Total lymphocyte CD8 expression is not a reliable marker of cytotoxic T-cell populations in human peripheral blood following an acute bout of high-intensity exercise.
Cytotoxic T-lymphocytes co-express the T-cell receptor, CD3 and the MHC I restricted antigen CD8. Although total CD8 expression is often used to identify CD8(+) T-cells in blood, errors are associated with this method as some CD3 negative natural killer (NK)-cells are known to express CD8. As greater relative proportions of NK-cells are found in the blood compartment after exercise, these errors are likely to be amplified in post exercise blood samples. To test this, isolated blood lymphocytes obtained from aerobically trained male subjects before, immediately after and 1h after an exhaustive treadmill-running protocol were surface stained for CD3, CD4, CD8, CD16, and CD56 and analysed by multi-colour flow cytometry. It was found that 25.4+/-16.9% of all CD8(+) cells at rest were CD3 negative, CD8(dim+) and expressed the NK-cell markers CD16 and CD56. The magnitude of this error increased to 40.8+/-20.7% immediately after exercise due to an influx of CD8(dim+) NK-cells. Although all CD8(bright+) cells expressed CD3, gating around the CD8(bright+) cells only identified 79.2+/-8.7% of the total CD3(+)/CD8(+) T-cell population; however, the magnitude of this error did not change after exercise despite the altered proportions of CD8(bright+) and CD8(dim+) cells. In conclusion, total lymphocyte expression of CD8 should not be used as a single antigenic marker to identify CD8(+) T-cells after an acute bout of exercise. Although there are errors associated with using CD8(bright+) as a single antigenic marker to identify CD3(+) T-cells, these are not amplified in response to exercise.


Influence of Fluorescein Angiography on the Diagnosis and Management of Retinopathy of Prematurity.
To examine the influence of fluorescein angiography (FA) on the diagnosis and management of retinopathy of prematurity (ROP). Prospective cohort study. Nine recognized ROP experts (3 pediatric ophthalmologists and 6 retina specialists) interpreted 32 sets (16 color fundus photographs and 16 color fundus photographs paired with the corresponding FA images) of wide-angle retinal images from infants with ROP. All experts independently reviewed the 32 image sets on a secure website and provided a diagnosis and management plan for the case presented, first based on color fundus photographs alone, and then based on color fundus photographs and corresponding FA images. Sensitivity and specificity of the ROP diagnosis (zone, stage, plus disease, and category, i.e., no ROP, mild ROP, type 2 ROP, and ROP requiring treatment) were calculated using a consensus reference standard diagnosis, determined from the diagnosis of the color fundus photographs by 3 experienced readers in combination with the clinical diagnosis based on ophthalmoscopic examination. The κ statistic was used to analyze the average intergrader agreement among experts for the diagnosis of zone, stage, plus disease, and category. Addition of FA to color fundus photography resulted in a significant improvement in sensitivity for diagnosis of stage 3 or worse disease (39.8% vs. 74.1%; P = 0.008), type 2 or worse ROP (69.4% vs. 86.8%; P = 0.013), and pre-plus or worse disease (50.5 vs. 62.6%; P = 0.031). There was a nonsignificant trend toward improved sensitivity for diagnosis of ROP requiring treatment (22.2% vs. 40.3%; P = 0.063). Using the κ statistic, addition of FA to color fundus photography significantly improved intergrader agreement for diagnosis of ROP requiring treatment. Addition of FA to color fundus photography did not affect intergrader agreement significantly for the diagnosis of stage, zone, or plus disease. Compared with color fundus photography alone, FA may improve the sensitivity of diagnosis of ROP by experts, particularly for stage 3 disease. In addition, intergrader agreement for diagnosis of ROP requiring treatment may improve with FA interpretation.


Indole-like urinary stress reactant in man.
Paper chromatograms on extracts from serial 6-hr urine samples from humans of both sexes on indole-controlled diets revealed either the appearance of or marked increment in "spot 32" (1) after ACTH gel injections. This corresponds in time and duration with the rise in 17-hydroxycorticoid excretion. 5-Hydroxyindoleacetic acid and 28 other urinary indoles failed to show this rise predictably.


Right on track? Performance of satellite telemetry in terrestrial wildlife research.
Satellite telemetry is an increasingly utilized technology in wildlife research, and current devices can track individual animal movements at unprecedented spatial and temporal resolutions. However, as we enter the golden age of satellite telemetry, we need an in-depth understanding of the main technological, species-specific and environmental factors that determine the success and failure of satellite tracking devices across species and habitats. Here, we assess the relative influence of such factors on the ability of satellite telemetry units to provide the expected amount and quality of data by analyzing data from over 3,000 devices deployed on 62 terrestrial species in 167 projects worldwide. We evaluate the success rate in obtaining GPS fixes as well as in transferring these fixes to the user and we evaluate failure rates. Average fix success and data transfer rates were high and were generally better predicted by species and unit characteristics, while environmental characteristics influenced the variability of performance. However, 48% of the unit deployments ended prematurely, half of them due to technical failure. Nonetheless, this study shows that the performance of satellite telemetry applications has shown improvements over time, and based on our findings, we provide further recommendations for both users and manufacturers.


Genus-Wide Comparative Genomics of Malassezia Delineates Its Phylogeny, Physiology, and Niche Adaptation on Human Skin.
Malassezia is a unique lipophilic genus in class Malasseziomycetes in Ustilaginomycotina, (Basidiomycota, fungi) that otherwise consists almost exclusively of plant pathogens. Malassezia are typically isolated from warm-blooded animals, are dominant members of the human skin mycobiome and are associated with common skin disorders. To characterize the genetic basis of the unique phenotypes of Malassezia spp., we sequenced the genomes of all 14 accepted species and used comparative genomics against a broad panel of fungal genomes to comprehensively identify distinct features that define the Malassezia gene repertoire: gene gain and loss; selection signatures; and lineage-specific gene family expansions. Our analysis revealed key gene gain events (64) with a single gene conserved across all Malassezia but absent in all other sequenced Basidiomycota. These likely horizontally transferred genes provide intriguing gain-of-function events and prime candidates to explain the emergence of Malassezia. A larger set of genes (741) were lost, with enrichment for glycosyl hydrolases and carbohydrate metabolism, concordant with adaptation to skin's carbohydrate-deficient environment. Gene family analysis revealed extensive turnover and underlined the importance of secretory lipases, phospholipases, aspartyl proteases, and other peptidases. Combining genomic analysis with a re-evaluation of culture characteristics, we establish the likely lipid-dependence of all Malassezia. Our phylogenetic analysis sheds new light on the relationship between Malassezia and other members of Ustilaginomycotina, as well as phylogenetic lineages within the genus. Overall, our study provides a unique genomic resource for understanding Malassezia niche-specificity and potential virulence, as well as their abundance and distribution in the environment and on human skin.


Objective measures of executive functioning are highly discrepant with parent-report in fetal alcohol spectrum disorders.
The purpose of the current study was to evaluate the relationship between parent-report and objective measures of executive function in children diagnosed with Fetal Alcohol Spectrum Disorder (FASD). The participants were a clinical sample of 551 children who completed 597 evaluations, including initial and re-evaluations. Participants were 6-16 years old, with a mean age of 10. Pearson correlations were used to determine the relationship between performance-based measures and parent-report measures of executive functioning. Relationships among the same types of measures, that is, performance based or parent report, were also evaluated. The data largely demonstrate low nonsignificant correlations between performance-based measures and parental report of executive function. Parent-report measures were internally consistent as were objective measures. It is possible that a third variable, for example, parental frustration, significantly influences parent reports. It is also likely that objective measures, which are administered in a controlled environment, do not fully capture children's day-to-day functioning. That is, a child may have the executive function abilities (i.e., good performance on objective measures) but may be unable to deploy the appropriate skills in their daily lives, as evidenced by parental report. Children with FASD who have executive function abilities but not implementation skills likely require different interventions than children who lack abilities and skills.


Reaction dynamics study of O- + C2H2 with crossed beams and density-functional theory calculations.
The reactions between O(-) and C(2)H(2) have been studied using the crossed-beam technique and density-functional theory (DFT) calculations in the collision energy range from 0.35 to 1.5 eV (34-145 kJmol). Both proton transfer and C-O bond formation are observed. The proton transfer channel forming C(2)H(-) is the dominant pathway. The center-of-mass flux distributions of the C(2)H(-) product ions are highly asymmetric, with maxima close to the velocity and direction of the precursor acetylene beam, characteristic of direct reactions. The reaction quantitatively transforms the entire reaction exothermicity into internal excitation of the products, consistent with mixed energy release in which the proton is transferred in a configuration in which both the breaking and the forming bonds are extended. The C-O bond formation channel producing HC(2)O(-) displays a distinctive kinematic picture in which the product distribution switches from predominantly forward scattering with a weak backward peak to sideways scattering as the collision energy increases. At low collision energies, the reaction occurs through an intermediate that lives a significant fraction of a rotational period. The asymmetry in the distribution leads to a lifetime estimate of 600 fs, in reasonable agreement with DFT calculations showing that hydrogen-atom migration is rate limiting. At higher collision energies, the sideways-scattered products arise from repulsive energy release from a bent transition state.


Relating prognosis in chromophobe renal cell carcinoma to the chromophobe tumor grading system.
The chromophobe subtype of renal cell carcinoma (chRCC) has generally been associated with a better prognosis than the clear cell type; however, debate continues as to absolute prognosis as well as the significance of certain prognostic variables. We investigated the significance of pathologic stage and a recently proposed chromophobe tumor grading (CTG) scheme in predicting chRCC outcomes. All available chRCCs were identified from our surgical pathology archives from 1987-2010. Original slides were reviewed to verify diagnoses and stage, and each case was graded following a novel chromophobe tumor grade system criteria. Disease status was obtained from a clinical outcome database, and cancer specific deaths and recurrences were recorded. Eighty-one cases of chRCC were identified, and 73 had adequate follow-up information available. There were only 3 instances of cancer related recurrence or mortality, which included 1 disease specific mortality and 2 disease recurrences. Pathologic stage and CTG 3 were found to be significantly associated with the recurrences or death from chRCC, but there was no association with CTG 1 and CTG 2. chRCC is associated with a very low rate of cancer specific events (4.1%) even at a tertiary referral center. In our study, pathologic stage and CTG 3, but not CTG 1 or 2, were significantly associated with the development of these events.


