The battle for iron in enteric infections.
Iron is an essential element for almost all living organisms, but can be extremely toxic in high concentrations. All organisms must therefore employ homeostatic mechanisms to finely regulate iron uptake, usage and storage in the face of dynamic environmental conditions. The critical step in mammalian systemic iron homeostasis is the fine regulation of dietary iron absorption. However, as the gastrointestinal system is also home to >1014 bacteria, all of which engage in their own programmes of iron homeostasis, the gut represents an anatomical location where the inter-kingdom fight for iron is never-ending. Here, we explore the molecular mechanisms of, and interactions between, host and bacterial iron homeostasis in the gastrointestinal tract. We first detail how mammalian systemic and cellular iron homeostasis influences gastrointestinal iron availability. We then focus on two important human pathogens, Salmonella and Clostridia; despite their differences, they exemplify how a bacterial pathogen must navigate and exploit this web of iron homeostasis interactions to avoid host nutritional immunity and replicate successfully. We then reciprocally explore how iron availability interacts with the gastrointestinal microbiota, and the consequences of this on mammalian physiology and pathogen iron acquisition. Finally, we address how understanding the battle for iron in the gastrointestinal tract might inform clinical practice and inspire new treatments for important diseases.


Strengthening routine immunization in Papua New Guinea: a cross-sectional provincial assessment of front-line services.
Routine immunization programs face many challenges in settings such as Papua New Guinea with dispersed rural populations, rugged geography and limited resources for transport and health. Low routine coverage contributes to disease outbreaks such as measles and the polio that re-appeared in 2018. We report on an in-depth local assessment that aimed to document immunization service provision so as to review a new national strategy, and consider how routine immunization could be better strengthened. In East New Britain Province, over 2016 and 17, we carried out a cross-sectional assessment of 12 rural health facilities, staff and clients. The study was timed to follow implementation of a new national strategy for strengthening routine immunization. We used interview, structured observation, and records review, informed by theory-based evaluation, a World Health Organization quality checklist, and other health services research tools. We documented strengths and weaknesses across six categories of program performance relevant to national immunization strategy and global standards. We found an immunization service with an operational level of staff, equipment and procedures in place; but one that could reach only half to two thirds of its target population. Stronger routine services require improvement in: understanding of population catchments, tracking the unvaccinated, reach and efficiency of outreach visits, staff knowledge of vaccination at birth and beyond the first year of life, handling of multi-dose vials, and engagement of community members. Many local suggestions to enhance national plans, included more reliable on-demand services, integration of other family health services and increased involvement of men. The national strategy addresses most local gaps, but implementation and resourcing requires greater commitment. Long-term strengthening requires a major increase in centrally-allocated resources, however there are immediate locally feasible steps within current resources that could boost coverage and quality of routine immunization especially through better population-based local planning, and stronger community engagement. Our results also suggest areas where vaccination campaigns in PNG can contribute to routine immunization services.


RNAcmap: a fully automatic pipeline for predicting contact maps of RNAs by evolutionary coupling analysis.
The accuracy of RNA secondary and tertiary structure prediction can be significantly improved by using structural restraints derived from evolutionary coupling or direct coupling analysis. Currently, these coupling analyses relied on manually curated multiple sequence alignments collected in the Rfam database, which contains 3016 families. By comparison, millions of non-coding RNA sequences are known. Here, we established RNAcmap, a fully automatic pipeline that enables evolutionary coupling analysis for any RNA sequences. The homology search was based on the covariance model built by INFERNAL according to two secondary structure predictors: a folding-based algorithm RNAfold and the latest deep-learning method SPOT-RNA. We showed that the performance of RNAcmap is less dependent on the specific evolutionary coupling tool but is more dependent on the accuracy of secondary structure predictor with the best performance given by RNAcmap (SPOT-RNA). The performance of RNAcmap (SPOT-RNA) is comparable to that based on Rfam-supplied alignment and consistent for those sequences that are not in Rfam collections. Further improvement can be made with a simple meta predictor RNAcmap (SPOT-RNA/RNAfold) depending on which secondary structure predictor can find more homologous sequences. Reliable base-pairing information generated from RNAcmap, for RNAs with high effective homologous sequences, in particular, will be useful for aiding RNA structure prediction. RNAcmap is available as a web server at https://sparks-lab.org/server/rnacmap/ and as a standalone application along with the datasets at https://github.com/sparks-lab-org/RNAcmap_standalone. A platform independent and fully configured docker image of RNAcmap is also provided at https://hub.docker.com/r/jaswindersingh2/rnacmap. Supplementary data are available at Bioinformatics online.


Novel microscopy-based screening method reveals regulators of contact-dependent intercellular transfer.
Contact-dependent intercellular transfer (codeIT) of cellular constituents can have functional consequences for recipient cells, such as enhanced survival and drug resistance. Pathogenic viruses, prions and bacteria can also utilize this mechanism to spread to adjacent cells and potentially evade immune detection. However, little is known about the molecular mechanism underlying this intercellular transfer process. Here, we present a novel microscopy-based screening method to identify regulators and cargo of codeIT. Single donor cells, carrying fluorescently labelled endocytic organelles or proteins, are co-cultured with excess acceptor cells. CodeIT is quantified by confocal microscopy and image analysis in 3D, preserving spatial information. An siRNA-based screening using this method revealed the involvement of several myosins and small GTPases as codeIT regulators. Our data indicates that cellular protrusions and tubular recycling endosomes are important for codeIT. We automated image acquisition and analysis to facilitate large-scale chemical and genetic screening efforts to identify key regulators of codeIT.


An asymmetric sheath controls flagellar supercoiling and motility in the leptospira spirochete.
Spirochete bacteria, including important pathogens, exhibit a distinctive means of swimming via undulations of the entire cell. Motility is powered by the rotation of supercoiled 'endoflagella' that wrap around the cell body, confined within the periplasmic space. To investigate the structural basis of flagellar supercoiling, which is critical for motility, we determined the structure of native flagellar filaments from the spirochete Leptospira by integrating high-resolution cryo-electron tomography and X-ray crystallography. We show that these filaments are coated by a highly asymmetric, multi-component sheath layer, contrasting with flagellin-only homopolymers previously observed in exoflagellated bacteria. Distinct sheath proteins localize to the filament inner and outer curvatures to define the supercoiling geometry, explaining a key functional attribute of this spirochete flagellum.


A combined mass spectrometry strategy for complete posttranslational modification mapping of Neisseria meningitidis major pilin.
Herein, we report a new approach, based on the combination of mass profiling and tandem mass spectrometry, to address the issue of localising all post-translational modifications (PTMs) on the major pilin protein PiIE expressed by the pathogenic Neisseria species. PilE is the main component of type IV pili; filamentous organelles expressed at the surface of many bacterial pathogens and important virulence factors. Previous reports have shown that PilE can harbour various combinations of PTMs and have established strong links between PTM and pathogenesis. Complete PTM mapping of proteins involved in bacterial infection is therefore highly desirable. The methodology we propose here allowed us to fully characterise the PilE proteoforms of Neisseria meningitidis strain 8013, definitively identifying all PTMs present on all proteoforms and localising their position on the protein backbone. These modifications include a processed and methylated N-terminus, disulfide bridge, glycosylation and glycerophosphorylation at two different sites. A key element of our approach is high resolution, intact mass measurement of the proteoforms, a piece of information completely lacking in all classical bottom-up proteomics strategies used for PTM analysis and without which it is difficult to ensure complete PTM mapping.


Plasma homocysteine level in patients with Behcet's disease with or without thrombosis.
To find the possible role of plasma homocysteine level as a contributing factor in venous and arterial thrombosis in patients with Behcet's disease (BD). In a case control study, two groups of BD patients were included: 47 with thrombosis and 49 without thrombosis. All patients fulfilled the International Study Group Criteria for BD and the confirming diagnostic procedures for vascular thrombosis were either Doppler sonography or angiography. Forty-nine controls were selected by consecutive sampling among age and sex matched healthy subjects. Plasma homocysteine level was measured by ELISA in all. The clinical and laboratory characteristics of the disease were compared between the two groups of BD patients. Comparisons were done by ANOVA and Chi square tests; correlations were analyzed with Pearson test. The mean plasma homocysteine level was significantly higher in BD patients (14.9±13.9 μMol/L) than in healthy controls (9.9±6.7 μMol/L), P<0.02. The difference was also significant when comparing the three groups by ANOVA: BD patients with thrombosis (24.2±13.2 μMol/L), BD patients without thrombosis (5.9±7.0 μMol/L), and healthy controls (P<0.0001). We found no correlation between plasma homocysteine level and any organ involvement other than thrombosis. The mean plasma homocysteine level was lower in HLA-B51 positive BD patients (11.6±12.1 vs. 21.7±16.3 μMol/L, P<0.05), but the difference was not significant in those with thrombosis (20.9±13.2 vs. 29.5±12.7 μMol/L, P=0.18). Hyperhomocysteinaemia may be an independent risk factor for vascular thrombosis in patients with BD. This is the first study showing a negative correlation between HLA-B51 and plasma homocysteine level.


