Prediction of novel target genes and pathways involved in irinotecan-resistant colorectal cancer.
Acquired drug resistance to the chemotherapeutic drug irinotecan (the active metabolite of which is SN-38) is one of the significant obstacles in the treatment of advanced colorectal cancer (CRC). The molecular mechanism or targets mediating irinotecan resistance are still unclear. It is urgent to find the irinotecan response biomarkers to improve CRC patients' therapy. Genetic Omnibus Database GSE42387 which contained the gene expression profiles of parental and irinotecan-resistant HCT-116 cell lines was used. Differentially expressed genes (DEGs) between parental and irinotecan-resistant cells, protein-protein interactions (PPIs), gene ontologies (GOs) and pathway analysis were performed to identify the overall biological changes. The most common DEGs in the PPIs, GOs and pathways were identified and were validated clinically by their ability to predict overall survival and disease free survival. The gene-gene expression correlation and gene-resistance correlation was also evaluated in CRC patients using The Cancer Genomic Atlas data (TCGA). The 135 DEGs were identified of which 36 were upregulated and 99 were down regulated. After mapping the PPI networks, the GOs and the pathways, nine genes (GNAS, PRKACB, MECOM, PLA2G4C, BMP6, BDNF, DLG4, FGF2 and FGF9) were found to be commonly enriched. Signal transduction was the most significant GO and MAPK pathway was the most significant pathway. The five genes (FGF2, FGF9, PRKACB, MECOM and PLA2G4C) in the MAPK pathway were all contained in the signal transduction and the levels of those genes were upregulated. The FGF2, FGF9 and MECOM expression were highly associated with CRC patients' survival rate but not PRKACB and PLA2G4C. In addition, FGF9 was also associated with irinotecan resistance and poor disease free survival. FGF2, FGF9 and PRKACB were positively correlated with each other while MECOM correlated positively with FGF9 and PLA2G4C, and correlated negatively with FGF2 and PRKACB after doing gene-gene expression correlation. Targeting the MAPK signal transduction pathway through the targeting of the FGF2, FGF9, MECOM, PLA2G4C and PRKACB might increase tumor responsiveness to irinotecan treatment.


Clinical Usefulness of Serial Duplex Ultrasound in Cervical Artery Dissection Patients.
To study the clinical usefulness of serial color-coded duplex ultrasound (DUS) examinations in cervical artery dissection (CeAD) patients. Single-center, CeAD registry-based re-review of serial, routine DUS exams in consecutive CeAD patients treated at the Stroke Center Basel, Switzerland (2009-2015). Two experienced raters reassessed all DUS for the occurrence of new arterial findings during follow-up, that is. (i) recanalization of the dissected artery (if occluded at baseline), (ii) delayed occlusion of a patent dissected artery, and (iii) recurrent CeAD. We studied whether these new arterial findings were associated with clinical symptoms. In 94 CeAD patients (n = 40 female [42.6%], median age 46 years [interquartile range (IQR) 36.2-53]), 506 DUS examinations were reviewed covering a median length of follow-up of 54.1 weeks (IQR 30.5-100.5). In total, 105 dissected arteries were detected, of which 27 (25.7%) were occluded. In 28/94 patients (29.8%), 31 new arterial findings were recorded, which were associated with clinical symptoms in 9/31 (30%) patients. Recanalization of occluded CeAD was observed in 22/27 (81.5%) arteries and occurred in 20/22 arteries within 3 months. In 4/22 patients (18.2%), recanalization was associated with clinical symptoms (ischemic events [n = 2], pure local symptoms [n = 2]). Delayed occlusions were observed in 4/78 (5.1%) dissected arteries patent at baseline. All were clinically asymptomatic and occurred within 14 days from baseline. Recurrent CeAD (all symptomatic) occurred in 5 previously non-dissected arteries. In CeAD patients, follow-up DUS identified new arterial findings, of which several were associated with clinical symptoms: we found that about 1 of 5 recanalizations were associated with clinical symptoms, of whom half were ischemic symptoms. Further, delayed occlusions occurred in patients with no or mild stenosis at baseline and were asymptomatic. This study emphasizes the potential importance of repeated DUS in CeAD particularly in the early phase of up to 4 weeks.


Lactones in the Synthesis of Prostaglandins and Prostaglandin Analogs.
In the total stereo-controlled synthesis of natural prostaglandins (PGs) and their structural analogs, a vast class of compounds and drugs, known as the lactones, are encountered in a few key steps to build the final molecule, as: δ-lactones, γ-lactones, and 1,9-, 1,11-, and 1,15-macrolactones. After the synthesis of 1,9-PGF2α and 1,15-PGF2α lactones, many 1,15-lactones of E2, E3, F2, F3, A2, and A3 were found in the marine mollusc Tethys fimbria and the quest for understanding their biological role stimulated the research on their synthesis. Then 1,9-, 1,11-, and 1,15-PG lactones of the drugs were synthesized as an alternative to the corresponding esters, and the first part of the paper describes the methods used for their synthesis. The efficient Corey procedure for the synthesis of prostaglandins uses the key δ-lactone and γ-lactone intermediates with three or four stereocenters on the cyclopentane fragment to link the PG side chains. The paper describes the most used procedures for the synthesis of the milestone δ-Corey-lactones and γ-Corey-lactones, their improvements, and some new promising methods, such as interesting, new stereo-controlled and catalyzed enantioselective reactions, and methods based on the chemical/enzymatic resolution of the compounds in different steps of the sequences. The many uses of δ-lactones not only for the synthesis of γ-lactones, but also for obtaining 9β-halogen-PGs and halogen-substituted cyclopentane intermediates, as synthons for new 9β-PG analogs and future applications, are also discussed.


Boosting with missing predictors.
Boosting is an important tool in classification methodology. It combines the performance of many weak classifiers to produce a powerful committee, and its validity can be explained by additive modeling and maximum likelihood. The method has very general applications, especially for high-dimensional predictors. For example, it can be applied to distinguish cancer samples from healthy control samples by using antibody microarray data. Microarray data are often high-dimensional and many of them are incomplete. One natural idea is to impute a missing variable based on the observed predictors. However, the calculation of imputation for high-dimensional predictors with missing data may be rather tedious. In this paper, we propose 2 conditional mean imputation methods. They can be applied to the situation even when a complete-case subset does not exist. Simulation results indicate that the proposed methods are superior than other naive methods. We apply the methods to a pancreatic cancer study in which serum protein microarrays are used for classification.


Complement bridges between cells analysis of a possible cell-cell interaction mechanism.
Different leukocytes (Raji, Daudi, Rael lymphoid cells; human peripheral blood lymphocytes, and guinea pig granulocytes), which had been coated with C3 by incubation of 37 degrees C for 20 min in a C3 solution, were demonstrated to form rosettes with erythrocytes coated with complement components (EAC142). The percentage of rosettes was dependent of the amount of C3 present on the cells. Loading of the lymphoid cells with C3 was a time- and temperature-dependent process. C3b was unable to serve the same purposes, although C3 and C3b occupied the C3 receptors on the lymphoid cells to a comparable degree. C3 functions in a similar manner. The C42 enzyme can be replaced by trypsin, so that bridging units may consist of C3 + C42, C5 + C42 OR C3 + trypsin, and C5 + trypsin. Bridging units can be constructed also from C4 + C1. It is suggested that enzymes on one cell liberate labile binding groups of complement components on adjacent cells, thus inducing coupling of the two cells. The possibility is raised that this type of cell interlinkage may play a role in vivo, since there is accumulating evidence that complement components are expressed in the plasma membrane of different cells.


Subthalamic nucleus deep brain stimulation does not improve visuo-motor impairment in Parkinson's disease.
To evaluate how bilateral subthalamic nucleus deep brain stimulation (STN-DBS) affects visuo-motor coordination (VMC) in patients with Parkinson's disease (PD). VMC involves multi-sensory integration, motor planning, executive function and attention. VMC deficits are well-described in PD. STN-DBS conveys marked motor benefit in PD, but pyscho-cognitive complications are recognized and the effect on VMC is not known. Thirteen PD patients with bilateral STN-DBS underwent neurological, cognitive, and mood assessment before VMC testing with optimal DBS stimulation parameters ('on-stimulation') and then, on the same day without any medication changes, after DBS silencing and establishing motor function deterioration ('off-stimulation'). Twelve age-matched healthy controls performed 2 successive VMC testing sessions, with a break of similar duration to that of the PD group. The computer cursor was controlled with a dome-shaped 'mouse' hidden from view that minimized tremor effects. Movement duration, hand velocity, tracking continuity, directional control variables, and feedback utilization variables were measured. MANOVA was performed on (1) clinically measured motor function, (2) VMC performance and (3) mood and attention, looking for main and interaction effects of: (1) group (controls/PD), (2) test-order (controls: first/second, PD: on-stimulation/off-stimulation), (3) path (sine/square/circle) and (4) hand (dominant/non-dominant). Unified PD Rating Scale (UPDRS) Part III worsened off-stimulation versus on-stimulation (mean: 42.3 versus 21.6, p = 0.02), as did finger tapping (p = 0.02), posture-gait (p = 0.01), upper limb function (p<0.001) and backwards digit span (p = 0.02). Stimulation state did not affect mood. PD patients performed worse in non-velocity related VMC variables than controls (F(5,18) = 8.5, p<0.001). In the control group there were significant main effects of hand (dominant/non-dominant), path (sine/square/circle) and test-order (Test_1/Test_2). In the PD group, hand and path effects, but no test-order (on-stimulation/off-stimulation), were found. 'Low-level' clinically-measured motor function responds to STN-DBS but 'high-level' motor and cognitive functions relating to VMC may be unresponsive to STN-DBS.


Phylogenetic characterization of a novel radiation-resistant bacterium from irradiated pork: description of Hymenobacter actinosclerus sp. nov.
A phylogenetic analysis was performed on a red-pigmented, radiation-resistant, Gram-negative, rod-shaped organism originating from irradiated pork. Comparative 16S rRNA gene sequencing showed the bacterium was a member of the Cytophaga-Flavobacterium-Bacteroides line of descent and represents a new subline within the genus Hymenobacter. A new species, Hymenobacter actinosclerus, is described for this novel radiation-resistant bacterium. The type strain of Hymenobacter actinosclerus is CCUG 39621T.


