FairPRS: adjusting for admixed populations in polygenic risk scores using invariant risk minimization.
Polygenic risk scores (PRS) are increasingly used to estimate the personal risk of a trait based on genetics. However, most genomic cohorts are of European populations, with a strong under-representation of non-European groups. Given that PRS poorly transport across racial groups, this has the potential to exacerbate health disparities if used in clinical care. Hence there is a need to generate PRS that perform comparably across ethnic groups. Borrowing from recent advancements in the domain adaption field of machine learning, we propose FairPRS - an Invariant Risk Minimization (IRM) approach for estimating fair PRS or debiasing a pre-computed PRS. We test our method on both a diverse set of synthetic data and real data from the UK Biobank. We show our method can create ancestry-invariant PRS distributions that are both racially unbiased and largely improve phenotype prediction. We hope that FairPRS will contribute to a fairer characterization of patients by genetics rather than by race.


Couples' coping in prodromal Huntington disease: a mixed methods study.
Huntington disease (HD) includes a prodromal phase with behavioral, cognitive, and motor function decline occurring up to 15 years prior to diagnosis. This study used mixed methods to examine how people in the prodromal phase and their companions coped with noticed changes. Twenty-three couples completed a semi-structured interview and Brief COPE. Participants with prodromal HD used acceptance, emotional support, and planning most frequently; companions used acceptance, planning, and active coping. Least frequently used coping strategies for each were denial, behavioral disengagement, and substance use. Qualitative interviews revealed coping strategies not included in the Brief COPE. Participants with prodromal HD used prescription medications, coping as a couple, hope, and self-monitoring; companions used hope and helping their partners. Many of the coping procedures were rated as effective, especially when changes were not severe. Couples may benefit from counseling that emphasizes using active coping strategies for changes that can be compensated for and acceptance for changes that cannot in prodromal HD. Findings from this study may be helpful for counseling patients and significant others facing other neurodegenerative conditions with prodromal or early phases, such as Alzheimer disease and Parkinson disease.


Impact of hepatitis C treatment on pain intensity, prescription opioid use and arthritis.
To assess the impact of direct acting anti-viral (DAA) therapy for hepatitis C virus (HCV) infection on changes in pain intensity and prescription opioid use among Veterans. We conducted a retrospective cohort study of Veterans with HCV who were seen in a rheumatology clinic at least once while receiving DAA therapy between January 1, 2010 and December 31st 2016. Demographic characteristics, HCV status, HCV treatment characteristics, numeric rating scale (NRS) pain scores and opioid prescription data were extracted from the electronic medical record. Pain scores were averaged over 6 months prior to HCV treatment and 6 months after completion of treatment. Prescription opioid dose was converted to a morphine equivalent daily dose (MEDD) and averaged across the two 6-month intervals. Generalized estimating equations were used to model the change in average pain and MEDD from pre- to post-HCV treatment. Effect size was assessed using Cohen's d. A total of 121 Veterans, 91% male with average age of 59 were included. Average pre-treatment pain was 4.4 (SD 2.4). The average reduction in pain scores was 0.6 points (P = 0.02, Cohen's d = 0.22) after treatment. Among 67 patients prescribed chronic opioid therapy at baseline, average pre-treatment MEDD was 52.4 mg (SD = 62.5 mg) and post-DAA treatment average MEDD was 49.5 mg (SD = 69.3 mg), representing a decrease by 2.9 mg (P < 0.01, Cohen's d = 0.14). Opioid dose reduction was seen in 43/67 patients and 12 patients discontinued opioids entirely. Among US Veterans, subjective pain scores had modest improvement and opioid prescriptions were mildly reduced following treatment with DAA.


Identification of Endogenous Adenomatous Polyposis Coli Interaction Partners and β-Catenin-Independent Targets by Proteomics.
Adenomatous Polyposis Coli (APC) is the most frequently mutated gene in colorectal cancer. APC negatively regulates the Wnt signaling pathway by promoting the degradation of β-catenin, but the extent to which APC exerts Wnt/β-catenin-independent tumor-suppressive activity is unclear. To identify interaction partners and β-catenin-independent targets of endogenous, full-length APC, we applied label-free and multiplexed tandem mass tag-based mass spectrometry. Affinity enrichment-mass spectrometry identified more than 150 previously unidentified APC interaction partners. Moreover, our global proteomic analysis revealed that roughly half of the protein expression changes that occur in response to APC loss are independent of β-catenin. Combining these two analyses, we identified Misshapen-like kinase 1 (MINK1) as a putative substrate of an APC-containing destruction complex. We validated the interaction between endogenous MINK1 and APC and further confirmed the negative, and β-catenin-independent, regulation of MINK1 by APC. Increased Mink1/Msn levels were also observed in mouse intestinal tissue and Drosophila follicular cells expressing mutant Apc/APC when compared with wild-type tissue/cells. Collectively, our results highlight the extent and importance of Wnt-independent APC functions in epithelial biology and disease. IMPLICATIONS: The tumor-suppressive function of APC, the most frequently mutated gene in colorectal cancer, is mainly attributed to its role in β-catenin/Wnt signaling. Our study substantially expands the list of APC interaction partners and reveals that approximately half of the changes in the cellular proteome induced by loss of APC function are mediated by β-catenin-independent mechanisms.


Bovine gamma/delta TcR+ T lymphocytes are stimulated to proliferate by autologous Theileria annulata-infected cells in the presence of interleukin-2.
An in vitro model system has been developed in which freshly isolated resting WC1+ gamma/delta TcR+ T cells proliferate in response to cells transformed by the protozoan parasite Theileria annulata, providing a strategy in which the basis of activation of naive gamma/delta T cells can be investigated. Irradiated parasite-transformed cells stimulate the proliferation, but not cytolytic activity, of autologous peripheral blood mononuclear cells (PBMC) from non-immune animals. The proliferating cells are mainly WC1+ gamma/delta T cells. The majority of WC1+ gamma/delta T cells in freshly isolated PBMC express CD25 at a low level that increases when stimulated with T. annulata-infected cells. Purified WC1+ gamma/delta T cells fail to proliferate when cultured with irradiated T. annulata-infected cells and produce a small proliferative response to IL-2, but proliferate strongly to irradiated or lightly fixed Theileria-infected cells in combination with IL-2. The Theileria-infected cells express cytokine transcripts encoding IL-1 alpha, IL-1 beta, IL-6 and IL-10, but not IFN gamma, IL-2, IL-4 and IL-7. Purified WC1+ gamma/delta T cells stimulated with T. annulata-infected cells with or without IL-2 fail to produce IL-2 transcripts, but do produce those for TNF alpha. These experiments show that WC1+ gamma/delta T cells recognize a surface determinant on T. annulata-infected cells, that together with a second signal, which can be provided by exogenous IL-2, stimulates their proliferation.


De Novo Genome Assembly Shows Genome Wide Similarity between Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense.
Trypanosoma brucei is a eukaryotic pathogen which causes African trypanosomiasis. It is notable for its variant surface glycoprotein (VSG) coat, which undergoes antigenic variation enabled by a large suite of VSG pseudogenes, allowing for persistent evasion of host adaptive immunity. While Trypanosoma brucei rhodesiense (Tbr) and T. b gambiense (Tbg) are human infective, related T. b. brucei (Tbb) is cleared by human sera. A single gene, the Serum Resistance Associated (SRA) gene, confers Tbr its human infectivity phenotype. Potential genetic recombination of this gene between Tbr and non-human infective Tbb strains has significant epidemiological consequences for Human African Trypanosomiasis outbreaks. Using long and short read whole genome sequencing, we generated a hybrid de novo assembly of a Tbr strain, producing 4,210 scaffolds totaling approximately 38.8 megabases, which comprise a significant proportion of the Tbr genome, and thus represents a valuable tool for a comparative genomics analyses among human and non-human infective T. brucei and future complete genome assembly. We detected 5,970 putative genes, of which two, an alcohol oxidoreductase and a pentatricopeptide repeat-containing protein, were members of gene families common to all T. brucei subspecies, but variants specific to the Tbr strain sequenced in this study. Our findings confirmed the extremely high level of genomic similarity between the two parasite subspecies found in other studies. We confirm at the whole genome level high similarity between the two Tbb and Tbr strains studied. The discovery of extremely minor genomic differentiation between Tbb and Tbr suggests that the transference of the SRA gene via genetic recombination could potentially result in novel human infective strains, thus all genetic backgrounds of T. brucei should be considered potentially human infective in regions where Tbr is prevalent.


Predicting dental school performance based on prior dental experience and exposure.
The purpose of this study was to evaluate whether the variables of students with prior dental assisting experience and students with a parent who is a dentist can be used as predictors of students' pre-clinical and clinical course performance in dental school. The study population consisted of a cohort of 159 students in the Harvard School of Dental Medicine (HSDM) DMD graduation classes of 2001-2005. Data were collected via self-report using students' applications for admission to the HSDM DMD programme on which students provided information regarding whether they had prior dental assisting experience, including the type and duration of the experience and whether one or both of their parents were dentists. Data on the students' undergraduate science grade point average, Dental Admission Test academic average, Perceptual Ability Test (PAT) score, NBDE Part I and HSDM course grades (three pre-clinical and five clinical assessment categories) were collected from the Office of the Registrar. The pre-clinical categories included the first Oral Comprehensive Exam and the first two classes of the pre-clinical portion of the dental school, Treatment of Active Disease (TxAD) and Restorative Treatment (RTx). The clinical categories included the second Oral Comprehensive Exam and the cumulative grades received for the clinical procedures performed during the third and fourth years in the fields of Endodontics, Operative Dentistry, Periodontics and Prosthodontics. Descriptive and bivariate statistical analyses were performed and included in a multiple logistic regression model. The results revealed that for the variable of prior dental-assisting experience, no statistically significant differences were noted in the pre-clinical and clinical assessment categories. However, students who had any amount of assisting experience were 2.2 times more likely to earn a grade of honours in TxAD compared with students who did not have assisting experience (P = 0.05). Students with a parent who was a dentist performed better only in Operative Dentistry clinical assessment compared with students without a dentist parent (P < 0.05). Information on prior dental-assisting experience and having a parent who is a dentist have minimal merits for use as predictive agents based on these findings. Dental school admissions committees should continue to review a full spectrum of variables and ensure an applicant's true interest and motivation to pursue a career in dentistry.


