Chemical effects of diceCT staining protocols on fluid-preserved avian specimens.
Diffusible iodine-based contrast-enhanced computed tomography (diceCT) techniques allow visualization of soft tissues of fluid-preserved specimens in three dimensions without dissection or histology. Two popular diceCT stains, iodine-potassium iodide (I2KI) dissolved in water and elemental iodine (I2) dissolved in 100% ethanol (EtOH), yield striking results. Despite the widespread use of these stains in clinical and biological fields, the molecular mechanisms that result in color change and radiopacity attributed to iodine staining are poorly understood. Requests to apply these stains to anatomical specimens preserved in natural history museums are increasing, yet curators have little information about the potential for degradation of treated specimens. To assess the molecular effects of iodine staining on typical museum specimens, we compared the two popular stains and two relatively unexplored stains (I2KI in 70% EtOH, I2 in 70% EtOH). House sparrows (Passer domesticus) were collected and preserved under uniform conditions following standard museum protocols, and each was then subjected to one of the stains. Results show that the three ethanol-based stains worked equally well (producing fully stained, life-like, publication quality scans) but in different timeframes (five, six, or eight weeks). The specimen in I2KI in water became degraded in physical condition, including developing flexible, demineralized bones. The ethanol-based methods also resulted in some demineralization but less than the water-based stain. The pH of the water-based stain was notably acidic compared to the water used as solvent in the stain. Our molecular analyses indicate that whereas none of the stains resulted in unacceptable levels of protein degradation, the bones of a specimen stained with I2KI in water demineralized throughout the staining process. We conclude that staining with I2KI or elemental I2 in 70% EtOH can yield high-quality soft-tissue visualization in a timeframe that is similar to that of better-known iodine-based stains, with lower risk of negative impacts on specimen condition.


Psychological and neuroendocrinological effects of odor of saffron (Crocus sativus).
The purpose of this study was to clarify the effects of saffron odor on symptoms unique to women, such as premenstrual syndrome (PMS), dysmenorrhea (menstrual pain) and irregular menstruation. Thirty-five women with a normal sense of smell were exposed to saffron odor for 20 min. Saliva samples were then collected to measure levels of cortisol (C), testosterone (T) and 17-β estradiol (E) by enzyme immunoassay, and the State-Trait Anxiety Inventory (STAI) was administered as a psychological test. Saffron odor significantly decreased C levels after short-term stimulation (20 min) in both follicular and luteal phases. E level after exposure to saffron odor was increased in both the follicular- and luteal-phase groups. STAI score decreased in the follicular and luteal phases in the saffron group. The present findings support the existence of physiological and psychological effects of saffron odor in women. Our results indicate that saffron odor exert some effects in the treatment of PMS, dysmenorrhea and irregular menstruation. This is the first report to suggest that saffron odor may be effective in treating menstrual distress.


Spectroscopic and photorefractive properties of infrared-sensitive rhodium-doped barium titanate.
We have grown and characterized crystals of BaTiO(3) doped with Rh. These crystals have a blue-green color that is probably due to charge-transfer optical transitions involving Rh(4+) and/or Rh(3+). Electron paramagnetic resonance spectroscopy confirmed the presence of Rh(4+) centers. Self-pumped phase-conjugation measurements were performed at wavelengths between 776 and 990 nm. Reflectivities near 80% were obtained throughout this wavelength range. In addition, self-pumped phase-conjugation buildup times were measured as a function of input power at 851 nm and are significantly faster than in undoped or Co-doped crystals studied previously. BaTiO(3):Rh is therefore a promising material for near-infrared photorefractive applications.


Revisiting Projective Structure from Motion: A Robust and Efficient Incremental Solution.
This paper presents a solution to the Projective Structure from Motion (PSfM) problem able to deal efficiently with missing data, outliers and, for the first time, large scale 3D reconstruction scenarios. By embedding the projective depths into the projective parameters of the points and views, we decrease the number of unknowns to estimate and improve computational speed by optimizing standard linear Least Squares systems instead of homogeneous ones. In order to do so, we show that an extension of the linear constraints from the Generalized Projective Reconstruction Theorem can be transferred to the projective parameters, ensuring also a valid projective reconstruction in the process. We use an incremental approach that, starting from a solvable sub-problem, incrementally adds views and points until completion with a robust, outliers free, procedure. To prevent error accumulation, a refinement based on alternation between new estimations of views and points is used. This can also be done with constrained non-linear optimization. Experiments with simulated data shows that our approach is performing well, both in term of the quality of the reconstruction and the capacity to handle missing data and outliers with a reduced computational time. Finally, results on real datasets shows the ability of the method to be used in medium and large scale 3D reconstruction scenarios with high ratios of missing data (up to 98 percent).


Osseous variations of the hypoglossal canal area.
The hypoglossal canal is a paired bone passage running from the posterior cranial fossa to the nasopharyngeal carotid space. Hyperostotic variations of this structure have been described. One hundred sixteen adult cadaveric dried skull specimens were analyzed. Several canal features, dimensions, and distances relative to constant and reliable landmarks were recorded. One osseous spur in the inner or outer orifice of the canal was present in 18.10% of specimens (42/232). Two or more osseous spurs were evident in 0.86% of specimens (2/232). However, complete osseous bridging, in the outer or inner part of the canal, was evident in 19.83% of specimens (46/232). Osseous bridging extending through the entire course of the canal was visible in 1.72% of the specimens (4/232). The mean lateral length of the canal was 10.22 mm, the mean medial length was 8.93 mm, the mean transverse and vertical diameters of the internal orifice were 7.44 mm and 4.42 mm, respectively, and the mean transverse and vertical diameters of the external orifice were 6.15 mm and 3.91 mm, respectively. The mean inclination of single hypoglossal canals was 42.3 degrees and 32.4 degrees on the right and left side, respectively. A detailed and accurate evaluation of the hypoglossal canal topographic anatomy with regard to specific, standard osseous landmarks was performed. Additional data with respect to several morphologic features of the hypoglossal canal area also was obtained. Results of this study provide important information that will enable effective and reliable surgical intervention in the area of the hypoglossal canal.


Men who have sex with men and HIV/AIDS in sub-Saharan Africa.
Globally, men who have sex with men (MSM) continue to bear a high burden of HIV infection. In sub-Saharan Africa, same-sex behaviours have been largely neglected by HIV research up to now. The results from recent studies, however, indicate the widespread existence of MSM groups across Africa, and high rates of HIV infection, HIV risk behaviour, and evidence of behavioural links between MSM and heterosexual networks have been reported. Yet most African MSM have no safe access to relevant HIV/AIDS information and services, and many African states have not begun to recognise or address the needs of these men in the context of national HIV/AIDS prevention and control programmes. The HIV/AIDS community now has considerable challenges in clarifying and addressing the needs of MSM in sub-Saharan Africa; homosexuality is illegal in most countries, and political and social hostility are endemic. An effective response to HIV/AIDS requires improved strategic information about all risk groups, including MSM. The belated response to MSM with HIV infection needs rapid and sustained national and international commitment to the development of appropriate interventions and action to reduce structural and social barriers to make these accessible.


Anti-tumour activity of a first-in-class agent NUC-1031 in patients with advanced cancer: results of a phase I study.
Gemcitabine is used to treat a wide range of tumours, but its efficacy is limited by cancer cell resistance mechanisms. NUC-1031, a phosphoramidate modification of gemcitabine, is the first anti-cancer ProTide to enter the clinic and is designed to overcome these key resistance mechanisms. Sixty-eight patients with advanced solid tumours who had relapsed after treatment with standard therapy were recruited to a dose escalation study to determine the recommended Phase II dose (RP2D) and assess the safety of NUC-1031. Pharmacokinetics and anti-tumour activity was also assessed. Sixty-eight patients received treatment, 50% of whom had prior exposure to gemcitabine. NUC-1031 was well tolerated with the most common Grade 3/4 adverse events of neutropaenia, lymphopaenia and fatigue occurring in 13 patients each (19%). In 49 response-evaluable patients, 5 (10%) achieved a partial response and 33 (67%) had stable disease, resulting in a 78% disease control rate. Cmax levels of the active intracellular metabolite, dFdCTP, were 217-times greater than those reported for equimolar doses of gemcitabine, with minimal toxic metabolite accumulation. The RP2D was determined as 825 mg/m2 on days 1, 8 and 15 of a 28-day cycle. NUC-1031 was well tolerated and demonstrated clinically significant anti-tumour activity, even in patients with prior gemcitabine exposure and in cancers not traditionally perceived as gemcitabine-responsive.


CREST maps somatic structural variation in cancer genomes with base-pair resolution.
We developed 'clipping reveals structure' (CREST), an algorithm that uses next-generation sequencing reads with partial alignments to a reference genome to directly map structural variations at the nucleotide level of resolution. Application of CREST to whole-genome sequencing data from five pediatric T-lineage acute lymphoblastic leukemias (T-ALLs) and a human melanoma cell line, COLO-829, identified 160 somatic structural variations. Experimental validation exceeded 80%, demonstrating that CREST had a high predictive accuracy.


Soluble epoxide inhibition is protective against cerebral ischemia via vascular and neural protection.
Inhibition of soluble epoxide hydrolase (SEH), the enzyme responsible for degradation of vasoactive epoxides, protects against cerebral ischemia in rats. However, the molecular and biological mechanisms that confer protection in normotension and hypertension remain unclear. Here we show that 6 weeks of SEH inhibition via 2 mg/day of 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) in spontaneously hypertensive stroke-prone (SHRSP) rats protects against cerebral ischemia induced by middle cerebral artery occlusion, reducing percent hemispheric infarct and neurodeficit score without decreasing blood pressure. This level of cerebral protection was similar to that of the angiotensin-converting enzyme inhibitor, enalapril, which significantly lowered blood pressure. SEH inhibition is also protective in normotensive Wistar-Kyoto (WKY) rats, reducing both hemispheric infarct and neurodeficit score. In SHRSP rats, SEH inhibition reduced wall-to-lumen ratio and collagen deposition and increased cerebral microvessel density, although AUDA did not alter middle cerebral artery structure or microvessel density in WKY rats. An apoptosis mRNA expression microarray of brain tissues from AUDA-treated rats revealed that AUDA modulates gene expression of mediators involved in the regulation of apoptosis in neural tissues of both WKY and SHRSP rats. Hence, we conclude that chronic SEH inhibition protects against cerebral ischemia via vascular protection in SHRSP rats and neural protection in both the SHRSP and WKY rats, indicating that SEH inhibition has broad pharmacological potential for treating ischemic stroke.