Investigation of the molecular assembly of beta-cell K(ATP) channels.
We have investigated the protein interactions involved in the assembly of pancreatic beta-cell ATP-sensitive potassium channels. The channels are a heterooligomeric complex of pore-forming Kir6.2 subunits and sulfonylurea receptor (SUR1) subunits. SUR1 belongs to the ATP binding cassette (ABC) family of proteins and has two nucleotide binding domains (NBD1 and NBD2) and 17 putative transmembrane (TM) sequences. Previously we showed that co-expression in a baculovirus expression system of two parts of SUR1 divided at Pro1042 between TM12 and 13 leads to restoration of glibenclamide binding activity, whereas expression of either individual N- or C-terminal domain alone gave no glibenclamide binding activity [M.V. Mikhailov and S.J.H. Ashcroft (2000) J. Biol. Chem. 275, 3360-3364]. Here we show that the two half-molecules formed by division of SUR1 between NBD1 and TM12 or between TM13 and 14 also self-assemble to give glibenclamide binding activity. However, deletion of NBD1 from the N-part of SUR1 abolished SUR1 assembly, indicating a critical role for NBD1 in SUR1 assembly. We found that differences in glibenclamide binding activity obtained after co-expression of different half-molecules are attributable to different amounts of binding sites, but the binding affinities remained nearly the same. Simultaneous expression of Kir6.2 resulted in enhanced glibenclamide binding activity only when the N-half of SUR1 included TM12. We conclude that TM12 and 13 are not essential for SUR1 assembly whereas TM12 takes part in SUR1 Kir6.2 interaction. This interaction is specific for Kir 6.2 because no enhancement of glibenclamide binding was observed when half-molecules were expressed together with Kir4.1. We propose a model of K(ATP) channel organisation based on these data.


The etiology of hypertransaminasemia in Turkish children.
The aim of this study was to investigate the causes of elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in children. We analyzed the medical records for children aged 3 months to 18 years who presented to the hospital with ALT >45 IU/L and/or AST >50 IU/L, between 2012 and 2014, for various reasons, including those not related to liver disease. In total, 281 children met the study criteria. This group comprised of 125 (44.5%) females and 156 (55.5%) males. At the presentation, the most common patient complaint was fatigue (53.4%), while 15.7% of the patients reported no symptoms. The most common findings on the physical examination were jaundice and hepatomegaly. In 15% of the cases, the findings were normal. According to the diagnosis, the most common cause of the elevated transaminases were infections (34%), with hepatitis A virus (HAV) infection as the leading cause (18.9%). Drug-induced liver injury (DILI) was the cause in 18.1% of the cases and non-alcoholic fatty liver disease (NAFLD) in 11.1%. The highest transaminase levels were associated with HAV infection, while DILI and NAFLD caused only slightly elevated transaminases. Overall, our results show that the elevated transaminases in children are most often caused by infections, DILI, and NAFLD. In a majority of cases, elevated ALT and AST indicate liver disease, however, they could also be associated with conditions other than liver damage. Additionally, the elevated enzymes can be detected in completely healthy individuals.


A Population-Based Study on Nighttime Road Traffic Noise and Insomnia.
The aims of the present study were to investigate how nighttime road traffic noise relates to self-reported symptoms of insomnia and sleep medication use. We used questionnaire data from the population-based study Health and Environment in Oslo (HELMILO) (2009-2010; n = 13019). The insomnia symptoms difficulties falling asleep, awakenings during the night, and waking up too early in the morning as well as self-reported sleep medication use were included as outcomes. Modeled noise levels (Lnight) were assigned to each participant's home address. For selecting covariates to the statistical model, we used a directed acyclic graph. The associations between noise and sleep were analyzed using logistic regression models. After adjustment for potential confounders, we found an odds ratio (OR) of 1.05 (95% confidence interval [CI]: 1.01-1.09) for the association between traffic noise and difficulties falling asleep, in the total study population. For the association between traffic noise and awakenings during the night, the OR was 1.04 (95% CI: 1.00-1.08) and for waking up too early, the OR was 1.06 (95% CI: 1.02-1.11). The effect estimates are given per 5-dB increase in traffic noise level (Lnight). Self-reported sleep medication use was not statistically significantly associated with traffic noise exposure. In an adult population from Oslo, traffic noise was associated with difficulties falling asleep and waking up too early. These findings indicate that sleep quantity may be compromised for individuals living in areas highly exposed to nighttime traffic noise.


Polarization Engineered p-Type Electron Blocking Layer Free AlGaN Based UV-LED Using Quantum Barriers with Heart-Shaped Graded Al Composition for Enhanced Luminescence.
In this paper, in order to address the problem of electron leakage in AlGaN ultra-violet light-emitting diodes, we have proposed an electron-blocking free layer AlGaN ultra-violet (UV) light-emitting diode (LED) using polarization-engineered heart-shaped AlGaN quantum barriers (QB) instead of conventional barriers. This novel structure has decreased the downward band bending at the interconnection between the consecutive quantum barriers and also flattened the electrostatic field. The parameters used during simulation are extracted from the referred experimental data of conventional UV LED. Using the Silvaco Atlas TCAD tool; version 8.18.1.R, we have compared and optimized the optical as well as electrical characteristics of three varying LED structures. Enhancements in electroluminescence at 275 nm (52.7%), optical output power (50.4%), and efficiency (61.3%) are recorded for an EBL-free AlGaN UV LED with heart-shaped Al composition in the barriers. These improvements are attributed to the minimized non-radiative recombination on the surfaces, due to the progressively increasing effective conduction band barrier height, which subsequently enhances the carrier confinement. Hence, the proposed EBL-free AlGaN LED is the potential solution to enhance optical power and produce highly efficient UV emitters.


Voluntary wheel running from early adolescence reduces disease progression, and anxiety- and depression-related symptoms in an adult male mouse model of rheumatoid arthritis.
Rheumatoid arthritis (RA) is a multifactorial autoimmune disease that progressively destroys synovial joints and leads to chronic systemic inflammation. This autoimmune disorder is associated with increased anxiety- and depression-related symptoms, which reduces quality of life. Clinical and experimental evidence suggests that higher physical activity from early adolescence may prevent chronic diseases and reduce the risk of mental health problems in adulthood. This study aimed to assess whether voluntary wheel running from early adolescence can decrease clinical symptoms, anxiety- and depression-related behaviors in adult mice with rheumatoid arthritis. Adolescent male mice were exposed to voluntary wheel running until adulthood and got collagen-induced arthritis. We measured body weight, the thickness of the hind paw and knee joint (clinical signs), anxiety- and depression-related behaviors, serum testosterone, and cytokines (IFN-γ IL-1β, IL-6, TNF-α, IL-10). The findings showed that collagen-induced arthritis resulted in anxious-like behavior, increased anhedonia, elevated IL-6, IL-1β, TNF-α, and IFN-γ, and decreased testosterone levels in the serum of mice. However, no change was observed in behavioral despair. We found that higher physical activity from early adolescence significantly reduced the severity of clinical signs, anxiety- and anhedonia-like behaviors, and decreased behavioral despair in RA-induced mice. In addition, the running wheel exposure normalized RA-induced abnormalities in testosterone and inflammatory cytokines in mice. Altogether, this study suggests that higher physical activity from early adolescence may make mice less vulnerable or resistant to RA-induced clinical symptoms and anxiety- and depression-related behaviors by changing testosterone and inflammatory cytokines productions in adulthood.


Application of low-pressure cell seeding system in tissue engineering.
Tissue engineering has been one of the most promising strategies for the regeneration of impaired tissue. Application of three-dimensional porous scaffolds has greatly improved the outcome of tissue engineering in many categories. Cell seeding is one of the key issues in tissue regeneration. It depends not only on the biocompatibility and affinity of the scaffold, but also on the seeding techniques. Current seeding techniques such as centrifugation and perfusion have enhanced better cell seeding, but still have their limitations. How to seed cells more efficiently and uniformly, especially in the inner parts of the scaffolds, and with no impairment to the cells, has been one of the major challenges in using porous scaffolds for tissue engineering. Low pressure seeding meets the above requirements and can easily be integrated into other seeding systems. Here we review, based on the literature, and discuss the feasibility and application of this low pressure system to promote tissue regeneration.


Association between residential proximity to PERC dry cleaning establishments and kidney cancer in New York City.
Perchloroethylene (PERC) is commonly used as a dry cleaning solvent and is believed to be a human carcinogen, with occupational exposure resulting in elevated rates of kidney cancer. Living near a dry cleaning facility using PERC has been demonstrated to increase the risk of PERC exposure throughout the building where the dry cleaning is conducted, and in nearby buildings. We designed this study to test the hypothesis that living in an area where there are many PERC dry cleaners increases PERC exposure and the risk of kidney cancer. We matched the diagnosis of kidney cancer from hospitalization discharge data in New York City for the years 1994-2004 by zip code of patient residence to the zip code density of dry cleaners using PERC, as a surrogate for residential exposure. We controlled for age, race, gender, and median household income. We found a significant association between the density of PERC dry cleaning establishments and the rate of hospital discharges that include a diagnosis of kidney cancer among persons 45 years of age and older living in New York City. The rate ratio increased by 10 to 27% for the populations in zip codes with higher density of PERC dry cleaners. Because our exposure assessment is inexact, we are likely underestimating the real association between exposure to PERC and rates of kidney cancer. Our results support the hypothesis that living near a dry cleaning facility using PERC increases the risk of PERC exposure and of developing kidney cancer. To our knowledge, this study is the first to demonstrate an association between residential PERC exposure and cancer risk.


Evolution of viral variants in remdesivir-treated and untreated SARS-CoV-2-infected pediatrics patients.
Detailed information on intrahost viral evolution in SARS-CoV-2 with and without treatment is limited. Sequential viral loads and deep sequencing of SARS-CoV-2 from the upper respiratory tract of nine hospitalized children, three of whom were treated with remdesivir, revealed that remdesivir treatment suppressed viral load in one patient but not in a second infected with an identical strain without any evidence of drug resistance found. Reduced levels of subgenomic RNA during treatment of the second patient, suggest an additional effect of remdesivir on viral replication. Haplotype reconstruction uncovered persistent SARS-CoV-2 variant genotypes in four patients. These likely arose from within-host evolution, although superinfection cannot be excluded in one case. Although our dataset is small, observed sample-to-sample heterogeneity in variant frequencies across four of nine patients suggests the presence of discrete viral populations in the lung with incomplete population sampling in diagnostic swabs. Such compartmentalization could compromise the penetration of remdesivir into the lung, limiting the drugs in vivo efficacy, as has been observed in other lung infections.