Automatic clustering of orthologs and in-paralogs from pairwise species comparisons.
Orthologs are genes in different species that originate from a single gene in the last common ancestor of these species. Such genes have often retained identical biological roles in the present-day organisms. It is hence important to identify orthologs for transferring functional information between genes in different organisms with a high degree of reliability. For example, orthologs of human proteins are often functionally characterized in model organisms. Unfortunately, orthology analysis between human and e.g. invertebrates is often complex because of large numbers of paralogs within protein families. Paralogs that predate the species split, which we call out-paralogs, can easily be confused with true orthologs. Paralogs that arose after the species split, which we call in-paralogs, however, are bona fide orthologs by definition. Orthologs and in-paralogs are typically detected with phylogenetic methods, but these are slow and difficult to automate. Automatic clustering methods based on two-way best genome-wide matches on the other hand, have so far not separated in-paralogs from out-paralogs effectively. We present a fully automatic method for finding orthologs and in-paralogs from two species. Ortholog clusters are seeded with a two-way best pairwise match, after which an algorithm for adding in-paralogs is applied. The method bypasses multiple alignments and phylogenetic trees, which can be slow and error-prone steps in classical ortholog detection. Still, it robustly detects complex orthologous relationships and assigns confidence values for both orthologs and in-paralogs. The program, called INPARANOID, was tested on all completely sequenced eukaryotic genomes. To assess the quality of INPARANOID results, ortholog clusters were generated from a dataset of worm and mammalian transmembrane proteins, and were compared to clusters derived by manual tree-based ortholog detection methods. This study led to the identification with a high degree of confidence of over a dozen novel worm-mammalian ortholog assignments that were previously undetected because of shortcomings of phylogenetic methods.A WWW server that allows searching for orthologs between human and several fully sequenced genomes is installed at http://www.cgb.ki.se/inparanoid/. This is the first comprehensive resource with orthologs of all fully sequenced eukaryotic genomes. Programs and tables of orthology assignments are available from the same location.


Juveniles Are More Resistant to Warming than Adults in 4 Species of Antarctic Marine Invertebrates.
Juvenile stages are often thought to be less resistant to thermal challenges than adults, yet few studies make direct comparisons using the same methods between different life history stages. We tested the resilience of juvenile stages compared to adults in 4 species of Antarctic marine invertebrate over 3 different rates of experimental warming. The species used represent 3 phyla and 4 classes, and were the soft-shelled clam Laternula elliptica, the sea cucumber Cucumaria georgiana, the sea urchin Sterechinus neumayeri, and the seastar Odontaster validus. All four species are widely distributed, locally abundant to very abundant and are amongst the most important in the ecosystem for their roles. At the slowest rate of warming used (1°C 3 days(-1)) juveniles survived to higher temperatures than adults in all species studied. At the intermediate rate (1°C day(-1)) juveniles performed better in 3 of the 4 species, with no difference in the 4(th), and at the fastest rate of warming (1°C h(-1)) L. elliptica adults survived to higher temperatures than juveniles, but in C. georgiana juveniles survived to higher temperatures than adults and there were no differences in the other species. Oxygen limitation may explain the better performance of juveniles at the slower rates of warming, whereas the loss of difference between juveniles and adults at the fastest rate of warming suggests another mechanism sets the temperature limit here.


Test-retest reliability of dynamic functional connectivity in resting state fMRI.
While static functional connectivity (sFC) of resting state fMRI (rfMRI) measures the average functional connectivity (FC) over the entire rfMRI scan, dynamic FC (dFC) captures the temporal variations of FC at shorter time windows. Although numerous studies have implemented dFC analyses, only a few studies have investigated the reliability of dFC and this limits the biological interpretation of dFC. Here, we used a large cohort (N = 820) of subjects and four rfMRI scans from the Human Connectome Project to systematically explore the relationship between sFC, dFC and their test-retest reliabilities through intra-class correlation (ICC). dFC ICC was explored through the sliding window approach with three dFC statistics (standard deviation, ALFF, and excursion). Excursion demonstrated the highest dFC ICC and the highest age prediction accuracy. dFC ICC was generally higher at window sizes less than 40 s. sFC and dFC were negatively correlated. Compared to sFC, dFC was less reliable. While sFC and sFC ICC were positively correlated, dFC and dFC ICC were negatively correlated, indicating that FC that was more dynamic was less reliable. Intra-network FCs in the frontal-parietal, default mode, sensorimotor and visual networks demonstrated high sFC and low dFC. Moreover, ICCs of both sFC and dFC in these regions were higher. The above results were consistent across two brain atlases and independent component analysis-based networks, multiple window sizes and all three dFC statistics. In summary, dFC is less reliable than sFC and additional experiments are required to better understand the neurophysiological relevance of dFC.


Marital processes, arranged marriage, and contraception to limit fertility.
An international transition away from familially arranged marriages toward participation in spouse choice has endured for decades and continues to spread through rural Asia today. Although we know that this transformation has important consequences for childbearing early in marriage, we know much less about longer-term consequences of this marital revolution. Drawing on theories of family and fertility change and a rural Asian panel study designed to measure changes in both marital and childbearing behaviors, this study seeks to investigate these long-term consequences. Controlling for social changes that shape both marital practices and childbearing behaviors, and explicitly considering multiple dimensions of marital processes, we find evidence consistent with an independent, long-standing association of participation in spouse choice with higher rates of contraception to terminate childbearing. These results add a new dimension to the evidence linking revolutions in marital behavior to long-term declines in fertility and suggest that new research should consider a broader range of long-term consequences of changing marital processes.


Ovicidal effects of a neem seed extract preparation on eggs of body and head lice.
The eggs (nits) of head and body lice (Pediculus humanus capitis, Pediculus humanus corporis) were incubated for 5, 10, 15, 20, 30 or 45 min into a neem seed extract contained in a fine shampoo formulation (e.g. Wash Away® Louse), which is known for its significant killing effects of larvae and adults of head lice. The aim of the study was to test whether the developmental stages inside the eggs are also killed after the incubation into the shampoo. It was found that an incubation time of only 5 min was sufficient to prohibit any hatching of larvae, whilst 93 ± 4% of the larvae in the untreated controls of body lice hatched respectively about 76% of the controls in the case of head lice. Apparently, the neem-based shampoo blocked the aeropyles of the eggs, thus preventing the embryos of both races of lice from accessing oxygen and from releasing carbon dioxide. Thus, this product offers a complete cure from head lice upon a single treatment, if the lice (motile stages, eggs) are fully covered for about 10 min.


Dynamic single-slice CT estimates whole-lung dual-energy CT variables in pigs with and without experimental lung injury.
Dynamic single-slice CT (dCT) is increasingly used to examine the intra-tidal, physiological variation in aeration and lung density in experimental lung injury. The ability of dCT to predict whole-lung values is unclear, especially for dual-energy CT (DECT) variables. Additionally, the effect of inspiration-related lung movement on CT variables has not yet been quantified. Eight domestic pigs were studied under general anaesthesia, including four following saline-lavage surfactant depletion (lung injury model). DECT, dCT and whole-lung images were collected at 12 ventilatory settings. Whole-lung single energy scans images were collected during expiratory and inspiratory apnoeas at positive end-expiratory pressures from 0 to 20 cmH2O. Means and distributions of CT variables were calculated for both dCT and whole-lung images. The cranio-caudal displacement of the anatomical slice was measured from whole-lung images. Mean CT density and volume fractions of soft tissue, gas, iodinated blood, atelectasis, poor aeration, normal aeration and overdistension correlated between dCT and the whole lung (r2 0.75-0.94) with agreement between CT density distributions (r 0.89-0.97). Inspiration increased the matching between dCT and whole-lung values and was associated with a movement of 32% (SD 15%) of the imaged slice out of the scanner field-of-view. This effect introduced an artefactual increase in dCT mean CT density during inspiration, opposite to that caused by the underlying physiology. Overall, dCT closely approximates whole-lung aeration and density. This approximation is improved by inspiration where a decrease in CT density and atelectasis can be interpreted as physiological rather than artefactual.


Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment.
Traumatic injury to the central nervous system results in the disruption of the blood brain/spinal barrier, followed by the invasion of cells and other components of the immune system that can aggravate injury and affect subsequent repair and regeneration. Although studies of chronic neuroinflammation in the injured spinal cord of animals are clinically relevant to most patients living with traumatic injury to the brain or spinal cord, very little is known about chronic neuroinflammation, though several studies have tested the role of neuroinflammation in the acute period after injury. The present study characterizes a novel cell preparation method that assesses, quickly and effectively, the changes in the principal immune cell types by flow cytometry in the injured spinal cord, daily for the first 10 days and periodically up to 180 days after spinal cord injury. These data quantitatively demonstrate a novel time-dependent multiphasic response of cellular inflammation in the spinal cord after spinal cord injury and are verified by quantitative stereology of immunolabelled spinal cord sections at selected time points. The early phase of cellular inflammation is comprised principally of neutrophils (peaking 1 day post-injury), macrophages/microglia (peaking 7 days post-injury) and T cells (peaking 9 days post-injury). The late phase of cellular inflammation was detected after 14 days post-injury, peaked after 60 days post-injury and remained detectable throughout 180 days post-injury for all three cell types. Furthermore, the late phase of cellular inflammation (14-180 days post-injury) did not coincide with either further improvements, or new decrements, in open-field locomotor function after spinal cord injury. However, blockade of chemoattractant C5a-mediated inflammation after 14 days post-injury reduced locomotor recovery and myelination in the injured spinal cord, suggesting that the late inflammatory response serves a reparative function. Together, these data provide new insight into cellular inflammation of spinal cord injury and identify a surprising and extended multiphasic response of cellular inflammation. Understanding the role of this multiphasic response in the pathophysiology of spinal cord injury could be critical for the design and implementation of rational therapeutic treatment strategies, including both cell-based and pharmacological interventions.