Remedy of dye manufacturing process effluent by UV/H2O2 process.
The effluent from dye manufacturing industry is more difficult to be treated than laboratory synthesized wastewater according to high variability of composition and color intensity. Thus, this study aimed to propose the method for remedying industrial effluent by UV/H2O2 process in a recirculated batch reactor system while considering the effects on hydrogen peroxide dosage, UV power and wastewater intensity for the removal of color and COD. From the experimental results, it was feasibly treated that the distinguished removal of color and COD by increasing the hydrogen peroxide dosage and UV power, but not by the strong intensity of industrial effluent. Therefore, UV/H2O2 process of the developed reactor was a positively superior treatment or pre-treatment for dye manufacturing plant effluent to comply the regulated requirements.


Temporal labyrinths of eastern Eurasian Pleistocene humans.
One of the morphological features that has been identified as uniquely derived for the western Eurasian Neandertals concerns the relative sizes and positions of their semicircular canals. In particular, they exhibit a relatively small anterior canal, a relatively larger lateral one, and a more inferior position of the posterior one relative to the lateral one. These discussions have not included full paleontological data on eastern Eurasian Pleistocene human temporal labyrinths, which have the potential to provide a broader context for assessing Pleistocene Homo trait polarities. We present the temporal labyrinths of four eastern Eurasian Pleistocene Homo, one each of Early (Lantian 1), Middle (Hexian 1), and Late (Xujiayao 15) Pleistocene archaic humans and one early modern human (Liujiang 1). The labyrinths of the two earlier specimens and the most recent one conform to the proportions seen among western early and recent modern humans, reinforcing the modern human pattern as generally ancestral for the genus Homo. The labyrinth of Xujiayao 15 is in the middle of the Neandertal variation and separate from the other samples. This eastern Eurasian labyrinthine dichotomy occurs in the context of none of the distinctive Neandertal external temporal or other cranial features. As such, it raises questions regarding possible cranial and postcranial morphological correlates of Homo labyrinthine variation, the use of individual "Neandertal" features for documenting population affinities, and the nature of late archaic human variation across Eurasia.


Expression of transgenes from newcastle disease virus with a segmented genome.
Paramyxoviruses belong to the Paramyxoviridae family of the order Mononegavirales. They have a nonsegmented negative-stranded RNA genome and can cause a number of diseases in humans and animals. We generated a recombinant Newcastle disease virus (NDV) possessing a two-segmented genome. Each genomic segment is flanked by authentic NDV 3' and 5' noncoding termini allowing for efficient replication and transcription. A reporter gene encoding green fluorescent protein (GFP) was inserted into one segment, and a red fluorescent protein dsRed gene was inserted into the other segment in order to easily detect the replication and transcription of segments in infected cells. The rescued viruses grew well and were stable in embryonated chicken eggs over multiple passages. We were able to detect the expression of both reporter genes in the same cell infected with the virus possessing a segmented genome, and viral particles can contain either one or two types of RNA segments. We also rescued a two-segmented virus expressing GFP and the severe acute respiratory syndrome-associated coronavirus spike S protein, which is about 200 kDa. The chimeric virus extends the coding capacity of NDV by 30%, suggesting that the two-segmented NDV can be used for development of vaccines or gene therapy vectors carrying long and multiple transgenes.


Differential rates of cesarean delivery by maternal geographical origin: a cohort study in France.
In many Western countries, higher rates of cesarean have been described among migrant women compared to natives of receiving countries. We aimed to estimate this difference comparing women originating from France and Sub-Saharan Africa (SSA), identify the clinical situations explaining most of this difference and assess whether maternal origin was independently associated with cesarean risk. The PreCARE prospective multicenter cohort study was conducted in 2010-2012 in the north Paris area. Our sample was restricted to 1500 women originating from Sub-Saharan Africa and 2206 from France. Profiles of cesarean section by maternal origin were described by the Robson classification. Independent associations between maternal origin and 1) cesarean before labor versus trial of labor, then 2) intrapartum cesarean versus vaginal delivery were assessed by logistic regression models to adjust for other maternal and pregnancy characteristics. Rates of cesarean for women originating from France and SSA were 17 and 31%. The Robson 5A category "unique uterine scar, single cephalic ≥37 weeks" was the main contributor to this difference. Within this category, SSA origin was associated with cesarean before labor after adjustment for medical risk factors (adjusted odds ratio [aOR] = 2.30 [1.12-4.71]) but no more significant when adjusting on social deprivation (aOR = 1.45 [0.63-3.31]). SSA origin was associated with cesarean during labor after adjustment for both medical and social factors (aOR = 2.95 [1.35-6.44]). The wide difference in cesarean rates between SSA and French native women is mainly explained by the Robson 5A category. Within this group, medical factors alone do not explain the increased risk of cesarean in SSA women.


An approach to improve LOINC mapping through augmentation of local test names.
Mapping medical test names into a standardized vocabulary is a prerequisite to sharing test-related data between health care entities. One major barrier in this process is the inability to describe tests in sufficient detail to assign the appropriate name in Logical Observation Identifiers, Names, and Codes (LOINC®). Approaches to address mapping of test names with incomplete information have not been well described. We developed a process of "enhancing" local test names by incorporating information required for LOINC mapping into the test names themselves. When using the Regenstrief LOINC Mapping Assistant (RELMA) we found that 73/198 (37%) of "enhanced" test names were successfully mapped to LOINC, compared to 41/191 (21%) of original names (p=0.001). Our approach led to a significantly higher proportion of test names with successful mapping to LOINC, but further efforts are required to achieve more satisfactory results.


Effect of octopamine on the activity of juvenile-hormone esterase in the silkworm Bombyx mori and the red flour beetle Tribolium freemani.
This study focuses on the effect of octopamine (OA) on metamorphosis of the silkworm Bombyx mori and the red flour beetle Tribolium freemani Hinton. Titers of OA and juvenile-hormone esterase (JHE) were measured at various larval and pupal stadia of both insects. Effects of OA, OA agonists, and antagonists on metamorphosis and JHE activity were also examined. At day 2, peaks of OA and JHE activity were observed in third instars, and at day 3, a sharp peak of OA was observed, followed by a large peak of JHE activity at day 4 in last instars of B. mori. However, no peaks of OA and JHE activity were observed in fourth instars. A high titer of OA appeared at days 2-4, followed by a peak of JHE activity at day 7 and the second OA peak at day 9 after the start of assay of T. freemani. At pupation, a small peak of OA and the highest activity of JHE were observed. The effects of OA on JHE activity were examined in vitro, because the relationship could be responsible for triggering pupation in B. mori and T. freemani larvae. Exogeneous OA (0.1-10 mM) stimulated the JHE activity of final instars (day 2) of B. mori in vitro. Similarly, the presence of OA (10 mM) activated the JHE activity of newly ecdysed T. freemani pupae in vitro. OA antagonists chlorpromazine and gramine delayed the start of spinning and reduced the JHE activity of B. mori, when applied in diet at 10-100 ppm. Some OA agonists stimulated the pupation and JHE activity of T. freemani larvae reared under crowded conditions, when topically applied. Thus, OA may contribute to activation of the events preparatory to a pupal molt, i.e., the secretion of OA increases JHE activity followed by stimulation of pupation.


An information-gain approach to detecting three-way epistatic interactions in genetic association studies.
Epistasis has been historically used to describe the phenomenon that the effect of a given gene on a phenotype can be dependent on one or more other genes, and is an essential element for understanding the association between genetic and phenotypic variations. Quantifying epistasis of orders higher than two is very challenging due to both the computational complexity of enumerating all possible combinations in genome-wide data and the lack of efficient and effective methodologies. In this study, we propose a fast, non-parametric, and model-free measure for three-way epistasis. Such a measure is based on information gain, and is able to separate all lower order effects from pure three-way epistasis. Our method was verified on synthetic data and applied to real data from a candidate-gene study of tuberculosis in a West African population. In the tuberculosis data, we found a statistically significant pure three-way epistatic interaction effect that was stronger than any lower-order associations. Our study provides a methodological basis for detecting and characterizing high-order gene-gene interactions in genetic association studies.


Biomechanical influence of cartilage homeostasis in health and disease.
There is an urgent demand for long term solutions to improve osteoarthritis treatments in the ageing population. There are drugs that control the pain but none that stop the progression of the disease in a safe and efficient way. Increased intervention efforts, augmented by early diagnosis and integrated biophysical therapies are therefore needed. Unfortunately, progress has been hampered due to the wide variety of experimental models which examine the effect of mechanical stimuli and inflammatory mediators on signal transduction pathways. Our understanding of the early mechanopathophysiology is poor, particularly the way in which mechanical stimuli influences cell function and regulates matrix synthesis. This makes it difficult to identify reliable targets and design new therapies. In addition, the effect of mechanical loading on matrix turnover is dependent on the nature of the mechanical stimulus. Accumulating evidence suggests that moderate mechanical loading helps to maintain cartilage integrity with a low turnover of matrix constituents. In contrast, nonphysiological mechanical signals are associated with increased cartilage damage and degenerative changes. This review will discuss the pathways regulated by compressive loading regimes and inflammatory signals in animal and in vitro 3D models. Identification of the chondroprotective pathways will reveal novel targets for osteoarthritis treatments.


Smoking, quitting, and the risk of cardiovascular disease among women and men in the Asia-Pacific region.
Although smoking is a major risk factor for cardiovascular disease, it has been suggested that Asians may be less susceptible to the adverse effects of smoking than Caucasians. This may have contributed to the high prevalence of smoking, and the low quitting rates, in Asian men. Worldwide, smoking rates are increasing for women, amongst whom cardiovascular awareness is relatively poor. An individual participant data analysis of 40 cohort studies was carried out, involving 463 674 Asians (33% female) and 98 664 Australasians (45% female). Cox proportional hazard models, stratified by study and sex where appropriate, were employed. The HR [95% confidence interval (CI)], comparing current smokers with non-smokers, for coronary heart disease (CHD) was 1.60 (1.49-1.72); haemorrhagic stroke 1.19 (1.06-1.33); ischaemic stroke 1.38 (1.24-1.54). There was a clear dose-response relationship between the number of cigarettes smoked per day and both CHD and stroke, with no significant difference (P >/= 0.20) between populations from Asia and Australia/New Zealand. Although there was no sex difference for stroke in the effect of amount smoked (P = 0.16), for CHD, women tended to have higher hazard ratios than men (P = 0.011). Quitting gave a clear benefit, which was not significantly different between the sexes or regions (P > 0.63). The HR (CI) for ex-smokers compared with current smokers was 0.71 (0.64-0.78) for CHD and 0.84 (0.76-0.92) for stroke. Unless urgent public health measures are put into place, the impact of the smoking epidemic in Asia, and among women, will be enormous. Tobacco control policies that specifically target these populations are essential.