Lessons learned: patient recruitment strategies for a type 2 diabetes intervention in a primary care setting [corrected].
This study reports on methods and strategies employed to increase participation rates in diabetes interventions and discusses the reach and representativeness of the Diabetes Priority Program. A passive mail-out procedure was used to contact patients of participating primary care physicians. Patients who did not return the refusal postcard were contacted. Several attempts were made to contact potential participants. Brochures, "wrong number" postcards, posters, and reports for clinic staff were strategies used to increase participation. The recruitment process resulted in a participation rate of 83% among patients who were contacted and eligible. These participants appeared to be representative of both nonparticipants and persons with diabetes in Colorado. In contrast, a low percentage of primary care physicians, estimated at 3%, took part in the program despite efforts to make the program brief, nonintrusive, and compatible with usual care. Recruitment is currently challenging and will become even more difficult with the privacy regulations that affect healthcare research and the public distrust of solicitations. To increase participation rates, it is important that the clinic staff promotes and supports the program, and that participant lists are accurate and adequate in size.


In vivo evaluation of an injectable Macroporous Calcium Phosphate Cement.
Although Calcium Phosphate Cements (CPC) are highly biocompatible and osteconductive materials, its resorption rate still remains too slow for some applications. In this work the introduction of Macroporosity in an injectable CPC is evaluated as a way to accelerate resorption and to increase bone ingrowth. A Macroporous and a standard CPC were injected just after preparation in a defect drilled in rabbit femur for their in vivo evaluation. The foaming agent used was Albumen, which gave up to a 75% porosity. Sodium Alginate was added to promote the cohesion of the foamed paste after implantation. In the case of the Macroporous Cement, bone growth and neovascularisation was observed inside the pores of the material, not only at the margins of the cement but also in some central pores. After 12 weeks of implantation, the residual material volume of the Macroporous Cement was approximately 35% of the initial value, whereas only the outer layers of non-Macroporous CPC were resorbed, being the residual material volume close to 100%. The higher resorption rate was due to the higher surface contact with body fluids which increased the dissolution rate, and to the enhancement of the cellular activity.


Exercise headcount: what do you do with 800 scientists who cannot return to the building they have just evacuated?
Annual fire drills serve a valuable purpose in ensuring familiarity with evacuation procedures. However, the limited duration of these exercises may be far from the reality of a real incident. In this situation, the ability to return back into a building may be restricted for hours or days. As an emergency manager, this raises a number of questions, including what to do with the evacuated colleagues, how to provide welfare support and how to identify those people who require the most immediate assistance. This paper focuses on these questions through a case study of 'Exercise Headcount'. Developed in response to the situation Pfizer faced as a result of the 2007 New York steam-pipe explosion, the paper provides an overview of the post-evacuation mustering and triage system that was developed for the Pfizer Research & Development site at Sandwich, UK.


Design, Development, and Evaluation of SA-F127:TPGS Polymeric Mixed Micelles for Improved Delivery of Glipizide Drug: In-vitro, Ex-vivo, and In-vivo Investigations.
The anti-diabetic glipizide (GLN) drug has notable pharmaceutical advantages, but poor aqueous solubility restricts its wide applications. The present work was to develop a mixed polymeric micelle system composed of SA-F127 and TPGS to improve the water solubility and effective delivery of the GLN. First, we synthesized SA-F127 and confirmed it through FTIR, NMR, and GPC techniques. The GLN-PMM were fabricated with the thin-film technique and optimized with CCD design. The developed GLN-PMM was characterized using DLS, Zeta, TEM, Rheology, FTIR, DSC, and XRD measurements. The GLN-PMM manifested a spherical morphology with 67.86 nm particle size, a -3.85 mV zeta potential, and a 0.582±0.06 PDI value. The polymeric mixed micelles showed excellent compatibility with GLN and were amorphous in nature. NMR studies confirmed the encapsulation of GLN in the core of the mixed micelle. In addition, the GLN-PMM micelles were tested in vitro for cumulative drug release, ex vivo for permeation, and in vivo for anti-diabetic investigations. The GLN-PMM release profile in the various pH environments showed over 90% after 24 h, clearly indicating sustained release. The GLN-PMM micelles gave higher 88.86±3.39% GLN permeation from the goat intestine compared with free GLN. In-vivo anti-diabetic investigation proves the powerful anti-diabetic properties of GLN-PMM in comparison to the marketed formulation. These findings demonstrated that the polymeric mixed micelles of SA-F127 and TPGS could be a promising, effective, and environment-friendly approach for oral delivery of the GLN.


Inhibitory effects of beta-carotene, palm carotene, and green tea polyphenols on pancreatic carcinogenesis initiated by N-nitorsobis(2-oxopropyl)amine in Syrian golden hamsters.
The effects of alpha-carotene, beta-carotene, palm carotene, and green tea polyphenols (GTP) on the progression stage of pancreatic carcinogenesis after rapid production of ductal lesions were studied in Syrian hamsters. Dose threshold inhibitory effects were noted for beta-carotene, 25 ppm, and palm carotene, 40 ppm, which includes 24 ppm beta-carotene reducing the numbers of putative preneoplastic lesions of duct epithelial hyperplasia and atypical hyperplasia, as well as carcinoma in situ and invasive carcinomas. GTP at doses of 500 and 5000 ppm, but not 100 ppm, also significantly decreased the numbers of hyperplasia and total duct lesions. Combined administration of 40 ppm palm carotene, and 50 ppm GTP similarly inhibited the lesion development. Alpha-carotene, however, did not affect pancreatic carcinogenesis. The results suggest that chemopreventive effects are exerted by beta-carotene and GTP above critical doses and that combined administration of palm carotene and GTP might be a candidate chemoprevention strategy for pancreatic cancer in humans.


How does income affect mental health and health behaviours? A quasi-experimental study of the earned income tax credit.
Although research has repeatedly demonstrated the association between poverty, mental health, and health behaviours, there is limited evidence on the effects of interventions to improve these outcomes by addressing poverty directly. Moreover, most prior studies are often confounded by unobserved characteristics of individuals, making it difficult to inform possible interventions. We addressed this gap in the literature by leveraging quasi-random variation in the earned income tax credit (EITC)-the largest US poverty alleviation programme for families with children-to examine the effects on overall health, psychological distress, smoking, and alcohol consumption. We used a large diverse national sample drawn from the Panel Study of Income Dynamics (N=34 824). We first conducted ordinary least squares (OLS) models to estimate the association of income and the EITC with the outcomes of interest. We subsequently employed a quasi-experimental instrumental variables (IV) analysis-in which EITC refund size was the instrument-to estimate the effect of income itself. In OLS models, higher income was associated with reductions in psychological distress, increased drinking, increased smoking, and more cigarettes per day, and larger EITC refunds were associated with reductions in psychological distress. In IV models, higher income was associated with decreased psychological distress. These results suggest that typical correlational studies of the health effects of income may be confounded, although results may not generalise to income distributed in different ways than the EITC. The findings also provide valuable information for policymakers and researchers seeking to address socioeconomic disparities in mental health.


Correlation between emotion dysregulation and mood symptoms of bipolar disorder: A systematic review and meta-analysis.
Emotion dysregulation (ED) is a transdiagnostic construct characterized by difficulties regulating intense emotions. People with bipolar disorder (BD) are more likely to show ED and use maladaptive emotion regulation strategies than adaptive ones. However, little is known about whether ED in BD is a trait or it is rather an epiphenomenon of mood symptoms. We conducted a systematic review and meta-analysis of the evidence across major literature databases reporting correlations between measures of emotion regulation (overall ED and different emotion regulation strategies) and measures of depressive and (hypo)manic symptoms in BD from inception until April 12th, 2022. Fourteen studies involving 1371 individuals with BD were included in the qualitative synthesis, of which 11 reported quantitative information and were included in the meta-analysis. ED and maladaptive strategies were significantly higher during periods with more severe mood symptoms, especially depressive ones, while adaptive strategies were lower. ED significantly correlates with BD symptomatology, and it mainly occurs during mood alterations. ED may be a target for specific psychotherapeutic and pharmacological treatments, according to precision psychiatry. However, further studies are needed, including patients with mood episodes and longitudinal design, to provide more robust evidence and explore the causal direction of the associations.


Krüppel-like factor 6 regulates mitochondrial function in the kidney.
Maintenance of mitochondrial structure and function is critical for preventing podocyte apoptosis and eventual glomerulosclerosis in the kidney; however, the transcription factors that regulate mitochondrial function in podocyte injury remain to be identified. Here, we identified Krüppel-like factor 6 (KLF6), a zinc finger domain transcription factor, as an essential regulator of mitochondrial function in podocyte apoptosis. We observed that podocyte-specific deletion of Klf6 increased the susceptibility of a resistant mouse strain to adriamycin-induced (ADR-induced) focal segmental glomerulosclerosis (FSGS). KLF6 expression was induced early in response to ADR in mice and cultured human podocytes, and prevented mitochondrial dysfunction and activation of intrinsic apoptotic pathways in these podocytes. Promoter analysis and chromatin immunoprecipitation studies revealed that putative KLF6 transcriptional binding sites are present in the promoter of the mitochondrial cytochrome c oxidase assembly gene (SCO2), which is critical for preventing cytochrome c release and activation of the intrinsic apoptotic pathway. Additionally, KLF6 expression was reduced in podocytes from HIV-1 transgenic mice as well as in renal biopsies from patients with HIV-associated nephropathy (HIVAN) and FSGS. Together, these findings indicate that KLF6-dependent regulation of the cytochrome c oxidase assembly gene is critical for maintaining mitochondrial function and preventing podocyte apoptosis.


Cytotoxicity of bracket identification dyes.
To investigate the potential cytotoxicity of the bracket identification dyes commonly used in orthodontic fixed appliances. Six bracket brands representing the market in various aspects were selected. Ten sets of each bracket brand were acquired, and the identification dyes on them were scraped. They were tested for cytotoxicity at three different levels of concentration (2.5 mg/mL, 5 mg/mL, and 10 mg/mL), with the aid of a real-time cell analysis system. The results were compared within and between the groups. One-way analysis of variance and Tukey's post hoc test were used for statistical analysis. None of the six investigated dyes displayed cytotoxicity at the 2.5 mg/mL concentration. Of the investigated brands, three at 5 mg/mL and four at 10 mg/mL displayed cytotoxicity. Some of the identification dyes in this study did display cytotoxicity at the higher concentrations tested. Alternative methods for bracket identification should be considered.


