The Circular RNA Profiles of Colorectal Tumor Metastatic Cells.
Circular RNAs (circRNAs) have been reported that can be used as biomarkers for colorectal cancers (CRC) and other types of tumors. However, a limited number of studies have been performed investigating the potential role of circRNAs in tumor metastasis. Here, we examined the circRNAs in two CRC cell lines (a primary tumor cell SW480 and its metastasis cell SW620), and found a large set of circRNA (2,919 ncDECs) with significantly differential expression patterns relative to normal cells (NCM460). In addition, we uncovered a set of 623 pmDECs that differ between the primary CRC cells and its metastasis cells. Both differentially expressed circRNA (DEC) sets contain many previously unknown putative CRC-related circRNAs, thereby providing many new circRNAs as candidate biomarkers for CRC development and metastasis. These studies are the first large-scale identification of metastasis-related circRNAs for CRC and provide valuable candidate biomarkers for diagnostic and a starting point for additional investigations of CRC metastasis.


Rehabilitation of Cognitive Dysfunction Following Traumatic Brain Injury.
This article outlines key principles and considerations in the rehabilitation of cognitive challenges following mild, moderate, and severe traumatic brain injuries, with a focus on the needs of the service member and veteran population. The authors highlight specific evidence-based strategies and interventions and provide functional examples to support implementation. By emphasizing the array of tools and resources that have been designed to address cognitive challenges in the service member and veteran population, they focus on optimizing cognition to support successful community reintegration and the resumption of a full and meaningful life.


Sequencing of endocrine therapies in breast cancer--integration of recent data.
A wide range of endocrine therapies has demonstrated activity in the treatment of hormone receptor-positive metastatic breast cancer and sequential tumor responses to sequential hormonal therapies are common. However, the optimal sequence of the hormonal therapies has not yet been determined. The selection of endocrine therapies in women with hormone receptor-positive breast cancer is strongly influenced by the menopausal status of the patient. For premenopausal women, tamoxifen alone or combined with ovarian suppression using a luteinizing hormone-releasing hormone (LHRH) agonist - such as goserelin or leuprolide - is an appropriate first-line hormonal therapy. Ovarian ablation or megestrol acetate is an appropriate second-line hormonal therapy for premenopausal women treated with tamoxifen as first-line therapy, or ovarian ablation plus an aromatase inhibitor (AI) or megestrol acetate for women treated with first-line tamoxifen plus an LHRH agonist. For postmenopausal women, the non-steroidal AIs anastrozole and letrozole now represent the preferred first-line hormonal treatment for metastatic breast cancer, based upon both efficacy and toxicity considerations. For second-line therapy in postmenopausal women, a number of options now exist, including tamoxifen, the steroidal AI exemestane, and the new agent fulvestrant. Fulvestrant, a novel estrogen receptor (ER) antagonist that downregulates the ER and has no known agonist effects, has been demonstrated to be at least as effective as anastrozole in postmenopausal women whose tumors progress on tamoxifen. The establishment of the optimal sequence of the endocrine therapies should offer significant benefits to women with hormone-sensitive metastatic breast cancer.


Estimating the effect of smoking cessation on weight gain: an instrumental variable approach.
To propose and test a method that produces an unbiased estimate of the average effect of smoking cessation on weight gain. Previous estimates may be biased due to unobservable differences in attributes of quitters and continuing smokers. An accurate estimate of weight gain due to cessation is important for policymakers, health managers, clinicians, consumers, and developers of smoking cessation aids. Our analysis consisted of an instrumental variables (IVs) approach in which treatment assignment in randomized smoking cessation trials served as a random source of variation in probability of quitting. We searched the medical literature for previously conducted smoking cessation trials that contained data suitable for our reanalysis. We identified one trial for our reanalysis, the Lung Health Study, a randomized smoking cessation trial with 5,887 smokers aged 35-60 from 1986 to 1994 in several sites across the United States. In our IV reanalysis, we estimated a 9.7 kg weight gain over 5 years due to cessation, as compared with the conventional estimate of 5.3 kg. The true effect of smoking cessation on weight gain may be larger than previously estimated. This result indicates the importance of fully understanding the possible weight effects of cessation and underscores the need to accompany cessation programs with weight management interventions. The result, however, does not overturn the conclusion that the net health benefits of quitting are positive and very large. The application of the IV technique we propose is likely to be useful in a variety of contexts in which one is interested in the effect of one health condition on another.


The coronary circulation in exercise training.
Exercise training (EX) induces increases in coronary transport capacity through adaptations in the coronary microcirculation including increased arteriolar diameters and/or densities and changes in the vasomotor reactivity of coronary resistance arteries. In large animals, EX increases capillary exchange capacity through angiogenesis of new capillaries at a rate matched to EX-induced cardiac hypertrophy so that capillary density remains normal. However, after EX coronary capillary exchange area is greater (i.e., capillary permeability surface area product is greater) at any given blood flow because of altered coronary vascular resistance and matching of exchange surface area and blood flow distribution. The improved coronary capillary blood flow distribution appears to be the result of structural changes in the coronary tree and alterations in vasoreactivity of coronary resistance arteries. EX also alters vasomotor reactivity of conduit coronary arteries in that after EX, α-adrenergic receptor responsiveness is blunted. Of interest, α- and β-adrenergic tone appears to be maintained in the coronary microcirculation in the presence of lower circulating catecholamine levels because of increased receptor responsiveness to adrenergic stimulation. EX also alters other vasomotor control processes of coronary resistance vessels. For example, coronary arterioles exhibit increased myogenic tone after EX, likely because of a calcium-dependent PKC signaling-mediated alteration in voltage-gated calcium channel activity in response to stretch. Conversely, EX augments endothelium-dependent vasodilation throughout the coronary arteriolar network and in the conduit arteries in coronary artery disease (CAD). The enhanced endothelium-dependent dilation appears to result from increased nitric oxide bioavailability because of changes in nitric oxide synthase expression/activity and decreased oxidant stress. EX also decreases extravascular compressive forces in the myocardium at rest and at comparable levels of exercise, mainly because of decreases in heart rate and duration of systole. EX does not stimulate growth of coronary collateral vessels in the normal heart. However, if exercise produces ischemia, which would be absent or minimal under resting conditions, there is evidence that collateral growth can be enhanced. While there is evidence that EX can decrease the progression of atherosclerotic lesions or even induce the regression of atherosclerotic lesions in humans, the evidence of this is not strong due to the fact that most prospective trials conducted to date have included other lifestyle changes and treatment strategies by necessity. The literature from large animal models of CAD also presents a cloudy picture concerning whether EX can induce the regression of or slow the progression of atherosclerotic lesions. Thus, while evidence from research using humans with CAD and animal models of CAD indicates that EX increases endothelium-dependent dilation throughout the coronary vascular tree, evidence that EX reverses or slows the progression of lesion development in CAD is not conclusive at this time. This suggests that the beneficial effects of EX in CAD may not be the result of direct effects on the coronary artery wall. If this suggestion is true, it is important to determine the mechanisms involved in these beneficial effects.


A Systematic Evaluation of State Laws Governing Optometric Glaucoma Management in the United States Upto 2015.
To describe state laws that govern the optometric practice of glaucoma management in the United States and to correlate those laws with state demographics upto 2015. We performed a cross-sectional ecological study of the 50 United States and the District of Columbia. Regulations governing optometric scope of practice as written by each state Board of Optometry were reviewed. Specific optometric privileges assessed included: ability to manage glaucoma independently, use of diagnostic pharmaceutical agents, use of therapeutic pharmaceutical agents (including topical and oral steroids and other oral pharmaceutical agents), IV injections, intraocular injections, therapeutic lasers, presence of defined referral, and comanagement guidelines, and hours of yearly continuing education needed for glaucoma management. Optometric privilege was compared with demographic and employment information for each state. Optometrists in all states, except for Massachusetts, and the District of Columbia are allowed to manage glaucoma; 16 states have defined comanagement guidelines. Therapeutic lasers are allowed in 3 states: Kentucky, Louisiana, and Oklahoma. States with defined comanagement guidelines had a mean of 6.9±1.9 ophthalmologists per 100,000 people, significantly more than the 5.3±1.1 in states without defined comanagement of glaucoma (P<0.01). Binary logistic regression showed that, accounting for population and area, the higher the number of optometrists in a state, the less likely there is to be defined comanagement [β (SE)=-0.008 (0.003), P=0.02] and the greater the number of ophthalmologists in a given state, the more likely a state has defined comanagement [β (SE)=-0.13 (0.006)]. There is a diversity of regulations that govern optometric management of glaucoma in each of the 50 states and the District of Columbia. The number of optometrists and ophthalmologists in a state may influence state regulations governing optometric practice and referral guidelines.


The association between the phenotype of excessive daytime sleepiness and blood pressure in patients with obstructive sleep apnea-hypopnea syndrome.
Investigate the clinical features and the blood pressure (BP) pattern of the phenotype of excessive daytime sleepiness (EDS) in OSAHS. A total of 508 Chinese adults with suspected OSAHS were referred to our sleep laboratory from October 2009 to May 2012. On the same night of polysomnography (PSG), the levels of blood pressure were measured before sleeping (bedtime BP) and immediately after waking up in the next morning (morning BP). EDS was recognized as Epworth Sleepiness Scale (ESS)≥9. Subjects were classified into four groups based on the apnea-hypopnea index (AHI) from PSG as follows: control (simple snoring) group (control, n=104) with AHI<5; mild group (mild, n=89) with AHI≥5 and <15; moderate group (moderate, n=70) with AHI≥15 and<30; and severe group (severe, n=245) with AHI ≥30. The differences and correlations between BP and PSG parameters in EDS and non-EDS group of OSAHS patients were analyzed. In all subjects, ESS was positively correlated with morning diastolic blood pressure (DBP), Mean arterial pressure (MAP) and bedtime DBP (r=0.144, 0.102 and 0.114, respectively, each P value<0.05). In OSAHS patients, ESS was only positively correlated with morning DBP (r=0.137, P<0.05). OSAHS patients with EDS phenotype were younger and were more likely to have the symptom of waking up feeling tired (36.1% vs. 23.2%, p=0.023), who had lower MSaO2, longer SIT90 (the ratio of time of SpO2 below 90% in total sleep time) and higher DBP (bedtime as well as morning). In patients with AHI≥15, ESS was correlated positively with both bedtime and morning DBP after controlling the confounding effects of age, sex, BMI, AHI and nadir nocturnal oxygen saturation( r=0.126,0.143, respectively, both P values<0.05). And in OSAHS patients of EDS phenotype, the bedtime DBP, bedtime MAP, morning DBP, and morning MAP were 3~5 mm Hg higher than that in patients of non-EDS phenotype(P<0.05). In the moderate and severe OSAHS group, patients with EDS phenotype were younger and had a lower mean blood oxygen saturation (MSaO2), longer time of SpO2 below 90% and higher SIT90 than patients with non-EDS phenotype (P<0.05). In hypertensive OSAHS patients, patients with EDS were also younger and had higher micro-arousal index (MiI), as well as higher morning DBP, morning MAP and bedtime DBP than that in non-EDS group (P<0.05). EDS in OSAHS patients is a special phenotype, which was characterized by younger age, higher DBP and more severe hypoxic load. This feature is mainly manifested in moderate and severe OSAHS patients. It is very important to identify the phenotype of EDS in patients with OSAHS, who may meet more benefits from effective treatment of OSAHS by correcting the intermittent nocturnal hypoxia and sleep fragmentation.