Increasing the incidence of drain-free day-case mastectomies with the use of a fibrin tissue sealant; data from a single surgical center in the United Kingdom.
Day-case mastectomy surgery provides benefits to both patients and hospitals. Key barriers are the use of a drain and the risk of postoperative seroma formation. We introduced the use of a tissue sealant (Artiss) into the surgical site (post-mastectomy without immediate reconstruction and postaxillary clearance) and evaluated its effect on our practice, particularly day-case rates. A prospective audit of 177 patients who underwent a simple mastectomy with or without axillary surgery, or axillary node clearance with or without breast-conserving surgery was conducted at a single surgical center in the UK between November 2015 and November 2016. Artiss was used in all operations and, where appropriate, the drain was omitted to facilitate day-case surgery. The clinical outcomes were compared between patients undergoing different operations and duration of hospital stay. There was no statistically significant difference between day-case patients and inpatients in seroma aspiration rates (24.5% and 21.7%, respectively; P = 0.381) or other complications (22.4% and 16.1%, respectively; P = 0.106). The day-case mastectomy rate increased from 3.9% in the first quarter to 45.5% in the final quarter, which was a significant increase reaching well beyond the national target. The use of Artiss enabled us to increase the drain-free day-case surgery rates over a 1-year period, exceeding the 30% target recommended by the British Association of Day Surgery. We did not observe any increase in patient morbidity, and the change was cost-effective. We have now implemented the routine use of Artiss in women undergoing simple mastectomy with or without axillary surgery and stand-alone axillary node clearances as part of enhanced recovery clinical pathways.


Study of vitrified, unstained frozen tissue sections by cryoimmunoelectron microscopy.
We describe the development and application of a novel approach to high-resolution ultrastructural analysis of cells and tissues. It is based on the preparation of ultrathin frozen sections of fixed tissues, rinsing of the sections, followed by their embedding on the grid in a layer of vitrified ice, and direct observation with a cryoelectron microscope. Examination of smooth muscle, kidney and heart tissues showed that although no heavy metal staining was used, high-contrast images are obtained. Fine details of cytoplasmic filaments and organelles, membranes and membrane-associated structures, as well as connective-tissue elements are all visible. The new method is suitable for immunolabeling, including high resolution localization of specific molecules within the cytoplasm.


Plasmid-Encoded Transferable mecB-Mediated Methicillin Resistance in Staphylococcus aureus.
During cefoxitin-based nasal screening, phenotypically categorized methicillin-resistant Staphylococcus aureus (MRSA) was isolated and tested negative for the presence of the mecA and mecC genes as well as for the SCCmec-orfX junction region. The isolate was found to carry a mecB gene previously described for Macrococcus caseolyticus but not for staphylococcal species. The gene is flanked by β-lactam regulatory genes similar to mecR, mecI, and blaZ and is part of an 84.6-kb multidrug-resistance plasmid that harbors genes encoding additional resistances to aminoglycosides (aacA-aphD, aphA, and aadK) as well as macrolides (ermB) and tetracyclines (tetS). This further plasmidborne β-lactam resistance mechanism harbors the putative risk of acceleration or reacceleration of MRSA spread, resulting in broad ineffectiveness of β-lactams as a main therapeutic application against staphylococcal infections.


Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update.
Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ∼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2).


The Use of Mixed Effects Models for Obtaining Low-Cost Ecosystem Carbon Stock Estimates in Mangroves of the Asia-Pacific.
Mangroves provide extensive ecosystem services that support local livelihoods and international environmental goals, including coastal protection, biodiversity conservation and the sequestration of carbon (C). While voluntary C market projects seeking to preserve and enhance forest C stocks offer a potential means of generating finance for mangrove conservation, their implementation faces barriers due to the high costs of quantifying C stocks through field inventories. To streamline C quantification in mangrove conservation projects, we develop predictive models for (i) biomass-based C stocks, and (ii) soil-based C stocks for the mangroves of the Asia-Pacific. We compile datasets of mangrove biomass C (197 observations from 48 sites) and soil organic C (99 observations from 27 sites) to parameterize the predictive models, and use linear mixed effect models to model the expected C as a function of stand attributes. The most parsimonious biomass model predicts total biomass C stocks as a function of both basal area and the interaction between latitude and basal area, whereas the most parsimonious soil C model predicts soil C stocks as a function of the logarithmic transformations of both latitude and basal area. Random effects are specified by site for both models, which are found to explain a substantial proportion of variance within the estimation datasets and indicate significant heterogeneity across-sites within the region. The root mean square error (RMSE) of the biomass C model is approximated at 24.6 Mg/ha (18.4% of mean biomass C in the dataset), whereas the RMSE of the soil C model is estimated at 4.9 mg C/cm3 (14.1% of mean soil C). The results point to a need for standardization of forest metrics to facilitate meta-analyses, as well as provide important considerations for refining ecosystem C stock models in mangroves.


Beyond optical rotation: what's left is not always right in total synthesis.
This work describes the application of vibrational (VCD) and electronic (ECD) circular dichroism spectroscopy to solve the longstanding debate around the absolute configuration of (+)-frondosin B (1). The absolute configuration of (+)-1 could confidently be assigned as (R) using these spectroscopic techniques. The discrepancy in the optical rotation (OR) values obtained in previous studies can be attributed to an undetected minor impurity (ca. 7%) that arose unexpectedly in a key step late in the synthesis. Additionally, the conditions used in the final step of the previous reports for demethylation to form the natural product proceeded with significant loss of enantiopurity. The large OR measured for the impurity at its observed level, when compared to the small rotation for the less enantiopure natural product 1, led to a measured OR value for the synthetic material that had the opposite sign of the natural product.


The effect of adding a surfeit of autologous CD8+ T cells to SCID mice after secondary rexenografts of Graves' thyroid tissue.
To investigate the effect of adding a surfeit of CD8+ T cells as a potential immunoregulator in Graves' disease (GD), thyroid tissues from 4 patients with GD and 2 normal subjects (N) were initially xenografted into nude mice. Eight weeks after xenografting, the thyroid tissues, which were then devoid of lymphocytes and appeared normal, were retrieved from the nude mouse, and rexenografted (rexenografts) into severe combined immuno-deficient (SCID) mice; 20 x 10(6) of autologous peripheral blood mononuclear cells (PMBC) or 20 x 10(6) of CD8(+)-depleted PBMC ("non-CD8 cells," i.e., CD4-enriched PBMC) were simultaneously engrafted into SCID mice with thyroid rexenografts. In addition, 20 x 10(6) of CD8(+)-enriched PBMC ("CD8-doubled" cells, which were prepared to double the percentage of CD8+ T cells compared to that of PBMC) were engrafted into SCID mice with rexenografts from 2 GD and 2 N; finally, 20 x 10(6) of PBMC plus an extra 10 x 10(6) of CD8+ T cells ("extra-CD8 added" cells, total 30 x 10(6) of CD8-enriched cells) were engrafted into separate SCID mice with rexenografts from 2 GD. The reengraftment of GD rexenografts or N rexenografts alone did not result in the detection of thyroperoxidase (TPO)-antibodies (Abs), thyroglobulin (Tg)-Abs, thyroid-stimulating Ab (TSAb) production, human IgG, or lymphocytic infiltration in the xenografts. However, the engraftment of either autologous PBMC or non-CD8 cells from patients with GD and N into SCID mice with rexenografts caused human IgG to become detectable and then rise further in 10 of 17 SCID mice; when human IgG, TPO-Ab, Tg-Ab, and TSAb were quantitated, GD rexenografts plus non-CD8 cells engrafted into SCID mice showed a higher production of each antibody and human IgG than in GD rexenografts plus PBMC, or GD rexenografts plus CD8-doubled cells, or GD rexenografts plus extra "CD8-added" cells. Moreover, when CD8-doubled cells or extra CD8-added cells with rexenografts were engrafted to SCID mice with rexenografts, they showed generally lower production of human IgG and thyroid antibodies compared to SCID mice into which PBMC were engrafted with rexenografts, despite the fact that 50% more cells (30 x 10(6)) were engrafted in the preparations of extra CD8-added cells. In conclusion, CD8+ T cells from patients with GD appeared to suppress the induction of thyroid antibodies, TSAb, and human IgG. The CD8+ cells thus are acting as suppressor or regulatory T cells. Such cells might be important in the pathogenesis of autoimmune thyroid disease.


Accommodative performance of children with unilateral amblyopia.
The purpose of this study was to compare the accommodative performance of the amblyopic eye of children with unilateral amblyopia to that of their nonamblyopic eye, and also to that of children without amblyopia, during both monocular and binocular viewing. Modified Nott retinoscopy was used to measure accommodative performance of 38 subjects with unilateral amblyopia and 25 subjects with typical vision from 3 to 13 years of age during monocular and binocular viewing at target distances of 50, 33, and 25 cm. The relationship between accommodative demand and interocular difference (IOD) in accommodative error was assessed in each group. The mean IOD in monocular accommodative error for amblyopic subjects across all three viewing distances was 0.49 diopters (D) (95% confidence interval [CI], ±1.12 D) in the 180° meridian and 0.54 D (95% CI, ±1.27 D) in the 90° meridian, with the amblyopic eye exhibiting greater accommodative errors on average. Interocular difference in monocular accommodative error increased significantly with increasing accommodative demand; 5%, 47%, and 58% of amblyopic subjects had monocular errors in the amblyopic eye that fell outside the upper 95% confidence limit for the better eye of control subjects at viewing distances of 50, 33, and 25 cm, respectively. When viewing monocularly, children with unilateral amblyopia had greater mean accommodative errors in their amblyopic eyes than in their nonamblyopic eyes, and when compared with control subjects. This could lead to unintended retinal image defocus during patching therapy for amblyopia.