Primary Epstein-Barr virus infection.
Epstein-Barr virus (EBV) infects about 90% of adults worldwide. It is the main cause of infectious mononucleosis, which is observed most frequently in adolescents. The disease can last several weeks and is characterized by lymphocytosis, sore throat, lymphadenopathy, and fatigue. Exposure to oral secretions during deep kissing has been identified as the major source for primary EBV infection in adolescents. Oral secretions are also thought to be the source for younger children through intimate intact or sharing food and eating utensils, although this has not been confirmed. Unlike most acute viral illnesses such as influenza, the incubation period of symptomatic primary EBV infection is unusually long, lasting about six weeks. Diagnosis is typically made by heterophile antibody tests and/or EBV-specific antibody tests. Long-term consequences may result from acquisition of the virus, including nasopharyngeal carcinoma and lymphomas. Nevertheless, there remains a surprising dearth of knowledge regarding the establishment of an immune response to persistent EBV infection, especially during the incubation period. This lack of knowledge has impaired our ability to develop an effective prophylactic EBV vaccine, despite various attempts. Our greatest challenges in EBV research are to develop a prophylactic vaccine and devise treatment strategies for persons already infected with EBV.


Temperature-, pH-, and magnetic-field-sensitive hybrid microgels.
We demonstrate a simple route for the preparation of novel hybrid particles with multiple sensitivities. Aqueous polymeric microgels are modified by magnetite nanoparticles in the preparation of temperature- and pH-sensitive hybrids with a high magnetic response. Up to 15 wt % of magnetite nanoparticles are loaded into microgels. The influence of the amount of magnetite in the microgel structure on the morphology and colloidal properties is discussed. The presence of the magnetite nanoparticles in the microgel decreases its degree of swelling and shifts the volume phase-transition temperature to higher values. Nanostructured composite films with controlled morphologies can be prepared by water evaporation and deposition of the hybrid microgels on a solid substrate.


The value of seizure semiology in lateralizing and localizing partially originating seizures.
Diagnosing epilepsy depends heavily on a detailed, and accurate description of the abnormal transient neurological manifestations. Observing the seizures yields important semiologic features that characterize epilepsy. Video-EEG monitoring allows the identification of important lateralizing (left versus right), and localizing (involved brain region) semiologic features. This information is vital for identifying the seizure origin for possible surgical interventions. The aim of this review is to present a summary of important semiologic characteristics of various seizures that are important for accurate seizure lateralization and localization. This would most likely help during reviewing video-EEG recorded seizures of intractable patients for possible epilepsy surgery. Semiologic features of partial and secondarily generalized seizures can be grouped into one of 4 categories including; automatism, speech, motor, and autonomic features. These features will be discussed in detail in this review. However, seizure semiology should be correlated with EEG and MRI findings. Accurate identification of the seizure origin is more likely if focal EEG onset and MRI findings were concordant with the clinical semiology.


Dietary lipid content reorganizes gut microbiota and probiotic L. rhamnosus attenuates obesity and enhances catabolic hormonal milieu in zebrafish.
In the present study, we explored whether dietary lipid content influences the gut microbiome in adult zebrafish. Diets containing three different lipid levels (high [HFD], medium [MFD], and low [LFD]) were administered with or without the supplementation of Lactobacillus rhamnosus (P) to zebrafish in order to explore how the dietary lipid content may influence the gut microbiome. Dietary lipid content shifted the gut microbiome structure. The addition of L. rhamnosus in the diets, induced transcriptional reduction of orexigenic genes, upregulation of anorexigenic genes, and transcriptional decrease of genes involved in cholesterol and triglyceride (TAG) metabolism, concomitantly with lower content of cholesterol and TAG. Probiotic feeding also decreased nesfatin-1 peptide in HFD-P and attenuated weight gain in HFD-P and MFD-P fed zebrafish, but not in LFD-P group. Intestinal ultrastructure was not affected by dietary fat level or probiotic inclusion. In conclusion, these findings underline the role of fat content in the diet in altering gut microbiota community by shifting phylotype composition and highlight the potential of probiotics to attenuate high-fat diet-related metabolic disorder.


Rapid changes in carbohydrate metabolism in muscle induced by triiodothyronine; the role of glucose 1,6-bisphosphate.
All of the past research on glucose utilization by muscles focused on the slow action of thyroid hormones. Here we show that experimental hyperthyroidism, which was induced in rats by a single intramuscular injection of 3,3', 5-triiodothyronine (T3) at high concentration, resulted in rapid changes (within minutes) in carbohydrate metabolism in tibialis anterior muscle. There was an increase in lactate content, in the allosteric activity of soluble phosphofructokinase (the rate-limiting enzyme in glycolysis), and in its product fructose 1,6-bisphosphate, 5 min following the injection of T3, suggesting stimulation of glycolysis. The allosteric activity of mitochondrial-bound, and, to a lesser extent, of soluble hexokinase, was also enhanced. However, the intracellular distribution of the enzymes was unchanged by the hormone. The allosteric stimulation of hexokinase may be attributed to the decrease in glucose 1,6-bisphosphate, which is a potent inhibitor of hexokinase. The level of glucose 6-phosphate, another unknown inhibitor of hexokinase, was not changed by the hormone. The activation of phosphofructokinase following T3 injection may be attributed to the decrease in ATP, an allosteric inhibitor of the enzyme, and the increase in the levels of Pi and fructose 1,6-bisphosphate, allosteric activators of the enzyme. Glycogen content was also significantly decreased in muscle 5 min following the injection of T3. These results suggest that in hyperthyroidism, muscle reacts rapidly to the excess of thyroid hormones by stimulation of glycogenolysis, glucose phosphorylation, and glycolysis, to provide ATP, which may serve as a compensatory mechanism to ATP depletion.


Highly regio- and stereoselective halohydroxylation reaction of 1,2-allenyl phenyl sulfoxides. Reaction scope, mechanism, and the corresponding pd- or ni-catalyzed selective coupling reactions.
A highly regio- and stereoselective halohydroxylation of 1,2-allenyl sulfoxides with X(+) and water was developed. The reaction shows E-stereoselectivity. In the iodohydroxylation reaction, I(2) was used to introduce the iodine atom. For bromohalohydroxylation, CuBr(2), NBS, or Br(2) can be used. When using I(2), NBS, or Br(2), the addition of LiOAc.2H(2)O is necessary for high yields of the halohydroxylation products. The chlorohydroxylation reaction was preformed by milling 1,2-allenyl sulfoxides and CuCl(2).2H(2)O with silica gel. Under the catalysis of a Pd(0) complex, the halohydroxylation products, that is, E-2-halo-1-phenylsulfinyl-1-alken-3-ols, can undergo Sonogashira, Suzuki, and Negishi cross-coupling reactions leading to Z-2-substituted-1-phenylsulfonyl-1-alken-3-ols. The C-S bond of the coupling product may undergo a further coupling reaction with organozincs under the catalysis of an Ni catalyst. Here, the presence of a hydroxyl group is important for a smooth coupling involving the C-S bond. Thus, optically active stereodefined multisubstituted allylic alcohols can be prepared by the reaction of the easily available optically active propargylic alcohols with sulfinyl chloride followed by E-halohydroxylation and a selective Pd- or Ni-coupling reaction.


Interaction between cochleata and stipule-reduced mutations results in exstipulate hypertrophied leaves in Pisum sativum L.
In the wild type P. sativum, each of the adult plant stem nodes, bears a pair of sessile foliaceous stipules and a petiolated unipinnately compound leaf of 4 to 6 leaflets and 7-9 tendrils. The stipule-reduced (st) and cochleata (coch) single null mutants and coch st double null mutant differ fom the wild type in respectively having sessile stipules of much reduced size, petiolated simple and/or compound leaf-like stipules and no stipules. It is also known that coch leaves are somewhat bigger than st and wild type leaves. Here, pleiotropic phenotype of coch st double mutant was investigated. The morphologies of stipules and leaf were quantified in the field grown plants and microcultured shoots, latter in the presence and absence of gibberellic acid and N-1-naphthylphthalamic acid. The observations showed that as compared to the corresponding plants or shoots of COCH ST (WT) genotype, (a) coch st plants bore leaves in which all the organs were hypertrophied; (b) full complement of leaflets and 3-5 tendrils were formed on leaf; (c) the microcultured coch st shoots were taller despite lower number of nodes, and (d) they also produced leaves in which all the organs were bigger and the ratio of leaflets/tendrils was higher. It was concluded that in coch st double mutant (a) ST function is essential for stipule primordium differentiation, in the absence of COCH function and (b) absence of negative feedback loops between simple stipules and compound leaf for metabolite utilization allows hypertrophied growth in leaves.


Intensity-modulated radiation therapy for oropharyngeal carcinoma: impact of tumor volume.
To assess the therapeutic outcomes in oropharyngeal cancer patients treated with intensity-modulated radiotherapy (IMRT) and analyze the impact of primary gross tumor volume (GTV) and nodal GTV (nGTV) on survival and locoregional control rates. Between February 1997 and September 2001, 74 patients with squamous cell carcinoma of the oropharynx were treated with IMRT. Thirty-one patients received definitive IMRT; 17 also received platinum-based chemotherapy. Forty-three patients received combined surgery and postoperative IMRT. The median follow-up for all patients was 33 months (range, 9-60 months). Fifty-two patients (70.3%) had Stage IV disease, 17 patients (23%) had Stage III, 3 patients (4.1%) had Stage II, and 2 patients (2.7%) had Stage I tumors. The mean prescription dose was 70 and 66 Gy, respectively, for the definitive and postoperative cohorts. The daily fraction dose was either 1.9 or 2 Gy, five times weekly. The GTV and/or nGTV were determined and derived using the Computational Environment for Radiotherapy Research, a free software package developed at Washington University. The mean GTV was 30.5 +/- 22.3 cm(3), and the mean nGTV was 23.2 +/- 20.6 cm(3). Ten locoregional failures were observed. Six patients died of disease and three died of concurrent disease. Distant metastasis developed in 6 patients. The 4-year estimate of overall survival was 87%, and the 4-year estimate of disease-free survival was 81% (66% in the definitive vs. 92% in the postoperative RT group). The 4-year estimate of locoregional control was 87% (78% in the definitive vs. 95% in the postoperative RT group); the 4-year estimate of distant metastasis-free survival was 90% (84% in the definitive vs. 94% in the postoperative group). Multivariate analysis showed that GTV and nGTV were independent risk factors determining locoregional control and disease-free survival for definitive oropharyngeal IMRT patients. The worst late toxicities documented were as follows: 32 patients with Grade 1 and 9 with Grade 2 xerostomia; 2 with Grade 1 and 1 with Grade 2 skin toxicity; 3 with Grade 1 late mucositis; and 3 with Grade 1 trismus. Seventeen patients required gastrostomy tube placement. IMRT is an effective treatment modality for locally advanced oropharyngeal carcinoma. The GTV and nGTV are the most important factors predictive of therapeutic outcome.