Expedition medicine in the tropics: through heat and sleet.
Expeditionary travel-for the purposes of scientific discovery, personal challenge, or survival-represents an essential human instinct. Risks come with the territory although not all the risks can be anticipated. This is part of the appeal of exploration. Risks can be minimised through proper planning and preparation. High risk appetite does not necessarily mean recklessness. For the expedition medic, behavioural modification and communication skills are every bit as important as clinical acumen. Extreme endurance events and unfamiliar surroundings provide both physical and mental challenges. These challenges are not uncommonly exploited by consumer reality television shows when novices are placed in such situations. Studies of human adaptation to extreme environments, such as at or near the summit of Everest, may provide new insights into human physiology that could translate into important medical interventions. Working in extreme environments-such as in tropical jungle heat or within Everest's 'death zone'-presents unique challenges but it also brings unique rewards and discovery. As long as humans have the urge to explore, whatever perils lie ahead boredom will not be one of them.


Role of fatty acid synthase in the development of Dictyostelium discoideum.
Fatty acids are fundamental cellular components, and provide essential building blocks for membrane biosynthesis. Although the use of gene knockout mutants is a robust method for examining the function of specific cellular metabolic networks, fatty acid synthase knockout mutants are extremely difficult to isolate. In the Dictyostelium discoideum genome, we found two putative fatty acid synthase genes, and we created a knockout mutant for one of them to examine the physiological consequences. In this study, we found that a continuous fatty acid supply was necessary for normal development, and the fatty acid synthase knockout mutant showed severe developmental delay. This developmental defect was corrected in chimeras composed of wild type cells and knockout mutant cells (3:7, respectively). The knockout mutant also showed aberrant expression of fatty acid biosynthesis genes. These results showed that D. discoideum needs correct fatty acid synthesis for normal development.


Malaria and amphetamine 'horse tablets' in Thailand.
During recent clinical malaria research in Thailand we found a high frequency of amphetamine misuse and withdrawal amongst patients admitted to hospital with Plasmodium falciparum malaria. This comorbidity may cause diagnostic confusion, alter malaria pathophysiology and lead to drug interactions.


Three-dimensional reconstruction of the crystalline lens gradient index distribution from OCT imaging.
We present an optimization method to retrieve the gradient index (GRIN) distribution of the in-vitro crystalline lens from optical path difference data extracted from OCT images. Three-dimensional OCT images of the crystalline lens are obtained in two orientations (with the anterior surface up and posterior surface up), allowing to obtain the lens geometry. The GRIN reconstruction method is based on a genetic algorithm that searches for the parameters of a 4-variable GRIN model that best fits the distorted posterior surface of the lens. Computer simulations showed that, for noise of 5 μm in the surface elevations, the GRIN is recovered with an accuracy of 0.003 and 0.010 in the refractive indices of the nucleus and surface of the lens, respectively. The method was applied to retrieve three-dimensionally the GRIN of a porcine crystalline lens in vitro. We found a refractive index ranging from 1.362 in the surface to 1.443 in the nucleus of the lens, an axial exponential decay of the GRIN profile of 2.62 and a meridional exponential decay ranging from 3.56 to 5.18. The effect of GRIN on the aberrations of the lens also studied. The estimated spherical aberration of the measured porcine lens was 2.87 μm assuming a homogenous equivalent refractive index, and the presence of GRIN shifted the spherical aberration toward negative values (-0.97 μm), for a 6-mm pupil.


Abnormal morphology of fibrillin microfibrils in fibroblast cultures from patients with neonatal Marfan syndrome.
The Marfan syndrome (MFS) is a connective tissue disorder manifested by variable and pleiotropic features in the skeletal, ocular, and cardiovascular systems. The average life span in MFS is about 35 years. A group with much more severe cardiovascular disease and a mean life span of approximately 1 year also exists. We refer to this latter group as "neonatal Marfan syndrome" (nMFS). Fibrillin defects are now known to be the cause of MFS and nMFS. Immunofluorescence studies were the first to demonstrate this association. Here we describe immunofluorescence studies in a series of 10 neonates and summarize their salient clinical features. In vitro accumulation of fibrillin reactive fibers was assayed using monoclonal antibodies to fibrillin in hyperconfluent fibroblast cultures. As was previously observed in MFS, fibroblast cultures from nMFS patients showed an apparent decrease in accumulation of immunostainable fibrillin. Significantly, however, the morphology of the immunostained fibrils in the nMFS cultures were abnormal and differed not only from control cultures, but also from those seen in cultures of MFS fibroblasts. The nMFS fibrils appeared short, fragmented, and frayed, characteristics that are not seen in MFS. Both the clinical and fibrillin morphology data provide evidence to suggest a useful subclassification of nMFS in the spectrum of MFS.


Does the majority always know best? Young children's flexible trust in majority opinion.
Copying the majority is generally an adaptive social learning strategy but the majority does not always know best. Previous work has demonstrated young children's selective uptake of information from a consensus over a lone dissenter. The current study examined children's flexibility in following the majority: do they overextend their reliance on this heuristic to situations where the dissenting individual has privileged knowledge and should be trusted instead? Four- to six- year-olds (N = 103) heard conflicting claims about the identity of hidden drawings from a majority and a dissenter in two between-subject conditions: in one, the dissenter had privileged knowledge over the majority (he drew the pictures); in the other he did not (they were drawn by an absent third party). Overall, children were less likely to trust the majority in the Privileged Dissenter condition. Moreover, 5- and 6- year-olds made majority-based inferences when the dissenter had no privileged knowledge but systematically endorsed the dissenter when he drew the pictures. The current findings suggest that by 5 years, children are able to make an epistemic-based judgment to decide whether or not to follow the majority rather than automatically following the most common view.


Distance and orientation measurement in the nanometric scale based on polarization anisotropy of metallic dimers.
We show that the orientation of a dimer and the distance between the nanoparticles that form it can be determined by measuring the scattering under polarized light illumination. Scattering microscopy has shown to be an alternative to fluorescence as it provides nonbleaching and highly biocompatible probes, that can be manufactured in different sizes with different ligands. We propose a method based on measuring the polarization anisotropy of metallic dimers to determine distances in the range from 10 nm to 200 nm, thus filling the gap between fluorescence resonance energy transfer (FRET) and conventional microscopy. By calculating the scattering cross section of metallic dimers we show that it is also possible to gather orientation information, relevant to understand many biological processes.


Microspheres and Nanotechnology for Drug Delivery.
Ocular drug delivery to the posterior segment of the eye can be accomplished by invasive drug injections into different tissues of the eye and noninvasive topical treatment. Invasive treatment involves the risks of surgical trauma and infection, and conventional topical treatments are ineffective in delivering drugs to the posterior segment of the eye. In recent years, nanotechnology has become an ever-increasing part of ocular drug delivery. In the following, we briefly review microspheres and nanotechnology for drug delivery to the eye, including different forms of nanotechnology such as nanoparticles, microparticles, liposomes, microemulsions and micromachines. The permeation barriers and anatomical considerations linked to ocular drug delivery are discussed and a theoretical overview on drug delivery through biological membranes is given. Finally, in vitro, in vivo and human studies of x03B3;-cyclodextrin nanoparticle eyedrop suspensions are discussed as an example of nanotechnology used for drug delivery to the eye.


Blinking and thinking.
Blinking is related to certain cognitive processes. For example, individuals "punctuate" their speech by blinking between phrases and at the end of sentences. Daydreaming is associated with low rates of blinking. Blinking occurs between fixations and may be timed so as not to interfere with significant visual input. Apparently, blinking occurs at transitions between internal events and is inhibited at other times. In the experiment reported here, blinking was measured while the activity of operational memory was manipulated with mental load kept constant. The rate of blinking was significantly reduced when the cognitive operation of internal counting was being performed. It is inferred that the blink rate is low when information in memory is being operated on. To suspend blinking during certain cognitive activities would be adaptive if blinking disrupts them. Since the blackout period of the blink produces a rapid change in visual level, blinking disrupts those cognitive processes utilizing display areas accessible to visual input. Operational memory and the visual imagination may share components with the visual perceptual system. To protect these vulnerable processes from interference, blinking may be inhibited when they are active.


Effect of Anti-Hypertensive Medication History on Arteriovenous Fistula Maturation Outcomes.
The arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis. However, approximately half of AVFs fail to mature. The use of angiotensin converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs) exerts favorable endothelial effects and may promote AVF maturation. We tested associations of ACE-I and ARBs, CCBs, beta-blockers, and diuretics with the maturation of newly created AVFs. We evaluated 602 participants from the Hemodialysis Fistula Maturation Study, a multi-center, prospective cohort study of AVF maturation. We ascertained the use of each medication class within 45 days of AVF creation surgery. We defined maturation outcomes by clinical use within 9 months of surgery or 4 weeks of initiating hemodialysis. Unassisted AVF maturation failure without intervention occurred in 54.0% of participants, and overall AVF maturation failure (with or without intervention) occurred in 30.1%. After covariate adjustment, CCB use was associated with a 25% lower risk of overall AVF maturation failure (95% CI 3%-41% lower) but a non-significant 10% lower risk of unassisted maturation failure (95% CI 23% lower to 5% higher). ACE-I/ARB, beta-blocker, and diuretic use was not significantly associated with AVF maturation outcomes. None of the antihypertensive medication classes were associated with changes in AVF diameter or blood flow over 6 weeks following surgery. CCB use may be associated with a lower risk of overall AVF maturation failure. Further studies are needed to determine whether CCBs might play a causal role in improving AVF maturation outcomes.


