Exercise training before and after lung transplantation.
The benefits of exercise training in individuals with chronic lung diseases such as chronic obstructive pulmonary disease, cystic fibrosis, and interstitial lung disease have been well documented. Although there is limited research available, it appears that exercise is safe and beneficial for people with severe end-stage chronic lung disease who are awaiting lung transplantation in addition to recipients of lung transplants. Evidence-based guidelines for exercise training in the pre- and post-lung transplantation phases have not yet been developed. However, by considering exercise guidelines for people with chronic lung disease and in older adults in light of the physiological changes that can occur either pre- or post-lung transplantation, a safe and appropriate exercise training program can be developed. Depending on the individual's exercise capacity and goals, the training program may include aerobic and resistance exercise, and flexibility and balance training. In the pre-transplant and acute post-transplant phases, the intensity of exercise is dictated primarily by symptom limitation and adequate rest, which is required between exercise bouts to allow for recovery. In the post-transplant phase, it is possible for lung transplant recipients to increase their exercise capacity and even participate in sports. Further research needs to be conducted to determine the optimal training guidelines and the long-term benefits of exercise, both in lung transplant candidates and recipients.


Expressions of N-methyl-D-aspartate receptors NR2A and NR2B subunit proteins in normal and sulfite-oxidase deficient rat's hippocampus: effect of exogenous sulfite ingestion.
Sulfites whether ingested or produced through the sulfur-containing amino acids metabolism of the animal are very active molecules and can cause cellular toxicity. Sulfite oxidase (SOX), a heme- and molybdenum containing mitochondrial enzyme, prevents mammalian cells from adverse effects of sulfite toxicity by metabolizing sulfite to sulfate. The present study was aimed to investigate effect of sulfite on the N-methyl-D-aspartate (NMDA) receptor (NMDAR) NR2A and NR2B subunits in hippocampus of normal and SOX-deficient rats. Rats were divided into four groups; (1) control group, which was given rat chow and tap water ad libitum (C), (2) sulfite group, treated with sulfite (25 mg/kg) in drinking water and commercial rat chow ad libitum (S), (3) SOX-deficient group, maintained on high-W/Mo-deficient regimen to produce SOX deficiency (D), and (4) SOX-deficient + sulfite group (DS), prepared as those in the third group and were afterwards given sulfite (25 mg/kg) additionally. Whole treatment schedule were continued for 6 weeks. Sulfite treatment caused a decrease of NR2A and NR2B subunits of the NMDAR in hippocampus of rats in S and DS groups. Interestingly, similar decrement was observed in D group, probably due to increased endogenous sulfite production. In summary, the results indicated that feeding sulfite to the rats may cause down-regulation of NMDARs by degrading NR2A and NR2B subunits of it, which may be considered as a neuro-compensatory mechanism.


Mortality in heroin-assisted treatment in Switzerland 1994-2000.
A major goal of heroin-assisted treatment in Switzerland has been to reduce the drug-related mortality of heroin users. Therefore, a continuous monitoring of deaths under treatment is essential. To assess mortality of participants in heroin-assisted treatment in Switzerland over a 7-year period from 1994 to 2000, and to compare this mortality to the general population and to other populations of opioid users, as reported in the literature. Estimation of person years under heroin-assisted treatment from the complete case registry of heroin-assisted treatment in Switzerland. Estimation of standardized mortality ratios comparing the population in treatment to the Swiss population (standardized to the year 2000). Over the 7-year period, the crude death rate of patients in heroin-assisted treatment, and including one month after discharge from treatment, was 1% per year. The standardized mortality ratio for the entire observation period was 9.7 (95% C.I. 7.3-12.8), with females having higher standardized mortality ratios (SMR 17.2) than males (SMR 8.4). There was no clear time trend. Mortality in heroin-assisted treatment was low compared to the mortality rate of Swiss opioid users 1990s (estimated to be between 2.5 and 3%). It was also low compared to mortality rates of opioid users in other maintenance treatments in other countries as reported in the literature. The SMR was also lower than that reported in the only meta-analysis in the literature: 13.2 (95% C.I. 12.3-14.1). The low mortality rate is all the more noteworthy as heroin-assisted treatment in Switzerland included only refractory opioid addicts with existing severe somatic and/or mental problems. No conflicts of interest declared.


An update on the use of rifapentine for tuberculosis therapy.
Tuberculosis (TB) remains rampant throughout the world, in large part due to the lengthy treatment times of current therapeutic options. Rifapentine, a rifamycin antibiotic, is currently approved for intermittent dosing in the treatment of TB. Recent animal studies have shown that more frequent administration of rifapentine could shorten treatment times, for both latent and active TB infection. However, these results were not replicated in a subsequent human clinical trial. This review analyses the evidence for more frequent administration of rifapentine and the reasons for the apparent lack of efficacy in shortening treatment times in human patients. Inhaled delivery is discussed as a potential option to achieve the therapeutic effect of rifapentine by overcoming the barriers associated with oral administration of this drug. Avenues for developing an inhalable form of rifapentine are also presented. Rifapentine is a promising active pharmaceutical ingredient with potential to accelerate treatment of TB if delivered by inhaled administration. Progression of current fundamental work on inhaled anti-tubercular therapies to human clinical trials is essential for determining their role in future treatment regimens. While the ultimate goal for global TB control is a vaccine, a short and effective treatment option is equally crucial.


Icosahedral quasicrystals for visible wavelengths by optical interference holography.
Quasicrystals, realized in metal alloys, are a class of lattices exhibiting symmetries that fall outside the usual classification for periodic crystals. They do not have translational symmetry and yet the lattice points are well ordered. Furthermore, they exhibit higher rotational symmetry than periodic crystals. Because of the higher symmetry (more spherical), they are more optimal than periodic crystals in achieving complete photonic bandgaps in a new class of materials called photonic crystals in which the propagation of light in certain frequency ranges is forbidden. The potential of quasicrystals has been demonstrated in two dimensions for the infrared range and, recently, in three-dimensional icosahedral quasicrystals fabricated using a stereo lithography method for the microwave range and direct laser writing for the IR range. Here, we report the fabrication and optical characterization of icosahedral quasicrystals using a holographic lithography method for the visible range. The icosahedral pattern, generated using a novel 7-beam optical interference holography, is recorded on photoresists and holographic plates. Electron micrographs of the photoresist samples show clearly the symmetry of the icosahedral quasicrystals in the submicron range, while the holographic plate samples exhibit bandgaps in the angular-dependent transmission spectra in the visible range. Calculations of the bandgaps due to reflection planes inside the icosahedral quasicrystal show good agreement with the experimental results.


Novel Monte Carlo scheme for systems with short-ranged interactions.
We propose a Monte Carlo (MC) sampling algorithm to simulate systems of particles interacting via very short-ranged discontinuous potentials. Such models are often used to describe protein solutions or colloidal suspensions. Most normal MC algorithms fail for such systems because, at low temperatures, they tend to get trapped in local potential-energy local minima due to the short range of the pair potential. To circumvent this problem, we have devised a scheme that changes the construction of trial moves in such a way that the potential-energy difference between initial and final states drops out of the acceptance rule for the Monte Carlo trial moves. This approach allows us to simulate systems with short-ranged attraction under conditions that were unreachable up to now.


Early development and tissue distribution of Pseudoloma neurophilia in the zebrafish, Danio rerio.
The early proliferative stages of the microsporidian parasite, Pseudoloma neurophilia were visualized in larval zebrafish, Danio rerio, using histological sections with a combination of an in situ hybridization probe specific to the P. neurophilia small-subunit ribosomal RNA gene, standard hematoxylin-eosin stain, and the Luna stain to visualize spores. Beginning at 5 d post fertilization, fish were exposed to P. neurophilia and examined at 12, 24, 36, 48, 72, 96, and 120 h post exposure (hpe). At 12 hpe, intact spores in the intestinal lumen and proliferative stages developing in the epithelial cells of the anterior intestine and the pharynx and within hepatocytes were observed. Proliferative stages were visualized in the pancreas and kidney at 36-48 hpe and in the spinal cord, eye, and skeletal muscle beginning at 72 hpe. The first spore stages of P. neurophilia were observed at 96 hpe in the pharyngeal epithelium, liver, spinal cord, and skeletal muscle. The parasite was only observed in the brain of larval fish at 120 hpe. The distribution of the early stages of P. neurophilia and the lack of mature spores until 96 hpe indicates that the parasite gains access to organs distant from the initial site of entry, likely by penetrating the intestinal wall with the polar tube.


Use of web 2.0 to recruit Australian gay men to an online HIV/AIDS survey.
Continuous prevention efforts for human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) are recommended among those men who have sex with men (MSM). Creative use of e-technologies coupled with a better understanding of social networks could lead to improved health interventions among this risk population. The aims of the study were to (1) compare the impact of various advertising strategies on recruiting MSM participants to an online HIV/AIDS survey, and (2) explore the feasibility of using a social network service (SNS) for study advertising. A cross-sectional online survey was conducted in 2009. South Australian men over 18 years were invited to participate if they had had sexual intercourse with men in the previous year. A short questionnaire was used to collect demographics and information on sexual behavior, HIV history, use of the Internet for dating purposes, and sources of health information. The survey was promoted in community settings and online, including advertisements through social networks. A total of 243 men completed the online survey during the 8-week data collection period. Online advertisements recruited 91.7% (220/240) of the sample. Conversely, traditional advertisements in the community recruited only 5.8% (14/240) of the sample. Ten volunteers were asked to advertise on their personal SNS application, but only 2 effectively did so. Only 18/240 (7.5%) of the respondents reported having learned of our study through the SNS application. In this sample, 19.3% (47/243) of participants had never been tested for HIV. Among the participants who had been tested, 12.8% (25/196) reported being HIV-positive. Regarding Internet use, 82.3% (200/243) of participants had dated online in the previous 6 months. Among the participants who had dated online, most (175/200, 87.5%) had found an Internet sexual partner and two-thirds (132/200, 66.0%) had had anal sex with these partner(s). Among men who had anal sex with an Internet partner, 68.2% (90/132) used a condom during sex. The MSM participants in this study had high-risk profiles for HIV and other sexually transmitted diseases (STDs), which highlights the need for ongoing health interventions among this group. In this study, the SNS marketing strategy did not appear to create a viral effect and it had a relatively poor yield.


