muscle (RyR2) ryanodine receptors has been reported to modulate channel activity. Abnormally high phosphorylation levels (hyperphosphorylation) at Ser-2843 in RyR1 and Ser-2809 in RyR2 and dissociation of FK506-binding proteins from the receptors have been implicated as one of the causes of altered calcium homeostasis observed during human heart failure. Using site-directed mutagenesis, we prepared recombinant RyR1 and RyR2 mutant receptors mimicking constitutively phosphorylated and dephosphorylated channels carrying a Ser/Asp (RyR1-S2843D and RyR2-S2809D) and Ser/Ala (RyR1-S2843A and RyR2-S2809A) substitution, respectively. Following transient expression in human embryonic kidney 293 cells, the effects of Ca2+, Mg2+, and ATP on channel function were determined using single channel and [3H]ryanodine binding measurements. In both assays, neither the skeletal nor cardiac mutants showed significant differences compared with wild type. Similarly essentially identical caffeine responses were observed in Ca2+ imaging measurements. Co-immunoprecipitation and Western blot analysis showed comparable binding of FK506-binding proteins to wild type and mutant receptors. Finally metabolic labeling experiments showed that the cardiac ryanodine receptor was phosphorylated at additional sites. Taken together, the results did not support the view that phosphorylation of a single site (RyR1-Ser-2843 and RyR2-Ser-2809) substantially changes RyR1 and RyR2 channel function.


Gadoxetic acid-enhanced magnetic resonance imaging: Hepatocellular carcinoma and mimickers.
Gadoxetic acid, a hepatocyte-specific magnetic resonance imaging (MRI) contrast agent, has emerged as an important tool for hepatocellular carcinoma (HCC) diagnosis. Gadoxetic acid-enhanced MRI is useful for the evaluation of earlystage HCC, diagnosis of HCC precursor lesions, and highly sensitive diagnosis of HCC. Furthermore, functional information provided by gadoxetic acid-enhanced MRI can aid in the characterization of focal liver lesions. For example, whereas lesions lack functioning hepatocytes appear hypointense in the hepatobiliary phase, preserved or enhanced expression of organic anion transporting polypeptides in some HCCs as well as focal nodular hyperplasia lead to hyperintensity in the hepatobiliary phase; and a targetoid appearance on transitional phase or hepatobiliary phase imaging can be helpful for identifying the histopathological composition of tumors. While gadoxetic acid-enhanced MRI may improve the sensitivity of HCC diagnosis and provide new insights into the characterization of focal liver lesions, there are many challenges associated with its use. This article reviews the pros and cons of HCC diagnosis with gadoxetic acid-enhanced MRI and discuss some clues in the radiological differentiation of HCC from HCC mimickers.


Inherent spatiotemporal uncertainty of renewable power in China.
Solar and wind resources are vital for the sustainable energy transition. Although renewable potentials have been widely assessed in existing literature, few studies have examined the statistical characteristics of the inherent renewable uncertainties arising from natural randomness, which is inevitable in stochastic-aware research and applications. Here we develop a rule-of-thumb statistical learning model for wind and solar power prediction and generate a year-long dataset of hourly prediction errors of 30 provinces in China. We reveal diversified spatiotemporal distribution patterns of prediction errors, indicating that over 60% of wind prediction errors and 50% of solar prediction errors arise from scenarios with high utilization rates. The first-order difference and peak ratio of generation series are two primary indicators explaining the uncertainty distribution. Additionally, we analyze the seasonal distributions of the provincial prediction errors that reveal a consistent law in China. Finally, policies including incentive improvements and interprovincial scheduling are suggested.


Ribosomal DNA polymorphisms reveal genetic structure and a phylogeographic pattern in the Burgundy truffle Tuber aestivum Vittad.
Ectomycorrhizal ascomycetes belonging to the genus Tuber produce edible fruiting bodies known as truffles. Tuber aestivum, in particular, is a fungus appreciated worldwide and has a natural distribution throughout Europe. Most of the molecular studies conducted on this species have been focused on the question as to whether or not T. aestivum and the morphologically similar T. uncinatum are conspecific. Conversely, only a handful of studies have assessed the level and distribution of genetic diversity and occurrence of phylogeographic patterns in this species. Here, we analyzed the genetic diversity of T. aestivum over a wide geographic range, performing an extensive sampling of specimens from Turkey, which is novel, to the best of our knowledge. We compared the internal transcribed spacer (ITS) profiles of 45 samples collected in different Turkish areas with those of 144 samples from all over Europe. We identified 63 haplotypes, 32 of which were exclusively present in Turkey. The majority of these haplotyes were also population specific. Haplotype network analysis and statistical tests highlighted the presence of a genetic structure and phylogeographic pattern, with three spatially distinct genetic clusters (northeastern Europe, southern Europe, and Turkey), with Turkey representing a diversity hotspot. Based on these results, we hypothesize the presence of glacial refugia for T. aestivum in Turkey, whereas European populations likely experienced a population bottleneck. The possible occurrence of cryptic species among Turkish T. aestivum samples also emerged. Our results are of practical relevance for the marketing of T. aestivum truffles and mycorrhizal seedlings and the preservation of the biodiversity of this species.


Dental evaluation is helpful in the differentiation of functional heartburn and gastroesophageal reflux disease.
Heartburn is identically the key symptom of both, gastroesophageal reflux disease (GERD) and functional heartburn (FHB), making the differential diagnosis resource-intensive. Oral manifestations of GERD can be easily examined; therefore, their exploration might be a cheap, widely available, and useful tool in the differentiation of GERD and FHB. To evaluate the prevalence of dental erosions (DE) and periodontal diseases (PD) in patients with heartburn and their association with GERD and FHB. A total of 116 [M/F: 51/65, mean age: 54 (17-80) years] consecutive patients with heartburn were enrolled for detailed esophageal function and orodental examinations. Dental disorders were detected in 89% (103/116). Patients with PD + DE had significantly more often pathologic reflux (90.0% vs 27.8%; P < 0.05), higher esophagitis scores (1.8 vs 0.9; P < 0.05), and a significantly different mean impedance curve (P = 0.04) than those without any dental diseases. The opposite approach established that patients with GERD had significantly higher prevalence of DE and PD, especially if both were present (28.9% vs 2.0%; P < 0.01), more severe PD (1.5 vs 1.0; P < 0.01), and longer history of heartburn (15 years vs 9 years; P < 0.01) than those with FHB. The dental evaluation of patients with heartburn seems to be useful in the differential diagnosis of GERD and FHB. Among the studied parameters, the co-appearance of DE and PD seems to be the best predictor of GERD, whereas the absence of dental disorders was mostly observed in FHB.


The use of confocal laser-scanning microscopy in microsurgery for invasive squamous cell carcinoma.
Ex-vivo confocal laser-scanning microscopy offers rapid imaging of excised tissue specimens without conventional histotechnical procedures. As vertical sections are prepared, morphological features can be assessed according to standard criteria used in conventional histopathology. To validate the diagnostic confocal examination of squamous cell carcinoma (SCC) in microscopy-guided surgery. Four independent observers received standardized instructions about diagnostic confocal microscopy features of SCC. Subsequently, 120 confocal images of fresh excisions from SCC or normal skin, imaged using a commercially available, near-infrared, reflectance confocal laser-scanning microscope, were evaluated by each observer. General morphology, such as location, size and shape of the cancer area could be visualized by the imaging system. Furthermore, densely packed and irregularly organized nuclei and nuclear atypia could be delineated. Overall, a sensitivity of 95% and a specificity of 96.25% were achieved by the four observers (positive predictive value 96.25%, negative predictive value 95.23%). This study provides a set of well-described morphological criteria with obvious diagnostic impact which should be used in further investigations. In the future, confocal laser-scanning microscopy may guide microsurgery of any skin cancer.


Illusory Motion Reversal in Touch.
Psychophysical visual experiments have shown illusory motion reversal (IMR), in which the perceived direction of motion is the opposite of its actual direction. The tactile form of this illusion has also been reported. However, it remains unclear which stimulus characteristics affect the magnitude of IMR. We closely examined the effect of stimulus characteristics on IMR by presenting moving sinusoid gratings and random-dot patterns to 10 participants' fingerpads at different spatial periods, speeds, and indentation depths. All participants perceived a motion direction opposite to the veridical direction some of the time. The illusion was more prevalent at spatial periods of 1 and 2 mm and at extreme speeds of 20 and 320 mm/s. We observed stronger IMR for gratings and much weaker IMR for a random-dot pattern, indicating that edge orientation might be a major contributor to this illusion. These results show that the optimal parameters for IMR are consistent with the characteristics of motion-selective neurons in the somatosensory cortex, as most of these neurons are also orientation-selective. We speculate that these neurons could be the neural substrate that accounts for tactile IMR.