A living mapping review for COVID-19 funded research projects: 21 month update.
Background: The coronavirus disease 2019 (COVID-19) has resulted in an unprecedented research response, demonstrating exceptional examples of rapid research and collaboration. There has however been an ongoing need for greater coordination, with limited resources for research and the shifting global pandemic. Methods: The UK Collaborative on Development Research (UKCDR) and Global Research Collaboration for Infectious Disease Preparedness (GloPID-R), two funder coordination groups have collaborated to develop a live database of funded research projects across the world relating to COVID-19. Drawing data continually from their members and further global funding bodies, as of 15 th April 2022 the database contains 16,353 projects, funded by 319 funders, taking place across 157 countries representing an investment of at least $6.2 billion. To our knowledge it is one of the most comprehensive databases. The database is aligned to the World Health Organisation and GloPID-R Global Research Roadmap: 2019 Novel Coronavirus and the UN Research Roadmap for the COVID-19 Recovery. It is being used by the WHO, governments and further policy makers, research funders and researchers. This living mapping review aims to supplement the database by providing an open accessible and frequently updated resource summarising the characteristics of the COVID-19 funded research portfolio. Both descriptive and thematic analysis are presented and updated frequently to aid interpretation of the global COVID-19 funded research portfolio. Results: In this version eight analysis we provide an updated detailed descriptive analysis of the database (on data from three months after version seven) and focus our thematic analysis on research gaps, research areas in need of coordination, study populations and research locations (with a focus on resource-limited countries). Conclusions: As the global funding response to COVID-19 plateaus, this living mapping review helps both funders and researchers to prioritise resources to areas where there is continued unmet research need.


Glucocorticoid effects on memory retrieval require concurrent noradrenergic activity in the hippocampus and basolateral amygdala.
Previous findings indicate that administration of abeta-adrenoceptor antagonist systemically blocks glucocorticoid impairment of memory retrieval. Here, we report that beta-adrenoceptor activation in the hippocampus and the basolateral complex of the amygdala (BLA) is implicated in the impairing effects of glucocorticoids on memory retrieval. The specific glucocorticoid receptor (GR) agonist 11beta,17beta-dihydroxy-6,21-dimethyl-17alpha-pregna-4,6-trien-20yn-3-one (RU 28362) (15 ng) infused into the hippocampus of male Sprague Dawley rats 60 min before water maze retention testing, 24 hr after training, impaired probe trial retention performance, as assessed by quadrant search time and initial latency to cross the platform location. Because we found previously that RU 28362 infused into the hippocampus does not affect water maze acquisition or immediate recall, the findings suggest that the GR agonist-induced retention impairment was attributable to a selective influence on long-term memory retrieval. Likewise, systemic injections of the beta1-adrenoceptor partial agonist xamoterol (3.0 or 10.0 mg/kg, s.c.) 60 min before the probe trial dose-dependently impaired retention performance. The beta-adrenoceptor antagonist propranolol (2.0 mg/kg) administered subcutaneously before retention testing did not affect retention performance alone, but blocked the memory retrieval impairment induced by concurrent intrahippocampal infusions of RU 28362. Pretest infusions of the beta1-adrenoceptor antagonist atenolol into either the hippocampus (1.25 microg in 0.5 microl) or the BLA (0.5 microg in 0.2 microl) also prevented the GR agonist-induced memory retrieval impairment. These findings suggest that glucocorticoids impair retrieval of long-term spatial memory by facilitating noradrenergic mechanisms in the hippocampus, and additionally, that norepinephrine-mediated BLA activity is critical in enabling hippocampal glucocorticoid effects on memory retrieval.


MR angiography of the portal venous system: techniques, interpretation, and clinical applications.
Magnetic resonance (MR) angiography is a noninvasive means of assessing the portal venous system that has potential advantages over currently used modalities. Time-of-flight and phase-contrast MR angiography are useful techniques that differ fundamentally in their means of data acquisition but are comparable in their ability to demonstrate normal anatomy as well as abnormalities of the portal venous system. Occasionally, artifacts caused by respiratory motion, implanted metallic devices or surgical clips, in-plane saturation, or areas of complex flow are seen at MR angiography of the portal venous system. However, most artifacts can easily be identified as such and either remedied or ignored. In addition, the suppression of signal from surrounding soft tissues may result in poor detection of parenchymal lesions. The utility of standard projection angiograms and source images can be increased through the use of intravenously administered contrast material and postprocessing techniques such as partial-volume maximum intensity projection reconstructions and shaded surface renderings. In addition to providing information on portal venous anatomy and portosystemic collateral vessels, MR angiography of the portal vein has clinical application in portal venous thrombosis and stenosis, liver transplantation, and the evaluation and planning of surgical and transjugular intrahepatic portosystemic shunts.


Relationships between transforming growth factor-beta1, myostatin, and decorin: implications for skeletal muscle fibrosis.
Recent studies have shown that myostatin, first identified as a negative regulator of skeletal muscle growth, may also be involved in the formation of fibrosis within skeletal muscle. In this study, we further explored the potential role of myostatin in skeletal muscle fibrosis, as well as its interaction with both transforming growth factor-beta1 and decorin. We discovered that myostatin stimulated fibroblast proliferation in vitro and induced its differentiation into myofibroblasts. We further found that transforming growth factor-beta1 stimulated myostatin expression, and conversely, myostatin stimulated transforming growth factor-beta1 secretion in C2C12 myoblasts. Decorin, a small leucine-rich proteoglycan, was found to neutralize the effects of myostatin in both fibroblasts and myoblasts. Moreover, decorin up-regulated the expression of follistatin, an antagonist of myostatin. The results of in vivo experiments showed that myostatin knock-out mice developed significantly less fibrosis and displayed better skeletal muscle regeneration when compared with wild-type mice at 2 and 4 weeks following gastrocnemius muscle laceration injury. In wild-type mice, we found that transforming growth factor-beta1 and myostatin co-localize in myofibers in the early stages of injury. Recombinant myostatin protein stimulated myofibers to express transforming growth factor-beta1 in skeletal muscles at early time points following injection. In summary, these findings define a fibrogenic property of myostatin and suggest the existence of co-regulatory relationships between transforming growth factor-beta1, myostatin, and decorin.


Patellar instability.
Recurrent patellar instability can result from osseous abnormalities, such as patella alta, a distance of >20 mm between the tibial tubercle and the trochlear groove, and trochlear dysplasia, or it can result from soft-tissue abnormalities, such as a torn medial patellofemoral ligament or a weakened vastus medialis obliquus. Nonoperative treatment includes physical therapy, focusing on strengthening of the gluteal muscles and the vastus medialis obliquus, and patellar taping or bracing. Acute medial-sided repair may be indicated when there is an osteochondral fracture fragment or a retinacular injury. The recent literature does not support the use of an isolated lateral release for the treatment of patellar instability. A patient with recurrent instability, with or without trochlear dysplasia, who has a normal tibial tubercle-trochlear groove distance and a normal patellar height may be a candidate for a reconstruction of the medial patellofemoral ligament with autograft or allograft. Distal realignment procedures are used in patients who have an increased tibial tubercle-trochlear groove distance or patella alta. The degree of anteriorization, distalization, and/or medialization depends on associated arthrosis of the lateral patellar facet and the presence of patella alta. Associated medial or proximal patellar chondrosis is a contraindication to distal realignment because of the potential to overload tissues that have already undergone degeneration.


Vascularized appendicular lymph node transfer for treatment of extremity lymphedema: A case report.
Vascularized lymph node transfer has demonstrated promising results for the treatment of extremity lymphedema. In an attempt to find the ideal donor site, several vascularized lymph nodes have been described. Each has a common goal of decreasing morbidity and avoiding iatrogenic lymphedema while obtaining good clinical results. Herein, we present the preliminary clinical outcomes of an intra-abdominal lymph node flap option based on the appendicular artery and vein used for the treatment of extremity lymphedema. A 62 year-old woman with moderate lower extremity lymphedema, on chronic antibiotics because of recurrent infections and unsatisfactory outcomes after conservative treatment underwent a vascularized appendicular lymph node (VALN) transfer. At a follow-up of 6 months, the reduction rate of the limb circumference was 17.4%, 15.1%, 12.0% and 9% above the knee, below the knee, above the ankle and foot respectively. In addition, no further episodes of infection or other complications were reported after VALN transfer. Postoperative lymphoscintigraphy demonstrated that the VALN flap was able to improve the lymphatic drainage of the affected limb. According to our findings, the use of VALN transfer minimizes donor-site morbidity, avoids iatrogenic lymphedema and may provide a strong clearance of infection because of the strong immunologic properties of the appendiceal lymphatic tissue in selected patients. Despite these promising results, further research with larger number of patients and longer follow- up is needed.


High-resolution, hybrid optical trapping methods, and their application to nucleic acid processing proteins.
Optical tweezers have become a powerful tool to investigate nucleic-acid processing proteins at the single-molecule level. Recent advances in this technique have now enabled measurements resolving the smallest units of molecular motion, on the scale of a single base pair of DNA. In parallel, new instrumentation combining optical traps with other functionalities have been developed, incorporating mechanical manipulation along orthogonal directions or fluorescence imaging capabilities. Here, we review these technical advances, their capabilities, and limitations, focusing on benchmark studies of protein-nucleic acid interactions they have enabled. We highlight recent work that combines several of these advances together and its application to nucleic-acid processing enzymes. Finally, we discuss future prospects for these exciting developments. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 704-714, 2016.