Strand asymmetry of +1 frameshift mutagenesis at a homopolymeric run by DNA polymerase III holoenzyme of Escherichia coli.
We have recently shown that single-base frameshifts were predominant among mutations induced within the rpsL target sequence upon oriC plasmid DNA replication in vitro. We found that the occurrence of +1 frameshifts at a run of 6 residues of dA/dT could be increased proportionally by increasing the concentration of dATP present in the in vitro replication. Using single-stranded circular DNA containing either the coding sequence of the rpsL gene or its complementary sequence, the +1 frameshift mutagenesis by DNA polymerase III holoenzyme of Escherichia coli was extensively examined. A(6) --> A(7) frameshifts occurred 30 to 90 times more frequently during DNA synthesis with the noncoding sequence (dT tract) template than with the coding sequence (dA tract). Excess dATP enhanced the occurrence of +1 frameshifts during DNA synthesis with the dT tract template, but no other dNTPs showed such an effect. In the presence of 0.1 mM dATP, the A(6) --> A(7) mutagenesis with the dT tract template was not inhibited by 1.5 mM dCTP, which is complementary to the residue immediately upstream of the dT tract. These results strongly suggested that the A(6) --> A(7) frameshift mutagenesis possesses an asymmetric strand nature and that slippage errors leading to the +1 frameshift are made during chain elongation within the tract rather than by misincorporation of nucleotides opposite residues next to the tract.


Human XPF controls TRF2 and telomere length maintenance through distinctive mechanisms.
XPF-ERCC1, a structure-specific endonuclease, is involved in nucleotide excision repair, crosslink repair and homologous recombination. XPF-ERCC1 is also found to interact with TRF2, a duplex telomeric DNA binding protein. We have previously shown that XPF-ERCC1 is required for TRF2-promoted telomere shortening. However, whether XPF-ERCC1 by itself has a role in telomere length maintenance has not been determined. Here we report that overexpression of XPF induces telomere shortening in XPF-proficient cells whereas XPF complementation suppresses telomere lengthening in XPF-deficient cells. These results suggest that XPF-ERCC1 can function as a negative mediator of telomere length maintenance. In addition, we find that introduction of wild type XPF into XPF-deficient cells leads to over 40% reduction in TRF2 association with telomeric DNA, indicating that XPF-ERCC1 negatively regulates TRF2 binding to telomeric DNA. Furthermore, we show that XPF carrying mutations in the conserved nuclease domain fails to control TRF2 association with telomeric DNA but it is competent for modulating telomere length maintenance. These results imply that XPF-ERCC1 controls TRF2 and telomere length maintenance through two distinctive mechanisms, with the former requiring its nuclease activity. Our results further imply that TRF2 association with telomeres may be deregulated in cells derived from XPF patients.


Sequence specific recognition of ligand-DNA complexes studied by NMR.
The last few years have represented an accelerated accumulation in detailed information about ligand-DNA interactions. A collected view of literature information is essential for advancing our understanding of the principles of ligand-DNA recognition, utilizing this valuable information for construction of a modeling database, and eventually the rational design of DNA-binding ligands possessing desired properties. This review is concentrated on structure-based information on ligand-oligodeoxyribonucleotide (DON) complexes published since 1995, especially focusing on the results obtained from NMR structure elucidation. The discussions emphasize the sequence specific recognition of novel binding motifs or binding modules of ligand molecules rather than specific atomic details. A comprehensive list of DNA binding ligands are discussed in the text and are also summarized in a table. The DNA sequences that are recognized by specific ligand molecules as studied by NMR are annotated in a figure to provide a clear view of target selection. This review also briefly describes NMR methods for characterization and structure elucidation of ligand-DNA complexes.


Responsiveness of stem-like human glioma cells to all-trans retinoic acid and requirement of retinoic acid receptor isotypes α, β and γ.
Retinoic acid (RA) is required for development and homeostasis of the normal mammalian brain and may play a role in the initiation and progression of malignant brain tumors, such as the glioblastoma multiforme (GBM) and the gliosarcoma (Gsarc). The subpopulation of stem-like glioma cells (SLGCs) was shown to resist standard glioma radio-/chemotherapy and to propagate tumor regrowth. We used phenotypically distinct, self-renewing SLGC lines from six human GBMs, two Gsarcs, and two subcloned SLGC derivatives in order to investigate their responsiveness to all-trans retinoic acid (atRA) and to identify the RA-receptor (RAR) isotypes involved. In general, atRA exerted a pro-proliferative and pro-survival effect on SLGCs, though the efficacy was distinct. By means of RAR isotype-selective retinoids we disclosed that these effects were mediated by RARα and RARγ, except for one SLGC line, in which the pro-proliferative signal was induced by the RARβ-selective retinoid. Only one GBM-derived cell line (T1338) and a subpopulation of another (T1389) displayed neural differentiation in response to atRA. Differentiation of T1338 was induced by RARα and RARγ isotype-selective retinoids, associated with down-regulation of Sox2, and the failure to induce orthotopic tumors in the brains of SCID mice. The differential responsiveness of the SLGC lines appeared unrelated to the expression of RARβ, as (i) atRA augmented RAR isotype mRNA expression and particularly rarβ mRNA in all SLGC lines, (ii) rarβ promoter hypomethylation in the SLGC lines was not related to differentiation and (iii) the induction of T1338 differentiation was by RARα- and RARγ-selective ligands.


Consensus Development Conference on the Management of Clinically Localized Prostate Cancer. Overview: historical and contemporary.
Recognition of the clinical importance of prostate cancer undoubtedly was delayed by the failure of clinicians or pathologists to distinguish consistently between benign and malignant prostatic growths until well into the 19th century. White used castration for prostatic enlargements in 1895, but Huggins and Hodges first placed endocrine therapy on a rational basis in 1941. Although a number of surgeons had attempted excision of prostate cancer, Young is credited with planning and performing the first radical perineal prostatectomy in 1904. Orthovoltage irradiation and various techniques of interstitial and intracavitary radium therapy were used in the treatment of prostate cancer early in the 20th century, but it was the development of megavoltage irradiation that reopened the door to the exploration of irradiation for localized prostate cancer following World War II. Endocrine manipulation, surgery, and irradiation remain the keystones of treatment. The management of prostate cancer is controversial for several reasons: 1) The disease occurs in an age range in which competing causes of mortality are high. 2) The natural evolution of the disease is varied, often long, and not consistently predictable. 3) Long-term survival has been reported for each of the principal modes of therapy, but randomized controlled studies have been limited. Uniformity in histologic grading, clinical staging, and evaluation of response to treatment would improve the quality of the data. Predictions of host life expectancy, tumor growth rate, metastatic potential, and tumor responsiveness to irradiation and endocrine therapy would enhance the rationale of treatment.


[Syndromes 9. Hemifacial microsomia].
Hemifacial microsomia is also known under quite a number of synonyms. Pathognomonic for these usually sporadic cases are: marked three dimensional asymmetry of the mandible, the ear, the maxilla, the zygoma and the orbit. The more distal the structure, the more marked the asymmetry. Many other optional symptoms are described. The differential diagnosis is almost never a problem in this aspecific complex of symptoms. Surgical therapy asks for expert treatment. The treatment contains usually several operations of which one to three are really major. Even then, very good results are mainly obtained in the less pronounced cases only.


Deletion analysis of the FliM flagellar switch protein of Salmonella typhimurium.
The flagellar switch of Salmonella typhimurium and Escherichia coli is composed of three proteins, FliG, FliM, and FliN. The switch complex modulates the direction of flagellar motor rotation in response to information about the environment received through the chemotaxis signal transduction pathway. In particular, chemotaxis protein CheY is believed to bind to switch protein FliM, inducing clockwise filament rotation and tumbling. To investigate the function of FliM and its interactions with FliG and FliN, we engineered a series of 34 FliM deletion mutant proteins, each lacking a different 10-amino-acid segment. We have determined the phenotype associated with each mutant protein, the ability of each mutant protein to interfere with the motility of wild-type cells, and the effect of additional FliG and FliN on the function of selected FliM mutant proteins. Overall, deletions at the N terminus produced a counterclockwise switch bias, deletions in the central region of the protein produced poorly motile or nonflagellate cells, and deletions near the C terminus produced only nonflagellate cells. On the basis of this evidence and the results of a previous study of spontaneous FliM mutants (H. Sockett, S. Yamaguchi, M. Kihara, V. M. Irikura, and R. M. Macnab, J. Bacteriol. 174:793-806, 1992), we propose a division of the FliM protein into four functional regions: an N-terminal region primarily involved in switching, an extended N-terminal region involved in switching and assembly, a middle region involved in switching and motor rotation, and a C-terminal region primarily involved in flagellar assembly.


Effects of demand-side financing on utilisation, experiences and outcomes of maternity care in low- and middle-income countries: a systematic review.
Demand-side financing, where funds for specific services are channelled through, or to, prospective users, is now employed in health and education sectors in many low- and middle-income countries. This systematic review aimed to critically examine the evidence on application of this approach to promote maternal health in these settings. Five modes were considered: unconditional cash transfers, conditional cash transfers, short-term payments to offset costs of accessing maternity services, vouchers for maternity services, and vouchers for merit goods. We sought to assess the effects of these interventions on utilisation of maternity services and on maternal health outcomes and infant health, the situation of underprivileged women and the healthcare system. The protocol aimed for collection and synthesis of a broad range of evidence from quantitative, qualitative and economic studies. Nineteen health and social policy databases, seven unpublished research databases and 27 websites were searched; with additional searches of Indian journals and websites. Studies were included if they examined demand-side financing interventions to increase consumption of services or goods intended to impact on maternal health, and met relevant quality criteria. Quality assessment, data extraction and analysis used Joanna Briggs Institute standardised tools and software. Outcomes of interest included maternal and infant mortality and morbidity, service utilisation, factors required for successful implementation, recipient and provider experiences, ethical issues, and cost-effectiveness. Findings on Effectiveness, Feasibility, Appropriateness and Meaningfulness were presented by narrative synthesis. Thirty-three quantitative studies, 46 qualitative studies, and four economic studies from 17 countries met the inclusion criteria. Evidence on unconditional cash transfers was scanty. Other demand-side financing modes were found to increase utilisation of maternal healthcare in the index pregnancy or uptake of related merit goods. Evidence of effects on maternal and infant mortality and morbidity outcomes was insufficient. Important implementation aspects include targeting and eligibility criteria, monitoring, respectful treatment of beneficiaries, suitable incentives for providers, quality of care and affordable referral systems. Demand-side financing schemes can increase utilisation of maternity services, but attention must be paid to supply-side conditions, the fine-grain of implementation and sustainability. Comparative studies and research on health impact and cost-effectiveness are required.


IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030.
Diabetes is an increasingly important condition globally and robust estimates of its prevalence are required for allocating resources. Data sources from 1980 to April 2011 were sought and characterised. The Analytic Hierarchy Process (AHP) was used to select the most appropriate study or studies for each country, and estimates for countries without data were modelled. A logistic regression model was used to generate smoothed age-specific estimates which were applied to UN population estimates for 2011. A total of 565 data sources were reviewed, of which 170 sources from 110 countries were selected. In 2011 there are 366 million people with diabetes, and this is expected to rise to 552 million by 2030. Most people with diabetes live in low- and middle-income countries, and these countries will also see the greatest increase over the next 19 years. This paper builds on previous IDF estimates and shows that the global diabetes epidemic continues to grow. Recent studies show that previous estimates have been very conservative. The new IDF estimates use a simple and transparent approach and are consistent with recent estimates from the Global Burden of Disease study. IDF estimates will be updated annually.


Pyloric gland adenoma: an entity distinct from gastric foveolar type adenoma.
Pyloric gland adenoma (PGA) is a rare neoplasm demonstrating gastric epithelial differentiation. In this series, we studied 41 PGAs from 36 patients. We compared them to 28 gastric foveolar type gastric adenomas (GTAs) from 25 patients. PGAs occurred in an older population with a mean age of 73 compared with 48 in GTAs (P<0.001). There was a significant female predominance, particularly for gastric PGAs. Morphologically, PGAs were characterized by closely packed pyloric gland-type tubules with a monolayer of cuboidal to low columnar epithelial cells containing round nuclei and pale to eosinophilic cytoplasm with a ground glass appearance. The cells lacked an apical mucin cap, a feature distinct from GTAs. An immunohistochemical panel of mucin core peptides (MUCs) and CDX2 was performed on a subset of the lesions. All PGAs expressed MUC6 with coexpression of MUC5AC, whereas GTAs expressed predominantly MUC5AC without MUC6. Both lesions lacked CDX2 and MUC2 except in areas of intestinal metaplasia (IM) found in some PGAs. Histologic features consistent with conventional dysplasia were found in 26 (63.4%) PGAs. Using a 2-tier grading system, 5 (12.2%) cases demonstrated low-grade dysplasia whereas 21 (51.2%) cases showed high-grade dysplasia including 5 (12.2%) cases with an associated intramucosal or more deeply invasive adenocarcinoma. This was significantly different from GTAs; all cases showed only low-grade dysplasia (P<0.001). In addition, 60% of gastric PGAs were associated with IM in the surrounding mucosa and 40% of lesions arose in a background of autoimmune gastritis, whereas these 2 conditions were only associated with 1 case (3%) of GTA. In summary, PGA is a distinct entity. Despite its bland histologic appearance, it is much more likely to be accompanied by background IM and autoimmune gastritis and can evolve into invasive adenocarcinoma displaying pyloric gland differentiation.


Safety and efficacy of the MitraClip® system for severe mitral regurgitation: a systematic review.
The MitraClip® system is a newer percutaneous device that has shown promising results but data on its safety and efficacy in low- and high-surgical risk populations continues to evolve. We performed a systematic review of the published studies reporting the safety and efficacy of MitraClip® implantation for treatment of moderate to severe and severe mitral regurgitation (MR). Reviewers independently searched for relevant articles in Medline and abstracted clinical information based on pre-defined criteria and end-points. Patients were classified as low- or high-surgical risk for conventional mitral valve (MV) surgery based on Society of Thoracic Surgeons score, EuroSCORE, or surgeon discretion. Primary safety outcome was 30-day mortality and primary efficacy outcomes were freedom from death, ≥3+ MR, and requirement for MV surgery during follow-up. Immediate and long-term outcomes of 16 studies, including 2980 patients (age 73.7 ± 0.6 years; 63.3% males) receiving the MitraClip®, were analyzed. Acute procedural success rate was 91.4% with a procedural mortality of 0.1%. Mortality at 30 days and long-term (310 days) follow-up was 4.2 and 15.8%, respectively and was significantly higher in the high-risk group (P = 0.003 and 0.019, respectively). Incidence of major procedural adverse outcomes was relatively low with blood transfusion accounting for most events. At follow-up, the number of patients with ≥3+ MR reduced from 96.3% to 14.7% (P < 0.001), and those with NYHA class III/IV reduced from 83.2% to 23.4% (P < 0.001). MitraClip® implantation for moderate to severe or severe MR appears to be safe with a very low procedural mortality. There is significant improvement in functional outcomes although long-term mortality is high, especially in high surgical risk patients.


Lower soil carbon stocks in exotic vs. native grasslands are driven by carbonate losses.
Global change includes invasion by exotic (nonnative) plant species and altered precipitation patterns, and these factors may affect terrestrial carbon (C) storage. We measured soil C changes in experimental mixtures of all exotic or all native grassland plant species under two levels of summer drought stress (0 and +128 mm). After 8 yr, soils were sampled in 10-cm increments to 100-cm depth to determine if soil C differed among treatments in deeper soils. Total soil C (organic + inorganic) content was significantly higher under native than exotic plantings, and differences increased with depth. Surprisingly, differences after 8 yr in C were due to carbonate and not organic C fractions, where carbonate was ~250 g C/m2 lower to 1-m soil depth under exotic than native plantings. Our results indicate that soil carbonate is an active pool and can respond to differences in plant species traits over timescales of years. Significant losses of inorganic C might be avoided by conserving native grasslands in subhumid ecosystems.


[Purification and breaking techniques for cysts of Giardia spp].
The purpose of this study was to optimize and evaluate the purification techniques, isolation and breaking of cysts of Giardia spp from fecal samples to isolate DNA. Filtrated fecal samples were tested in 3 purification techniques: Telleman solution, sucrose and Telleman plus sucrose. The sucrose solution let us to isolate the cysts with less detritus. The cleaned cysts were splited in 3 techniques to test the breaking: osmotic shock and heat, chemistry degradation and thermic shock, enzymatic action and mechanic effect. Only the last method was successful and showed bands in agarose gel. The result of this study shows a routine and common method which could be used in the previous steps to the PCR technique for the genotypification of these parasites.


Storage Management Strategy in Mobile Phones for Photo Crowdsensing.
In mobile crowdsensing, some users jointly finish a sensing task through the sensors equipped in their intelligent terminals. In particular, the photo crowdsensing based on Mobile Edge Computing (MEC) collects pictures for some specific targets or events and uploads them to nearby edge servers, which leads to richer data content and more efficient data storage compared with the common mobile crowdsensing; hence, it has attracted an important amount of attention recently. However, the mobile users prefer uploading the photos through Wifi APs (PoIs) rather than cellular networks. Therefore, photos stored in mobile phones are exchanged among users, in order to quickly upload them to the PoIs, which are actually the edge services. In this paper, we propose a utility-based Storage Management strategy in mobile phones for Photo Crowdsensing (SMPC), which makes a sending/deleting decision on a user's device for either maximizing photo delivery ratio (SMPC-R) or minimizing average delay (SMPC-D). The decision is made according to the photo's utility, which is calculated by measuring the impact of reproducing or deleting a photo on the above performance goals. We have done simulations based on the random-waypoint model and three real traces: roma/taxi, epfl, and geolife. The results show that, compared with other storage management strategies, SMPC-R gets the highest delivery ratio and SMPC-D achieves the lowest average delay.


Rapid DNA-protein cross-linking and strand scission by an abasic site in a nucleosome core particle.
Apurinic/apyrimidinic (AP) sites are ubiquitous DNA lesions that are highly mutagenic and cytotoxic if not repaired. In addition, clusters of two or more abasic lesions within one to two turns of DNA, a hallmark of ionizing radiation, are repaired much less efficiently and thus present greater mutagenic potential. Abasic sites are chemically labile, but naked DNA containing them undergoes strand scission slowly with a half-life on the order of weeks. We find that independently generated AP sites within nucleosome core particles are highly destabilized, with strand scission occurring ∼60-fold more rapidly than in naked DNA. The majority of core particles containing single AP lesions accumulate DNA-protein cross-links, which persist following strand scission. The N-terminal region of histone protein H4 contributes significantly to DNA-protein cross-links and strand scission when AP sites are produced approximately 1.5 helical turns from the nucleosome dyad, which is a known hot spot for nucleosomal DNA damage. Reaction rates for AP sites at two positions within this region differ by ∼4-fold. However, the strand scission of the slowest reacting AP site is accelerated when it is part of a repair resistant bistranded lesion composed of two AP sites, resulting in rapid formation of double strand breaks in high yields. Multiple lysine residues within a single H4 protein catalyze double strand cleavage through a mechanism believed to involve a templating effect. These results show that AP sites within the nucleosome produce significant amounts of DNA-protein cross-links and generate double strand breaks, the most deleterious form of DNA damage.


Anterior capsular repair in total hip arthroplasty performed for late-presenting displaced femoral neck fractures.
Dislocation after total hip arthroplasty performed for femoral neck fractures occurs frequently due to the significantly higher range of movement of the postoperative hip joint. Proper wound closure can prevent the loss of structural support provided by the capsule and myofascial structures, and is essential for postoperative hip stability. On 32 consecutive patients (four men, 28 women; mean age 64 years, range 48-83 years) with unilateral late-presenting displaced femoral neck fractures, a careful anterior capsule repair technique during total hip arthroplasty was performed by a single surgeon between 1997 and 2000. At one-year follow-up, no dislocation had occurred in any patient. Intraoperative protection and careful anatomic reattachment of the hip joint capsule may increase the stability of the hip joint after total hip arthroplasty and lead to a lower incidence of dislocation.


Decomposing racial and ethnic disparities in the use of postacute rehabilitation care.
To determine the degree to which racial and ethnic disparities in the use of postacute rehabilitation care (PARC) are explained by observed characteristics. State inpatient databases (SIDs) for 2005 and 2006 from four diverse states were used to identify patients with stays for joint replacement, stroke, or hip fracture. Our primary outcomes were use of institutional PARC (versus discharge home) and, conditional on discharge to an institution, skilled nursing facility (versus inpatient rehabilitation facility) care. We modified the Oaxaca-Blinder decomposition method to account for the dichotomous outcome and multilevel nature of the data. Discharges from the four SIDs were included if the principal diagnosis (stroke, hip fracture) or procedure (joint replacement) was in the sample inclusion criteria. Observed characteristics explained roughly half of the unadjusted differences in use of institutional PARC. Patient-level factors (clinical, age) were more explanatory of disparities in institutional PARC use, while hospital-level factors were more explanatory of skilled nursing facility versus inpatient rehabilitation facility care. Adjustment for characteristics influencing PARC use both mitigated and exacerbated racial/ethnic disparities in use. The degree to which the characteristics explained the disparity varied across conditions and outcomes.


