Initial genome-wide scan for linkage with schizophrenia in the Japanese Schizophrenia Sib-Pair Linkage Group (JSSLG) families.
To determine if there are common genes that contribute to the susceptibility for schizophrenia, first-stage genome-wide scan was carried out by genotyping 417 short-tandem repeat (STR) markers in 338 individuals from 130 families with 148 affected sib-pairs identified at 16 sites nationwide in Japan. Data was from the Japanese Schizophrenia Sib-pair Linkage Group (JSSLG), which is a multi-site collaborative study group established to create a national resource for genetic studies of schizophrenia in Japan. All subjects were Japanese, and the probands and their siblings had schizophrenia. Multipoint non-parametric linkage analysis and exclusion mapping were performed with GENEHUNTER software. Simulation studies suggested that in the absence of linkage we could expect one multipoint maximum LOD score (MLS) of 1.9 per genome scan. An MLS of 3.7 would be expected only once in every 20 genome scans and thus corresponds to a genome-wide significance of 0.05. No loci in the initial screen fulfilled the criteria for significant or suggestive evidence for linkage. Ten chromosomes (1, 2, 3, 4, 5, 8, 9, 14, 17, and 20) had at least one region with a nominal P value < 0.05. Susceptibility genes with lambdas of 3 and 2 were excluded from 98 and 70% of the genome, respectively. Our results suggest that common genes that contribute significantly to susceptibility for schizophrenia are unlikely to exist in the Japanese population.


Drugs Polypharmacology by In Silico Methods: New Opportunities in Drug Discovery.
Polypharmacology, defined as the modulation of multiple proteins rather than a single target to achieve a desired therapeutic effect, has been gaining increasing attention since 1990s, when industries had to withdraw several drugs due to their adverse effects, leading to permanent injuries or death, with multi-billiondollar legal damages. Therefore, if up to then the "one drug one target" paradigm had seen many researchers interest focused on the identification of selective drugs, with the strong expectation to avoid adverse drug reactions (ADRs), very recently new research strategies resulted more appealing even as attempts to overcome the decline in productivity of the drug discovery industry. Polypharmacology consists of two different approaches: the former, concerning a single drug interacting with multiple targets related to only one disease pathway; the latter, foresees a single drug's action on multiple targets involved in multiple disease pathways. Both new approaches are strictly connected to the discovery of new feasible off targets for approved drugs. In this review, we describe how the in silico facilities can be a crucial support in the design of polypharmacological drug. The traditional computational protocols (ligand based and structure based) can be used in the search and optimization of drugs, by using specific filters to address them against the polypharmacology (fingerprints, similarity, etc.). Moreover, we dedicated a paragraph to biological and chemical databases, due to their crucial role in polypharmacology. Multitarget activities provide the basis for drug repurposing, a slightly different issue of high interest as well, which is mostly applied on a single target involved in more than one diseases. In this contest, computational methods have raised high interest due to the reached power of hardware and software in the manipulation of data.


Impact of inflammation on the relationship among alcohol consumption, mortality, and cardiac events: the health, aging, and body composition study.
Uncertainty remains about the overall survival benefit of alcohol consumption and the mechanisms underlying the cardioprotective effect of light to moderate alcohol intake. Recent evidence suggests an anti-inflammatory effect of light to moderate alcohol consumption. We investigated the relationship of alcohol intake with all-cause mortality and cardiac events and evaluated whether this relationship is mediated or modified by inflammatory markers. The analysis included 2487 subjects, aged 70 to 79 years, without baseline coronary heart disease (CHD) or heart failure (HF), participating in the Health, Aging, and Body Composition study. All-cause mortality and incident cardiac events (CHD and HF) were detected during a mean follow-up of 5.6 years. Alcohol consumption and serum levels of interleukin-6 (IL-6) and C-reactive protein (CRP) were assessed at baseline. A total of 397 participants died, and 383 experienced an incident cardiac event. Compared with never or occasional drinkers, subjects drinking 1 to 7 drinks per week had lower age-, sex-, and race-adjusted incidences of death (27.4 vs 20.1 per 1000 person-years, respectively) and cardiac events (28.9 vs 20.8 per 1000 person-years). After adjustment for confounders, compared with never or occasional drinkers, light to moderate drinkers (1-7 drinks per week) showed a decreased risk of death (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.56-1.00) and cardiac events (HR, 0.72; CI, 0.54-0.97). Adjustment for potential mediators, and particularly inflammatory marker levels, did not affect the strength of this association. Light to moderate alcohol consumption was associated with significantly lower rates of cardiac events and longer survival, independent of its anti-inflammatory effect.


Outlining the Ancestry Landscape of Colombian Admixed Populations.
The ancestry of the Colombian population comprises a large number of well differentiated Native communities belonging to diverse linguistic groups. In the late fifteenth century, a process of admixture was initiated with the arrival of the Europeans, and several years later, Africans also became part of the Colombian population. Therefore, the genepool of the current Colombian population results from the admixture of Native Americans, Europeans and Africans. This admixture occurred differently in each region of the country, producing a clearly stratified population. Considering the importance of population substructure in both clinical and forensic genetics, we sought to investigate and compare patterns of genetic ancestry in Colombia by studying samples from Native and non-Native populations living in its 5 continental regions: the Andes, Caribe, Amazonia, Orinoquía, and Pacific regions. For this purpose, 46 AIM-Indels were genotyped in 761 non-related individuals from current populations. Previously published genotype data from 214 Colombian Natives from five communities were used for population comparisons. Significant differences were observed between Native and non-Native populations, among non-Native populations from different regions and among Native populations from different ethnic groups. The Pacific was the region with the highest African ancestry, Amazonia harboured the highest Native ancestry and the Andean and Orinoquían regions showed the highest proportion of European ancestry. The Andean region was further sub-divided into 6 sub-regions: North East, Central West, Central East, West, South West and South East. Among these regions, the South West region showed a significantly lower European admixture than the other regions. Hardy-Weinberg equilibrium and variance values of ancestry among individuals within populations showed a potential stratification of the Pacific population.


Involvement of silicon influx transporter OsNIP2;1 in selenite uptake in rice.
Rice (Oryza sativa) as a staple food, provides a major source of dietary selenium (Se) for humans, which essentially requires Se, however, the molecular mechanism for Se uptake is still poorly understood. Herein, we show evidence that the uptake of selenite, a main bioavailable form of Se in paddy soils, is mediated by a silicon (Si) influx transporter Lsi1 (OsNIP2;1) in rice. Defect of OsNIP2;1 resulted in a significant decrease in the Se concentration of the shoots and xylem sap when selenite was given. However, there was no difference in the Se concentration between the wild-type rice and mutant of OsNIP2;1 when selenate was supplied. A short-term uptake experiment showed that selenite uptake greatly increased with decreasing pH in the external solution. Si as silicic acid did not inhibit the Se uptake from selenite in both rice and yeast (Saccharomyces cerevisiae) at low pHs. Expression of OsNIP2;1 in yeast enhanced the selenite uptake at pH 3.5 and 5.5 but not at pH 7.5. On the other hand, defect of Si efflux transporter Lsi2 did not affect the uptake of Se either from selenite or selenate. Taken together, our results indicate that Si influx transporter OsNIP2;1 is permeable to selenite.


In situ aromatization enhances breast tumor estradiol levels and cellular proliferation.
The high concentrations of estradiol (E2) found in breast tumors of postmenopausal women could be the result of enhanced uptake from plasma or in situ aromatization of androgens to estrogens. To test the relative importance of these two mechanisms, a model system allowing precise distinction between each is required. Such a model was established using aromatase (A+)- and sham (A-)-transfected MCF-7 cells inoculated into ovariectomized (OVX) nude mice. To validate the model, the confounding effect of peripheral aromatization was first excluded experimentally. A- cells were inoculated into OVX mice as homoimplants (A- cells on both flanks) or heteroimplants (A- cells on one flank and A+ cells on the other), and growth of A- cells in response to exogenous aromatase substrate, androstenedione (delta4A), was evaluated. A- cells did not grow in either group during the 8 weeks of observation, indicating the lack of peripheral aromatization in OVX mice. The biological effects of in situ aromatization were then directly examined. We found that A+ cells in the heteroimplant group grew rapidly, and that the average weight of A+ tumor was 7.6-fold larger and tissue E2 concentration was 3-4-fold higher than A- tumors grown in the same animals. These results demonstrate that in situ aromatization rather than uptake can be a determinant of tumor E2 content and growth stimulation. An additional experiment was then designed to evaluate the relative importance of in situ synthesis versus uptake under conditions reflecting postmenopausal physiology. Groups of OVX mice bearing A+ cells received E2 Silastic implants to clamp plasma levels at 5, 7, 10, and 20 pg/ml or delta4A by injection. The highest tumor E2 concentration and growth rate were found in the group receiving delta4A. E2 delivered by Silastic implants always produced lower tissue E2 levels and tumor growth rates than resulted from in situ synthesis. These data provide direct evidence that under physiological conditions reflecting those in postmenopausal women, in situ aromatization in breast tumor makes a major contribution to tissue E2 content. As further validation that our experimental paradigm models the postmenopausal state, we studied OVX animals not given delta4A as substrate. A+ cells also grew under these conditions, and the aromatase inhibitor 4-hydroxyandrostenedione reduced both tumor E2 level and growth rate, providing additional evidence of the importance of in situ synthesis. These studies provide the first direct evidence that in situ synthesis of E2 in breast tumors, as opposed to peripheral aromatization and uptake from plasma, can enhance tissue E2 levels and stimulate tumor growth.