Expanded clinical-grade membrane-bound IL-21/4-1BBL NK cell products exhibit activity against acute myeloid leukemia in vivo.
Adoptive NK cell infusion is a promising immunotherapy for acute myeloid leukemia (AML) patients. The aim of this study was to test the activity of clinical-grade membrane-bound IL-21/4-1BBL-expanded NK cell products against AML in vivo. Fresh peripheral blood mononuclear cells (PBMCs) were incubated with equal numbers of irradiated membrane-bound IL-21/4-1BBL-expressing K562 cells for 2-3 weeks to induce clinical-grade NK cell expansion. Expansion for 2 and 3 weeks produced ∼4 and 8 × 109 NK cells from 2 × 107 PBMCs. The production of CD107a and TNF-α in NK cell products in response to AML cell lines and primary blasts was higher than that observed in resting NK cells. The 2-week expanded NK cell products were xenografted into immunodeficient mice with leukemia and were persistently found in the BM, spleen, liver, lung, and peripheral blood for at least 13 days; furthermore, these expanded products reduced the AML burden in vivo. Compared with matched AML patients with persistent or relapsed minimal residual disease (MRD+ ) who underwent regular consolidation therapy, MRD+ patients who underwent NK treatment had better overall survival and showed no major adverse events. Clinical-grade mbIL-21/4-1BBL-expanded NK cells exhibited antileukemic activity against AML in vitro and in vivo.


Inhibition of multi-species oral biofilm by bromide doped bioactive glass.
Bioactive glass is an attractive biomaterial that has shown excellent osteogenic and angiogenic effects for oral bone repairing procedures. However, anti-biofilm potential related to such biomaterial has not been completely validated, mainly against multi-species biofilms involved in early tissue infections. The aim of the present study was to evaluate the anti-biofilm effect of 58 S bioactive glass embedding calcium bromide compounds at different concentrations. Bioactive glass free or containing 5, or 10 wt % CaBr2 was synthesized by alkali sol-gel method and then characterized by physco-chemical analyses and scanning electron microscopy (SEM). Then, samples were tested by microbiological assays using optical density, real time q-PCR, and SEM. Bioactive glass particles showed accurate chemical composition and an angular shape with a bimodal size distribution ranging from 0.6 to 110 µm. The mean particle size was around 29 µm. Anti-biofilm effect was recorded for 5 wt % CaBr2 -doped bioactive glass against S. mitis, V. parvula, P. gingivais, S. gordoni, A. viscosus, F, nucleatum, P. gingivais. F. nucleatum, and P. gingivalis. Such species are involved in the biofilm structure related to infections on hard and soft tissues in the oral cavity. The incorporation of calcium bromide into bioactive glass can be a strategy to enhance the anti-biofilm potential of bioactive glasses for bone healing and infection treatment. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1994-2003, 2017.


Nanomachining of permalloy for fabricating nanoscale ferromagnetic structures using atomic force microscopy.
It is well-known that the tip of an Atomic Force Microscope (AFM) can act as a cutting tool for machining various types of materials. In this article, AFM machining experiments have been conducted to investigate the machining characteristics of a nickel-iron thin film material. The influences of the machining parameters on the resulting machined geometries and surfaces are specifically investigated. The machining parameters considered include the normal applied force, number of machining cycles, machining speed, and machining direction. To demonstrate its versatility, the machining technique developed has been applied for fabricating a NiFe based nanostructure required by many ferromagnetic devices. All results indicate that the machined groove size can be well correlated with and precisely controlled by the applied force and the machining cyclic number. The AFM machining technique is indeed simple and predictable for machining nanostructures with specified dimension and controllable precision.


Sequential intrastromal corneal ring implantation and cataract surgery in a severe keratoconus patient with cataract.
A 49-year-old man with an uncorrected visual acuity (UCVA) of 20 / 1000, a best spectacle-corrected visual acuity (BSCVA) of 20 / 400, keratometric readings of K1 = 59.88 × 82° / K2 = 45.88 × 172°, and an inferior steepening that was consistent with keratoconus in his left eye was treated with clear-cornea phacoemulsification and an intraocular lens (IOL) implantation after insertion of keraring intrastromal corneal ring segments for severe keratoconus and cataract. An asymmetrical pair of kerarings was implanted with the assistance of a femtosecond laser in September 2008; the one segment was 250 µm and the other was 150 µm and both were placed at 70°. Three months after the kerarings were implanted, clear-cornea phacoemulsification and IOL implantation were performed on the left eye. After surgery, both the UCVA and the BSCVA of the left eye improved by eight lines. Postoperative central keratometry showed a decrease of 7.35 diopters in the left eye. Both the postoperative refraction (-0.75 -0.75 × 60°) and the keratometric reading (K1 = 50.05 × 93° / K2 = 48.83 × 3°) remained stable one month following the procedures. Thus, the sequential order of intrastromal corneal rings implantation and cataract surgery can be considered as a treatment option in patients with severe keratoconus and cataract.


CT-derived muscle remodelling after bronchoscopic lung volume reduction in advanced emphysema.
Muscle wasting frequently occurs in severe emphysema. Improving respiratory mechanics by bronchoscopic lung volume reduction using endobronchial valves (EBV) might prevent further loss or even increase in muscle mass. CT-derived skeletal muscle mass gain was observed in 39/49 patients 6 months after EBV. Multiple linear regression showed that gain in muscle (β=2.4; 95% CI 0.2 to 4.6; p=0.036) and intramuscular fat (β=3.1; 95% CI 0.2 to 5.9; p=0.035) is associated with improved 6 min walk distance independent of the change in residual volume. Skeletal muscle remodelling associates with improved exercise capacity after EBV, independent of hyperinflation reduction. TRIAL REGISTRATION NUMBER: Clinical trial registered with the Dutch trial register www.trialregister.nl (NTR2876), Results.


Healthcare resource utilization among commercially insured patients with cold agglutinin disease in the United States.
Aims: Cold agglutinin disease (CAD) is a rare subtype of autoimmune hemolytic anemia associated with increased thromboembolism risk and early mortality. Healthcare resource utilization (HRU) in CAD has not been reported. We aimed to compare HRU of patients with CAD with a matched non-CAD cohort in the United States.Materials and methods: Patients with CAD were identified from 2006 to 2016 in the Optum-Humedica database using CAD terms in clinical notes and hematologist review. Patients were required to have Integrated Delivery Network records and ≥6 months' follow-up before and after the first CAD mention date (index date). Patients with CAD were matched to a non-CAD cohort based on demographics. Multivariate analyses assessed inpatient hospitalizations, outpatient visits, emergency room visits, and transfusion use between cohorts 6 months before and 12 months after the index date.Results: Of 814 patients with CAD, 410 met inclusion criteria and were matched to 3,390 patients without CAD. Mean age of patients with CAD was 68.0 years; approximately 62% were female. In the 12 months after the index date, mean inpatient hospitalizations (0.83 vs. 0.25), outpatient visits (17.26 vs. 6.77), emergency room visits (0.55 vs. 0.32), and transfusion days (1.05 vs. 0.05) were higher for patients with CAD than the matched non-CAD cohort (all p < .0001). Similarly, in the 6 months before the index date, patients with CAD had higher HRU than matched patients without CAD for all measures evaluated.Limitations: Results of this study are based on patient information from the Optum-Humedica database, which is limited to commercially insured patients and may not represent the overall CAD population.Conclusions: CAD places a substantial burden on patients and healthcare systems. In addition, the high HRU for patients with CAD observed in the 6 months before diagnosis indicates that disease awareness and better diagnostic practices may be needed.


Saturation mutagenesis of a +1 programmed frameshift-inducing mRNA sequence derived from a yeast retrotransposon.
Errors during the process of translating mRNA information into protein products occur infrequently. Frameshift errors occur less frequently than other types of errors, suggesting that the translational machinery has more robust mechanisms for precluding that kind of error. Despite these mechanisms, mRNA sequences have evolved that increase the frequency up to 10,000-fold. These sequences, termed programmed frameshift sites, usually consist of a heptameric nucleotide sequence, at which the change in frames occurs along with additional sequences that stimulate the efficiency of frameshifting. One such stimulatory site derived from the Ty3 retrotransposon of the yeast Saccharomyces cerevisiae (the Ty3 stimulator) comprises a 14 nucleotide sequence with partial complementarity to a Helix 18 of the 18S rRNA, a component of the ribosome's accuracy center. A model for the function of the Ty3 stimulator predicts that it base pairs with Helix 18, reducing the efficiency with which the ribosome rejects erroneous out of frame decoding. We have tested this model by making a saturating set of single-base mutations of the Ty3 stimulator. The phenotypes of these mutations are inconsistent with the Helix 18 base-pairing model. We discuss the phenotypes of these mutations in light of structural data on the path of the mRNA on the ribosome, suggesting that the true target of the Ty3 stimulator may be rRNA and ribosomal protein elements of the ribosomal entry tunnel, as well as unknown constituents of the solvent face of the 40S subunit.


Copper and Zinc Particles as Regulators of Cardiovascular System Function-A Review.
Copper and zinc are micronutrients that play a crucial role in many cellular pathways, act as cofactors in enzymatic systems, and hence, modulate enzyme activity. The regulation of these elements in homeostasis is precisely controlled by various mechanisms. Superoxide dismutase (SOD) is an enzyme requiring both copper and zinc for proper functioning. Additionally, there is an interaction between the concentrations of copper and zinc. Dietary ingestion of large amounts of zinc augments intestinal absorption of this trace element, resulting in copper deficiency secondary to zinc excess. The presence of an overabundance of copper and zinc has a detrimental impact on the cardiovascular system; however, the impact on vascular contractility varies. Copper plays a role in the modulation of vascular remodeling in the cardiac tissue, and the phenomenon of cuproptosis has been linked to the pathogenesis of coronary artery disease. The presence of copper has an observable effect on the vasorelaxation mediated by nitric oxide. The maintenance of proper levels of zinc within an organism influences SOD and is essential in the pathogenesis of myocardial ischemia/reperfusion injury. Recently, the effects of metal nanoparticles have been investigated due to their unique characteristics. On the other hand, dietary introduction of metal nanoparticles may result in vascular dysfunction, oxidative stress, and cellular DNA damage. Copper and zinc intake affect cardiovascular function, but more research is needed.