Ursolic acid induces ER stress response to activate ASK1-JNK signaling and induce apoptosis in human bladder cancer T24 cells.
Here we studied the cellular mechanisms of ursolic acid's anti-bladder cancer ability by focusing on endoplasmic reticulum stress (ER stress) signaling. We show that ursolic acid induces a significant ER stress response in cultured human bladder cancer T24 cells. ER stress inhibitor salubrinal, or PERK silencing, diminishes ursolic acid-induced anti-T24 cell effects. Salubrinal inhibits ursolic acid-induced CHOP expression, Bim ER accumulation and caspase-3 activation in T24 cells. Ursolic acid induces IRE1-TRAF2-ASK1 signaling complex formation to activate pro-apoptotic ASK1-JNK signaling. We suggest that ER stress contributes to ursolic acid's effects against bladder cancer cells.


Abnormal synaptic plasticity and impaired spatial cognition in mice transgenic for exon 1 of the human Huntington's disease mutation.
Huntington's disease (HD) is an autosomal dominant progressive and fatal neurodegenerative brain disorder caused by an expanded CAG/polyglutamine repeat in the coding region of the gene. Presymptomatic Huntington's disease patients often exhibit cognitive deficits before the onset of classical symptoms. To investigate the possibility that changes in synaptic plasticity might underlie cognitive impairment in HD, we examined hippocampal synaptic plasticity and spatial cognition in a transgenic mouse (R6/2 line) expressing exon 1 of the human Huntington's disease gene containing an expanded CAG repeat. This mouse exhibits a progressive and fatal neurological phenotype that resembles Huntington's disease. We report that R6/2 mice show marked alterations in synaptic plasticity at both CA1 and dentate granule cell synapses, and impaired spatial cognitive performance in the Morris water maze. The changes in hippocampal plasticity were age dependent, appearing at CA1 synapses several weeks before they were observed in the dentate gyrus. Deficits in synaptic plasticity at CA1 synapses occurred before an overt phenotype. This suggests that altered synaptic plasticity contributes to the pre-symptomatic changes in cognition reported in human carriers of the Huntington' disease gene. The temporal and regional changes in synaptic plasticity within the hippocampus mirror the appearance of neuronal intranuclear inclusions, suggesting a relationship between polyglutamine aggregation and dysfunction.


Update on the clinical pharmacogenomics of organ transplantation.
Organ transplantation suffers from a static graft and patient survival rate, and a high incidence of serious adverse drug effects. The pharmacogenomics of organ transplantation has emerged only recently and is complementary to the immunogenetic information that has accumulated over the past decade. Gene polymorphism studies have focused on the genes that interact across the group of immunosuppressants, including ciclosporin, tacrolimus, sirolimus and corticosteroids. The polymorphisms that hold the most potential for use in a drug selection algorithm are in genes CYP3A5, ABCB1, IMPDH1 and IMPDH2, and cytokines and growth factors. Gene-expression arrays have led to gene-expression testing, such as the use of AlloMap((R)) with heart transplant patients. The expanded use of gene-expression assays, proteomics and drug selection algorithms in organ transplantation will progress slowly and may be outpaced by drug test co-development programs for new transplant drugs. In the future, clinical pharmacogenomics will be a routine part of patient care for organ transplant patients.


Physical mapping of the mec region of an American methicillin-resistant Staphylococcus aureus strain.
We mapped part of the mec region of a locally prevalent strain of Staphylococcus aureus. The mec region was found to harbor an insert of the transposon Tn554, which encodes spectinomycin and macrolide-lincosamide-streptogramin B resistance, and a 4.6-kb segment of DNA that contains the kanamycin resistance gene aadD. This 4.6-kb segment appears to be an integrated form of a previously described plasmid, pUB110, and is flanked by copies of the insertion sequence IS257. The integration event may be an example of processes that have led to accretion of resistance determinants in the mec region of S. aureus.


Amelioration of cardio-renal injury with aging in dahl salt-sensitive rats by H2-enriched electrolyzed water.
Recent studies have revealed the biological effects of H2 in suppressing organ injuries due to acute inflammation and oxidative stress. Dahl salt-sensitive (SS) rats naturally develop elevated blood pressure (BP) and kidney injury with aging. The present study examined the effect of long-term supplementation of H2 in drinking water on age-related changes.Four-week-old male Dahl SS rats were fed 3 types of water (n = 30 each) for up to 48 weeks: filtered water (FW), water with a high H2 content (492.5 ppb) obtained with water electrolysis (EW), or dehydrogenated EW (DW). Animals were subjected to histological analysis at 16, 24, and 48 weeks.The FW group showed progressive BP elevation and increases in albuminuria and cardiac remodeling during the course of treatment. Histologically, there were significant changes as a function of aging, i.e., glomerular sclerosis with tubulointerstitial fibrosis in the kidney, and increased cardiomyocyte diameter with interstitial fibrosis in the heart at 48 weeks. These changes were related to the enhanced inflammation and oxidative stress in the respective organs. However, there were no striking differences in BP among the groups, despite histological alterations in the EW group being significantly decreased when compared to FW and DW in both organs, with concurrently lower oxidative stress and inflammatory markers at 48 weeks. Long-term ad libitum consumption of H2-enriched electrolyzed water can ameliorate the processes of kidney injury and cardiac remodeling with aging in Dahl SS rats by suppressing, at least partly, elevated inflammation and oxidative stress.


Gene transfer efficiency and genome-wide integration profiling of Sleeping Beauty, Tol2, and piggyBac transposons in human primary T cells.
In this study, we compared the genomic integration efficiencies and transposition site preferences of Sleeping Beauty (SB or SB11), Tol2, and piggyBac (PB) transposon systems in primary T cells derived from peripheral blood lymphocytes (PBL) and umbilical cord blood (UCB). We found that PB demonstrated the highest efficiency of stable gene transfer in PBL-derived T cells, whereas SB11 and Tol2 mediated intermediate and lowest efficiencies, respectively. Southern hybridization analysis demonstrated that PB generated the highest number of integrants when compared to SB and Tol2 in both PBL and UCB T cells. Tol2 and PB appeared more likely to promote clonal expansion than SB, which may be in part due to the dysregulated expression of cancer-related genes near the insertion sites. Genome-wide integration analysis demonstrated that SB, Tol2, and PB integrations occurred in all the chromosomes without preference. Additionally, Tol2 and PB integration sites were mainly localized near transcriptional start sites (TSSs), CpG islands and DNaseI hypersensitive sites, whereas SB integrations were randomly distributed. These results suggest that SB may be a preferential choice of the delivery vector in T cells due to its random integration site preference and relatively high efficiency, and support continuing development of SB-mediated T-cell phase I trials.


The Prevalence of Cubital Tunnel Syndrome: A Cross-Sectional Study in a U.S. Metropolitan Cohort.
Although cubital tunnel syndrome is the second most common peripheral mononeuropathy (after carpal tunnel syndrome) encountered in clinical practice, its prevalence in the population is unknown. The objective of this study was to evaluate the prevalence of cubital tunnel syndrome in the general population. We surveyed a cohort of adult residents of the St. Louis metropolitan area to assess for the severity and localization of hand symptoms using the Boston Carpal Tunnel Questionnaire Symptom Severity Scale (BCTQ-SSS) and the Katz hand diagram. We identified subjects who met our case definitions for cubital tunnel syndrome and carpal tunnel syndrome: self-reported hand symptoms associated with a BCTQ-SSS score of >2 and localization of symptoms to the ulnar nerve or median nerve distributions. Of 1,001 individuals who participated in the cross-sectional survey, 75% were women and 79% of the cohort was white; the mean age (and standard deviation) was 46 ± 15.7 years. Using a more sensitive case definition (lax criteria), we identified 59 subjects (5.9%) with cubital tunnel syndrome and 68 subjects (6.8%) with carpal tunnel syndrome. Using a more specific case definition (strict criteria), we identified 18 subjects (1.8%) with cubital tunnel syndrome and 27 subjects (2.7%) with carpal tunnel syndrome. The prevalence of cubital tunnel syndrome in the general population may be higher than that reported previously. When compared with previous estimates of disease burden, the active surveillance technique used in this study may account for the higher reported prevalence. This finding suggests that a proportion of symptomatic subjects may not self-identify and may not seek medical treatment. This baseline estimate of prevalence for cubital tunnel syndrome provides a valuable reference for future diagnostic and prognostic study research and for the development of clinical practice guidelines.


Accelerometer and GPS Data to Analyze Built Environments and Physical Activity.
Purpose: Most built environment studies have quantified characteristics of the areas around participants' homes. However, the environmental exposures for physical activity (PA) are spatially dynamic rather than static. Thus, merged accelerometer and global positioning system (GPS) data were utilized to estimate associations between the built environment and PA among adults. Methods: Participants (N = 142) were recruited on trails in Massachusetts and wore an accelerometer and GPS unit for 1-4 days. Two binary outcomes were created: moderate-to-vigorous PA (MVPA vs. light PA-to-sedentary); and light-to-vigorous PA (LVPA vs. sedentary). Five built environment variables were created within 50-meter buffers around GPS points: population density, street density, land use mix (LUM), greenness, and walkability index. Generalized linear mixed models were fit to examine associations between environmental variables and both outcomes, adjusting for demographic covariates. Results: Overall, in the fully adjusted models, greenness was positively associated with MVPA and LVPA (odds ratios [ORs] = 1.15, 95% confidence interval [CI] = 1.03, 1.30 and 1.25, 95% CI = 1.12, 1.41, respectively). In contrast, street density and LUM were negatively associated with MVPA (ORs = 0.69, 95% CI = 0.67, 0.71 and 0.87, 95% CI = 0.78, 0.97, respectively) and LVPA (ORs = 0.79, 95% CI = 0.77, 0.81 and 0.81, 95% CI = 0.74, 0.90, respectively). Negative associations of population density and walkability with both outcomes reached statistical significance, yet the effect sizes were small. Conclusions: Concurrent monitoring of activity with accelerometers and GPS units allowed us to investigate relationships between objectively measured built environment around GPS points and minute-by-minute PA. Negative relationships between street density and LUM and PA contrast evidence from most built environment studies in adults. However, direct comparisons should be made with caution since most previous studies have focused on spatially fixed buffers around home locations, rather than the precise locations where PA occurs.


Including employees with disabilities in emergency evacuation plans: 9/11's effect on the demand for information.
Interest in emergency evacuation planning has increased since the September 11 terrorist attacks (9/11). In turn, the Job Accommodation Network (JAN) started receiving more questions about how to include employees with disabilities in such plans. JAN case data on the emergency evacuation of people with disabilities were reviewed. Case data from the four years prior to 9/11 (from September 11, 1997, to September 11, 2001) were compared to case data from the four years after 9/11 (from September 11, 2001, to September 11, 2005).