Towards preparedness for PrEP: PrEP awareness and acceptability among MSM at high risk of HIV transmission who use sociosexual media in four Celtic nations: Scotland, Wales, Northern Ireland and The Republic of Ireland: an online survey.
To assess the awareness and acceptability of pre-exposure prophylaxis (PrEP) among men who have sex with men (MSM) and use sociosexual media at high risk of HIV infection in four Celtic nations. Cross-sectional study. Online self-complete survey of 386 HIV-negative/status unknown MSM who reported condomless anal intercourse (CAI) with ≥2 men in the last year, recruited from gay sociosexual media. One-third (34.5%, 132/386) of the participants were aware of PrEP but over half (58.5%, 226/356) reported that they would be willing to use PrEP if it were available to them. Only men who regularly tested for HIV every 6 months (adjusted OR 2.89, 95% CI 1.54 to 5.42) were more likely to be aware of PrEP. PrEP acceptability was only associated with reporting ≥5 CAI partners (OR 2.04, 95% CI 1.2 to 3.46) in the last year. Low levels of PrEP awareness were reported across these Celtic nations. Only one-third of high-risk MSM had heard of PrEP but over one-half would be willing to take a daily pill to prevent HIV infection. Sociodemographic factors, commercial gay scene proximity and social network use were unrelated to considering PrEP use. However, those reporting most CAI partners were more likely to consider PrEP use.


Magneto-orbital helices as a route to coupling magnetism and ferroelectricity in multiferroic CaMn₇O₁₂.
Orbital physics drives a rich phenomenology in transition-metal oxides, providing the microscopic underpinning for effects such as Colossal Magnetoresistance. In particular, magnetic and lattice degrees of freedom are coupled through orbital ordering, and it has long been hoped that this coupling could be exploited to create high-temperature multiferroics with large values of the electrical polarization. Here we report an unprecedented magneto-orbital texture in multiferroic CaMn(7)O(12), found to give rise to the largest magnetically induced ferroelectric polarization measured to date. X-ray diffraction characterization of the structural modulation in these 'magneto-orbital helices', and analysis of magnetic exchange shows that orbital order is crucial in stabilising a chiral magnetic structure, thus allowing for electric polarization. Additionally, the presence of a global structural rotation enables the coupling between this polarization and magnetic helicity required for multiferroicity. These novel principles open up the possibility of discovering new multiferroics with even larger polarization and higher transition temperatures.


Type-1 cannabinoid receptors reduce membrane fluidity of capacitated boar sperm by impairing their activation by bicarbonate.
Mammalian spermatozoa acquire their full fertilizing ability (so called capacitation) within the female genital tract, where they are progressively exposed to inverse gradients of inhibiting and stimulating molecules. In the present research, the effect on this process of anandamide, an endocannabinoid that can either activate or inhibit cannabinoid receptors depending on its concentration, and bicarbonate, an oviductal activatory molecule, was assessed, in order to study the role exerted by the type 1 cannabinoid receptor (CB1R) in the process of lipid membrane remodeling crucial to complete capacitation. To this aim, boar sperm were incubated in vitro under capacitating conditions (stimulated by bicarbonate) in the presence or in the absence of methanandamide (Met-AEA), a non-hydrolysable analogue of anandamide. The CB1R involvement was studied by using the specific inhibitor (SR141716) or mimicking its activation by adding a permeable cAMP analogue (8Br-cAMP). By an immunocytochemistry approach it was shown that the Met-AEA inhibits the bicarbonate-dependent translocation of CB1R from the post-equatorial to equatorial region of sperm head. In addition it was found that Met-AEA is able to prevent the bicarbonate-induced increase in membrane disorder and the cholesterol extraction, both preliminary to capacitation, acting through a CB1R-cAMP mediated pathway, as indicated by MC540 and filipin staining, EPR spectroscopy and biochemical analysis on whole membranes (CB1R activity) and on membrane enriched fraction (C/P content and anisotropy). Altogether, these data demonstrate that the endocannabinoid system strongly inhibits the process of sperm capacitation, acting as membrane stabilizing agent, thus increasing the basic knowledge on capacitation-related signaling and potentially opening new perspectives in diagnostics and therapeutics of male infertility.


U-73122: a potent inhibitor of human polymorphonuclear neutrophil adhesion on biological surfaces and adhesion-related effector functions.
We have reported that U-73122 (1-[6-[[17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole- 2,5-dione) an inhibitor of phospholipase C-dependent processes in human polymorphonuclear neutrophils (PMN) and platelets, potently suppresses the responsiveness of suspended PMN and platelets to receptor agonists. We demonstrate here that U-73122 caused a concentration-dependent (10-800 nM) inhibition of N-formyl-methionyl-leucyl-phenylalanine, tumor necrosis factor-alpha (TNF alpha), interleukin-8 and phorbol myristate acetate (PMA)-triggered PMN adhesion on fibronectin, fetal bovine serum or keyhole limpet hemocyanincoated microtiter plates. U-73122 also inhibited PMN adherence to and transmigration through TNF-alpha-activated endothelium (IC50 < 50 nM). Further, U-73122 suppressed interleukin-8, N-formylmethionyl-leucyl-phenylalanine and PMA-stimulated up-regulation of the beta 2-integrin, Mac-1 (CD11b/CD18), on the PMN surface (IC50 < 1.3 microM). U-73122 also caused a time-(15-120 min) and concentration-dependent inhibition (IC50 = 25-100 nM) of the N-formyl-methionyl-leucyl-phenylalanine-, TNF alpha- and PMA-elicited adhesion-dependent, oxidative burst, measured as hydrogen peroxide (H2O2) production, in PMN. The CD18-dependent extracellular release of lactoferrin from PMN activated with these stimuli was also suppressed by U-73122. U-73343 (1-[6-[[17 beta-3- methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-2,5-pyrrolidine dione), a close analog of U-73122, did not affect PMN responsiveness.


Monitoring, analysis, and correction of magnetic field fluctuations in echo planar imaging time series.
To assess the utility of concurrent magnetic field monitoring for observing and correcting for variations in k-space trajectories and global background fields that occur in single-shot echo planar imaging (EPI) time series as typically used in functional MRI (fMRI). Field monitoring was performed using an array of NMR field probes operated concurrently with series of single-shot EPI acquisitions from a static phantom. The observed fluctuations in field evolution were analyzed in terms of their temporal and spatial behavior at the field level as well as at the level of reconstructed image series. The potential to correct for such fluctuations was assessed by accounting for them upon image reconstruction. An indication of the number and relative magnitude of underlying effects was obtained via principal component analysis. Trajectory and global field variations were found to induce substantial image fluctuations. Global field fluctuations induced standard deviations in image intensity up to 31%. Fluctuations in the trajectory induced ghosting artifacts with standard deviations up to 2%. Concurrent magnetic field monitoring reduced the fluctuations in the EPI time series to a maximum of 1.2%. Concurrent magnetic field monitoring holds the potential to improve the net sensitivity of fMRI by reducing signal fluctuations unrelated to brain activity.


Transcriptome and DNA methylome analyses reveal underlying mechanisms for the racial disparity in uterine fibroids.
Uterine fibroids (leiomyomas) affect Black women disproportionately compared with women of other races and ethnicities in terms of prevalence, incidence, and severity of symptoms. The causes of this racial disparity are essentially unknown. We hypothesized that myometria of Black women are more susceptible to developing fibroids, and we examined the transcriptomic and DNA methylation profiles of myometria and fibroids from Black and White women for comparison. Myometrial samples cluster by race in both their transcriptome and DNA methylation profiles, whereas fibroid samples only cluster by race in the latter. More differentially expressed genes (DEGs) were detected in the Black and White myometrial sample comparison than in the fibroid comparison. Leiomyoma gene set expression analysis identified 4 clusters of DEGs, including a cluster of 24 genes with higher expression in myometrial samples from Black women. One of the DEGs in this group, von Willibrands factor (VWF), was significantly hypomethylated in both myometrial samples from Black women and in all fibroids at 2 CpG probes that are near a putative enhancer site and that are correlated with VWF expression levels. These results suggest that the molecular basis for the disparity in fibroid disease between Black and White women could be found in the myometria before fibroid development and not in the fibroids themselves.


Collateral benefits arising from mass administration of azithromycin in the control of active trachoma in resource limited settings.
The benefits of the use of antibiotics in the mass treatment for active trachoma and other diseases have been documented, but the secondary effects arising from such a programme have not been fully elucidated. The purpose of this study was to investigate the potential secondary benefits arising from the use of azithromycin in mass treatment of active trachoma in an economically challenged Kenyan nomadic community. Health information reports for January 2005 to December 2010 were reviewed to determine the annual trends of infectious diseases in the two districts, Narok and Transmara. The year 2007 was considered as the baseline for mass drug administration (MDA). Odds ratios (OR) were used to describe the association. The mass distribution coverage in Narok was 83% in 2008, 74% in 2009 and 63% in 2010. The odds for malaria (OR = 1.13; 95% CI 1.12-1.14), diarrhoeal diseases (OR = 1.04; 95% CI 1.01-1.06), urinary tract infections (UTIs) (OR = 1.21; 95% CI 1.17-1.26), intestinal worms (OR, 4.98; 95% CI 4.68-5.3), and respiratory diseases other than pneumonia (OR, 1.15; 95% CI 1.13-1.16) were higher after three rounds of mass treatment, indicating a better outcome. Before the intervention, there was a reducing trend in the odds for respiratory diseases. In Transmara (control), there was an increase in odds for malaria, respiratory infections, UTIs and intestinal worms. The odds for diarrhoeal diseases, skin diseases and pneumonia decreased throughout the study period. Mass distribution of azithromycin may have contributed to the decrease in the prevalence of the respiratory infections in Narok District.


Host carbon sources modulate cell wall architecture, drug resistance and virulence in a fungal pathogen.
The survival of all microbes depends upon their ability to respond to environmental challenges. To establish infection, pathogens such as Candida albicans must mount effective stress responses to counter host defences while adapting to dynamic changes in nutrient status within host niches. Studies of C. albicans stress adaptation have generally been performed on glucose-grown cells, leaving the effects of alternative carbon sources upon stress resistance largely unexplored. We have shown that growth on alternative carbon sources, such as lactate, strongly influence the resistance of C. albicans to antifungal drugs, osmotic and cell wall stresses. Similar trends were observed in clinical isolates and other pathogenic Candida species. The increased stress resistance of C. albicans was not dependent on key stress (Hog1) and cell integrity (Mkc1) signalling pathways. Instead, increased stress resistance was promoted by major changes in the architecture and biophysical properties of the cell wall. Glucose- and lactate-grown cells displayed significant differences in cell wall mass, ultrastructure, elasticity and adhesion. Changes in carbon source also altered the virulence of C. albicans in models of systemic candidiasis and vaginitis, confirming the importance of alternative carbon sources within host niches during C. albicans infections.