Turner syndrome and Cushing disease - the coexistence with overlapping complications: case report and literature review.
We present an unusual case of Turner syndrome (TS) and Cushing disease (CD) in a young woman, admitted to our department seven years after a successful surgical removal of ACTH-secreting pituitary tumor. To our knowledge, this is the first ever report of these two disorders coexisting. Our patient was diagnosed with TS at the age of 16 due to primary amenorrhea and short stature. Hormone replacement therapy with estrogen was initiated, but she did not receive growth hormone therapy. At the age of 28, she developed clinical and biochemical abnormalities consistent with hypercortisolism, but the definitive diagnosis of CD was established nine years later when she was admitted to our department. Appropriate treatment was applied, however, the patient developed serious complications: a myocardial infarction, diabetes and osteoporosis. Surgical treatment appeared to improve some, but not all of the symptoms, indicating a significant contribution of concomitant TS to the severity of adverse cardiovascular and bone turnover outcomes in a subject with a genetic susceptibility to these complications. Thus, multidisciplinary evaluation in such patients is strongly indicated, particularly if more predisposing conditions are present.


Psychotherapeutic approaches in the treatment of pain.
Pain is best conceptualized as a perceptual, rather than a sensory, phenomenon. As a purely sensory event, pain is a response to tissue damage generated by a stimulus to a nociceptor. Patients, however, have vastly different responses to very similar pain-generating stimuli, suggesting that the patients' perception of pain cannot be caused solely by the intensity of the initial stimulus. Viewing pain in a perceptual framework allows a much greater recognition of the attentional, cognitive, affective, and social components to the pain experience. Psychotherapeutic approaches to patients in pain utilize a perceptual framework and will be the focus of this article.


Factors affecting eye donation from postmortem cases in a tertiary care hospital.
To evaluate the responses to requests for eye donation from relatives of postmortem cases in a tertiary care hospital in India. In a prospective study, the cases brought for postmortem to the Forensic Medicine Department were screened as potential donors by our team. The next of kin of potential donors were approached and counseled in a systematic manner following a standard interview pattern. Responses were noted in a predesigned performa. The religion, level of literacy, socioeconomic status, relationship with the deceased, prior knowledge of eye donation, willingness for eye donation, and reasons for not donating eyes of the deceased were recorded. One hundred fifty-nine potential donors were identified from a total of 721 postmortem cases. There were 119 (74.8%) men and 40 (25.2%) women. None of the deceased had previously pledged their eyes for eye donation. Eighty-eight (55.4%) next of kin were already aware of the concept of eye donation, but 71 (44.7%) families had not heard of it before. Willingness for eye donation was seen in 66 (41.5%), whereas 93 (58.5%) families refused eye donation. Of those already aware of eye donation, 39 (44.3%) gave consent for donation. Prior knowledge of eye donation had no influence on willingness for eye donation (P = 0.424). Similarly, literacy (P = 0.338) and socioeconomic status as estimated by a composite socioeconomic scale based on literacy and family income did not have any influence on willingness for eye donation (P = 0.338). Major reasons for not donating eyes included refusal to discuss the issue and dissuasion by distant relatives, legal problems, and religious beliefs. In our experience, literacy, socioeconomic status, and prior knowledge of eye donation of next kin had no correlation with donor corneal tissue procurement. Active counseling by a motivated team can be effective even in families with no prior knowledge and low socioeconomic status.


[Rational choice of technologies and equipment in the logistic support of a pathomorphology laboratory].
The purpose of the present communication is to provide specialists with the comparative characteristics of the most important user qualities of the major histological labware by the world's leading manufacturers introduced on the market. These are comparatively estimated solely from technologically significant criteria on the basis of the materials of open references, general public technical documents, and the authors' experience. Fabric processors, embedding complexes, microtomes, autostainers, and coverslippers are comparatively characterized from the viewpoint of a practical user. The presented materials may be useful to specialties to take decisions on logistics and re-equipment of morphological laboratories.


Tissue influx of neutrophils and monocytes is delayed during development of trovafloxacin-induced tumor necrosis factor-dependent liver injury in mice.
Idiosyncratic drug-induced liver injury (iDILI) has a poorly understood pathogenesis. However, iDILI is often associated with inflammatory stress signals in human patients as well as animal models. Tumor necrosis factor (TNF) and neutrophils play a key role in onset of trovafloxacin (TVX)-induced iDILI, but the exact role of neutrophils and other leukocytes remains to be defined. We therefore set out to study the kinetics of immunological changes during the development of TVX-induced iDILI in the established murine model of acute liver injury induced by administration of TVX and TNF. Initially, TNF stimulated the appearance of leukocytes, in particular neutrophils, into the liver of TVX-treated mice, but even more so in control mice treated with the non-DILI inducing analogue levofloxacin (LVX) or saline as vehicle (Veh). This difference was apparent at 2 hours after TNF administration, but at 4 hours, the relative neutrophil amounts were reduced again in Veh- and LVX-treated mice whereas the amounts in TVX-treated mice remained at the same increased level as at 2 hours. The influx of monocytes/macrophages, which was unaffected in Veh- and LVX-treated mice was markedly reduced or even absent in TVX-treated mice. Unlike controls, mice receiving TVX + TNF display severe hepatotoxicity with clear pathology and apoptosis, coagulated hepatic vessels and increased alanine aminotransferase levels and interleukin 6/10 ratios. Findings indicate that TVX delays the acute influx of neutrophils and monocytes/macrophages. Considering their known anti-inflammatory functions, the disruption of influx of these innate immune cells may hamper the resolution of initial cytotoxic effects of TVX and thus contribute to liver injury development.


Cholinesterase inhibition reduces arrhythmias in asymptomatic Chagas disease.
Parasympathetic dysfunction may play a role in the genesis of arrhythmias in Chagas disease. This study evaluates the acute effects of pyridostigmine (PYR), a reversible cholinesterase inhibitor, on the occurrence of arrhythmias in patients with Chagas cardiac disease. Following a double-blind, randomized, placebo-controlled, cross-over protocol, 17 patients (age 50±2 years) with Chagas cardiac disease type B underwent 24-hour Holter recordings after oral administration of either pyridostigmine bromide (45 mg, 3 times/day) or placebo (PLA). Pyridostigmine reduced the 24-hours incidence (median [25%-75%]) of premature ventricular beats-PLA: 2998 (1920-4870), PYR: 2359 (940-3253), P=.044; ventricular couplets-PLA: 84 (15-159), PYR: 33 (6-94), P=.046. Although the total number of nonsustained ventricular tachycardia in the entire group was not different (P=.19) between PLA (1 [0-8]) and PYR (0 [0-4]), there were fewer episodes under PYR in 72% of the patients presenting this type of arrhythmia (P=.033). Acute administration of pyridostigmine reduced the incidence of nonsustained ventricular arrhythmias in patients with Chagas cardiac disease. Further studies that address the use of pyridostigmine by patients with Chagas cardiac disease under a more prolonged follow-up are warranted.


Pattern-forming instabilities in nematic liquid crystals under oscillatory Couette flow.
We consider instabilities, either homogeneous or periodic in space, which develop in a nematic liquid crystal layer under rectilinear oscillatory Couette flow for planar surface alignment of the director perpendicular to the flow plane. On the basis of a numerical and analytical linear stability analysis we determine the critical amplitude of the oscillatory flow, the wave number, and the symmetry of the destabilizing mode and present a comprehensive phase diagram of the flow instabilities. In particular it is found that by varying the frequency of the Couette flow the instability changes its temporal symmetry. This transition is shown to be related to the inertia effects of the nematic fluid, which become more important with increasing flow frequency. We also show that an electric field applied perpendicularly to the nematic layer can induce an exchange of instabilities with different spatial and temporal symmetries. The theoretical results are compared with experiments, when available.


The effect of antacid on gastric and duodenal bulb acidity.
A small glass pH electrode was positioned in the duodenal bulb and connected to a digital pH meter. The pH registered every half second was stored on a minidiskette with a capacity of 32.400 pH data on a single mini-disc. A microcomputer controlled electrode calibration, data collection, formating and storage. Four patients with duodenal ulcer were given a liquid test meal, and one hour later when gastric and duodenal acidity had reached high levels they were given 10 ml of antacid. From the stored pH data the mean pH and the mean hydrogen ion concentration was calculated. During the 10 min. period before antacid was given gastric pH was on average 1.5 and the duodenal pH on average 4 with a CH+ of 2.500 mumol/. Ingestion of antacid reduced gastric acidity to around pH 3, and the duodenal pH to 6 with a CH+ of 250 mumol/l. This effect of antacid was observed in all subjects, but the degree and the duration of the effect varied very much between the individuals.