A primer on metagenomics.
Metagenomics is a discipline that enables the genomic study of uncultured microorganisms. Faster, cheaper sequencing technologies and the ability to sequence uncultured microbes sampled directly from their habitats are expanding and transforming our view of the microbial world. Distilling meaningful information from the millions of new genomic sequences presents a serious challenge to bioinformaticians. In cultured microbes, the genomic data come from a single clone, making sequence assembly and annotation tractable. In metagenomics, the data come from heterogeneous microbial communities, sometimes containing more than 10,000 species, with the sequence data being noisy and partial. From sampling, to assembly, to gene calling and function prediction, bioinformatics faces new demands in interpreting voluminous, noisy, and often partial sequence data. Although metagenomics is a relative newcomer to science, the past few years have seen an explosion in computational methods applied to metagenomic-based research. It is therefore not within the scope of this article to provide an exhaustive review. Rather, we provide here a concise yet comprehensive introduction to the current computational requirements presented by metagenomics, and review the recent progress made. We also note whether there is software that implements any of the methods presented here, and briefly review its utility. Nevertheless, it would be useful if readers of this article would avail themselves of the comment section provided by this journal, and relate their own experiences. Finally, the last section of this article provides a few representative studies illustrating different facets of recent scientific discoveries made using metagenomics.


Trans-9-octadecenoic acid is biologically neutral and does not regulate the low density lipoprotein receptor as the cis isomer does in the hamster.
The concentration of cholesterol carried in low density lipoproteins (LDL-C) is primarily determined by the rate at which LDL-C is produced (Jt) and the rate at which the liver takes up this particle through receptor-dependent transport (Jm). The accumulation of specific dietary fatty acids in the liver profoundly alters these kinetic parameters and will either increase hepatic receptor activity or further suppress Jm, depending upon the particular fatty acid that enriches the various lipid pools. This study tests the thesis that the cellular effects of each fatty acid are determined by the ability of that lipid to act as an effective substrate for cholesteryl ester formation by examining the metabolic effects of either cis-9-octadecenoic acid (18:1(9c)), the preferred substrate for esterification, or trans-9-octadecenoic acid (18:1(9t)), a poor substrate for this reaction. When fed to hamsters for 30 days, the steady-state concentration of cholesteryl esters was markedly increased by the 18:1(9c), as compared to the 18:1(9t), compound. In animals receiving the 18:1(9c) fatty acid, hepatic receptor activity was significantly increased, LDL-C production was suppressed, and the steady-state LDL-C concentration was reduced. In contrast, the 18:1(9t) fatty acid did not significantly alter Jm, Jt, or the plasma LDL-C level from those values found in the control animals fed an isocaloric amount of a biologically neutral fatty acid, octanoic acid. Despite these different effects on the parameters of LDL metabolism, neither the cis nor trans fatty acid altered net cholesterol delivery to the liver from de novo sterol synthesis in any tissue in the body or from uptake of dietary cholesterol across the intestine. Therefore, these studies provide strong support for the thesis that fatty acids exert regulatory effects on hepatic LDL receptor activity by altering the distribution of cholesterol in the hepatocyte between a putative regulatory pool and the inert pool of cholesteryl esters. The direction and magnitude of the effects of specific fatty acids on receptor-dependent LDL transport appear to relate directly to the capacity of specific fatty acids to either promote or inhibit cholesteryl ester formation.


Dominant protein interactions that influence the pathogenesis of conformational diseases.
Misfolding of exportable proteins can trigger endocrinopathies. For example, misfolding of insulin can result in autosomal dominant mutant INS gene-induced diabetes of youth, and misfolding of thyroglobulin can result in autosomal recessive congenital hypothyroidism with deficient thyroglobulin. Both proinsulin and thyroglobulin normally form homodimers; the mutant versions of both proteins misfold in the ER, triggering ER stress, and, in both cases, heterozygosity creates potential for cross-dimerization between mutant and WT gene products. Here, we investigated these two ER-retained mutant secretory proteins and the selectivity of their interactions with their respective WT counterparts. In both cases and in animal models of these diseases, we found that conditions favoring an increased stoichiometry of mutant gene product dominantly inhibited export of the WT partner, while increased relative level of the WT gene product helped to rescue secretion of the mutant partner. Surprisingly, the bidirectional consequences of secretory blockade and rescue occur simultaneously in the same cells. Thus, in the context of heterozygosity, expression level and stability of WT subunits may be a critical factor influencing the effect of protein misfolding on clinical phenotype. These results offer new insight into dominant as well as recessive inheritance of conformational diseases and offer opportunities for the development of new therapies.


Deep-apical tubules: dynamic lipid-raft microdomains in the brush-border region of enterocytes.
The brush border of small intestinal enterocytes is highly enriched in cholesterol- and glycosphingolipid-containing membrane microdomains, commonly termed as lipid 'rafts'. Functionally, transcytosis of IgA and exocytosis of newly made brush-border proteins in enterocytes occur through apical lipid raft-containing compartments, but little is otherwise known about these raft microdomains. We therefore studied in closer detail apical lipid-raft compartments in enterocytes by immunogold electron microscopy and biochemical analyses. Novel membrane structures, deep-apical tubules, were visualized by the non-permeable surface marker Ruthenium Red in the brush-border region of the cells. The surface-connected tubules were labelled by antibodies to caveolin-1 and the glycolipid asialo G(M1), and they were sensitive to cholesterol depletion by methyl-beta-cyclodextrin, indicating the presence of raft microdomains. Deep-apical tubules were positioned close to the actin rootlets of adjacent microvilli in the terminal web region, which had a diameter of 50-100 nm, and penetrated up to 1 microm into the cytoplasm. Markers for transcytosis, IgA and the polymeric immunoglobulin receptor, as well as the resident brush-border enzyme aminopeptidase N, were present in these deep-apical tubules. We propose that deep-apical tubules are a specialized lipid-raft microdomain in the brush-border region functioning as a hub in membrane trafficking at the brush border. In addition, the sensitivity to cholesterol depletion suggests that deep-apical tubules function as a cell-surface membrane reservoir for cholesterol and for rapid adaptive changes in the size of microvilli at the brush border.


Label-free, mass-sensitive single-molecule imaging using interferometric scattering microscopy.
Single-molecule imaging has mostly been restricted to the use of fluorescence labelling as a contrast mechanism due to its superior ability to visualise molecules of interest on top of an overwhelming background of other molecules. Recently, interferometric scattering (iSCAT) microscopy has demonstrated the detection and imaging of single biomolecules based on light scattering without the need for fluorescent labels. Significant improvements in measurement sensitivity combined with a dependence of scattering signal on object size have led to the development of mass photometry, a technique that measures the mass of individual molecules and thereby determines mass distributions of biomolecule samples in solution. The experimental simplicity of mass photometry makes it a powerful tool to analyse biomolecular equilibria quantitatively with low sample consumption within minutes. When used for label-free imaging of reconstituted or cellular systems, the strict size-dependence of the iSCAT signal enables quantitative measurements of processes at size scales reaching from single-molecule observations during complex assembly up to mesoscopic dynamics of cellular components and extracellular protrusions. In this review, I would like to introduce the principles of this emerging imaging technology and discuss examples that show how mass-sensitive iSCAT can be used as a strong complement to other routine techniques in biochemistry.


Use of posterior predictive checks as an inferential tool for investigating individual heterogeneity in animal population vital rates.
The investigation of individual heterogeneity in vital rates has recently received growing attention among population ecologists. Individual heterogeneity in wild animal populations has been accounted for and quantified by including individually varying effects in models for mark-recapture data, but the real need for underlying individual effects to account for observed levels of individual variation has recently been questioned by the work of Tuljapurkar et al. (Ecology Letters, 12, 93, 2009) on dynamic heterogeneity. Model-selection approaches based on information criteria or Bayes factors have been used to address this question. Here, we suggest that, in addition to model-selection, model-checking methods can provide additional important insights to tackle this issue, as they allow one to evaluate a model's misfit in terms of ecologically meaningful measures. Specifically, we propose the use of posterior predictive checks to explicitly assess discrepancies between a model and the data, and we explain how to incorporate model checking into the inferential process used to assess the practical implications of ignoring individual heterogeneity. Posterior predictive checking is a straightforward and flexible approach for performing model checks in a Bayesian framework that is based on comparisons of observed data to model-generated replications of the data, where parameter uncertainty is incorporated through use of the posterior distribution. If discrepancy measures are chosen carefully and are relevant to the scientific context, posterior predictive checks can provide important information allowing for more efficient model refinement. We illustrate this approach using analyses of vital rates with long-term mark-recapture data for Weddell seals and emphasize its utility for identifying shortfalls or successes of a model at representing a biological process or pattern of interest. We show how posterior predictive checks can be used to strengthen inferences in ecological studies. We demonstrate the application of this method on analyses dealing with the question of individual reproductive heterogeneity in a population of Antarctic pinnipeds.


zebraflash transgenic lines for in vivo bioluminescence imaging of stem cells and regeneration in adult zebrafish.
The zebrafish has become a standard model system for stem cell and tissue regeneration research, based on powerful genetics, high tissue regenerative capacity and low maintenance costs. Yet, these studies can be challenged by current limitations of tissue visualization techniques in adult animals. Here we describe new imaging methodology and present several ubiquitous and tissue-specific luciferase-based transgenic lines, which we have termed zebraflash, that facilitate the assessment of regeneration and engraftment in freely moving adult zebrafish. We show that luciferase-based live imaging reliably estimates muscle quantity in an internal organ, the heart, and can longitudinally follow cardiac regeneration in individual animals after major injury. Furthermore, luciferase-based detection enables visualization and quantification of engraftment in live recipients of transplanted hematopoietic stem cell progeny, with advantages in sensitivity and gross spatial resolution over fluorescence detection. Our findings present a versatile resource for monitoring and dissecting vertebrate stem cell and regeneration biology.