Validation of the 2014 European Society of Cardiology guidelines risk prediction model for the primary prevention of sudden cardiac death in hypertrophic cardiomyopathy.
The recently released 2014 European Society of Cardiology guidelines of hypertrophic cardiomyopathy (HCM) use a new clinical risk prediction model for sudden cardiac death (SCD), based on the HCM Risk-SCD study. Our study is the first external and independent validation of this new risk prediction model. The study population consisted of a consecutive cohort of 706 patients with HCM without prior SCD event, from 2 tertiary referral centers. The primary end point was a composite of SCD and appropriate implantable cardioverter-defibrillator therapy, identical to the HCM Risk-SCD end point. The 5-year SCD risk was calculated using the HCM Risk-SCD formula. Receiver operating characteristic curves and C-statistics were calculated for the 2014 European Society of Cardiology guidelines, and risk stratification methods of the 2003 American College of Cardiology/European Society of Cardiology guidelines and 2011 American College of Cardiology Foundation/American Heart Association guidelines. During follow-up of 7.7±5.3 years, SCD occurred in 42 (5.9%) of 706 patients (ages 49±16 years; 34% women). The C-statistic of the new model was 0.69 (95% CI, 0.57-0.82; P=0.008), which performed significantly better than the conventional risk factor models based on the 2003 guidelines (C-statistic of 0.55: 95% CI, 0.47-0.63; P=0.3), and 2011 guidelines (C-statistic of 0.60: 95% CI, 0.50-0.70; P=0.07). The HCM Risk-SCD model improves the risk stratification of patients with HCM for primary prevention of SCD, and calculating an individual risk estimate contributes to the clinical decision-making process. Improved risk stratification is important for the decision making before implantable cardioverter-defibrillator implantation for the primary prevention of SCD.


Relighting photographs of tree canopies.
We present an image-based approach to relighting photographs of tree canopies. Our goal is to minimize capture overhead; thus the only input required is a set of photographs of the tree taken at a single time of day, while allowing relighting at any other time. We first analyze lighting in a tree canopy both theoretically and using simulations. From this analysis, we observe that tree canopy lighting is similar to volumetric illumination. We assume a single-scattering volumetric lighting model for tree canopies, and diffuse leaf reflectance; we validate our assumptions with synthetic renderings. We create a volumetric representation of the tree from 10-12 images taken at a single time of day and use a single-scattering participating media lighting model. An analytical sun and sky illumination model provides consistent representation of lighting for the captured input and unknown target times. We relight the input image by applying a ratio of the target and input time lighting representations. We compute this representation efficiently by simultaneously coding transmittance from the sky and to the eye in spherical harmonics. We validate our method by relighting images of synthetic trees and comparing to path-traced solutions. We also present results for photographs, validating with time-lapse ground truth sequences.


Encephalitic Alphaviruses Exploit Caveola-Mediated Transcytosis at the Blood-Brain Barrier for Central Nervous System Entry.
Venezuelan and western equine encephalitis viruses (VEEV and WEEV, respectively) invade the central nervous system (CNS) early during infection, via neuronal and hematogenous routes. While viral replication mediates host shutoff, including expression of type I interferons (IFN), few studies have addressed how alphaviruses gain access to the CNS during established infection or the mechanisms of viral crossing at the blood-brain barrier (BBB). Here, we show that hematogenous dissemination of VEEV and WEEV into the CNS occurs via caveolin-1 (Cav-1)-mediated transcytosis (Cav-MT) across an intact BBB, which is impeded by IFN and inhibitors of RhoA GTPase. Use of reporter and nonreplicative strains also demonstrates that IFN signaling mediates viral restriction within cells comprising the neurovascular unit (NVU), differentially rendering brain endothelial cells, pericytes, and astrocytes permissive to viral replication. Transmission and immunoelectron microscopy revealed early events in virus internalization and Cav-1 association within brain endothelial cells. Cav-1-deficient mice exhibit diminished CNS VEEV and WEEV titers during early infection, whereas viral burdens in peripheral tissues remained unchanged. Our findings show that alphaviruses exploit Cav-MT to enter the CNS and that IFN differentially restricts this process at the BBB.IMPORTANCE VEEV, WEEV, and eastern equine encephalitis virus (EEEV) are emerging infectious diseases in the Americas, and they have caused several major outbreaks in the human and horse population during the past few decades. Shortly after infection, these viruses can infect the CNS, resulting in severe long-term neurological deficits or death. Neuroinvasion has been associated with virus entry into the CNS directly from the bloodstream; however, the underlying molecular mechanisms have remained largely unknown. Here, we demonstrate that following peripheral infection alphavirus augments vesicular formation/trafficking at the BBB and utilizes Cav-MT to cross an intact BBB, a process regulated by activators of Rho GTPases within brain endothelium. In vivo examination of early viral entry in Cav-1-deficient mice revealed significantly lower viral burdens in the brain than in similarly infected wild-type animals. These studies identify a potentially targetable pathway to limit neuroinvasion by alphaviruses.


STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis.
The STAT3 transcription factor is an important regulator of stem cell self-renewal, cancer cell survival, and inflammation. In the pancreas, STAT3 is dispensable for normal development, whereas the majority of pancreatic ductal adenocarcinomas (PDAC) show constitutive activation of STAT3, suggesting its potential as a therapeutic target in this cancer. Here, we sought to define the mechanisms of STAT3 activation and its functional importance in PDAC pathogenesis. Large-scale screening of cancer cell lines with a JAK2 inhibitor that blocks STAT3 function revealed a more than 30-fold range in sensitivity in PDAC, and showed a close correlation of sensitivity with levels of tyrosine-phosphorylated STAT3 and of the gp130 receptor, an upstream signaling component. Correspondingly, upregulation of the IL6/LIF-gp130 pathway accounted for the strong STAT3 activation in PDAC subsets. To define functions of STAT3 in vivo, we developed mouse models that test the impact of conditional inactivation of STAT3 in KRAS-driven PDAC. We showed that STAT3 is required for the development of the earliest premalignant pancreatic lesions, acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). Moreover, acute STAT3 inactivation blocked PDAC initiation in a second in vivo model. Our results show that STAT3 has critical roles throughout the course of PDAC pathogenesis, supporting the development of therapeutic approaches targeting this pathway. Moreover, our work suggests that gp130 and phospho-STAT3 expression may be effective biomarkers for predicting response to JAK2 inhibitors.


Presentation and immunogenicity of the hepatitis B surface antigen and a poliovirus neutralization antigen on mixed empty envelope particles.
Insertion of a synthetic DNA fragment encoding a poliovirus neutralization epitope into the S gene encoding the major envelope protein of hepatitis B virus has yielded hybrid (HBsPolioAg) particles closely resembling authentic 22-nm antigen (HBsAg) particles by expression of the modified gene in mammalian cells. In mice, these hybrid particles induce neutralizing antibodies against poliovirus but only weak immune response to HBsAg (F. Delpeyroux, N. Chenciner, A. Lim, Y. Malpièce, B. Blondel, R. Crainic, S. Van der Werf, and R. E. Streeck, Science 233:472-474, 1986). By cotransfection with different plasmids carrying either modified or unmodified S genes, we have now obtained mixed particles presenting both HBsAg and HBsPolioAg. When such particles were inoculated into rabbits, antibodies to both poliovirus and to HBsAg were induced. Moreover, the titers of neutralizing antibodies to poliovirus induced by HBsPolioAg were much higher than those previously obtained in mice. The design of multivalent particles carrying various peptide sequences or presenting several heterologous epitopes may therefore be possible.


Hypothalamic Paraventricular Nucleus Gαi2 (Guanine Nucleotide-Binding Protein Alpha Inhibiting Activity Polypeptide 2) Protein-Mediated Neural Control of the Kidney and the Salt Sensitivity of Blood Pressure.
We have previously reported that in salt-resistant rat phenotypes brain, Gαi2 (guanine nucleotide-binding protein alpha inhibiting activity polypeptide 2) proteins are required to maintain blood pressure and sodium balance. However, the impact of hypothalamic paraventricular nucleus (PVN) Gαi2 proteins on the salt sensitivity of blood pressure is unknown. Here, by the bilateral PVN administration of a targeted Gαi2 oligodeoxynucleotide, we show that PVN-specific Gαi2 proteins are required to facilitate the full natriuretic response to an acute volume expansion (peak natriuresis [μeq/min] scrambled (SCR) oligodeoxynucleotide 41±3 versus Gαi2 oligodeoxynucleotide 18±4; P<0.05) via a renal nerve-dependent mechanism. Furthermore, in response to chronically elevated dietary sodium intake, PVN-specific Gαi2 proteins are essential to counter renal nerve-dependent salt-sensitive hypertension (mean arterial pressure [mm Hg] 8% NaCl; SCR oligodeoxynucleotide 128±2 versus Gαi2 oligodeoxynucleotide 147±3; P<0.05). This protective pathway involves activation of PVN Gαi2 signaling pathways, which mediate sympathoinhibition to the blood vessels and kidneys (renal norepinephrine [pg/mg] 8% NaCl; SCR oligodeoxynucleotide 375±39 versus Gαi2 oligodeoxynucleotide 850±27; P<0.05) and suppression of the activity of the sodium chloride cotransporter assessed as peak natriuresis to hydrochlorothiazide. Additionally, central oligodeoxynucleotide-mediated Gαi2 protein downregulation prevented PVN parvocellular neuron activation, assessed by FosB immunohistochemistry, in response to increased dietary salt intake. In our analysis of the UK BioBank data set, it was observed that 2 GNAI2 single nucleotide polymorphism (SNP) (rs2298952, P=0.041; rs4547694, P=0.017) significantly correlate with essential hypertension. Collectively, our data suggest that selective targeting and activation of PVN Gαi2 proteins is a novel therapeutic approach for the treatment of salt-sensitive hypertension.


Defining the Role of Physiotherapy in Palliative Care in Multiple Sclerosis.
With increasing prevalence of multiple sclerosis worldwide, India too has transitioned from low to medium prevalence region. This increases the overall burden of a number of people suffering from a chronic progressive disorder. Such scenario underlines the need for an early comprehensive and holistic patient management plan, aiming to provide a better quality of life. The presented case is one such example of a patient-centered, and interdisciplinary team approach for better management of a patient suffering from an incurable, progressive disorder. As physiotherapists tend to spend a considerable amount of time with their patients on a regular basis, it becomes imperative to view all the patient related problems from a wider angle and endeavor to address each of them individually/collaboratively. In a palliative care setting, physiotherapy can no longer be considered as only physical symptom management approach but a patient care approach considering their entire physical, emotional, psychosocial, and spiritual needs. This novel case report shall serve as a guiding strategy for physiotherapists to work in the domain of palliative care.