Cholinergic dependence of taste memory formation: evidence of two distinct processes.
Learning the aversive or positive consequences associated with novel taste solutions has a strong significance for an animal's survival. A lack of recognition of a taste's consequences could prevent ingestion of potential edibles or encounter death. We used conditioned taste aversion (CTA) and attenuation of neophobia (AN) to study aversive and safe taste memory formation. To determine if muscarinic receptors in the insular cortex participate differentially in both tasks, we infused the muscarinic antagonists scopolamine at distinct times before or after the presentation of a strong concentration of saccharin, followed by either an i.p. injection of a malaise-inducing agent or no injection. Our results showed that blockade of muscarinic receptors before taste presentation disrupts both learning tasks. However, the same treatment after the taste prevents AN but not CTA. These results clearly demonstrate that cortical cholinergic activity participates in the acquisition of both safe and aversive memory formation, and that cortical muscarinic receptors seem to be necessary for safe but not for aversive taste memory consolidation. These results suggest that the taste memory trace is processed in the insular cortex simultaneously by at least two independent mechanisms, and that their interaction would determine the degree of aversion or preference learned to a novel taste.


Disease-specific quality of life in patients with lupus nephritis.
Background Patient-reported outcomes in lupus nephritis (LN) are not well studied. Studies with disease-targeted PRO tool in LN do not exist. Herein, we describe quality of life (QOL: HRQOL & non-HRQOL) among LN patients using LupusPRO. Methods International, cross-sectional data from 1259 patients with systemic lupus erythematosus (SLE) and LupusPRO were compared, stratified by (a) presence of LN (ACR classification criteria (ACR-LN)) at any time and, (b) active LN (on SLEDAI) at study visit. Damage was assessed by SLICC/ACR-SDI. Multivariate regression analyses for QOL against ACR-LN (active LN) after adjusting for age, gender, ethnicity and country of recruitment were performed. Results Mean (SD) age was 41.7 (13.5) yrs, 93% were women. Five hundred and thirty-nine of 1259 SLE patients had ACR-LN. ACR-LN group was younger, were more often on immunosuppressive medications, had worse QOL on lupus medications and procreation than non-ACR-LN patients. HRQOL and non-HRQOL scores were similar in both groups. One hundred and twenty-nine of 539 ACR-LN patients had active LN. Active LN group was younger, had greater disease activity and had worse HRQOL and non-HRQOL compared to patients without active LN. Specific domains adversely affected were lupus symptoms, lupus medications, procreation, emotional health, body image and desires-goals domains. Patients with ACR-LN and active LN fared significantly worse in lupus medications and procreation HRQOL domains, even after adjusting for age, ethnicity, gender and country of recruitment. Conclusions Lupus nephritis patients have poor QOL. Patients with active LN have worse HRQOL and non-HRQOL. Most domains affected are not included in the generic QOL tools used in SLE. LN patients must receive discussion on lupus medications and procreation issues. Patients with active LN need comprehensive assessments and addressal of QOL, along with treatment for active LN.


Pegylated fluorescent peptides as substrates of proteolytic enzymes.
In this work the efficient and simple method of improvement specificity and solubility of low molecular weight proteinase substrates is described. The series of fluorescent substrates of selected proteolytic enzymes (neutrophil elastase, cathepsin G and proteinase 3 along with human airway trypsin like protease) were synthesized and modified by selective pegylation by the attachment of 2-(2-(2-aminoethoxy)ethoxy)acetic acid. Modification of the C-terminal carboxyl group resulted in the decrease in the specificity constants (k(cat)/K(M)) for all obtained analogues. The covalent attachment of PEG to N-terminal amino group has the opposite effect, as the increase in specificity constant was observed for all studied compounds. This outcome was pronounced the most for proteinase 3 substrate PEG-ABZ-Tyr-Tyr-Abu-ANB-NH2, whose catalytic constant (k(cat)) increased over three fold. The introduction of PEG moieties at both C- and N-terminal yielded the substrates with lower specificity constants. For substrate (ABZ-Arg-Gln-Asp-Arg-ANB-NH2) the influence of the PEG chain length on its kinetic parameters was investigated. Elongation of the PEG chain at N-terminal of this peptide decreased the specificity constant. In addition to the effect of pegylation on the kinetic parameters of the studied substrates, the introduced modifications significantly improved their solubility in buffer solutions applied for enzymatic investigations.


Ectopic Expression of DREB Transcription Factor, AtDREB1A, Confers Tolerance to Drought in Transgenic Salvia miltiorrhiza.
Drought decreases crop productivity more than any other type of environmental stress. Transcription factors (TFs) play crucial roles in regulating plant abiotic stress responses. The Arabidopsis thaliana gene DREB1A/CBF3, encoding a stress-inducible TF, was introduced into Salvia miltiorrhiza Ectopic expression of AtDREB1A resulted in increased drought tolerance, and transgenic lines had higher relative water content and Chl content, and exhibited an increased photosynthetic rate when subjected to drought stress. AtDREB1A transgenic plants generally displayed lower malondialdehyde (MDA), but higher superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD) activities under drought stress. In particular, plants with ectopic AtDREB1A expression under the control of the stress-induced RD29A promoter exhibited more tolerance to drought compared with p35S::AtDREB1A transgenic plants, without growth inhibition or phenotypic aberrations. Differential gene expression profiling of wild-type and pRD29A::AtDREB1A transgenic plants following drought stress revealed that the expression levels of various genes associated with the stress response, photosynthesis, signaling, carbohydrate metabolism and protein protection were substantially higher in transgenic plants. In addition, the amount of salvianolic acids and tanshinones was significantly elevated in AtDREB1A transgenic S. miltiorrhiza roots, and most of the genes in the related biosynthetic pathways were up-regulated. Together, these results demonstrated that inducing the expression of a TF can effectively regulate multiple genes in the stress response pathways and significantly improve the resistance of plants to abiotic stresses. Our results also suggest that genetic manipulation of a TF can improve production of valuable secondary metabolites by regulating genes in associated pathways.


Effects of URB597 as an inhibitor of fatty acid amide hydrolase on modulation of nociception in a rat model of cholestasis.
Cholestasis is associated with increased activity of the endogenous opioid system that results in analgesia. Endocannabinoid system can reduce pain sensitivity. The use of inhibitors of endocannabinoid metabolism is a novel means of pharmacologically increasing endocannabinoid levels. Considering the interaction that has been shown between the endogenous opioid and endocannabinoid systems in nociception processing, we studied the effects of URB597, a selective inhibitor of FAAH (fatty acid amide hydrolase), on modulation of nociception in a model of elevated endogenous opioid tone, cholestasis. Cholestasis was induced by ligation of the main bile duct using two ligatures and then transection of the duct at the midpoint between them. Seven days after surgery, tail-flick latencies were measured at 60 min after drug administration. A significant increase (P<0.001) in nociception threshold was observed in cholestatic rats compared to unoperated and sham groups. Administration of URB597 (0.3 mg/kg, i.p.) in cholestatic animals significantly (P<0.001) increased tail-flick latency compared to the vehicle treated cholestatic group. URB597 injection to unoperated and sham groups caused a significant (P<0.05, P<0.05) increase in tail-flick latency compared to their respective vehicle treated groups. The antinociceptive effect of URB597 was blocked by coadministration of a cannabinoid CB(1) receptor antagonist, AM251 (1 mg/kg, i.p.) but not by a cannabinoid CB(2) receptor antagonist, SR144528 (1 mg/kg, i.p.) with URB597. These data showed that URB597 as a FAAH inhibitor potentiates antinociception induced by cholestasis in tail-flick test and that the inhibitory effects of URB597 in this model are mediated by cannabinoid CB(1) and not CB(2) receptors.


Virulence genes of Rickettsia rickettsii are differentially modulated by either temperature upshift or blood-feeding in tick midgut and salivary glands.
Rickettsia rickettsii, the etiological agent of Rocky Mountain spotted fever, is transmitted to humans by ticks. During tick feeding, R. rickettsii is exposed to both temperature elevation and components of the blood meal, which have previously been associated with the reactivation of its virulence. These environmental stimuli were also reported to modulate virulence genes of R. rickettsii infecting a set of organs of adult females of its natural vector, Amblyomma aureolatum. In this study, we determined the effects of a temperature upshift, blood-feeding, and both stimuli simultaneously on the expression of 85 selected genes of R. rickettsii infecting either the midgut (MG) or salivary glands (SG) of male and female A. aureolatum by microfluidic high-throughput RT-qPCR. These two organs are key for acquisition of this bacterium by the tick and transmission to the vertebrate host, respectively. Data showed that these environmental stimuli exert distinct effects on rickettsial transcription depending on the colonized organ and gender of the vector. Temperature upshift induced the majority of differentially expressed genes of R. rickettsii in tick SG, including tRNA synthetases encoding genes. On the contrary, blood-feeding downregulated most of differentially expressed genes in both organs, but induced type IV secretion system components and OmpB in tick MG. The combined effects of both stimuli resulted in a merged gene expression profile representing features of each stimulus analyzed independently, but was more similar to the profile induced by blood-feeding. The upregulation of the majority of differentially expressed genes in tick SG by temperature upshift suggests that this stimulus is important to prepare R. rickettsii for transmission to the vertebrate host. Blood-feeding, on the other hand, induced important virulence genes in the tick MG, which might be associated with colonization of the tick and transmission to the vertebrate host. The role of the proteins identified in this study must be addressed and might help to define future targets to block tick infection, thereby preventing RMSF. To our knowledge, this is the first transcriptional tissue-specific study of a virulent strain of R. rickettsii infecting a natural tick vector.


