Invasion thresholds for fungicide resistance: deterministic and stochastic analyses
Fungicide resistance is an important practical problem, but one that is poorly understood at the population level. Here we introduce a simple nonlinear model for fungicide resistance in botanical epidemics which includes the dynamics of the chemical control agent and the host population, while also allowing for demographic stochasticity in the host-parasite dynamics. This provides a mathematical framework for analysing the risk of fungicide resistance developing by including the parameters for the amount applied, longevity and application frequency of the fungicide. The model demonstrates the existence of thresholds for the invasion of the resistant strain in the parasite population which depend on two quantities: the relative fitness of the resistant strain and the effectiveness of control. This threshold marks a change from definite elimination of the resistant strain below the threshold to a finite probability of invasion which increases above the threshold. The fungicide decay rate, the amount of fungicide applied and the period between applications affect the effectiveness of control and, consequently, they influence whether or not resistance develops and the time taken to achieve a critical frequency of resistance. All three parameters are amenable to control by the grower or by coordinating the activity of a population of growers. Providing crude estimates of the effectiveness of control and relative fitness are available, the results can be used to predict the consequences of changing these parameters for the risk of invasion and the proportion of sites at which this might be expected to occur. Although motivated for fungicide resistance, the model has broader application to herbicide, antibiotic and antiviral resistance. The modelling approach and results are discussed in the context of resistance to chemical control in general.


Emergence and devopment of the Pauls Stradiņs Museum of the History of Medicine in Rīga.
This paper reviews the establishment, development and present day of the Pauls Stradins Museum of the History of Medicine in Rīga, Latvia. The museum initially represented the hopes of one very excited enthusiast, and what was decisive was that he was able to fill the vacuum of knowledge and information, expand on it, and legalise it as an institution protected by the state. No less important, however, has been the approach taken by government structures and the public at large in support of Pauls Stradins' hopes. This comparatively liberal approach toward what could be seen as a private museum can be attributed to the fact that health care had been declared a priority in the Soviet Union at that time, and in ideological terms, the history of medicine was a fairly neutral issue. The museum celebrated its 50th anniversary in 2007. This paper reviews the basic functions and structures of the museum, as well as the changes which have occurred in the complex era of the 20th century. Some areas of activity are reviewed in greater detail, and there are statistics to offer a look at the museum today.


EVALUATION OF DRUG USE INDICATORS FOR NON-COMMUNICABLE DISEASES IN PAKISTAN.
Irrational drug use practices are a burden to healthcare facilities. Poor prescribing practices affect the overall management and cost of treatment of non-communicable diseases that are the major cause of mortality and morbidity worldwide. In an effort to improve prescribing practices, this study was designed to assess prescribing, consultation and facility indicators in healthcare facilities of Punjab and Sindh provinces of Pakistan from December 2012 to December 2013. In this cross-sectional study, random and convenient sampling were used to collected data from both private and public healthcare facilities. Quantitative data were collected using structured questionnaire, observations and prescription analysis, whereas qualitative information on factors influencing prescribing practices was obtained by interviewing medical practitioners. A total of 13693 prescriptions were obtained from 500 patient-prescriber encounters. Results show that history taking, physical examination and diagnoses were adequate while generic prescribing was four-fold less than drugs prescribed by brands. Average number of drugs prescribed was 4.63 with more prescribing tendency in private facilities. 45.07% prescription costs were less than Rs. 150. Sulfonylureas, statins and ACE inhibitors were highly prescribed drugs for diabetes, hyperlipidemia and hypertension. Prescribing practices were dominantly influenced by severity of disease (73% Punjab; 81% Sindh), patient age (75% Punjab; 68% Sindh) and availability of drugs (62% Punjab; 56% Sindh) whereby 91% practitioners in Sindh and 52% in Punjab rely on medical representatives as the source of drug information. Moreover, the pharmacy and therapeutic committees in all facilities were non-functional along with non-availability of essential drug list in 87% health facilities. Thus, there are considerable opportunities to improve the rational use of medicines in Pakistan including low prices for generics, physician education, prescribing guidelines and formularies.