Obstruction is unimportant in the pathophysiology of hypertrophic cardiomyopathy.
There has been a longstanding controversy about the significance of intracavitary pressure gradients in hypertrophic cardiomyopathy (HCM). It has been generally assumed that the gradient is the result of an 'obstruction' that impedes left ventricular outflow and which can be relieved by operative intervention. In the first decade after the discovery of HCM (1957-66), the site of 'obstruction' was thought to be a muscular sphincter or contraction ring in the submitral region of the left ventricle, and operations designed to emulate pyloromyectomy (for hypertrophic pyloric stenosis) were developed. Following a challenge to the existence of the 'contraction ring' and an alternative non-obstructive explanation of the pressure gradient, the site of 'obstruction' was translocated to a point of apposition between the anterior mitral leaflet and the interventricular septum, a result of systolic anterior motion (SAM) of the mitral valve. Despite the translocation of the site and mechanism of 'obstruction', the operation for 'relief of obstruction' has not changed significantly. The newer site of 'obstruction' has been challenged on the grounds that the ventricle is not demonstrably impeded in its emptying; when a gradient is provoked, the ventricle empties more rapidly and more completely than it does without a gradient. In addition to a non-obstructive explanation of the gradient, other phenomena thought to be indicative of 'obstruction' can be explained by rapid and complete emptying of the ventricle (cavitary obliteration). Since the morbidity and mortality of symptomatic HCM patients without pressure gradients may exceed that of patients with pressure gradients, it is suggested that 'obstruction' may be unimportant in the pathophysiology of HCM and attention should be focused on abnormal diastolic function and life threatening arrhythmias.


SLCO2B1 genetic polymorphisms in a Korean population: pyrosequencing analyses and comprehensive comparison with other populations.
SLCO2B1, also known as OATP2B1 (Organic Anion Transporter) or OATP-B or SLC21A9, is an organic anion uptake transporter that is encoded by the SLCO2B1 gene. In this study we assessed the frequencies of SLCO2B1 polymorphisms in a Korean population using newly developed pyrosequencing methods and compared their frequencies with those in other ethnic groups. We developed pyrosequencing methods to identify the following six SLCO2B1 non-synonymous polymorphisms: c.1175C > T (rs1621378), c.1457C > T (rs2306168), c.43C > T (rs56837383), c.935G > A (rs12422149), c.601G > A (rs35199625) and c.644A > T (rs72559740). The allele frequencies of these polymorphisms were analyzed in 227 Korean subjects. The allele frequencies of SLCO2B1 polymorphisms in the population tested were as follows: 0.0 for c.1175C > T, c.43C > T and c.644A > T; 0.2687 for c.1457C > T; 0.4273 for c.935G > A; and 0.0727 for c. 601G > A. Even though the allele frequencies of the c.1175C > T and c.1457C > T polymorphisms were comparable to those in Japanese subjects, the frequencies in this Korean population differed from those in other ethnic groups. The developed pyrosequencing methods are rapid and reliable for detecting non-synonymous SLCO2B1 polymorphisms. Large ethnic differences in the frequency of SLCO2B1 genetic polymorphisms were noted among ethnic groups. The SLCO2B1 polymorphisms at c.1175C > T, c.43C > T and c.644A > T were not found in the Korean population while c.1457C > T, c.935G > A and c.601G > A exhibited mostly higher frequencies in Koreans compared with Finnish, Caucasian and African-American populations.


Fiber optic lever displacement transducer.
Intrinsic performance limits of noncontacting fiber lever displacement measuring systems are quantitatively described. Generalized relationships linking displacement detection limit, frequency response, dynamic range, linearity, and working distance to fiber diameter, illumination irradiance and coupling angle, photodetector characteristics, and reflection and transmission losses were obtained by analysis and confirmed by measurement. Both procedures showed performance limits to be functions of the square root of the flux density coupled into the target-illuminating fiber(s) by the electroluminescent source. Displacement detection and bandwidth limits achievable with tungsten or LED sources were in the 2 x 10(-11) to 2 x 10(-12) [equation] and MHz, range respectively. A basis for optimizing levers for different applications and determination of intrinsic performance limits is provided.


Not all suffering is pain: sources of patients' suffering in the emergency department call for improvements in communication from practitioners.
Provision of prompt, effective analgesia is rightly considered as a standard of care in the emergency department (ED). However, much suffering is not 'painful' and may be under-recognised. We sought to describe the burden of suffering in the ED and explore how this may be best addressed from a patient centred perspective. In a prospective cohort study, we included undifferentiated patients presenting to the ED. We undertook two face to face questionnaires with the first immediately following triage. We asked patients: (a) if they were 'suffering'; (b) how they were suffering; and (c) what they hoped would be done to ease this. Prior to leaving the ED, we asked patients what had been done to ease their suffering. Data were analysed thematically. Of 125 patients included, 77 (61.6%) reported suffering on direct questioning and 92 (73.6%) listed at least one way in which they were suffering. 90 (72.0%) patients had a pain score >0/10 but only 37 (29.6%) reported that pain was causing suffering. Patients reported suffering from both physical symptoms (especially pain, nausea, vomiting and dizziness) and emotional distress (notably anxiety). Treatment (to ease physical and emotional symptoms), information (particularly diagnosis, reassurance and explanation), care (notably friendly staff) and closure (being seen, resolving the problem and going home) were the key themes identified as important for relief of suffering. In seeking to ease suffering in the ED, clinicians must focus not only on providing analgesia but on treating Emotional distress, Physical symptoms, providing Information, Care and Closure (EPICC).


Inhibition of osteoclast differentiation and bone resorption by sauchinone.
Osteoclasts are bone-specific multinucleated cells generated by differentiation of monocyte/macrophage lineage precursors. Regulation of osteoclast differentiation is considered an effective therapeutic approach to the treatment of bone-lytic diseases. In this study, we investigated effects of sauchinone, a lignan from Saururus chinensis, on osteoclastogenesis induced by the differentiation factor RANKL (receptor activator of nuclear factor kappa B ligand). Sauchinone strongly inhibited the osteoclastogenesis from primary bone marrow-derived macrophages (BMMs). This effect was accompanied by a significant decrease in the level of carbonic anhydrase II, calcitonin receptor, MMP9, and TRAP, which are normally upregulated during osteoclast differentiation. For the induction of osteoclastogenesis-associated genes, RANKL activates multiple transcription factors through mechanisms involving mitogen-activated protein kinases (MAPK) and reactive oxygen species (ROS). Sauchinone greatly attenuated the activation of ERK and, less prominently, that of p38 MAPKs by RANKL. The RANKL-stimulated induction of c-Fos and NFATc1 transcription factors was also abrogated by sauchinone. In addition, the activation of AP-1, NFAT, and NF-kappaB transcription factors was alleviated in sauchinone-treated cells. Sauchinone also diminished the RANKL-stimulated increase of ROS production in BMMs. Consistent with the in vitro anti-osteoclastogenic effect, sauchinone inhibited bone destruction and osteoclast formation caused by lipopolysaccharide in an animal model. Taken together, our data demonstrate that sauchinone inhibits RANKL-induced osteoclastogenesis by reducing ROS generation, which attenuates MAPK and NF-kappaB activation, ultimately leading to the suppression of c-Fos and NFATc1 induction. Also the in vivo effect of sauchinone on bone erosion strengthens the potential usefulness of this compound for diseases involving bone resorption.


Clinical assessment of oxygen conserving devices in chronic bronchitis and emphysema.
We have studied the efficacy of three devices designed to conserve oxygen delivered to patients with hypoxic chronic bronchitis and emphysema. Devices A and B are valve systems, which deliver oxygen only during inspiration. Device C is a modified nasal prongs system incorporating a "moustache reservoir" (Oxymizer, Chad Therapeutics Inc, Woodland Hills, California), which is claimed to produce a higher arterial oxygen saturation (SaO2) from a given flow of oxygen than does continuous delivery through nasal prongs. Devices A and B were found to give the same oxygen saturation as continuous flow oxygen, but only device B reduced the flow of oxygen significantly (p less than 0.01). The flow characteristics of device A were likely to be the cause of this failure to conserve oxygen. Device C produced a higher mean rise in SaO2 than did standard nasal prongs at all oxygen flow rates, and was able to achieve the same rise in SaO2 as standard nasal prongs with a small (25-33%) saving in oxygen delivery. There was, however, considerable variation between patients in the oxygen saving efficiency of device C, with little or no oxygen saving in seven of the 12 patients studied.


Iron overload in mild sideroblastic anaemias.
Life-threatening iron overload may occur without severe anaemia in patients with sideroblastic disorders. Assessment of erythroid expansion in bone-marrow aspirates may be as useful as ferrokinetic studies in predicting both the risk of iron loading and the need for prophylactic phlebotomy or iron-chelation therapy.


Actin, microtubule, septin and ESCRT filament remodeling during late steps of cytokinesis.
Cytokinesis is the process by which a mother cell is physically cleaved into two daughter cells. In animal cells, cytokinesis begins with the contraction of a plasma membrane-associated actomyosin ring that is responsible for the ingression of a cleavage furrow. However, the post-furrowing steps of cytokinesis are less understood. Here, we highlight key recent findings that reveal a profound remodeling of several classes of cytoskeletal elements and cytoplasmic filaments (septins, microtubules, actin and ESCRT) in the late steps of cytokinesis. We review how this remodeling is required first for the stabilization of the intercellular bridge connecting the daughter cells and then for the steps leading up to abscission. New players regulating the abscission (NoCut) checkpoint, which delays abscission via cytoskeleton and ESCRT remodeling in response to various cytokinetic stresses, will also be emphasized. Altogether, the latest discoveries reveal a crucial role for posttranslational modifications of the cytoskeleton (actin oxidation, septin SUMOylation) and an unexpected requirement of ESCRT-III polymer dynamics for successful abscission.