Genetic variation associated with differential educational attainment in adults has anticipated associations with school performance in children.
Genome-wide association study results have yielded evidence for the association of common genetic variants with crude measures of completed educational attainment in adults. Whilst informative, these results do not inform as to the mechanism of these effects or their presence at earlier ages and where educational performance is more routinely and more precisely assessed. Single nucleotide polymorphisms exhibiting genome-wide significant associations with adult educational attainment were combined to derive an unweighted allele score in 5,979 and 6,145 young participants from the Avon Longitudinal Study of Parents and Children with key stage 3 national curriculum test results (SATS results) available at age 13 to 14 years in English and mathematics respectively. Standardised (z-scored) results for English and mathematics showed an expected relationship with sex, with girls exhibiting an advantage over boys in English (0.433 SD (95%CI 0.395, 0.470), p<10(-10)) with more similar results (though in the opposite direction) in mathematics (0.042 SD (95%CI 0.004, 0.080), p = 0.030). Each additional adult educational attainment increasing allele was associated with 0.041 SD (95%CI 0.020, 0.063), p = 1.79×10(-04) and 0.028 SD (95%CI 0.007, 0.050), p = 0.01 increases in standardised SATS score for English and mathematics respectively. Educational attainment is a complex multifactorial behavioural trait which has not had heritable contributions to it fully characterised. We were able to apply the results from a large study of adult educational attainment to a study of child exam performance marking events in the process of learning rather than realised adult end product. Our results support evidence for common, small genetic contributions to educational attainment, but also emphasise the likely lifecourse nature of this genetic effect. Results here also, by an alternative route, suggest that existing methods for child examination are able to recognise early life variation likely to be related to ultimate educational attainment.


[Mechanism of amylase action on glucoside starch bonds].
Functional groups of glucoamylase and alpha-amylase from Asp. awamori, alpha-amylase from Asp. oryzae and alpha- and beta-amylases from barley malt are identified. Kinetic curves of the activity dependency on pH, values of ionization heats and photooxidative inactivation draw to the conclusion that carboxyl-imidazole system enters into the active site of the enzymes. A hypothetic mechanism of hydrolysis of alpha-1,4-glucoside bond in starch molecule by alpha- and beta-amylases and of alpha-1,4- and alpha-1,6-glucoside bonds by glucoamylase is given. A theory of induced correspondence of enzyme and substrate satisfactorily explains the specificity of the enzyme action and the cause of complete starch convertion into glucose under glucoamylase action and of terminal starch hydrolysis by alpha- and beta-amylases.


Bone-anchored devices in single-sided deafness.
Single sided deafness (SSD) implies sensorineural hearing loss in one ear with normal contralateral hearing function. Traditionally, SSD patients have been overlooked due to a belief that the preserved functioning of the contralateral ear compensates for the nonhearing side. SSD patients however experience multiple audiological difficulties, particularly when the sound source is situated on the non-hearing side or in the presence of competing sounds. Through reviewing current literature, we describe the role of bone-anchored devices (Baha) in the management of SSD patients. Recent publications for Baha in SSD have demonstrated consistent objective and subjective improvement in audiologic metrics when compared to unaided conditions. There is also evidence of benefit provided by Baha by the Abbreviated Profile of Hearing Aid Benefit, in global measures of ease of communication, reverberation, and background noise, but not typically in aversiveness to sounds. Interestingly, despite some patients gaining minimal objective or subjective benefits, the majority of these patients still report improved quality of life and would recommend the procedure. Despite increasing evidence for the role of Baha in the management of SSD in the literature, much of these data are based on older technology. Further reports should specify the processor type used and the etiology of the hearing loss to ensure accuracy of future data.


High-Throughput Affinity Selection Mass Spectrometry Using SAMDI-MS to Identify Small-Molecule Binders of the Human Rhinovirus 3C Protease.
Affinity selection mass spectrometry (ASMS) has emerged as a powerful high-throughput screening tool used in drug discovery to identify novel ligands against therapeutic targets. This report describes the first high-throughput screen using a novel self-assembled monolayer desorption ionization (SAMDI)-ASMS methodology to reveal ligands for the human rhinovirus 3C (HRV3C) protease. The approach combines self-assembled monolayers of alkanethiolates on gold with matrix-assisted laser desorption ionization time-of-flight (MALDI TOF) mass spectrometry (MS), a technique termed SAMDI-ASMS. The primary screen of more than 100,000 compounds in pools of 8 compounds per well was completed in less than 8 h, and informs on the binding potential and selectivity of each compound. Initial hits were confirmed in follow-up SAMDI-ASMS experiments in single-concentration and dose-response curves. The ligands identified by SAMDI-ASMS were further validated using differential scanning fluorimetry (DSF) and in functional protease assays against HRV3C and the related SARS-CoV-2 3CLpro enzyme. SAMDI-ASMS offers key benefits for drug discovery over traditional ASMS approaches, including the high-throughput workflow and readout, minimizing compound misbehavior by using smaller compound pools, and up to a 50-fold reduction in reagent consumption. The flexibility of this novel technology opens avenues for high-throughput ASMS assays of any target, thereby accelerating drug discovery for diverse diseases.


High systemic bone mineral density increases the risk of incident knee OA and joint space narrowing, but not radiographic progression of existing knee OA: the MOST study.
Previous studies suggest that high systemic bone mineral density (BMD) is associated with incident knee osteoarthritis (OA) defined by osteophytes but not with joint space narrowing (JSN), and are inconsistent regarding BMD and progression of existing OA. The association of BMD with incident and progressive tibiofemoral OA was tested in a large prospective study of men and women aged 50-79 years with or at risk for knee OA. Baseline and 30-month weight-bearing posteroanterior and lateral knee radiographs were scored for Kellgren-Lawrence (K-L) grade, JSN and osteophytes. Incident OA was defined as the development of K-L grade > or =2 at follow-up. All knees were classified for increases in grade of JSN and osteophytes from baseline. The association of gender-specific quartiles of baseline BMD with risk of incident and progressive OA was analysed using logistic regression, adjusting for covariates. The mean (SD) age of 1754 subjects was 63.2 (7.8) years and body mass index was 29.9 (5.4) kg/m(2). In knees without baseline OA, higher femoral neck and whole body BMD were associated with an increased risk of incident OA and increases in grade of JSN and osteophytes (p<0.01 for trends); adjusted odds were 2.3-2.9-fold greater in the highest compared with the lowest BMD quartiles. In knees with existing OA, progression was not significantly related to BMD. In knees without OA, higher systemic BMD was associated with a greater risk of the onset of JSN and K-L grade > or =2. The role of systemic BMD in early knee OA pathogenesis warrants further investigation.


Behavioral economics holds potential to deliver better results for patients, insurers, and employers.
Many programs being implemented by US employers, insurers, and health care providers use incentives to encourage patients to take better care of themselves. We critically review a range of these efforts and show that many programs, although well-meaning, are unlikely to have much impact because they require information, expertise, and self-control that few patients possess. As a result, benefits are likely to accrue disproportionately to patients who already are taking adequate care of their health. We show how these programs could be made more effective through the use of insights from behavioral economics. For example, incentive programs that offer patients small and frequent payments for behavior that would benefit the patients, such as medication adherence, can be more effective than programs with incentives that are far less visible because they are folded into a paycheck or used to reduce a monthly premium. Deploying more-nuanced insights from behavioral economics can lead to policies with the potential to increase patient engagement and deliver dividends for patients and favorable cost-effectiveness ratios for insurers, employers, and other relevant commercial entities.


Energy transfer kinetics in whole cells and isolated chlorosomes of green photosynthetic bacteria.
Time-resolved fluorescence spectroscopy and global data analysis techniques have been used to study the flow of excitations in antennae of the green photosynthetic bacteria Chloroflexus aurantiacus and Chlorobium vibrioforme f. thiosulfatophilum. The transfer of energy from bacteriochlorophyll (BChl) c in Chloroflexus or BChl d in Chlorobium to BChl a 795 was resolved in both whole cells and isolated chlorosomes. In Chloroflexus, the decay of excitations in BChl c occurs in ∼16 ps and a corresponding rise in BChl a emission at 805 nm is detected in global analyses. This band then decays in 46 ps in whole cells due to energy transfer into the membrane. The 805 nm fluorescence in isolated chlorosomes shows a fast decay component similar to that of whole cells, which is consistent with trapping by residual membrane antenna complexes. In Chlorobium, the kinetics are sensitive to the presence of oxygen. Under anaerobic conditions, BChl d decays in 66 ps while the lifetime shortens to 11 ps in aerobic samples. The effect is reversible and occurs in both whole cells and isolated chlorosomes. Emission from BChl a is similarly affected by oxygen, indicating that oxidant-induced quenching can occur from all chlorosome pigments.


A Prospective Review of the Results of Patients Treated and Followed up for a Diagnosis of Sarcoidosis.
The present study reports the treatment and follow-up results of patients prospectively diagnosed and treated in a public hospital. The present study reports the prospective follow-up data of 21 sarcoidosis cases followed up and treated in the Department of Chest Diseases of Dörtyol State Hospital from January 2010 to December 2014. The 21 cases had a mean age of 44±10 years and a mean follow-up period of 38±13 months. While 10 cases were given steroid treatment, 11 cases were radiologically followed up. Besides pulmonary involvement, skin findings were detected in 7 cases and ophthalmologic findings were detected in 3 cases. In the treatment group, regression was observed in the radiographic findings of 6 cases, while no radiologically significant changes were seen in 4 cases. In the follow-up group, regression was observed in the radiographic findings of 9 cases, while no significant changes were seen in mediastinal LAPs of 2 cases. At the end of the treatment, it was found that 1 case developed steroid-induced myopathy, 1 case developed fungus ball of the sequelae, 1 case had loss of vision secondary to posterior uveitis, and 1 case had a risk of steroid-induced osteoporosis. Choice of treatment procedure based on the stage and clinical results of the patient is still the most effective method in sarcoidosis treatment.