Renovascular hypertension identified by captopril-induced changes in the renogram.
Radioisotope renography was performed in 21 patients with hypertension and unilateral renal artery stenosis with and without premedication with 25 mg of captopril, and the results were compared with the effect of percutaneous transluminal angioplasty on the blood pressure, assessed 6 weeks after angioplasty. Angioplasty caused a considerable decrease in blood pressure in 15 of the 21 patients. In 12 of these 15 patients, captopril induced changes in the time-activity curves of the affected kidney only, suggesting deterioration of the excretory function of that kidney, while the function of the contralateral kidney remained normal. After angioplasty the asymmetry in the time-activity curves diminished despite identical pretreatment with captopril. Such captopril-induced unilateral impairment of the renal function was not seen in the six patients with unilateral renal artery stenosis whose blood pressure did not change after percutaneous transluminal angioplasty or in 13 patients with hypertension and normal renal arteries. The functional impairment of the affected kidneys was characterized by a decrease of 99mTc-diethylenetriamine pentaacetic acid uptake and a delay of 131I-hippurate excretion, while the 131I-hippurate uptake remained unaffected. These data are in agreement with a reduced glomerular filtration rate and diuresis during preservation of the renal blood flow, changes that can be expected after converting enzyme inhibition in a kidney with low perfusion and an active, renin-mediated autoregulation of the glomerular filtration rate. These data suggest that functional captopril-induced unilateral changes, shown by split renal function studies with noninvasive gamma camera scintigraphy, can be used as a diagnostic test for renovascular hypertension caused by unilateral renal artery stenosis.(ABSTRACT TRUNCATED AT 250 WORDS)


Mechanisms of Disease: new insights into the cellular and molecular pathology of Peyronie's disease.
Peyronie's disease (PD) is characterized by fibrotic plaques in the penile tunica albuginea that cause curvature of the erect penis, and is often accompanied by pain and/or erectile dysfunction. This condition affects up to 9% of men. Treatment is mainly surgical, as pharmacologic therapy has limited efficacy. The pathophysiology of PD is poorly understood, but development of two rat models, extrapolation of what is known about the molecular pathology of other fibrotic conditions, and emphasis on the role of myofibroblasts and adult stem cells are helping to clarify etiology and identify new pharmacologic targets. Recent studies demonstrate a role for oxidative stress and cytokine release-primarily transforming-growth-factor beta1-in development of PD fibrotic plaques. There is evidence indicating that these profibrotic factors interact with antifibrotic defense mechanisms, such as decrease of myofibroblast accumulation, elimination of reactive oxygen species by inducible nitric oxide synthase and neutralization of transforming-growth-factor beta1 by decorin, such that some plaques are in dynamic turnover. Injury to the erect penis is thought to trigger PD by inducing extravasation of fibrin and subsequent synthesis of transforming-growth-factor beta1. Despite the lack of statistical support for a causal association between trauma and PD, it is possible that undetected microtrauma is involved. It is not known whether ossification of PD plaques is linked to fibrosis progression or is a manifestation of an alternative pathway. Both processes seem to be related to activation of fibroblast/myofibroblast differentiation in the tunica albuginea and to osteogenic commitment of stem cells in this tissue.


Change over Time in Police Interactions and HIV Risk Behavior Among Female Sex Workers in Andhra Pradesh, India.
Little is known about the effectiveness of intervening to change interactions between female sex workers (FSWs) and police in order to reduce HIV risk. Using data collected in the context of a HIV prevention intervention that included components to change policing practices (n = 1,680), we examine the association of FSWs' reports of negative police interactions and HIV risk behaviors and whether these associations varied over time. Results show negative police interactions declined significantly over time. FSWs who had more than one negative police interaction were more likely to experience STI symptoms (AOR 2.97 [95 % CI 2.27-3.89]), inconsistently use condoms with their clients (AOR 1.36 [95 % CI 1.03-1.79]), and accept more money for condomless sex (AOR 2.37 [95 % CI 1.76-3.21]). Over time, these associations were stable or increased. Even where interventions have reduced the number of police incidents experienced by FSWs, stakeholders in HIV prevention must remain vigilant in challenging these incidents.


Giving me hope: women's reflections on a breastfeeding peer support service.
Breastfeeding peer support has been identified as a key intervention to help improve breastfeeding and exclusive breastfeeding rates. The World Health Organization, and, in the UK, the National Institute for Health and Clinical Excellence, recommend the implementation of sustainable peer support programmes. As part of an evaluation into a comprehensive breastfeeding peer support service in north-west England, in-depth interviews were conducted with 47 women who had received a breastfeeding peer support service. In this paper, we have drawn upon the work of Morse and colleagues to interpret the data in relation to behavioural manifestations of hope, together with insights into the strategies used by the peer supporters to augment hopefulness for women's breastfeeding goals. These theoretical and practice-based findings offer insights into how the breastfeeding peer supporters provided realistic assessments across varying situational contexts, formed strategies and plans to help women overcome any obstacles, made women aware of any negative outcomes, mobilised external and personal resources to facilitate goal attainment, provided evaluations and feedback on women's (and infants') progress, and through praise, reassurance and instilling calm, the peer supporters helped women to focus their energy to achieve their breastfeeding goals. Practice-based implications are considered.


The influence of socio-economic status on adolescent attitude to social noise and hearing protection.
The focus of the present study, of 1285 adolescents, was young people's attitudes towards noise and their use of hearing protection at discos and pop concerts. Comparisons were made between adolescents from different age groups, and with different socio-economic status. Logistic regressions indicated that "worry before attending noisy activities" and "hearing symptoms" such as tinnitus and noise sensitivity could, to some degree, explain the use of hearing protection in noisy environments. Another conclusion to be drawn from this study was that adolescents' attitudes and behaviours regarding hearing protection use differed between levels of socio-economic status. Individuals with high SES expressed more negative attitudes and used ear protection to a greater extent than those with lower SES. This result might indicate differences in the development of future auditory problems among individuals with different levels of socio-economic status. The cause of hearing impairment and tinnitus may not be restricted merely to noise exposure. Psychological aspects, such as attitudes towards noisy environments and the individual's behaviour regarding the use of hearing protection may be considered as important factors in the understanding of why the prevalence of hearing related problems has increased among adolescents.


Mental health professionals' pathologization of compulsive sexual behavior: Does clients' gender and sexual orientation matter?
It has recently been proposed that compulsive sexual behavior disorder should be included in the 11th version of the International Statistical Classification of Diseases and Related Health Problems. Concerns have been repeatedly expressed regarding the overpathologizing of sexual behaviors and the potential for false-positive results in clinical practice. Empirical evidence indicates that stereotypes related to gender and sexual orientation might influence therapists' assessments of clients. Those stereotypes are likely to be associated with different levels of pathologization and stigmatization of high levels of sexual interest and behavior. The aim of this study was to explore the possible connections between clients' gender and sexual orientation and mental health professionals' (MHP) pathologization of compulsive sexual behavior. A sample of MHPs (N = 546) were presented with a case vignette describing a client with compulsive sexual behavior. The information on the client varied by gender (male or female), sexual orientation (homosexual or heterosexual), and clinical condition (ambiguous diagnostic criteria and fulfilled compulsive sexual behavior disorder diagnostic criteria). After reading the vignette, the MHPs rated the client's mental health status and gave an opinion about causation (psychological vs. biological etiology) and stigmatization indicators (blaming the affected individual for their problems, desire for social distance, perception of dangerousness). The MHPs showed significantly fewer tendencies to pathologize when the client was a homosexual woman or man independent of their clinical condition. Mediation analyses revealed that the biological etiological model partly mediated the effects of reduced pathologization in homosexual clients. These results indicate that clinical decisions relating to compulsive sexual behavior are influenced by nosologically irrelevant beliefs about the biological causation of sexual behavior. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Humoral and cellular response induced by a second booster of an inactivated SARS-CoV-2 vaccine in adults.
The Omicron variant has challenged the control of the COVID-19 pandemic due to its immuno-evasive properties. The administration of a booster dose of a SARS-CoV-2 vaccine showed positive effects in the immunogenicity against SARS-CoV-2, effect that is even enhanced after the administration of a second booster. During a phase-3 clinical trial, we evaluated the effect of a second booster of CoronaVac®, an inactivated vaccine administered 6 months after the first booster, in the neutralization of SARS-CoV-2 (n = 87). In parallel, cellular immunity (n = 45) was analyzed in stimulated peripheral mononuclear cells by flow cytometry and ELISPOT. Although a 2.5-fold increase in neutralization of the ancestral SARS-CoV-2 was observed after the second booster when compared with prior its administration (Geometric mean units p < 0.0001; Geometric mean titer p = 0.0002), a poor neutralization against the Omicron variant was detected. Additionally, the activation of specific CD4+ T lymphocytes remained stable after the second booster and, importantly, equivalent activation of CD4+ T lymphocytes against the Omicron variant and the ancestral SARS-CoV-2 were found. Although the neutralizing response against the Omicron variant after the second booster of CoronaVac® was slightly increased, these levels are far from those observed against the ancestral SARS-CoV-2 and could most likely fail to neutralize the virus. In contrast, a robust CD4+T cell response may confer protection against the Omicron variant. The Ministry of Health, Government of Chile, the Confederation of Production and Commerce, Chile and SINOVAC Biotech.NIHNIAID. The Millennium Institute on Immunology and Immunotherapy.


Replication errors in hematological neoplasias: genomic instability in progression of disease is different among different types of leukemia.
Genetic alteration, including genomic instability, is an ultimate step toward the malignant process. One approach to delineating replication errors in cancer cells is to determine the alterations of microsatellites, which are short, repeated nucleotide sequences existing throughout the genomes. We used a fluorescent system to assess microsatellite changes in seven loci (D2S123, D3S643, D5S107, LPL, D17S261, TP53, and D18S34) of 73 consecutive patients with various hematological neoplasias. De novo acute leukemia patients had a low frequency (<1%) of microsatellite alterations at each locus, and none of them demonstrated multiple microsatellite changes. In chronic myeloid leukemia patients, no microsatellite instability was detected in the chronic phase, whereas a relatively high frequency (25%) of multiple microsatellite changes was evident in the blastic phase, and half of these patients had multiple microsatellite changes. About 50% of the patients with myelodysplastic syndrome (MDS) and post-MDS acute myeloid leukemia (post-MDS AML) had microsatellite alterations. We next compared microsatellite alterations in two different hematological phases (MDS and post-MDS AML phases); 5 of 11 patients with post-MDS AML had de novo appearance of microsatellite instability during disease progression. This indicates that genomic instability at multiple microsatellite loci could occur either before or after leukemic transformation in MDS patients. We concluded that genomic instability in chronic myeloid leukemia might be linked to blastic transformation in combination with cytogenetic changes. In contrast, MDS patients had replication errors as a relatively early genetic event as well as a late genetic event. These results suggest that the involvement of genomic instability in the progression of disease is different among various types of leukemia.


Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1.
The sphingolipid metabolite sphingosine-1-phosphate (SPP) has been implicated as a second messenger in cell proliferation and survival. However, many of its biological effects are due to binding to unidentified receptors on the cell surface. SPP activated the heterotrimeric guanine nucleotide binding protein (G protein)-coupled orphan receptor EDG-1, originally cloned as Endothelial Differentiation Gene-1. EDG-1 bound SPP with high affinity (dissociation constant = 8.1 nM) and high specificity. Overexpression of EDG-1 induced exaggerated cell-cell aggregation, enhanced expression of cadherins, and formation of well-developed adherens junctions in a manner dependent on SPP and the small guanine nucleotide binding protein Rho.


High intralocus variability and interlocus recombination promote immunological diversity in a minimal major histocompatibility system.
The genes of the major histocompatibility complex (MHC/MH) have attracted considerable scientific interest due to their exceptional levels of variability and important function as part of the adaptive immune system. Despite a large number of studies on MH class II diversity of both model and non-model organisms, most research has focused on patterns of genetic variability at individual loci, failing to capture the functional diversity of the biologically active dimeric molecule. Here, we take a systematic approach to the study of MH variation, analyzing patterns of genetic variation at MH class IIα and IIβ loci of the seahorse, which together form the immunologically active peptide binding cleft of the MH class II molecule. The seahorse carries a minimal class II system, consisting of single copies of both MH class IIα and IIβ, which are physically linked and inherited in a Mendelian fashion. Both genes are ubiquitously expressed and detectible in the brood pouch of male seahorses throughout pregnancy. Genetic variability of the two genes is high, dominated by non-synonymous variation concentrated in their peptide-binding regions. Coding variation outside these regions is negligible, a pattern thought to be driven by intra- and interlocus recombination. Despite the tight physical linkage of MH IIα and IIβ loci, recombination has produced novel composite alleles, increasing functional diversity at sites responsible for antigen recognition. Antigen recognition by the adaptive immune system of the seahorse is enhanced by high variability at both MH class IIα and IIβ loci. Strong positive selection on sites involved in pathogen recognition, coupled with high levels of intra- and interlocus recombination, produce a patchwork pattern of genetic variation driven by genetic hitchhiking. Studies focusing on variation at individual MH loci may unintentionally overlook an important component of ecologically relevant variation.


Variation in the Ovine Abomasal Lymph Node Transcriptome between Breeds Known to Differ in Resistance to the Gastrointestinal Nematode.
Texel lambs are known to be more resistant to gastrointestinal nematode (GIN) infection than Suffolk lambs, with a greater ability to limit infection. The objectives of this study were to: 1) profile the whole transcriptome of abomasal lymph node tissue of GIN-free Texel and Suffolk lambs; 2) identify differentially expressed genes and characterize the immune-related biological pathways and networks associated with these genes. Abomasal lymph nodes were collected from Texel (n = 6) and Suffolk (n = 4) lambs aged 19 weeks that had been GIN-free since 6 weeks of age. Whole transcriptome profiling was performed using RNA-seq on the Illumina platform. At the time of conducting this study, a well annotated Ovine genome was not available and hence the sequence reads were aligned with the Bovine (UMD3.1) genome. Identification of differentially expressed genes was followed by pathway and network analysis. The Suffolk breed accounted for significantly more of the differentially expressed genes, (276 more highly expressed in Suffolk v 162 in Texel; P < 0.001). The four most significant differentially expressed pathways were all related to immunity and were classified as: Role of Pattern Recognition Receptors in Recognition of Bacteria and Viruses, Activation of IRF by Cytosolic Pattern Recognition Receptors, Role of RIG-I-like Receptors in Antiviral Innate Immunity, and Interferon Signaling. Of significance is the fact that all of these four pathways were more highly expressed in the Suffolk. These data suggest that in a GIN-free environment, Suffolk lambs have a more active immune profile relative to the Texel: this immune profile may contribute to the poorer efficiency of response to a GIN challenge in the Suffolk breed compared to the Texel breed.


Phenotypic and Genetic Characterization of Avian Influenza H5N2 Viruses with Intra- and Inter-Duck Variations in Taiwan.
Human infections with avian influenza viruses (AIVs) have frequently raised global concerns of emerging, interspecies-transmissible viruses with pandemic potential. Waterfowl, the predominant reservoir of influenza viruses in nature, harbor precursors of different genetic lineages that have contributed to novel pandemic influenza viruses in the past. Two duck influenza H5N2 viruses, DV518 and DV413, isolated through virological surveillance at a live-poultry market in Taiwan, showed phylogenetic relatedness but exhibited different replication capabilities in mammalian Madin-Darby Canine Kidney (MDCK) cells. This study characterizes the replication properties of the two duck H5N2 viruses and the determinants involved. The DV518 virus replicated more efficiently than DV413 in both MDCK and chicken DF1 cells. Interestingly, the infection of MDCK cells by DV518 formed heterogeneous plaques with great differences in size [large (L) and small (S)], and the two viral strains (p518-L and p518-S) obtained from plaque purification exhibited distinguishable replication kinetics in MDCK cells. Nonetheless, both plaque-purified DV518 strains still maintained their growth advantages over the plaque-purified p413 strain. Moreover, three amino acid substitutions in PA (P224S), PB2 (E72D), and M1 (A128T) were identified in intra-duck variations (p518-L vs p518-S), whereas other changes in HA (N170D), NA (I56T), and NP (Y289H) were present in inter-duck variations (DV518 vs DV413). Both p518-L and p518-S strains had the N170D substitution in HA, which might be related to their greater binding to MDCK cells. Additionally, polymerase activity assays on 293T cells demonstrated the role of vRNP in modulating the replication capability of the duck p518-L viruses in mammalian cells. These results demonstrate that intra-host phenotypic variation occurs even within an individual duck. In view of recent human infections by low pathogenic AIVs, this study suggests possible determinants involved in the stepwise selection of virus variants from the duck influenza virus population which may facilitate inter-species transmission.


Reproductive and thyroid hormone levels in rats following 90-day dietary exposure to PCB 28 (2,4,4'-trichlorobiphenyl) or PCB 77 (3,3'4,4'-tetrachlorobiphenyl).
Subchronic exposure to the PCB congener 77 (PCB 77) and 28 (PCB 28) was previously shown to induce histological changes in the thyroid and in the brain biogenic amines levels, suggesting possible effects on thyroid and reproductive hormone levels. Thus, the effects of a 90-day dietary exposure to PCB 28 or 77 on luteinizing hormone, follicle-stimulating hormone, and testosterone concentrations were studied in male rats, as well as the levels of thyroid-stimulating hormone, thyroxine (T4) and uridine diphosphate-glucuronyl transferase (UDP-GT) activity in both genders. Weanling Sprague Dawley rats were randomly distributed into groups of 10 rats and were fed, for the next 13 weeks, purina lab chow containing 50, 500, 5,000 or 50 000 ppb of PCB 28 or 10, 100, 1000, or 10 000 ppb of PCB 77. The serum concentrations of T4 were decreased in rats of both sexes receiving 1000 ppb or more of PCB 77, and was associated with an increased activity of UDP-GT which reached significance only in the females. There was a tendency for the highest dose of PCB 28 also to decrease serum T4 concentrations in the female rats. None of the PCB treatments significantly altered gonadotropin, TSH, or testosterone concentrations. These results suggest that thyroid functions may be more susceptible or adapt less readily than the pituitary gland and the testes to endocrine disruption caused by PCB congeners.


Polarization controller using nematic liquid crystals.
In this Letter we demonstrate a polarization controller capable of changing any state of polarization of light from one arbitrary state to another. The controller consists of a stack of three homogeneous nematic liquid-crystal cells. The polarization state is controlled by proper adjustment of the voltages applied across each of the cells. The mathematical algorithm and principles of this polarization controller are developed in the framework of the Stokes parameters, allowing easy visualization by use of a Poincaré sphere representation. The transformation functions are given for conversion of an arbitrary input state to any output state. Experiments are carried out to demonstrate arbitrary polarization transformation.


Distinct neural processes for the perception of familiar versus unfamiliar faces along the visual hierarchy revealed by EEG.
Humans recognize faces with ease, despite the complexity of the task and of the visual system which underlies it. Different spatial regions, including both the core and extended face processing networks, and distinct temporal stages of processing have been implicated in face recognition, but there is ongoing controversy regarding the extent to which the mechanisms for recognizing a familiar face differ from those for an unfamiliar face. Here, we used electroencephalogram (EEG) and flicker SSVEP, a high signal-to-noise approach, and searchlight decoding methods to elucidate the mechanisms mediating the processing of familiar and unfamiliar faces in the time domain. Familiar and unfamiliar faces were presented periodically at 15 Hz, 6 Hz and 3.75 Hz either upright or inverted in separate blocks, with the rationale that faster frequencies require shorter processing times per image and tap into fundamentally different levels of visual processing. The 15 Hz trials, likely to reflect early visual processing, exhibited enhanced neural responses for familiar over unfamiliar face trials, but only when the faces were upright. In contrast, decoding methods revealed similar classification accuracies for upright and inverted faces for both familiar and unfamiliar faces. For the 6 Hz frequency, familiar faces had lower amplitude responses than unfamiliar faces, and decoding familiarity was more accurate for upright compared with inverted faces. Finally, the 3.75 Hz frequency revealed no main effects of familiarity, but decoding showed significant correlations with behavioral ratings of face familiarity, suggesting that activity evoked by this slow presentation frequency reflected higher-level, cognitive aspects of familiarity processing. This three-way dissociation between frequencies reveals that fundamentally different stages of the visual hierarchy are modulated by face familiarity. The combination of experimental and analytical approaches used here represent a novel method for elucidating spatio-temporal characteristics within the visual system.