Total synthesis, biosynthesis and biological profiles of clavine alkaloids.
This review highlights noteworthy synthetic and biological aspects of the clavine subfamily of ergot alkaloids. Recent biosynthetic insights have laid the groundwork for a better understanding of the diverse biological pathways leading to these indole derivatives. Ergot alkaloids were among the first fungal-derived natural products identified, inspiring pharmaceutical applications in CNS disorders, migraine, infective diseases, and cancer. Pergolide, for example, is a semi-synthetic clavine alkaloid that has been used to treat Parkinson's disease. Synthetic activities have been particularly valuable to facilitate access to rare members of the Clavine family and empower medicinal chemistry research. Improved molecular target identification tools and a better understanding of signaling pathways can now be deployed to further extend the biological and medical utility of Clavine alkaloids.


Temperature Dependence of Hydroxymethyl Group Rotamer Populations in Cellooligomers.
Empirical force fields for computer simulations of carbohydrates are often implicitly assumed to be valid also at temperatures different from room temperature for which they were optimized. Herein, the temperature dependence of the hydroxymethyl group rotamer populations in short oligosaccharides is investigated using molecular dynamics simulations and NMR spectroscopy. Two oligosaccharides, viz., methyl β-cellobioside and β-cellotetraose were simulated using three different carbohydrate force fields (CHARMM C35, GLYCAM06, and GROMOS 56Acarbo) in combination with different water models (SPC, SPC/E, and TIP3P) using replica exchange molecular dynamics simulations. For comparison, hydroxymethyl group rotamer populations were investigated for methyl β-cellobioside and cellopentaose based on measured NMR (3)JH5,H6 coupling constants, in the latter case by using a chemical shift selective NMR-filter. Molecular dynamics simulations in combination with NMR spectroscopy show that the temperature dependence of the hydroxymethyl rotamer population in these short cellooligomers, in the range 263-344 K, generally becomes exaggerated in simulations when compared to experimental data, but also that it is dependent on simulation conditions, and most notably properties of the water model.


A qualitative analysis of the perception of stigma among Latinos receiving antidepressants.
This study sought to describe the role of stigma in antidepressant adherence among Latinos. The study utilized data generated from six focus groups of Latino outpatients receiving antidepressants (N=30). By using a grounded theory approach, qualitative analysis focused specifically on the role of stigma in antidepressant treatment, as well as salient Latino values. Perceptions of stigma were related to both the diagnosis of depression and use of antidepressant medication. Qualitative analyses showed that antidepressant use was seen as implying more severe illness, weakness or failure to cope with problems, and being under the effects of a drug. Reports of stigma were also related to social consequences. Also, the perceived negative attributes of antidepressant use were at odds with self-perceived cultural values. Stigma was a prominent concern among Latinos receiving antidepressants, and stigma often affected adherence. Furthermore, culture is likely to play an important role in the communication of stigma and its associated complications.


Acousto-optic parallel read/write head for optical disk data storage.
Parallel read and write of optical disks has traditionally used a static grating for read or a linear array of independent lasers for read and write. Depending on the implementation, these systems suffer from coherent cross talk, excessive space between spots, and an inability to independently track. We show that a dynamic acousto-optic grating can generate multiple parallel read/write spots on the disk, each of which can be independently modulated and tracked and all of which are incoherent in less that a bit period. The resulting disk pickup can potentially reach gigabit per second transfer rates with only a modest increase in the drive complexity.


Tofacitinib therapy intercepts macrophage metabolic reprogramming instigated by SARS-CoV-2 Spike protein.
The molecular mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein was characterized to identify novel therapies. The impact of tofacitinib, IL-6R Ab, or TNFi therapy was determined on Spike protein or LPS/IFN-γ-induced signaling, inflammation, and metabolic reprogramming in MΦs and/or rheumatoid arthritis (RA) fibroblast-like synoviocyte (FLS). ACE2 frequency was markedly expanded in MΦs compared to T cells and RA FLS. Tofacitinib suppresses Spike protein potentiated STAT1 signaling, whereas this function was unchanged by TNFi. Tofacitinib impairs IL-6/IFN/LPS-induced STAT1 and STAT3 phosphorylation in RA MΦs and FLS. Interestingly, tofacitinib had a broader inhibitory effect on the monokines, glycolytic regulators, or oxidative metabolites compared to IL-6R Ab and TNFi in Spike-protein-activated MΦs. In contrast, all three therapies disrupted IFN-α and IFN-β secretion in response to Spike protein; nonetheless, the IFN-γ was only curtailed by tofacitinib or IL-6R Ab. While tofacitinib counteracted MΦ metabolic rewiring instigated by Spike protein, it was inconsequential on the glycolysis expansion mediated via HK2 and/or LDHA in the activated RA MΦ and FLS. Nevertheless, the potentiated inflammatory response and the diminished oxidative phosphorylation modulated by Spike protein and/or LPS/IFN-γ stimulation in MΦs or RA FLS were reversed by tofacitinib. In conclusion, tofacitinib suppresses MΦ inflammation and immunometabolism triggered by Spike protein and may provide a promising strategy for COVID-19 patients.


Immunologic parameters during NOTES compared with laparoscopy in a randomized blinded porcine trial.
It remains unclear if the natural orifice translumenal endoscopic surgery (NOTES) technique is less invasive than laparoscopy. Serum interleukins and peritoneal cellular response have been utilized to support the immunologic difference between open and laparoscopic surgery. We hypothesized that there would be no difference between cytokine levels during NOTES or laparoscopic peritoneoscopy. Twelve pigs were assigned to NOTES or standard laparoscopy with permuted block randomization. Each group underwent 90 min of diagnostic peritoneoscopy using CO(2) for laparoscopy and air for NOTES pneumoperitoneum. Blood draws were obtained at baseline, at procedure end, and on postoperative days (POD) 1, 2, and 7. Quantification of cytokines (IL-1b and TNF-alpha) was performed with a Duo Set Porcine enzyme-linked immunosorbent assay (ELISA). Laboratory results were captured by a technician blinded to the research question, and data analysis was performed by an investigator blinded to the procedure using t-test and repeated measures linear model. The study was approved by the institutional animal care and use committee (IACUC). All procedures were successfully completed. One NOTES animal succumbed to hemorrhagic gastritis (day 3). All other animals thrived to POD 14, with no gross infections at necropsy. Animals undergoing laparoscopy had lower mean arterial pH than NOTES animals (p < 0.001). Serum and intraperitoneal white blood cell (WBC) counts were similar between the groups. Mean interleukin-1b levels at baseline, at the end of the procedure and at 48 h did not differ (0.50 and 0.31; p = 0.65). TNF-alpha levels did not differ at baseline or procedure end but increased in the NOTES group on POD 1, persisting to POD 7. Tumor necrosis factor-alpha (TNF-alpha) decreased in the laparoscopy group (p = 0.005). Cytokines and WBC did not differ between laparoscopic and NOTES groups during the initial 24 h. These findings do not currently support the assumption that NOTES is less invasive than laparoscopy. The late TNF-alpha elevation contradicts other studies and requires further examination.


A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder.
To assess the efficacy and safety of duloxetine, a serotonin and norepinephrine reuptake inhibitor, in subjects with primary fibromyalgia, with or without current major depressive disorder. This study was a randomized, double-blind, placebo-controlled trial conducted in 18 outpatient research centers in the US. A total of 207 subjects meeting the American College of Rheumatology criteria for primary fibromyalgia were enrolled (89% female, 87% white, mean age 49 years, 38% with current major depressive disorder). After single-blind placebo treatment for 1 week, subjects were randomly assigned to receive duloxetine 60 mg twice a day (n = 104) or placebo (n = 103) for 12 weeks. Co-primary outcome measures were the Fibromyalgia Impact Questionnaire (FIQ) total score (score range 0-80, with 0 indicating no impact) and FIQ pain score (score range 0-10). Secondary outcome measures included mean tender point pain threshold, number of tender points, FIQ fatigue, tiredness on awakening, and stiffness scores, Clinical Global Impression of Severity (CGI-Severity) scale, Patient Global Impression of Improvement (PGI-Improvement) scale, Brief Pain Inventory (short form), Medical Outcomes Study Short Form 36, Quality of Life in Depression Scale, and Sheehan Disability Scale. Compared with placebo-treated subjects, duloxetine-treated subjects improved significantly more (P = 0.027) on the FIQ total score, with a treatment difference of -5.53 (95% confidence interval -10.43, -0.63), but not significantly more on the FIQ pain score (P = 0.130). Compared with placebo-treated subjects, duloxetine-treated subjects had significantly greater reductions in Brief Pain Inventory average pain severity score (P = 0.008), Brief Pain Inventory average interference from pain score (P = 0.004), number of tender points (P = 0.002), and FIQ stiffness score (P = 0.048), and had significantly greater improvement in mean tender point pain threshold (P = 0.002), CGI-Severity (P = 0.048), PGI-Improvement (P = 0.033), and several quality-of-life measures. Duloxetine treatment improved fibromyalgia symptoms and pain severity regardless of baseline status of major depressive disorder. Compared with placebo-treated female subjects (n = 92), duloxetine-treated female subjects (n = 92) demonstrated significantly greater improvement on most efficacy measures, while duloxetine-treated male subjects (n = 12) failed to improve significantly on any efficacy measure. The treatment effect on significant pain reduction in female subjects was independent of the effect on mood or anxiety. Duloxetine was safely administered and well tolerated. In this randomized, controlled, 12-week trial (with a 1-week placebo lead-in phase), duloxetine was an effective and safe treatment for many of the symptoms associated with fibromyalgia in subjects with or without major depressive disorder, particularly for women, who had significant improvement across most outcome measures.