Noncontrast Hybrid Arterial Spin-Labeled Imaging of the Intracranial Arteries.
The purpose of this study is to evaluate feasibility, image quality (IQ), and accuracy of noncontrast hybrid arterial spin labeling (NoHASL) magnetic resonance angiography (MRA) compared with time of flight (TOF) MRA and contrast-enhanced (CE) MRA in patients with known/suspected cerebrovascular ischemia. Thirty inpatients were imaged at 1.5 T. Two neuroradiologists assessed 630 intracranial arterial segments for IQ (1, nondiagnostic; 3, satisfactory for diagnosis; and 5, excellent). Hemodynamically significant stenosis (>50%) was assessed against all combined techniques as reference. The NoHASL MRA IQ was diagnostic (3.32 ± 0.86) but affected by signal to noise ratio and spatial resolution limitations and significantly inferior to TOF (3.48 ± 0.68) and CE MRA (3.44 ± 0.78) (P < 0.0001 in both comparisons). Fourteen (2.2%) of 630 segments had hemodynamically significant stenoses at the reference standard. Sensitivity/specificity was not significantly different between techniques: NoHASL MRA, 67.9%/90.0%; TOF MRA, 67.9%/97.7%; and CE MRA, 50.0%/98.7%. The NoHASL MRA is feasible, with diagnostic quality imaging of proximal intracranial vessels. Low disease prevalence limited the assessment of technique accuracy.


Centrosome polarization in T cells: a task for formins.
T-cell antigen receptor (TCR) engagement triggers the rapid reorientation of the centrosome, which is associated with the secretory machinery, toward the immunological synapse (IS) for polarized protein trafficking. Recent evidence indicates that upon TCR triggering the INF2 formin, together with the formins DIA1 and FMNL1, promotes the formation of a specialized array of stable detyrosinated MTs that breaks the symmetrical organization of the T-cell microtubule (MT) cytoskeleton. The detyrosinated MT array and TCR-induced tyrosine phosphorylation should coincide for centrosome polarization. We propose that the pushing forces produced by the detyrosinated MT array, which modify the position of the centrosome, in concert with Src kinase dependent TCR signaling, which provide the reference frame with respect to which the centrosome reorients, result in the repositioning of the centrosome to the IS.


Angiostrongylus mackerrasae and A. cantonensis (Nematoda: Metastrongyloidea) belong to same genetic lineage: evidence from mitochondrial protein-coding genes.
Angiostrongylus mackerrasae is a parasitic nematode of rats found in Australia. When first reported, it was referred to as A. cantonensis. Recent molecular studies, including the mitochondrial genome, indicate that it is highly similar to A. cantonensis. These studies did not include A. malaysiensis, another member of the A. cantonensis species complex, for comparison. The present study examined the genetic distance and phylogenetic relationship between the component taxa (A. cantonensis, A. mackerrasae and A. malaysiensis) of the A. cantonensis species complex, based on the 12 protein-coding genes (PCGs) of their mitochondrial genome. Both the nucleotide and amino acid sequences were analysed. Angiostrongylus mackerrasae and A. cantonensis are members of the same genetic lineage and both are genetically distinct from A. malaysiensis. The genetic distance based on concatenated nucleotide sequences of 12 mt-PCGs between A. mackerrasae and A. cantonensis from Thailand is p = 1.73%, while that between the Thai and Chinese taxa of A. cantonensis is p = 3.52%; the genetic distance between A. mackerrasae and A. cantonensis from China is p = 3.70%. The results indicate that A. mackerrasae and A. cantonensis belong to the same genetic lineage, and that A. mackerrasae may be conspecific with A. cantonensis. It remains to be resolved whether A. mackerrasae is conspecific with A. cantonensis or undergoing incipient speciation.


[A study on a local epidemic of dengue fever in Shaxi district of Zhongshan city, 1991].
An epidemic of dengue fever occurred in Shengshi Village of Shaxi District in the last ten-day period of August, 1991. A wrong diagnosis was made on account of atypical clinical symptoms and careless investigation during early days. Effective measures had not been taken in time, so that the disease spread to neighbouring three villages and the town. The epidemic lasted for 64 days and 112 cases were found. It had been proven by etiologic studies that type 1 dengue virus caused this epidemic.


QM/MM determination of kinetic isotope effects for COMT-catalyzed methyl transfer does not support compression hypothesis.
Secondary alpha-D3 kinetic isotope effects calculated by the hybrid AM1/TIP3P/CHARMM method for the reaction of S-adenosylmethionine with catecholate anion in aqueous solution and catalyzed by rat liver catechol O-methyltransferase at 298 K are 0.94 and 0.85, respectively, in good accord with experiment. The large inverse effect for the enzymatic reaction is not due to compression but arises from significant increases in the stretching and bending force constants involving the isotopically substituted atoms of the transferring methyl group as between the reactant complex and the transition structure, larger than for the reaction in water.


Low Pathogenic Avian Influenza and Coinfecting Pathogens: A Review of Experimental Infections in Avian Models.
Low pathogenic avian influenza virus (LPAIV) usually causes mild disease or asymptomatic infection in poultry. LPAIV has, however, become a great threat to poultry industry due to mixed infections with other pathogens. Coinfections do frequently occur in the field but are not easily detected, and their impact on pathobiology is not clearly defined due to their complicated nature, but it is well known that there is an impact. One way to increase our knowledge of coinfections in poultry is to challenge birds in experimental and controlled conditions. While many articles report in vivo experiments with LPAIV in avian models, only a few have studied coinfections. Moreover, researchers tend to choose different bird types, ages, inoculation routes, and doses for their experiments, making it difficult to compare between studies. This review describes the state of the art for experimental infections with LPAIV alone or associated with coinfecting pathogens in avian models. It also discusses how best to mimic field infections in laboratory settings. In the field of avian diseases, experimental design is obviously directly linked with the research question addressed, but there is a gap between field and experimental data, and further studies are warranted to better understand how to bring laboratory settings closer to field situations.


Acute abdomen. The teenage girl.
The evaluation of abdominal pain in the adolescent female is a common and often challenging problem. The unique anatomy and biology of the postmenarcheal teenager necessitates the consideration of a broad variety of additional genitourinary problems not encountered in the male. Further complicating this issue, the differential diagnoses involves not only pathological considerations, but normal physiological processes that may, in and of themselves, be symptomatic. One must be skillful enough to avoid unnecessary intervention, while aggressively pursuing significant intraabdominal problems. Occasionally, however, only invasive modalities will enable definitive diagnosis, and facility with these techniques significantly enhances both diagnostic and therapeutic capabilities in these patients.


Longitudinal relationships between bullying and prosocial behavior: The mediating roles of trauma-related guilt and shame.
The present study examined the relationships between bullying, trauma-related guilt, trauma-related shame, and prosocial behaviors. We investigated 1,322 college students using a longitudinal approach to explore the internal mechanism between bullying, prosocial behaviors, and the probable mediating effects of trauma-related guilt and shame. The results suggested that bullying negatively predicted prosocial behaviors and that trauma-related guilt played a positive mediating role. In contrast, trauma-related shame played a negative mediating role in the relationship between bullying and prosocial behaviors. These findings indicated that trauma-related guilt and shame played adaptive and maladaptive roles after bullying victimization, which also provided a theoretical basis for the relevant intervention.


Torsion dystonia in Panay, Philippines.
There is an unusually high frequency of torsion dystonia in Panay. Of the 28 Filipino cases, 23 (82%) are from the island of Panay and 19 of the 23 (82%) are from the province of Capiz. The 28 cases belong to 25 families Six sets of brothers are noted. All are males. Pedigree analysis reveals six families with several members affected. Two families show features suggesting possible sex-linked recessive transmission, a mode of inheritance previously undescribed in the literature. The clinical features of the cases seen in this series differ from previously described cases in the literature in several aspects: (a) sex preponderance--all males; (b) age at onset--older age of onset, mean of 31; (c) hereditary--possible sex-linked recessive transmission; (d) spasmodic eye blinking as first symptom in four patients.


[A case study with bladder metastasis of renal cell carcinoma and stomach cancer].
A 64-year-old woman received nephrectomy and lymph expurgation surgery for renal cell carcinoma on Jury 1, 1981. The pathologic diagnosis was adenocarcinoma of the clear cell type at Robson's stage 2. She next visited the Department of Gastroenterology complaining of stomach discomfort on November 5, 1981. Stomach cancer of Borrmann's type IV was identified in the lesser gastric curvature, but only biopsy was performed because it was inoperable. The pathologic diagnosis was undifferentiated adenocarcinoma. On January 23, 1982, there was microscopic hematuria. A cystoscopic examination revealed one soy bean-sized, smooth, pedicle tumor to which coagula were partially adhered in the center of the triangular region. After TUR-Bt performed on March 3 the pathologic diagnosis was adenocarcinoma of the clear cell type with no submucosal infiltration. Based on these findings, the patient was diagnosed as having suffered metastasis of renal cell carcinoma to the bladder. She died of bleeding from stomach cancer on June 15. Based on the fact that the tumor was localized in the bladder mucosa, implantation through the urinary tract was strongly suspected as the metastatic route of the renal cell carcinoma to the bladder.