Decreased bilateral thalamic gray matter volume in first-episode schizophrenia with prominent hallucinatory symptoms: A volumetric MRI study.
Studies comparing gray matter (GM) volume of schizophrenic patients with or without auditory verbal hallucinations (AVHs) to that of normal controls remain controversial. This project aims to investigate changes of GM volumes of drug-naïve schizophrenic patients with and without AVHs. Eighteen first episode schizophrenic (FES) patients with AVHs, 18 FES patients without AVHs, and 18 healthy controls were scanned using structural MRI. Voxel-based morphometry (VBM) analysis was conducted to investigate changes of GM volume among the three groups. Patients with and without AVHs exhibited reduced GM volumes relative to normal controls in the left superior temporal gyrus, frontal regions, cerebellum and caudate. Further analysis of the GM of subcortical structures found that patients with AVHs had reduced thalamic volume than healthy controls. No significant difference was found between patients with and without AVHs. Significant correlation was found between the total scores of the Positive and Negative Syndrome Scale and bilateral thalamic volume. ROC analysis of thalamic volumes of the patients with AVHs and normal controls showed that the area under the curve was 0.698 (P = 0.043). The decreased thalamic volumes might serve as a biomarker for discriminating FES AVHs patients from normals.


Dopamine, motivation, and the evolutionary significance of gambling-like behaviour.
If given a choice between certain and uncertain rewards, animals tend to prefer the uncertain option, even when the net gain is suboptimal. Animals are also more responsive to reward-related cues in uncertain situations. This well-documented phenomenon in many animal species is in opposition to the basic principles of reinforcement as well as the optimal foraging theory, which suggest that animals will prefer the option associated with the highest reward rate. How does the brain code the attractiveness of unreliable/poor reward sources? And how can we interpret this evidence from an adaptive point of view? I argue that unpredictability and deprivation - whether physiological or psychological - enhance motivation to seek valuable stimuli for the same reason: compensating the difficulty an organism has to predict significant objects and events in the environment.


Hierarchical linear modeling of longitudinal pedigree data for genetic association analysis.
Genetic association analysis on complex phenotypes under a longitudinal design involving pedigrees encounters the problem of correlation within pedigrees, which could affect statistical assessment of the genetic effects. Approaches have been proposed to integrate kinship correlation into the mixed-effect models to explicitly model the genetic relationship. These have proved to be an efficient way of dealing with sample clustering in pedigree data. Although current algorithms implemented in popular statistical packages are useful for adjusting relatedness in the mixed modeling of genetic effects on the mean level of a phenotype, they are not sufficiently straightforward to handle the kinship correlation on the time-dependent trajectories of a phenotype. We introduce a 2-level hierarchical linear model to separately assess the genetic associations with the mean level and the rate of change of a phenotype, integrating kinship correlation in the analysis. We apply our method to the Genetic Analysis Workshop 18 genome-wide association studies data on chromosome 3 to estimate the genetic effects on systolic blood pressure measured over time in large pedigrees. Our method identifies genetic variants associated with blood pressure with estimated inflation factors of 0.99, suggesting that our modeling of random effects efficiently handles the genetic relatedness in pedigrees. Application to simulated data captures important variants specified in the simulation. Our results show that the method is useful for genetic association studies in related samples using longitudinal design.


Heterogeneous generation of new cells in the adult echinoderm nervous system.
Adult neurogenesis, generation of new functional cells in the mature central nervous system (CNS), has been documented in a number of diverse organisms, ranging from humans to invertebrates. However, the origin and evolution of this phenomenon is still poorly understood for many of the key phylogenetic groups. Echinoderms are one such phylum, positioned as a sister group to chordates within the monophyletic clade Deuterostomia. They are well known for the ability of their adult organs, including the CNS, to completely regenerate after injury. Nothing is known, however, about production of new cells in the nervous tissue under normal physiological conditions in these animals. In this study, we show that new cells are continuously generated in the mature radial nerve cord (RNC) of the sea cucumber Holothuria glaberrima. Importantly, this neurogenic activity is not evenly distributed, but is significantly more extensive in the lateral regions of the RNC than along the midline. Some of the new cells generated in the apical region of the ectoneural neuroepithelium leave their place of origin and migrate basally to populate the neural parenchyma. Gene expression analysis showed that generation of new cells in the adult sea cucumber CNS is associated with transcriptional activity of genes known to be involved in regulation of various aspects of neurogenesis in other animals. Further analysis of one of those genes, the transcription factor Myc, showed that it is expressed, in some, but not all radial glial cells, suggesting heterogeneity of this CNS progenitor cell population in echinoderms.


Customized, single-incision, three-wall orbital decompression.
To present the clinical outcome in 55 consecutive patients by using a customized, single-incision, 3-wall orbital decompression. A retrospective chart review was performed of 97 customized, single-incision, 3-wall decompressions in 55 consecutive patients within one surgeon's practice. A standardized surgical technique featuring lateral small-incision, 3-wall decompression with specific "strut" preservation was used in all patients. Success of the procedure was assessed on the basis of the amount of proptosis reduction achieved, as measured by the difference in Hertel exophthalmometry measurements, and by improvement in or preservation of preoperative visual acuity and color vision in the setting of compressive optic neuropathy. Subjective diplopia was recorded before and after surgery, as was the presence of extraocular muscle restriction. A total of 97 orbital decompressions in 55 consecutive patients were reviewed. The majority of surgeries were performed for disfiguring proptosis with some degree of exposure-related symptoms (81%), with other indications including compressive optic neuropathy (17%), and pain (2%). The average amount of proptosis reduction achieved at 3 months was 5 mm (range, 1 to 11 mm). Visual acuity in patients with compressive optic neuropathy improved an average of 2 lines on the standard Snellen chart testing (range, 1 to 5). Color vision improved an average of 5 Ishihara plates (range, 0 to 13). Seventy-one percent of patients had subjective diplopia before surgery; 21% of these patients reported improvement or complete resolution of diplopia after surgery. Of the 29% of patients without preoperative subjective diplopia, all but one (1.8 of total patients) remained symptom free. We find that a customized, single-incision, 3-wall orbital decompression provides adequate decompression and proptosis reduction while minimizing postoperative strabismus and providing an aesthetically desirable result.


LncRNA profile in Hashimoto's thyroiditis and potential function of NONHSAT079547.2.
Hashimoto's thyroiditis (HT) is a common organ-specific autoimmune disease, which develops in 0.3-1.5/1000 subjects annually. The aims of this study were to determine the lncRNA profile in peripheral blood CD4+ T cells from HT patients and then to characterize the potential function of NONHSAT079547.2. A total of 37 HT patients and 50 sex- and age-matched healthy controls were enrolled for high-throughput sequencing. Another 43 HT patients and 50 sex- and age-matched controls were enrolled for validation via real-time PCR. Flow cytometry and CCK8 assays were used to measure cell apoptosis and growth levels. Western blotting was used for measuring the expression of growth- and apoptosis-associated proteins. IL-17 serum concentration and transcriptional level in CD4+ T cells of participants were detected by ELISA and real-time PCR, respectively. The mechanism of competitive endogenous RNA was determined using real-time PCR, ELISA, RNA immunoprecipitation, and dual-luciferase assays in Jurkat cells. A total of 7564 significantly differentially expressed lncRNAs were found, of which 3913 lncRNAs were upregulated and 3651 lncRNAs were downregulated in HT group when compared to control group. NONHSAT079547.2 was significantly upregulated in HT patients and was positively correlated with serum thyroid peroxidase antibody level. Further studies confirmed that NONHSAT079547.2 could promote cell growth and control IL-17 expression and secretion via the NONHSAT079547.2/miR-4716-5p/IL-17 axis.This is the first study to describe the lncRNA profile in CD4+ T cells of HT patients. The studies on the function of NONHSAT079547.2 might elucidate the underlying molecular mechanisms and represent potential biomarkers for HT.


Influence of quercetin-rich onion peel extracts on adipokine expression in the visceral adipose tissue of rats.
We examined the effects of quercetin-rich onion peel extract supplementation on adipokine expressions from adipose tissues in a diet-induced obese animal model. Male Sprague-Dawley rats (n = 24) were randomly assigned into control (n = 8), high fat diet (HF, n = 8) and high fat diet with onion peel extract (HFOE, n = 8). After 8 weeks, serum biochemical parameters, weights of adipose tissues (epididymal, perirenal and mesenteric fats) and adipokine mRNA levels (adiponectin, IL (interleukin)-6 and visfatin) along with PPAR (peroxisome proliferator-activated receptor) γ2 from adipose tissues were measured. After the 8 week supplementation, mesenteric fat weights were lower in the HFOE group than the HF group (p < 0.05). Adiponectin mRNA levels (mesenteric fats) were remarkably higher in the HFOE group than the other groups (p < 0.05 for both). Levels of PPARγ2 mRNA (mesenteric fats) were significantly higher in the HF group (p < 0.05) than those in the control group, but those in the HFOE group were not different from those in the control group. The IL-6 mRNA levels (perirenal and mesenteric fats) were higher in the HF and HFOE groups, but those in the HFOE group were slightly lower than those in the HF group. In conclusion, quercetin-rich onion peel extract supplementation influenced adipokine expressions, particularly from mesenteric fat, addressing the modulatory effect of this substance on obesity-induced inflammation.


Novel low-risk commercial sex practices in the parks of Vietnam.
This is a paper about a novel form of commercial sex practice recorded in Vietnam, and its implications for HIV/AIDS prevention strategies. Female commercial sex workers occupy urban parks in the evenings, offering on-site masturbation services to clients at cheap prices even by local standards. All sex acts are performed in public by workers who sit on benches, path edges or stools,often behind bicycles or open umbrellas in the quest for some semblance of privacy. Clients are local men, with only an occasional foreigner involved Many sex workers were involved, some having 15 to 20 or more clients a night. Sex workers and clients in Vietnam, a s elsewhere, operate at high risk of HIV/AIDS infection. As a service which minimizes risks, this form of commercial sex practice should perhaps be given serious consideration by policy makers and authorities for formal deployment in the fight against AIDS.


Quantum de Finetti Theorem under Fully-One-Way Adaptive Measurements.
We prove a version of the quantum de Finetti theorem: permutation-invariant quantum states are well approximated as a probabilistic mixture of multifold product states. The approximation is measured by distinguishability under measurements that are implementable by fully-one-way local operations and classical communication (LOCC). Our result strengthens Brandão and Harrow's de Finetti theorem where a kind of partially-one-way LOCC measurements was used for measuring the approximation, with essentially the same error bound. As main applications, we show (i) a quasipolynomial-time algorithm which detects multipartite entanglement with an amount larger than an arbitrarily small constant (measured with a variant of the relative entropy of entanglement), and (ii) a proof that in quantum Merlin-Arthur proof systems, polynomially many provers are not more powerful than a single prover when the verifier is restricted to one-way LOCC operations.