Metabolism and cytotoxicity of acetaminophen in hepatocyte cultures from rat, rabbit, dog, and monkey.
Acetaminophen (APAP)-induced cytotoxicity and metabolism were studied in hepatocyte cultures isolated from the rat, rabbit, dog, and monkey. Cytotoxicity was evaluated by morphological examination and by alanine aminotransferase and aspartate aminotransferase released into the cell culture medium. The toxicity results obtained by these two methods were in agreement and can be explained by the biotransformation of APAP in each species. Rat and dog hepatocyte cultures contained the most APAP-sulfate conjugates, while the rabbit, dog, and monkey hepatocyte cultures contained the most APAP-glucuronide conjugates. The percentage of APAP-glutathione conjugate was very low in all species, indicating that either very little of the toxic APAP metabolite, N-acetylbenzoquinoneimine, was formed, or in the species susceptible to N-acetylbenzoquinoneimine-induced cytotoxicity, the glutathione S-transferase activity or the amount of glutathione was low. Rabbit hepatocytes transformed the most APAP during both short and long periods of exposure. Of the four species, the dog hepatocytes exhibited the highest level of APAP-induced cytotoxicity. The sensitivity of dog hepatocytes to APAP may be due to their low conjugating enzyme activity. Rat hepatocytes utilized all three pathways of APAP-biotransformation to prevent APAP-induced cytotoxicity. Monkey hepatocyte cultures had a very large capacity to transform APAP to a glucuronide conjugate and a very high level of glutathione S-transferase activity, and therefore did not exhibit any cytotoxicity. These studies indicate that the competing pathways of APAP conjugation in hepatocyte cultures from different species explain the differences observed in APAP-induced cytotoxicity.


Postsurgical treatment landscape and economic burden of locoregional and distant recurrence in patients with operable nonmetastatic melanoma.
Surgery is the mainstay treatment for operable nonmetastatic melanoma, but recurrences are common and limit patients' survival. This study aimed to describe real-world patterns of treatment and recurrence in patients with melanoma and to quantify healthcare resource utilization (HRU) and costs associated with episodes of locoregional/distant recurrences. Adults with nonmetastatic melanoma who underwent melanoma lymph node surgery were identified from the Truven Health MarketScan database (1 January 2008 to 31 July 2017). Locoregional and distant recurrence(s) were identified on the basis of postsurgery recurrence indicators (i.e. initiation of new melanoma pharmacotherapy, new radiotherapy, or new surgery; secondary malignancy diagnoses). Of 6400 eligible patients, 219 (3.4%) initiated adjuvant therapy within 3 months of surgery, mostly with interferon α-2b (n=206/219, 94.1%). A total of 1191/6400 (18.6%) patients developed recurrence(s) over a median follow-up of 23.1 months (102/6400, 1.6% distant recurrences). Among the 219 patients initiated on adjuvant therapy, 73 (33.3%) experienced recurrences (distant recurrences: 13/219, 5.9%). The mean total all-cause healthcare cost was $2645 per patient per month (PPPM) during locoregional recurrence episodes and $12 940 PPPM during distant recurrence episodes. In the year after recurrence, HRU was particularly higher in patients with distant recurrence versus recurrence-free matched controls: by 9.2 inpatient admissions, 54.4 inpatient days, 8.8 emergency department admissions, and 185.9 outpatient visits (per 100 person-months), whereas all-cause healthcare costs were higher by $14 953 PPPM. It remains to be determined whether the new generation of adjuvant therapies, such as immune checkpoint inhibitors and targeted agents, will increase the use of adjuvant therapies, and reduce the risk of recurrences and associated HRU/cost.


Environmental factors and their timing in adult-onset multiple sclerosis.
Multiple sclerosis (MS) is a common, complex neurological disease. Epidemiological data implicate both genetic and environmental factors in the etiology of MS, with various factors interacting with one another. Environmental exposures might occur long before the disease becomes clinically evident, as suggested by the wide range in onset age. In this Review, we examine the key time periods during which the environment might contribute to MS susceptibility, as well as the potential environmental factors involved. Understanding the nature of environmental influences in MS is highly relevant to the development of public health measures that are aimed at preventing this debilitating disease.


T cell contact with Ia antigens on nonhemopoietic cells in vivo can lead to immunity rather than tolerance.
Long-term H-2-heterozygous a----(a x b)F1 bone marrow (BM) chimeras prepared with supralethal irradiation (1,300 rad) are devoid of Ia+ host BM-derived antigen-presenting cells (APC), but show quite strong host Ia expression in germinal centers, probably on follicular dendritic cells (a class of nonhemopoietic stromal cells). To examine whether Ia expression on these non-BM-derived cells is capable of inducing post-thymic tolerance of T cells, thymectomized irradiated (a x b)F1 mice were reconstituted with parent alpha stem cells and then, 6 mo later, given parent alpha thymus grafts. As measured by primary mixed lymphocyte reactions and V beta expression, the CD4+ cells differentiating in the thymus-grafted mice showed no detectable tolerance to the H-2 (Ia) antigens of the host. To examine whether the thymus-grafted mice contained immunologically significant quantities of host Ia antigens, long-term alpha----(alpha x b)F1 chimeras were injected with normal strain alpha CD4+ cells; the donor cells were recovered from thoracic duct lymph of the chimeras and tested for host reactivity in vitro. The results showed that Ia expression in the chimeras was sufficient to cause selective trapping of a substantial proportion of host-Ia-reactive CD4+ cells soon after transfer and, at later stages, to induce strong priming. Tolerance was not seen. The data place constraints on the view that T cell recognition of antigen expressed on cells other than typical BM-derived APC leads to tolerance induction.


Breast reconstruction: Updated overview for primary care physicians.
To offer primary care providers a comprehensive summary of breast reconstruction options and complications. A literature search was conducted in PubMed with no time restriction using the search terms breast reconstruction, summary, review, complications, and options. Levels of evidence range from I to III. As breast cancer survival rates increase, the focus of breast cancer management must shift to include the restoration of a patient's quality of life after cancer. Breast reconstruction plays a crucial role in the restoration of normality for these women. Women who undergo mastectomy often suffer from challenges related to body image, self-esteem, and a decrease in quality of life scores. Cancer Care Ontario's Breast Cancer Treatment Pathway Map mandates that all women diagnosed with breast cancer who might require mastectomy be referred to a plastic surgeon to discuss reconstructive options before surgery. The knowledge and guidance of primary care providers is critical to effectively guiding and supporting patients who might undergo breast reconstruction in their decision-making processes. A thorough understanding of patient selection factors, modern options for breast reconstruction, and expected outcomes is essential.


2-Hydroxy-dATP is incorporated opposite G by Escherichia coli DNA polymerase III resulting in high mutagenicity.
Four kinds of oxidatively damaged DNA precursors, 8-hydroxydeoxyguanosine 5'-triphosphate (8-OH-dGTP), 2-hydroxydeoxyadenosine 5'-triphosphate (2-OH-dATP), 5-hydroxydeoxycytidine 5'-triphosphate (5-OH-dCTP) and 5-formyldeoxyuridine 5'-triphosphate (5-CHO-dUTP), were employed in in vitro gap-filling reactions of the supF gene conducted by the Escherichia coli DNA polymerase III holoenzyme, and these treated DNAs were transfected into various E.coli strains. When the manipulated DNAs were transfected into the repair-proficient strain, supF mutants were obtained much more frequently by the purine nucleotides than by the pyrimidine nucleotides (2-OH-dATP > 8-OH-dGTP >> 5-OH-dCTP approximately 5-CHO-dUTP). This result is in contrast to our previous observation that these four oxidatively damaged nucleotides induce chromosomal gene mutations with similar frequencies when incorporated directly into E.coli. 2-OH-dATP elicited G-->T transversions, indicating the formation of G*2-OH-dATP pairs. These results demonstrate that 2-OH-dATP was highly mutagenic in this assay system containing the in vitro DNA synthesis by the E.coli replicative DNA polymerase, in addition to in the in vivo assay system reported previously. Slight increases in the mutant frequencies were observed when alkA (for 8-OH-dGTP and 2-OH-dATP) and mutY (for 2-OH-dATP) strains were used as hosts. This is the first report that clearly shows the formation of G*2-OH-dATP pairs.


Farm exposure and time trends in early childhood may influence DNA methylation in genes related to asthma and allergy.
Genetic susceptibility and environmental influences are important contributors to the development of asthma and atopic diseases. Epigenetic mechanisms may facilitate gene by environment interactions in these diseases. We studied the rural birth cohort PASTURE (Protection against allergy: study in rural environments) to investigate (a) whether epigenetic patterns in asthma candidate genes are influenced by farm exposure in general, (b) change over the first years of life, and (c) whether these changes may contribute to the development of asthma. DNA was extracted from cord blood and whole blood collected at the age of 4.5 years in 46 samples per time point. DNA methylation in 23 regions in ten candidate genes (ORMDL1, ORMDL2, ORMDL3, CHI3L1, RAD50, IL13, IL4, STAT6, FOXP3, and RUNX3) was assessed by pyrosequencing, and differences between strata were analyzed by nonparametric Wilcoxon-Mann-Whitney tests. In cord blood, regions in ORMDL1 and STAT6 were hypomethylated in DNA from farmers' as compared to nonfarmers' children, while regions in RAD50 and IL13 were hypermethylated (lowest P-value (STAT6) = 0.001). Changes in methylation over time occurred in 15 gene regions (lowest P-value (IL13) = 1.57*10(-8)). Interestingly, these differences clustered in the genes highly associated with asthma (ORMDL family) and IgE regulation (RAD50, IL13, and IL4), but not in the T-regulatory genes (FOXP3, RUNX3). In this first pilot study, DNA methylation patterns change significantly in early childhood in specific asthma- and allergy-related genes in peripheral blood cells, and early exposure to farm environment seems to influence methylation patterns in distinct genes.


Unsteady flow in a rigid 3-D model of the carotid artery bifurcation.
In the present study, finite element calculations are performed of blood flow in the carotid artery bifurcation under physiological flow conditions. The numerical results are compared in detail with laser-Doppler velocity measurements carried out in a perspex model. It may be concluded that the numerical model as presented here is well capable in predicting axial and secondary flow of incompressible Newtonian fluids in rigid-walled three-dimensional geometries. With regard to the flow phenomena occurring, a large region with reversed axial flow is found in the carotid sinus opposite to the flow divider. This region starts to grow at peak systole, has its maximal shape at minimal flow rate and totally disappears at the start of the acceleration phase. C-shaped axial velocity contours are formed in the deceleration phase, which are highly influenced by secondary flows. These latter flows are mainly induced by centrifugal forces, flow branching, and tapering of the carotid sinus. Lowering the sinus angle, the angle between the main branch and the carotid sinus, results in a smaller region with reversed axial flow.