A longitudinal study of morning, evening, and night light intensities and nocturnal sleep quality in a working population.
We aimed to investigate whether higher light intensity in the morning is associated with better nocturnal sleep quality and whether higher light intensities in the evening or night have the opposite effect. Light intensity was recorded for 7 consecutive days across the year among 317 indoor and outdoor daytime workers in Denmark (55-56° N) equipped with a personal light recorder. Participants reported sleep quality after each nocturnal sleep. Sleep quality was measured using three parameters; disturbed sleep index, awakening index, and sleep onset latency. Associations between increasing light intensities and sleep quality were analyzed using mixed effects models with participant identity as a random effect. Overall, neither white nor blue light intensities during morning, evening, or night were associated with sleep quality, awakening, or sleep onset latency of the subsequent nocturnal sleep. However, secondary analyses suggested that artificial light during the morning and day contrary to solar light may increase vulnerability to evening light exposure. Altogether, we were not able to confirm that higher morning light intensity significantly improves self-reported sleep quality or that higher evening or night light intensities impair self-reported sleep quality at exposure levels encountered during daily life in a working population in Denmark. This suggests that light intensities alone are not important for sleep quality to a degree that it is distinguishable from other important parameters in daily life settings.


A multicenter phase II trial of vinorelbine plus gemcitabine in previously untreated inoperable (Stage IIIB/IV) non-small cell lung cancer.
Vinorelbine and gemcitabine are two active single agents used in the treatment of non-small cell lung cancer (NSCLC). A clinical trial was conducted to evaluate the efficacy and toxicity of vinorelbine plus gemcitabine in patients with inoperable (stage IIIB or IV) NSCLC. A multicenter phase II study. Vinorelbine, 20 mg/m(2), was given as a 10-min IV infusion, followed by a 30-min IV infusion of gemcitabine, 800 mg/m(2), on days 1, 8, and 15 of each 28-day cycle. From March 1998 to August 1998, 40 patients were enrolled in the study. The efficacy and toxicity of the treatment were recorded. All patients are evaluable for treatment response and toxicity profile. Two patients achieved a complete response, and 27 patients achieved a partial response, with an overall response rate of 72.5% (95% confidence interval, 58.7 to 86.3%). Median survival time was 11 months. The significant (World Health Organization grade, 3/4) toxicities were myelosuppression, including leukopenia (47.5% of patients), anemia (17.5% of patients), and thrombocytopenia (12.5% of patients). However, febrile neutropenia occurred in three patients and accounted for one treatment-related death. Fatigue, or flu-like syndrome, occurred in 17 patients, and the symptoms were reversed spontaneously 1 to 2 days after injection in 10 patients. Another seven patients needed dose reduction to ameliorate symptoms. Interstitial pneumonitis occurred in six patients who recovered after steroid treatment. No patient suffered from grade 3 or 4 nausea/vomiting. The combination of vinorelbine and gemcitabine in patients with advanced NSCLC is a highly active non-cisplatin-containing regimen with an acceptable toxicity profile.


Easy pan-detection of human IgA immunoglobulins.
IgA antibodies are key immune effectors against invading pathogens but also possess essential immunoregulatory functions. Detecting and quantifying human IgA+ B-cell subsets and secreted IgA molecules is needed for investigating the protective, modulatory and pathophysiologic roles of IgAs. Here, we produced a recombinant tagged trimeric form of the streptococcal IgA-binding peptide (SAP) by transient transfection-based eukaryotic expression system. The trimeric SAP (tSAP) probe had a higher production yield and apparent binding affinity to human IgA1 and IgA2 immunoglobulins when compared to the dimeric SAP molecule classically used to purify IgAs. tSAP bound both monomeric and dimeric IgAs, and allowed immunoblot detection and ELISA quantification of serum IgA antibodies in humans and non-human primates. Fluorescently labeled tSAP also permitted an accurate quantification of circulating human blood IgA-expressing memory B cells by flow-cytometric analyses. Thus, the easy-to-produce high affinity recombinant tSAP probe we developed is a versatile and valuable tool to quantify secreted and membrane-bound human but also primate IgA immunoglobulins.


Diffuse reflectance spectroscopy with a self-calibrating fiber optic probe.
Calibration of the diffuse reflectance spectrum for instrument response and time-dependent fluctuation as well as interdevice variations is complicated, time consuming, and potentially inaccurate. We describe a novel fiber optic probe with a real-time self-calibration capability that can be used for tissue optical spectroscopy. The probe was tested in a number of liquid phantoms over a relevant range of tissue optical properties. Absorption and scattering coefficients are extracted with an average absolute error and standard deviation of 6.9%+/-7.2% and 3.5%+/-1.5%, respectively.


Role of deoxyribose catabolism in colonization of the murine intestine by pathogenic Escherichia coli strains.
We previously suggested that the ability to metabolize deoxyribose, a phenotype encoded by the deoK operon, is associated with the pathogenic potential of Escherichia coli strains. Carbohydrate metabolism is thought to provide the nutritional support required for E. coli to colonize the intestine. We therefore investigated the role of deoxyribose catabolism in the colonization of the gut, which acts as a reservoir, by pathogenic E. coli strains. Molecular and biochemical characterization of 1,221 E. coli clones from various collections showed this biochemical trait to be common in the E. coli species (33.6%). However, multivariate analysis evidenced a higher prevalence of sugar-metabolizing E. coli clones in the stools of patients from countries in which intestinal diseases are endemic. Diarrhea processes frequently involve the destruction of intestinal epithelia, so it is plausible that such clones may be positively selected for in intestines containing abundant DNA, and consequently deoxyribose. Statistical analysis also indicated that symptomatic clinical disorders and the presence of virulence factors specific to extraintestinal pathogenic E. coli were significantly associated with an increased risk of biological samples and clones testing positive for deoxyribose. Using the streptomycin-treated-mouse model of intestinal colonization, we demonstrated the involvement of the deoK operon in gut colonization by two pathogenic isolates (one enteroaggregative and one uropathogenic strain). These results, indicating that deoxyribose availability promotes pathogenic E. coli growth during host colonization, suggest that the acquisition of this trait may be an evolutionary step enabling these pathogens to colonize and persist in the mammalian intestine.


A pilot treatment study for mild traumatic brain injury: Neuroimaging changes detected by MEG after low-intensity pulse-based transcranial electrical stimulation.
Mild traumatic brain injury (mTBI) is a leading cause of sustained impairments in military service members, Veterans, and civilians. However, few treatments are available for mTBI, partially because the mechanism of persistent mTBI deficits is not fully understood. We used magnetoencephalography (MEG) to investigate neuronal changes in individuals with mTBI following a passive neurofeedback-based treatment programme called IASIS. This programme involved applying low-intensity pulses using transcranial electrical stimulation (LIP-tES) with electroencephalography monitoring. Study participants included six individuals with mTBI and persistent post-concussive symptoms (PCS). MEG exams were performed at baseline and follow-up to evaluate the effect of IASIS on brain functioning. At the baseline MEG exam, all participants had abnormal slow-waves. In the follow-up MEG exam, the participants showed significantly reduced abnormal slow-waves with an average reduction of 53.6 ± 24.6% in slow-wave total score. The participants also showed significant reduction of PCS scores after IASIS treatment, with an average reduction of 52.76 ± 26.4% in PCS total score. The present study demonstrates, for the first time, the neuroimaging-based documentation of the effect of LIP-tES treatment on brain functioning in mTBI. The mechanisms of LIP-tES treatment are discussed, with an emphasis on LIP-tES's potentiation of the mTBI healing process.


Desmopressin and bleeding time in patients with cirrhosis.
Desmopressin acetate 0.3 microgram/kg was given intravenously to nine patients with chronic liver disease and to a further six such patients in a double blind controlled study versus placebo. Desmopressin acetate significantly shortened the bleeding time compared with basal values in both groups and compared with placebo. There was also a significant decrease in partial thromboplastin time (but not prothrombin time) and significant increases in factor VIII and its components, von Willebrand factor and ristocetin cofactor activity, but not in factors VII, IX, X, XI, or XII. Increased fibrinolysis could be blocked by concomitant administration of tranexamic acid. No important side effects were seen. The multimer pattern of von Willebrand factor was studied for the first time in chronic liver disease. It was normal, but after administration of desmopressin acetate the percentage of multimers of higher molecular weight increased significantly. This may be an important mechanism in the shortening of the bleeding time in cirrhosis, as has been shown in uraemia and other conditions after administration of desmopressin acetate. Desmopressin acetate may be useful in correcting defects in primary haemostasis in chronic liver disease.