Helical magnetorotational instability in magnetized Taylor-Couette flow.
Hollerbach and Rüdiger have reported a new type of magnetorotational instability (MRI) in magnetized Taylor-Couette flow in the presence of combined axial and azimuthal magnetic fields. The salient advantage of this "helical" MRI (HMRI) is that marginal instability occurs at arbitrarily low magnetic Reynolds and Lundquist numbers, suggesting that HMRI might be easier to realize than standard MRI (axial field only), and that it might be relevant to cooler astrophysical disks, especially those around protostars, which may be quite resistive. We confirm previous results for marginal stability and calculate HMRI growth rates. We show that in the resistive limit, HMRI is a weakly destabilized inertial oscillation propagating in a unique direction along the axis. But we report other features of HMRI that make it less attractive for experiments and for resistive astrophysical disks. Large axial currents are required. More fundamentally, instability of highly resistive flow is peculiar to infinitely long or periodic cylinders: finite cylinders with insulating endcaps are shown to be stable in this limit, at least if viscosity is neglected. Also, Keplerian rotation profiles are stable in the resistive limit regardless of axial boundary conditions. Nevertheless, the addition of a toroidal field lowers thresholds for instability even in finite cylinders.


Harnessing the properties of dendritic cells in the pursuit of immunological tolerance.
The acquisition of self-perpetuating, immunological tolerance specific for graft alloantigens has long been described as the "holy grail" of clinical transplantation. By removing the need for life-long immunosuppression following engraftment, the adverse consequences of immunosuppressive regimens, including chronic infections and malignancy, may be avoided. Furthermore, autoimmune diseases and allergy are, by definition, driven by aberrant immunological responses to ordinarily innocuous antigens. The re-establishment of permanent tolerance towards instigating antigens may, therefore, provide a cure to these common diseases. Whilst various cell types exhibiting a tolerogenic phenotype have been proposed for such a task, tolerogenic dendritic cells (tol-DCs) are exquisitely adapted for antigen presentation and interact with many facets of the immune system: as such, they are attractive candidates for use in strategies for immune intervention. We review here our current understanding of tol-DC mediated induction and maintenance of immunological tolerance. Additionally, we discuss recent in vitro findings from animal models and clinical trials of tol-DC immunotherapy in the setting of transplantation, autoimmunity and allergy which highlight their promising therapeutic potential, and speculate how tol-DC therapy may be developed in the future.


Junín virus infection of human hematopoietic progenitors impairs in vitro proplatelet formation and platelet release via a bystander effect involving type I IFN signaling.
Argentine hemorrhagic fever (AHF) is an endemo-epidemic disease caused by Junín virus (JUNV), a member of the arenaviridae family. Although a recently introduced live attenuated vaccine has proven to be effective, AHF remains a potentially lethal infection. Like in other viral hemorrhagic fevers (VHF), AHF patients present with fever and hemorrhagic complications. Although the causes of the bleeding are poorly understood, impaired hemostasis, endothelial cell dysfunction and low platelet counts have been described. Thrombocytopenia is a common feature in VHF syndromes, and it is a major sign for its diagnosis. However, the underlying pathogenic mechanism has not yet been elucidated. We hypothesized that thrombocytopenia results from a viral-triggered alteration of the megakaryo/thrombopoiesis process. Therefore, we evaluated the impact of JUNV on megakaryopoiesis using an in vitro model of human CD34+ cells stimulated with thrombopoietin. Our results showed that CD34+ cells are infected with JUNV in a restricted fashion. Infection was transferrin receptor 1 (TfR1)-dependent and the surface expression of TfR1 was higher in infected cultures, suggesting a novel arenaviral dissemination strategy in hematopoietic progenitor cells. Although proliferation, survival, and commitment in JUNV-infected cultures were normal, viral infection impaired thrombopoiesis by decreasing in vitro proplatelet formation, platelet release, and P-selectin externalization via a bystander effect. The decrease in platelet release was also TfR1-dependent, mimicked by poly(I:C), and type I interferon (IFN alpha/beta) was implicated as a key paracrine mediator. Among the relevant molecules studied, only the transcription factor NF-E2 showed a moderate decrease in expression in megakaryocytes from either infected cultures or after type I IFN treatment. Moreover, type I IFN-treated megakaryocytes presented ultrastructural abnormalities resembling the reported thrombocytopenic NF-E2(-/-) mouse phenotype. Our study introduces a potential mechanism for thrombocytopenia in VHF and other diseases associated with increased bone marrow type I IFN levels.


Growth hormone for in vitro fertilization.
In an effort to improve outcomes of in-vitro fertilisation cycles the use of growth hormone has been considered. Improving the outcomes of in-vitro fertilisation is especially important for subfertile women who are considered 'poor responders'. To assess the effectiveness of adjuvant growth hormone in in-vitro fertilisation protocols. We searched the Cochrane Menstrual Disorders and Subfertility Groups trials register (June 2009), the Cochrane Central Register of Controlled Trials (Cochrane Library Issue 2, 2009), MEDLINE (1966 to June 2009), EMBASE (1988 to June 2009) and Biological Abstracts (1969 to June 2009). All randomised controlled trials were included if they addressed the research question and provided outcome data for intervention and control participants. Assessment of trial risk of bias and extraction of relevant data was performed independently by two reviewers. Ten studies (440 subfertile couples) were included. Results of the meta-analysis demonstrated no difference in outcome measures and adverse events in the routine use of adjuvant growth hormone in in-vitro fertilisation protocols. However, meta-analysis demonstrated a statistically significant difference in both live birth rates and pregnancy rates favouring the use of adjuvant growth hormone in in-vitro fertilisation protocols in women who are considered poor responders without increasing adverse events, OR 5.39, 95% CI 1.89 to 15.35 and OR 3.28, 95% CI 1.74 to 6.20 respectively. Although the use of growth hormone in poor responders has been found to show a significant improvement in live birth rates, we were unable to identify which sub-group of poor responders would benefit the most from adjuvant growth hormone. The result needs to be interpreted with caution, the included trials were few in number and small sample size. Therefore, before recommending growth hormone adjuvant in in-vitro fertilisation further research is necessary to fully define its role.


Measurement of all orthogonal components of displacement in the volume of scattering materials using wavelength scanning interferometry.
A wavelength scanning interferometry system is proposed that provides displacement fields inside the volume of semitransparent scattering materials with high spatial resolution and three-dimensional (3D) displacement sensitivity. This effectively extends digital speckle pattern interferometry into three dimensions. The sample is illuminated by three noncoplanar collimated beams around the observation direction. Sequences of two-dimensional interferograms are recorded while tuning the laser frequency at a constant rate. Different optical paths along each illumination direction ensure that the signals corresponding to each sensitivity vector do not overlap in the frequency domain. All the information required to reconstruct the location and the 3D displacement vector of scattering points within the material is thus recorded simultaneously. A controlled validation experiment is performed, which confirms the ability of the technique to provide 3D displacement distributions inside semitransparent scattering materials.


In situ coating--an approach for particle modification and encapsulation of proteins during spray-drying.
In this paper, we present a method for in situ coating of individual protein particles in a respirable size. The aim of the coating was to influence the particle/powder properties, and to reduce or prevent surface-induced conformational changes of the protein, during spray-drying, which was the method used for simultaneously preparing and coating particles. The investigated formulations included bovine serum albumin (BSA), trehalose and either of the two non-ionic polymers, hydroxypropyl methylcellulose (HPMC) and poly(ethylene oxide)-poly(propylene oxide) triblock co-polymer (Poloxamer 188). Complete protein coating as measured by electron spectroscopy for chemical analysis (ESCA) was achieved at a polymer concentration of approximately 1% of the total solids weight, and could be predicted from the dynamic surface tension at the air/water interface, as measured by the pendant drop method. Further, particle properties such as: size, dissolution time, powder flowability, and apparent particle density, as measured by gas pycnometry, were affected by the type and concentration of the polymer. In addition, the particle surface morphology could possibly be correlated to the surface elasticity of the droplet surface during drying. Moreover, an extensive investigation (Fourier transform infrared spectroscopy, circular dichroism and size exclusion chromatography) of the structural effects of protein encapsulated in a polymeric coating suggested that in situ coating provide particulate formulations with preserved native conformation and with a high stability during rehydration.


Altered risk-aversion and risk-seeking behavior in bipolar disorder.
Bipolar disorder (BD) is associated with high-risk behaviors, such as gambling and impulsivity. However, little is known about the psychological factors that influence these behaviors or their significance for the development of the disorder. In this study, we investigated the effects of highlighting rewards versus highlighting punishments in the risky decision-making of euthymic individuals with bipolar disorder. Twenty euthymic, medication-free men and women with previously undiagnosed bipolar II or bipolar disorder not otherwise specified and 20 age- and IQ-matched healthy men and women completed a computerized risky decision-making task in which mathematically equivalent dilemmas were presented in terms of opportunities to gain rewards ("positively-framed") or to avoid suffering losses ("negatively-framed"). The dependent measures were the proportion of risk-seeking choices (and deliberation times) when making decisions in positively versus negatively framed dilemmas. As expected, healthy control participants made more risky-seeking choices in response to the negatively framed dilemmas compared with the positively framed dilemmas. However, this effect was significantly attenuated in BD participants who also took significantly longer to make risk-averse responses to the positively framed dilemmas. The BD participants overestimated the number of bad outcomes arising out of positively framed dilemmas. These data demonstrate that risky choice in BD is associated with reduced sensitivity to emotional contexts that highlight rewards or punishments, possibly reflecting altered valuations of prospective gains and losses associated with behavioral options.