Structure-guided identification of C3d residues essential for its binding to complement receptor 2 (CD21).
A vital role for complement in adaptive humoral immunity is now beyond dispute. The crucial interaction is that between B cell and follicular dendritic cell-resident complement receptor 2 (CR2, CD21) and its Ag-associated ligands iC3b and C3dg, where the latter have been deposited as a result of classical pathway activation. Despite the obvious importance of this interaction, the location of a CR2 binding site within C3d, a proteolytic limit fragment of C3dg retaining CR2 binding activity, has not been firmly established. The recently determined x-ray structure of human C3d suggested a candidate site that was remote from the site of covalent attachment to Ag and consisted of an acidic residue-lined depression, which accordingly displays a significant electronegative surface potential. These attributes were consistent with the known ionic strength dependence of the CR2-C3d interaction and with the fact that a significant electropositive surface was apparent in a modeled structure of the C3d-binding domains of CR2. Therefore, we have performed an alanine scan of all of the residues within and immediately adjacent to the acidic pocket in C3d. By testing the mutant iC3b molecules for their ability to bind CR2, we have identified two separate clusters of residues on opposite sides of the acidic pocket, specifically E37/E39 and E160/D163/I164/E166, as being important CR2-contacting residues in C3d. Within the second cluster even single mutations cause near total loss of CR2 binding activity. Consistent with the proposed oppositely charged nature of the interface, we have also found that removal of a positive charge immediately adjacent to the acidic pocket (mutant K162A) results in a 2-fold enhancement in CR2 binding activity.


[Exercise-induced anaphylaxis--a review].
Exercise-induced anaphylaxis (EIA) is a syndrome in which patients experience the symptoms of anaphylaxis, which occur only after increased physical activity. It is characterised by a gradual development of symptoms: itching, erythema, urticaria, angioedema, anaphylactic shock (hypotension, syncope, loss of consciousness, shortness of breath, wheezing, nausea and vomiting), and at the end of the late phase prolonged urticaria and headache. The triggering factors for EIA are as follows: significant exposure to airborne allergens, insect sting, weather extremes, higher air humidity, taking nonsteroidal anti-inflammatory drugs. The most frequent causative nutritive allergens include wheat, crabs and shells. Prophylactic management for EIA comprises avoding the triggers. Exercise or other physical activity should be performed in proximity of medically trained companion.


The effect of intra-articular injection of ultracain in the temporomandibular joint in patients with preauricular pain: a randomized prospective double-blind placebo-controlled crossover study.
To evaluate the distinguishing ability of intra-articular anesthesia from placebo in orofacial pain patients with pain located in the temporomandibular joint (TMJ) region, aiming at a validation of intra-articular anesthesia injection as a diagnostic test of pain in the TMJ region. A randomized prospective double-blind, placebo-controlled crossover study was conducted among 19 patients (18 females, 1 male) with pain in the TMJ region. The short-term effects of intra-articular ultracain and saline injections on pain and maximum mouth opening were measured and analyzed. Compared with placebo injections, a statistically significant difference in pain scores was found after intra-articular injection of a local anesthetic on Visual Analog Scale values. The maximum mouth opening scores did, however, not differ between the 2 groups. TMJ injection with local anesthesia leads to the decrease of pain in patients with preauricular pain. To establish the source of pain, injection of a local anesthetic in the TMJ may be used as a diagnostic tool. However, the results of diagnostic injections should still be interpreted cautiously.


[Interpretation of the low rate of polypeptide synthesis in mitochondria in vitro].
The distribution of radioactivity between the growing and finally formed polypeptides in rat liver mitochondria incubated with labelled amino acids was studied. The rate of an "average" polypeptide synthesis in the mitochondrial translation system is much lower than that in bacterial and eukaryotic cytoplasmic protein synthesizing systems. A kinetic study of mitochondrial polypeptide labelling suggests that the rate of ribosomal movement along mRNA in mitochondrial translation systems is variable. It is assumed that the low rate of polypeptide synthesis in mitochondria is due to the delay in ribosome movement along the middle part of mRNA.


A 4-methyl-substituted meta-iodobenzylguanidine analogue with prolonged retention in human neuroblastoma cells.
As a part of our efforts to develop a meta-iodobenzylguanidine (MIBG) analogue with improved characteristics for the diagnosis and treatment of neuroendocrine tumours, 3-[131I]iodo-4-methyl-benzylguanidine ([131I]MeIBG) has been developed. The purpose of this study was to evaluate [131I]MeIBG in vitro using the uptake-1 positive SK-N-SH neuroblastoma cell line and in vivo in normal mice and mice bearing human neuroblastoma xenografts. The ability of SK-N-SH human neuroblastoma cells to retain [131I]MeIBG in vitro over a period of 4 days, in comparison to [125I]MIBG, was determined by a paired-label assay. Paired-label biodistributions of [131I]MeIBG and [125I]MIBG were performed in normal mice as well as in athymic mice bearing SK-N-SH and IMR-32 human neuroblastoma xenografts. Retention of [131I]MeIBG by SK-N-SH cells in vitro was increased by factors of 1.2, 1.5, 2.0, 2.5 and 3.1 compared with [125I]MIBG at 8, 24, 48, 72 and 96 h, respectively. In normal mice, the uptake of [131I]MeIBG in the heart was similar to that of [125I]MIBG at 1 and 4 h; in contrast, myocardial uptake of [131I]MeIBG was 1.6-fold higher than that of [125I]MIBG (p<0.05) at 24 h. When mice were pre-treated with the uptake-1 inhibitor desipramine (DMI), the heart uptake of both tracers was reduced to about half that in untreated controls at 1 h post injection (p<0.05). The hepatic uptake of [131I]MeIBG was two- to threefold lower than that of [125I]MIBG. On the other hand, blood levels of [131I]MeIBG were substantially higher (up to sixfold), especially at early time points. Uptake of [131I]MeIBG in heart and tumour at 1 h in the murine SK-N-SH model was specific and comparable to that of [125I]MIBG. However, [131I]MeIBG uptake was 1.6- to 1.7-fold lower than that of [125I]MIBG over 4-48 h. While the uptake of both tracers in IMR32 xenografts was similar, it was not uptake-1 mediated. Introduction of a methyl group at the 4-position of MIBG seems to be advantageous in terms of higher tumour retention in vitro and lower hepatic uptake in vivo. However, the slower blood clearance of MeIBG may be problematic for some applications.


Methylation associated inactivation of RASSF1A from region 3p21.3 in lung, breast and ovarian tumours.
Previously we analysed overlapping homozygous deletions in lung and breast tumours/tumour lines and defined a small region of 120 kb (part of LCTSGR1) at 3p21.3 that contained putative lung and breast cancer tumour suppressor gene(s) (TSG). Eight genes including RASSF1 were isolated from the minimal region. However, extensive mutation analysis in lung tumours and tumour lines revealed only rare inactivating mutations. Recently, de novo methylation at a CpG island associated with isoform A of RASSF1 (RASSF1A) was reported in lung tumours and tumour lines. To investigate RASSF1A as a candidate TSG for various cancers, we investigated: (a) RASSF1A methylation status in a large series of primary tumour and tumour lines; (b) chromosome 3p allele loss in lung tumours and (c) RASSF1 mutation analysis in breast tumours. RASSF1A promoter region CpG island methylation was detected in 72% of SCLC, 34% of NSCLC, 9% of breast, 10% of ovarian and 0% of primary cervical tumours and in 72% SCLC, 36% NSCLC, 80% of breast and 40% of ovarian tumour lines. In view of the lower frequency of RASSF1 methylation in primary breast cancers we proceeded to RASSF1 mutation analysis in 40 breast cancers. No mutations were detected, but six single nucleotide polymorphisms were identified. Twenty of 26 SCLC tumours with 3p21.3 allelic loss had RASSF1A methylation, while only six out of 22 NSCLC with 3p21.3 allele loss had RASSF1A methylation (P=0.0012), one out of five ovarian and none out of six cervical tumours with 3p21.3 loss had RASSF1A methylation. These results suggest that (a) RASSF1A inactivation by two hits (methylation and loss) is a critical step in SCLC tumourigenesis and (b) RASSF1A inactivation is of lesser importance in NSCLC, breast, ovarian and cervical cancers in which other genes within LCTSGR1 are likely to be implicated.


Computational modeling of bone density profiles in response to gait: a subject-specific approach.
The goal of this study is to explore the potential of computational growth models to predict bone density profiles in the proximal tibia in response to gait-induced loading. From a modeling point of view, we design a finite element-based computational algorithm using the theory of open system thermodynamics. In this algorithm, the biological problem, the balance of mass, is solved locally on the integration point level, while the mechanical problem, the balance of linear momentum, is solved globally on the node point level. Specifically, the local bone mineral density is treated as an internal variable, which is allowed to change in response to mechanical loading. From an experimental point of view, we perform a subject-specific gait analysis to identify the relevant forces during walking using an inverse dynamics approach. These forces are directly applied as loads in the finite element simulation. To validate the model, we take a Dual-Energy X-ray Absorptiometry scan of the subject's right knee from which we create a geometric model of the proximal tibia. For qualitative validation, we compare the computationally predicted density profiles to the bone mineral density extracted from this scan. For quantitative validation, we adopt the region of interest method and determine the density values at fourteen discrete locations using standard and custom-designed image analysis tools. Qualitatively, our two- and three-dimensional density predictions are in excellent agreement with the experimental measurements. Quantitatively, errors are less than 3% for the two-dimensional analysis and less than 10% for the three-dimensional analysis. The proposed approach has the potential to ultimately improve the long-term success of possible treatment options for chronic diseases such as osteoarthritis on a patient-specific basis by accurately addressing the complex interactions between ambulatory loads and tissue changes.


Supercoils in prokaryotic DNA restrained in vivo.
Cells of Escherichia coli containing the plasmid F were gamma-irradiated with various doses to introduce determined numbers of single-strand breaks in the F DNA. The cells were then incubated to permit repair of the breaks while DNA gyrase was inhibited with coumermycin to limit restoration of any relaxed supercoil. Repaired, covalently continuous F DNA was isolated and its superhelical density was measured by two different methods. Both indicated that a major part (50-60%) of the negative superhelical turns were maintained in the repaired molecules, suggesting that the supercoils are restrained in vivo.