Extreme ultraviolet multilayer mirror with near-zero IR reflectance.
We have developed a multilayer mirror for extreme ultraviolet (EUV) radiation that has low reflectance for IR radiation at 10.6 mum wavelength. The mirror is based on a multilayer coating comprising alternating layers of diamondlike carbon and silicon, for which we demonstrate an EUV reflectance of up to 49.7%. We have made a functional prototype in which the multilayer coating is included as part of an antireflection coating for IR radiation, resulting in reflectance values of 42.5% and 4.4% for EUV and IR, respectively. The mirror can replace a standard Mo/Si mirror in an EUV lithography tool to form an efficient solution for the suppression of unwanted CO(2) laser radiation.


Detection of Theileria annulata in blood samples of carrier cattle by PCR.
We report the detection of Theileria annulata, the causative agent of tropical theileriosis, by PCR in blood samples obtained from carrier cattle. The assay employs primers specific for the gene encoding the 30-kDa major merozoite surface antigen of T. annulata. A 721-bp fragment was amplified from blood samples taken monthly from calves experimentally infected with one of four different stocks of T. annulata originating in either Mauritania, Portugal, Spain, or Turkey. At the end of the experiment, five animals carried the infection for 12 months and two animals remained infected for 15 months. DNAs from six other Theileria species, T. parva, T. mutans, T. sergenti, T. buffeli, T. velifera, and T. taurotragi, were not amplified. Moreover, DNAs from four other hemoparasites (Anaplasma centrale, Anaplasma marginale, Babesia bovis, and Babesia bigemina) were also not amplified. As a control, primers derived from the small subunit rRNA gene of Theileria spp. amplified a 1.1-kb DNA fragment from all Theileria species examined but not from the other four hemoparasites. As few as two to three parasites per microliter of infected blood in a 50-microliters sample volume were detected by Southern or microplate hybridization with a T. annulata-specific cDNA probe. In addition, 92 field samples obtained from cattle in Spain were tested; 22% were positive in blood smears, 40% were positive by immunofluorescent antibody test, and 75% were positive for T. annulata by PCR. The method provides a useful diagnostic tool for detecting T. annulata carrier cattle.


Nuanced roles of cytokines in three major human brain disorders.
The three most prevalent human disorders of the CNS in which immunity and inflammation are likely to have vital roles (excluding infection of the CNS) are fever, multiple sclerosis (MS), and Alzheimer disease (AD). As reviewed here, cytokines are critical in the induction of fever, the pathogenesis of MS, and the pathobiology of AD. Indeed, antibodies targeting cytokines have been used as a therapy for individuals with unusual and persistent febrile reactions not responsive to common antipyretics, while a recombinant cytokine is the most popular treatment for the relapsing-remitting form of MS. Although cytokine-modulating therapies are not currently in clinical use for the treatment of AD, cytokines can ameliorate disease pathology in certain experimental models of AD, suggesting a potential for future therapeutic opportunities.


Synthetically encoded ultrashort-channel nanowire transistors for fast, pointlike cellular signal detection.
Nanostructures, which have sizes comparable to biological functional units involved in cellular communication, offer the potential for enhanced sensitivity and spatial resolution compared to planar metal and semiconductor structures. Silicon nanowire (SiNW) field-effect transistors (FETs) have been used as a platform for biomolecular sensors, which maintain excellent signal-to-noise ratios while operating on lengths scales that enable efficient extra- and intracellular integration with living cells. Although the NWs are tens of nanometers in diameter, the active region of the NW FET devices typically spans micrometers, limiting both the length and time scales of detection achievable with these nanodevices. Here, we report a new synthetic method that combines gold-nanocluster-catalyzed vapor-liquid-solid (VLS) and vapor-solid-solid (VSS) NW growth modes to produce synthetically encoded NW devices with ultrasharp (<5 nm) n-type highly doped (n(++)) to lightly doped (n) transitions along the NW growth direction, where n(++) regions serve as source/drain (S/D) electrodes and the n-region functions as an active FET channel. Using this method, we synthesized short-channel n(++)/n/n(++) SiNW FET devices with independently controllable diameters and channel lengths. SiNW devices with channel lengths of 50, 80, and 150 nm interfaced with spontaneously beating cardiomyocytes exhibited well-defined extracellular field potential signals with signal-to-noise values of ca. 4 independent of device size. Significantly, these "pointlike" devices yield peak widths of ∼500 μs, which is comparable to the reported time constant for individual sodium ion channels. Multiple FET devices with device separations smaller than 2 μm were also encoded on single SiNWs, thus enabling multiplexed recording from single cells and cell networks with device-to-device time resolution on the order of a few microseconds. These short-channel SiNW FET devices provide a new opportunity to create nanoscale biomolecular sensors that operate on the length and time scales previously inaccessible by other techniques but necessary to investigate fundamental, subcellular biological processes.


Pharmacological activity of the Ginkgo biloba extract (EGb 761) on equilibrium function recovery in the unilateral vestibular neurectomized cat.
Locomotor balance recovery after unilateral vestibular neurectomy has been found strongly accelerated in the cat when the animals received a postoperative treatment with Ginkgo biloba Extract (EGb 761:50 mg/kg/d, i.p.), a result due to the improvement of plasticity mechanisms involved in vestibular compensation. The aim of this study was to determine which of the two main biochemical components (terpenes vs. flavonoids) contained in the extract was the most active in the recovery process, to test the influence of the route of administration, and to look for dose-dependent effects. Experiments were performed in six experimental groups of cats that were compared with each other and with three control groups. Comparisons were done on the recovery profile and time course of equilibrium function restoration, as quantified by the rotating beam test. Four experimental groups were treated with the standardized extract EGb 761 given orally (p.o.:2 groups; 40 mg and 80 mg/kg) or intraperitoneally (i.p.: 2 groups; 50 mg and 25 mg/kg), whereas the two others received only a special extract that did not contain the terpenes (i.p. administration: 25 mg and 10 mg/kg). Treatment was always given until complete recovery of locomotor balance function. The control groups received either no treatment (untreated cats), an oral vehicle (placebo cats), or a sham i.p. injection (sham cats). Results showed that locomotor balance recovery was significantly improved in all the experimental groups as compared to the control groups of cats, which recovered similarly and more slowly. Efficacy of the special extract without the terpenes was comparable to that of the total extract, indicating that the nonterpenic fraction was the most active biochemical constituent in this experimental model of central nervous system (CNS) plasticity. Pharmacological activity of the extract was also significantly better when given i.p. as compared to the p.o. route of administration, and dose-dependent effects were evidenced with the i.p. administration of the special extract without the terpenes, with a lower efficacy for the lowest dose (10 mg/kg). These data confirm that EGb 761 treatment serves as useful therapy in supporting brain functional recovery in this animal model of vestibular compensation and lead to a more precise understanding of the biochemical component that is active in this recovery process.


The Pace of Hybrid Incompatibility Evolution in House Mice.
Hybrids between species are often sterile or inviable. This form of reproductive isolation is thought to evolve via the accumulation of mutations that interact to reduce fitness when combined in hybrids. Mathematical formulations of this "Dobzhansky-Muller model" predict an accelerating buildup of hybrid incompatibilities with divergence time (the "snowball effect"). Although the Dobzhansky-Muller model is widely accepted, the snowball effect has only been tested in two species groups. We evaluated evidence for the snowball effect in the evolution of hybrid male sterility among subspecies of house mice, a recently diverged group that shows partial reproductive isolation. We compared the history of subspecies divergence with patterns of quantitative trait loci (QTL) detected in F2 intercrosses between two pairs of subspecies (Mus musculus domesticus with M. m. musculus and M. m. domesticus with M. m. castaneus). We used a recently developed phylogenetic comparative method to statistically measure the fit of these data to the snowball prediction. To apply this method, QTL were partitioned as either shared or unshared in the two crosses. A heuristic partitioning based on the overlap of QTL confidence intervals produced unambiguous support for the snowball effect. An alternative approach combining data among crosses favored the snowball effect for the autosomes, but a linear accumulation of incompatibilities for the X chromosome. Reasoning that the X chromosome analyses are complicated by low mapping resolution, we conclude that hybrid male sterility loci have snowballed in house mice. Our study illustrates the power of comparative genetic mapping for understanding mechanisms of speciation.


Solitons in dispersion-inverted AlGaAs nanowires.
We demonstrate that optical solitons can exist in dispersion-inverted highly-nonlinear AlGaAs nanowires. This is accomplished by strongly reversing the dispersion of these nano-structures to anomalous over a broad frequency range. These self-localized waves are possible at very low power levels and can form in millimeter long nanowire structures. The intensity and spectral evolution of solitons propagating in such AlGaAs nanowaveguides is investigated in the presence of loss, multiphoton absorption and higher-order dispersion.


The role of citicoline in neuroprotection and neurorepair in ischemic stroke.
Advances in acute stroke therapy resulting from thrombolytic treatment, endovascular procedures, and stroke units have improved significantly stroke survival and prognosis; however, for the large majority of patients lacking access to advanced therapies stroke mortality and residual morbidity remain high and many patients become incapacitated by motor and cognitive deficits, with loss of independence in activities of daily living. Therefore, over the past several years, research has been directed to limit the brain lesions produced by acute ischemia (neuroprotection) and to increase the recovery, plasticity and neuroregenerative processes that complement rehabilitation and enhance the possibility of recovery and return to normal functions (neurorepair). Citicoline has therapeutic effects at several stages of the ischemic cascade in acute ischemic stroke and has demonstrated efficiency in a multiplicity of animal models of acute stroke. Long-term treatment with citicoline is safe and effective, improving post-stroke cognitive decline and enhancing patients' functional recovery. Prolonged citicoline administration at optimal doses has been demonstrated to be remarkably well tolerated and to enhance endogenous mechanisms of neurogenesis and neurorepair contributing to physical therapy and rehabilitation.


Anatomical predilection of intestinal metaplasia based on 78,335 endoscopic cases.
Gastric intestinal metaplasia (IM) is an important risk factor for intestinal-type gastric carcinoma, and successful treatment critically depends on its timely detection. In order to guide appropriate endoscopic surveillance, objective knowledge on the anatomical predilection of intestinal metaplasia development is urgently needed. A total of 78,335 cases who underwent gastroduodenoscopy from 2008 to 2013 in Jiangsu and Anhui provinces in China, were studied. Demographic and clinical characteristics, as well as biopsy location and histological results, were analyzed. This study revealed that intestinal metaplasia incidence was 28.5% in angulus, 20.24% in lesser curvature of the antrum, and 25.48% in corpus; and all these were significantly higher than those observed in other sites (P < 0.01). Histological grading of intestinal metaplasia in the lesser curvature of the antrum and angulus was generally worse than the grading observed in the greater curvature of the antrum. For Helicobacter pylori-positive patients, acute inflammation was more severe in the lesser curvature of the antrum compared with the greater curvature. In the H. Pylori-negative group, both acute and chronic inflammations were more severe in the lesser curvature of the antrum. The angulus, lesser curvature in the antrum, and corpus are most prone to the development of intestinal metaplasia. Inflammation is most severe in the lesser curvature of the antrum, which corresponds to a higher predilection to develop intestinal metaplasia at this site. The lesser curvature of the antrum and corpus require the most attention during endoscopic biopsy surveillance.