Immunization with the malaria heat shock like protein hsp70-1 enhances transmission to the mosquito.
Mosquitoes fed on mice infected with Plasmodium yoelii after an immunization with the i72 recombinant form of the heat shock protein hsp70-1 developed significantly more oocysts than mosquitoes fed on controls. This effect was due to a marked increase in the relative numbers of gametocytes during the early stages of infection. A comparison of blood-induced and sporozoite-initiated infection showed that these gametocytes were derived from merozoites released from the liver. The stimulus for increased gametocyte production is unknown but is likely to be linked with antibody-dependent cellular cytotoxicity and associated cytokine responses.


Allostasis and allostatic load in the context of poverty in early childhood.
This paper examined the relation of early environmental adversity associated with poverty to child resting or basal level of cortisol in a prospective longitudinal sample of 1135 children seen at 7, 15, 24, 35, and 48 months of age. We found main effects for poor housing quality, African American ethnicity, and low positive caregiving behavior in which each was uniquely associated with an overall higher level of cortisol from age 7 to 48 months. We also found that two aspects of the early environment in the context of poverty, adult exits from the home and perceived economic insufficiency, were related to salivary cortisol in a time-dependent manner. The effect for the first of these, exits from the home, was consistent with the principle of allostatic load in which the effects of adversity on stress physiology accumulate over time. The effect for perceived economic insufficiency was one in which insufficiency was associated with higher levels of cortisol in infancy but with a typical but steeper decline in cortisol with age at subsequent time points.


Siloxane compounds in biogas from manure and mixed organic waste: Method development and speciation analysis with GC-ICP-MS.
A novel method for the determination of linear and cyclic siloxane compounds (L2, L3, D3, D4, D5, and D6) in biogas was developed by combining gas chromatography (GC) with inductively coupled plasma mass spectrometry (ICP-MS). Using a continuous liquid quench sampling system, biogas samples were collected from a Swiss biogas production plant processing manure and mixed organic wastes. Although significant concentrations of siloxanes are normally linked to biogas from wastewater treatment plants (WWTP) or landfill gas, manure and mixed organic waste samples also showed values in the range of 0.1 mgSi Nm-3, which would be particularly critical for appliances such as solid oxide fuel cells (SOFC). The GC-ICP-MS method showed very good linearity for all the investigated compounds (R2 between 0.999 and 1.000). The limits of detection and quantification (LOD and LOQ) in the gas for cyclic compounds, such as D5, vary based upon the used sampling conditions (approximate range of 0.002-0.004 mgSi Nm-3 and 0.007-0.014 mgSi Nm-3, respectively). To the best of our knowledge, these LOD and LOQ values are by far among the lowest reported in literature and they satisfy the EURAMET (the European Association of National Metrology Institutes) requirements, which fix recommended levels for Si total amounts between 0.1 and 0.3 mgSi Nm-3 for measurement in biogas or bio-methane. The GC-ICP-MS method was evaluated by comparing its performances with a flame ionization detector (FID), operated in parallel with ICP-MS, and with GC-MS (gas chromatography - mass spectrometry). The GC-FID showed higher detection limits and matrix effects than GC-ICP-MS. Nevertheless, it can still be suitable for an initial estimation of the siloxane compounds present in the biogas, at least for samples having relatively high concentration, by following some data treatment optimization. The GC-MS analyses were considered here as a further confirmation of the accuracy of the GC-ICP-MS results.


Developing the Geriatric Injury Documentation Tool (Geri-IDT) to Improve Documentation of Physical Findings in Injured Older Adults.
Standardization in tools and documentation of child abuse and intimate partner violence have proven helpful in completely documenting injuries and suspected abuse among these populations. Similar tools do not yet exist for older adults and elder abuse. To (1) use insights from experts to develop a tool to assist clinicians in appropriately and completely documenting physical findings in injured older adults for potential future forensic investigation of abuse or neglect and (2) to assess the feasibility of incorporating this tool into clinical practice. Two-phase, exploratory qualitative study. Phase 1: individual interviews with elder abuse experts from various specialties in medicine and criminal justice. Phase 2: focus groups with anticipated end users of the tool. Phase 1 telephone-based key informant interviews were conducted with 11 elder abuse experts (2 detectives, 3 prosecutors, 1 forensic pathologist, 2 geriatricians, and 3 emergency medicine physicians). Phase 2 focus groups were conducted among emergency medicine (n = 10) and primary care (n = 8) providers. Key informant interviews were conducted telephonically while the two focus groups were held in-person at an emergency medicine site in New York, NY, and a primary care site in Los Angeles, CA. Experts agreed that medical providers' documentation of geriatric injuries is usually inadequate for investigating alleged elder abuse/neglect. They highlighted elements needed for forensic investigation: initial appearance before treatment is initiated, complete head-to-toe evaluation, documentation of all injuries (even minor ones), and documentation of pertinent negatives. Several noted the value of photographs to supplement written documentation. End users identified practical challenges to utilizing a tool, including the burden of additional or parallel documentation in a busy clinical setting, and how to integrate it into existing electronic medical records. A practical tool to improve medical documentation of geriatric injuries for potential forensic use would be valuable. Practical challenges to utilization must be overcome.


Role of envelope protein gE endocytosis in the pseudorabies virus life cycle.
Several groups have reported that certain herpesvirus envelope proteins do not remain on the surface of cells that express them but rather are internalized by endocytosis in a recycling process. The biological function of membrane protein endocytosis in the virus life cycle remains a matter of speculation and debate. In this report, we demonstrate that some, but not all, membrane proteins encoded by the alphaherpesvirus pseudorabies virus (PRV) are internalized after reaching the plasma membrane. Glycoproteins gE and gB are internalized from the plasma membrane of cells, while gI and gC are not internalized efficiently. We show for gE that the cytoplasmic domain of the protein is required for endocytosis. While the gI protein is incapable of endocytosis on its own, it can be internalized when complexed with gE. We demonstrate that endocytosis of the gE-gI complex and gB occurs early after infection of tissue culture cells but that this process stops completely after 6 h of infection, a time that correlates with significant shutoff of host protein synthesis. We also show that gE protein internalized at 4 h postinfection is not present in virions formed at a later time. We discuss the differences in PRV gE and gI endocytosis compared to that of the varicella-zoster virus homologs and the possible roles of glycoprotein endocytosis in the virus life cycle.


Three-year clinical comparison of survival of endodontically treated teeth restored with either full cast coverage or with direct composite restoration.
Little information exists regarding the outcome of crown build-ups on endodontically treated teeth restored with metal-ceramic crowns or with only a direct-placed composite. The aim of this study was to evaluate the clinical success rate of endodontically treated premolars restored with fiber posts and direct composite restorations and compare that treatment with a similar treatment of full-coverage with metal-ceramic crowns. Subjects included in this study had one maxillary or mandibular premolar for which endodontic treatment and crown build up was indicated and met specific inclusion/exclusion criteria. Only premolars with Class II carious lesions and preserved cusp structure were included. Subjects were randomly assigned to 1 of the following 2 experimental groups: (1) teeth endodontically treated and restored with adhesive techniques and composite or (2) teeth endodontically treated, restored with adhesive techniques and composite, and then restored with full-coverage metal-ceramic crowns. Sixty teeth were included in the first group and 57 in the second. All restorations were performed by one operator. Causes of failure were categorized as root fracture, post fracture, post decementation, clinical and/or radiographic evidence of marginal gap between tooth and restoration, and clinical and/or radiographic evidence of secondary caries contiguous with restoration margins. Subjects were examined for the listed clinical and radiographic causes of failure by 2 calibrated examiners at intervals of 1, 2, and 3 years. Exact 95% confidence intervals for the difference between the 2 experimental groups were calculated. At the 1-year recall, no failures were reported. The only failure modes observed at 2 and 3 years were decementations of posts and clinical and/or radiographic evidence of marginal gap between tooth and restoration. There was no difference in the failure frequencies of the 2 groups (95% confidence interval, -17.5 to 12.6). There was no difference between the number of failures caused by post decementations and the presence of marginal gaps observed in the 2 groups (95% confidence intervals, -9.7 to 16.2 and -17.8 to 9.27). Within the limitations of this study, the results upheld the research hypothesis that the clinical success rates of endodontically treated premolars restored with fiber posts and direct composite restorations after 3 years of service were equivalent to a similar treatment of full coverage with metal-ceramic crowns.


CHL12, a gene essential for the fidelity of chromosome transmission in the yeast Saccharomyces cerevisiae.
We have analyzed the CHL12 gene, earlier identified in a screen for yeast mutants with increased rates of mitotic loss of chromosome III and circular centromeric plasmids. A genomic clone of CHL12 was isolated and used to map its physical position on the right arm of chromosome XIII near the ADH3 locus. Nucleotide sequence analysis of CHL12 revealed a 2.2-kb open reading frame with a 84-kD predicted protein sequence. Analysis of the sequence upstream of the CHL12 open reading frame revealed the presence of two imperfect copies of MluI motif, ACGCGT, a sequence associated with many DNA metabolism genes in yeast. Analysis of the amino acid sequence revealed that the protein contains a NTP-binding domain and shares a low degree of homology with subunits of replication factor C (RF-C). A strain containing a null allele of CHL12 was viable under standard growth conditions, and as well as original mutants exhibited an increase in the level of spontaneous mitotic recombination, slow growth and cold-sensitive phenotypes. Most of cells carrying the null chl12 mutation arrested as large budded cells with the nucleus in the neck at nonpermissive temperature that typical for cell division cycle (cdc) mutants that arrest in the cell cycle at a point either immediately preceding M phase or during S phase. Cell cycle arrest of the chl12 mutant requires the RAD9 gene. We conclude that the CHL12 gene product has critical role in DNA metabolism.


Assessment of the noise annoyance among subway train conductors in Tehran, Iran.
Subway transportation system is a new phenomenon in Iran. Noise annoyance interferes with the individual's task performance, and the required alertness in the driving of subway trains. This is the first study conducted to measure the level of noise and noise annoyance among conductors of subway organization in Tehran, Iran. This cross sectional study was conducted among 167 randomly selected train conductors. Information related to noise annoyance was collected by using a self-administered questionnaire. The dosimetry and sound metering was done for the conductors and inside the cabins. There were 41 sound metering measuring samples inside the conductors' cabin, and there were 12 samples of conductors' noise exposure. The results of sound level meter showed that the mean Leq was 73.0 dBA ± 8.7 dBA and the dosimetry mean measured Leq was 82.1 dBA ± 6.8 dBA. 80% of conductors were very annoyed/annoyed by noise in their work place. 53.9% of conductors reported that noise affected their work performance and 63.5% reported that noise causes that they lose their concentration. The noise related to movement of train wheels on rail was reported as the worst by 83.2% followed by the noise of brakes (74.3%) and the ventilation noise (71.9%). 56.9% of conductors reported that they are suffering from sleeplessness, 40.1% from tinnitus and 80.2% feeling fatigue and sleepy. The study results showed the high level of noise and noise annoyance among train conductors and the poor health outcome of their exposure to this level of noise.