Switchable NLO response induced by rotation of metallacarboranes [Ni(III/IV)(C2B9H11)2](-/0) and C-,B-functionalized derivatives.
The rotary motion based on metallacarboranes around a molecular axis can be controlled by simple electron transfer processes, which provides a basis for the structure-property relationship for the nonlinear optical (NLO) switching. However, this phenomenon has not been previously reported in the development of NLO properties of metallacarboranes. In this work, the metallacarboranes [Ni(III/IV)(C2B9H11)2](-/0) and their C-,B-functionalized derivatives are studied by the density functional theory (DFT) method. By calculating relative energies, we obtained the stable states before and after rotation controlled by simple electron transfer. Then, the static and frequency-dependent second-order NLO properties were calculated by several DFT functionals. According to the TDDFT results, the large NLO responses of the studied compounds are mainly caused by substituent group-to-carborane cage charge transfer (L'LCT) and substituent group-to-metal charge transfer (L'MCT) processes. The order of first hyperpolarizabilities (β values) illustrates that the NLO response can be enhanced by introducing a strong electron-donating group. Significantly, the geometric interconversions resulting from the redox reaction of 1C/1T-6C/6T allow the NLO responses to be switched "ON" or "OFF". The B(9,9')-methoxyphenyl-functionalized derivative of nickelacarborane, having low energetic cost and large different NLO responses between two states (from 0 to 20 998 a.u.), can be an excellent switchable NLO material.


A scoping review on bio-aerosols in healthcare and the dental environment.
Bio-aerosols originate from different sources and their potentially pathogenic nature may form a hazard to healthcare workers and patients. So far no extensive review on existing evidence regarding bio-aerosols is available. This study aimed to review evidence on bio-aerosols in healthcare and the dental setting. The objectives were 1) What are the sources that generate bio-aerosols?; 2) What is the microbial load and composition of bio-aerosols and how were they measured?; and 3) What is the hazard posed by pathogenic micro-organisms transported via the aerosol route of transmission? Systematic scoping review design. Searched in PubMed and EMBASE from inception to 09-03-2016. References were screened and selected based on abstract and full text according to eligibility criteria. Full text articles were assessed for inclusion and summarized. The results are presented in three separate objectives and summarized for an overview of evidence. The search yielded 5,823 studies, of which 62 were included. Dental hand pieces were found to generate aerosols in the dental settings. Another 30 sources from human activities, interventions and daily cleaning performances in the hospital also generate aerosols. Fifty-five bacterial species, 45 fungi genera and ten viruses were identified in a hospital setting and 16 bacterial and 23 fungal species in the dental environment. Patients with certain risk factors had a higher chance to acquire Legionella in hospitals. Such infections can lead to irreversible septic shock and death. Only a few studies found that bio-aerosol generating procedures resulted in transmission of infectious diseases or allergic reactions. Bio-aerosols are generated via multiple sources such as different interventions, instruments and human activity. Bio-aerosols compositions reported are heterogeneous in their microbiological composition dependent on the setting and methodology. Legionella species were found to be a bio-aerosol dependent hazard to elderly and patients with respiratory complaints. But all aerosols can be can be hazardous to both patients and healthcare workers.


The fluffy gene of Neurospora crassa is necessary and sufficient to induce conidiophore development.
The fl (fluffy) gene of Neurospora crassa encodes a binuclear zinc cluster protein that regulates the production of asexual spores called macroconidia. Two other genes, acon-2 and acon-3, play major roles in controlling development. fl is induced specifically in differentiating tissue during conidiation and acon-2 plays a role in this induction. We examined the function of fl by manipulating its level of expression in wild-type and developmental mutant strains. Increasing expression of fl from a heterologous promoter in a wild-type genetic background is sufficient to induce conidiophore development. Elevated expression of fl leads to induction of development of the acon-2 mutant in nitrogen-starved cultures, but does not bypass the conidiation defect of the acon-3 mutant. These findings indicate that fl acts downstream of acon-2 and upstream of acon-3 in regulating gene expression during development. The eas, con-6, and con-10 genes are induced at different times during development. Morphological changes induced by artificially elevated fl expression in the absence of environmental cues were correlated with increased expression of eas, but not con-6 or con-10. Thus, although inappropriate expression of fl in vegetative hyphae is sufficient to induce conidial morphogenesis, complete reconstitution of development leading to the formation of mature conidia may require environmental signals to regulate fl activity and/or appropriate induction of fl expression in the developing conidiophore.


Patient safety and patient assessment in pre-hospital care: a study protocol.
Patient safety issues in pre-hospital care are poorly investigated. The aim of the planned study is to survey patient safety problems in pre-hospital care in Sweden. The study is a retro-perspective structured medical record review based on the use of 11 screening criteria. Two instruments for structured medical record review are used: a trigger tool instrument designed for pre-hospital care and a newly development instrument designed to compare the pre-hospital assessment with the final hospital assessment. Three different ambulance organisations are participating in the study. Every month, one rater in each organisation randomly collects 30 medical records for review. With guidance from the review instrument, he/she independently reviews the record. Every month, the review team meet for a discussion of problematic reviews. The results will be analysed with descriptive statistics and logistic regression. The findings will make an important contribution to knowledge about patient safety issues in pre-hospital care.


Involvement of G-quadruplex regions in mammalian replication origin activity.
Genome-wide studies of DNA replication origins revealed that origins preferentially associate with an Origin G-rich Repeated Element (OGRE), potentially forming G-quadruplexes (G4). Here, we functionally address their requirements for DNA replication initiation in a series of independent approaches. Deletion of the OGRE/G4 sequence strongly decreased the corresponding origin activity. Conversely, the insertion of an OGRE/G4 element created a new replication origin. This element also promoted replication of episomal EBV vectors lacking the viral origin, but not if the OGRE/G4 sequence was deleted. A potent G4 ligand, PhenDC3, stabilized G4s but did not alter the global origin activity. However, a set of new, G4-associated origins was created, whereas suppressed origins were largely G4-free. In vitro Xenopus laevis replication systems showed that OGRE/G4 sequences are involved in the activation of DNA replication, but not in the pre-replication complex formation. Altogether, these results converge to the functional importance of OGRE/G4 elements in DNA replication initiation.


Vitamin D Deficiency in ambulatory patients.
To determine the frequency of subclinical vitamin D deficiency in an ambulatory care setting. This was an observational study which measured 25 vitamin D levels in medical clinic patients. Patients with chronic renal failure, known osteomalacia and rickets were excluded. A total of 119 patients were evaluated. They were divided in three diagnostic categories based on their serum 25 vitamin D levels. Those with levels below 8 ng/ml were categorized to have severe deficiency, levels between 8 - 20 ng/ml as moderate deficiency and levels of 21-35 mg/ml as mild deficiency. Of 119 patients, 92% had vitamin D deficiency. Their mean age was 44.3 +/- 18.3 years, with female to male ratio of 5:1. Sixty two percent (62%) had severe, 24% moderate and 8% had mild deficiency. Nearly half of all these patients (including those with severe deficiency) were asymptomatic. Whereas a low serum calcium, elevated phosphate and elevated alkaline phosphatase were reflective of severe deficiency. It was only an elevated iPTH that correlated with mild to moderate deficiency. Subclinical vitamin D deficiency is extensive in the adult ambulatory care patients. Serum calcium, phosphate and alkaline phosphatase are poor markers of moderate to mild deficiency. A serum 25 vitamin D level and an iPTH are better biofunctional markers of this deficiency.


Detection of mutual phase synchronization in multivariate signals and application to phase ensembles and chaotic data.
This work presents a method for the detection of mutual phase synchronization in nonstationary time series. We show how the application of a cluster algorithm that considers spatiotemporal structures of data follows from the general condition of phase-synchronized data. In view of the topology of phasic data, we reformulate the K-means cluster algorithm on a flat torus and apply a segmentation index derived in an earlier work [A. Hutt and H. Riedel, Physica D 177, 203 (2003)]. This index is extended by means of averaging in order to reflect phase synchronization in ensembles of multivariate time series. The method is illustrated using simulated multivariate phase dynamics and arrays of chaotic systems, in which temporal segments of phase-synchronized states are registered. A comparison with results from an existing bivariate synchronization index reveals major advantages of our method.


Groundwater monitoring plans at small-scale sites--an innovative spatial and temporal methodology.
An innovative methodology for improving existing groundwater monitoring plans at small-scale sites is presented. The methodology consists of three stand-alone methods: a spatial redundancy reduction method, a well-siting method for adding new sampling locations, and a sampling frequency determination method. The spatial redundancy reduction method eliminates redundant wells through an optimization process that minimizes the errors in plume delineation and the average plume concentration estimation. The well-siting method locates possible new sampling points for an inadequately delineated plume via regression analysis of plume centerline concentrations and estimation of plume dispersivity values. The sampling frequency determination method recommends the future frequency of sampling for each sampling location based on the direction, magnitude, and uncertainty of the concentration trend derived from representative historical concentration data. Although the methodology is designed for small-scale sites, it can be easily adopted for large-scale site applications. The proposed methodology is applied to a small petroleum hydrocarbon-contaminated site with a network of 12 monitoring wells to demonstrate its effectiveness and validity.


Graft contraction: a comparison of acellular dermis versus hard palate mucosa in lower eyelid surgery.
To compare graft contraction rates of acellular dermis versus hard palate mucosa when used as free spacer grafts in lower eyelid surgery and to provide clinical outcome data. A prospective, nonrandomized clinical trial involving the placement of 19 spacer grafts in the lower eyelids of 14 patients was performed. Indications for spacer graft placement included lower eyelid retraction and mildly contracted socket. Patients with lower eyelid retraction also underwent an endoscopic subperiosteal midface lift. For all procedures, the height of each graft was measured during and after surgery. The amount of contraction was measured for each graft, and a mean was calculated for each spacer material. The clinical success was evaluated for all procedures, based on improvement of the functional concern being addressed. The mean graft contraction rate was 57% for the acellular dermis and 16% for the hard palate mucosal grafts (P <0.005). Of the 7 procedures using acellular dermis for lower eyelid retraction, 6 were considered a success, and 1 was considered a partial success. Of the 6 procedures using hard palate for lower eyelid retraction, 5 were considered a success, and 1 was considered a failure unrelated to the graft. Of the 5 procedures with acellular dermis used for mildly contracted socket, 2 were considered a success, 2 were considered a partial success, and 1 was considered a failure because of graft contraction. The one case using hard palate for mildly contracted socket was considered a success. Acellular dermis contracts significantly more than hard palate mucosa when used as a lower eyelid spacer graft. Acellular dermis and hard palate mucosa were both associated with a high rate of clinical success in all categories except for patients with a mildly contracted socket who received acellular dermis; more than 60% of these patients (n=5) had only partial success or failure caused by graft contraction.