Derivation of human embryonic stem cell lines in serum replacement medium using postnatal human fibroblasts as feeder cells.
Derivation and culture of human embryonic stem cells (hESCs) without animal-derived material would be optimal for cell transplantation. We derived two new hES (HS293 and HS306) and 10 early cell lines using serum replacement (SR) medium instead of conventional fetal calf serum and human foreskin fibroblasts as feeder cells. Line HS293 has been in continuous culture, with a passage time of 5-8 days, since October 2003 and is at passage level 56. Line HS306 has been cultured since February 2004, now at passage 41. The lines express markers of pluripotent hESCs (Oct-4, SSEA-4, TRA-1-60, TRA-1-81, GCTM-2, and alkaline phosphatase). The pluripotency has been shown in embryoid bodies in vitro, and the pluripotency of line 293 has also been shown in vivo by teratoma formation in severe combined immunodeficiency/beige mice. The karyotype of HS293 is 46,XY, and that of HS306 is 46,XX. Ten more early lines have been derived under similar conditions since September 2004. We conclude that hESC lines can be successfully derived using SR medium and postnatal human fibroblasts as feeder cells. This is a step toward xeno-free conditions and facilitates the use of these cells in transplantation.


Task-specific effects of orientation information: neuropsychological evidence.
The deficits underlying orientation agnosia in a patient (MB) with a right fronto-temporo-parietal lesion were examined. Like similar patients in the literature, MB was impaired at discriminating whether objects were upright or not and, in copying, she tended to re-represent stimuli as upright. In addition, MB failed to show the normal effects of rotation on object identification; her naming of objects rotated 45 degrees from upright was no slower than her naming of upright items. Effects of the degree of rotation did emerge, however, when she had to perform a matching task that required mental rotation. The evidence suggests that orientation may be coded in several ways (e.g. separately between objects and relative to the viewer), and that brain-damage can selectively affect the use of some but not all types of orientation information.


Impact of Center Experience on Patient Radiation Exposure During Transradial Coronary Angiography and Percutaneous Intervention: A Patient-Level, International, Collaborative, Multi-Center Analysis.
The adoption of the transradial (TR) approach over the traditional transfemoral (TF) approach has been hampered by concerns of increased radiation exposure-a subject of considerable debate within the field. We performed a patient-level, multi-center analysis to definitively address the impact of TR access on radiation exposure. Overall, 10 centers were included from 6 countries-Canada (2 centers), United Kingdom (2), Germany (2), Sweden (2), Hungary (1), and The Netherlands (1). We compared the radiation exposure of TR versus TF access using measured dose-area product (DAP). To account for local variations in equipment and exposure, standardized TR:TF DAP ratios were constructed per center with procedures separated by coronary angiography (CA) and percutaneous coronary intervention (PCI). Among 57 326 procedures, we demonstrated increased radiation exposure with the TR versus TF approach, particularly in the CA cohort across all centers (weighted-average ratios: CA, 1.15; PCI, 1.05). However, this was mitigated by increasing TR experience in the PCI cohort across all centers (r=-0.8; P=0.005). Over time, as a center transitioned to increasing TR experience (r=0.9; P=0.001), a concomitant decrease in radiation exposure occurred (r=-0.8; P=0.006). Ultimately, when a center's balance of TR to TF procedures approaches 50%, the resultant radiation exposure was equivalent. The TR approach is associated with a modest increase in patient radiation exposure. However, this increase is eliminated when the TR and TF approaches are used with equal frequency-a guiding principle for centers adopting the TR approach.


Functional analysis of GNG2 in human malignant melanoma cells.
Previous studies have revealed that heterotrimeric G protein is composed of a Gα-subunit and a Gβγ-dimer and is correlated with c-Src and AKT activities. Our recent study showed reduced G protein γ2 subunit (Gng2/GNG2) expression levels in malignant melanoma cells compared with those in benign melanocytic cells in both mice and humans. At present, however, there is no evidence showing an effect of Gng2/GNG2 alone on cancer biology. The purpose of this study was to examine the biological significance of GNG2 in human malignant melanoma cells. Levels of proliferation and activities of signal transduction molecules were examined in both GNG2-overexpressed and -depleted human malignant melanoma cells. Proliferation of GNG2-overexpressed SK-Mel28 human malignant melanoma cells was suppressed with decreased c-SRC and AKT activities and increased p21(Cip/WAF1) expression level in vitro. In contrast, proliferation of GNG2-depleted A375P human malignant melanoma cells was enhanced with increased c-SRC and AKT activities and decreased p21(Cip/WAF1) expression level in vitro. In the in vivo experiment, the mean tumor size of GNG2-overexpressed SK-Mel28 cells was less than 1/45th of that of control SK-Mel28 cells in nude mice at 95 days after inoculation. We demonstrated for the first time that increased protein expression level of GNG2 alone inhibits proliferation of malignant melanoma cells in vitro and in vivo, suggesting that GNG2 could be a novel molecular target for malignant melanoma therapy.


International Olympic Committee consensus statement on youth athletic development.
The health, fitness and other advantages of youth sports participation are well recognised. However, there are considerable challenges for all stakeholders involved-especially youth athletes-in trying to maintain inclusive, sustainable and enjoyable participation and success for all levels of individual athletic achievement. In an effort to advance a more unified, evidence-informed approach to youth athlete development, the IOC critically evaluated the current state of science and practice of youth athlete development and presented recommendations for developing healthy, resilient and capable youth athletes, while providing opportunities for all levels of sport participation and success. The IOC further challenges all youth and other sport governing bodies to embrace and implement these recommended guiding principles.


Fabrication of elliptic microfibers with CO2 laser for high-sensitivity refractive index sensing.
We propose a convenient method for achieving highly birefringent (HiBi) elliptic microfibers by use of the CO2-laser machining and the flame-brushing techniques. With optimization of fabrication process, a high birefringence of up to 2.10×10(-2) is experimentally obtained. Especially, within a polarization Sagnac interferometer acting as a refractive index (RI) sensor, both positive and abnormal negative sensitivity is measured, dependent on the geometrical variables of the HiBi microfiber. The maximum RI sensitivity is ∼195,348 nm/RI-unit around RI=1.35887, which is the highest among the microfiber devices as reported, to our knowledge.


Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells.
Dithiocarbamates and iron chelators were recently considered for the treatment of AIDS and neurodegenerative diseases. In this study, we show that dithiocarbamates and metal chelators can potently block the activation of nuclear factor kappa B (NF-kappa B), a transcription factor involved in human immunodeficiency virus type 1 (HIV-1) expression, signaling, and immediate early gene activation during inflammatory processes. Using cell cultures, the pyrrolidine derivative of dithiocarbamate (PDTC) was investigated in detail. Micromolar amounts of PDTC reversibly suppressed the release of the inhibitory subunit I kappa B from the latent cytoplasmic form of NF-kappa B in cells treated with phorbol ester, interleukin 1, and tumor necrosis factor alpha. Other DNA binding activities and the induction of AP-1 by phorbol ester were not affected. The antioxidant PDTC also blocked the activation of NF-kappa B by bacterial lipopolysaccharide (LPS), suggesting a role of oxygen radicals in the intracellular signaling of LPS. This idea was supported by demonstrating that treatment of pre-B and B cells with LPS induced the production of O2- and H2O2. PDTC prevented specifically the kappa B-dependent transactivation of reporter genes under the control of the HIV-1 long terminal repeat and simian virus 40 enhancer. The results from this study lend further support to the idea that oxygen radicals play an important role in the activation of NF-kappa B and HIV-1.


Increased Risk of Rehospitalization for Acute Diabetes Complications and Suicide Attempts in Patients With Type 1 Diabetes and Comorbid Schizophrenia.
The aim of this large retrospective cohort study was to estimate the supplementary morbidity and mortality risks conferred by the co-occurrence of schizophrenia among young people with type 1 diabetes. This nationwide population-based study included individuals aged 15-35 years hospitalized in France for type 1 diabetes from 2009 to 2012 with or without schizophrenia. For assessment of the occurrence of rehospitalization for acute diabetes complications, suicide attempts, and hospital mortality, multivariate logistic regressions and survival analysis adjusted for age, sex, and Charlson comorbidity index scores were performed. The association between hospitalization for suicide attempts and acute diabetes complications was further explored in a survival analysis, with the exposure of acute diabetes complications as a time-dependent covariate. Among 45,655 individuals aged 15-35 years who were hospitalized for type 1 diabetes, 341 (0.75%) had a previous or contemporary hospitalization for schizophrenia. Within 3 years of follow-up, schizophrenia was associated with increased risks of rehospitalization for hypoglycemia (adjusted odds ratio 3.21 [95% CI 1.99-5.20]), hyperglycemia (7.01 [3.53-13.90]), ketoacidosis (2.01 [1.49-2.70]), and coma (3.17 [1.90-5.27]); hospitalization for suicide attempts (12.15 [8.49-17.38]); and hospital mortality (2.83 [1.50-5.36]). Hospitalization for a suicide attempt was associated with an increased risk of hospitalization for acute diabetes complications independently from schizophrenia (hazard ratio 3.46 [95% CI 2.74-4.38]). Patients suffering from the combination of type 1 diabetes and schizophrenia are at increased risk of hospitalization for acute diabetes complications as well as suicide and hospital mortality. These individuals may require specific care programs and close monitoring of mental, somatic, and social health.