Characterization of cassava vein mosaic virus: a distinct plant pararetrovirus.
Cassava vein mosaic virus (CVMV) was found to be widespread throughout the north-eastern region of Brazil. The complete sequence of CVMV was determined, and the genome was 8158 bp in size. A cytosolic initiator methionine tRNA (tRNA met1)-binding site that probably acts as a primer for minus-strand synthesis was present. The genome contained five open reading frames that potentially encode proteins with predicted molecular masses of 186 kDa, 9 kDa, 77 kDa, 24 kDa and 26 kDa. The putative 186 kDa protein had regions with similarity to the zinc finger-like RNA-binding domain that is a common element in the capsid proteins and similarity to the intercellular transport domain of the plant pararetroviruses. The predicted 77 kDa protein had regions with similarity to aspartic proteases, reverse transcriptase and RNase H of pararetroviruses. This gene order was confirmed by the amplification of similar PCR products from total DNA extracted from CVMV-infected cassava plants. The genomic organization of CVMV was different from the organization of either the caulimoviruses or badnaviruses. In comparisons of the regions with the reverse transcriptase motif, CVMV was grouped between the caulimoviruses and badnaviruses. It appears that CVMV is distinct from the other well-characterized plant pararetroviruses.


Methodological Issues in Assessing the Economic Value of Next-Generation Sequencing Tests: Many Challenges and Not Enough Solutions.
Clinical use of next-generation sequencing (NGS) tests has been increasing, but few studies have examined their economic value. Several studies have noted that there are methodological challenges to conducting economic evaluations of NGS tests. Our objective was to examine key methodological challenges for conducting economic evaluations of NGS tests, prioritize these challenges for future research, and identify how studies have attempted solutions to address these challenges. We identified challenges for economic evaluations of NGS tests using prior literature and expert judgment of the co-authors. We used a modified Delphi assessment to prioritize challenges, based on importance and probability of resolution. Using a structured literature review and article extraction we then assessed whether published economic evaluations had addressed these challenges. We identified 11 challenges for conducting economic evaluations of NGS tests. The experts identified three challenges as the top priorities for future research: complex model structure, timeframe, and type of analysis and comparators used. Of the 15 published studies included in our literature review, four studies described specific solutions relevant to five of the 11 identified challenges. Major methodological challenges to economic evaluations of NGS tests remain to be addressed. Our results can be used to guide future research and inform decision-makers on how to prioritize research on the economic assessment of NGS tests.


Scaffolding reflective learning in clinical practice: a comparison of two types of reflective activities.
The development of reflective learning skills is a continuous process that needs scaffolding. It can be described as a continuum, with the focus of reflection differing in granularity from recent, concrete activities to global competency development. To explore learners' perceptions regarding the effects of two reflective writing activities designed to stimulate reflection at different degrees of granularity during clinical training. Totally 142 respondents (students and recent graduates) completed a questionnaire. Quantitative and qualitative data were triangulated. Immediate reflection-on-action was perceived to be more valuable than delayed reflection-on-competency-development because it facilitated day-to-day improvement. Delayed reflection was perceived to facilitate overall self-assessment, self-confidence and continuous improvement, but this perception was mainly found among graduates. Detailed reflection immediately after a challenging learning experience and broad reflection on progress appeared to serve different learning goals and consequently require different arrangements regarding feedback and timing. Granularity of focus has consequences for scaffolding reflective learning, with immediate reflection on concrete events and reflection on long-term progress requiring different approaches. Learners appeared to prefer immediate reflection-on-action.


Concordance of qualitative bone scintigraphy results with presence of clinical complex regional pain syndrome 1: meta-analysis of test accuracy studies.
To date, no attempt has been made to investigate the agreement between qualitative bone scintigraphy (BS) and the presence of complex regional pain syndrome 1 (CRPS 1) and the agreement between a negative BS in the absence of CRPS 1. To summarize the existing evidence quantifying the concordance of qualitative BS in the presence or absence of clinical CRPS 1. We searched Medline, Embase, Dare and the Cochrane Library and screened bibliographies of all included studies. We selected diagnostic studies investigating the association between qualitative BS results and the clinical diagnosis of CRPS 1. The minimum requirement for inclusion was enough information to fill the two-by-two tables. Twelve studies met our inclusion criteria and were included in the meta-analysis. The pooled mean sensitivity of 12 two-by-two tables was 0.87 (95% CI, 0.68-0.97) and specificity was 0.69 (95% CI, 0.47-0.85). The pooled mean sensitivity for the subgroup with clearly defined diagnostic criteria (seven two-by-two tables) was 0.80 (95% CI, 0.44-0.95) and specificity was 0.73 (95% CI, 0.40-0.91). Based on this study, clinicians must be advised that a positive BS is not necessarily concordant with presence of absence or CRPS 1. Given the moderate level of concordance between a positive BS in the absence of clinical CRPS 1, discordant results potentially impede the diagnosis of CRPS 1.


M6P/IGF2R imprinting evolution in mammals.
Imprinted gene identification in animals has been limited to eutherian mammals, suggesting a significant role for intrauterine fetal development in the evolution of imprinting. We report herein that M6P/IGF2R is not imprinted in monotremes and does not encode for a receptor that binds IGF2. In contrast, M6P/IGF2R is imprinted in a didelphid marsupial, the opossum, but it strikingly lacks the differentially methylated CpG island in intron 2 postulated to be involved in imprint control. Thus, invasive placentation and gestational fetal growth are not required for imprinted genes to evolve. Unless there was convergent evolution of M6P/ IGF2R imprinting and receptor IGF2 binding in marsupials and eutherians, our results also demonstrate that these two functions evolved in a mammalian clade exclusive of monotremes.


Engineering Enzyme-Cleavable Oligonucleotides by Automated Solid-Phase Incorporation of Cathepsin B Sensitive Dipeptide Linkers.
Oligonucleotides containing cleavable linkers have emerged as versatile tools to achieve stimulus-responsive and site-specific cleavage of DNA. However, the limitations of previously reported cleavable linkers including photolabile and disulfide linkers have restricted their applications in vivo. Inspired by the cathepsin B-sensitive dipeptide linkers in antibody-drug conjugates (ADCs) such as Adcetris, we have developed Val-Ala-02 and Val-Ala-Chalcone phosphoramidites for the automated synthesis of enzyme-cleavable oligonucleotides. Cathepsin B digests Val-Ala-02 and Val-Ala-Chalcone linkers efficiently, enabling cleavage of oligonucleotides into two components or release of small-molecule payloads. Based on the prior success of dipeptide linkers in ADCs, we believe that these dipeptide linker phosphoramidites will promote new clinical applications of therapeutic oligonucleotides.


The effect of active immunization against aldosterone on the colonic potential response and sodium excretion in rabbits.
1. A group of rabbits was actively immunized against aldosterone and their subsequent response to infused aldosterone and to dietary sodium restriction was compared with that of a control group. 2. Colonic electrical potential difference (CP) was used as an index of relative mineralocorticoid activity in both groups of animals. 3. Infusion of aldosterone produced a rise in CP to a maximum of -50 to -70 mV at rates of infusion of 55-270 pmol min-1 kg-1. In contrast, the immune group showed no change until infusion dose rates of 2700 pmol min-1 kg-1 were used. 4. During dietary sodium restriction, CP increased in normal rabbits to a significantly greater degree than in immune animals although cumulative urinary sodium losses were the same in both groups. 5. The ability of the immune animals to remain in sodium balance despite physiological aldosterone blockade suggests that aldosterone is not an essential component of their sodium-conservation mechanisms.


Hemoglobin vesicles, polyethylene glycol (PEG)ylated liposomes developed as a red blood cell substitute, do not induce the accelerated blood clearance phenomenon in mice.
The hemoglobin vesicle (HbV) is an artificial oxygen carrier encapsulating a concentrated hemoglobin solution in a liposome of which the surface is covered with polyethylene glycol (PEG). It was recently reported that repeated injections of PEGylated liposomes induce the accelerated blood clearance (ABC) phenomenon, in which serum anti-PEG IgM plays an essential role. To examine this issue, we investigated whether HbV induces the ABC phenomenon in mice at a dose of 0.1 mg Hb/kg, a dose that is generally known to induce the ABC phenomenon, or at 1400 mg Hb/kg, which is proposed for clinical use. At 7 days after the first injection of nonlabeled HbV (0.1 mg Hb/kg), the mice received HbV in which the Hb had been labeled with (125)I. After a second injection, HbV was rapidly cleared from the circulation, and uptake clearances in liver and spleen were significantly increased. In contrast, at a dose of 1400 mg Hb/kg, the pharmacokinetics of HbV was negligibly affected by repeated injection. It is interesting to note that IgM against HbV was produced 7 days postinjection at both of the above doses, and their recognition site was determined to be 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-PEG in HbV. These results suggest that a clinical dose of HbV does not induce the ABC phenomenon, and that suppression of ABC phenomenon is caused by the saturation of phagocytic processing by the mononuclear phagocyte system. Thus, we conclude that induction of the ABC phenomenon would not be an issue in the dose regimen used in clinical settings.


Dementia and friendship: the quality and nature of the relationships that remain.
Friendships are an integral part of the human experience. Yet, dementia often takes a toll on social relationships, and many friends withdraw. This research, however, focuses on friendships that remain, despite a diagnosis of dementia. It examines the quality of the friendships of people with dementia and long-term friendships. Data were collected through focus group interviews with people with early stage dementia and their care partners, and through interviews with designated friends. The findings show that people with dementia do have friends that remain and they have a wide variety of friendships, from those based on one shared activity to those of multifaceted deep relationships. The long-term friendships, which last across the various stages of dementia, appear to fall into two types: one, where the person with dementia has become more like a family member than a friend (suffusion); and the other where the diagnosis of dementia was the impetus for the relationship to become closer (progressive friendship).