[Sociodemographic differences in adherence to the Mediterranean dietary pattern in Spanish populations].
Lower social classes tend to eat a less healthy diet. The aim of this study was to compare adherence to the Mediterranean dietary pattern among different demographic and social groups in the adult population. A cross-sectional study was performed in southern and northern regions of Spain in healthy volunteers (15,634 men and 25,812 women), aged 29-69 years, who were members of the European Prospective Investigation on Cancer cohort in Spain. Nine groups of food were included in the definition of the Mediterranean diet: vegetables and garden products, fruits, pulses, cereals, red meat, fish, olive oil, milk and milk products, and wine. Two techniques were used in the analysis: comparison of the mean daily intake of each group and calculation of an overall score for all the foods according to educational level and original social class. Groups with the lowest educational levels consumed more cereals and pulses and lower quantities of vegetables, olive oil (women), milk and milk products (men). Wine consumption was positively associated with education in women and was negatively associated in men. Calculation of a score to measure overall adherence to the Mediterranean dietary pattern eliminated differences according to each food category. No variations were found according to educational level, but small differences were found in original social class. The adherence score was lowest in young adults and women and was slightly higher in the south than in the north of Spain. The results suggest that the Mediterranean dietary pattern is fairly uniform, at least in the adult population of the regions included in this study.


Characterization of DNA-Binding Proteins from Pea Mitochondria
We studied transcription initiation in the mitochondria of higher plants, with particular respect to promoter structures. Conserved elements of these promoters have been successfully identified by in vitro transcription systems in different species, whereas the involved protein components are still unknown. Proteins binding to double-stranded oligonucleotides representing different parts of the pea (Pisum sativum) mitochondrial atp9 were analyzed by denaturation-renaturation chromatography and mobility-shift experiments. Two DNA-protein complexes were detected, which appeared to be sequence specific in competition experiments. Purification by hydroxyapatite, phosphocellulose, and reversed-phase high-pressure liquid chromatography separated two polypeptides with apparent molecular masses of 32 and 44 kD. Both proteins bound to conserved structures of the pea atp9 and the heterologous Oenothera berteriana atp1 promoters and to sequences just upstream. Possible functions of these proteins in mitochondrial promoter recognition are discussed.


Sustained attention and heart rate variability in children and adolescents with ADHD.
The autonomic nervous system (ANS) plays an important role in attention and self-regulation by modulating physiological arousal to meet environmental demands. Core symptoms of ADHD such as inattention and behavioral disinhibition may be related to dysregulation of the ANS, however previous findings have been equivocal. We examined autonomic activity and reactivity by assessing heart rate variability (HRV) in a large sample of un-medicated children and adolescents (6-19 years) with ADHD (n=229) compared to typically-developing controls (n=244) during rest and sustained attention. Four heart rate variability measures were extracted: Root mean square of successive differences between inter-beat-intervals (rMSSD), absolute high frequency (HFA) power, absolute low frequency (LFA) power and ratio of low frequency power to high frequency power (LF/HF). There were no group differences in HFA or rMSSD, even when assessing across child and adolescent groups separately, by gender or ADHD subtype. LF/HF however was higher in ADHD during both rest and sustained attention conditions, particularly in male children. Sustained attention was impaired in ADHD relative to controls, and a higher LF/HF ratio during sustained attention was associated with poorer performance in both groups. Lower rMSSD and HFA were associated with higher anxiety, oppositional behaviors and social problems, supporting prevailing theories that these measures index emotion regulation and adaptive social behavior. Different measures of heart rate variability provide important insights into the sustained attention and emotional and behavioral regulation impairments observed in ADHD and may aid in delineating ADHD pathophysiology.


isomiR2Function: An Integrated Workflow for Identifying MicroRNA Variants in Plants.
In plants, post transcriptional regulation by non-coding RNAs (ncRNAs), in particular miRNAs (19-24 nt) has been involved in modulating the transcriptional landscape in developmental, biotic and abiotic interactions. In past few years, considerable focus has been leveraged on delineating and deciphering the role of miRNAs and their canonical isomiRs in plants. However, proper classification and accurate prediction of plant isomiRs taking into account the relative features by which we define isomiRs, such as templated or non-templated is still lacking. In the present research, we present isomiR2Function, a standalone easily deployable tool that allows for the robust and high-throughput discovery of templated and non-templated isomiRs. Additionally, isomiR2Function allows for identification of differentially expressed isomiRs and in parallel target prediction based on both transcripts or PARE-Seq either using Targetfinder or Cleaveland. isomiR2Function allows for the functional enrichment of the detected targets using TopGO package. Benchmarking of isomiR2Function revealed highly accurate prediction and classification of isomiRs as compared to the previously developed isomiR prediction tools. Additionally, the downstream implementation of additional features allows isomiR2Function to be classified as a single standalone tool for isomiR profiling from discovery to functional roles. All in all, isomiR2Function allows the streamline processing of the miRNA-seq for the identification and characterization of isomiRs with minimal efforts. isomiR2Function can be accessed through: https://github.com/347033139/isomiR2Function.


Generalized k-core percolation on correlated and uncorrelated multiplex networks.
It has been recognized that multiplexes and interlayer degree correlations can play a crucial role in the resilience of many real-world complex systems. Here we introduce a multiplex pruning process that removes nodes of degree less than k_{i} and their nearest neighbors in layer i for i=1,...,m, and establish a generic framework of generalized k-core (Gk-core) percolation over interlayer uncorrelated and correlated multiplex networks of m layers, where k=(k_{1},...,k_{m}) and m is the total number of layers. Gk-core exhibits a discontinuous phase transition for all k owing to cascading failures. We have unraveled the existence of a tipping point of the number of layers, above which the Gk-core collapses abruptly. This dismantling effect of multiplexity on Gk-core percolation shows a diminishing marginal utility in homogeneous networks when the number of layers increases. Moreover, we have found the assortative mixing for interlayer degrees strengthens the Gk-core but still gives rise to discontinuous phase transitions as compared to the uncorrelated counterparts. Interlayer disassortativity on the other hand weakens the Gk-core structure. The impact of correlation effect on Gk-core tends to be more salient systematically over k for heterogenous networks than homogeneous ones.


DPY-26, a link between dosage compensation and meiotic chromosome segregation in the nematode.
The DPY-26 protein is required in the nematode Caenorhabditis elegans for X-chromosome dosage compensation as well as for proper meiotic chromosome segregation. DPY-26 was shown to mediate both processes through its association with chromosomes. In somatic cells, DPY-26 associates specifically with hermaphrodite X chromosomes to reduce their transcript levels. In germ cells, DPY-26 associates with all meiotic chromosomes to mediate its role in chromosome segregation. The X-specific localization of DPY-26 requires two dosage compensation proteins (DPY-27 and DPY-30) and two proteins that coordinately control both sex determination and dosage compensation (SDC-2 and SDC-3).


Matrix elasticity, cytoskeletal forces and physics of the nucleus: how deeply do cells 'feel' outside and in?
Cellular organization within a multicellular organism requires that a cell assess its relative location, taking in multiple cues from its microenvironment. Given that the extracellular matrix (ECM) consists of the most abundant proteins in animals and contributes both structure and elasticity to tissues, ECM probably provides key physical cues to cells. In vivo, in the vicinity of many tissue cell types, fibrous characteristics of the ECM are less discernible than the measurably distinct elasticity that characterizes different tissue microenvironments. As a cell engages matrix and actively probes, it senses the local elastic resistance of the ECM and nearby cells via their deformation, and--similar to the proverbial princess who feels a pea placed many mattresses below--the cell seems to possess feedback and recognition mechanisms that establish how far it can feel. Recent experimental findings and computational modeling of cell and matrix mechanics lend insight into the subcellular range of sensitivity. Continuity of deformation from the matrix into the cell and further into the cytoskeleton-caged and -linked nucleus also supports the existence of mechanisms that direct processes such as gene expression in the differentiation of stem cells. Ultimately, cells feel the difference between stiff or soft and thick or thin surroundings, regardless of whether or not they are of royal descent.


Monocyte Phenotype and Polyfunctionality Are Associated With Elevated Soluble Inflammatory Markers, Cytomegalovirus Infection, and Functional and Cognitive Decline in Elderly Adults.
Monocytes are mediators of the inflammatory response and include three subsets: classical, intermediate, and nonclassical. Little is known about the phenotypical and functional age-related changes in monocytes and their association with soluble inflammatory biomarkers, cytomegalovirus infection, and functional and mental decline. We assayed the activation ex vivo and the responsiveness to TLR2 and TLR4 agonists in vitro in the three subsets and assessed the intracellular production of IL1-alpha (α), IL1-beta (β), IL-6, IL-8, TNF-α, and IL-10 of elderly adults (median 83 [67-90] years old;n= 20) compared with young controls (median 35 [27-40] years old;n= 20). Ex vivo, the elderly adults showed a higher percentage of classical monocytes that expressed intracellular IL1-α (p= .001), IL1-β (p= .001), IL-6 (p= .002), and IL-8 (p= .007). Similar results were obtained both for the intermediate and nonclassical subsets and in vitro. Polyfunctionality was higher in the elderly adults. The functionality ex vivo was strongly associated with soluble inflammatory markers. The activation phenotype was independently associated with the anti-cytomegalovirus IgG levels and with functional and cognitive decline. These data demonstrate that monocytes are key cell candidates for the source of the high soluble inflammatory levels. Our findings suggest that cytomegalovirus infection might be a driving force in the activation of monocytes and is associated with the functional and cognitive decline.


Issues involved in the definition and classification of chronic health conditions.
The need for a widely applicable definition of chronic conditions for research, policy, and program development has led to an extensive review of the development of such definitions, the considerations involved in their use, and some recommendations for a new approach. This paper examines some of the methodologic and conceptual issues related to defining and classifying chronic conditions and describes some consequences resulting from decisions made about these issues. While most examples are taken from child health applications, the basic concepts apply to all age groups. The dominant method for identifying and classifying children as having a chronic condition has relied on the presence of an individual health condition of lengthy duration. This condition-specific or "categorical" approach has increasingly seemed neither pragmatically nor conceptually sound. Thus, the development of a "generic" approach, which focuses on elements that are shared by many conditions, children, and families, is recommended. Such a definition might reflect the child's functional status or ongoing use of medical services over a specified time period. In addition, it is suggested that conditions be classified based on the experience of individual children, thus emphasizing the tremendous variability in expression of seemingly similar conditions.