Impact of MIF gene promoter polymorphism on F508del cystic fibrosis patients.
Macrophage migration Inhibitory Factor (MIF) is a pro-inflammatory cytokine sustaining the acute response to gram-negative bacteria and a regulatory role for MIF in Cystic Fibrosis has been suggested by the presence of a functional, polymorphic, four-nucleotide repeat in this gene's promoter at position -794, with the 5-repeat allele displaying lower promoter activity. We aimed at assessing the association of this polymorphism with disease severity in a group of Cystic Fibrosis patients homozygous for F508del CFTR gene mutation. Genotype frequencies were determined in 189 Cystic Fibrosis and 134 control subjects; key clinical features of patients were recorded and compared among homozygous 5-allele patients and the other MIF genotypes. Patients homozygous for the 5-repeat allele of MIF promoter displayed a slower rate of lung function decline (p = 0.027) at multivariate survival analysis. Multiple regression analysis on age-normalized respiratory volume showed no association of the homozygous 5-repeat genotype with lung function under stable conditions and no correlation with P.aeruginosa chronic colonization. Therefore, only the Homozygous 5-repeat genotype at MIF -794 is associated with milder disease in F508del Cystic Fibrosis patients.


Treating overweight children and adolescents in the clinic.
The increasing prevalence of pediatric overweight has caused the medical community to begin searching for ways to deal with this new pediatric medical problem. The Centers for Disease Control developed the Body Mass Index (BMI) growth charts, which came into use in 2000. Primary care providers are seeking education on this relatively new topic. This article provides fundamental information based on the medical evidence for pediatricians to learn how to care for their overweight pediatric patients in the office setting.


Magnon Valve Effect between Two Magnetic Insulators.
The key physics of the spin valve involves spin-polarized conduction electrons propagating between two magnetic layers such that the device conductance is controlled by the relative magnetization orientation of two magnetic layers. Here, we report the effect of a magnon valve which is made of two ferromagnetic insulators (YIG) separated by a nonmagnetic spacer layer (Au). When a thermal gradient is applied perpendicular to the layers, the inverse spin Hall voltage output detected by a Pt bar placed on top of the magnon valve depends on the relative orientation of the magnetization of two YIG layers, indicating the magnon current induced by the spin Seebeck effect at one layer affects the magnon current in the other layer separated by Au. We interpret the magnon valve effect by the angular momentum conversion and propagation between magnons in two YIG layers and conduction electrons in the Au layer. The temperature dependence of the magnon valve ratio shows approximately a power law, supporting the above magnon-electron spin conversion mechanism. This work opens a new class of valve structures beyond the conventional spin valves.


Manual joint mobilisation techniques, supervised physical activity, psychological treatment, acupuncture and patient education in migraine treatment. A systematic review and meta-analysis.
Many people suffering from migraine combine pharmacological and non-pharmacological treatments. The purpose of this systematic review is to provide an updated guideline for some widely used non-pharmacological treatment options for migraine. We conducted a systematic literature review of randomized studies of adults with migraine treated with manual joint mobilisation techniques, supervised physical activity, psychological treatment, acupuncture and patient education. The main outcomes measured were days with headache and quality of life. Recommendations were formulated based on the Grade of Recommendation, Assessment, Development and Evaluation (GRADE) approach including patient preferences based on expert opinion and questionnaire data. The overall level of certainty of the evidence was low to very low. Manual therapy techniques and psychological treatment did not change the studied outcomes. Supervised physical activity might have a positive impact on quality of life, acupuncture on headache frequency, intensity, quality of life and the use of attack-medicine. Patient education might improve self-rated health and quality of life and increase the number of well-informed patients. Based on observed effects, the lack of serious adverse events, and patients' preferences, we make weak recommendations for considering the investigated interventions as a supplement to standard treatment.Protocol registration: Prospero CRD42020220132.


Case Report: Fatal Acute Liver Failure With Giant Cell Transformation in a Pediatric Patient Associated With MIS-C.
Background: We describe the first pediatric case of a 10-month-old boy with MIS-C who developed fulminant acute liver failure with associated giant cell transformation and a fatal outcome, after ruling out other infectious, metabolic, genetic, and autoimmune causes of liver failure following the usual algorithms for approaching the etiology. Although the patient received the main treatment strategies for liver failure, he had a fatal outcome. A clinical autopsy was considered as part of the diagnostic approach, which showed evidence of giant cell transformation.


Involvement of promyelocytic leukemia protein in the ethanol-induced apoptosis in mouse embryo fibroblasts.
The promyelocytic leukemia (PML) gene is a tumor suppressor gene associated with cell apoptosis, cell proliferation, and senescence. However, the role of PML in the ethanol-induced apoptosis is not fully-known. In this study, using wild-type mouse embryo fibroblasts (MEF) and PML null MEF cells, we found that (1) ethanol (100 mM and 200 mM) could obviously induce apoptosis of wild-type MEF cells, whereas, in PML null MEF cells, the pro-apoptotic function of ethanol was partially blocked; (2) the expression levels of phosphorylated p53 and two of its target genes, p21 and Bax, could be significantly up-regulated by ethanol (200 mM) in wild-type MEF cells in a time-dependent manner, but not in PML null MEF cells. These results indicate that PML plays an important role in ethanol-induced apoptosis, and p53-dependent apoptotic pathway may be involved in this process.


One-stage complete unifocalization in infants: when should the ventricular septal defect be closed?
The decision whether to close the ventricular septal defect at the time of unifocalization in patients with pulmonary atresia, ventricular septal defect, and major aortopulmonary collaterals may be difficult. The purpose of this study was to develop morphologic and physiologic methods to aid in deciding whether to close the ventricular septal defect in patients undergoing one-stage unifocalization. Between July 1992 and April 1996, 27 infants with pulmonary atresia, ventricular septal defect, and aortopulmonary collaterals were treated at our institution. Midline complete unifocalization was performed in 25 patients-the ventricular septal defect was closed in 17 and left open in eight. Two patients with severe distal collateral stenoses underwent staged unifocalization. Pulmonary artery and collateral sizes were measured from preoperative angiograms and used to calculate the indexed cross-sectional area of the total neopulmonary artery bed. An intraoperative pulmonary flow study previously validated with experiments in neonatal lambs was performed in six patients: the unifocalized neopulmonary arteries were perfused with a known flow and pulmonary artery pressures were recorded. The neopulmonary artery index was greater in patients who underwent ventricular septal defect closure than in those who did not (p = 0.001), although the values did overlap. This index correlated with the postoperative right ventricular/left ventricular pressure ratio (p = 0.037). Mean pulmonary artery pressures obtained during the intraoperative flow study and after bypass were comparable. The total neopulmonary artery index correlates with postrepair right ventricular/left ventricular pressure ratio and is useful in deciding when to close the ventricular septal defect if it is larger than 200 mm2/m2. The pulmonary flow study is helpful in deciding whether to close the ventricular septal defect in all patients.


Regional variations in mechanical strain in the posterior human sclera.
The goal of this study was to establish sectorial and regional variability in the mechanical strain of peripapillary and mid-peripheral sclera in normal eyes from elderly human donors. Ten pairs of normal eyes from human donors aged 57 to 90 years old were mechanically inflation-tested within 48 hours post mortem. The intact posterior scleral shells were pressurized from 5 to 45 mm Hg while the full-field three-dimensional displacements of the scleral surface were measured using laser speckle interferometry. The displacement field was fit to continuous and differentiable analytical functions, from which the full strain tensor of the outer scleral surface was calculated. Mean maximum principal (tensile) strain was computed for eight circumferential sectors (45° wide) within the peripapillary and mid-peripheral regions surrounding the optic nerve head (ONH). Overall, the peripapillary sclera exhibited significantly higher tensile strain (1.2%) than mid-peripheral sclera (0.95%) for a 40 mm Hg IOP elevation (P < 0.00001). In the peripapillary region, the inferotemporal sector exhibited the highest tensile strain (1.45%) while the superior sector had the lowest (1.19%; P < 0.00001). Mid-peripheral scleral strains were lower but exhibited a similar sectorial pattern. Human posterior sclera exhibits complex regional mechanical behavior in response to acute IOP elevations from 5 to 45 mm Hg. Results indicate 1) the peripapillary sclera is subjected to significantly higher tensile strain than the adjacent mid-peripheral sclera, and 2) strains are significantly higher in the temporal and inferior quadrants of the peripapillary sclera, which may contribute to the increased prevalence of glaucomatous damage associated with these regions of the ONH.