Bacillus licheniformis levan as a functional biopolymer in topical drug dosage forms: From basic colloidal considerations to actual pharmaceutical application.
Ongoing demand in sustainable and biocompatible drug dosage forms is reflected in the search for novel pharmaceutical excipients with equal properties. A group of microbial exopolysaccharides offers a variety of biopolymers with many alleged uses and effects. This study aims to assess applicative properties of levan obtained from Bacillus licheniformis NS032, focusing on its potential co-stabilizing and drug release-controlling functions in pertaining emulsion systems. Despite its high molecular weight and partial existence in globular nanometric structures (180-190 nm), levan was successfully incorporated into both tested colloidal systems: those stabilized with synthetic/anionic or natural-origin/non-ionic emulsifiers. In the tested levan concentrations range (0.2-3.0% w/w) the monitored flow and thermal parameters failed to show linear concentration dependence, which prompted us to revisit certain colloidal fundamentals of this biopolymer. Being a part of the external phase of the investigated emulsion systems, levan contributed to formation of a matrix-like environment, offering additional stabilization of the microstructure and rheology modifying properties (hysteresis loop elevation as high as 4167±98 to 20792±3166 Pa•s-1), especially in case of the samples where lamellar liquid crystalline formation occurred. Apart from its good water solubility and considerable conformational flexibility, the investigated homofructan easily saturated the external phase of the samples stabilized with a conventional anionic emulsifier, leading to similar properties of 0.2% and 3.0% levan-containing samples. After closer consideration of thermal and release behavior, this was considered as a favorable property for a novel excipient, offering tailored formulation characteristics even with lower levan concentrations, consequently not compromising the potential cost of the final drug dosage form.


Online tuning of fuzzy inference systems using dynamic fuzzy Q-learning.
This paper presents a dynamic fuzzy Q-learning (DFQL) method that is capable of tuning fuzzy inference systems (FIS) online. A novel online self-organizing learning algorithm is developed so that structure and parameters identification are accomplished automatically and simultaneously based only on Q-learning. Self-organizing fuzzy inference is introduced to calculate actions and Q-functions so as to enable us to deal with continuous-valued states and actions. Fuzzy rules provide a natural mean of incorporating the bias components for rapid reinforcement learning. Experimental results and comparative studies with the fuzzy Q-learning (FQL) and continuous-action Q-learning in the wall-following task of mobile robots demonstrate that the proposed DFQL method is superior.


Host-Derived Nitric Oxide and Its Antibacterial Effects in the Urinary Tract.
Urinary tract infection (UTI) is one of the most common bacterial infections in humans, and the majority are caused by uropathogenic Escherichia coli (UPEC). The rising antibiotic resistance among UPEC and the frequent failure of antibiotics to effectively treat recurrent UTI and catheter-associated UTI motivate research on alternative ways of managing UTI. Abundant evidence indicates that the toxic radical nitric oxide (NO), formed by activation of the inducible nitric oxide synthase, plays an important role in host defence to bacterial infections, including UTI. The major source of NO production during UTI is from inflammatory cells, especially neutrophils, and from the uroepithelial cells that are known to orchestrate the innate immune response during UTI. NO and reactive nitrogen species have a wide range of antibacterial targets, including DNA, heme proteins, iron-sulfur clusters, and protein thiol groups. However, UPEC have acquired a variety of defence mechanisms for protection against NO, such as the NO-detoxifying enzyme flavohemoglobin and the NO-tolerant cytochrome bd-I respiratory oxidase. The cytotoxicity of NO-derived intermediates is nonspecific and may be detrimental to host cells, and a balanced NO production is crucial to maintain the tissue integrity of the urinary tract. In this review, we will give an overview of how NO production from host cells in the urinary tract is activated and regulated, the effect of NO on UPEC growth and colonization, and the ability of UPEC to protect themselves against NO. We also discuss the attempts that have been made to develop NO-based therapeutics for UTI treatment.


Is acupuncture beneficial in depression: a meta-analysis of 8 randomized controlled trials?
Depression is one of the most common mental health disorders. Acupuncture is a popular complementary and alternative medicine intervention suggested in the treatment of depression, but its effectiveness is uncertain. This updated meta-analysis was conducted to more precisely assess the beneficial effect of acupuncture in depression therapy. The following databases were searched: MEDLINE, EMBASE, BIOSIS, Cochrane Central Register of Controlled Trials, and Chinese Scientific Journal Database. The following terms were used: acupuncture, acupressure, depression, depressive disorder, clinical trial, and randomized controlled trial. Eight small-randomized controlled trials comparing 477 subjects were included in the meta-analysis. Our results confirmed that acupuncture could significantly reduce the severity of depression, which was indicated by decreased scores of Hamilton rating scale for depression (HAMD) or Beck Depression Inventory (BDI). The pooled standardized mean difference of the 'Improvement of depression' was -0.65 (95% CI -1.18, -0.11; P=0.02) by random effect model. However, no significant effect of active acupuncture was found on the response rate (RR 1.32, 95% CI 0.83 to 2.10; P=0.25) and remission rate (RR 1.30, 95% CI 0.57 to 2.95; P=0.53). Although this meta-analysis might be discounted due to the low quality of individual trials, it supported that acupuncture was an effective treatment that could significantly reduce the severity of disease in the patients with depression. More full-scale randomized clinical trials with reliable designs are recommended to further warrant the effectiveness of acupuncture.


Maternal constraint of fetal growth and its consequences.
The major non-genetic factor determining the size of the fetus at term is maternal constraint. This term refers to a set of poorly defined processes by which maternal and uteroplacental factors act to limit the growth of the fetus, presumably by limiting nutrient availability and/or the metabolic-hormonal drive to grow. Maternal constraint can be divided into supply-limited constraint (e.g. maternal size) and demand-driven constraint (e.g. twinning). Maternal constraint acts in all pregnancies, but is greater in some situations, particularly those involving young maternal age, small maternal size, nulliparous and multiple pregnancies. Maternal constraint is an important physiological cause of the variation in birth size, but is not without longer-term consequences. There is increasing evidence that maternal constraint is an important factor in determining the increased risk of adult diseases in those who have poor fetal growth due to pathophysiological factors. The evidence is reviewed and placed in the context of discussing the evolutionary significance of maternal constraint. The role of predictive adaptive responses as the basis of programming, and the effects of maternal constraint on these responses are discussed. Changing demography means that maternal constraint must increasingly be considered as a significant factor in determining the pattern of disease.


Curcumin improves outcomes and attenuates focal cerebral ischemic injury via antiapoptotic mechanisms in rats.
Curcumin, a member of the curcuminoid family of compounds, is a yellow colored phenolic pigment obtained from the powdered rhizome of C. longa Linn. Recent studies have demonstrated that curcumin has protective effects against cerebral ischemia/reperfusion injury. However, little is known about its mechanism. In the present study, we tested the effects of curcumin in focal cerebral ischemia in rats and the possible mechanisms. Adult male Sprague-Dawley rats were treated with curcumin (100, 300 and 500 mg/kg) administered intraperitoneally after 60 min of occlusion (beginning of reperfusion). Neurological score and infarct volume were assessed at 24 and 72 h. Oxidative stress was evaluated by malondialdehyde assay and the apoptotic mechanisms were studied by Western blotting. Curcumin treatment significantly reduced infarct volume and improved neurological scores at different time points compared with the vehicle-treated group. Curcumin treatment decreased malondialdehyde levels, cytochrome c, and cleaved caspase 3 expression and increased mitochondrial Bcl-2 expression. Inhibition of oxidative stress with curcumin treatment improves outcomes after focal cerebral ischemia. This neuroprotective effect is likely exerted by antiapoptotic mechanisms.


Demonstration of hypomethylation of proteins in the brain of pigs (but not in rats) associated with chronic vitamin B12 inactivation.
1. Pigs treated with nitrous oxide for periods of 1, 2 and 4 months demonstrated markedly reduced levels of methionine synthase and concomitant reduction in the ratio of S-adenosylmethionine to S-adenosylhomocysteine, the methylation ratio, at all time intervals. 2. Both 'O' and 'N' methylations were significantly reduced in pigs after 4 months in nitrous oxide but not after shorter periods. 3. Hypomethylation correlated with the development of clinical ataxia, but was absent when the pigs were clinically normal. It also only occurred when the S-adenosylmethionine level fell. 4. Rats maintained in nitrous oxide for 4 months showed a marked reduction of methionine synthase but no reduction in the methylation ratio or in brain hypomethylation. None of the rats became clinically ataxic. 5. Using an exogenous protein as a methyl group acceptor, it was demonstrated in an in vitro assay that the methyltransferase enzymes responsible for brain 'O' and 'N' methylation were not affected per se by nitrous oxide treatment. 6. It is concluded that reduction of the methylation ratio in the brain of pigs as a consequence of methionine synthase inhibition leads to brain hypomethylation. This hypomethylation could affect critical components of nerve tissue, inducing the vacuolar myelopathic changes seen in the spinal cord of these animals, which mimic those of subacute combined degeneration in man.


Effects of bud-flushing strategies on tree growth.
Allocation of carbohydrates between competing organs is fundamental to plant development, growth and productivity. Carbohydrates are synthesized in mature leaves and distributed via the phloem vasculature to developing buds where they are consumed to produce new biomass. The distribution and mass-allocation processes within the plant remain poorly understood and may involve complex feedbacks between different plant functions, with implications for the emergent structure of the plant. Here, we investigate how the order in which dormant buds are flushed affects the development of tree size and reproductive output during the first 20 years of growth in full light and shaded canopy environments. We report the following findings: (i) Bud-flushing strategies strongly affect the temporal dynamics of height, mass and the size of reproduction pool, as well as the resulting architectures. (ii) Bud-flushing strategies affect tree growth by altering the rate of growth and final size of trees. (iii) No single bud-flushing strategy performs best when both the size and allocation for reproduction of the resulting trees are compared. However, we observe that the strategy that optimizes the net carbon gain for the entire tree architecture always results in a high reproduction output. (iv) Branch turnover and meristem regeneration enhance the performance of certain strategies with respect to the measured quantities. These results highlight the importance of employing generic models of architecture (i.e., non-species-specific) to identify general mechanisms of carbon allocation and the spatial distribution of newly formed biomass in growing trees.