Intra-rater reliability of hallux flexor strength measures using the Nintendo Wii Balance Board.
The purpose of this study was to investigate the intra-rater reliability of a new method in combination with the Nintendo Wii Balance Board (NWBB) to measure the strength of hallux flexor muscle. Thirty healthy individuals (age: 34.9 ± 12.9 years, height: 170.4 ± 10.5 cm, weight: 69.3 ± 15.3 kg, female = 15) participated. Repeated testing was completed within 7 days. Participants performed strength testing in sitting using a wooden platform in combination with the NWBB. This new method was set up to selectively recruit an intrinsic muscle of the foot, specifically the flexor hallucis brevis muscle. Statistical analysis was performed using intra-class coefficients and ordinary least product analysis. To estimate measurement error, standard error of measurement (SEM), minimal detectable change (MDC) and percentage error were calculated. Results indicate excellent intra-rater reliability (ICC = 0.982, CI = 0.96-0.99) with an absence of systematic bias. SEM, MDC and percentage error value were 0.5, 1.4 and 12 % respectively. This study demonstrates that a new method in combination with the NWBB application is reliable to measure hallux flexor strength and has potential to be used for future research and clinical application.


Left atrial volume index as an independent determinant of pulmonary hypertension in patients with chronic organic mitral regurgitation.
The common pathophysiological consequences of chronic mitral regurgitation (MR) are left atrial (LA) remodeling/dilatation and pulmonary hypertension (PH). We aimed to study the association between LA volume (LAV) and PH in patients with chronic organic MR. We prospectively studied 154 patients (age 55.0 ± 16.4 years, 39.6 % female) with isolated moderate to severe chronic organic MR. Severity of MR was assessed using proximal isovelocity surface area method. LAV was assessed using the area-length biplane method. PH was defined as pulmonary artery systolic pressure > 50 mmHg. Ruptured chordae and flail leaflets were the most common etiology of MR (53.2 %). Severe MR (effective regurgitant orifice area (EROA) > 40 mm(2)) was described in 123 (79.9 %) patients. Dyspnea, history of heart failure and atrial fibrillation was reported in 37.7 %, 20.1 % and 29.4 % of patients, respectively. Left ventricular (LV) ejection fraction was 68.1 ± 5.9 %. LAV index and EROA were 67.1 (24.7-391.3) ml/m(2)and 60.3 (10.5-250.9) mm(2), respectively. Age, presence of atrial fibrillation, EROA, LV end-systolic and end-diastolic volume, LV mass index, LAV index and tricuspid annular plane systolic excursion were all factors univariately associated with PH. In multiple logistic regression analysis, age (OR = 1.03, 95 % CI: 1.001-1.06, p = 0.04), EROA (OR = 1.02, 95 % CI: 1.003-1.03, p = 0.017) and LAV index (OR = 1.01, 95 % CI: 1.002-1.02, p = 0.021) were independently associated with PH. In patients with chronic organic MR, a significant association exists between LAV index and PH. Age, the severity of MR as assessed by EROA, and LAV index are the independent determinants of PH.


The four and a half LIM-only protein 2 regulates liver homeostasis and contributes to carcinogenesis.
The four and a half LIM-only protein 2 (FHL2) is upregulated in diverse pathological conditions. Here, we analyzed the effects of FHL2 overexpression in the liver of FHL2 transgenic mice (Apo-FHL2). We first examined cell proliferation and apoptosis in Apo-FHL2 livers and performed partial hepatectomy to investigate high FHL2 expression in liver regeneration. Expression of FHL2 was then analyzed by real time PCR in human hepatocellular carcinoma and adjacent non-tumorous livers. Finally, the role of FHL2 in hepatocarcinogenesis was assessed using Apo-FHL2;Apc(lox/lox) mice. Six-fold increase in cell proliferation in transgenic livers was associated with concomitant apoptosis, resulting in normal liver mass. In Apo-FHL2 livers, both cyclin D1 and p53 were markedly increased. Evidence supporting a p53-dependent cell death mechanism was provided by the findings that FHL2 bound to and activated the p53 promoter, and that a dominant negative p53 mutant compromised FHL2-induced apoptosis in hepatic cells. Following partial hepatectomy in Apo-FHL2 mice, hepatocytes displayed advanced G1 phase entry and DNA synthesis leading to accelerated liver weight restoration. Interestingly, FHL2 upregulation in human liver specimens showed significant association with increasing inflammation score and cirrhosis. Finally, while Apo-FHL2 mice developed no tumors, the FHL2 transgene enhanced hepatocarcinogenesis induced by liver-specific deletion of the adenomatous polyposis coli gene and aberrant Wnt/β-catenin signaling in Apc(lox/lox) animals. Our results implicate FHL2 in the regulation of signaling pathways that couple proliferation and cell death machineries, and underscore the important role of FHL2 in liver homeostasis and carcinogenesis.


The reliable measurement of temporal trends in mortality attributed to epilepsy and status epilepticus in Northern Ireland between 2001-2015.
Epilepsy mortality is of considerable public health concern, as a leading cause of premature neurological death. Recent English and Welsh mortality data suggests a falling mortality rate where epilepsy was the underlying cause of death, predominantly due to a reduction in status epilepticus (SE) mortality. We sought to validate this finding in Northern Ireland. Officially recorded death certificate data related to epilepsy and SE were obtained from the Northern Ireland statistics and research agency. Data were analysed from 2001 to 2015. The outcomes were the age-adjusted mortality rate for epilepsy and SE. External validation of SE deaths was carried out using data from an intensive care national audit and research centre database. From 2001 until end of 2015, epilepsy was recorded at death certification in 1484 cases. 458 deaths were considered due to epilepsy. Among 75 in whom SE was recorded, SE was the cause of death in 46 patients. External validation found 103 total deaths related to SE in ICU departments in Northern Ireland, suggesting an overall under-ascertainment of officially recorded statistics. With respect to the 2013 European Standard Population, the mean age-adjusted mortality rate for epilepsy was 1.9 (95% C.I. 1.73-2.07) per 100,000 person years. For SE the mean age-adjusted mortality rate was 2.1 (95% C.I. 0.15-0.27) per 100,000 person years. Death certification in SE is likely to be an underestimate of the reality. Further efforts are urgently needed to determine the extent of SE-related deaths and all deaths in patients with epilepsy.


Lay and expert interpretations of cancer cluster evidence.
Conflict frequently occurs between community members and environmental/public health officials when an unusual number of cancer cases is reported. This conflict may result from different ways in which laypeople and experts interpret facts to judge whether there is an environmental cause of the cancer cases, but little is known about this issue. Volunteer laypeople (N= 551) and epidemiologists (N= 105) read a hypothetical scenario about cases of cancer on one neighborhood block. Participants judged whether each of the 23 facts about the situation made it "much more likely" to "much less likely" that something in town was causing the cancer cases (7-point scale). The facts were designed to be "alarming,""reassuring," or "neutral" (i.e., according to epidemiological principles, should increase, decrease, or have no impact on the likelihood of an environmental cause). The laypeople were alarmed by most of the facts (mean response significantly greater than the scale midpoint), including all of the neutral facts and over half of the reassuring facts. The experts were more balanced: they were alarmed by none of the neutral or reassuring facts. Their responses showed significantly less alarm than the laypeople's responses (p < 0.0001 for all comparisons). This study reveals that laypeople are not reassured by information that substantially lowers the chance of an environmental cause for cancer cases. Lay responses differ significantly and systematically from experts who are far less alarmed by relevant facts. These findings may help explain the conflicts between the two groups in situations where concern about cases of cancer arises in a community.


Evaluating factors associated with uncontrolled hypertension: Isfahan cohort study, Iran.
Hypertension (HTN) considers as one of the most common risk factors, which potentially raises the risk of cardiovascular disease. Regarding high prevalence of HTN among Iranian population this study designed to examine a range of socio-demographic and clinical variables to determine the association with failure to achieve blood pressure control in a cohort of hypertensive subjects. This retrospective cohort study is a part of Isfahan cohort study which carried out on adults aged 35 years old or more. Subjects with confirmed HTN entered in this sub-study. For all subjects questionnaire included socio-demographic characteristics, clinical data and lifestyle behavior completed by trained nurses. Uncontrolled HTN was defined as systolic and diastolic blood pressure more than 140/90 in the presence or absent of pharmacological treatment. The prevalence of uncontrolled men was significantly higher than controlled in both 2001 and 2007 (P < 0.001). A significant association was found between sex and control of blood pressure: compared with women, being men [odds ratio (OR) = 2.31; 95 % confidence interval (CI) = 1.64-3.24] was significantly associated with uncontrolled HTN in 2001 and (OR = 2.38; 95% CI = 1.78-3.18). Among lifestyle behaviors, tendency for more consumption of salty foods increased the risk of uncontrolled HTN in 2001 by 1.73 times [OR = 1.73, 95% CI = 1.20-2.50, (P = 0.003)]. Patients who were naive to mono-therapy without considering the type of antihypertensive drug were found to be associated with uncontrolled blood pressure (OR = 0.14; 95 % CI =0.1-0.2). Uncontrolled HTN was sex, marital status, diabetes, tendency to salty foods and medication adherence. Assessment of them presence of these risk factors is warranted to recommend an aggressive HTN management with the goal of reducing excessive risk of cardiovascular events caused by uncontrolled HTN.


From supramolecular polymersomes to stimuli-responsive nano-capsules based on poly(diene-b-peptide) diblock copolymers.
This paper discusses the self-assembly of block copolymers into vesicular morphology. After a brief state of art of the field, a system based on an amphiphilic poly(butadiene)- b-poly(-L-glutamic acid) (PB- b-PGA) diblock copolymer in aqueous solution is discussed in detail. The aggregation behavior of this block copolymer has been investigated by means of fluorescence spectroscopy, dynamic (DLS) and static (SLS) light scattering as well as transmission electron microscopy (TEM). The diblock copolymer was found to form well-defined vesicles in water. The size of these so-called polymersomes or peptosomes could be reversibly manipulated as a function of both pH and ion strength. Depending on the pH of the aqueous solution, the hydrodynamic radii of these vesicles were found to vary from 100 nm to 150 nm. By cross-linking the 1,2-vinyl double bonds present in the polybutadiene block, the ability to transform a transient supramolecular self-organized aggregate into a permanent "shape-persistent stimuli-responsive nanoparticle" has been demonstrated.