De novo characterization of the Chinese fir (Cunninghamia lanceolata) transcriptome and analysis of candidate genes involved in cellulose and lignin biosynthesis.
Chinese fir (Cunninghamia lanceolata) is an important timber species that accounts for 20-30% of the total commercial timber production in China. However, the available genomic information of Chinese fir is limited, and this severely encumbers functional genomic analysis and molecular breeding in Chinese fir. Recently, major advances in transcriptome sequencing have provided fast and cost-effective approaches to generate large expression datasets that have proven to be powerful tools to profile the transcriptomes of non-model organisms with undetermined genomes. In this study, the transcriptomes of nine tissues from Chinese fir were analyzed using the Illumina HiSeq™ 2000 sequencing platform. Approximately 40 million paired-end reads were obtained, generating 3.62 gigabase pairs of sequencing data. These reads were assembled into 83,248 unique sequences (i.e. Unigenes) with an average length of 449 bp, amounting to 37.40 Mb. A total of 73,779 Unigenes were supported by more than 5 reads, 42,663 (57.83%) had homologs in the NCBI non-redundant and Swiss-Prot protein databases, corresponding to 27,224 unique protein entries. Of these Unigenes, 16,750 were assigned to Gene Ontology classes, and 14,877 were clustered into orthologous groups. A total of 21,689 (29.40%) were mapped to 119 pathways by BLAST comparison against the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The majority of the genes encoding the enzymes in the biosynthetic pathways of cellulose and lignin were identified in the Unigene dataset by targeted searches of their annotations. And a number of candidate Chinese fir genes in the two metabolic pathways were discovered firstly. Eighteen genes related to cellulose and lignin biosynthesis were cloned for experimental validating of transcriptome data. Overall 49 Unigenes, covering different regions of these selected genes, were found by alignment. Their expression patterns in different tissues were analyzed by qRT-PCR to explore their putative functions. A substantial fraction of transcript sequences was obtained from the deep sequencing of Chinese fir. The assembled Unigene dataset was used to discover candidate genes of cellulose and lignin biosynthesis. This transcriptome dataset will provide a comprehensive sequence resource for molecular genetics research of C. lanceolata.


Variation in sexual behaviors in a group of captive male Yangtze finless porpoises (Neophocaena phocaenoides asiaeorientalis): motivated by physiological changes?
Most male mammals in temperate regions demonstrate seasonal sexual behaviors that coincide with seasonal variations in gonadal activities and androgen hormones. The Yangtze finless porpoise is a temperate freshwater cetacean species and an obvious seasonal breeder. To investigate the relationship between sexual behavior and gonadal activity in this animal, testicular size (volume) and structure (ultrasonogram pixel intensity) of two adult male porpoises (AF, AB) and one sub-adult male (TT) were longitudinally monitored from November 2008 to November 2009. Serum testosterone concentration was also monitored during the same period. Variations in the frequency of sexual behavior in AF and AB had similar, but seasonal trends. Their testicular size and pixel intensity also varied seasonally. Testicular size increased in March, peaked from April through June, and decreased gradually from August through September, whereas testicular pixel intensity started to increase in early February. The frequency of sexual behavior was positively correlated with testicular volume and pixel intensity (P = 0.000018 and P = 0.00012, respectively) in AF. Serum testosterone concentrations also varied. The sub-adult male porpoise, TT, was undergoing puberty, as evidenced by its marked increase in testicular volume, testicular pixel intensity, and serum testosterone concentrations from the beginning of 2009. Interestingly, TT exhibited the highest frequency of sexual behavior, most of which was same-sex pairing. However, its oversexed behavior neither quantitatively correlated with its smaller testicular volume (P = 0.61) nor with its testicular pixel intensity (P = 0.69).


[Analysis of visceral leishmaniasis reports by the capture-recapture method].
To analyze the number of cases, deaths, incidence and fatality rate due to visceral leishmaniasis, and to estimate its underreporting, as well as the coverage of the national information systems. Confirmed cases of visceral leishmaniasis were analyzed, based on the following systems: the Sistema de Informação de Agravos de Notificação (SINAN - Information System on Disease Notification), the Sistema de Informações sobre Mortalidade (SIM - Mortality Information System) and the Sistema de Informações Hospitalares (SIH - Hospital Information System), between 2002 and 2003. The variables utilized in relationship for pair identification were: patient's name, mother's name, date of birth, gender, city of residence, and mailing address. The capture-recapture method was applied to calculate the estimates, by means of the Chapman formula. The estimated underreporting of visceral leishmaniasis in the SINAN, in relation to the SIH and the SIM, was 42.2% and 45.0% respectively. The estimated underreporting of deaths was 53% and 46.5%, when compared to SINAN-deaths and SIH-deaths respectively. The estimated incidence was 2.9 per 100,000 inhabitants, from the comparison between the SINAN and the SIH, 70.5% higher than the one found when SINAN's data were the only ones utilized. Furthermore, when comparing data from SIM and SINAN-deaths, an estimated fatality rate of 8% was observed, representing an increase in 16% from the one initially registered in the SINAN-deaths. The results show high estimated underreporting of cases and deaths due to visceral leishmaniasis in Brazil. The relationship between information systems and the capture-recapture method application enabled to know and improve the epidemiological estimates, making its utilization in health services feasible.


ON EXTRACELLULAR AND INTRACELLULAR VENOM ACTIVATORS OF THE BLOOD, WITH ESPECIAL REFERENCE TO LECITHIN AND FATTY ACIDS AND THEIR COMPOUNDS.
In normal serums of the majority of mammalian and avian blood there exists certain substances capable of activating venom haemolysin. They are extractable from serum by means of ether, and are capable of conferring upon the originally non-activating serum a power to activate venom, when mixed with the latter. The ethereal extract consists of fatty acids, neutral fats and possibly also some ether soluble organic soaps. The fatty acids and soaps, especially of the oleinic series, acquire certain characteristics of complements in general, when they are mixed with serum. They are inactive without the venom in the mixture; they are inactivable with calcium chloride; they exhibit a tendency to go off in activity with age; they are inactive or only weakly active at 0 degrees C., and they are extractable by ether. In testing the serum from which the ether soluble substances are removed, it is found that no venom activating property is left. Warm alcoholic extraction of such serum yields, however, a large quantity of lecithin. In the case of non-activating serums no venom activating fats appear in the ethereal extract. Lecithin exists in such serum in no less quantity than in the activating kind. The addition of oleinic acid or its soluble soaps to a non-activating serum, in a ratio which corresponds to the percentage of fatty acids or soaps contained in some of the easily activating serums, will make the serum highly active in regard to venom. In normal serum of dog there exists, besides the group of activators already mentioned, another kind of venom activators which has been identified as a lecithin compound acting in the manner of free lecithin. A very sharp differentiation of the haemolysis produced by this activator and by the other groups of activators is obtained by means of calcium chloride, which is powerless against lecithin or lecithin compounds, but effective in removing the action of the latter. This lecithin containing proteid can be precipitated by half saturation with ammonium sulphate, but is perfectly soluble in water, and is not coagulated in neutral alkaline salt solutions upon boiling. Alcohol precipitates a proteid-like coagulum and extracts lecithin from it; ether does not extract lecithin from this compound. Non-activating serums do not contain any such lecithin compound. Lecithin contained in other serum proteids, mainly as lecithalbumin, and perhaps as contained in globulin, is not able to activate venom. This is true of all the serums with which I worked; it matters not whether these fractions (obtained with ammonium sulphate) belong to the most activating serum (dog) or to the non-activating serum (ox). The non-coagulable portion of all heated serum contains a venom activator of the nature of lecithin. This activator is contained in a non-coagulable proteid described by Howell which is identical with Chabrie's albumon. As there is no ether-extractable lecithin in this portion of the serum, the activating property of heated serum must be due to this proteid compound of lecithin. That this lecithin proteid does not pre-exist in normal serum but is produced by the action of high temperature is true of all serums except that of the dog. In venom activation we know now that lecithin becomes reactive with venom when it is transformed from other proteid compounds into the non-coagulable form, the albumon. Howell's view of the non-existence of the non-coagulable proteid in normal serum seems to receive a biological support from venom haemolysis. Ovovitellin derived from hen's egg is one of the best venom activators of the lecithin proteid type. The cause of venom susceptibility of various kinds of blood corpuscles does not depend upon the existence of lecithin in the corpuscles, but solely upon the amount of fatty acids, and perhaps, also, soaps and fats, contained in the corpuscles. The protection which calcium chloride gives against venom haemolysis is proof of the absence of lecithin activation. From the stroma of susceptible corpuscles fatty acids or some fats can be extracted with ether. After ethereal extraction the stroma becomes non-activating, while the extract contains fatty acids and some soaps or fats, which when added to venom-resistant corpuscles render the latter vulnerable to venom. The corpuscular solution of non-activating corpuscles does not contain enough fatty acids. The larger the amount of fatty acids and soaps in the corpuscles, the easier the cells undergo venom haemolysis. Lecithin exists in the strorna of all kinds of corpuscles, but in a form unavailable for venom activation. The somatic cytolytic processes caused by venom requires intracellular complements. The experiments performed on the cells of liver, kidney, testis and brain of the guinea-pig and rat indicate that the substances which act as complements are inactivable by calcium chloride.