A systematic review of economic studies on biological agents used to treat Crohn's disease.
Identifying clinical scenarios that maximize the cost-effectiveness of biological treatments can lead to optimized health care cost-saving and clinical effectiveness from a society's perspective. Published articles between January 1995 and June 2012 were searched in PubMed, EMBASE, ABI/INFORM, Tuft's Cost-Effectiveness Analysis Registry Database, Cochrane National Health Service Economic Evaluation Database, International Pharmaceutical Abstracts, Web of Science, and Google Scholar. Studies of interest included the following: (1) cost studies, (2) economic evaluations, or (3) narrative or systematic reviews related to economic evaluations of biological treatments for moderate-to-severe Crohn's disease (CD). The primary outcomes of interest included costs associated with biological treatments and cost-effectiveness measures, including incremental cost-effectiveness ratios. A threshold of $100,000/quality-adjusted life year (£60,000/quality-adjusted life year) gained was used for treatment cost-effectiveness. Thirty-eight studies were identified, including 15 economic evaluations and 23 cost studies or reviews of economic evaluations. Economic evaluations found that infliximab and adalimumab were more cost-effective than standard therapy for luminal CD when provided as an induction therapy followed by episodic therapy over 5 or more years. The cost-effectiveness of infliximab and adalimumab versus standard therapy for luminal CD was less certain when used as 1-year maintenance treatment with or without previous induction therapy. Cost studies revealed that infliximab therapy reduced health care resource utilization and cost. Older reviews were inconclusive about the cost-effectiveness of biological treatments used for CD. Current evidence suggests that biological treatments may be cost-effective for CD under certain clinical scenarios. Future studies evaluating all biological treatments are needed to compare their respective benefits and costs.


Involvement of miRNAs and Cell-Secreted Vesicles in Mammalian Ovarian Antral Follicle Development.
Ovarian follicular development is a controlled series of events culminating with an ovulatory or atretic follicle. MicroRNAs (miRNAs) are small noncoding RNAs involved in translational regulation of genes in different developmental processes. Deletion of Dicer in mice ovaries demonstrated the importance of miRNAs in reproduction, which led to infertility. The miRNAs were thought to act only within host cells; however, these molecules are also present in cell-secreted vesicles. These vesicles are present in body fluids such as milk, serum, and ovarian follicular fluid. Vesicles are secreted in extracellular fluids and travel from donor to target cells, mediating transfer of bioactive material. Herein we discuss the role of hormonal-regulated miRNAs within different ovarian follicular cells as well as cell-secreted vesicles participation in mammalian ovarian follicular fluid. Furthermore, we discuss the possibility of miRNAs transference mediated by cell-secreted vesicles present in ovarian follicular fluid, increasing the versatility of miRNA functions during antral follicle development.


Importance of therapeutic patient education in ichthyosis: results of a prospective single reference center study.
Ichthyoses are a heterogeneous group of rare genodermatoses. Patients and their families face difficulties related to daily care and management that may be aggravated by social isolation. To evaluate the impact of therapeutic educational programs in improving the knowledge of ichthyosis patients, and their relatives, about their disease. We organized a two sessions-program of "know-how" dedicated to the overall management of ichthyoses. These sessions were conducted based on a tool specifically designed for the study, which addressed our various areas of expertise through a collective game. The participants (patients and their parents and siblings) were divided into groups, and the questions were tailored according to the participants' age. The program was conceived as a knowledge reinforcement program that took place during a weekend of education and rest, organized away from healthcare structures. Our aim was to facilitate the program in a neutral place to encourage respite care and to ensure the availability of a multidisciplinary healthcare team. After the reinforcement session, children aged from 6 to 12 years and their families acquired the targeted know-how and social skills. Benefits of TPE in the management of ichthyoses are the following: (1) the trust between patients their families and the caregivers was strengthened; (2) the context of the program encouraged self-expression, answered questions and provided mutual aid; and (3) the more self-sufficient families could better manage emergencies.


Co-incidence of Human Papillomaviruses and Epstein-Barr Virus Is Associated With High to Intermediate Tumor Grade in Human Head and Neck Cancer in Syria.
High-risk human papillomaviruses (high-risk HPVs) have been recently reported to be co-present with Epstein-Barr virus (EBV) in different types of human cancers including head and neck (HN), where they can cooperate in the initiation and/or progression of this cancer. Accordingly, we herein explored the prevalence of high-risk HPVs and EBV in 80 HN cancer tissues from the Syrian population using polymerase chain reaction, immunohistochemistry, and tissue microarray methodologies. We report that high-risk HPVs and EBV are present in 35/80 (43.7%) and 41/80 (51.2%) of our samples, respectively, and the most frequent HPV types are 33, 16, 18, 45, 52, 58, 35, 51, and 31, in this order. More significantly, our data reveal that 25/80 (31.2%) of cancer cases are positive for high-risk HPVs as well as EBV, and their co-presence is associated with high/intermediate-grade squamous cell carcinomas. These data confirm the co-presence of high-risk HPVs and EBV in HN cancers in the Syrian population of the Middle East and demonstrate that their co-incidence is linked to a more aggressive cancer phenotype. Thus, future studies are required to confirm these data and elucidate the exact role of high-risk and EBV cooperation in human HN carcinogenesis.


Submandibular gland pleomorphic adenoma in a seven-year-old child: a case report.
Salivary gland neoplasms are rare in the pediatric age group. Pleomorphic adenomas in the submandibular gland are rarer. In this article, we present a seven-year-old female with a slowly growing mass in her right submandibular area. The firm, mobile and painless mass was about 2x3 cm in size and with bimanual palpation it was indiscriminated from the submandibular gland. Magnetic resonance imaging with contrast revealed a heterogeneous and minimally lobulated mass within the submandibular gland with clearly defined borders. Fine needle aspiration biopsy revealed a diagnosis of pleomorphic adenoma and we performed right submandibular gland excision under general anesthesia. The histopathological diagnosis was pleomorphic adenoma with sparse mitotic figures that may be interpreted as having a potential of malignant transformation. This patient who was followed up for one year without any complication is to our knowledge the youngest case cited in the English-language literature.


Exploring the Potential of a Thermionic LaB6 Virtual Source Mode Electron Gun for a High Angular Current Density and a Narrow Energy Distribution.
To date, lanthanum hexaboride (LaB6) thermionic electron sources have not been able fully to capitalize on their inherent potential, resulting in an ambiguous position within the application area. Although they exhibit higher brightness compared with a tungsten filament source, they still fall short of the performance of Schottky electron sources. This study aims to explore the capabilities of the LaB6 electron source under different operating conditions to bridge the gap, ultimately to realize its untapped potential. Simulations in virtual source mode indicated enhanced beam brightness and a reduced beam half-angle with an increase the extraction voltage, promising up to tenfold times higher beam brightness compared with the crossover mode. The energy distribution measured using a prelens retarding field energy analyzer revealed an energy distribution of 0.55 eV and a high angular current density of 33 mA/sr in the virtual source mode. Therefore, the virtual source mode of LaB6 can provide a narrow energy distribution akin to that of a ZrO/W Schottky electron gun (1600 K) while having an angular current density over 2,000 times higher. In addition, the stability of the virtual source mode is ±0.022%, while that of the crossover mode is ±0.138%.


[The course of generalized tuberculosis in a northern region].
The course of generalized tuberculosis in a northern region is mainly characterized by its subacute onset; moreover, the symptoms of intoxication and the bronchopulmonary manifestations of the disease are observed practically in all patients. Socially dysadapted individuals are most susceptible to this disease. Even if patients with generalized tuberculosis have significant symptoms of the diseases, only a few of them resort to a health care facility within a month after their occurrence. Hematological changes suggest the implication of suppressed immunity in the development of this form of tuberculosis and support the intensiveness of the disease. Bacterial discharge is noted in all virtually patients (80%). However, the Mantoux test is frequently of no informative value in diagnosing generalized tuberculosis. X-ray is always widely used; decay cavities are encountered in most patients. In addition to lung lesions, generalization of a tuberculous process is attended by the appearance of specific changes in the liver, spleen, kidneys, serous membranes, and peripheral lymph nodes.


Vitamin D receptor genotypes influence the success of calcitriol therapy for recurrent vertebral fracture in osteoporosis.
Osteoporosis is a complex multi-factorial disease where environment, diet and genetics play a role in determining susceptibility. Patients with existing vertebral fracture have a heightened risk of further recurrent vertebral fracture. The efficacy of new osteoporosis therapies is often compared to calcium supplementation. 1,25-dihydroxyvitamin D3 (calcitriol) acts through the vitamin D receptor (VDR) and is effective at reducing recurrent vertebral fracture risk. Because the VDR controls calcium metabolism, we hypothesized that genetic variation at the VDR locus may influence response to both calcium and calcitriol therapy. Postmenopausal women with osteoporosis from a 3-year study comparing calcitriol versus calcium for prevention of vertebral fractures were genotyped for VDR alleles detected by FokI, BsmI, ApaI and TaqI. Data were analysed by hierarchical log-linear analysis and robust analysis of variance for relationships to fracture outcomes. Significant differences in the vertebral fracture rate in response to calcium therapy were observed between VDR genotypes (P<0.001). Calcium appeared to be equally effective as calcitriol in particular genotypes. The response to calcitriol therapy was most pronounced in patients carrying the TaqI t allele in combination with the FokI f initiation codon variant: f+t+ carriers were 11.3-fold less likely to sustain recurrent vertebral fracture in the last 2 years of the trial while on calcitriol therapy compared to calcium (P=1.4x10(-5)). Response to both calcium and calcitriol therapy is dependent on genetic variation at the VDR locus and two loci in the VDR gene may contribute to this effect.


The federal medical loss ratio rule: implications for consumers in year 2.
For the past two years, the Affordable Care Act has required health insurers to pay out a minimum percentage of premiums in the form of medical claims or quality improvement expenses--known as a medical loss ratio (MLR). Insurers with MLRs below the minimum must rebate the difference to consumers. This issue brief finds that total rebates for 2012 were $513 million, half the amount paid out in 2011, indicating greater compliance with the MLR rule. Spending on quality improvement remained low, at less than 1 percent of premiums. Insurers continued to reduce their administrative and sales costs, such as brokers' fees, without increasing profit margins, for a total reduction in overhead of $1.4 billion. In the first two years under this regulation, total consumer benefits related to the medical loss ratio--both rebates and reduced overhead--amounted to more than $3 billion.