Five roles for using theory and evidence in the design and testing of behavior change interventions.
The prevailing wisdom in the field of health-related behavior change is that well-designed and effective interventions are guided by theory. Using the framework of intervention mapping, we describe and provide examples of how investigators can effectively select and use theory to design, test, and report interventions. We propose five roles for theory and evidence about theories: a) identification of behavior and determinants of behavior related to a specified health problem (i.e., the logic model of the problem); b) explication of a causal model that includes theoretical constructs for producing change in the behavior of interest (i.e., the logic model of change); c) selection of intervention methods and delivery of practical applications to achieve changes in health behavior; d) evaluation of the resulting intervention including theoretical mediating variables; and e) reporting of the active ingredients of the intervention together with the evaluation results. In problem-driven applied behavioral or social science, researchers use one or multiple theories, empiric evidence, and new research, both to assess a problem and to solve or prevent a problem. Furthermore, the theories for description of the problem may differ from the theories for its solution. In an applied approach, the main focus is on solving problems regarding health behavior change and improvement of health outcomes, and the criteria for success are formulated in terms of the problem rather than the theory. Resulting contributions to theory development may be quite useful, but they are peripheral to the problem-solving process.


Left Ventricular Rotational and Twist Mechanics in the Human Fetal Heart.
The authors investigated left ventricular (LV) rotational indices, twist, and torsion in a large cohort of fetuses using two-dimensional speckle-tracking echocardiography. Pregnant women (N = 102) were prospectively recruited for fetal two-dimensional speckle-tracking echocardiography. Because of variable fetal position, ventricular orientation was established using the location of the liver and LV position in relation to the right ventricle. Twist measurements required correction to account for fetal position, reconciling directionality across all fetal orientations. Peak apical and basal rotations, global longitudinal strain, global circumferential strain (GCS), longitudinal strain rate, circumferential strain rate (CSR), twist, and torsion were reported and tested for associations with gestational age (GA) and estimated fetal weight (EFW). Measurement of rotational indices was feasible in 175 examinations (73%). The mean maternal age was 31 ± 6 years, the mean GA 24 ± 6 weeks, and the EFW 1.0 ± 1.0 kg. Mean peak apical rotation, basal rotation, twist, and torsion were 9.5 ± 2.0°, -4.4 ± 1.1°, 13.1 ± 2.3°, and 7.9 ± 3.4°/cm, respectively. Mean global longitudinal strain, GCS, longitudinal strain rate, and CSR were -22.3 ± 4.3%, -25.0 ± 6.1%, -1.4 ± 0.5 sec-1, and -1.6 ± 0.5 sec-1, respectively. Absolute GCS, CSR, apical rotation, and twist declined moderately with GA and EFW (P < .05). There were strong negative nonlinear correlations of torsion with GA and EFW: torsion = 1,104 × GA-1.591 (r2 = 0.760, P < .001); torsion = 115.88 × EFW-0.427 (r2 = 0.772, P < .001). Determination of fetal LV rotational mechanics is feasible and reproducible using two-dimensional speckle-tracking echocardiography. Basal rotation, longitudinal strain, and strain rate vary little with EFW and GA. Interpretation of LV apical rotation, twist, torsion, GCS, and CSR, however, must take GA or EFW into account. These data form the basis for comparison with findings in fetuses with abnormal cardiac anatomy and function.


Non-Linear Dynamical Analysis of Resting Tremor for Demand-Driven Deep Brain Stimulation.
Parkinson's Disease (PD) is currently the second most common neurodegenerative disease. One of the most characteristic symptoms of PD is resting tremor. Local Field Potentials (LFPs) have been widely studied to investigate deviations from the typical patterns of healthy brain activity. However, the inherent dynamics of the Sub-Thalamic Nucleus (STN) LFPs and their spatiotemporal dynamics have not been well characterized. In this work, we study the non-linear dynamical behaviour of STN-LFPs of Parkinsonian patients using ε -recurrence networks. RNs are a non-linear analysis tool that encodes the geometric information of the underlying system, which can be characterised (for example, using graph theoretical measures) to extract information on the geometric properties of the attractor. Results show that the activity of the STN becomes more non-linear during the tremor episodes and that ε -recurrence network analysis is a suitable method to distinguish the transitions between movement conditions, anticipating the onset of the tremor, with the potential for application in a demand-driven deep brain stimulation system.


A novel, nontoxic iron chelator, super-polyphenol, effectively induces apoptosis in human cancer cell lines.
Iron chelation therapy is the main treatment for iron overload disease. Iron chelators were recently reported to be useful for cancer therapy; however, they cause side effects that make them difficult to use in some cancer patients. Thus, a novel oral iron chelator, super-polyphenol (SP), was developed for cancer therapy to decrease the side effects. SP is either water soluble or insoluble, and has different isoforms according to the number of side chains. Of these isoforms, water-soluble SP6 and SP10 appear to be the best candidates, as they have the strongest chelating abilities. In this study, we focused on the usefulness and safety of SP6 and SP10 as anti-cancer drugs, and examined their anti-cancer effects and toxicity. The results showed that SP6 and SP10 inhibited cancer cell proliferation by inducing apoptosis in HCT116, HSC-2, A549, and MCF-7 cancer cells. SP10 also inhibited tumor growth in an HCT116 xenograft model. SP6 and SP10 had no acute toxicities. An intravenous injection test revealed that SP6 and SP10 had better safety profiles than the iron chelator deferoxamine. In conclusion, SP is a novel oral iron chelator with anti-cancer effects and few adverse side effects. This is the first report of SP in the literature.


Role of EPAC in cAMP-Mediated Actions in Adrenocortical Cells.
Adrenocorticotropic hormone regulates adrenal steroidogenesis mainly via the intracellular signaling molecule cAMP. The effects of cAMP are principally relayed by activating protein kinase A (PKA) and the more recently discovered exchange proteins directly activated by cAMP 1 and 2 (EPAC1 and EPAC2). While the intracellular roles of PKA have been extensively studied in steroidogenic tissues, those of EPACs are only emerging. EPAC1 and EPAC2 are encoded by the genes RAPGEF3 and RAPGEF4, respectively. Whereas EPAC1 is ubiquitously expressed, the expression of EPAC2 is more restricted, and typically found in endocrine tissues. Alternative promoter usage of RAPGEF4 gives rise to three different isoforms of EPAC2 that vary in their N-termini (EPAC2A, EPAC2B, and EPAC2C) and that exhibit distinct expression patterns. EPAC2A is expressed in the brain and pancreas, EPAC2B in steroidogenic cells of the adrenal gland and testis, and EPAC2C has until now only been found in the liver. In this review, we discuss current knowledge on EPAC expression and function with focus on the known roles of EPAC in adrenal gland physiology.


Retrospectively Estimating Energy Intake and Misreporting From a Qualitative Food Frequency Questionnaire: An Example Using Australian Cohort and National Survey Data.
Qualitative food frequency questionnaires (Q-FFQ) omit portion size information from dietary assessment. This restricts researchers to consumption frequency data, limiting investigations of dietary composition (i.e., energy-adjusted intakes) and misreporting. To support such researchers, we provide an instructive example of Q-FFQ energy intake estimation that derives typical portion size information from a reference survey population and evaluates misreporting. A sample of 1,919 Childhood Determinants of Adult Health Study (CDAH) participants aged 26-36 years completed a 127-item Q-FFQ. We assumed sex-specific portion sizes for Q-FFQ items using 24-h dietary recall data from the 2011-2012 Australian National Nutrition and Physical Activity Survey (NNPAS) and compiled energy density values primarily using the Australian Food Composition Database. Total energy intake estimation was daily equivalent frequency × portion size (g) × energy density (kJ/g) for each Q-FFQ item, summed. We benchmarked energy intake estimates against a weighted sample of age-matched NNPAS respondents (n = 1,383). Median (interquartile range) energy intake was 9,400 (7,580-11,969) kJ/day in CDAH and 9,055 (6,916-11,825) kJ/day in weighted NNPAS. Median energy intake to basal metabolic rate ratios were 1.43 (1.15-1.78) in CDAH and 1.35 (1.03-1.74) in weighted NNPAS, indicating notable underreporting in both samples, with increased levels of underreporting among the overweight and obese. Using the Goldberg and predicted total energy expenditure methods for classifying misreporting, 65 and 41% of CDAH participants had acceptable/plausible energy intake estimates, respectively. Excluding suspected CDAH misreporters improved the plausibility of energy intake estimates, concordant with expected body weight associations. This process can assist researchers wanting an estimate of energy intake from a Q-FFQ and to evaluate misreporting, broadening the scope of diet-disease investigations that depend on consumption frequency data.


SPHK1 (sphingosine kinase 1) induces epithelial-mesenchymal transition by promoting the autophagy-linked lysosomal degradation of CDH1/E-cadherin in hepatoma cells.
SPHK1 (sphingosine kinase 1), a regulator of sphingolipid metabolites, plays a causal role in the development of hepatocellular carcinoma (HCC) through augmenting HCC invasion and metastasis. However, the mechanism by which SPHK1 signaling promotes invasion and metastasis in HCC remains to be clarified. Here, we reported that SPHK1 induced the epithelial-mesenchymal transition (EMT) by accelerating CDH1/E-cadherin lysosomal degradation and facilitating the invasion and metastasis of HepG2 cells. Initially, we found that SPHK1 promoted cell migration and invasion and induced the EMT process through decreasing the expression of CDH1, which is an epithelial marker. Furthermore, SPHK1 accelerated the lysosomal degradation of CDH1 to induce EMT, which depended on TRAF2 (TNF receptor associated factor 2)-mediated macroautophagy/autophagy activation. In addition, the inhibition of autophagy recovered CDH1 expression and reduced cell migration and invasion through delaying the degradation of CDH1 in SPHK1-overexpressing cells. Moreover, the overexpression of SPHK1 produced intracellular sphingosine-1-phosphate (S1P). In response to S1P stimulation, TRAF2 bound to BECN1/Beclin 1 and catalyzed the lysine 63-linked ubiquitination of BECN1 for triggering autophagy. The deletion of the RING domain of TRAF2 inhibited autophagy and the interaction of BECN1 and TRAF2. Our findings define a novel mechanism responsible for the regulation of the EMT via SPHK1-TRAF2-BECN1-CDH1 signal cascades in HCC cells. Our work indicates that the blockage of SPHK1 activity to attenuate autophagy may be a promising strategy for the prevention and treatment of HCC.