The role of protein-solvent interactions in protein unfolding.
Protein unfolding occurs when the balance of forces between the protein's interaction with itself and the protein's interaction with its environment is disrupted. The disruption of this balance of forces may be as simple as a perturbance of the normal water structure around the protein. A decrease in the normal water-water interaction will result in an increase in the relative interaction of water with the protein. An increase in the number of interactions between water and the protein may initiate a protein's unfolding. This model for protein unfolding is supported by a range of recent experimental and computational data.


Noncontrast Computed Tomography Alberta Stroke Program Early CT Score May Modify Intra-Arterial Treatment Effect in DAWN.
Background and Purpose- It is unknown whether noncontrast computed tomography (NCCT) can identify patients who will benefit from intra-arterial treatment (IAT) in the extended time window. We sought to characterize baseline Alberta Stroke Program Early CT Score (ASPECTS) in DAWN (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo) and to assess whether ASPECTS modified IAT effect. Methods- Core lab adjudicated ASPECTS scores were analyzed. The trial cohort was divided into 2 groups by qualifying imaging (computed tomography versus magnetic resonance imaging). ASPECTS-by-treatment interaction was tested for the trial coprimary end points (90-day utility-weighted modified Rankin Scale (mRS) score and mRS, 0-2), mRS 0 to 3, and ordinal mRS. ASPECTS was evaluated separately as an ordinal and a dichotomized (0-6 versus 7-10) variable. Results- Of 205 DAWN subjects, 123 (60%) had NCCT ASPECTS, and 82 (40%) had diffusion weighted imaging ASPECTS. There was a significant ordinal NCCT ASPECTS-by-treatment interaction for 90-day utility-weighted mRS (interaction P=0.04) and mRS 0 to 2 (interaction P=0.02). For both end points, IAT effect was more pronounced at higher NCCT ASPECTS. The dichotomized NCCT ASPECTS-by-treatment interaction was significant only for mRS 0 to 2 (interaction P=0.04), where greater treatment benefit was seen in the ASPECTS 7 to 10 group (odds ratio, 7.50 [2.71-20.77] versus odds ratio, 0.48 [0.04-5.40]). A bidirectional treatment effect was observed in the NCCT ASPECTS 0 to 6 group, with treatment associated with not only more mRS 0 to 3 outcomes (50% versus 25%) but also more mRS 5 to 6 outcomes (40% versus 25%). There was no significant modification of IAT effect by diffusion weighted imaging ASPECTS. Conclusions- Baseline NCCT ASPECTS appears to modify IAT effect in DAWN. Higher NCCT ASPECTS was associated with greater benefit from IAT. No treatment interaction was observed for diffusion weighted imaging ASPECTS.


Probing neuronal activation by functional quantitative susceptibility mapping under a visual paradigm: A group level comparison with BOLD fMRI and PET.
Dynamic changes of brain-tissue magnetic susceptibility provide the basis for functional MR imaging (fMRI) via T2*-weighted signal-intensity modulations. Promising initial work on a detection of neuronal activity via quantitative susceptibility mapping (fQSM) has been published but consistently reported on ill-understood positive and negative activation patterns (Balla et al., 2014; Chen and Calhoun, 2015a). We set out to (i) demonstrate that fQSM can exploit established fMRI data acquisition and processing methods and to (ii) better describe aspects of the apparent activation patterns using fMRI and PET as standards of reference. Under a standardized visual-stimulation paradigm PET and 3-T gradient-echo EPI-based fQSM, fMRI data from 9 healthy volunteers were acquired and analyzed by means of Independent Component Analysis (ICA) at subject level and, for the first time, at group level. Numbers of activated (z-score>2.0) voxels were counted and their mean z-scores calculated in volumes of interest (occipital lobe (Nocc_lobe), segmented occipital gray-matter (NGM_occ_lobe), large veins (Nveins)), and in occipital-lobe voxels commonly activated in fQSM and fMRI component maps. Common but not entirely congruent regions of apparent activation were found in the occipital lobe in z-score maps from all modalities, fQSM, fMRI and PET, with distinct BOLD-negatively correlated regions in fQSM data. At subject-level, Nocc_lobe, NGM_occ_lobe and their mean z-scores were significantly smaller in fQSM than in fMRI, but their ratio, NGM_occ_lobe/Nocc_lobe, was comparable. Nveins did not statistically differ and the ratio Nveins/NGM_occ_lobe as well as the mean z-scores were higher for fQSM than for fMRI. In veins and immediate vicinity, z-score maps derived from both phase and fQSM-data showed positive and negative lobes resembling dipole shapes in simulated field and phase maps with no correlate in fMRI or PET data. Our results show that standard fMRI tools can directly be used for fQSM processing, and suggest that fQSM may have the potential to detect gray-matter activation distant from large veins, to improve detection of veins with stimulus-induced venous oxygen saturation (SvO2) variations, and to better localize areas of activation. However, our results seem to clearly expose issues that phenomenologically resemble an incomplete dipolar inversion and that need to be subject to further investigation.


Surgical decision making around paediatric preoperative anaemia in low-income and middle-income countries.
Prevalence of anaemia is high among children in low-income and middle-income countries. Anaemia is an important factor to consider preoperatively as low haemoglobin concentrations can have a negative effect on surgical outcomes and can also lead to surgeries being cancelled or postponed, which can have adverse health implications and stretch already limited resources in these countries. Additionally, blood transfusions to correct anaemia exposes children to safety issues. Therefore, where anaemia is known to be prevalent and resources are scarce, a contextually appropriate and relatively safe minimum haemoglobin concentration for proceeding to surgery could substantially improve patient management and efficiency of the health system. In this Review, we consider why paediatric anaemia is a major public health issue in low-income and middle-income countries, the value of preoperative testing of anaemia, and methods of optimising haemoglobin concentrations in the context of paediatric surgeries taking place in resource-limited settings.


Frequency-specific brain dynamics related to prediction during language comprehension.
The brain's remarkable capacity to process spoken language virtually in real time requires fast and efficient information processing machinery. In this study, we investigated how frequency-specific brain dynamics relate to models of probabilistic language prediction during auditory narrative comprehension. We recorded MEG activity while participants were listening to auditory stories in Dutch. Using trigram statistical language models, we estimated for every word in a story its conditional probability of occurrence. On the basis of word probabilities, we computed how unexpected the current word is given its context (word perplexity) and how (un)predictable the current linguistic context is (word entropy). We then evaluated whether source-reconstructed MEG oscillations at different frequency bands are modulated as a function of these language processing metrics. We show that theta-band source dynamics are increased in high relative to low entropy states, likely reflecting lexical computations. Beta-band dynamics are increased in situations of low word entropy and perplexity possibly reflecting maintenance of ongoing cognitive context. These findings lend support to the idea that the brain engages in the active generation and evaluation of predicted language based on the statistical properties of the input signal.


Axonal inclusions in spinocerebellar ataxia type 3.
Protein aggregation is a major pathological hallmark of many neurodegenerative disorders including polyglutamine diseases. Aggregation of the mutated form of the disease protein ataxin-3 into neuronal nuclear inclusions is well described in the polyglutamine disorder spinocerebellar ataxia type 3 (SCA3 or Machado-Joseph disease), although these inclusions are not thought to be directly pathogenic. Neuropil aggregates have not yet been described in SCA3. We performed a systematic immunohistochemical study of serial thick sections through brains of seven clinically diagnosed and genetically confirmed SCA3 patients. Using antibodies against ataxin-3, p62, ubiquitin, the polyglutamine marker 1C2 as well as TDP-43, we analyzed neuronal localization, composition and distribution of aggregates within SCA3 brains. The analysis revealed widespread axonal aggregates in fiber tracts known to undergo neurodegeneration in SCA3. Similar to neuronal nuclear inclusions, the axonal aggregates were ubiquitinated and immunopositive for the proteasome and autophagy associated shuttle protein p62, indicating involvement of neuronal protein quality control mechanisms. Rare TDP-43 positive axonal inclusions were also observed. Based on the correlation between affected fiber tracts and degenerating neuronal nuclei, we hypothesize that these novel axonal inclusions may be detrimental to axonal transport mechanisms and thereby contribute to degeneration of nerve cells in SCA3.


Construing and body dissatisfaction in chronic depression: A study of body psychotherapy.
The frequent association of depression with somatic symptoms suggests that body psychotherapy may be an appropriate therapeutic intervention for people with chronic depression. Using a subset of twenty-three participants from a randomized controlled trial that had demonstrated the effectiveness of such an intervention in reducing depressive symptoms, the present study investigated whether it may also impact aspects of construing which have been associated with depression. Patients presenting with chronic depression were randomly allocated to a treatment group or a waiting list group, which received body psychotherapy after a period on a waiting list. Correlations between repertory grid, questionnaire, and visual analogue measures indicated that depression and bodily dissatisfaction were associated with features of the content and structure of construing. There were no significant changes while patients were on the waiting list, but during treatment reduction in depression and bodily dissatisfaction, together with increase in self-esteem and quality of life, were accompanied by an increase in the salience of construing of the bodily self.