High-resolution near-field optical imaging of single nuclear pore complexes under physiological conditions.
Scanning near-field optical microscopy (SNOM) circumvents the diffraction limit of conventional light microscopy and is able to achieve optical resolutions substantially below 100 nm. However, in the field of cell biology SNOM has been rarely applied, probably because previous techniques for sample-distance control are less sensitive in liquid than in air. Recently we developed a distance control based on a tuning fork in tapping mode, which is also well-suited for imaging in solution. Here we show that this approach can be used to visualize single membrane protein complexes kept in physiological media throughout. Nuclear envelopes were isolated from Xenopus laevis oocytes at conditions shown recently to conserve the transport functions of the nuclear pore complex (NPC). Isolated nuclear envelopes were fluorescently labeled by antibodies against specific proteins of the NPC (NUP153 and p62) and imaged at a resolution of approximately 60 nm. The lateral distribution of epitopes within the supramolecular NPC could be inferred from an analysis of the intensity distribution of the fluorescence spots. The different number densities of p62- and NUP153-labeled NPCs are determined and discussed. Thus we show that SNOM opens up new possibilities for directly visualizing the transport of single particles through single NPCs and other transporters.


StarPEG/heparin-hydrogel based in vivo engineering of stable bizonal cartilage with a calcified bottom layer.
Repaired cartilage tissue lacks the typical zonal structure of healthy native cartilage needed for appropriate function. Current grafts for treatment of full thickness cartilage defects focus primarily on a nonzonal design and this may be a reason why inferior nonzonal regeneration tissue developed in vivo. No biomaterial-based solutions have been developed so far to induce a proper zonal architecture into a non-mineralized and a calcified cartilage layer. The objective was to grow bizonal cartilage with a calcified cartilage bottom zone wherein main tissue development is occurring in vivo. We hypothesized that starPEG/heparin-hydrogel owing to the glycosaminoglycan heparin contained as a building-block would prevent mineralization of the upper cartilage zone and be beneficial in inhibiting long-term progression of calcified cartilage into bone. MSCs were pre-cultured as self-assembling non-mineralized cell discs before a chondrocyte-seeded fibrin- or starPEG/heparin-hydrogel layer was cast on top directly before ectopic implantation. Bizonal cartilage with a calcified bottom-layer developed in vivo showing stronger mineralization compared to in vitro samples, but the hydrogel strongly determined outcome. Zonal fibrin-constructs lost volume and allowed non-organized expansion of collagen type X, ALP-activity and mineralization from the bottom-layer into upper regions, whereas zonal starPEG/heparin-constructs were of stable architecture. While non-zonal MSCs-derived discs formed bone over 12 weeks, the starPEG/heparin-chondrocyte layer prevented further progression of calcified cartilage into bone tissue. Conclusively, starPEG/heparin-hydrogel-controlled and cell-type mediated spatiotemporal regulation allowed in vivo growth of bizonal cartilage with a stable calcified cartilage layer. Altogether our work is an important milestone encouraging direct in vivo growth of organized cartilage after biofabrication.


Evidence for a role of sterol 27-hydroxylase in glucocorticoid metabolism in vivo.
The intracellular availability of glucocorticoids is regulated by the enzymes 11β-hydroxysteroid dehydrogenase 1 (HSD11B1) and 11β-hydroxysteroid dehydrogenase 2 (HSD11B2). The activity of HSD11B1 is measured in the urine based on the (tetrahydrocortisol+5α-tetrahydrocortisol)/tetrahydrocortisone ((THF+5α-THF)/THE) ratio in humans and the (tetrahydrocorticosterone+5α-tetrahydrocorticosterone)/tetrahydrodehydrocorticosterone ((THB+5α-THB)/THA) ratio in mice. The cortisol/cortisone (F/E) ratio in humans and the corticosterone/11-dehydrocorticosterone (B/A) ratio in mice are markers of the activity of HSD11B2. In vitro agonist treatment of liver X receptor (LXR) down-regulates the activity of HSD11B1. Sterol 27-hydroxylase (CYP27A1) catalyses the first step in the alternative pathway of bile acid synthesis by hydroxylating cholesterol to 27-hydroxycholesterol (27-OHC). Since 27-OHC is a natural ligand for LXR, we hypothesised that CYP27A1 deficiency may up-regulate the activity of HSD11B1. In a patient with cerebrotendinous xanthomatosis carrying a loss-of-function mutation in CYP27A1, the plasma concentrations of 27-OHC were dramatically reduced (3.8 vs 90-140 ng/ml in healthy controls) and the urinary ratios of (THF+5α-THF)/THE and F/E were increased, demonstrating enhanced HSD11B1 and diminished HSD11B2 activities. Similarly, in Cyp27a1 knockout (KO) mice, the plasma concentrations of 27-OHC were undetectable (<1 vs 25-120 ng/ml in Cyp27a1 WT mice). The urinary ratio of (THB+5α-THB)/THA was fourfold and that of B/A was twofold higher in KO mice than in their WT littermates. The (THB+5α-THB)/THA ratio was also significantly increased in the plasma, liver and kidney of KO mice. In the liver of these mice, the increase in the concentrations of active glucocorticoids was due to increased liver weight as a consequence of Cyp27a1 deficiency. In vitro, 27-OHC acts as an inhibitor of the activity of HSD11B1. Our studies suggest that the expression of CYP27A1 modulates the concentrations of active glucocorticoids in both humans and mice and in vitro.


In vivo and in vitro characterization of the biochemical and pathological changes induced by lionfish (pterios volitans) venom in mice.
Accidents caused by lionfish (Pterios volitans) envenomation are characterized by edema, intense pain, and necrosis at the site of sting. The mode of action and biochemistry of venoms are obviously complex and require a better knowledge and investigation to explore the toxic action and resulting biochemical changes. In the present study the LD(50) value of lionfish venom was found to be 42.5 mug/kg body weight (intraperitoneal injection) in Albino Swiss mice and was associated with reduced motor activity and asphyxiation followed by respiratory failure. The effect on vital organs revealed spongiosis in brain, vascular congestion in liver, cloudy swelling of renal tubules, congested blood vessels in renal tubules, and degeneration of myofibrils in heart. Whereas, the 10% of LD(50) (was 4.25 mug/kg b.w.), the sublethal dose showed reversible changes in the hematological (blood cell count, hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, and platelet count) parameters, serum enzymes (aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase, and creatinine phosphokinase), blood sugar, urea, creatinine, triglycerides, cholesterol, and total protein in mouse in vivo. The in vitro analysis of lionfish venom on mouse brain acetyl cholinesterase and Na(+), K(+), ATPase showed significant increased activity in a dose-dependent manner (10 to 40 mug). Moreover, the lionfish venom was observed to have a protease with a molecular weight of 45 kDa. Hence, the present study suggests the presence of bioactive proteins and peptides with excellent target specificity, which could be trapped for drug development in near future.


A willow sex chromosome reveals convergent evolution of complex palindromic repeats.
Sex chromosomes have arisen independently in a wide variety of species, yet they share common characteristics, including the presence of suppressed recombination surrounding sex determination loci. Mammalian sex chromosomes contain multiple palindromic repeats across the non-recombining region that show sequence conservation through gene conversion and contain genes that are crucial for sexual reproduction. In plants, it is not clear if palindromic repeats play a role in maintaining sequence conservation in the absence of homologous recombination. Here we present the first evidence of large palindromic structures in a plant sex chromosome, based on a highly contiguous assembly of the W chromosome of the dioecious shrub Salix purpurea. The W chromosome has an expanded number of genes due to transpositions from autosomes. It also contains two consecutive palindromes that span a region of 200 kb, with conspicuous 20-kb stretches of highly conserved sequences among the four arms that show evidence of gene conversion. Four genes in the palindrome are homologous to genes in the sex determination regions of the closely related genus Populus, which is located on a different chromosome. These genes show distinct, floral-biased expression patterns compared to paralogous copies on autosomes. The presence of palindromes in sex chromosomes of mammals and plants highlights the intrinsic importance of these features in adaptive evolution in the absence of recombination. Convergent evolution is driving both the independent establishment of sex chromosomes as well as their fine-scale sequence structure.


Responses of wheat and rice to factorial combinations of ambient and elevated CO2 and temperature in FACE experiments.
Elevated CO2 and temperature strongly affect crop production, but understanding of the crop response to combined CO2 and temperature increases under field conditions is still limited while data are scarce. We grew wheat (Triticum aestivum L.) and rice (Oryza sativa L.) under two levels of CO2 (ambient and enriched up to 500 μmol mol(-1) ) and two levels of canopy temperature (ambient and increased by 1.5-2.0 °C) in free-air CO2 enrichment (FACE) systems and carried out a detailed growth and yield component analysis during two growing seasons for both crops. An increase in CO2 resulted in higher grain yield, whereas an increase in temperature reduced grain yield, in both crops. An increase in CO2 was unable to compensate for the negative impact of an increase in temperature on biomass and yield of wheat and rice. Yields of wheat and rice were decreased by 10-12% and 17-35%, respectively, under the combination of elevated CO2 and temperature. The number of filled grains per unit area was the most important yield component accounting for the effects of elevated CO2 and temperature in wheat and rice. Our data showed complex treatment effects on the interplay between preheading duration, nitrogen uptake, tillering, leaf area index, and radiation-use efficiency, and thus on yield components and yield. Nitrogen uptake before heading was crucial in minimizing yield loss due to climate change in both crops. For rice, however, a breeding strategy to increase grain number per m(2) and % filled grains (or to reduce spikelet sterility) at high temperature is also required to prevent yield reduction under conditions of global change.