Alpha-Santalol, a Component of Sandalwood Oil Inhibits Migration of Breast Cancer Cells by Targeting the β-catenin Pathway.
Alpha-santalol, a terpenoid found in sandalwood oil has been shown to inhibit breast cancer cell growth in vitro by inducing apoptosis, but the mechanisms underlying the growth inhibitory effects of alpha-santalol are not fully understood. In this study, we demonstrate that α-santalol treatment targets Wnt/β-catenin pathway to inhibit migration of cultured breast cancer cells. Migration assays, immunoblotting and immunofluorescence were used to examine the mechanism of action of a-santalol in breast cancer cells. Exposure of MDA-MB 231 and MCF-7 cells to α-santalol resulted in a significant reduction in their migratory potential and wound healing ability. In addition, α-santalol affected the localization of β-catenin from cytosol to nucleus in MDA-MB 231 cells. Alpha-santalol inhibited migration of breast cancer cells may be mediated, in part, by targeting Wnt//β-catenin pathway. β-catenin represents an important target of α-santalol's response for future pre-clinical studies.


Cell-penetrating peptides: tools for intracellular delivery of therapeutics.
The main problem of therapeutic efficiency lies in the crossing of cellular membranes. Therefore, significant effort is being made to develop agents which can cross these barriers and deliver therapeutic agents into cellular compartments. In recent years, a large amount of data on the use of peptides as delivery agents has accumulated. Several groups have published the first positive results using peptides for the delivery of therapeutic agents in relevant animal models. These peptides, called cell-penetrating peptides (CPPs), are short peptides (fewer than 30 residues) with a net positive charge and acting in a receptor- and energy-independent manner. Here, we give an extensive review of peptide-mediated delivery systems and discuss their applications, with particular focus on the mechanisms leading to cellular internalization.


Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter.
Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na(+) conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined. The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers. G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p<0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p<0.005). Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism.


Manipulation of magnetic nanorod clusters in liquid by non-uniform alternating magnetic fields.
It is discovered that a non-uniform alternating magnetic field can induce a translational motion of an anisotropic magnetic particle or cluster near a surface. Unlike a permanent magnet pulling a magnetic particle, the particle moves away from the magnetic source with a periodic fluctuation in its trajectory that varies with a frequency that is twice that of the field frequency. The moving speed can be tuned by varying the magnetic field strength and gradient, its alternating frequency, and the particle size. A hydrodynamic model is developed that can qualitatively explain all of the phenomena observed. Such a simple particle manipulation method has a great potential in applications such as cell biology and microfluidics.


Supporting people in mental health crisis in 21st-century Britain.
Recent years have seen a surge in interest in mental healthcare and some reduction in stigma. Partly as a result of this, alongside a growing population and higher levels of societal distress, many more people are presenting with mental health needs, often in crisis. Systems that date back to the beginning of the National Health Service still form the basis for much care, and the current system is complex, hard to navigate and often fails people. Law enforcement services are increasingly being drawn into providing mental healthcare in the community, which most believe is inappropriate. We propose that it is now time for a fundamental root and branch review of mental health emergency care, taking into account the views of patients and the international evidence base, to 'reset' the balance and commission services that are humane and responsive - services that are fit for the 21st century.


Symmetric Decomposition of Asymmetric Games.
We introduce new theoretical insights into two-population asymmetric games allowing for an elegant symmetric decomposition into two single population symmetric games. Specifically, we show how an asymmetric bimatrix game (A,B) can be decomposed into its symmetric counterparts by envisioning and investigating the payoff tables (A and B) that constitute the asymmetric game, as two independent, single population, symmetric games. We reveal several surprising formal relationships between an asymmetric two-population game and its symmetric single population counterparts, which facilitate a convenient analysis of the original asymmetric game due to the dimensionality reduction of the decomposition. The main finding reveals that if (x,y) is a Nash equilibrium of an asymmetric game (A,B), this implies that y is a Nash equilibrium of the symmetric counterpart game determined by payoff table A, and x is a Nash equilibrium of the symmetric counterpart game determined by payoff table B. Also the reverse holds and combinations of Nash equilibria of the counterpart games form Nash equilibria of the asymmetric game. We illustrate how these formal relationships aid in identifying and analysing the Nash structure of asymmetric games, by examining the evolutionary dynamics of the simpler counterpart games in several canonical examples.


Determinants of medicare all-cause costs among elderly patients with renal cell carcinoma.
Renal cell carcinoma (RCC) is the third most common genitourinary cancer and the most common primary renal neoplasm. Estimates of the economic burden of RCC in the United States range from approximately $400 million (in year 2000 dollars) to $4.4 billion (in year 2005 dollars). Actual costs associated with RCC, particularly for elderly Medicare patients who account for 46% of U.S. patients hospitalized for RCC, are poorly understood. To estimate all-cause health care costs associated with RCC using the combined Surveillance Epidemiology and End Results (SEER)-Medicare database. The sample was limited to non-HMO patients aged 65 years or older who were diagnosed with a first primary RCC (SEER site recode 59, kidney and renal pelvis) between 1995 and 2002. Our final sample included 4,938 patients with RCC and 9,876 non-HMO noncancer comparison group cases without chronic renal disease drawn from the SEER 5% Medicare sample and matched by a propensity score calculated from age, gender, race/ethnicity, and comorbidities. Costs were defined as payments made by Medicare for all-cause medical treatments including inpatient stays, emergency room visits, outpatient procedures, office visits, home health visits, durable medical equipment, and hospice care, but excluding out-patient prescription drugs. Using the method of Bang and Tsiatis (2000), we estimated cumulative costs at 1 and 5 years by estimating average costs for each patient in each month up to 60 months following diagnosis. Total costs were weighted sums of monthly costs, where weights were the inverse probability that the patient was not censored, and inverse probabilities were estimated by Kaplan-Meier estimates of time to censoring. Using the method of Lin (2000), we performed multivariate analyses of costs by fitting each of the 60 monthly costs to linear models that controlled for demographic characteristics and comorbidities. Marginal effects of covariates on 1- and 5-year costs were obtained by summing the coefficients for months 1 through 12 and months 1 through 60, respectively. Confidence intervals were obtained by bootstrapping. Patients with RCC and matched comparison group cases had similar demographic characteristics, comorbidities, and chronic conditions. At the start of the fifth year post-diagnosis, there were 1,208 Medicare RCC cases of the original 4,938 (20.8%). Mean costs per patient per month (PPPM) in the first year were $3,673 for patients with RCC and $793 for comparison group patients. PPPM costs were higher for RCC patients with more advanced stage (i.e., regional or distant) disease. Average cumulative total costs for RCC patients were $33,605 per patient in the first year following diagnosis and $59,397 per patient in the first 5 years following diagnosis. Several patient-specific factors were associated with 1- and 5-year costs in multivariate analyses, including age, race/ethnicity, and comorbidities. Among RCC patients, treatment with surgery and radiation was associated with higher costs per patient than treatment with surgery alone at 1 year ($24,556, 95% CI = $16,673-$32,940) and 5 years ($30,540, 95% CI = $17,853-$43,648). RCC patients who received chemotherapy as part of their treatment regimen also had significantly higher costs per patient than those who received surgery alone at 1 year ($15,144, 95% CI = $ 9,979-$20,344) and 5 years ($13,440, 95% CI = $1,257-$27,572). Newly diagnosed RCC is associated with a significant economic burden, which is largely determined by several patient characteristics, disease stage, and treatment choice.


T2-Weighted fast MR imaging with true FISP versus HASTE: comparative efficacy in the evaluation of normal fetal brain maturation.
This study compares the relative efficacy of two fast T2-weighted MR imaging techniques-fast imaging with steady-state free precession (true FISP) and half-Fourier acquisition single-shot turbo spin-echo (HASTE)-in the evaluation of the normal fetal brain maturation during the second and third trimesters of gestation. The brain maturation of 10 normal nonsedated fetuses (5 during the second trimester and 6 during the third trimester of gestation [1 fetus underwent 2 examinations]) was examined by both techniques using a Vision+ 1.5-T MR system. We specifically looked for developing events, including white matter myelination, neuronal migration, and cortical sulcation. Image quality was graded according to the presence or absence of undesirable blurring. The specific absorption rate was lower for true FISP than for HASTE by a factor of 3 at equivalent imaging conditions. HASTE and true FISP provide comparable image quality in the second trimester when myelination of the cerebrum has not begun. Neuronal migration could be recognized as hypodense bands on both sequences during the second trimester. Myelination beginning at the third trimester was better delineated with true FISP than with HASTE because of point spread function-related blurring effects inherent in HASTE that hampered visualization of short-T2 structures. Cortical sulcation was well delineated by both sequences. With relatively superior image quality and significantly lower radiofrequency absorption than HASTE, true FISP is a safer and more effective alternative in the prenatal evaluation of normal fetal brain.