Properties of K-currents in unmyelinated presynaptic axons of brain revealed revealed by extracellular polarisation.
Thin pial surface slices of guinea-pig olfactory cortex contain unmyelinated axons derived from the lateral olfactory tract (LOT). The severed ends of the groups of these axons were drawn into a suction electrode to record the currents resulting from propagated action potentials. On stimulating these unmyelinated axons, a tetrodotoxin-sensitive positive current of 22.5 +/- 3.0 nA was recorded by the suction electrode. The positive current was often followed by a small negative current. A 100 mV positive polarisation applied to the suction electrode revealed a large negative after-current (25.8 +/- 3.5 nA). In contrast, the positive current was slightly reduced by the polarisation. The early phases of the negative after-current induced by the electrode polarisation were blocked by 3,4-diaminopyridine, 4-aminopyridine or 2,3-diaminopyridine (in order of potency). The entire negative after-current was blocked by prolonged (3 h) equilibration in a medium containing 3.5 mmol/l Cs and 1.5 mmol/l K. Tetraethylammonium (TEA) or Ba2+ by themselves had little effect. In aminopyridine, the residual negative after-current was blocked by TEA (10 mmol/l) or 1 mmol/l Ba2+. Muscarinic agonists had no effect on these currents. These experiments show that some axonal currents can be revealed by extracellular polarisation and that these axons rely on an 'A' type of current for the rapid repolarisation of the membrane although slower K-channels are present.


The effect of frequency and grounding on whole-body absorption of humans in E-polarized radiofrequency fields.
The radiofrequency absorption rates of five male human volunteers have been measured from 3 to 41 MHz. The subjects were exposed at about 10 microW /cm2 inside a very large transverse electromagnetic (TEM) cell and never absorbed more than 1 W. Both the EKH and EHK orientations were employed under both free-space and grounded conditions. Absorption rates for the EKH orientation exceed those of the EHK orientation by 40% in free space, but only by 6% when grounded. The absorption rates for the grounded men vary with frequency, f, as f1.9 from 3 to 25 MHz and then level off at peak. The free-space absorption rates vary as f1.7 from 3 to 18 MHz and as f2.9 from 18 to 41 MHz. The average measured absorption rates at 10 MHz exceed the average of the standard model calculations by a factor of three (for free space) or four (grounded). The average man, when exposed grounded in an EKH orientation to the maximum permitted exposure levels under ANSI standard C95 .1-1982, will absorb 0.58 +/- 0.14 W/kg over most of the 3 to 41-MHz frequency range. This slightly exceeds the whole-body maximum of 0.40 W/kg underlying the standard.


Heterogeneous Family of Cyclomodulins: Smart Weapons That Allow Bacteria to Hijack the Eukaryotic Cell Cycle and Promote Infections.
Some bacterial pathogens modulate signaling pathways of eukaryotic cells in order to subvert the host response for their own benefit, leading to successful colonization and invasion. Pathogenic bacteria produce multiple compounds that generate favorable conditions to their survival and growth during infection in eukaryotic hosts. Many bacterial toxins can alter the cell cycle progression of host cells, impairing essential cellular functions and impeding host cell division. This review summarizes current knowledge regarding cyclomodulins, a heterogeneous family of bacterial effectors that induce eukaryotic cell cycle alterations. We discuss the mechanisms of actions of cyclomodulins according to their biochemical properties, providing examples of various cyclomodulins such as cycle inhibiting factor, γ-glutamyltranspeptidase, cytolethal distending toxins, shiga toxin, subtilase toxin, anthrax toxin, cholera toxin, adenylate cyclase toxins, vacuolating cytotoxin, cytotoxic necrotizing factor, Panton-Valentine leukocidin, phenol soluble modulins, and mycolactone. Special attention is paid to the benefit provided by cyclomodulins to bacteria during colonization of the host.


Estimating trans-seasonal variability in water column biomass for a highly migratory, deep diving predator.
The deployment of animal-borne electronic tags is revolutionizing our understanding of how pelagic species respond to their environment by providing in situ oceanographic information such as temperature, salinity, and light measurements. These tags, deployed on pelagic animals, provide data that can be used to study the ecological context of their foraging behaviour and surrounding environment. Satellite-derived measures of ocean colour reveal temporal and spatial variability of surface chlorophyll-a (a useful proxy for phytoplankton distribution). However, this information can be patchy in space and time resulting in poor correspondence with marine animal behaviour. Alternatively, light data collected by animal-borne tag sensors can be used to estimate chlorophyll-a distribution. Here, we use light level and depth data to generate a phytoplankton index that matches daily seal movements. Time-depth-light recorders (TDLRs) were deployed on 89 southern elephant seals (Mirounga leonina) over a period of 6 years (1999-2005). TDLR data were used to calculate integrated light attenuation of the top 250 m of the water column (LA(250)), which provided an index of phytoplankton density at the daily scale that was concurrent with the movement and behaviour of seals throughout their entire foraging trip. These index values were consistent with typical seasonal chl-a patterns as measured from 8-daySea-viewing Wide Field-of-view Sensor (SeaWiFs) images. The availability of data recorded by the TDLRs was far greater than concurrent remotely sensed chl-a at higher latitudes and during winter months. Improving the spatial and temporal availability of phytoplankton information concurrent with animal behaviour has ecological implications for understanding the movement of deep diving predators in relation to lower trophic levels in the Southern Ocean. Light attenuation profiles recorded by animal-borne electronic tags can be used more broadly and routinely to estimate lower trophic distribution at sea in relation to deep diving predator foraging behaviour.


Whole-cell Patch-clamp Recordings for Electrophysiological Determination of Ion Selectivity in Channelrhodopsins.
Over the past decade, channelrhodopsins became indispensable in neuroscientific research where they are used as tools to non-invasively manipulate electrical processes in target cells. In this context, ion selectivity of a channelrhodopsin is of particular importance. This article describes the investigation of chloride selectivity for a recently identified anion-conducting channelrhodopsin of Proteomonas sulcata via electrophysiological patch-clamp recordings on HEK293 cells. The experimental procedure for measuring light-gated photocurrents demands a fast switchable - ideally monochromatic - light source coupled into the microscope of an otherwise conventional patch-clamp setup. Preparative procedures prior to the experiment are outlined involving preparation of buffered solutions, considerations on liquid junction potentials, seeding and transfection of cells, and pulling of patch pipettes. The actual recording of current-voltage relations to determine the reversal potentials for different chloride concentrations takes place 24 h to 48 h after transfection. Finally, electrophysiological data are analyzed with respect to theoretical considerations of chloride conduction.


Aflatoxin B1 Contamination of Dairy Feeds after Storage in Farm Practice in Tropical Environmen.
The objective of this study was to determine the contamination of aflatoxin B1 (AF-B1) when keeping various dairy feeds in a farm environment. The study was carried out from March to May 2011 and involved 63 small holder dairy farms belonging to a single dairy cooperative in Chiang Mai province, Thailand. All feed samples used for milking cows including 4 commercial concentrates (CC1 to CC4), by-products from local corn processing factories fermented in plastic bags (SIL), and corn and cob meal or corn dust (CCD). Feed samples were collected 2 times at before and after storage. Farmers were requested to store CC1 to CC4 and CCD for a month and SIL for a week using their routine on-farm storage arrangements. All samples were measured for their AF-B1 concentrations by ELISA. Results showed that AF-B1 concentrations of CC1 to CC4, SIL and CCD before storage were 5.1, 4.1, 4.0, 4.2, 5.5 and 5.5 μg/kg, respectively, and after storage the concentration of AF-B1 were 9.7, 6.5, 9.8, 12.3, 11.4 and 20.0 μg/kg, respectively. CCD at after storage was the only feed that had mean level more than 20 μg/kg. Concentrations of AF- B1 at before storage in all feeds were significantly lower than after storage (P<0.01), and the increased ratio of AF-B1 levels was approximately 2 to 3 times. The study concluded that increased AF-B1 levels are related to feed types and farm conditions.


On national flags and language tags: Effects of flag-language congruency in bilingual word recognition.
French-English bilinguals performed a generalized lexical decision experiment with mixed lists of French and English words and pseudo-words. In Experiment 1, each word/pseudo-word was superimposed on the picture of the French or UK flag, and flag-word congruency was manipulated. The flag was not informative with respect to either the lexical decision response or the language of the word. Nevertheless, lexical decisions to word stimuli were faster following the congruent flag compared with the incongruent flag, but only for French (L1) words. Experiment 2 replicated this flag-language congruency effect in a priming paradigm, where the word and pseudo-word targets followed the brief presentation of the flag prime, and this time effects were seen in both languages. We take these findings as evidence for a mechanism that automatically processes linguistic and non-linguistic information concerning the presence or not of a given language. Language membership information can then modulate lexical processing, in line with the architecture of the BIA model, but not the BIA+ model.