Yellow-green and red firefly bioluminescence from 5,5-dimethyloxyluciferin.
Beetle luciferases (including those of the firefly) use the same luciferin substrate to naturally display light ranging in color from green (lambda(max) similar 530 nm) to red (lambda(max) similar 635 nm). The original mechanism of bioluminescence color determination advanced by White and co-workers was based on the concept that the keto and enol tautomers of the emitter oxyluciferin produce red and green light, respectively. Alternatively, McCapra proposed that color variation is associated with conformations of the keto form of excited-state oxyluciferin. We have prepared the adenylate of D-5,5-dimethylluciferin and shown that it is transformed into the putative emitter 5,5-dimethyloxyluciferin in bioluminescence reactions catalyzed by luciferases from Photinus pyralis and the green-emitting click beetle. 5,5-Dimethyloxyluciferin is constrained to exist in the keto form and fluoresces in the red. However, bioluminescence spectra revealed that green light emission was produced by the firefly enzyme and red light was observed with the click beetle protein. These results, augmented with steady-state kinetic studies, may be taken as the first experimental support for McCapra's mechanism of firefly bioluminescence color or any other proposal that requires only a single keto form of oxyluciferin.


Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801.
Nelarabine (506U78) is a soluble pro-drug of 9-beta-D-arabinofuranosylguanine (ara-G), a deoxyguanosine derivative. We treated 26 patients with T-cell acute lymphoblastic leukemia (T-ALL) and 13 with T-cell lymphoblastic lymphoma (T-LBL) with nelarabine. All patients were refractory to at least one multiagent regimen or had relapsed after achieving a complete remission. Nelarabine was administered on an alternate day schedule (days 1, 3, and 5) at 1.5 g/m(2)/day. Cycles were repeated every 22 days. The median age was 34 years (range, 16-66 years); 32 (82%) patients were male. The rate of complete remission was 31% (95% confidence interval [CI], 17%, 48%) and the overall response rate was 41% (95% CI, 26%, 58%). The principal toxicity was grade 3 or 4 neutropenia and thrombocytopenia, occurring in 37% and 26% of patients, respectively. There was only one grade 4 adverse event of the nervous system, which was a reversible depressed level of consciousness. The median disease-free survival (DFS) was 20 weeks (95% CI, 11, 56), and the median overall survival was 20 weeks (95% CI, 13, 36). The 1-year overall survival was 28% (95% CI, 15%, 43%). Nelarabine is well tolerated and has significant antitumor activity in relapsed or refractory T-ALL and T-LBL.


Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.
Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.


Differences in the psychological and hormonal presentation of lean and obese patients with polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders found in women of reproductive age. Differences in hormonal and metabolic profiles are observed in groups of patients with normal and elevated BMI. Cause of disturbances observed in the two groups of patients with PCOS is analyzed. The aim of the study is to assess whether psychological parameters of lean and obese patients with PCOS are comparably significantly different and whether there is a correlation between these characteristics and the concentration of various hormones. The study consisted of 20 patients with diagnosed polycystic ovary syndrome and 20 healthy women of similar age. Both groups were stratified according to BMI. Specific psychological parameters and hormones were estimated in all patients. In our study, we found that patients with BMI <25 represented personality traits associated with lower resistance to stress. We also observed significantly higher ACTH levels in the same group as compared to patients with BMI >25. A correlation between plasma ghrelin and the severity of anxiety experienced by test subjects was also observed. The type of personality and emotional disorders in lean PCOS patients may lead to the activation of the hypothalamic-pituitary-adrenal (HPA) axis and disturbences in hypothalamic-pituitary-ovary (HPO) axis. The results suggest participation of primary hypothalamic dysfunction in the pathogenesis of PCOS in patients with specific fenotype. Ghrelin is a hormone that may affect the symptoms of PCOS in lean patients. Psychological therapy should be considered as a permanent element in the therapeutic plan provided to PCOS patients.


The NS segment of H5N1 avian influenza viruses (AIV) enhances the virulence of an H7N1 AIV in chickens.
Some outbreaks involving highly pathogenic avian influenza viruses (HPAIV) of subtypes H5 and H7 were caused by avian-to-human transmissions. In nature, different influenza A viruses can reassort leading to new viruses with new characteristics. We decided to investigate the impact that the NS-segment of H5 HPAIV would have on viral pathogenicity of a classical avian H7 HPAIV in poultry, a natural host. We focussed this study based on our previous work that demonstrated that single reassortment of the NS-segment from an H5 HPAIV into an H7 HPAIV changes the ability of the virus to replicate in mammalian hosts. Our present data show that two different H7-viruses containing an NS-segment from H5-types (FPV NS GD or FPV NS VN) show an overall highly pathogenic phenotype compared with the wild type H7-virus (FPV), as characterized by higher viral shedding and earlier manifestation of clinical signs. Correlating with the latter, higher amounts of IFN-β mRNA were detected in the blood of NS-reassortant infected birds, 48 h post-infection (pi). Although lymphopenia was detected in chickens from all AIV-infected groups, also 48 h pi those animals challenged with NS-reassortant viruses showed an increase of peripheral monocyte/macrophage-like cells expressing high levels of IL-1β, as determined by flow cytometry. Taken together, these findings highlight the importance of the NS-segment in viral pathogenicity which is directly involved in triggering antiviral and pro-inflammatory cytokines found during HPAIV pathogenesis in chickens.


A Randomized Controlled Trial Evaluating the Role of Honey in Reducing Pain Due to Radiation Induced Mucositis in Head and Neck Cancer Patients.
There are various drugs tried for relieving pain associated with radiation-induced mucositis. This paper aims to study role of honey in relieving pain due to radiation induced mucositis in head and neck cancer patients receiving concomitant chemoradiation. A randomized controlled trial on 78 subjects (40 in test group and 38 in control group) was undertaken to study the analgesic effect of honey, but the analysis of 69 patients was done as nine patients (four in test and five in control group) were lost to follow-up or left treatment in between the study. All patients were advised to do salt-soda and benzydamine mouth gargles, alternatively every 3 hours. Test group patients additionally received 20 ml honey three times a day during the entire course of radiation treatment and 3 months following radiation therapy (RT). Honey significantly reduced the severity of mucositis associated pain and resulted in lesser treatment gaps and a decrease in overall radiotherapy treatment duration. None of the test group and majority of controls (51.5%) had severe pain score during the 7(th) week of RT. The same pattern was seen in the post-RT period. Mean pain score was significantly different in both groups during all weeks during and upto 6 weeks post-RT (mean score of 3.08 and 6.54 for test and control respectively at 7(th) week RT, P < 0.001). Honey being a cheap, palatable, and natural medicament can be used for decreasing pain associated with radiation-induced mucositis in cancer patients.


Butein induces apoptosis in human uveal melanoma cells through mitochondrial apoptosis pathway.
To study the cytotoxic effects and related signaling pathways of butein on human uveal melanoma cells in vitro. Three human uveal melanoma cell lines (M17, SP6.5, and C918), retinal pigment epithelial (RPE) cells and scleral fibroblasts were treated with butein at different dosages. The effects of butein on cell viability were assessed by using the MTT assay. Cell apoptosis was determined using annexin V-FITC/ethidium homodimer III flow cytometry. Mitochondrial transmembrane potential changes were assessed by using the JC-1 fluorescent reader, cytosol cytochrome c levels, and the activities of caspase-3, -8, and -9 were measured by using an enzyme-linked immunosorbent assay or colorimetric assay. Butein reduced the cell viability of cultured human uveal melanoma cells in a dose-dependent manner (10, 30, and 100 μM), with IC50 at 13.3 μM and 15.8 μM in SP6.5 and M17 cell lines, respectively. Similar effects were also found in a highly aggressive and metastatic C918 cell line (IC50 16.7 μM). Butein at lower concentrations (10-30 μM) selectively reduced the cell viability of uveal melanoma cells, without affecting cell viability of RPE cells and fibroblasts. Butein-induced apoptosis of melanoma cells, increased mitochondrial permeability and the level of cytosol cytochrome c, caspase-9 and -3 activities (but not caspase-8) in a dose-dependent manner. Butein has selectively potent pro-apoptotic effects on cultured human uveal melanoma cells via the intrinsic mitochondrial pathway.


Emotional arousal in agenesis of the corpus callosum.
While the processing of verbal and psychophysiological indices of emotional arousal have been investigated extensively in relation to the left and right cerebral hemispheres, it remains poorly understood how both hemispheres normally function together to generate emotional responses to stimuli. Drawing on a unique sample of nine high-functioning subjects with complete agenesis of the corpus callosum (AgCC), we investigated this issue using standardized emotional visual stimuli. Compared to healthy controls, subjects with AgCC showed a larger variance in their cognitive ratings of valence and arousal, and an insensitivity to the emotion category of the stimuli, especially for negatively-valenced stimuli, and especially for their arousal. Despite their impaired cognitive ratings of arousal, some subjects with AgCC showed large skin-conductance responses, and in general skin-conductance responses discriminated emotion categories and correlated with stimulus arousal ratings. We suggest that largely intact right hemisphere mechanisms can support psychophysiological emotional responses, but that the lack of interhemispheric communication between the hemispheres, perhaps together with dysfunction of the anterior cingulate cortex, interferes with normal verbal ratings of arousal, a mechanism in line with some models of alexithymia.


Sampling biases and missing data in explorations of sexual partner networks for the spread of sexually transmitted diseases.
The structures of sexual partner networks are important in determining patterns of transmission of STDs including HIV. Empirical data on sexual partnerships and sexual partner networks collected through sampling individuals are a non-random sample of partnerships and network structures even if individuals are sampled randomly. This has the potential to bias estimates of measures describing the sexual partner network. In addition, biases may be introduced through non-response and missing data. Using Monte Carlo simulation, we investigate the biases that are introduced in estimates measures of the sexual partner network through three common sampling methods. The results indicate that substantial systematic biases are introduced. The direction and magnitude of these biases suggest that, by ignoring them, the risk for the establishment and persistence of infection in a population may be underestimated.