Race and gender differences in attitudes toward help seeking among marginalized young adults with mood disorders: A mixed-methods investigation.
Race and gender differences in help seeking are well-established; however, reasons for these differences are less clear. This study examined race and gender differences in two potential contributors-perceptions of illness and attitudes toward treatment-in a sample of marginalized young adults. Interviews were conducted with young adults (age 18-25) with prior involvement in public systems of care and mood disorder diagnoses (n = 60). A quantitative interview assessed illness perceptions and attitudes followed by a qualitative interview focused on perceptions of mental illness and treatment. Analyses examined quantitative differences across four race/gender subgroups-White women (n = 13), White men (n = 6), women of color (n = 27), and men of color (n = 14), then qualitative results were reviewed for a subset of cases (n = 30) to understand differences revealed in the quantitative analyses. Women of color had lower scores on illness understanding compared to other groups and men of color had lower scores on chronicity. Attitudes including propensity toward help seeking and stigma resistance were lowest in men of color, followed by women of color. Qualitative findings supported that men of color viewed their symptoms as less chronic and managed symptoms by changing their mindset rather than formal treatments. White participants talked more about their illnesses as chronic conditions and spoke more positively of treatment. Race/gender differences were identified, particularly in relation to views of mental illness and stigma. Messaging that highlights independence and strength in relation to managing symptoms may be particularly important for young people of color. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Copper Hydride Catalyzed Enantioselective Synthesis of Axially Chiral 1,3-Disubstituted Allenes.
The general enantioselective synthesis of axially chiral disubstituted allenes from prochiral starting materials remains a long-standing challenge in organic synthesis. Here, we report an efficient enantio- and chemoselective copper hydride catalyzed semireduction of conjugated enynes to furnish 1,3-disubstituted allenes using water as the proton source. This protocol is sufficiently mild to accommodate an assortment of functional groups including keto, ester, amino, halo, and hydroxyl groups. Additionally, applications of this method for the selective synthesis of monodeuterated allenes and chiral 2,5-dihydropyrroles are described.


Clinical summary and course of idiopathic anaphylaxis in 73 patients.
Seventy-three patients with anaphylaxis of unknown cause were studied. Repeated histories and physical examinations were performed by the Northwestern University (Chicago) allergy service in an attempt to find a cause for the anaphylaxis. Documentation of abnormal physical findings during an episode of anaphylaxis was necessary in each patient. Prior to our initial consultation, these 73 patients had required 115 emergency room visits and 37 hospitalizations. No deaths have occurred in 224 patient years of follow-up from initial presentation. Thirty-eight (52%) patients have infrequent reactions (defined as one episode only or mild episodes less than six times per year) requiring acute treatment alone. Thirty-five (48%) patients have severe or frequent life-threatening reactions (defined as episodes that include syncope, documented hypotension, and airway compromise as major manifestations) requiring maintenance antihistamines and prednisone. Laboratory studies were not helpful in finding a cause of anaphylaxis in any of the 73 patients. Associated atopic conditions were present in 45 patients. Twenty-three patients had chronic idiopathic angioedema, urticaria, or both prior to developing idiopathic anaphylaxis. Sixteen patients only treated acutely for each episode of anaphylaxis and seven patients previously receiving maintenance medication are now asymptomatic without medication for longer than one year.


Yakson touch as a part of early intervention in the Neonatal Intensive Care Unit: A systematic narrative review.
Yakson is a Korean therapeutic touch given to neonates and infants by caressing their abdomen with one hand while the other hand is placed on the back of the neonate\infant either to relieve their pain or to calm them down. It was traditionally used by Koreans by caressing the aching body part of their children with a belief that it would relieve their pain. In spite of clinical evidence of its usefulness, there is limited literature available on Yakson touch. A systematic narrative review (SNR) was undertaken on studies that were carried out on the effectiveness of Yakson touch on infants and neonates. Only seven studies were detected from five major electronic databases, searched with the keywords: "Yakson," "Yakson touch," and "Yakson in neonates". One of the studies has been included in two Cochrane reviews by the same group of researchers published in 2011 and 2015, respectively, and also in a literature review. The evidence from these articles suggests that Yakson touch is able to increase the sleep scores of infants, affects their behavioral response, decreases the stress levels, increases maternal attachment, and has calming effects on them. However, the number of studies is limited, and thus the efficacy of this intervention has not been sufficiently established. Hence, there is a definite need for future studies to prove the efficacy of Yakson to include it in the early intervention programs. This SNR is aimed at compiling the studies which determined to prove the efficacy of the intervention of Yakson.


Sensitivity of dark mutants of various strains of luminescent bacteria to reactive oxygen species.
Recent studies indicated that bioluminescence of the marine bacterium Vibrio harveyi may both stimulate DNA repair and contribute to detoxification of deleterious oxygen derivatives. Therefore, it was also proposed that these reactions can be considered biological roles of bacterial luminescence and might act as evolutionary drives in development of luminous systems. However, experimental evidence for the physiological role of luciferase in protection of cells against oxidative stress has been demonstrated only in one bacterial species, raising the question whether this is a specific or a more general phenomenon. Here we demonstrate that in the presence of various oxidants (hydrogen peroxide, cumene hydroperoxide, t-butyl hydroperoxide and ferrous ions) growth of dark mutants of different strains of Vibrio fischeri and Photobacterium leiognathi is impaired relative to wild-type bacteria, though to various extents. Deleterious effects of oxidants on the mutants could be reduced (with different efficiency) by addition of antioxidants, A-TEMPO or 4OH-TEMPO. These results support the hypotheses that (1) activities of bacterial luciferases may detoxify deleterious oxygen derivatives, and (2) significantly different efficiencies of this reaction are characteristic for various luciferases.


Observations of tetrel bonding between sp3-carbon and THF.
We report the direct observation of tetrel bonding interactions between sp3-carbons of the supramolecular synthon 3,3-dimethyl-tetracyanocyclopropane (1) and tetrahydrofuran in the gas and crystalline phase. The intermolecular contact is established via σ-holes and is driven mainly by electrostatic forces. The complex manifests distinct binding geometries when captured in the crystalline phase and in the gas phase. We elucidate these binding trends using complementary gas phase quantum chemical calculations and find a total binding energy of -11.2 kcal mol-1 for the adduct. Our observations pave the way for novel strategies to engineer sp3-C centred non-covalent bonding schemes for supramolecular chemistry.


Effect of lymph leakage on renal allograft outcome from living donors.
Lymph leakage is a cause of prolonged fluid discharge in renal transplant patients. Lymph leakage during early post-transplantation is responsible for extracting immune substances; therefore, it may play a role in prognosis of the transplanted kidney. In this study, we aimed to investigate the effects of lymph leakage on different factors that play significant roles in renal allograft outcome. During the present case-control study, we evaluated 62 renal allograft recipients in which 31 subjects were complicated with lymph leakage and enrolled as the study group. The other 31 subjects were included in the control group who did not experience any lymph leakage during their post-transplantation period. All kidneys were transplanted from living donors. We investigated and compared the renal allograft rejection rate, hospitalization duration, serum urea, creatinine (Cr) and cyclosporine (CsA) levels, antithymoglobin (ATG) administration and treatment duration between the study and the control groups. There were no significant difference in the urea and Cr levels between the two groups (P >0.05). Early (one week) and late (one month) serum CsA levels of the study group were significantly higher than in the control group (P = 0.005 and P = 0.006). The number of days in which ATG receivers responded to therapy was significantly lower for the control group (P = 0.008). 21.93% of the study group subjects experienced allograft rejection, while this rejection probability was 28.38% for the control group (P = 0.799). Lymph leakage has no prominent role in renal function, which is estimated by Cr and urea levels in patients' serum during the days after transplantation. CsA level was higher in patients with lymph leakage, and all cases of allograft rejection were in the subjects with lymph leakage.


Search for quantum black hole production in high-invariant-mass lepton+jet final states using pp collisions at √s=8 TeV and the ATLAS detector.
This Letter presents a search for quantum black-hole production using 20.3 fb-1 of data collected with the ATLAS detector in pp collisions at the LHC at √s = 8 TeV. The quantum black holes are assumed to decay into a final state characterized by a lepton (electron or muon) and a jet. In either channel, no event with a lepton-jet invariant mass of 3.5 TeV or more is observed, consistent with the expected background. Limits are set on the product of cross sections and branching fractions for the lepton+jet final states of quantum black holes produced in a search region for invariant masses above 1 TeV. The combined 95% confidence level upper limit on this product for quantum black holes with threshold mass above 3.5 TeV is 0.18 fb. This limit constrains the threshold quantum black-hole mass to be above 5.3 TeV in the model considered.


Daytime urinary incontinence among kindergarten children in Aden Governorate, 2003.
Daytime urinary incontinence is an involuntary or intentional voiding of urine in an awake child who is old enough to have developed control, and has a variable prevalence throughout the world. In Yemen, data regarding this problem are almost absent. In this study from the capital city of Aden, we aimed to: (1) determine the prevalence of daytime incontinence in kindergarten children aged 4-6 years, (2) identify the relation between daytime enuresis with personal and family characteristics of the children studied, and (3) describe the severity and characteristics of daytime enuresis in the studied children. A cross-sectional comparative study was undertaken in all kindergarten children aged 4-6 years in Aden Governorate and 1061 responded. Data were obtained by using a precoded self-administered questionnaire completed by the parents. The questionnaire consisted of two parts: personal and family characteristics of the studied children and the presence of daytime incontinence. The second part was responded if there was history of daytime incontinence, and contained information on the severity and possible associated factors. Daytime incontinence was encountered in 34 cases (3.2%); 18 were females. Significant differences between cases and incontinence-free children were encountered in birth order and type of kindergarten (P < 0.05). Majority (85.3%) had severe form of daytime incontinence. Bed wetting and combined day and night wetting were more frequent among males, whereas urinary symptoms (urgency, squatting, dysuria, dribbling) were more frequent among females. Working mother and frightening and emotionally stressful events in the 6 months preceding the study were significantly associated with daytime incontinence, while parents' education, punishment for daytime incontinence, and the presence of family history of incontinence were insignificant. In conclusion, this is the first study from Yemen reporting the prevalence of enuresis, similar to previous reports. Further studies are needed to explore this problem in our region to end the misery of the child and the family.