Report on WHO meeting on immunization in older adults: Geneva, Switzerland, 22-23 March 2017.
Many industrialized countries have implemented routine immunization policies for older adults, but similar strategies have not been widely implemented in low- and middle-income countries (LMICs). In March 2017, the World Health Organization (WHO) convened a meeting to identify policies and activities to promote access to vaccination of older adults, specifically in LMICs. Participants included academic and industry researchers, funders, civil society organizations, implementers of global health interventions, and stakeholders from developing countries with adult immunization needs. These experts reviewed vaccine performance in older adults, the anticipated impact of adult vaccination programs, and the challenges and opportunities of building or strengthening an adult and older adult immunization platforms. Key conclusions of the meeting were that there is a need for discussion of new opportunities for vaccination of all adults as well as for vaccination of older adults, as reflected in the recent shift by WHO to a life-course approach to immunization; that immunization in adults should be viewed in the context of a much broader model based on an individual's abilities rather than chronological age; and that immunization beyond infancy is a global priority that can be successfully integrated with other interventions to promote healthy ageing. As WHO is looking ahead to a global Decade of Healthy Ageing starting in 2020, it will seek to define a roadmap for interdisciplinary collaborations to integrate immunization with improving access to preventive and other healthcare interventions for adults worldwide.


Effectiveness of self-expanding metal stents for malignant antropyloric and duodenal obstruction with a comparison between covered and uncovered stents.
We evaluated overall clinical outcomes when self-expanding metal stents were used to treat malignant gastroduodenal obstruction; we also evaluated the differences in technical feasibility, effectiveness, and outcomes between covered and uncovered stents. We reviewed 134 patients who underwent endoscopic treatment for malignant antropyloric and duodenal obstructions with self-expanding metal stents. In all but two cases, the procedures were successful in restoring passage through the obstruction. Forty-two patients (31.8%) experienced stent failure during the follow-up period (23/79 (29.1%) with uncovered stents, 19/53 (35.8%) with covered stents). Stent migration was the most common cause for failure in covered stents (73.7%), while tumor ingrowth was the most common cause in uncovered stents (52.2%). The median technical survival in the uncovered stent group was similar to covered stent group (253 days vs. 247 days, p>0.05). Improvement of oral intake was associated with improvement in performance score, which was significantly improved following stent insertion (p<0.05). In addition, patients whose performance score was improved by stenting had better survival than those who did not (median survival 173 days vs. 74 days, p<0.05). Endoscopic stenting for malignant gastroduodenal obstruction appears to be an effective therapeutic modality in terminally ill patients, irrespective of the type of stent. Improvement in stent technology will improve patients' oral intake, which in turn will improve patients' quality of life and survival rate.


Environmental indicators of biofuel sustainability: what about context?
Indicators of the environmental sustainability of biofuel production, distribution, and use should be selected, measured, and interpreted with respect to the context in which they are used. The context of a sustainability assessment includes the purpose, the particular biofuel production and distribution system, policy conditions, stakeholder values, location, temporal influences, spatial scale, baselines, and reference scenarios. We recommend that biofuel sustainability questions be formulated with respect to the context, that appropriate indicators of environmental sustainability be developed or selected from more generic suites, and that decision makers consider context in ascribing meaning to indicators. In addition, considerations such as technical objectives, varying values and perspectives of stakeholder groups, indicator cost, and availability and reliability of data need to be understood and considered. Sustainability indicators for biofuels are most useful if adequate historical data are available, information can be collected at appropriate spatial and temporal scales, organizations are committed to use indicator information in the decision-making process, and indicators can effectively guide behavior toward more sustainable practices.


Casein kinase 1ε promotes cell proliferation by regulating mRNA translation.
Deregulation of translation initiation factors contributes to many pathogenic conditions, including cancer. Here, we report the definition of a novel regulatory pathway for translational initiation with possible therapeutic import in cancer. Specifically, we found that casein kinase 1ε (CK1ε) is highly expressed in breast tumors and plays a critical role in cancer cell proliferation by controlling mRNA translation. Eukaryotic translation initiation factor eIF4E, an essential component of the translation initiation complex eIF4F, is downregulated by binding the negative-acting factor 4E-BP1. We found that genetic or pharmacologic inhibition of CK1ε attenuated 4E-BP1 phosphorylation, thereby increasing 4E-BP1 binding to eIF4E and inhibiting mRNA translation. Mechanistic investigations showed that CK1ε interacted with and phosphorylated 4E-BP1 at two novel sites T41 and T50, which were essential for 4E-BP1 inactivation along with increased mRNA translation and cell proliferation. In summary, our work identified CK1ε as a pivotal regulator of mRNA translation and cell proliferation that acts by inhibiting 4E-BP1 function. As CK1ε is highly expressed in breast tumors, these findings offer an initial rationale to explore CK1ε blockade as a therapeutic strategy to treat cancers driven by deregulated mRNA translation.


Extrapulmonary tuberculosis, human immunodeficiency virus, and foreign birth in North Carolina, 1993 - 2006.
The proportion of extrapulmonary tuberculosis (EPTB) reported in the United States has been gradually increasing. HIV infection and foreign birth are increasingly associated with tuberculosis and understanding their effect on the clinical presentation of tuberculosis is important. Case-control study of 6,124 persons with tuberculosis reported to the North Carolina Division of Public health from January 1, 1993 to December 31, 2006. Multivariate logistic regression was used to obtain adjusted odds ratios measuring the associations of foreign birth region and US born race/ethnicity, by HIV status, with EPTB. Among all patients with tuberculosis, 1,366 (22.3%) had EPTB, 563 (9.2%) were HIV co-infected, and 1,299 (21.2%) were foreign born. Among HIV negative patients, EPTB was associated with being foreign born (adjusted ORs 1.36 to 5.09, depending on region of birth) and with being US born, Black/African American (OR 1.84; 95% CI 1.42, 2.39). Among HIV infected patients, EPTB was associated with being US born, Black/African American (OR 2.60; 95% CI 1.83, 3.71) and with foreign birth in the Americas (OR 5.12; 95% CI 2.84, 9.23). Foreign born tuberculosis cases were more likely to have EPTB than US born tuberculosis cases, even in the absence of HIV infection. Increasing proportions of foreign born and HIV-attributable tuberculosis cases in the United States will likely result in a sustained burden of EPTB. Further research is needed to explore why the occurrence and type of EPTB differs by region of birth and whether host genetic and/or bacterial variation can explain these differences in EPTB.


[Seroprevalence of measles, rubella, mumps and varicella in health workers in the Community of Madrid].
The vaccination of health workers has a large repercussion on the health of the workers, the patients and the population in general. Due to this, we proposed to discover the serological status for varicella, rubella, mumps and measles in the workers of a tertiary hospital in Madrid. We have conducted a retrospective epidemiological study of 1060 health workers, obtaining information such as age, sex, service area, employment status, pre-exposure vaccination and post-vaccination serology and vaccination status. In the population studied, 90.1% were protected against varicella, 65.6% against mumps, 95.6% against rubella and 92.9% against measles. There is no better protection against these illnesses for workers who treat patients directly, workers who treat immunosuppressed patients or for workers in services or units with a higher risk of infection. There is no better protection against varicella, rubella, mumps and measles for the workers who have higher risk of infection at work; and the workers who treat patients, that if they suffer these diseases, this could put their health at risk.


Support for Self-Management and Prenatal Health Behavior Change: Implications for Pediatric Promotion of Interconception Care.
Pediatricians increasingly endorse a dual generation approach to health, in which parental health behaviors are recognized as critical to promoting child health. Positive parental behaviors often emerge during pregnancy, for reasons that remain incompletely described. We surveyed mothers in the immediate postpartum period to identify beliefs about health behavior change and characteristics of prenatal care associated with successful change. Sampling at a tertiary care hospital captured an English-speaking adult population with healthy infants. Respondents (n = 225) were predominantly non-Hispanic Black (64%) and Medicaid insured (44%). Most (71%) reported successful behavior change during pregnancy. Of those reporting change, 91% intended to sustain behaviors postnatally. Most believed that sustained change was important for their own health (94%) and their infant's health (93%). In logistic regression, support for self-management was associated with prenatal health behavior change (odds ratio = 1.64, 95% confidence interval = 1.09-2.46). Continued support for self-management by pediatricians may benefit long-term family health.


Access to high-cost drugs for advanced breast cancer in Latin America, particularly trastuzumab.
Provision of high-level healthcare is a challenge for all low- to middle-income countries (LMICs) since healthcare systems are heterogeneous, face many challenges such as inadequate funding, inequitable distribution of resources and services and usually are not adequately equipped to deal with a huge problem such as breast cancer. The development of anti-HER2 therapies can be considered one of the most important examples of the translation of molecular biology knowledge into clinical benefits for cancer patients. While a variety of novel therapeutic strategies are emerging, current treatment regimens remain focussed on targeted therapy with monoclonal antibodies, mainly trastuzumab, the first agent developed in this field. While these results have revolutionised the outcome of HER2+ patients in clinical trials and in high-income countries where they are widely available, results have not impacted the natural history of this aggressive disease in most of the world. Unfortunately, the availability of these drugs is far from universal in many LMICs, and in Latin America, in particular, patients with HER2+ breast cancer are treated exclusively with standard chemotherapy, a more toxic and less efficient therapy. While the complexity of the situation and the multiple factors that have an impact in this scenario are recognised, we need to map the future and develop feasible strategies to address possible solutions to the problem of drug access. A clear and unbiased diagnosis of the situation is a good starting point. Defining healthcare priorities and a clear strategy for the allocation of resources is difficult but mandatory. In this article, we will discuss current and future challenges regarding access (and lack of access) to high-cost cancer drugs in Latin America, with a focus on anti-HER2 therapies.


dbNSFP v2.0: a database of human non-synonymous SNVs and their functional predictions and annotations.
dbNSFP is a database developed for functional prediction and annotation of all potential non-synonymous single-nucleotide variants (nsSNVs) in the human genome. This database significantly facilitates the process of querying predictions and annotations from different databases/web-servers for large amounts of nsSNVs discovered in exome-sequencing studies. Here we report a recent major update of the database to version 2.0. We have rebuilt the SNV collection based on GENCODE 9 and currently the database includes 87,347,043 nsSNVs and 2,270,742 essential splice site SNVs (an 18% increase compared to dbNSFP v1.0). For each nsSNV dbNSFP v2.0 has added two prediction scores (MutationAssessor and FATHMM) and two conservation scores (GERP++ and SiPhy). The original five prediction and conservation scores in v1.0 (SIFT, Polyphen2, LRT, MutationTaster and PhyloP) have been updated. Rich functional annotations for SNVs and genes have also been added into the new version, including allele frequencies observed in the 1000 Genomes Project phase 1 data and the NHLBI Exome Sequencing Project, various gene IDs from different databases, functional descriptions of genes, gene expression and gene interaction information, among others. dbNSFP v2.0 is freely available for download at http://sites.google.com/site/jpopgen/dbNSFP.