Changes in body composition of human immunodeficiency virus-infected males receiving insulin-like growth factor I and growth hormone.
Weight loss is a common, persistent characteristic of long term human immunodeficiency virus (HIV-1) infection; its full etiology remains unknown. Because treatment with GH has induced nitrogen retention in various catabolic conditions, we designed this study to determine whether a moderate dose of insulin-like growth factor I (IGF-I) combined with a low GH dose could impede the catabolic response seen in HIV-1 infection. A double blind, placebo-controlled study design was used. Subjects in the GH/IGF-I treatment group (n = 44) and control group (n = 22) continued to receive their routine stable antiretroviral therapy. No patient had a recent history of opportunistic infection, malignancy, or Kaposi's sarcoma and had dietary intakes of at least 25 Cal/kg weight.day at study entry. During the 12-week study period, dietary instruction was given, and subjects were encouraged to maintain an intake of 35 Cal/kg and 1 g protein/kg. All subjects had a body mass index of 19.8 kg/m2 or less at the time of study entry or a weight loss of 10% or more of their premorbid weight and a body mass index below 26.1 kg/m2. The treatment group received 0.34 mg (0.68 mg/day) GH, twice daily, and 5.0 mg (10 mg/day) IGF-I, twice daily. Changes in body composition of total body potassium (TBK), total body nitrogen (TBN), fat-free mass (FFM), and body fat (Fat) were examined at 6 and 12 weeks during the treatment period. TBK, TBN, FFM, and Fat for the treatment and placebo groups were, on the average, below normal at study entry. At 6 weeks, the GH/IGF-I group showed a significant increase in FFM (P < 0.0001), a minimal increase in TBK (P < 0.05), and a substantial decrease in Fat (P < 0.01) compared with baseline values. The loss of body fat continued to be significant (P < 0.01) in the GH/IGF-I group treatment at 12 weeks, whereas the increase in FFM was minimal (P < 0.05). No significant changes in the mean body composition occurred at 6 or 12 weeks in the placebo group. By 12 weeks, neither TBK (body cell mass) nor TBN (total protein mass) had significantly increased relative to the values at baseline, although the FFM remained elevated. Thus, the combined GH and IGF-I doses used in this study in adult males with HIV-associated weight loss were ineffective in producing a sustained anabolic response and, in fact, resulted primarily in a significant loss of body fat.


A decision aid for COPD patients considering inhaled steroid therapy: development and before and after pilot testing.
Decision aids (DA) are tools designed to help patients make specific and deliberative choices among disease management options. DAs can improve the quality of decision-making and reduce decisional conflict. An area not covered by a DA is the decision of a patient with chronic obstructive pulmonary disease (COPD) to use inhaled steroids which requires balancing the benefits and downsides of therapy. We developed a DA for COPD patients considering inhaled steroid therapy using the Ottawa Decision Support Framework, the best available evidence for using inhaled steroid in COPD and the expected utility model. The development process involved patients, pulmonologists, DA developers and decision making experts. We pilot tested the DA with 8 COPD patients who completed an evaluation questionnaire, a knowledge scale, and a validated decisional conflict scale. The DA is a computer-based interactive tool incorporating four different decision making models. In the first part, the DA provides information about COPD as a disease, the different treatment options, and the benefits and downsides of using inhaled steroids. In the second part, it coaches the patient in the decision making process through clarifying values and preferences. Patients evaluated 10 out of 13 items of the DA positively and showed significant improvement on both the knowledge scale (p = 0.008) and the decisional conflict scale (p = 0.008). We have developed a computer-based interactive DA for COPD patients considering inhaled steroids serving as a model for other DAs in COPD, in particular related to inhaled therapies. Future research should assess the DA effectiveness.


Serum 25 hydroxyvitamin D profile after single large oral doses of cholecalciferol (vitamin D3) in medical staff in North India: a pilot study.
Vitamin D deficiency is widely prevalent in India and subjects who have almost no exposure to sunlight are severely deficient. Daily oral doses of cholecalciferol (vitamin D3) are costly as compared to stoss doses and further, take a long time for the serum levels to reach a plateau. Compliance to supplementation may also be better if a regimen involves single oral doses of vitamin D at specified intervals rather than daily doses. Evidence-based guidelines regarding the dosing and the frequency of dosing for prophylactic intermittent supplementation (stoss doses) in severely-deficient subjects are few. In a prospective intervention study, we serially assessed 30 asymptomatic healthy medical staff for serum 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH); (a) at baseline; (b) monthly for 3 months after single oral 60,000 units (U) cholecalciferol; (c) monthly for 3 months after 120,000 (or 180,000 for those with elevated alkaline phosphatase) U cholecalciferol; and, (d) subsequently, at 3 months after a repeat dose of 60,000 U cholecalciferol by repeated measures analysis of variance. The baseline serum 25(OH)D was 7.1 ± 5.4 ng/mL (< 10 ng/mL in 85% subjects) which increased to 18.7 ± 8.9 ng/mL at 1 month after 60,000 U of cholecalciferol (P < 0.001) and decreased to 11.1 ± 5.3 ng/mL by the 3 rd month. The higher dose of 120,000 (or 180,000) U increased mean 25(OH)D to 28.9 ± 9.9 ng/mL at the end of 1 st month, declining to 17.9 ± 4.9 ng/mL (P < 0.001) at 3 months. With the subsequent 60,000 U the serum 25(OH)D was 18.4 ± 3.9 ng/mL at 3 months. PTH showed a corresponding negative trend. No hypercalcemia was observed. Vitamin D deficiency is highly prevalent amongst medical staff in Northern India. An initial dose of 120,000-180,000 U of cholecalciferol is required to elevate 25(OH)D out of the deficiency range. Maintenance dose is needed at 2 months.


Differences in food intake of tumour-bearing cachectic mice are associated with hypothalamic serotonin signalling.
Anorexia is a common symptom among cancer patients and contributes to malnutrition and strongly impinges on quality of life. Cancer-induced anorexia is thought to be caused by an inability of food intake-regulating systems in the hypothalamus to respond adequately to negative energy balance during tumour growth. Here, we show that this impaired response of food-intake control is likely to be mediated by altered serotonin signalling and by failure in post-transcriptional neuropeptide Y (NPY) regulation. Two tumour cachectic mouse models with different food intake behaviours were used: a C26-colon adenocarcinoma model with increased food intake and a Lewis lung carcinoma model with decreased food intake. This contrast in food intake behaviour between tumour-bearing (TB) mice in response to growth of the two different tumours was used to distinguish between processes involved in cachexia and mechanisms that might be important in food intake regulation. The hypothalamus was used for transcriptomics (affymetrix chips). In both models, hypothalamic expression of orexigenic NPY was significantly higher compared with controls, suggesting that this change does not directly reflect food intake status but might be linked to negative energy balance in cachexia. Expression of genes involved in serotonin signalling showed to be different between C26-TB mice and Lewis lung carcinoma-TB mice and was inversely associated with food intake. In vitro, using hypothalamic cell lines, serotonin repressed neuronal hypothalamic NPY secretion while not affecting messenger NPY expression, suggesting that serotonin signalling can interfere with NPY synthesis, transport, or secretion. Altered serotonin signalling is associated with changes in food intake behaviour in cachectic TB mice. Serotonins' inhibitory effect on food intake under cancer cachectic conditions is probably via affecting the NPY system. Therefore, serotonin regulation might be a therapeutic target to prevent the development of cancer-induced eating disorders.


1(st) National Conference on Family Medicine and Primary Care: A Journey Toward Stronger Primary Care in India.
Academy of Family Physicians of India organized the first National Conference on Family Medicine and Primary Care (FMPC) on 20-21 April 2013 at India International Centre New Delhi. The conference was a major success towards positioning of requirement for a distinct academic discipline (family medicine) within the medical and nursing education system as a means for strengthening of primary care in India. The event gained its prominence in the times when universal health coverage is being debated. A generalist approach in development of human resource prominently figured in the discussions. The deliberations and talks of the Indian as well as international experts were recorded and released as the report of national consultation on family medicine programme.


Evidence for new alleles in the protein kinase adenosine monophosphate-activated gamma(3)-subunit gene associated with low glycogen content in pig skeletal muscle and improved meat quality.
Several quantitative trait loci (QTL) affecting muscle glycogen content and related traits were mapped to pig chromosome 15 using a three-generation intercross between Berkshire x Yorkshire pigs. On the basis of the QTL location the PRKAG3 (protein kinase, AMP-activated, gamma(3)-subunit) gene was considered to be a good candidate for the observed effects. Differences in the PRKAG3 gene sequences of the founder animals of the intercross were analyzed. The RN(-) mutation previously reported was not present in the cross but three missense substitutions and a polymorphic short interspersed element (SINE) were identified. To confirm the hypothesis that at least one of these mutations was associated with differences in meat quality, >1800 animals from several unrelated commercial lines were genotyped for the candidate substitutions and an association study was performed. The results demonstrate the presence of new economically important alleles of the PRKAG3 gene affecting the glycogen content in the muscle and the resulting meat quality. Haplotype analysis was shown to resolve the effects of PRKAG3 more clearly than analysis of individual polymorphisms. Because of their prevalence in the more common commercial breeds, the potential implications for the pig industry and consumers are considerably greater than the original discovery of the RN(-) mutation. Furthermore, these results illustrate that additional alleles of genes involved in major mutations may play a significant role in quantitative trait variation.


Rheology of phosphonium ionic liquids: a molecular dynamics and experimental study.
We have studied the rheological behavior of the ionic liquid trihexyl(tetradecyl)phosphonium bis(mandelato)borate, [P66614][BMB], and compared it with that of another ionic liquid, namely trihexyl(tetradecyl)phosphonium chloride, [P66614][Cl]. The non-halogenated [P66614][BMB] has been selected as it is known to provide enhanced lubrication performance and is, consequently, of technological importance. The ionic liquid [P66614][Cl], despite its relatively simple anion, exhibits viscosities very similar to those of [P66614][BMB], making it an excellent reference fluid for the modeling study. The viscosities of the ionic liquids have been obtained by equilibrium atomistic simulations using the Green-Kubo relation, and by performing nonequilibrium shear flow simulations. The influence of the simulation system size and a reduction of the atomic charges on the viscosities of the ionic liquids are systematically studied. The atomic charges are reduced to mimic the temperature dependent charge transfer and polarization effects. It has been found that scaling the point charges with factors between 0.60 and 0.80 from full ion charges can provide reliable viscosities of [P66614][BMB], consistent with the experimentally measured viscosities within the studied temperature interval from 373 to 463 K. The viscosities of [P66614][Cl] have been obtained with scaling factors between 0.80 and 1.0 reflecting the lower polarizability and charge transfer effects of the chloride anion.