Distribution of glycine receptor subunits on primate retinal ganglion cells: a quantitative analysis.
This study investigates the distribution of inhibitory neurotransmitter receptors on sensory neurons. Ganglion cells in the retina of a New World monkey, the common marmoset Callithrix jacchus, were injected with Lucifer yellow and Neurobiotin and subsequently processed with antibodies against one (alpha1), or against all subunits, of the glycine receptor, or against the anchoring protein gephyrin. Immunoreactive (IR) puncta representing glycine receptor or gephyrin clusters were found on the proximal and the distal dendrites of all ganglion cell types investigated. For both parasol and midget cells, the density of receptor clusters was greater on distal than proximal dendrites for all antibodies tested. In parasol cells the average density for the alpha1 subunit of the glycine receptor was 0.087 IR puncta/microm of dendrite, and for all subunits it was 0.119 IR puncta/microm of dendrite. Thus, the majority of glycine receptors on parasol cells contain the alpha1 subunit. For parasol cells, we estimated an average of 1.5 glycinergic synapses/100 microm2 dendritic membrane on proximal dendrites and about 9.4 glycinergic synapses/100 microm2 on distal dendrites. The segregation of receptors to the distal dendrites appears to be a common feature of inhibitory neurotransmitter input to parasol and midget cells, and might be associated with the receptive field surround mechanism.


Immunogenicity of the mRNA-1273 COVID-19 vaccine in adult patients with inborn errors of immunity.
Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great importance in this group, but little is known about the immunogenicity of COVID-19 vaccines in these patients. We sought to study humoral and cellular immune responses after mRNA-1273 COVID-19 vaccination in adult patients with IEI. In a prospective, controlled, multicenter study, 505 patients with IEI (common variable immunodeficiency [CVID], isolated or undefined antibody deficiencies, X-linked agammaglobulinemia, combined B- and T-cell immunodeficiency, phagocyte defects) and 192 controls were included. All participants received 2 doses of the mRNA-1273 COVID-19 vaccine. Levels of severe acute respiratory syndrome coronavirus-2-specific binding antibodies, neutralizing antibodies, and T-cell responses were assessed at baseline, 28 days after first vaccination, and 28 days after second vaccination. Seroconversion rates in patients with clinically mild antibody deficiencies and phagocyte defects were similar to those in healthy controls, but seroconversion rates in patients with more severe IEI, such as CVID and combined B- and T-cell immunodeficiency, were lower. Binding antibody titers correlated well to the presence of neutralizing antibodies. T-cell responses were comparable to those in controls in all IEI cohorts, with the exception of patients with CVID. The presence of noninfectious complications and the use of immunosuppressive drugs in patients with CVID were negatively correlated with the antibody response. COVID-19 vaccination with mRNA-1273 was immunogenic in mild antibody deficiencies and phagocyte defects and in most patients with combined B- and T-cell immunodeficiency and CVID. Lowest response was detected in patients with X-linked agammaglobulinemia and in patients with CVID with noninfectious complications. The assessment of longevity of immune responses in these vulnerable patient groups will guide decision making for additional vaccinations.


Traumatic experiences and post-traumatic stress reactions in children from Kurdistan and Sweden.
This paper examines the types and scores of traumatic experiences, post-traumatic stress symptom and behavioural disorders among Kurdistanian refugee children in Sweden and a comparative Swedish group. The Harvard-Uppsala Trauma Questionnaire for Children (HUTQ-C), the Post-Traumatic Stress Disorder for Children (PTSS-C) and the Child Behaviour Checklist (CBCL) were administered in interview form to 32 children from each sample, controlled for age, gender and trauma levels. No significant differences were found between the 2 samples regarding types of traumatic events, frequencies of post-traumatic stress disorder, post-traumatic stress symptom scores or behavioural problem scores, except in 3 aspects: Kurdistanian children reported more war experience and being lost, while Swedish children presented higher frequencies of leisure-time accidents. This study supports the assumption that children differ from adults by showing more similarities than differences regarding traumatic experiences and post-traumatic stress reactions, after being exposed to an equivalent number of reported traumatic events. The refugee children's stay in Sweden can be considered as a healing factor.


The various and varying roles of specific chaperones in type III secretion systems.
The type III secretion pathway is used by numerous Gram-negative pathogenic bacteria to deliver proteins within the membrane or the cytoplasm of eukaryotic cells with which these bacteria interact. Secretion is regulated by external signals. This requires that, before being secreted, proteins are stored in the cytoplasm where they need to be stabilised, separated from other interaction partners, and maintained in a secretion-competent state. Specialised, energy-independent chaperones play various roles in these functions by associating in the cytoplasm with proteins before their secretion. Some chaperones are also directly involved in modulating transcription in response to secretion.


[Regulation of microglia on neurogenesis in adult mammals].
Adult neurogenesis had been confirmed in rodents and other mammals for decades. The mechanisms underlying neurogenesis have been investigated extensively in recent years. Microglial cells, an immuno-cell in the central nervous system, have been found playing important roles in modulating the process of adult neurogenesis. The inflammatory microenvironment contributed by microglia are harmful to the survival of new born neurons. On the other hand, by interacting with T cells, microglia could act as a trophic factor for neurogenesis, most possibly by releasing growth factors. We reviewed the progress on how microglia regulating adult neurogenesis in variant pathological conditions. To understand the relationship between microglia and neurogenesis will help us to approach for promising therapeutic strategy for neuronal injury.


The Neuroprotective Effects of 17β-Estradiol Pretreatment in a Model of Neonatal Hippocampal Injury Induced by Trimethyltin.
Hippocampal dysfunction plays a central role in neurodevelopmental disorders, resulting in severe impairment of cognitive abilities, including memory and learning. On this basis, developmental studies represent an important tool both to understanding the cellular and molecular phenomena underlying early hippocampal damage and to study possible therapeutic interventions, that may modify the progression of neuronal death. Given the modulatory role played by 17β-estradiol (E2) on hippocampal functions and its neuroprotective properties, the present study investigates the effects of pretreatment with E2 in a model of neonatal hippocampal injury obtained by trimethyltin (TMT) administration, characterized by neuronal loss in CA1 and CA3 subfields and astroglial and microglial activation. At post-natal days (P)5 and P6 animals received E2 administration (0.2 mg/kg/die i.p.) or vehicle. At P7 they received a single dose of TMT (6.5 mg/kg i.p.) and were sacrificed 72 h (P10) or 7 days after TMT treatment (P14). Our findings indicate that pretreatment with E2 exerts a protective effect against hippocampal damage induced by TMT administration early in development, reducing the extent of neuronal death in the CA1 subfield, inducing the activation of genes involved in neuroprotection, lowering the neuroinflammatory response and restoring neuropeptide Y- and parvalbumin- expression, which is impaired in the early phases of TMT-induced damage. Our data support the efficacy of estrogen-based neuroprotective approaches to counteract early occurring hippocampal damage in the developing hippocampus.


Spliced exons of adenovirus late RNAs colocalize with snRNP in a specific nuclear domain.
Posttranscriptional steps in the production of mRNA include well characterized polyadenylation and splicing reactions, but it is also necessary to understand how RNA is transported within the nucleus from the site of its transcription to the nuclear pore, where it is translocated to the cytoplasmic compartment. Determining the localization of RNA within the nucleus is an important aspect of understanding RNA production and may provide clues for investigating the trafficking of RNA within the nucleus and the mechanism for its export to the cytoplasm. We have previously shown that late phase adenovirus-infected cells contain large clusters of snRNP and non-snRNP splicing factors; the presence of these structures is correlated with high levels of viral late gene transcription. The snRNP clusters correspond to enlarged interchromatin granules present in late phase infected cells. Here we show that polyadenylated RNA and spliced tripartite leader exons from the viral major late transcription unit are present in these same late phase snRNP-containing structures. We find that the majority of the steady state viral RNA present in the nucleus is spliced at the tripartite leader exons. Tripartite leader exons are efficiently exported from the nucleus at a time when we detect their accumulation in interchromatin granule clusters. Since the enlarged interchromatin granules contain spliced and polyadenylated RNA, we suggest that viral RNA may accumulate in this late phase structure during an intranuclear step in RNA transport.


The influence of geographical location, host maturity and sex on intestinal helminth communities of the double-crested cormorant Phalacrocorax auritus from the eastern United States.
Here the intestinal helminth infracommunities of 218 double-crested cormorants (Phalacrocorax auritus) from 11 locations in Alabama, Minnesota, Mississippi and Vermont are documented. Trematode infections were present in 98% of hosts; 65% of cormorants carried cestode infections, 4% were infected with acanthocephalans and 66% had nematode intestinal parasites. Parasite infracommunities of hosts collected on wintering grounds had higher richness and diversity than did birds collected on breeding grounds. Differences in parasite richness and diversity between male and female P. auritus were also detected, but not between immature and mature bird hosts. Parasite intensity did not differ by sex, maturity, or between breeding and wintering season. The most common parasite was Drepanocephalus auritus (spathans), which is recognized as a disease agent that negatively impacts the catfish aquaculture industry in the US. Echinochasmus sp. in double-crested cormorants is documented for the first time in the United States. We suggest that the differences observed among parasite infracommunities could be associated with the foraging distances travelled by P. auritus during breeding and wintering seasons, which is limited by allocation of parental care during the breeding season.


Pegylated liposomal doxorubicin-associated hand-foot syndrome: recommendations of an international panel of experts.
Hand-foot syndrome (HFS) is dose-limiting and the most common cumulative toxicity associated with pegylated liposomal doxorubicin (PLD). It can cause considerable discomfort and lead to therapy interruption. Numerous approaches to HFS management have been reported, but there is no consensus. Published literature (identified via Medline and internet search) and expert experience regarding HFS and its pathogenesis, incidence, risk factors, prevention and treatment in patients undergoing treatment with PLD were collected and reviewed by a panel of experts. A consensus technique was used to develop recommendations. The pathogenesis of PLD-associated HFS has been recently elucidated. Systems used to grade, prevent and treat HFS in individuals treated with PLD vary widely. A randomised clinical study demonstrated that PLD dose intensity reduction can prevent HFS. While there is limited literature support, patient education and supportive measures were endorsed by the expert panel as effective strategies for HFS prevention and treatment. An easy to use HFS grading and management algorithm was developed, early signs and symptoms of HFS outlined and specific recommendations for supportive care developed. The paucity of data on the management of PLD-associated HFS led the expert panel to develop consensus-based recommendations. Patient education and supportive measures are important elements in the management of HFS and dose intensity reduction has documented efficacy in prevention. At a PLD dose intensity not exceeding 10mg/m(2) weekly, HFS can be easily managed. Phase III research to support the efficacy other interventions is lacking.