Does hybridization drive the transition to asexuality in diploid Boechera?
Gametophytic apomixis is a common form of asexual reproduction in plants. Virtually all gametophytic apomicts are polyploids, and some view polyploidy as a prerequisite for the transition to apomixis. However, any causal link between apomixis and polyploidy is complicated by the fact that most apomictic polyploids are allopolyploids, leading some to speculate that hybridization, rather than polyploidy, enables apomixis. Diploid apomixis presents a rare opportunity to isolate the role of hybridization, and a number of diploid apomicts have been documented in the genus Boechera (Brassicaceae). Here, we present the results of a microsatellite study of 1393 morphologically and geographically diverse diploid individuals, evaluating the hypothesis that diploid Boechera apomicts are hybrids. This genus-wide dataset was made possible by the applicability of a core set of microsatellite loci in 69 of the 70 diploid Boechera species and by our ability to successfully genotype herbarium specimens of widely varying ages. With few exceptions, diploid apomicts exhibited markedly high levels of heterozygosity resulting from the combination of disparate genomes. This strongly suggests that most apomictic diploid Boechera lineages are of hybrid origin, and that the genomic consequences of hybridization allow for the transition to gametophytic apomixis in this genus.


Positive selection neighboring functionally essential sites and disease-implicated regions of mammalian reproductive proteins.
Reproductive proteins are central to the continuation of all mammalian species. The evolution of these proteins has been greatly influenced by environmental pressures induced by pathogens, rival sperm, sexual selection and sexual conflict. Positive selection has been demonstrated in many of these proteins with particular focus on primate lineages. However, the mammalia are a diverse group in terms of mating habits, population sizes and germ line generation times. We have examined the selective pressures at work on a number of novel reproductive proteins across a wide variety of mammalia. We show that selective pressures on reproductive proteins are highly varied. Of the 10 genes analyzed in detail, all contain signatures of positive selection either across specific sites or in specific lineages or a combination of both. Our analysis of SP56 and Col1a1 are entirely novel and the results show positively selected sites present in each gene. Our findings for the Col1a1 gene are suggestive of a link between positive selection and severe disease type. We find evidence in our dataset to suggest that interacting proteins are evolving in symphony: most likely to maintain interacting functionality. Our in silico analyses show positively selected sites are occurring near catalytically important regions suggesting selective pressure to maximize efficient fertilization. In those cases where a mechanism of protein function is not fully understood, the sites presented here represent ideal candidates for mutational study. This work has highlighted the widespread rate heterogeneity in mutational rates across the mammalia and specifically has shown that the evolution of reproductive proteins is highly varied depending on the species and interacting partners. We have shown that positive selection and disease are closely linked in the Col1a1 gene.


The special case of self-perspective inhibition in mental, but not non-mental, representation.
The ventrolateral prefrontal cortex (vlPFC) has been implicated in studies of both executive and social functions. Recent meta-analyses suggest that vlPFC plays an important but little understood role in Theory of Mind (ToM). Converging neuropsychological and functional Magnetic Resonance Imaging (fMRI) evidence suggests that this may reflect inhibition of self-perspective. The present study adapted an extensively published ToM localizer to evaluate the role of vlPFC in inhibition of self-perspective. The classic false belief, false photograph vignettes that comprise the localizer were modified to generate high and low salience of self-perspective. Using a factorial design, the present study identified a behavioural and neural cost associated with having a highly salient self-perspective that was incongruent with the representational content. Importantly, vlPFC only differentiated between high versus low salience of self-perspective when representing mental state content. No difference was identified for non-mental representation. This result suggests that different control processes are required to represent competing mental and non-mental content.


Clustering of lifestyle risk factors and poor physical function in older adults: the Hertfordshire cohort study.
To examine the relationship between number of lifestyle risk factors (out of low physical activity, poor diet, obesity, smoking) and physical function in older community-dwelling men and women. Cross-sectional study, Hertfordshire, United Kingdom. Men (n = 1,682) and women (n = 1,540) aged 59 to 73. Physical activity was assessed using an administered questionnaire with a score from 0 to 100; low activity was defined as a score of 50 or less. Diet was assessed using a food frequency questionnaire; diet quality was assessed according to a score for a principal component analysis-defined "healthy" dietary pattern. Poor diet was categorized as a dietary pattern score in the lowest quarter of the distribution. Obesity was defined as a body mass index of 30.0 kg/m(2) or more. Physical function was assessed according to self-report (SF-36); poor function was defined as a score in lowest quarter of the distribution. A subgroup of participants had objective assessments of physical function (Timed Up-and-Go Test, timed 3-m walk, chair rises, one-legged standing balance). There was a graded increase in prevalence of poor self-reported physical function in men and women with increasing number of risk factors (men, adjusted odds ratio (AOR) for 3 or 4 risk factors vs none = 3.79, 95% confidence interval (CI) = 2.31-6.21; women, AOR = 5.37, 95% CI = 2.66-10.84). With the exception of balance, the objective assessments also showed graded relationships with number of risk factors, such that more risk factors was associated with poorer physical function. These modifiable lifestyle risk factors are linked to marked differences in risk of poorer physical function in older adults. Efforts to encourage healthy lifestyles have the potential to improve physical function and to promote healthier ageing.


Value of Molecular Classification for Prognostic Assessment of Adrenocortical Carcinoma.
The risk stratification of adrenocortical carcinoma (ACC) based on tumor proliferation index and stage is limited. Adjuvant therapy after surgery is recommended for most patients. Pan-genomic studies have identified distinct molecular groups closely associated with outcome. To compare the molecular classification for prognostic assessment of ACC with other known prognostic factors. In this retrospective biomarker analysis, ACC tumor samples from 368 patients who had undergone surgical tumor removal were collected from March 1, 2005, to September 30, 2015 (144 in the training cohort and 224 in the validation cohort) at 21 referral centers with a median follow-up of 35 months (interquartile range, 18-74 months). Data were analyzed from March 2016 to March 2018. Meta-analysis of pan-genomic studies (transcriptome, methylome, chromosome alteration, and mutational profiles) was performed on the training cohort. Targeted biomarker analysis, including targeted gene expression (BUB1B and PINK1), targeted methylation (PAX5, GSTP1, PYCARD, and PAX6), and targeted next-generation sequencing, was performed on the training and validation cohorts. Disease-free survival. Cox proportional hazards regression and C indexes were used to assess the prognostic value of each model. Of the 368 patients (mean [SD] age, 49 [16] years), 144 were in the training cohort (100 [69.4%] female) and 224 were in the validation cohort (142 [63.4%] female). In the training cohort, pan-genomic measures classified ACC into 3 molecular groups (A1, A2, and A3-B), with 5-year survival of 9% for group A1, 45% for group A2, and 82% for group A3-B (log-rank P < .001). Molecular class was an independent prognostic factor of recurrence in stage I to III ACC after complete surgery (hazard ratio, 55.91; 95% CI, 8.55-365.40; P < .001). The combination of European Network for the Study of Adrenal Tumors (ENSAT) stage, tumor proliferation index, and molecular class provided the most discriminant prognostic model (C index, 0.88). In the validation cohort, the molecular classification, determined by targeted biomarker measures, was confirmed as an independent prognostic factor of recurrence (hazard ratio, 5.96 [95% CI, 1.81-19.58], P = .003 for the targeted classifier combining expression, methylation, and chromosome alterations; and 2.61 [95% CI, 1.31-5.19], P = .006 for the targeted classifier combining methylation, chromosome alterations, and mutational profile). The prognostic value of the molecular markers was limited for patients with stage IV ACC. The findings suggest that in localized ACC, targeted classifiers may be used as independent markers of recurrence. The determination of molecular class may improve individual prognostic assessment and thus may spare unnecessary adjuvant treatment.


Degradation of postsynaptic scaffold GKAP and regulation of dendritic spine morphology by the TRIM3 ubiquitin ligase in rat hippocampal neurons.
Changes in neuronal activity modify the structure of dendritic spines and alter the function and protein composition of synapses. Regulated degradation of postsynaptic density (PSD) proteins by the ubiquitin-proteasome system is believed to play an important role in activity-dependent synaptic remodeling. Stimulating neuronal activity in vitro and in vivo induces the ubiquitination and degradation of GKAP/SAPAP and Shank, major scaffold proteins of the PSD. However, the specific ubiquitin ligases that regulate postsynaptic protein composition have not been identified. Here we identify the RING finger-containing protein TRIM3 as a specific E3 ubiquitin ligase for the PSD scaffold GKAP/SAPAP1. Present in PSD fractions from rat brain, TRIM3 stimulates ubiquitination and proteasome-dependent degradation of GKAP, and induces the loss of GKAP and associated scaffold Shank1 from postsynaptic sites. Suppression of endogenous TRIM3 by RNA interference (RNAi) results in increased accumulation of GKAP and Shank1 at synapses, as well as enlargement of dendritic spine heads. RNAi of TRIM3 also prevented the loss of GKAP induced by synaptic activity. Thus, TRIM3 is a novel E3 ligase that mediates activity-dependent turnover of PSD scaffold proteins and is a negative regulator of dendritic spine morphology.


Distractor-dependent frontal neglect.
The effect of distractor load on visual search was examined in a patient with visual neglect following infarction of the right frontal lobe. The spatial extent of his left-sided neglect was modified greatly by changing stimulus attributes. When targets were highly discriminable compared to distractors, or distractor density was low, or when the subject was asked to cancel distractors as well as targets, he was able to direct his search to the extreme left of search arrays and there was little or no evidence of neglect. By contrast, similar changes in distractor load had little or no effect on the neglect of a patient with a fronto-parietal lesion. These findings suggest that distractability towards ipsilesional stimuli may be an important component of neglect in individuals with only frontal lobe injury.