Resilience of Natural Phytoplankton Communities to Pulse Disturbances from Micropollutant Exposure and Vertical Mixing.
Freshwaters are increasingly exposed to complex mixtures of pharmaceutical and personal care products (PPCPs) from municipal wastewater, which are known to alter freshwater communities' structure and functioning. However, their interaction with other disturbances and whether their combined effects can impact ecological resilience (i.e., the ability of a system to tolerate disturbances without altering the system's original structure and processes) remain unexplored. Using in situ mesocosms in 2 lakes with different nutrient levels (mesotrophic and eutrophic), we assessed whether a pulse exposure to sublethal concentrations of 12 PPCPs affects the ecological resilience of natural phytoplankton communities that experienced an abrupt environmental change involving the destabilization of the water column through mixing. Such mixing events are predicted to increase as the effects of climate change unfold, leading to more frequent storms, which disrupt stratification in lakes and force communities to restructure. We assessed their combined effects on community metrics (biomass, species richness, and composition) and their relative resilience using 4 indicators (cross-scale, within-scale, aggregation length, and gap length), inferred from phytoplankton communities by discontinuity analysis. The mixing disturbance alone had negligible effects on the community metrics, but when combined with chemical contaminants significant changes were measured: reducing total biomass, species richness, and altered community composition of phytoplankton. Once these changes occurred, they persisted until the end of the experiment (day 20), when the communities' structures from the 2 highest exposure levels diverged from the controls. The resilience indicators were not affected by PPCPs but differed significantly between lakes, with lower resilience found in the eutrophic lake. Thus, PPCPs can significantly alter community structures and reinforce mechanisms that maintain ecosystems in a "degraded state." Environ Toxicol Chem 2019;38:2197-2208. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.


Viscoelastic, mechanical, and dielectric measurements on complex samples with the quartz crystal microbalance.
Piezoelectric resonators have been in use as mass-sensing devices for almost half a century. More recently it was recognized that shifts in frequency and bandwidth can come about by a diverse variety of interactions with the sample. The classical "load" consists of a thin film, which shifts the resonance frequency due to its inertia. Other types of loading include semi-infinite viscoelastic media, rough objects contacting the crystal via isolated asperities, mechanically nonlinear contacts, and dielectric films. All these interactions can be analyzed within the small-load approximation. The small-load approximation provides a unified frame for interpretation and thereby opens the way to new applications of the QCM.


Conformational behavior and stacking interactions of contorted polycyclic aromatics.
We present a systematic computational analysis of the conformations and stacking interactions of a set of 18 saddle-shaped, contorted polycyclic aromatic compounds at the B97-D3M(BJ)/TZV(2d,2p)//B97-D/TZV(2d,2p) level of theory. These doubly-concave systems offer a means of tuning the strength of stacking interactions through variations in molecular curvature, and understanding the intermolecular non-covalent interactions exhibited by these systems will aid the design of contorted polycyclic systems with precisely defined packing in the solid state. Computations reveal wide variations in both the nature of the low-lying conformations and the stacking affinities of these systems. In particular, the introduction of both thiophene rings around the periphery of these systems and the incorporation of B and N atoms into the coronene core can greatly enhance their tendency to form strongly stacked dimers. Overall, these data provide a reminder that curvature does not always lead to stronger stacking interactions.


Contact activation products are new potential biomarkers to evaluate the risk of thrombotic events in systemic lupus erythematosus.
Patients with systemic lupus erythematosus (SLE) have persistent platelet activation and an increased risk of thrombotic events, which cannot be accounted for by traditional cardiovascular risk factors. Factor (F)XII has a potentially important role in thrombus formation and is triggered by activated platelets. We therefore asked whether the contact system is involved in inflammation and vascular disease (VD) in SLE. Fibrin clots were incubated with purified FXII or whole blood, and the activation and regulation of FXII were studied. Plasma from SLE patients with (n = 31) or without (n = 38) previous VD and from matched healthy controls (n = 68) were analyzed for the presence of complexes formed between contact system enzymes and antithrombin (AT) or C1 inhibitor (C1INH) and evaluated with regard to clinical data and laboratory parameters. Fibrin clots elicited FXII activation and acted as co-factors for AT. In clotting plasma, the levels of FXIIa-AT increased, and FXIIa-C1INH decreased. A similar reciprocal relationship existed in SLE patients. FXIIa-AT was elevated in the SLE patients with a history of VD, while the corresponding levels of factor FXIIa-C1INH were significantly decreased. FXIIa-AT correlated strongly with platelet parameters. The odds ratio for VD among the SLE patients was 8.9 if they had low levels of FXIIa-C1INH, 6.1 for those with high levels of FXIIa-AT, and increased to 23.4 for those with both decreased levels of FXIIa-C1INH and increased levels of FXIIa-AT. Activation of FXII is elicited by fibrin during thrombotic reactions in vitro and in vivo, and fibrin acts as a heparin-like co-factor and regulates AT. Patients with SLE had altered levels of FXIIa-serpin complexes, supporting that the contact system is involved in this disease. FXIIa-serpin complexes are strongly associated with previous VD in SLE patients, suggesting that these complexes are potential biomarkers for monitoring and assessing the risk of thrombotic events in SLE.


Analysis of lawsuits filed against emergency physicians for point-of-care emergency ultrasound examination performance and interpretation over a 20-year period.
The study aims to define extent of lawsuits filed against emergency physicians (EPs) over point-of-care emergency ultrasound (US) during the last 20 years. We performed a nationwide search of the WESTLAW legal database for filed lawsuits involving EPs and US. WESTLAW covers all state and federal lawsuits dating back to 1939. Using an electronic search feature, all states were searched using emergency and US as key words. The database automatically accounts for different variants on US such as sonography. An attorney who is also boarded in and practices emergency medicine, as well as an emergency US expert, reviewed returned cases. Descriptive statistics were used to evaluate the data. Using the search criteria and excluding obvious radiology suits, 659 cases were returned and reviewed. There were no cases of EPs being sued for performance or interpretation of point-of-care US. There was one case alleging EP failure to perform point-of-care US and diagnose an ectopic before it ruptured. This case was won by the defense. There were no cases against EPs for common causes of radiology and obstetric litigation including sexual assault during endovaginal US. Cases of missed testicular torsion on US were frequent in the emergency setting but none linked EP US. Only one case filed against EPs over the last 2 decades was identified, it was over failure to perform US. Most frequent litigations against radiologists and obstetricians are unlikely to be duplicated in the emergency department, and future litigations may also come from EP failure to perform point-of-care US.


Auditory event-related potentials in children with attention deficit hyperactivity disorder.
Recording of event-related potentials (ERPs) from the scalp is a noninvasive technique reflecting the sensory and cognitive processes associated with attention tasks. Attention deficit hyperactivity disorder (ADHD) is a disorder involving deficits in attention and behavioral control. The aim of this study was to investigate the difference in ERPs between normal children and those with ADHD. We examined 50 children with ADHD and 51 age-matched controls. All children with ADHD met the full criteria for ADHD according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). The auditory oddball paradigm was applied, and event-related long-latency components (N1, P2, N2 and P3) from Fz, Cz and Pz were measured in each test subject. Children with ADHD showed a significantly longer latency and a lower amplitude of P3 compared to normal control children (p < 0.01). Delayed N2 latency at the Pz electrode was shown in children with ADHD compared to normal controls (p < 0.01). No differences in other ERP indices were found between children with ADHD and controls. When divided into four age groups, the latency of P3 was significantly increased in all age groups and a significantly smaller amplitude in P3 over the central region was found in children with ADHD > 10 years of age (p < 0.05). We found that the endogenous ERPs (P3 and N2) were significantly affected in children with ADHD, compared to exogenous ERPs (N1 and P2). Increased latency of P3 suggests a slower processing speed, and decreased P3 amplitude is interpreted as disruption of inhibitory control in children with ADHD. These results indicate a neurocognitive abnormality in ADHD, as presented by a reduction in ERP response.


Pathogenesis of hepatitis C during pregnancy and childhood.
The worldwide prevalence of HCV infection is between 1% and 8% in pregnant women and between 0.05% and 5% in children. Yet the pathogenesis of hepatitis C during pregnancy and in the neonatal period remains poorly understood. Mother-to-child transmission (MTCT), a leading cause of pediatric HCV infection, takes place at a rate of <10%. Factors that increase the risk of MTCT include high maternal HCV viral load and coinfection with HIV-1 but, intriguingly, not breastfeeding and mode of delivery. Pharmacological prevention of MTCT is not possible at the present time because both pegylated interferon alfa and ribavirin are contraindicated for use in pregnancy and during the neonatal period. However, this may change with the recent introduction of direct acting antiviral agents. This review summarizes what is currently known about HCV infection during pregnancy and childhood. Particular emphasis is placed on how pregnancy-associated immune modulation may influence the progression of HCV disease and impact MTCT, and on the differential evolution of perinatally acquired HCV infection in children. Taken together, these developments provide insights into the pathogenesis of hepatitis C and may inform strategies to prevent the transmission of HCV from mother to child.


Combined Parthenolide and Balsalazide Have Enhanced Antitumor Efficacy Through Blockade of NF-κB Activation.
Balsalazide is a colon-specific prodrug of 5-aminosalicylate that is associated with a reduced risk of colon cancer in patients with ulcerative colitis. Parthenolide, a strong NF-κB inhibitor, has recently been demonstrated to be a promising therapeutic agent, promoting apoptosis of cancer cells. In the current study, the antitumor effect of balsalazide combined with parthenolide in human colorectal cancer cells and colitis-associated colon cancers (CAC) was investigated. The results demonstrate that the combination of balsalazide and parthenolide markedly suppress proliferation, nuclear translocation of NF-κB, IκB-α phosphorylation, NF-κB DNA binding, and expression of NF-κB targets. Apoptosis via NF-κB signaling was confirmed by detecting expression of caspases, p53 and PARP. Moreover, treatment of a CAC murine model with parthenolide and balsalazide together resulted in significant recovery of body weight and improvement in histologic severity. Administration of parthenolide and balsalazide to CAC mice also suppressed carcinogenesis as demonstrated by uptake of 18F-fluoro-2-deoxy-D-glucose (FDG) using micro-PET/CT scans. These results demonstrate that parthenolide potentiates the efficacy of balsalazide through synergistic inhibition of NF-κB activation and the combination of dual agents prevents colon carcinogenesis from chronic inflammation. This study represents the first evidence that combination therapy with balsalazide and parthenolide could be a new regimen for colorectal cancer treatment. Mol Cancer Res; 15(2); 141-51. ©2016 AACR.