Environmental exposure to polychlorinated biphenyls (PCBs) and dioxins. Consequences for longterm neurological and cognitive development of the child lactation.
Polychlorinated biphenyls (PCBs) and dioxins are environmental pollutants. Prenatally, as well as postnatally through breast feeding, large amounts are transferred from mother to the child. Formula is free of these substances. Considering their potential developmental neurotoxicity, we investigated long term effects of perinatal exposure to PCBs and dioxins on neurological and cognitive development. Given the evidence that PCBs exert oestrogenic effects, and oestrogens are known to suppress lactation, we investigated the effect of maternal PCB body load on lactation performances as well. A group of 418 infants were followed from birth up to 6 years of age. Half of them were fully breast fed (BF) for at least 6 weeks. Prenatal PCB exposure was measured from cord and maternal blood. Postnatal exposure was reflected by PCB and dioxin levels in breast and formula milk and plasma PCB levels at 42 months of age. Both neurological and cognitive development were taken as outcome variable at 18, 42 months and at 6 years of age. At 18 and 42 months of age neurological condition was evaluated according to Hempel and at 6 years of age according to Touwen. Condition was evaluated in terms of optimality. Separately, the fluency of movements was scored. Cognitive abilities were measured at 18 months by the Bayley Scales of Infant Development, at 42 months of age by the Kaufman Assessment Battery for Children (K-ABC) and at 6 years of age by the McCarthy Scales. Daily breast milk volume and milk fat content in relation to PCB body load was evaluated in 102 mothers. Multivariate regression models were applied to analyse associations of measured exposure variables with independent variables adjusted for confounders. At 18 months of age cognitive development was not affected by either pre- or postnatal exposure to the measured PCBs and dioxins. However, neurological examination showed an adverse effect of prenatal exposure to the measured pollutants on neurological optimality score. At 42 months of age we found negative associations between prenatal PCB exposure on cognitive development. However no effect was demonstrated on postnatal exposure to the measured pollutants. Neurological development was not affected by either pre- or postnatal exposure to PCBs and dioxins. At 6 years of age the preliminary results revealed evidence that cognitive development is affected by prenatal exposure to these pollutants in children from young mothers. An adverse effect of prenatal exposure on neurological outcome was also demonstrated in the formula fed group but not in the breast fed group. Despite a higher PCB exposures from breast milk we found at 18 months, 42 months of age, and at 6 years of age a beneficial effect of breast feeding on the quality of movements, in terms of fluency, and on the cognitive development tests. Maternal PCB body load was inversely related to 24-h breast milk volume and milk fat content. These data give evidence that prenatal exposure to PCBs do have subtle negative effects on neurological and cognitive development of the child up to school-age. Human breast milk volume and fat content is adversely affected by the presently encountered PCB levels in W. Europe. Our studies showed evidence that breast feeding counteracts the adverse developmental effects of PCBs and dioxins.


Adaptive sequential prediction of multidimensional signals with applications to lossless image coding.
We investigate the problem of designing adaptive sequential linear predictors for the class of piecewise autoregressive multidimensional signals, and adopt an approach of minimum description length (MDL) to determine the order of the predictor and the support on which the predictor operates. The design objective is to strike a balance between the bias and variance of the prediction errors in the MDL criterion. The predictor design problem is particularly interesting and challenging for multidimensional signals (e.g., images and videos) because of the increased degree of freedom in choosing the predictor support. Our main result is a new technique of sequentializing a multidimensional signal into a sequence of nested contexts of increasing order to facilitate the MDL search for the order and the support shape of the predictor, and the sequentialization is made adaptive on a sample by sample basis. The proposed MDL-based adaptive predictor is applied to lossless image coding, and its performance is empirically established to be the best among all the results that have been published till present.


Safety of ultrasound-guided thoracentesis in patients with abnormal preprocedural coagulation parameters.
Despite a low incidence of hemorrhagic complications following thoracentesis, correction or attempted correction of abnormal preprocedural coagulation parameters is still commonly performed. We aimed to assess hemorrhagic complications following ultrasound-guided thoracentesis in patients with abnormal preprocedural coagulation parameters. We analyzed 1,009 ultrasound-guided thoracenteses performed between January 2005 and September 2011 on patients with international normalized ratio (INR) > 1.6, serum platelet values < 50 × 109/L, or both. Procedures were divided into two groups: those in whom abnormal preprocedural coagulation parameters were not corrected before the thoracentesis (group 1) and a second group in which patients received a transfusion of platelets or fresh frozen plasma prior to thoracentesis (group 2). All procedures were evaluated for hemorrhagic complications as defined by the National Institutes of Health Common Terminology Criteria for Adverse Events. A total of 1,009 ultrasound-guided thoracenteses were included in our study, consisting of 706 procedures in 538 patients in group 1 and 303 procedures in 235 patients in group 2. There were four hemorrhagic complications out of 1,009 procedures (0.40%; 95% CI, 0.15%-1.02%): zero in group 1 (0 of 706 or 0.0%; 95% CI, 0%-0.68%) and four in group 2 (four of 303 or 1.32%; 95% CI, 0.51%-3.36%). Hemorrhagic complications are infrequent after ultrasound-guided thoracentesis, and attempting to correct an abnormal INR or platelet level before the procedure is unlikely to confer any benefit. We consider the procedure safe in patients with abnormal preprocedural parameters when performed by expert personnel.


Trends in the characteristics of skin melanoma in accordance with time intervals: A single Turkish tertiary referral center experience.
The incidence of skin melanoma has increased dramatically in recent years. The aim of this study was to analyze the trends in the features of Turkish cutaneous melanoma patients in a 25-year period. A total of 1258 adult melanoma patients who had been managed and followed up at a tertiary referral center between 1993 and 2017 were included in the study. Males were predominant which did not vary between time intervals. There was an increase in the percentage of older patients over the years, whereas no change was observed in the percentage of younger patients. As the percentage of lower extremity melanoma dropped, the percentage of truncal melanomas rose. Both the incidences of thick (T3-T4) and thin melanomas (T1) were found to increase over time by 13.4% and 3.8%, respectively. There was no significant change in the percentage of the metastatic disease; however, Stage III disease was found to multiply by 10.1% and local disease was found to fall by 8.5% over the period. The percentages of patients with nodular histopathology and tumor-infiltrating lymphocytes were found to plummet, and there was a slight decline in the percentages of patients with high mitotic rate and lymphovascular invasion. Most likely because of the delayed diagnosis, cutaneous melanoma was found to be associated with less favorable prognostic features as the time lapsed. We suggest that effective campaigns for public awareness of melanoma be implemented so the screening and early diagnosis of the disease can be promoted.


Progressive multifocal leukoencephalopathy after allogeneic bone marrow transplantation for acute myeloid leukemia.
Progressive multifocal leukoencephalopathy (PML) is a rare fatal complication of allogeneic bone marrow transplantation (BMT) resulting from chronic immunosuppression and impaired cellular immunity. This report discusses 2 cases of PML in patients with acute myeloid leukemia after allogeneic BMT. Diagnosis was made based on characteristic brain MRI findings and positive PCR results for John Cunningham virus in the cerebrospinal fluid. Unfortunately, therapeutic options are limited and nearly always result in terminal outcomes. Although immunosuppression is an unavoidable risk of allogeneic BMT, these cases highlight a rare, yet fatal, consequence of prolonged T-cell lymphopenia and impaired cellular immunity after allogeneic BMT in this patient population.


Effects of Traditional Versus Horizontal Inertial Flywheel Power Training on Common Sport-Related Tasks.
This study aimed to analyze the effects of power training using traditional vertical resistance exercises versus direction specific horizontal inertial flywheel training on performance in common sport-related tasks. Twenty-three healthy and physically active males (age: 22.29 ± 2.45 years) volunteered to participate in this study. Participants were allocated into either the traditional training (TT) group where the half squat exercise on a smith machine was applied or the horizontal flywheel training (HFT) group performing the front step exercise with an inertial flywheel. Training volume and intensity were matched between groups by repetitions (5-8 sets with 8 repetitions) and relative intensity (the load that maximized power (Pmax)) over the period of six weeks. Speed (10 m and 20 m), countermovement jump height (CMJH), 20 m change of direction ability (COD) and strength during a maximal voluntary isometric contraction (MVIC) were assessed before and after the training program. The differences between groups and by time were assessed using a two-way analysis of variance with repeated measures, followed by paired t-tests. A significant group by time interaction (p=0.004) was found in the TT group demonstrating a significantly higher CMJH. Within-group analysis revealed statistically significant improvements in a 10 m sprint (TT: -0.17 0.27 s vs. HFT: -0.11 0.10 s), CMJH (TT: 4.92 2.58 cm vs. HFT: 1.55 2.44 cm) and MVIC (TT: 62.87 79.71 N vs. HFT: 106.56 121.63 N) in both groups (p < 0.05). However, significant differences only occurred in the 20 m sprint time in the TT group (-0.04 0.12 s; p = 0.04). In conclusion, the results suggest that TT at the maximal peak power load is more effective than HFT for counter movement jump height while both TT and HFT elicited significant improvements in 10 m sprint performance while only TT significantly improved 20 m sprint performance.


Redox Transformations of Iron at Extremely Low pH: Fundamental and Applied Aspects.
Many different species of acidophilic prokaryotes, widely distributed within the domains Bacteria and Archaea, can catalyze the dissimilatory oxidation of ferrous iron or reduction of ferric iron, or can do both. Microbially mediated cycling of iron in extremely acidic environments (pH < 3) is strongly influenced by the enhanced chemical stability of ferrous iron and far greater solubility of ferric iron under such conditions. Cycling of iron has been demonstrated in vitro using both pure and mixed cultures of acidophiles, and there is considerable evidence that active cycling of iron occurs in acid mine drainage streams, pit lakes, and iron-rich acidic rivers, such as the Rio Tinto. Measurements of specific rates of iron oxidation and reduction by acidophilic microorganisms show that different species vary in their capacities for iron oxido-reduction, and that this is influenced by the electron donor provided and growth conditions used. These measurements, and comparison with corresponding data for oxidation of reduced sulfur compounds, also help explain why ferrous iron is usually used preferentially as an electron donor by acidophiles that can oxidize both iron and sulfur, even though the energy yield from oxidizing iron is much smaller than that available from sulfur oxidation. Iron-oxidizing acidophiles have been used in biomining (a technology that harness their abilities to accelerate the oxidative dissolution of sulfidic minerals and thereby facilitate the extraction of precious and base metals) for several decades. More recently they have also been used to simultaneously remediate iron-contaminated surface and ground waters and produce a useful mineral by-product (schwertmannite). Bioprocessing of oxidized mineral ores using acidophiles that catalyze the reductive dissolution of ferric iron minerals such as goethite has also recently been demonstrated, and new biomining technologies based on this approach are being developed.