Comparative study on altered hepatic metabolism of CYP3A substrates in rats with glycerol-induced acute renal failure.
To examine the mechanism accounting for the diverse alteration of hepatic metabolism of CYP3A substrates observed with renal function being severely impaired, the hepatic drug metabolizing activity was evaluated using liver microsomes prepared from rats with glycerol-induced acute renal failure (ARF). Midazolam, nifedipine and rifabutin were employed as representative CYP3A substrates. When the Michaelis-Menten parameters, K(m) and V(max) , were examined in the incubation study, the K(m) values of midazolam and nifedipine in ARF rats were shown to decrease by 50.9% and 29.9% compared with the normal value, respectively. The V(max) values of midazolam and nifedipine in ARF rats also decreased by 49.3% and 28.0%, respectively, showing that their decreased K(m) values accompanied the decreased V(max) values. The parameters of nifedipine seemed to alter to a lesser extent than those of midazolam. As for rifabutin metabolism, the decrease in the K(m) value was observed in ARF rats, but it did not accompany the decrease in the V(max) value. Then, the hepatic expressions of the CYP3A subfamily were examined with western blotting using anti-CYP3A1 and anti-CYP3A2 antibodies. It was revealed that the hepatic expression of CYP3A2 decreased, while that of CYP3A1 was unaffected. Additionally, a band signal deduced to originate from CYP3A9 was clearly detected in ARF, but not in normal rats. Considering each substrate having different specificities for CYP3A subfamily member proteins, individual alterations of hepatic CYP3A subfamily expression seem to underlie the diverse alterations of hepatic metabolism of CYP3A substrates in ARF rats.


Evaluation of the Enterococcus faecalis Biofilm-Associated Virulence Factors AhrC and Eep in Rat Foreign Body Osteomyelitis and In Vitro Biofilm-Associated Antimicrobial Resistance.
Enterococcus faecalis can cause healthcare-associated biofilm infections, including those of orthopedic devices. Treatment of enterococcal prosthetic joint infection is difficult, in part, due to biofilm-associated antimicrobial resistance. We previously showed that the E. faecalis OG1RF genes ahrC and eep are in vitro biofilm determinants and virulence factors in animal models of endocarditis and catheter-associated urinary tract infection. In this study, we evaluated the role of these genes in a rat acute foreign body osteomyelitis model and in in vitro biofilm-associated antimicrobial resistance. Osteomyelitis was established for one week following the implantation of stainless steel orthopedic wires inoculated with E. faecalis strains OG1RF, ΩahrC, and ∆eep into the proximal tibiae of rats. The median bacterial loads recovered from bones and wires did not differ significantly between the strains at multiple inoculum concentrations. We hypothesize that factors present at the infection site that affect biofilm formation, such as the presence or absence of shear force, may account for the differences in attenuation in the various animal models we have used to study the ΩahrC and ∆eep strains. No differences among the three strains were observed in the planktonic and biofilm antimicrobial susceptibilities to ampicillin, vancomycin, daptomycin, linezolid, and tetracycline. These findings suggest that neither ahrC nor eep directly contribute to E. faecalis biofilm-associated antimicrobial resistance. Notably, the experimental evidence that the biofilm attachment mutant ΩahrC displays biofilm-associated antimicrobial resistance suggests that surface colonization alone is sufficient for E. faecalis cells to acquire the biofilm antimicrobial resistance phenotype.


Factors that influence ultrasound evaluation of breast tumor size.
To determine the factors influencing ultrasound breast tumor size assessment accuracy. Five factors (tumor type, molecular subtype, histological size, histological grade, and breast density) were used to assess the measurement accuracy of breast ultrasound in tumor size. Size underestimation was defined as ultrasound index lesion diameter < histological size by at least 5 mm. Breast ultrasound underestimated tumor size significantly, especially in cases with intraductal components (p=0.002). There was a tendency for higher size underestimation in breast cancer tumors with high-histological grade (p=0.03), human epidermal growth factor receptor type 2 (HER2)-overexpressing breast cancer tumors (p=0.02) and hormone receptor (HR)-/HER2+ breast cancer tumors (p=0.008). Furthermore, core biopsy revealedhigher probability of size underestimation with intraductal components (p=0.002). Size underestimation was more frequent with larger histological size (p<0.001). Masses in non-dense breasts were significantly underestimated (p=0.036) compared to dense breasts. The size underestimation was influenced by pathological type, molecular subtype, and histological size. The pathological results of core biopsy were conducive for predicting tumor size pre-surgery in precise breast cancer diagnosis.


Dynamics of Complex-Forming Bimolecular Reactions: A Comparative Theoretical Study of the Reactions of H Atoms with O2((3)Σg(-)) and O2((1)Δg).
The atomic-level mechanism of the reaction of H atoms with triplet and singlet molecular oxygen, H((2)S) + O2((3)Σg(-)) → O((3)P) + OH((2)Πg) ( R1 ) and H((2)S) + O2((1)Δg) → O((3)P) + OH((2)Πg) ( R2 ) is analyzed in terms of the topology of the potential energy surfaces (PES) of the two reactions. Both PES exhibit a deep potential well corresponding to the ground and first excited electronic state of HO2. The ground-state reaction is endothermic with no barrier on either side of the well; the excited-state reaction is exothermic with a barrier in the entrance valley of the PES. The differences of the PES are manifested in properties such as the excitation functions, which show reaction R1 to be much slower and the effect of rotational excitation on reactivity, which speeds up reaction R1 and has little effect on R2 . Numerous common dynamics features arise from the presence of the deep potential well on the PES. Such are the significant role of isomerization (for example, 90% of reactive collisions in R2 involve at least one H atom transfer from one of the O atoms to the other in reaction R2 ), which is shown to give rise to a significant rotational excitation of the product OH radicals. Common is the significant sideways scattering of the products that originates from collisions in propeller-type arrangements induced by the presence of two bands of acceptance around the O2 molecule. The HO2 complex in both reactions proves to behave nonstatistically, with signatures of the dynamics in lifetime distributions, angular distributions, opacity functions, and product quantum-state distributions.


Engaging general practitioners in public-private mix tuberculosis DOTS program in an urban area in Pakistan: need for context-specific approach.
A public-private mix tuberculosis (TB) DOTS project was implemented to enhance coverage and collaboration between the public and private sectors, with an objective to increase case detection and to improve TB case management in a large urban area. General practitioners (GPs) were trained to provide DOTS services. Patients were diagnosed and treated as per national guidelines and outcomes were reported to national TB control program. Treatment and sputum microscopy were provided free of cost. A total of 94 GPs were trained. In all, 57.4% of trained GPs remained actively involved in the project. Overall treatment success rate of the patients enrolled with the project was 86.3% with 8.7% default patients. Experience suggests that a more stringent selection criteria need to be followed for inclusion of GPs in the program to improve the success of the program. A multifaceted context specific approach is needed while working with private health care providers.


Importance of secondary sources in the atmospheric budgets of formic and acetic acids.
We present a detailed budget of formic and acetic acids, two of the most abundant trace gases in the atmosphere. Our bottom-up estimate of the global source of formic and acetic acids are ∼1200 and ∼1400Gmolyr-1, dominated by photochemical oxidation of biogenic volatile organic compounds, in particular isoprene. Their sinks are dominated by wet and dry deposition. We use the GEOS-Chem chemical transport model to evaluate this budget against an extensive suite of measurements from ground, ship and satellite-based Fourier transform spectrometers, as well as from several aircraft campaigns over North America. The model captures the seasonality of formic and acetic acids well but generally underestimates their concentration, particularly in the Northern midlatitudes. We infer that the source of both carboxylic acids may be up to 50% greater than our estimate and report evidence for a long-lived missing secondary source of carboxylic acids that may be associated with the aging of organic aerosols. Vertical profiles of formic acid in the upper troposphere support a negative temperature dependence of the reaction between formic acid and the hydroxyl radical as suggested by several theoretical studies.


Impact of the COVID-19 Pandemic on Mental Health among 157,213 Americans.
The coronavirus (COVID-19) pandemic presents an unprecedented crisis with potential negative mental health impacts. This study used data collected via Youper, a mental health app, from February through July 2020. Youper users (N = 157,213) in the United States self-reported positive and negative emotions and anxiety and depression symptoms during the pandemic. We examined emotions and symptoms before (pre), during (acute), and after (sustained) COVID-related stay-at-home orders. For changes in frequency of reported acute emotions, from the pre to acute periods, anxiety increased while tiredness, calmness, happiness, and optimism decreased. From the acute to sustained periods, sadness, depression, and gratitude increased. Anxiety, stress, and tiredness decreased. Between the pre and sustained periods, sadness and depression increased, as did happiness and calmness. Anxiety and stress decreased. Among symptom measures, anxiety increased initially, from the pre to the acute periods, but later returned to baseline. The study sample was primarily comprised of young people and women. The app does not collect racial or ethnicity data. These factors may limit generalizability. Sample size was also not consistent for all data collected. The present study suggests that although there were initial negative impacts on emotions and mental health symptoms in the first few weeks, many Americans demonstrated resilience over the following months. The impact of the pandemic on mental health may not be as severe as predicted, although future work is necessary to understand longitudinal effects as the pandemic continues.


Fourier-transform infrared spectroscopic studies on avidin secondary structure and complexation with biotin and biotin-lipid assemblies.
Fourier-transform infrared studies have been carried out to investigate the secondary structure and thermal stability of hen egg white avidin and its complexes with biotin and with a biotinylated lipid derivative, N-biotinyl dimyristoyl phosphatidylethanolamine (DMBPE) in aqueous dispersion. Analysis of the amide I stretching band of avidin yielded a secondary structural content composed of approximately 66% beta-sheet and extended structures, with the remainder being attributed to disordered structure and beta-turns. Binding of biotin or specific association with the biotinylated lipid DMBPE did not result in any appreciable changes in the secondary structure content of the protein, but a change in hydrogen bond stability of the beta-sheet or extended chain regions was indicated. The latter effect was enhanced by surface interactions in the case of the biotin-lipid assemblies, as was demonstrated by electrostatic binding to a nonspecific negatively charged lipid. Difference spectra of the bound biotin implicated a direct involvement of the ureido moiety in the ligand interaction that was consistent with hydrogen bonding to amino acid residues in the avidin protein. It was found that complexation with avidin leads to a decrease in bond length of the biotin ureido carbonyl group that is consistent with a reduction of sp3 character of the C-O bond when it is hydrogen bonded to the protein. Studies of the temperature dependence of the spectra revealed that for avidin alone the secondary structure was unaltered up to approximately 75 degrees C, above which the protein undergoes a highly cooperative transition to an unfolded state with concomitant loss of ordered secondary structure. The complexes of avidin with both biotin and membrane-bound DMBPE lipid assemblies display a large increase in thermal stability compared with the native protein.