Physical activity, depressed mood and pregnancy worries in European obese pregnant women: results from the DALI study.
The purpose of this study was to examine the association between mental health status (i.e. depressed mood and pregnancy-related worries) and objectively measured physical activity levels in obese pregnant women from seven European countries. Baseline data from the vitamin D and lifestyle intervention for the prevention of gestational diabetes mellitus (DALI) study were used. Time spent in moderate-to-vigorous physical activity (MVPA) and sedentary behaviour was measured with accelerometers. Depressed mood was measured with the WHO well-being index (WHO-5) and pregnancy-related worries with the Cambridge Worry Scale (CWS). In addition, socio-demographic characteristics, lifestyle factors, and perceptions and attitude regarding weight management and physical activity were measured. Linear regression analyses were performed to assess the association of mental health status with MVPA and sedentary behaviour. A total of 98 obese pregnant women from Austria, Belgium, Ireland, Italy, Poland, Spain and the Netherlands were included. Women had a mean age of 31.6 ± 5.8 years, a pre-pregnancy BMI of 34.1 ± 4.3 kg/m(2), and were on average 15.4 ± 2.8 weeks pregnant. WHO-5 scores indicative of depressed mood (<50) were reported by 27.1 % of the women and most frequently endorsed pregnancy-related worries pertained to own and the baby's health. Women with good well-being spent 85% more time in MVPA compared to women with a depressed mood (P = 0.03). No differences in MVPA levels were found for women with no, some, or many pregnancy worries. Depressed mood and pregnancy-related worries were not associated with sedentary behaviour. These findings suggest that in pregnant women who are obese, a depressed mood, but not pregnancy-related worries, may be associated with less physical activity. The combined risk of poor mental health and low physical activity levels makes women vulnerable for pregnancy complications. Whether a depressed mood may be a barrier for improving physical activity warrants further study.


The analysis of all-optical logic gates based with tunable femtosecond soliton self-frequency shift.
A type of tunable femtosecond soliton logic gate based on fiber Raman Self-Frequency Shift (SFS) is studied in this paper. The Raman SFSs of femtosecond solitons governed by the Newton's cradle mechanism in logic gate are analyzed with an Improved Split-Step Fast Fourier Transform (ISSFFT) algorithm. The impact factors of the solitonic pulse frequency shift and temporal time shift, which are included the Third-Order Dispersion (TOD) effect, are investigated. The existing theoretical equation of SFS is modified into a new expression for this type of soliton logic gate. A lower switching power and the small size of the soliton logic gate device is designed to realize the logic functions of AND, NOT, and XOR. The results demonstrate that the logic gate based on SFS is belonged to the asynchronous system and can be achieved with Milli-Watt switching power and good extinction ratio. ISSFFT is effective and accurately to analyze higher-order dispersive and nonlinear effects in the logic gates.


Assembly of forest communities across East Asia--insights from phylogenetic community structure and species pool scaling.
Local communities are assembled from larger-scale species pools via dispersal, environmental filtering, biotic interactions, and local stochastic demographic processes. The relative importance, scaling and interplay of these assembly processes can be elucidated by comparing local communities to variously circumscribed species pools. Here we present the first study applying this approach to forest tree communities across East Asia, focusing on community phylogenetic structure and using data from a global network of tropical, subtropical and temperate forest plots. We found that Net Relatedness Index (NRI) and Nearest Taxon Index (NTI) values were generally lower with geographically broad species pools (global and Asian species pools) than with an East Asian species pool, except that global species pool produced higher NTI than the East Asian species pool. The lower NRI for the global relative to the East Asian species pool may indicate an important role of intercontinental migration during the Neogene and Quaternary and climatic conservatism in shaping the deeper phylogenetic structure of tree communities in East Asia. In contrast, higher NTI for the global relative to the East Asian species pool is consistent with recent localized diversification determining the shallow phylogenetic structure.


Genomic, transcriptomic and physiological analyses of silver-resistant Saccharomyces cerevisiae obtained by evolutionary engineering.
Silver is a non-essential metal used in medical applications as an antimicrobial agent, but it is also toxic for biological systems. To investigate the molecular basis of silver resistance in yeast, we employed evolutionary engineering using successive batch cultures at gradually increased silver stress levels up to 0.25-mM AgNO3 in 29 populations and obtained highly silver-resistant and genetically stable Saccharomyces cerevisiae strains. Cross-resistance analysis results indicated that the silver-resistant mutants also gained resistance against copper and oxidative stress. Growth physiological analysis results revealed that the highly silver-resistant evolved strain 2E was not significantly inhibited by silver stress, unlike the reference strain. Genomic and transcriptomic analysis results revealed that there were mutations and/or significant changes in the expression levels of the genes involved in cell wall integrity, cellular respiration, oxidative metabolism, copper homeostasis, endocytosis and vesicular transport activities. Particularly the missense mutation in the RLM1 gene encoding a transcription factor involved in the maintenance of cell wall integrity and with 707 potential gene targets might have a key role in the high silver resistance of 2E, along with its improved cell wall integrity, as confirmed by the lyticase sensitivity assay results. In conclusion, the comparative physiological, transcriptomic and genomic analysis results of the silver-resistant S. cerevisiae strain revealed potential key factors that will help understand the complex molecular mechanisms of silver resistance in yeast.


Large-scale automated synthesis of human functional neuroimaging data.
The rapid growth of the literature on neuroimaging in humans has led to major advances in our understanding of human brain function but has also made it increasingly difficult to aggregate and synthesize neuroimaging findings. Here we describe and validate an automated brain-mapping framework that uses text-mining, meta-analysis and machine-learning techniques to generate a large database of mappings between neural and cognitive states. We show that our approach can be used to automatically conduct large-scale, high-quality neuroimaging meta-analyses, address long-standing inferential problems in the neuroimaging literature and support accurate 'decoding' of broad cognitive states from brain activity in both entire studies and individual human subjects. Collectively, our results have validated a powerful and generative framework for synthesizing human neuroimaging data on an unprecedented scale.


Psychological and immunological reactions of family members to patients undergoing bone marrow transplantation.
The authors' goal was to evaluate the impacts of patients' bone marrow transplant (BMT) on their spouse/partner's (subjects) psychological and immunological status at four key points in the course of their transplant. Subjects' (N = 24) psychological and immunological status was prospectively evaluated at four key points in the patient's BMT which included: at patients' admission to hospital and 0-, 20-, and 34-day intervals after BMT infusion. Psychological variables examined included: a) general psychological distress and negative affect; b) tendency to respond in a socially desirable manner; c) state negative affect; and d) coping style, specifically if escape-avoidance coping was used. Immune variables examined included: percentages of total T cells and of CD4+, CD8+ cells, B cells, and natural killer (NK) cells, and NK cytotoxicity. Greatest abnormality in immune variables was detected before the initiation of BMT (i.e., between admission and day 0) with normalization between days 21 and 34 thereafter. During the waiting period before BMT, the subjects had the highest scores on negative affects, escape-avoidance coping, and psychological symptoms. These progressively declined after the BMT procedure. Significant correlations were found among trait anxiety, escape-avoidance coping, and total percentage of T cells and of CD4+ cells. Escape-avoidance coping was reliably correlated with percentage of B cells. The greatest psychological and immunological impacts on spouse/partners of BMT patients were found in the period directly after hospital admission and before BMT infusion. Alterations in immune values occurred in anticipation of BMT in the spouse/partners. Psychological symptoms followed this same pattern, being most elevated before BMT and decreasing in the successive evaluations post-BMT for the spouse/partners. The most significant and consistent psychological variable in predicting immune changes was escape-avoidance coping, with less escape-avoidance coping predicting better immune functioning.


Uncovering hidden variance: pair-wise SNP analysis accounts for additional variance in nicotine dependence.
Results from genome-wide association studies of complex traits account for only a modest proportion of the trait variance predicted to be due to genetics. We hypothesize that joint analysis of polymorphisms may account for more variance. We evaluated this hypothesis on a case-control smoking phenotype by examining pairs of nicotinic receptor single-nucleotide polymorphisms (SNPs) using the Restricted Partition Method (RPM) on data from the Collaborative Genetic Study of Nicotine Dependence (COGEND). We found evidence of joint effects that increase explained variance. Four signals identified in COGEND were testable in independent American Cancer Society (ACS) data, and three of the four signals replicated. Our results highlight two important lessons: joint effects that increase the explained variance are not limited to loci displaying substantial main effects, and joint effects need not display a significant interaction term in a logistic regression model. These results suggest that the joint analyses of variants may indeed account for part of the genetic variance left unexplained by single SNP analyses. Methodologies that limit analyses of joint effects to variants that demonstrate association in single SNP analyses, or require a significant interaction term, will likely miss important joint effects.


Sensitivity and test-retest reliability of the international shopping list test in assessing verbal learning and memory in mild Alzheimer's disease.
The International Shopping List Test (ISLT) was developed specifically to assess verbal list learning and memory in people from different language and cultural backgrounds. In this paper, we describe three studies that examined the sensitivity and reliability of the ISLT in assessing verbal list learning and memory impairment in English-speaking people with mild Alzheimer's disease (AD) and evaluated whether measures of retention-weighted recall (RWR) provided greater sensitivity and/or reliability relative to conventional list learning performance measures (e.g., free recall). In Study 1, we compared ISLT performance between patients with AD and matched controls and found that AD patients showed a large magnitude impairment on all ISLT performance measures (Cohen's d values >2). The RWR measure was more sensitive to detecting AD-related impairment than the free recall measure for Trial 1, although the most sensitive measures of the ISLT were free recall from Trial 3 and delayed recall. In Study 2, we compared RWR and free recall measures between 10- and 12-word versions of the ISLT, but found no difference between performance measures for the different list lengths. In Study 3, we evaluated test-retest reliabilities of the different outcome measures derived from the ISLT and found that measures of free recall had higher reliabilities than the RWR measures. Taken together, results of these studies suggest that measures of total free recall during learning trials and delayed recall from the 12-word version of the ISLT provide the greatest sensitivity to detecting verbal list learning and memory impairment in AD and that this task shows good test-retest reliability.