Microwave ablation of giant hepatic cavernous hemangiomas.
This study was designed to explore the safety and efficacy of percutaneous microwave (MW) ablation as an alternative treatment for symptomatic giant hepatic hemangiomas. Patients (n = 7; 6 females, 1 male; mean age = 44 years) with symptomatic, giant hemangiomas (n = 8) were treated with ultrasound-guided percutaneous MW ablation and followed for a mean of 18 months. Patient pain was recorded both before and after the procedure according to the 10-point visual analog scale. All patients were treated using one or three gas-cooled 17-gauge antennas powered by a 2.4-GHz generator (Neuwave Medical, Madison, WI). Mean ablation time was 11.6 min. Four patients received hydrodissection to protect the abdominal wall, colon, or gallbladder (5 % dextrose in water, mean volume 900 mL). Immediate postablation biphasic CT of the abdomen was performed, and four of seven patients have undergone delayed follow-up imaging. All ablations were technically successful with no major or minor complications. Average pain score decreased from 4.6 to 0.9 (p < 0.05), and six of seven patients report resolution or improvement of symptoms at 18-month average follow-up (range 1-33 months). Immediately postablation, mean tumor diameter decreased 25 % (from 7.3 to 5.5 cm, p < 0.05) and volume decreased 62 % (from 301 to 113 cm(3), p < 0.05). In this series, percutaneous MW ablation was safe, well-tolerated, and effective in markedly shrinking large hepatic hemangiomas and improving symptoms in most patients.


Antigen presentation in acquired immunological tolerance.
In acquired tolerance, previous exposure to antigen under certain conditions induces specific unresponsiveness instead of specific immunological memory. It has been studied as an approach to the mechanisms of self-tolerance that operate on immunocompetent T and B lymphocytes once they leave their sites of origin in the thymus and the bone marrow. Possible mechanisms involve induction of specific suppressor cells or inactivation of antigen-specific lymphocytes (clonal anergy) as a consequence of abortive antigen presentation, in which the antigen receptor is effectively engaged but certain poorly defined accessory signals the T lymphocytes require are lacking. We propose that small, resting B lymphocytes, which lack these accessory signals, are the inactivating antigen-presenting cells in acquired tolerance to proteins and to the class II transplantation antigens. B lymphocytes, which can use their antigen receptors to gather and process antigens that are present at very low concentrations, may play a role in self-tolerance. In addition, B lymphocytes and T lymphocytes rendered anergic by encounter with self antigens could persist as self-specific suppressor cells to block an autoimmune response of autoreactive clones that had escaped deletion or anergy.


Clinical trial transparency and orphan drug development: recent trends in data sharing by the pharmaceutical industry.
Data sharing from clinical trials can be key to the development and approval of medicines for rare diseases. Many events during the first half of 2013 have contributed to the movement for increased transparency. These include the development of the European Medicines Agency's new data publication policy, the creation of the AllTrials petition and GlaxoSmithKline's choice to sign it, the launch of GlaxoSmithKline's system for access to patient-level clinical trial data and Roche's commitment to create a similar system, the release of results from the Yale University Open Data Access project's first medicine analysis for Medtronic, and the creation of the Reg4All website. This paper summarises major developments in clinical trial transparency between January and June 2013 and analyses the composition of datasets released by GlaxoSmithKline. GlaxoSmithKline's database of available trials was tabulated and graphs of relevant trial characteristics were produced. Due to current transparency initiatives, it is likely that much more data will be made available over the next few years through systems similar to GlaxoSmithKline's. Although some aspects of GlaxoSmithKline's model could limit its usefulness, the data currently listed is diverse and could be promising for researchers interested in rare disease treatment.


Under the skin: using theories from biology and the social sciences to explore the mechanisms behind the black-white health gap.
Equity and social well-being considerations make Black-White health disparities an area of important concern. Although previous research suggests that discrimination- and poverty-related stressors play a role in African American health outcomes, the mechanisms are unclear. Allostatic load is a concept that can be employed to demonstrate how environmental stressors, including psychosocial ones, may lead to a cumulative physiological toll on the body. We discuss both the usefulness of this framework for understanding how discrimination can lead to worse health among African Americans, and the challenges for conceptualizing biological risk with existing data and methods. We also contrast allostatic load with theories of historical trauma such as posttraumatic slavery syndrome. Finally, we offer our suggestions for future interdisciplinary research on health disparities.


Diurnal fluctuations and developmental changes in ocular dimensions and optical aberrations in young chicks.
To investigate further the emmetropization process in young chicks by studying the diurnal fluctuations and developmental changes in the ocular dimensions and optical aberrations, including refractive errors, of normal eyes and eyes that had the ciliary nerve sectioned (CNX). The ocular dimensions and aberrations in both eyes of eight CNX (surgery on right eyes only) and eight normal chicks were measured with high-frequency A-scan ultrasonography and aberrometry, respectively, four times a day on five different days from posthatching day 13 to 35. A fixed pupil size of 2 mm was used to analyze aberration data. Repeated-measures ANOVA was applied to examine the effects of age, time of day, and surgery. Refractive errors and most higher-order aberrations decreased with development in both normal and CNX eyes. However, although normal eyes showed a positive shift in spherical aberration with age, changing from negative spherical aberration initially, CNX eyes consistently exhibited positive spherical aberration. Anterior chamber depth, lens thickness, vitreous chamber depth, and thus optical axial length all increased with development. Many of these ocular parameters also underwent diurnal changes, and mostly these dynamic characteristics showed no age dependency and no effect of CNX. Anterior chamber depth, vitreous chamber depth, and optical axial length were all greater in the evening than in the morning, whereas the choroids were thinner in the evening. Paradoxically, eyes were more hyperopic in the evening, when they were longest. Although CNX eyes, having enlarged pupils, were exposed to larger higher-order aberrations, their growth pattern was similar to that of normal eyes. Young chicks that are still emmetropizing, show significant diurnal fluctuations in ocular dimensions and some optical aberrations, superimposed on overall increases in the former and developmental decreases in the latter, even when accommodation is prevented. The possibility that these diurnal fluctuations are used to decode the eye's refractive error status for emmetropization warrants investigation. That eyes undergoing ciliary nerve section have more higher-order aberrations but do not become myopic implies a threshold for retinal image degradation below which the emmetropization process is not affected.


Dopamine and migraine: biology and clinical implications.
In the last 30 years dopamine has been considered as playing a role in the pathogenesis of migraine. The literature indicates that migraineurs are hypersensitive to dopamine agonists with respect to some of the premonitory symptoms of migraine such as nausea and yawning. There are various non-specific dopamine D(2) receptor antagonists that show good clinical efficacy in migraine, and also a number of polymorphisms of dopaminergic genes related to migraine. Animal studies have also shown that dopamine receptors are present in the trigeminovascular system, the area believed to be involved in headache pain, and neuronal firing here is reduced by dopamine agonists. There appears to be little effect of dopamine on peripheral trigeminal afferents. We assess some of the limitations of the clinical studies with regard to the therapeutics, and those found in the studies that discovered differences in genetic polymorphisms in migraine, and consider the implications of this on a dopaminergic hypothesis of migraine.


Nutritional deficiency during colonoscopy preparation: the forgotten iatrogeny.
bowel preparation for colonoscopy induces a semi-fasting state, with a potential negative impact on fragile patients. The present study aims to quantify nutritional deficiency during colonoscopy preparation. this was an observational and cross-sectional study. A convenience sample was obtained that included adults that underwent colonoscopy after bowel preparation with Klean-Prep® according to the center protocol. Anthropometric evaluation was performed and nutritional deficiency was calculated via the quantification of energy and protein intake during the 48 hours prior to the examination which was compared with the individuals' needs. The association between nutritional deficiency with the quality of bowel preparation, age and status (hospitalized/ambulatory) was evaluated. the study included 131 patients aged 21-91 years (mean 63.6 ± 13.2 years); 73 cases were male. Malnutrition reached 67.2% using specific anthropometric tools. A median preparation quality of six points was found when the Boston Bowel Preparation Scale was considered. The mean intake 48 hours prior to the procedure was 1,795 kcal and 100 g of protein. A daily energy intake of less than 50% of the individual needs was observed in 88 patients and less than 25% in 29 cases. The mean energy and protein deficiency were 59% (p < 0.01) and 45% (p < 0.01), and there was no correlation with preparation quality (p > 0.05). Nutritional defiency is similar in hospitalized and ambulatory patients (p > 0.05), but higher in older individuals (p = 0.04). nutritional deficiency during colonoscopy preparation was significant, more so in older patients, and there was no correlation with the quality of bowel preparation. We conclude that bowel preparation regimens should be reformulated with an improved nutritional intake and the inclusion of nutritional supplements without residues.


A Protocol for the Production of Integrase-deficient Lentiviral Vectors for CRISPR/Cas9-mediated Gene Knockout in Dividing Cells.
Lentiviral vectors are an ideal choice for delivering gene-editing components to cells due to their capacity for stably transducing a broad range of cells and mediating high levels of gene expression. However, their ability to integrate into the host cell genome enhances the risk of insertional mutagenicity and thus raises safety concerns and limits their usage in clinical settings. Further, the persistent expression of gene-editing components delivered by these integration-competent lentiviral vectors (ICLVs) increases the probability of promiscuous gene targeting. As an alternative, a new generation of integrase-deficient lentiviral vectors (IDLVs) has been developed that addresses many of these concerns. Here the production protocol of a new and improved IDLV platform for CRISPR-mediated gene editing and list the steps involved in the purification and concentration of such vectors is described and their transduction and gene-editing efficiency using HEK-293T cells was demonstrated. This protocol is easily scalable and can be used to generate high titer IDLVs that are capable of transducing cells in vitro and in vivo. Moreover, this protocol can be easily adapted for the production of ICLVs.