Tibiofibular bone-bridging osteoplasty in transtibial amputation: case report and description of technique.
Transtibial amputation osteoplasty procedures were originally designed as a technique for achieving a functional end-bearing limb in the post-World War I era; the Ertl procedure is now often used as a reconstructive procedure for failed primary amputations. Modifications of the original periosteal sleeve-covering technique include the tibiofibular bone-bridging osteoplasty. The theoretical advantages to this procedure are highly debated among trauma surgeons. For the patient with a lower extremity injury that necessitates a transtibial amputation, there are many psychologic and physiologic factors to consider, and a persistently painful residual limb postamputation may be mentally and physically disabling. Although the advantages of these techniques may be unproven, they are fairly simple and add little additional operative time to the primary transtibial amputation. A surgeon who performs transtibial amputations should at least be aware of the osteoplasty techniques and how to perform them. The decision to use these techniques may then be made by the surgeon on a case-by-case basis, given the individual demands of the patient. This article presents a case report and outlines the use of the fibular bone-bridging osteoplasty technique in transtibial amputations.


IMP-L2: an essential secreted immunoglobulin family member implicated in neural and ectodermal development in Drosophila.
The Drosophila IMP-L2 gene was identified as a 20-hydroxyecdysone-induced gene encoding a membrane-bound polysomal transcript. IMP-L2 is an apparent secreted member of the immunoglobulin superfamily. We have used deficiencies that remove the IMP-L2 gene to demonstrate that IMP-L2 is essential in Drosophila. The viability of IMP-L2 null zygotes is influenced by maternal IMP-L2. IMP-L2 null progeny from IMP-L2+ mothers exhibit a semilethal phenotype. IMP-L2 null progeny from IMP-L2 null mothers are 100% lethal. An IMP-L2 transgene completely suppresses the zygotic lethal phenotype and partially suppresses the lethality of IMP-L2 null progeny from IMP-L2 null mothers. In embryos, IMP-L2 mRNA is first expressed at the cellular blastoderm stage and continues to be expressed through subsequent development. IMP-L2 mRNA is detected in several sites including the ventral neuroectoderm, the tracheal pits, the pharynx and esophagus, and specific neuronal cell bodies. Staining of whole-mount embryos with anti-IMP-L2 antibodies shows that IMP-L2 protein is localized to specific neuronal structures late in embryogenesis. Expression of IMP-L2 protein in neuronal cells suggests a role in the normal development of the nervous system but no severe morphological abnormalities have been detected in IMP-L2 null embryos.


Biological effects of essential oils--a review.
Since the middle ages, essential oils have been widely used for bactericidal, virucidal, fungicidal, antiparasitical, insecticidal, medicinal and cosmetic applications, especially nowadays in pharmaceutical, sanitary, cosmetic, agricultural and food industries. Because of the mode of extraction, mostly by distillation from aromatic plants, they contain a variety of volatile molecules such as terpenes and terpenoids, phenol-derived aromatic components and aliphatic components. In vitro physicochemical assays characterise most of them as antioxidants. However, recent work shows that in eukaryotic cells, essential oils can act as prooxidants affecting inner cell membranes and organelles such as mitochondria. Depending on type and concentration, they exhibit cytotoxic effects on living cells but are usually non-genotoxic. In some cases, changes in intracellular redox potential and mitochondrial dysfunction induced by essential oils can be associated with their capacity to exert antigenotoxic effects. These findings suggest that, at least in part, the encountered beneficial effects of essential oils are due to prooxidant effects on the cellular level.


Breast cancer prognostic significance of a single nucleotide polymorphism in the proximal androgen response element of the prostate specific antigen gene promoter.
Prostate Specific Antigen (PSA) expression by breast epithelial cells is associated with favorable breast cancer prognosis. In preliminary studies, we found that a nucleotide variation (G-->A) at position -158 in the androgen response element (ARE-1) of the PSA promoter was present in four out of 9 breast tumors examined and in a breast carcinoma cell line. We have now determined the nucleotide composition at position -158 of DNA extracted from 148 well-characterized breast tumors and compared tumor genotype with that of controls without cancer, with tumor PSA concentration and with clinicopathological variables, overall survival and disease free survival. The G-->A base change at position -158 is a polymorphism. Allelotypes were similarly distributed in breast cancer patients and controls. The Mann-Whitney U Test showed a significantly higher tumor PSA concentration in tumors that presented a homozygous G as opposed to homozygous A genotype. Genotype at position -158 was not associated with clinicopathological variables in contingency table analysis. Univariate Cox regression models showed a 28% reduction in risk for death in patients with homozygous G genotype compared to those with homozygous A genotype (P = 0.03). However, ARE-1 genotype did not significantly add to the prognostic power in the multivariate model of overall survival. In summary, the base change at position -158 is a polymorphism that may affect breast cancer prognosis, but further studies are required to confirm this possibility and to investigate the relevance of this polymorphism in terms of breast cancer susceptibility.


Breakdown of high-performance monolayer MoS2 transistors.
Two-dimensional (2D) materials such as monolayer molybdenum disulfide (MoS(2)) are extremely interesting for integration in nanoelectronic devices where they represent the ultimate limit of miniaturization in the vertical direction. Thanks to the presence of a band gap and subnanometer thickness, monolayer MoS(2) can be used for the fabrication of transistors exhibiting extremely high on/off ratios and very low power dissipation. Here, we report on the development of 2D MoS(2) transistors with improved performance due to enhanced electrostatic control. Our devices show currents in the 100 μA/μm range and transconductance exceeding 20 μS/μm as well as current saturation. We also record electrical breakdown of our devices and find that MoS(2) can support very high current densities, exceeding the current-carrying capacity of copper by a factor of 50. Our results push the performance limit of MoS(2) and open the way to their use in low-power and low-cost analog and radio frequency circuits.


The effects of visuomotor feedback training on the recovery of hemispatial neglect symptoms: assessment of a 2-week and follow-up intervention.
In patients suffering from left unilateral neglect, their right-biased attention to the phenomenal world can be ameliorated, short-term, by making motor responses to left-right extended objects (rods) that immediately reveal to them that their phenomenal world is in fact skewed. In this study the extent to which more intensive experiences of this type produced enduring and useful improvements in neglect, was assessed by first examining the effect of a 3-day experimenter-administered practice of rod lifting, then by examining the effects of a self-administered practice for a further 2-week period and a further 1 month post-training. Despite the fact that by the time the patients were able to undergo the intervention they had progressed to the chronic neglect stage, significant improvements of the intervention over the control group were found for a third of the tests given after the 3-day practice. Additionally, at the 1-month follow-up the intervention group again showed significantly better results in 46% of the direct neglect tests. As far as we are aware this is the first time that significant long-term improvements have been shown in a rehabilitation approach with neglect patients with a mean time of more than 12 months post-stroke and visuomotor feedback training can thus be seen as a most encouraging paradigm for future attempts.


Palliative beam radiotherapy offered real-world survival benefit to metastatic rectal cancer: A large US population-based and propensity score-matched study.
Purpose: Radiotherapy (RT) has been reported to effectively palliate many symptoms of patients with metastatic rectal cancer (mRC). The objective of this study was to evaluate the survival benefit of RT in mRC. Methods: A retrospective population-based cohort study was performed using the Surveillance, Epidemiology, and End Results Program (SEER) database. Patient baseline demographic characteristics between the RT and no-RT groups were compared using Pearson chi-square tests. The outcome of interest was cause-specific survival (CSS). Propensity score (PS) matching and Cox proportional hazards regression analyses were performed to evaluate the prognostic power of variables on CSS. Results: A total of 8851 patients with mRC were identified in the SEER database. Multivariable Cox regression analysis showed that RT was a protective factor in mRC (hazard ratio [HR]= 0.702, 95% confidence interval [CI]=0.665-0.741, p<0.001). In subgroup analysis, multivariate Cox analysis demonstrated that patients of both surgery and no-surgery subgroups treated with RT had better CSS than those not treated with RT (HR=0.654, 95%CI=0.607-0.704, p<0.001 for the surgery group; HR=0.779, 95%CI=0.717-0.847, p<0.001 for the no-surgery group), PS matching resulted in 4170 mRC patients and RT group presented significantly improved survival benefit than no-RT group (22.0 vs. 13.5%, P <0.001). In surgery subgroup after PS matching, in especial, RT group showed more evidently improved survival benefit than no-RT group (30.3 vs. 18.0%, p <0.001). Conclusion: Using the SEER database, we definitely demonstrated that RT was associated with a significant survival advantage beyond the relief of a variety of pelvic symptoms in the setting of mRC. This study strongly supports the use of RT in selected patients with mRC, especially in patients who have undergone surgery. More studies need to be conducted to accurately define the role of RT in mRC.


Myocardial Effective Transverse Relaxation Time T 2* is Elevated in Hypertrophic Cardiomyopathy: A 7.0 T Magnetic Resonance Imaging Study.
Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the myocardium and bares the risk of progression to heart failure or sudden cardiac death. Identifying patients at risk remains an unmet need. Recognizing the dependence of microscopic susceptibility on tissue microstructure and on cardiac macromorphology we hypothesized that myocardial T2* might be altered in HCM patients compared to healthy controls. To test this hypothesis, myocardial T2*-mapping was conducted at 7.0 Tesla to enhance T2*-contrast. 2D CINE T2*-mapping was performed in healthy controls and HCM patients. To ensure that T2* is not dominated by macroscopic magnetic field inhomogeneities, volume selective B0 shimming was applied. T2* changes in the interventricular septum across the cardiac cycle were analyzed together with left ventricular radius and ventricular septal wall thickness. The results show that myocardial T2* is elevated throughout the cardiac cycle in HCM patients compared to healthy controls. A mean septal T2* = 13.7 ± 1.1 ms (end-systole: T2*,systole = 15.0 ± 2.1, end-diastole: T2*,diastole = 13.4 ± 1.3 ms, T2*,systole/T2*,diastole ratio = 1.12) was observed in healthy controls. For HCM patients a mean septal T2* = 17.4 ± 1.4 ms (end-systole: T2*,systole = 17.7 ± 1.2 ms, end-diastole: T2*,diastole = 16.2 ± 2.5 ms, T2*,systole/T2*,diastole ratio = 1.09) was found. Our preliminary results provide encouragement that assessment of T2* and its changes across the cardiac cycle may benefit myocardial tissue characterization in HCM.