Meta-analysis in human neuroimaging: computational modeling of large-scale databases.
Spatial normalization--applying standardized coordinates as anatomical addresses within a reference space--was introduced to human neuroimaging research nearly 30 years ago. Over these three decades, an impressive series of methodological advances have adopted, extended, and popularized this standard. Collectively, this work has generated a methodologically coherent literature of unprecedented rigor, size, and scope. Large-scale online databases have compiled these observations and their associated meta-data, stimulating the development of meta-analytic methods to exploit this expanding corpus. Coordinate-based meta-analytic methods have emerged and evolved in rigor and utility. Early methods computed cross-study consensus, in a manner roughly comparable to traditional (nonimaging) meta-analysis. Recent advances now compute coactivation-based connectivity, connectivity-based functional parcellation, and complex network models powered from data sets representing tens of thousands of subjects. Meta-analyses of human neuroimaging data in large-scale databases now stand at the forefront of computational neurobiology.


Is HIV screening being requested appropriately? The experience of a Victorian public health laboratory.
From the start of clinical testing for human immunodeficiency virus (HIV) antibody in 1985 until the end of June 1994, the Microbiological Diagnostic Unit tested 134 346 serum samples from 109 391 individuals, identifying 672 as infected. A suitable database, using coded identities, was established from the beginning. Because the sera came from a variety of clinical settings, it was possible to extract information about patterns of requests for tests and about the yield of seropositive cases. The data were able to highlight factors associated with high rates of positive tests that can be lost in amalgamated statewide data. The discovery of HIV-positive females was sporadic and there was a much lower detection rate than from testing males. While males were most commonly diagnosed through specialist venereology services, 61 per cent of diagnoses in females were through nonspecialised practices, often those without previous experience in diagnosis and management of HIV infection. Despite some individual exceptions, the requesting of HIV tests appears generally to have been justifiable (particularly in view of the direction of official preventive campaigns) and not profligate. Overall, where practice was unsatisfactory, this lay less in thoughtless ordering of tests than in failing to include with the specimen the elementary, but vital, epidemiological information requested.


Sodium excretion in man, and adaptation to a low-sodium diet: effect of intravenous sodium chloride.
1. The aim of this study was to test whether a postulated gastrointestinal or portal monitor of sodium intake plays any part in adjusting renal sodium excretion when dietary sodium is reduced. 2. Normal male subjects were given 50 mmol of sodium chloride intravenously three times daily for 3 days to replace or to supplement a constant oral intake of sodium chloride. 3. When oral sodium chloride was replaced with intravenous sodium chloride, renal sodium excretion remained constant. 4. When oral sodium chloride was kept constant, sodium administered as intravenous sodium chloride was promptly excreted in three out of four subjects. There was a delay in the increase in sodium excretion in the fourth subject. 5. Infusions containing 50 mmol of sodium chloride in 50 ml given intravenously over 22 min produced a rise in plasma sodium concentration and a fall in concentration of total plasma solids. 6. These results provide no evidence for a gastrointestinal or portal monitor of sodium intake, but do not disprove the existence of such a monitor.


Mutations in the Spliceosomal Machinery Genes SRSF2, U2AF1, and ZRSR2 and Response to Decitabine in Myelodysplastic Syndrome.
Hypomethylating agents, such as azacitidine and decitabine, now constitute one of the mainstays of myelodysplastic syndrome (MDS) treatment. In recent years, novel recurrent mutations in multiple genes encoding RNA spliceosomal machinery (SRSF2, U2AF1, ZRSR2, SF3B1) were revealed. However, the clinical impact of these mutations on the outcomes of treatment of MDS patients with hypomethylating agents has not been described. A total of 58 de novo MDS patients were included in the study who had received first-line decitabine treatment. Polymerase chain reaction (PCR) followed by direct sequencing analyses was performed for the spliceosomal machinery genes including SRSF2, U2AF1 and ZRSR2. In the present analysis of 58 Korean MDS patients, mutations in the splicing machinery genes SRSF2, U2AF1 and ZRSR2 were detected in 5 (8.6%), 10 (17.2%) and 6 (10.3%) patients, respectively, and the incidence of SRSF2 mutation was lower than those of previous series. The overall response rates (ORRs) including complete remission (CR), partial response (PR), and marrow CR (mCR) were 42.9% in the spliceosome wild-type (WT) group and 46.7% in the spliceosome-mutated group (p>0.999). The median OS was 22.0 months in the spliceosome-WT group and 15.9 months in the spliceosome-mutated group (p=0.267) CONCLUSION: This study firstly reports the impact of mutations of the spliceosomal machinery genes on the outcomes of decitabine treatment in MDS. The mutational status of the SRSF2, U2AF1 and ZRSR2 did not affect the response rate or survival in MDS patients who had received first-line decitabine treatment. Further studies are needed to confirm the prognostic relevance of spliceosome mutations to the clinical outcomes of treatment with hypomethylating agents.


Increased Weight Gain During the Long Interdialytic Period Is Associated with Minor Effects on Blood Pressure Control in Clinically Stable In-Centre Haemodialysis Patients.
Three-day-a-week chronic haemodialysis (cHD) involves 1 long (72 h) and 2 short (48 h) inter-dialytic periods (IDPs). We aimed to determine whether BP control following the long IDP is inferior to the short IDPs. All pre- and post-dialysis BP and weight measurements over a 4-week period were retrospectively analyzed among 135 clinically stable cHD patients at 2 academic centres with comparisons between measurements recorded following short and long IDPs. Subsequently, 23 clinically stable cHD patients underwent 24-h ambulatory blood pressure monitoring (ABPM) during the final day/night cycle of the long IDP and 1 short IDP within the same week. In combined and separate analyses of the 2 retrospective cohorts, pre-dialysis BP parameters were not different following long and short IDPs despite greater inter-dialytic weight gain (IDWG) during the long IDP. Subgroup analyses of the total cohort showed no evidence for inferior BP control during the long IDP among those with high %IDWG. In the ABPM study, nocturnal hypertension and loss of nocturnal dipping were frequent. Furthermore, daytime systolic blood pressure (SBP) and pulse pressure were modestly higher during the last day/night cycle of the long compared with short IDP. In stable cHD patients, the greater IDWG that occurred during the long IDP was not associated with overtly inferior BP control as reflected in pre-dialysis BP measurements. However, modestly higher daytime SBP was evident towards the end of the long IDP by 24 h ABPM. Thus, while fluid gain has well-documented associations with hypertension and adverse cardiovascular outcomes, the excess IDWG that occurs during the long IDP exerts relatively minor effects on BP control in patients on well-established dialysis regimens that are better identified by ambulatory monitoring.


Mechanism of stretch-induced activation of the mechanotransducer zyxin in vascular cells.
Vascular cells respond to supraphysiological amounts of stretch with a characteristic phenotypic change that results in dysfunctional remodeling of the affected arteries. Although the pathophysiological consequences of stretch-induced signaling are well characterized, the mechanism of mechanotransduction is unclear. We focused on the mechanotransducer zyxin, which translocates to the nucleus to drive gene expression in response to stretch. In cultured human endothelial cells and perfused femoral arteries isolated from wild-type and several knockout mouse strains, we characterized a multistep signaling pathway whereby stretch led to a transient receptor potential channel 3-mediated release of the endothelial vasoconstrictor peptide endothelin-1 (ET-1). ET-1, through autocrine activation of its B-type receptor, elicited the release of pro-atrial natriuretic peptide (ANP), which caused the autocrine activation of the ANP receptor guanylyl cyclase A (GC-A). Activation of GC-A, in turn, led to protein kinase G-mediated phosphorylation of zyxin at serine 142, thereby triggering the translocation of zyxin to the nucleus, where it was required for stretch-induced gene expression. Thus, we have identified a stretch-induced signaling pathway in vascular cells that leads to the activation of zyxin, a cytoskeletal protein specifically involved in transducing mechanical stimuli.


Pointing the way to the products? Comparison of the stress tensor and the second-derivative tensor of the electron density.
The eigenvectors of the electronic stress tensor can be used to identify where new bond paths form in a chemical reaction. In cases where the eigenvectors of the stress tensor are not available, the gradient-expansion-approximation suggests using the eigenvalues of the second derivative tensor of the electron density instead; this approximation can be made quantitatively accurate by scaling and shifting the second-derivative tensor, but it has a weaker physical basis and less predictive power for chemical reactivity than the stress tensor. These tools provide an extension of the quantum theory of atoms and molecules from the characterization of molecular electronic structure to the prediction of chemical reactivity.


Molecular recognition of canonical and deaminated bases by P. abyssi family B DNA polymerase.
Euryarchaeal polymerase B can recognize deaminated bases on the template strand, effectively stalling the replication fork 4nt downstream the modified base. Using Pyrococcus abyssi DNA B family polymerase (PabPolB), we investigated the discrimination between deaminated and natural nucleotide(s) by primer extension assays, electrophoretic mobility shift assays, and X-ray crystallography. Structures of complexes between the protein and DNA duplexes with either a dU or a dH in position +4 were solved at 2.3Å and 2.9Å resolution, respectively. The PabPolB is found in the editing mode. A new metal binding site has been uncovered below the base-checking cavity where the +4 base is flipped out; it is fully hydrated in an octahedral fashion and helps guide the strongly kinked template strand. Four other crystal structures with each of the canonical bases were also solved in the editing mode, and the presence of three nucleotides in the exonuclease site caused a shift in the coordination state of its metal A from octahedral to tetrahedral. Surprisingly, we find that all canonical bases also enter the base-checking pocket with very small differences in the binding geometry and in the calculated binding free energy compared to deaminated ones. To explain how this can lead to stalling of the replication fork, the full catalytic pathway and its branches must be taken into account, during which the base is checked several times. Our results strongly suggest a switch from elongation to editing modes right after nucleotide insertion when the modified base is at position +5.