Combined effect of titanium particles and TNF-alpha on the production of IL-6 by osteoblast-like cells.
To clarify the role of tumor necrosis factor (TNF)-alpha on osteoblast functions in the presence of metal particles, two human osteoblast-like cell lines (MG-63 and SaOS-2) were cultured with TNF-alpha in the presence or absence of titanium particles in vitro. A combination of TNF-alpha and titanium particles showed additive effects on inhibition of cell proliferation and alkaline phosphatase production. On the other hand, production of interleukin-6, which is well known to induce osteoclastogenesis and to directly stimulate bone resorption, was additively stimulated by the combination of TNF-alpha and titanium particles. These results suggest that the association of TNF-alpha and titanium particles may play an important role in the pathogenesis of periprosthetic osteolysis through two different pathways: a reduced periprosthetic bone formation due to inhibition of osteoblast proliferation and alkaline phosphatase production, and osteoblast-mediated activation of osteoclastic bone resorption as suggested by the enhancement of interleukin-6 production.


The smart potential behind probability matching.
Probability matching is a classic choice anomaly that has been studied extensively. While many approaches assume that it is a cognitive shortcut driven by cognitive limitations, recent literature suggests that it is not a strategy per se, but rather another outcome of people's well-documented misperception of randomness. People search for patterns even in random sequences, which results in probability matching at the outcome level. Previous studies have supported this by the finding that distracting people with a secondary verbal working memory task presumably prevents the pattern search, resulting in more maximizing behavior that is considered more rational. The current paper demonstrates with two experiments that there is actually truth in both accounts. For some participants, probability matching indeed seems to be the result of a cognitive shortcut, a simple "win-stay, lose-shift" strategy, and in one experiment identified these as participants low in working memory capacity. For others, however, a potentially smart pattern search strategy underlies probability matching. These probability matchers (who still look irrational in the absence of patterns) actually have a higher chance of finding a pattern if one exists. Contrary to the almost uniformly negative perception of probability matching, we therefore conclude that there can be a potentially smart strategy behind probability matching.


On the time course of short-term forgetting: a human experimental model for the sense of balance.
The primary aim of this study was to establish whether the decline of the memory of an angular displacement, detected by the semicircular canals, is best characterized by an exponential function or by a power function. In 27 subjects a conflict was created between the semicircular canals and the graviceptive systems. Subjects were seated, facing forwards, in the gondola of a large centrifuge. The centrifuge was accelerated from stationary to 2.5Gz. While the swing out of the gondola (66°) during acceleration constitutes a frontal plane angular-displacement stimulus to the semicircular canals, the graviceptive systems persistently signal that the subject is upright. During 6 min at 2.5Gz the perceived head and body position was recorded; in darkness the subject repeatedly adjusted the orientation of a luminous line so that it appeared to be horizontal. Acceleration of the centrifuge induced a sensation of tilt which declined with time in a characteristic way. A three-parameter exponential function (Y = Ae(-bt) + C) and a power function (Y = At(-b) + C) were fitted to the data points. The inter-individual variability was considerable. In the vast majority of cases, however, the exponential function provided a better fit (in terms of RMS error) than the power function. The mean exponential function was: y = 27.8e(-0.018t) + 0.5°, where t is time in seconds. Findings are discussed with connection to possible underlying neural mechanisms; in particular, the head-direction system and short-term potentiation and persistent action potential firing in the hippocampus are considered.


Mapping genetic diversity of cherimoya (Annona cherimola Mill.): application of spatial analysis for conservation and use of plant genetic resources.
There is a growing call for inventories that evaluate geographic patterns in diversity of plant genetic resources maintained on farm and in species' natural populations in order to enhance their use and conservation. Such evaluations are relevant for useful tropical and subtropical tree species, as many of these species are still undomesticated, or in incipient stages of domestication and local populations can offer yet-unknown traits of high value to further domestication. For many outcrossing species, such as most trees, inbreeding depression can be an issue, and genetic diversity is important to sustain local production. Diversity is also crucial for species to adapt to environmental changes. This paper explores the possibilities of incorporating molecular marker data into Geographic Information Systems (GIS) to allow visualization and better understanding of spatial patterns of genetic diversity as a key input to optimize conservation and use of plant genetic resources, based on a case study of cherimoya (Annona cherimola Mill.), a Neotropical fruit tree species. We present spatial analyses to (1) improve the understanding of spatial distribution of genetic diversity of cherimoya natural stands and cultivated trees in Ecuador, Bolivia and Peru based on microsatellite molecular markers (SSRs); and (2) formulate optimal conservation strategies by revealing priority areas for in situ conservation, and identifying existing diversity gaps in ex situ collections. We found high levels of allelic richness, locally common alleles and expected heterozygosity in cherimoya's putative centre of origin, southern Ecuador and northern Peru, whereas levels of diversity in southern Peru and especially in Bolivia were significantly lower. The application of GIS on a large microsatellite dataset allows a more detailed prioritization of areas for in situ conservation and targeted collection across the Andean distribution range of cherimoya than previous studies could do, i.e. at province and department level in Ecuador and Peru, respectively.


Association between smoking and risk of bladder cancer among men and women.
Previous studies indicate that the population attributable risk (PAR) of bladder cancer for tobacco smoking is 50% to 65% in men and 20% to 30% in women and that current cigarette smoking triples bladder cancer risk relative to never smoking. During the last 30 years, incidence rates have remained stable in the United States in men (123.8 per 100,000 person-years to 142.2 per 100,000 person-years) and women (32.5 per 100,000 person-years to 33.2 per 100,000 person-years); however, changing smoking prevalence and cigarette composition warrant revisiting risk estimates for smoking and bladder cancer. To evaluate the association between tobacco smoking and bladder cancer. Men (n = 281,394) and women (n = 186,134) of the National Institutes of Health-AARP (NIH-AARP) Diet and Health Study cohort completed a lifestyle questionnaire and were followed up between October 25, 1995, and December 31, 2006. Previous prospective cohort studies of smoking and incident bladder cancer were identified by systematic review and relative risks were estimated from fixed-effects models with heterogeneity assessed by the I(2) statistic. Hazard ratios (HRs), PARs, and number needed to harm (NNH). During 4,518,941 person-years of follow-up, incident bladder cancer occurred in 3896 men (144.0 per 100,000 person-years) and 627 women (34.5 per 100,000 person-years). Former smokers (119.8 per 100,000 person-years; HR, 2.22; 95% confidence interval [CI], 2.03-2.44; NNH, 1250) and current smokers (177.3 per 100,000 person-years; HR, 4.06; 95% CI, 3.66-4.50; NNH, 727) had higher risks of bladder cancer than never smokers (39.8 per 100,000 person-years). In contrast, the summary risk estimate for current smoking in 7 previous studies (initiated between 1963 and 1987) was 2.94 (95% CI, 2.45-3.54; I(2) = 0.0%). The PAR for ever smoking in our study was 0.50 (95% CI, 0.45-0.54) in men and 0.52 (95% CI, 0.45-0.59) in women. Compared with a pooled estimate of US data from cohorts initiated between 1963 and 1987, relative risks for smoking in the more recent NIH-AARP Diet and Health Study cohort were higher, with PARs for women comparable with those for men.


Inspiratory muscle training, altitude, and arterial oxygen desaturation: a preliminary investigation.
Specific inspiratory muscle training (IMT) has been shown to significantly attenuate the fall in arterial oxygen saturation (SpO2) during exhaustive exercise while breathing a hypoxic gas mixture of 14% oxygen. The aim of the current study was to assess the impact of IMT on resting SpO2 over a range of altitudes in healthy individuals. Resting SpO2 and the Borg Score were examined at altitudes of 0 or 400 m (0-400 m; 0-1312.3 ft), 1400 m, 4880 m, and 5550 m (4593 ft, 16,011 ft, and 18,209 ft) in 14 military personnel who were part of a climbing expedition to the Nepali Himalaya. Volunteer participants were randomly assigned to either a control (N = 7) or IMT (N = 7) group: IMT consisted of 1 set of 30 breaths twice daily at 50% maximal inspiratory mouth pressure (MIP) for 4 wk prior to departure. MIP was similar between groups pre-IMT but increased significantly by 15% post-IMT. Baseline maximal expiratory mouth pressure was not different between groups. The Borg Score increased significantly from 1400 m, but was not different between groups at any altitude. Resting SpO2 declined significantly at ascending altitudes in both groups and was similar between groups at altitudes of 0-400 m and 1400 m. However, at altitudes of 4880 m and 5550 m, SpO2 was significantly higher (6%) in the IMT group. IMT can attenuate the fall in resting SpO2, but only at altitudes of 4880 m and above. Conversely, IMT had no effect on resting levels of dyspnea as measured by the Borg Score.


Microtopography of Immune Cells in Osteoporosis and Bone Lesions by Endocrine Disruptors.
Osteoporosis stems from an unbalance between bone mineral resorption and deposition. Among the numerous cellular players responsible for this unbalance bone marrow (BM) monocytes/macrophages, mast cells, T and B lymphocytes, and dendritic cells play a key role in regulating osteoclasts, osteoblasts, and their progenitor cells through interactions occurring in the context of the different bone compartments (cancellous and cortical). Therefore, the microtopography of immune cells inside trabecular and compact bone is expected to play a relevant role in setting initial sites of osteoporotic lesion. Indeed, in physiological conditions, each immune cell type preferentially occupies either endosteal, subendosteal, central, and/or perisinusoidal regions of the BM. However, in the presence of an activation, immune cells recirculate throughout these different microanatomical areas giving rise to a specific distribution. As a result, the trabeculae of the cancellous bone and endosteal free edge of the diaphyseal case emerge as the primary anatomical targets of their osteoporotic action. Immune cells may also transit from the BM to the depth of the compact bone, thanks to the efferent venous capillaries coursing in the Haversian and Volkmann canals. Consistently, the innermost parts of the osteons and the periosteum are later involved by their immunomodulatory action, becoming another site of mineral reabsorption in the course of an osteoporotic insult. The novelty of our updating is to highlight the microtopography of bone immune cells in the cancellous and cortical compartments in relation to the most consistent data on their action in bone remodeling, to offer a mechanist perspective useful to dissect their role in the osteoporotic process, including bone damage derived from the immunomodulatory effects of endocrine disrupting chemicals.