Microfluidic leukocyte isolation for gene expression analysis in critically ill hospitalized patients.
Microarray technology is becoming a powerful tool for diagnostic, therapeutic, and prognostic applications. There is at present no consensus regarding the optimal technique to isolate nucleic acids from blood leukocyte populations for subsequent expression analyses. Current collection and processing techniques pose significant challenges in the clinical setting. Here, we report the clinical validation of a novel microfluidic leukocyte nucleic acid isolation technique for gene expression analysis from critically ill, hospitalized patients that can be readily used on small volumes of blood. We processed whole blood from hospitalized patients after burn injury and severe blunt trauma according to the microfluidic and standard macroscale leukocyte isolation protocol. Side-by-side comparison of RNA quantity, quality, and genome-wide expression patterns was used to clinically validate the microfluidic technique. When the microfluidic protocol was used for processing, sufficient amounts of total RNA were obtained for genome-wide expression analysis from 0.5 mL whole blood. We found that the leukocyte expression patterns from samples processed using the 2 protocols were concordant, and there was less variability introduced as a result of harvesting method than there existed between individuals. The novel microfluidic approach achieves leukocyte isolation in <25 min, and the quality of nucleic acids and genome expression analysis is equivalent to or surpasses that obtained from macroscale approaches. Microfluidics can significantly improve the isolation of blood leukocytes for genomic analyses in the clinical setting.


Percutaneous radiologically guided gastrostomy tube placement: comparison of antegrade transoral and retrograde transabdominal approaches.
We aimed to compare the antegrade transoral and the retrograde transabdominal approaches for fluoroscopy-guided percutaneous gastrostomy tube (G-tube) placement. Following institutional review board approval, all G-tubes at two academic hospitals (January 2014 to May 2015) were reviewed retrospectively. Retrograde approach was used at Hospital 1 and both antegrade and retrograde approaches were used at Hospital 2. Chart review determined type of anesthesia used during placement, dose of radiation used, fluoroscopy time, procedure time, medical history, and complications. A total of 149 patients (64 women, 85 men; mean age, 64.4±1.3 years) underwent G-tube placement, including 93 (62%) placed via the retrograde transabdominal approach and 56 (38%) placed via the antegrade transoral approach. Retrograde placement entailed fewer anesthesiology consultations (P < 0.001), less overall procedure time (P = 0.023), and less fluoroscopy time (P < 0.001). A comparison of approaches for placement within the same hospital demonstrated that the retrograde approach led to significantly reduced radiation dose (P = 0.022). There were no differences in minor complication rates (13%-19%; P = 0.430), or major complication rates (6%-7%; P = 0.871) between the two techniques. G-tube placement using the retrograde transabdominal approach is associated with less fluoroscopy time, procedure time, radiation exposure, and need for anesthesiology consultation with similar safety profile compared with the antegrade transoral approach. Additionally, it is hypothesized that decreased procedure time and anesthesiology consultation using the transoral approach are likely associated with reduced cost.


Spontaneous perforation of Meckel's diverticulum: case report and review of literature.
Meckel's diverticulum is a congenital anomaly found in approximately 2% of the general population. The complications caused by Meckel's diverticulum include intussusception, volvulus in adolescents and acute bleeding in adults 3. This is an interesting and unusual case of spontaneous perforation of Meckel's diverticulum, in a Caucasian woman. A 46-year-old Caucasian woman was admitted because of severe abdominal pain and diarrhoea. A CT (Fig. 1) scan of the abdomen and pelvis was obtained, which demonstrated free air and a moderate amount of free fluid in the pelvis tracking up the gutters. The patient was consented and taken to theatre for diagnostic laparoscopy. A normal appendix was identified during laparoscopic examination of the abdomen. An inflammatory mass was seen with turbid fluid collection in the pelvic area on laparoscopy. The inflammatory mass turned out to be a perforated Meckel's diverticulum (Fig. 2). Wedge resection of the perforated Meckel's diverticulum was performed with endoGIA stapler fired at the base of diverticulum. Histopathology showed heterotopic gastric mucosa within the diverticulum and evidence of acute inflammation with perforation. The patient was followed up for two years and is symptom-free. The total lifetime rate of complications is widely accepted at 4%, with a male-to female ratio ranging from 1.8:1 to 3:1 4,5. Hemorrhage is the most common presentation in children and is reported in over 50% of cases 10. In adults, hemorrhage occurs often but only in 11.8% is present 5. 90% of bleeding diverticula contain heterotropic mucosa, most often gastric mucosa 13. In one study, 11% of children with complicated Meckel's diverticulum (MD) were initially diagnosed with appendicitis.8 The diagnosis of ruptured MD was ultimately made by laparoscopy. This case demonstrates that a healthy degree of suspicion for complicated MD should be present when dealing with a questionable diagnosis of appendicitis. Laparoscopy has a definite role in patients with symptomatic Meckel's diverticulum, especially when the diagnosis is in doubt and it has proved definitive in facilitating diagnosis.


Myeloid cell expressed proprotein convertase FURIN attenuates inflammation.
The proprotein convertase enzyme FURIN processes immature pro-proteins into functional end- products. FURIN is upregulated in activated immune cells and it regulates T-cell dependent peripheral tolerance and the Th1/Th2 balance. FURIN also promotes the infectivity of pathogens by activating bacterial toxins and by processing viral proteins. Here, we evaluated the role of FURIN in LysM+ myeloid cells in vivo. Mice with a conditional deletion of FURIN in their myeloid cells (LysMCre-fur(fl/fl)) were healthy and showed unchanged proportions of neutrophils and macrophages. Instead, LysMCre-fur(fl/fl) mice had elevated serum IL-1β levels and reduced numbers of splenocytes. An LPS injection resulted in accelerated mortality, elevated serum pro-inflammatory cytokines and upregulated numbers of pro-inflammatory macrophages. A genome-wide gene expression analysis revealed the overexpression of several pro-inflammatory genes in resting FURIN-deficient macrophages. Moreover, FURIN inhibited Nos2 and promoted the expression of Arg1, which implies that FURIN regulates the M1/M2-type macrophage balance. FURIN was required for the normal production of the bioactive TGF-β1 cytokine, but it inhibited the maturation of the inflammation-provoking TACE and Caspase-1 enzymes. In conclusion, FURIN has an anti-inflammatory function in LysM+ myeloid cells in vivo.


Oral health-related quality of life and its relationship with health locus of control among Indian dental university students.
The objectives of this study were to assess the relationship between Oral Health-Related Quality of Life (OHRQoL) and Health Locus of Control (HLC) among students in an Indian dental school. A cross sectional study design was used. Three hundred and twenty-five dental students returned completed forms containing the 14 item Oral Health Impact Profile (OHIP-14) and the 18 item Multidimensional Health Locus of Control Scale (MHLC). The results showed that the perceived OHRQoL differed among students studying in different stages of the dental course. The OHRQoL dimensions of 'Social Handicap' and 'Handicap' were significantly (P < 0.01) lower among the later years of the course than the freshman year students. There was a sharp increase in Self-reported dental problems, in particular, Malocclusion, Tooth decay, Calculus among the third year and final year students respectively. The OHIP-14 scores were significantly higher among those with self-reported oral problems. Correlation analysis between the OHIP-14 and the MHLC scores also showed a statistically significant (P < 0.01) correlation between the 'Chance' dimension of the MHLC and OHIP-14 scores. The results of this study underscored the relationship between the OHRQoL and HLC and of importance of assessing health attitudes and their impact on OHRQoL among the dental student community.


Programmed Death Ligand 1 Expression Among 700 Consecutive Endometrial Cancers: Strong Association With Mismatch Repair Protein Deficiency.
This study aims to determine the prevalence of programmed death ligand 1 (PD-L1) expression in endometrial carcinoma (EC) and determine clinical and pathological associations. Immunohistochemistry for PD-L1 was performed on sections of a triple-core tissue microarray of 700 ECs. Positive PD-L1 expression, defined as 1% of cells staining positive, was evaluated in tumor and stromal compartments. Using age-adjusted logistic regression, we estimated odds ratios and 95% confidence intervals for associations between PD-L1 expression (overall and by staining compartment) with clinical and tumor characteristics. Kaplan-Meier plots and log-rank tests were used to evaluate associations between PD-L1 expression and EC-specific survival. PD-L1 expression was observed in 100 cases (14.3%), including 27 (3.9%) with expression in tumor cells only, 35 (5.0%) with expression in both tumor cells and stroma, and 38 (5.4%) with expression in stroma only. Expression was observed in ECs of different histologic types. Tumors characterized by loss of mismatch repair proteins were significantly associated with tumoral PD-L1 expression (P < 0.0001), but not with stromal PD-L1 expression. Both tumoral and stromal PD-L1 expressions were associated with high-grade endometrioid histology, nonendometrioid histology, and lymphovascular space invasion. We observed no significant associations between PD-L1 expression and EC-specific survival. PD-L1 is expressed in a significant proportion of EC and is associated with mismatch repair deficiency, potentially representing a mechanism of tumor immune evasion and a therapeutic target in EC.


Loss of E-cadherin promotes migration and invasion of cholangiocarcinoma cells and serves as a potential marker of metastasis.
Tumor progression is characterized by loss of cell adhesion and increase of invasion and metastasis. E-cadherin, a cell adhesion molecule, is frequently downregulated and has been proposed as an important mediator in epithelial-mesenchymal transition (EMT) in tumors. In this study, we investigated the expression of E-cadherin and its association with cancer invasion and prognosis in cholangiocarcinoma (CCA). Immunohistochemistry results demonstrated a statistically significant association between the positive metastasis status with low E-cadherin protein expression in human CCA tissues (P = 0.04). Statistical trends were identified for low E-cadherin level and shorter survival time (P = 0.08). Targeting the E-cadherin expression in CCA cells with siRNA caused upregulation of vimentin, a mesenchymal marker, and disappearance of the E-cadherin/β-catenin adhesion complex from cell membranes. Moreover, migration and invasion abilities of the cells were increased under this condition. These findings suggest that reduction of E-cadherin contributes to CCA progression by attenuating the strength of cellular adhesion, which affects motility as well as regulating the expression of EMT-related genes during CCA invasion and metastasis. Thus, E-cadherin can act as a central modulator of tumor cell phenotype and is a potential metastasis marker in CCA.