Melatonin and associated signaling pathways that control normal breast epithelium and breast cancer.
This review article discusses recent work on the melatonin-mediated circadian regulation and integration of molecular and metabolic signaling mechanisms involved in human breast cancer growth and the associated consequences of circadian disruption by exposure to light-at-night (LAN). The anti-proliferative effects of the circadian melatonin signal are, in general, mediated through mechanisms involving the activation of MT(1) melatonin receptors expressed in human breast cancer cell lines and xenografts. In estrogen receptor-positive (ERα+) human breast cancer cells, melatonin suppresses both ERα mRNA expression and estrogen-induced transcriptional activity of the ERα via MT(1)-induced activation of G(αi2) signaling and reduction of cAMP levels. Melatonin also regulates the transcriptional activity of additional members of the nuclear receptor super-family, enzymes involved in estrogen metabolism, and the expression of core clock and clock-related genes. The anti-invasive/anti-metastatic actions of melatonin involve the blockade of p38 phosphorylation and matrix metalloproteinase expression. Melatonin also inhibits the growth of human breast cancer xenografts via MT(1)-mediated suppression of cAMP leading to a blockade of linoleic acid (LA) uptake and its metabolism to the mitogenic signaling molecule 13-hydroxyoctadecadienoic acid (13-HODE). Down-regulation of 13-HODE reduces the activation of growth factor pathways supporting cell proliferation and survival. Finally, studies in both rats and humans indicate that light-at-night (LAN) induced circadian disruption of the nocturnal melatonin signal activates human breast cancer growth, metabolism, and signaling, providing the strongest mechanistic support, thus far, for epidemiological studies demonstrating the elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LAN.


Shared Decision Making for Antidepressants in Primary Care: A Cluster Randomized Trial.
For antidepressants, the translation of evidence of comparative effectiveness into practice is suboptimal. This deficit directly affects outcomes and quality of care for patients with depression. To overcome this problem, we developed the Depression Medication Choice (DMC) encounter decision aid, designed to help patients and clinicians consider the available antidepressants and the extent to which they improved depression and other issues important to patients. Estimate the effect of DMC on quality of the decision-making process and depression outcomes. We conducted a cluster randomized trial of adults with moderate to severe depression considering treatment with an antidepressant. Primary care practices in 10 rural, suburban, and urban primary care practices across Minnesota and Wisconsin were randomly allocated to treatment of depression with or without use of the DMC decision aid. Depression Medication Choice, a series of cards, each highlighting the effect of the available options on an issue of importance to patients for use during face-to-face consultations. Decision-making quality as judged by patient knowledge and involvement in decision making, patient and clinician decisional comfort (Decisional Conflict Scale) and satisfaction, encounter duration, medication adherence, depression symptoms, and the Patient Health Questionnaire for depression (PHQ-9). We enrolled 117 clinicians and 301 patients (67% women; mean [SD] age, 44 [15] years; mean [SD] PHQ-9 score, 15 [4]) into the trial. Compared with usual care (UC), use of DMC significantly improved patients' decisional comfort (DMC, 80% vs UC, 75%; P = .02), knowledge (DMC, 65% vs UC, 56%; P = .03), satisfaction (risk ratio [RR], from 1.25 [P = .81] to RR, 2.4 [P = .002] depending on satisfaction domain), and involvement (DMC, 47% vs UC, 33%; P<.001). It also improved clinicians' decisional comfort (DMC, 80% vs UC, 68%; P < .001) and satisfaction (RR, 1.64; P = .02). There were no differences in encounter duration, medication adherence, or improvement of depression control between arms. The DMC decision aid helped primary care clinicians and patients with moderate to severe depression select antidepressants together, improving the decision-making process without extending the visit. On the other hand, DMC had no discernible effect on medication adherence or depression outcomes. By translating comparative effectiveness into patient-centered care, use of DMC improved the quality of primary care for patients with depression. clinicaltrials.gov Identifier: NCT01502891.


Perceived medication adherence barriers mediating effects between gastrointestinal symptoms and health-related quality of life in pediatric inflammatory bowel disease.
The primary objective was to investigate the mediating effects of patient-perceived medication adherence barriers in the relationship between gastrointestinal symptoms and generic health-related quality of life (HRQOL) in adolescents with inflammatory bowel disease (IBD). The secondary objective explored patient health communication and gastrointestinal worry as additional mediators with medication adherence barriers in a serial multiple mediator model. The Pediatric Quality of Life Inventory™ Gastrointestinal Symptoms, Medicines, Communication, Gastrointestinal Worry, and Generic Core Scales were completed in a 9-site study by 172 adolescents with IBD. Gastrointestinal Symptoms Scales measuring stomach pain, constipation, or diarrhea and perceived medication adherence barriers were tested for bivariate and multivariate linear associations with HRQOL. Mediational analyses were conducted to test the hypothesized mediating effects of perceived medication adherence barriers as an intervening variable between gastrointestinal symptoms and HRQOL. The predictive effects of gastrointestinal symptoms on HRQOL were mediated in part by perceived medication adherence barriers. Patient health communication was a significant additional mediator. In predictive analytics models utilizing multiple regression analyses, demographic variables, gastrointestinal symptoms (stomach pain, constipation, or diarrhea), and perceived medication adherence barriers significantly accounted for 45, 38, and 29 percent of the variance in HRQOL (all Ps < 0.001), respectively, demonstrating large effect sizes. Perceived medication adherence barriers explain in part the effects of gastrointestinal symptoms on HRQOL in adolescents with IBD. Patient health communication to healthcare providers and significant others further explain the mechanism in the relationship between gastrointestinal symptoms, perceived medication adherence barriers, and HRQOL.


Loss of polymeric immunoglobulin receptor expression is associated with lung tumourigenesis.
Polymeric immunoglobulin receptor (pIgR) expression is downregulated in lung cancer, but its implications in lung tumourigenesis remain unknown. We hypothesised that loss of pIgR expression occurs early, and is associated with cell proliferation and poor prognosis. pIgR expression was evaluated by immunohistochemistry in airways of patients with normal mucosa, pre-invasive lesions and invasive lesions, and correlated with clinical outcomes. 16-HBE and A549 cells stably transfected with pIgR were tested for proliferation, apoptosis and cell cycle progression. Immunostaining was strong in normal epithelium, but severely reduced in pre-invasive lesions and most lung cancers. Persistent expression was associated with younger age and adenocarcinoma subtype but not survival. pIgR overexpression significantly reduced A549 and 16-HBE proliferation. Growth inhibition was not due to cell cycle arrest, increased apoptosis or endoplasmic reticulum stress, but we observed altered expression of genes encoding for membrane proteins, including NOTCH3. Interestingly, NOTCH3 expression was inversely correlated with pIgR expression in cell lines and tissues. pIgR expression was lost in most lung cancers and pre-invasive bronchial lesions, suggesting that pIgR downregulation is an early event in lung tumourigenesis. pIgR overexpression in A549 and 16-HBE cells inhibited proliferation. Future investigations are required to determine the mechanisms by which pIgR contributes to cell proliferation.


Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: A Mendelian randomisation study.
Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis. We performed a Mendelian randomisation (MR) analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis (primary outcome), sepsis severity, other infections, and COVID-19 (secondary outcomes). We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP and gp130 in a similar analysis. In the UK Biobank cohort (N = 486,484, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of our primary outcome, sepsis (odds ratio (OR) = 0.80; 95% confidence interval (CI) 0.66 to 0.96, per unit of natural log-transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR = 0.74; 95% CI 0.47 to 1.15); critical care admission with sepsis (OR = 0.48, 95% CI 0.30 to 0.78) and critical care death with sepsis (OR = 0.37, 95% CI 0.14 to 0.98). Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 to 0.97) and for sepsis survival in critical care (OR = 0.22; 95% CI 0.04 to 1.31) in the GainS and GenOSept consortium, although this result had a large degree of imprecision. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR = 0.69, 95% CI 0.57 to 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. These results are subject to the limitations and assumptions of MR, which in this case reflects interpretation of these SNP effects as causally acting through blockade of IL6R, and reflect lifetime exposure to IL6R blockade, rather than the effect of therapeutic IL6R blockade. IL6R blockade is causally associated with reduced incidence of sepsis. Similar but imprecisely estimated results supported a causal effect also on sepsis related mortality and critical care admission with sepsis. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. These data suggest that a randomised trial of IL-6 receptor antagonists in sepsis should be considered.


Racial/Ethnic Disparities in Influenza Vaccination of Chronically Ill US Adults: The Mediating Role of Perceived Discrimination in Health Care.
Despite well-established programs, influenza vaccination rates in US adults are well below federal benchmarks and exhibit well-documented, persistent racial and ethnic disparities. The causes of these disparities are multifactorial and complex, though perceived racial/ethnic discrimination in health care is 1 hypothesized mechanism. To assess the role of perceived discrimination in health care in mediating influenza vaccination RACIAL/ETHNIC disparities in chronically ill US adults (at high risk for influenza-related complications). We utilized 2011-2012 data from the Aligning Forces for Quality Consumer Survey on health and health care (n=8127), nationally representative of chronically ill US adults. Logistic regression marginal effects examined the relationship between race/ethnicity and influenza vaccination, both unadjusted and in multivariate models adjusted for determinants of health service use. We then used binary mediation analysis to calculate and test the significance of the percentage of this relationship mediated by perceived discrimination in health care. Respondents reporting perceived discrimination in health care had half the uptake as those without discrimination (32% vs. 60%, P=0.009). The change in predicted probability of vaccination given perceived discrimination experiences (vs. none) was large but not significant in the fully adjusted model (-0.185; 95% CI, -0.385, 0.014). Perceived discrimination significantly mediated 16% of the unadjusted association between race/ethnicity and influenza vaccination, though this dropped to 6% and lost statistical significance in multivariate models. The causes of persistent racial/ethnic disparities are complex and a single explanation is unlikely to be sufficient. We suggest reevaluation in a larger cohort as well as potential directions for future research.