Influence of proximal side mutations on the molecular and electronic structure of cyanomet myoglobin: an 1H NMR study.
A series of proximal side mutants of sperm whale metmyoglobin (metMb) that involves residues which provide hydrogen bonds to the axial His and heme have been prepared, and the CO binding and solution molecular and electronic structure has been investigated by 1H NMR. These include Ser92(F7), whose O gamma serves as a hydrogen-bond acceptor to the axial His ring NdeltaH and whose O gamma H serves as hydrogen-bond donor to the 7-propionate carboxylate, and His97(FG3) whose ring provides the other hydrogen-bond donor to the 7-propionate carboxylate. 2D NMR data on the S92A-metMbCN, S92P-metMbCN and H97F-metMbCN show that the distal structure is completely conserved and that proximal side structural changes are highly localized. For the S92A-metMbCN, altered dipolar contacts to the F-helix backbone show that the axial His imidazole has rotated clockwise by approximately 10 degrees relative to a stationary heme, while in H97F-metMbCN, the altered heme-E helix backbone contacts reveal that the heme has rotated counterclockwise by approximately 3 degrees relative to a conserved axial His. The pattern of axial His rotation was qualitatively predicted by energy minimization calculations. The assignments and conserved structural elements allow the determination of a set of magnetic axes whose major magnetic axis is unchanged with respect to WT and confirms that local distal, and not proximal, interactions control the orientation of the major magnetic axis and, by inference, the degree and direction of tilt of the Fe-CN from the heme normal. The rhombic magnetic axes in S92A-metMbCN are rotated approximately 10 degrees in the opposite direction from the established approximately 10 degrees rotation for the axial His ring as expected. It is shown, moreover, that the pairwise alpha-, gamma-meso vs beta-, delta-meso-H hyperfine shift differences are well predicted by the change in the location of the rhombic magnetic axes. Carbon monoxide ligation rates experience minor but systematic perturbation for the S92A substitutions which confirms an influence (albeit very small) for axial His orientation on ligand affinity.


Ethics in medical research and publication.
To present the basic principles and standards of Ethics in medical research and publishing, as well as the need for continuing education in the principles and ethics in science and publication in biomedicine. An analysis of relevant materials and documents, sources from the published literature. Investing in education of researches and potential researches, already in the level of medical schools. Educating them on research ethics, what constitutes research misconduct and the seriousness of it repercussion is essential for finding a solution to this problem and ensuring careers are constructed on honesty and integrity.


Booklet for Childhood Fever in Out-of-Hours Primary Care: A Cluster-Randomized Controlled Trial.
Fever is the most common reason for a child to be taken to a physician, yet the level of unwarranted antibiotic prescribing remains high. We aimed to determine the effect on antibiotic prescribing of providing an illness-focused interactive booklet on fever in children to out-of-hours primary care clinicians. We conducted a cluster-randomized controlled trial in 20 out-of-hours general practice centers in the Netherlands. Children aged younger than 12 years with fever were included. Family physicians at the 10 intervention sites had access to an illness-focused interactive booklet between November 2015 and June 2016. The primary outcome was antibiotic prescribing during the index consultation. Analysis was performed by fitting 2-level random intercept logistic regression models. The trial took place among 3,518 family physicians and 25,355 children. The booklet was used in 28.5% of 11,945 consultations in the intervention group. Compared with usual care, access to the booklet did not significantly alter antibiotic prescribing during the index consultation (odds ratio = 0.90; 95% CI, 0.79-1.02; prescription rate, 23.5% vs 25.2%; intracluster correlation coefficient = 0.005). In contrast, use of the booklet significantly reduced antibiotic prescribing (odds ratio = 0.83; 95% CI, 0.74-0.94; prescription rate, 21.9% vs 25.2%; intracluster correlation coefficient = 0.002). Children managed by family physicians with access to the booklet were less likely to receive any drug prescription, and parents in the booklet group showed a reduced intention to consult again for similar illnesses. Benefit of an illness-focused interactive booklet in improving outcomes of childhood fever in out-of-hours primary care was largely restricted to the cases in which family physicians actually used the booklet. Insight into reasons for use and nonuse may inform future interventions of this type.


Assessment of fatigability, depression, and self-esteem among head-and-neck carcinoma patients in a tertiary care hospital in South India.
Head and Neck Carcinoma (HNCs) are the most common form of cancer in India. Patients with head-and-neck carcinomas often suffer from various distressing symptoms. The exact cause of these symptoms, as to whether disease or treatment or other factor induced, needs to be established. This study was done to assess fatigability, depression, and self-esteem among HNC study group before start, during, and in postradiation period and to find out the determinants of these parameters. Seventy newly diagnosed HNC patients and equivalent number of age- and gender-matched controls were interviewed using standardized questionnaires, before start of concurrent chemoradiotherapy (CCRT). The study group patients were interviewed again in the 4th week and postcompletion of CCRT in the 7th week. Mean age of the study group was 55.1 ± 11.3 years. Three-fourth of them (52 [74.3%]) were males. Majority of them (26 [37.1%]) had oral carcinomas. Baseline fatigue (P < 0.001) and depression scores (P < 0.001) were significantly more, while self-esteem scores (P = 0.004) were significantly less among the study group compared to controls before the onset of radiation. Mean fatigue and depression scores were found to significantly increase (P < 0.001), while self-esteem scores were found to significantly deteriorate (P < 0.001) over the course of CCRT among these patients. There was significant positive correlation (P < 0.001) between fatigue and depression scores and negative correlation (P < 0.001) of these parameters with self-esteem scores before, during, and after CCRT. There was no association between age and gender of the study group with any of these parameters. Multivariate analysis showed that baseline fatigue was significant (P < 0.001) and, depression after completion of the entire course of CCRT was significantly influenced by baseline depression levels (P = 0.011). Fatigue and depression need to be periodically screened among HNC study group on CCRT so as to initiate prompt remedial measures for its alleviation.


Addition of dexmedetomidine, tramadol and neostigmine to lidocaine 1.5% increasing the duration of postoperative analgesia in the lower abdominal pain surgery among children: A double-blinded randomized clinical study.
Pain is a common complication after surgery. Insufficient control of postoperative pain has adverse effects on the physiological, metabolic and psychological state of the child. The use of local analgesics and anesthetics alone cannot produce complete anesthesia and intraoperative comfort. The addition of adjuvant drugs is commonly used to improve the quality of the block. Therefore, adding new supplements may increase the duration of analgesia. The aim of this study was to compare the addition of dexmedetomidine, tramadol and neostigmine to lidocaine 1.5% in increasing the duration of postoperative analgesia in the lower abdominal pain surgery in children aged 2-8 years. This double-blind randomized clinical trial was conducted on children candidate for lower abdominal surgery. The 96 patients were randomly divided into 3 groups including dexmedetomidine, neostigmine, and tramadol. For all children, 3 mg of midazolam was administered orally before entering the operating room. The patients underwent general anesthesia with 2 μg/kg fentanyl, 0.03 mg/kg midazolam, 0.5 mg/kg atracurium and 5-6 mg/kg thiopental. After determining the hiatus membrane, 2 mL syringes containing air and distilled water (each of which 1 mL) slowly entered the space. After eliminating caudal resistance, 1.5% lidocaine was injected at dose of 0.5 mL/kg. A total of 96 patients were enrolled in this study. The results revealed that pain scores in the dexmedetomidine group in recovery, 2, 6 and 12 hours after surgery were less than the other two groups. Furthermore, the tramadol group showed a lower score in comparison with the neostigmine group and the duration of analgesia in the dexmedetomidine group was more than the other two groups. In addition, the mean of analgesic at 24 hours after operation in the dexmedetomidine group was lower as compared to the other two groups, indicating the effect of dexmedetomidine as an adjuvant in increasing the duration of analgesia and reducing postoperative pain in patients along with lidocaine 1.5%. All three drugs (neostigmine, tramadol and dexmedetomidine drugs), along with other local anesthetic, increased the duration of analgesia and decreased postoperative pain in children. The effect of dexmedetomidine was greater than the other two drugs. The study was approved by the Ethics Committee of Arak University of Medical Sciences, Iran (approved No. IR.ARAKMU.REC.1396.112) on October 28, 2017, and registered at Iranian Registry of Clinical Trials (registration No. IRCT20141209020258N83) on August 29, 2018.


Antimullerian hormone and obesity: insights in oral contraceptive users.
The study was conducted to examine the impact of oral contraceptives (OCs) on serum antimullerian hormone (AMH) levels by obesity status in reproductive-age women. Ovulatory women, ages 18-35 years, of normal (<25 kg/m(2); n=10) and obese (>30 kg/m(2); n=10) body mass index (BMI) received a low-dose OC (20 mcg ethinyl estradiol/100 mcg levonorgestrel) for two cycles. Serum samples obtained at several time points during active pill use and hormone-free intervals were analyzed for AMH, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol and inhibin B. AMH levels did not differ by OC cycle day in either BMI group. On average, AMH levels were 34% lower in the obese group (2.9+/-2.1 vs. 4.4+/-1.8 ng/mL, p<.05). Modeling to determine differences in AMH throughout the cycle based on obesity status demonstrated significantly lower levels (p<.05), whereas serum AMH, FSH, LH, estradiol and inhibin B levels revealed no correlations when all time points were included. In reproductive-age women, serum AMH levels do not appear to fluctuate during OC use, but AMH levels are significantly lower in obese women. Lower levels do not appear to be due to differences in gonadotropin levels or ovarian activity.


Neuroprotective effects of cognitive enhancement therapy against gray matter loss in early schizophrenia: results from a 2-year randomized controlled trial.
Cognitive rehabilitation has shown efficacy in improving cognition in patients with schizophrenia but the underlying neurobiologic changes that occur during these treatments and support cognitive improvement are not well known. To examine differential changes in brain morphology in early course schizophrenia during cognitive rehabilitation vs supportive therapy. Randomized controlled trial. An outpatient research clinic at a university-based medical center that provides comprehensive care services for patients with severe mental illness. A total of 53 symptomatically stable but cognitively disabled outpatients in the early course of schizophrenia or schizoaffective disorder. A 2-year trial with annual structural magnetic resonance imaging and cognitive assessments. Cognitive enhancement therapy is an integrated approach to the remediation of cognitive impairment in schizophrenia that uses computer-assisted neurocognitive training and group-based social-cognitive exercises. Enriched supportive therapy is an illness management approach that provides psychoeducation and teaches applied coping strategies. Broad areas of frontal and temporal gray matter change were analyzed with longitudinal, voxel-based morphometry methods using mixed-effects models followed by volumetric analyses of regions that demonstrated significant differential changes between treatment groups. Patients who received cognitive enhancement therapy demonstrated significantly greater preservation of gray matter volume over 2 years in the left hippocampus, parahippocampal gyrus, and fusiform gyrus, and significantly greater gray matter increases in the left amygdala (all corrected P < .04) compared with those who received enriched supportive therapy. Less gray matter loss in the left parahippocampal and fusiform gyrus and greater gray matter increases in the left amygdala were significantly related to improved cognition and mediated the beneficial cognitive effects of cognitive enhancement therapy. Cognitive enhancement therapy may offer neurobiologic protective and enhancing effects in early schizophrenia that are associated with improved long-term cognitive outcomes.