Meticillin-resistant Staphylococcus aureus and meticillin-susceptible S. aureus pneumonia: comparison of clinical and thin-section CT findings.
The purpose of this study was to compare the clinical and thin-section CT findings in patients with meticillin-resistant Staphylococcus aureus (MRSA) and meticillin-susceptible S. aureus (MSSA). We retrospectively identified 201 patients with acute MRSA pneumonia and 164 patients with acute MSSA pneumonia who had undergone chest thin-section CT examinations between January 2004 and March 2009. Patients with concurrent infectious disease were excluded from our study. Consequently, our study group comprised 68 patients with MRSA pneumonia (37 male, 31 female) and 83 patients with MSSA pneumonia (32 male, 51 female). Clinical findings in the patients were assessed. Parenchymal abnormalities, lymph node enlargement and pleural effusion were assessed. Underlying diseases such as cardiovascular were significantly more frequent in the patients with MRSA pneumonia than in those with MSSA pneumonia. CT findings of centrilobular nodules, centrilobular nodules with a tree-in-bud pattern, and bronchial wall thickening were significantly more frequent in the patients with MSSA pneumonia than those with MRSA pneumonia (p = 0.038, p = 0.007 and p = 0.039, respectively). In the group with MRSA, parenchymal abnormalities were observed to be mainly peripherally distributed and the frequency was significantly higher than in the MSSA group (p = 0.028). Pleural effusion was significantly more frequent in the patients with MRSA pneumonia than those with MSSA pneumonia (p = 0.002). Findings from the evaluation of thin-section CT manifestations of pneumonia may be useful to distinguish between patients with acute MRSA pneumonia and those with MSSA pneumonia.


Chemoselective bioconjugation of triazole phosphonites in aqueous media.
Readily accessible and versatile phosphonite building blocks with improved stability against hydrolysis were used for the efficient metal-free functionalization of peptides and proteins in aqueous buffers at low micromolar concentrations. The application of this protocol to the immobilization of a Rasa1-SH2 domain revealed high binding affinity to the human T-cell protein ADAP and supports the applicability of triazole phosphonites for protein modifications without harming their function.


Increase in muscle tone promotes the use of ankle strategies during perturbed stance.
To maintain an upright standing posture against external disturbances, the human body mainly employs two types of postural control strategies: "ankle strategy" and "hip strategy." While it has been reported that the magnitude of the disturbance alters the use of postural control strategies, it has not been elucidated how the level of muscle tone, one of the crucial parameters of bodily function, determines the use of each strategy. We have previously confirmed using forward dynamics simulations of human musculoskeletal models that an increased muscle tone promotes the use of ankle strategies. The objective of the present study was to experimentally evaluate a hypothesis: an increased muscle tone promotes the use of ankle strategies. Do changes in the muscle tone affect the use of ankle strategies? Participants were asked to maintain their standing posture on a movable platform sliding horizontally at several accelerations. Postural reactions for support surface translations were examined under three instructions with or without handgrips: relax state, squeezing a handgrip, and an increased muscle tone of the whole body. Surface-electromyography and marker locations of joints were measured to calculate the index of muscle tone and postural control strategies. The relationship of the indexes was evaluated based on correlation coefficients. In half of the conditions, weak negative correlations were noted between the muscle tone index and postural control strategy index. In other words, an increased muscle tone rather promoted the use of the ankle strategy than the hip strategy. These findings are consistent with our previous simulation results. The results recognized a positive response to the research question. This suggests that it is crucial to take muscle tone into account to understand postural control strategies.


Assessment of the Stability and Operability of Cobalt Phosphide Electrocatalyst for Hydrogen Evolution.
Transition metal phosphides have been investigated heavily as hydrogen evolution reaction (HER) catalysts. One of the most active transition metal phosphides, CoP, has been tested for its stability and operability under mild conditions that it may be exposed to in its applications (photoelectrochemistry and artificial photosynthesis). Surface-interrogation scanning electrochemical microscopy (SI-SECM) revealed that CoP HER catalyst is vulnerable to oxidation (by oxygen and chemical oxidants). The degradation mechanism was shown to be surface oxidation by dioxygen, followed by acid etching of the oxidized layer. The compositional integrity (unity ratio of cobalt and phosphorus) was maintained throughout the film decomposition progress.


Topology studies of hydrodynamics using two-particle correlation analysis.
The effects of fluctuating initial conditions are studied in the context of relativistic heavy ion collisions where a rapidly evolving system is formed. Two-particle correlation analysis is applied to events generated with the NEXSPHERIO hydrodynamic code, starting with fluctuating nonsmooth initial conditions (IC). The results show that the nonsmoothness in the IC survives the hydroevolution and can be seen as topological features of the angular correlation function of the particles emerging from the evolving system. A long range correlation is observed in the longitudinal direction and in the azimuthal direction a double peak structure is observed in the opposite direction to the trigger particle. This analysis provides clear evidence that these are signatures of the combined effect of tubular structures present in the IC and the proceeding collective dynamics of the hot and dense medium.


Uveal melanoma as a target for immune-therapy.
Uveal melanoma (UM) is a rare disease that can be deadly in spite of adequate local treatment. Systemic therapy with chemotherapy is usually ineffective and new-targeted therapies have not improved results considerably. The eye creates an immunosuppressive environment in order to protect eyesight. UM cells use similar processes to escape immune surveillance. Regarding innate immunity the production of macrophage inhibiting factor (MIF) and TGF-β, added to MHC class I upregulation, inhibits the action of natural killer (NK) cells. UM cells produce cytokines such as IL-6 and IL-10 that favor macrophage differentiation to the M2 subtype, which promote tumor growth instead of an effective immune response. UM cells also impair the adaptive immune response through production of indoleamine 2,3-dioxygenase (IDO), overexpression of programmed death ligand-1 (PD-L1), alteration of FasL expression, and resistance to perforin. This biological background suggests that immunotherapy could be effective in fighting UM. A Phase II clinical trial with Ipilimumab has shown promising results with mean Overall Survival rate of ten months, and close to 50% of the patients alive at one year. Clinical trials with anti-PD1 antibodies in monotherapy and in combination with anti-CTLA4 are currently recruiting patients worldwide.


The potential curative effect of rebamipide in hepatic ischemia/reperfusion injury.
Rebamipide (Reba), a gastroprotective drug, has signified its hepatoprotective activity; however, its possible post-therapeutic intervention in hepatic ischemia/reperfusion (I/R) remains elusive. Consequently, the intent of this study was to test Reba modulatory effect on nuclear factor (NF)-κB signaling in hepatic I/R model. Rats were randomized into sham, I/R, Reba 60, and Reba100 (60 and 100 mg/kg, respectively) groups. Ischemia was induced for 30 min followed by 3-day reperfusion to set up a model of partial (70%) warm hepatic ischemia. Post-treatment with Reba reduced the serum level of alanine transaminase, improved histopathological alterations of the liver, and elevated hepatic adenosine triphosphate. It also lowered hepatic lipid peroxides and increased both total antioxidant capacity and nitric oxide. Besides, Reba decreased tumor necrosis factor-α, interferon-γ, intercellular adhesion molecule-1, myeloperoxidase, prostaglandin E2, cyclooxygenase-2 expression/content, and caspase-3 activity. Reba also upregulated the gene expression/content of sirtuin 1 (SIRT-1), while it downregulated that of high mobility group box (HMGB)1 and reduced the expression/content of NF-κB p65/pS536-NF-κB and the content of pT180/Y182-p38MAPK. Reba provided tenable hepato-therapeutic mechanisms to mitigate events concomitant with hepatic I/R via inhibition of NF-κB p65 and modulation of its influential signals (SIRT-1, HMGB1, p38MAPK) associated with its antiinflammatory, antioxidant, and antiapoptotic impacts.


Regulatory Roles of Long Non-Coding RNAs in the Central Nervous System and Associated Neurodegenerative Diseases.
Accumulating studies have revealed that the human genome encodes tens of thousands of long non-coding RNAs (lncRNAs), which participate in multiple biological networks modulating gene expression via transcriptional, post-transcriptional and epigenetic regulation. Strikingly, a large fraction of tissue-specific lncRNAs are expressed in the Central Nervous System (CNS) with precisely regulated temporal and spatial expression patterns. These brain-specific lncRNAs are also featured with the cell-type specificity, the highest signals of evolutionary conservation, and their preferential location adjacent to brain-expressed protein-coding genes. Mounting evidence has indicated dysregulation or mutations in lncRNA gene loci are associated with a variety of CNS-associated neurodegenerative disorders, such as Alzheimer's, Parkinson's, Huntington's diseases, Amyotrophic Lateral Sclerosis and others. However, how lncRNAs contribute to these disorders remains to be further explored and studied. In this review article, we systematically and comprehensively summarize the current studies of lncRNAs, demonstrate the specificity of lncRNAs expressed in the brain, their functions during neural development and expression profiles in major cell types of the CNS, highlight the regulatory mechanisms of several studied lncRNAs that may play essential roles in the pathophysiology of neurodegenerative diseases, and discuss the current challenges and future perspectives of lncRNA studies involved in neurodegenerative and other diseases.


[A case of large arteriovenous malformation in the frontal lobe complicating attention-deficit/hyperactivity disorder].
We report a 4-year old boy with a large arteriovenous malformation (AVM) exhibiting attention-deficit hyperactivity disorder (AD/HD). He presented with hyperkinesis at the age of 3 years and jacksonian seizure at 3 years 11 months, when he was diagnosed as AVM by cranial computed tomography. Magnetic resonance imaging revealed an AVM of 6 cm in diameter in the left frontal lobe. After 1 year, the AVM developed a varix, and both were surgically removed. We speculate that the prefrontal area was affected by direct compression from AVM and chronic ischemia due to steal phenomenon. Although AD/HD is rarely caused by parenchymal lesions, such as AVM, physicians should carefully investigate causative lesions.