Increased CD40 Expression Enhances Early STING-Mediated Type I Interferon Response and Host Survival in a Rodent Malaria Model.
Both type I interferon (IFN-I) and CD40 play a significant role in various infectious diseases, including malaria and autoimmune disorders. CD40 is mostly known to function in adaptive immunity, but previous observations of elevated CD40 levels early after malaria infection of mice led us to investigate its roles in innate IFN-I responses and disease control. Using a Plasmodium yoelii nigeriensis N67 and C57BL/6 mouse model, we showed that infected CD40-/- mice had reduced STING and serum IFN-β levels day-2 post infection, higher day-4 parasitemia, and earlier deaths. CD40 could greatly enhance STING-stimulated luciferase signals driven by the IFN-β promoter in vitro, which was mediated by increased STING protein levels. The ability of CD40 to influence STING expression was confirmed in CD40-/- mice after malaria infection. Substitutions at CD40 TRAF binding domains significantly decreased the IFN-β signals and STING protein level, which was likely mediated by changes in STING ubiquitination and degradation. Increased levels of CD40, STING, and ISRE driven luciferase signal in RAW Lucia were observed after phagocytosis of N67-infected red blood cells (iRBCs), stimulation with parasite DNA/RNA, or with selected TLR ligands [LPS, poly(I:C), and Pam3CSK4]. The results suggest stimulation of CD40 expression by parasite materials through TLR signaling pathways, which was further confirmed in bone marrow derived dendritic cells/macrophages (BMDCs/BMDMs) and splenic DCs from CD40-/-, TLR3-/- TLR4-/-, TRIF-/-, and MyD88-/- mice after iRBC stimulation or parasite infection. Our data connect several signaling pathways consisting of phagocytosis of iRBCs, recognition of parasite DNA/RNA (possibly GPI) by TLRs, elevated levels of CD40 and STING proteins, increased IFN-I production, and longer host survival time. This study reveals previously unrecognized CD40 function in innate IFN-I responses and protective pathways in infections with malaria strains that induce a strong IFN-I response, which may provide important information for better understanding and management of malaria.


The crystal structure of human dipeptidyl peptidase I (cathepsin C) in complex with the inhibitor Gly-Phe-CHN2.
hDDPI (human dipeptidyl peptidase I) is a lysosomal cysteine protease involved in zymogen activation of granule-associated proteases, including granzymes A and B from cytotoxic T-lymphocytes and natural killer cells, cathepsin G and neutrophil elastase, and mast cell tryptase and chymase. In the present paper, we provide the first crystal structure of an hDPPI-inhibitor complex. The inhibitor Gly-Phe-CHN2 (Gly-Phe-diazomethane) was co-crystallized with hDPPI and the structure was determined at 2.0 A (1 A=0.1 nm) resolution. The structure of the native enzyme was also determined to 2.05 A resolution to resolve apparent discrepancies between the complex structure and the previously published structure of the native enzyme. The new structure of the native enzyme is, within the experimental error, identical with the structure of the enzyme-inhibitor complex presented here. The inhibitor interacts with three subunits of hDPPI, and is covalently bound to Cys234 at the active site. The interaction between the totally conserved Asp1 of hDPPI and the ammonium group of the inhibitor forms an essential interaction that mimics enzyme-substrate interactions. The structure of the inhibitor complex provides an explanation of the substrate specificity of hDPPI, and gives a background for the design of new inhibitors.


Establishing Content Validity of the CLEFT-Q: A New Patient-reported Outcome Instrument for Cleft Lip/Palate.
The CLEFT-Q is a new patient-reported outcome instrument designed to measure outcomes that matter to patients. The aim of this qualitative study was to establish content validity of the CLEFT-Q in patients who differ by age and culture. Patients aged between 6 and 29 years were recruited from plastic surgery clinics in Canada, India, Ireland, the Philippines, the Netherlands and the United States. Healthcare providers and other experts participated in a focus group or provided individual feedback. Input was sought on all aspects of the CLEFT-Q (item wording, instructions, and response options), and to identify missing content. Patient interviews and expert feedback took place between September 2013 and September 2014. Sixty-nine patients and 44 experts participated. The first draft of the CLEFT-Q consisted of 163 items measuring 12 constructs. The first round of feedback identified 92 items that required revision. In total, 3 rounds of interviews, and the involvement of an artist to create pictures for 17 items, were needed to establish content validity. At the conclusion of cognitive interviews, the CLEFT-Q consisted of 13 scales (total 171 items) that measure appearance, health-related quality of life, and facial function. The mean Flesch-Kincaid readability statistic for items was 1.4 (0 to 5.2). Cognitive interviews and expert review allowed us to identify items that required re-wording, re-conceptualizing, or to be removed, as well as any missing items. This process was useful for refining the CLEFT-Q scales for further testing.


Relationships between default-mode network connectivity, medial temporal lobe structure, and age-related memory deficits.
Advanced aging negatively impacts memory performance. Brain aging has been associated with shrinkage in medial temporal lobe structures essential for memory--including hippocampus and entorhinal cortex--and with deficits in default-mode network connectivity. Yet, whether and how these imaging markers are relevant to age-related memory deficits remains a topic of debate. Using a sample of 182 older (age 74.6 ± 6.2 years) and 66 young (age 22.2 ± 3.6 years) participants, this study examined relationships among memory performance, hippocampus volume, entorhinal cortex thickness, and default-mode network connectivity across aging. All imaging markers and memory were significantly different between young and older groups. Each imaging marker significantly mediated the relationship between age and memory performance and collectively accounted for most of the variance in age-related memory performance. Within older participants, default-mode connectivity and hippocampus volume were independently associated with memory. Structural equation modeling of cross-sectional data within older participants suggest that entorhinal thinning may occur before reduced default-mode connectivity and hippocampal volume loss, which in turn lead to deficits in memory performance.


Endothelin-1 levels and biomarkers of oxidative stress in glaucoma patients.
To investigate the levels of endothelin-1 (ET-1), homocysteine (Hcy), vitamins A, E, B12 and folic acid in plasma of patients with different types of glaucoma: primary open-angle glaucoma (POAG) and normotensive glaucoma (NTG). Patients were classified into 3 groups: group POAG comprised 48 patients, group NTG comprised 15 patients, and control group that comprised 75 healthy subjects. ET-1 levels were measured by ELISA, Vitamins A and E by HPLC, and Vitamin B12, homocysteine, and folic acid levels were determined by chemiluminescent immunoassay. The ET-1 and Hcy levels were significantly higher (p = 0.002) in the POAG group compared to NTG and control group. Vitamin E levels were significantly lower (p = 0.001) in the NTG group compared to POAG and control group. The increase of Hcy and ET-1 in POAG patients is related to vascular endothelial dysfunction. Thus results may play a key role in the development of this disease. Lower levels of Vitamin E in the NTG group suggest that oxidative process plays an early role in the development of this type of glaucoma.


Illuminating the circadian clock in monarch butterfly migration.
Migratory monarch butterflies use a time-compensated Sun compass to navigate to their overwintering grounds in Mexico. Here, we report that constant light, which disrupts circadian clock function at both the behavioral and molecular levels in monarchs, also disrupts the time-compensated component of flight navigation. We further show that ultraviolet light is important for flight navigation but is not required for photic entrainment of circadian rhythms. Tracing these distinct light-input pathways into the brain should aid our understanding of the clock-compass mechanisms necessary for successful migration.


What does the public know about Ebola? The public's risk perceptions regarding the current Ebola outbreak in an as-yet unaffected country.
The unexpected developments surrounding the Ebola virus in the United States provide yet another warning that we need to establish communication preparedness. This study examines what the Israeli public knew about Ebola after the initial stages of the outbreak in a country to which Ebola has not spread and assesses the association between knowledge versus worries and concerns about contracting Ebola. Online survey using Google Docs (Google, Mountain View, CA) of Israeli health care professionals and the general public (N = 327). The Israeli public has knowledge about Ebola (mean ± SD, 4.18 ± 0.83), despite the fact that the disease has not spread to Israel. No statistically significant difference was found between health care workers versus non-health care workers in the knowledge score. Additionally, no statistically significant association was found between knowledge and worry levels. The survey indicated that Israelis expect information about Ebola from the health ministry, including topics of uncertainty. More than half of the participants thought the information provided by the health ministry on Ebola and Ebola prevention was insufficient (50.5% and 56.4%, respectively), and almost half (45.2% and 41.1%, respectively) were unsure if the information was sufficient. The greatest challenges that the organizations face is not only to convey knowledge, but also to find ways to convey comprehensive information that reflects uncertainty and empowers the public to make fact-based decisions about health.


The Occlusion Effect and Ear Canal Sound Pressure Level.
Comparisons were made between changes in the audibility of bone-conduction stimuli to differences in the sound pressure present in the external auditory canal when ears were occluded. Fifteen listeners with normal middle ear function were tested using pure tones of 250, 500, and 1000 Hz, delivered via a bone-conduction oscillator placed on the mastoid process and the frontal bone. At all three frequencies, and both sites of stimulation, ear canal sound pressures were greater in the occluded than in the unoccluded conditions. Concurrently, the test signals were detected at lower intensities, although the changes in audibility and external canal sound pressure levels were not unity. The occlusion effect was attenuated slightly when the skull was vibrated from the frontal bone.


Nondestructive imaging of individual biomolecules.
Radiation damage is considered to be the major problem that still prevents imaging an individual biological molecule for structural analysis. So far, all known mapping techniques using sufficient short wavelength radiation, be it x rays or high energy electrons, circumvent this problem by averaging over many molecules. Averaging, however, leaves conformational details uncovered. Even the anticipated use of ultrashort but extremely bright x-ray bursts of a free electron laser shall afford averaging over 10{6} molecules to arrive at atomic resolution. Here, we present direct experimental evidence for nondestructive imaging of individual DNA molecules. In fact, we show that DNA withstands coherent low energy electron radiation with deBroglie wavelength in the Angstrom regime despite a vast dose of 10{8} electrons/nm{2} accumulated over more than one hour.