Products With High Purchase Frequency Require Greater Inhibitory Control: An Event-Related Potential Study.
One's past behavior influences their present behavior. The effects of such response history have often been tested using response inhibition tasks. Since previous studies have highlighted the effect of immediate action history formed directly before the subsequent response in a laboratory environment, we aimed to elucidate the longer-term effects of response history, using repetitive and habitual consumer behavior in daily life as the response history. We used event-related potentials recorded in a Go/No-go task to investigate brain activity related to inhibitory control, hypothesizing that stimuli with a high frequency of choice in everyday life would elicit stronger inhibition-related activity, that is, the No-go-N2 component. Participants were asked to evaluate the frequency of purchase and use of some products, such as food and drink or social networking services (SNS) in everyday situations. Images of each product were assigned as stimuli in the Go and No-go trials according to the frequency of choice. The results showed that frequently purchased No-go stimuli yielded a larger amplitude of the No-go-N2 component and a negative shift between 200 and 300ms after the presentation of No-go stimuli. The results suggest that frequently chosen products evoke stronger inhibition conflicts and require greater cognitive control to withhold a response. Our findings showed that repeated purchase behavior in daily life forms a response history and has a long-term influence on the inhibition of even simple approaching behaviors, such as button pressing.


DNA methylome and transcriptome sequencing in human ovarian granulosa cells links age-related changes in gene expression to gene body methylation and 3'-end GC density.
Diminished ovarian function occurs early and is a primary cause for age-related decline in female fertility; however, its underlying mechanism remains unclear. This study investigated the roles that genome and epigenome structure play in age-related changes in gene expression and ovarian function, using human ovarian granulosa cells as an experimental system. DNA methylomes were compared between two groups of women with distinct age-related differences in ovarian functions, using both Methylated DNA Capture followed by Next Generation Sequencing (MethylCap-seq) and Reduced Representation Bisulfite Sequencing (RRBS); their transcriptomes were investigated using mRNA-seq. Significant, non-random changes in transcriptome and DNA methylome features are observed in human ovarian granulosa cells as women age and their ovarian functions deteriorate. The strongest correlations between methylation and the age-related changes in gene expression are not confined to the promoter region; rather, high densities of hypomethylated CpG-rich regions spanning the gene body are preferentially associated with gene down-regulation. This association is further enhanced where CpG regions are localized near the 3'-end of the gene. Such features characterize several genes crucial in age-related decline in ovarian function, most notably the AMH (Anti-Müllerian Hormone) gene. The genome-wide correlation between the density of hypomethylated intragenic and 3'-end regions and gene expression suggests previously unexplored mechanisms linking epigenome structure to age-related physiology and pathology.


A new statistical model for the Day Reconstruction Method.
The Day Reconstruction Method (DRM) is a method to measure one's subjective affective status by soliciting information in a questionnaire about the previous day's activities. We developed a new model to examine the association of daily activities, the friendliness of interacting partners, and time-of-day on net affect scores among 10,377 adults participating in the World Health Organization's Study on global ageing and adult health (SAGE). A multilevel regression was fitted and the time-of-day effect was modeled by restricted cubic spline. The net affect score was a serpentine curve; stable from 4 a.m. to 6 a.m., increased from 7 a.m. to 12 noon, and became stable onwards. Participants had the highest net affect scores during religious activities (0.48, 95% confidence interval [CI]: 0.44, 0.53), and they enjoyed leisure activities, exercising, and household responsibilities more than work. Compared with events that lacked interacting partners, activities with very friendly interacting partners were associated with higher net affect scores (0.21, 95% CI: 0.19, 0.22), but events with slightly friendly interacting partners, slightly irritating or very irritating partners had lower net affect scores. To conclude, researchers using DRM for assessing well-being status across time should include the type of activities and the friendliness of the interacting partners.


Hepatitis B virus reactivation or reinfection in a FEM-PrEP participant: a case report.
The FEM-PrEP trial was a pre-exposure prophylaxis clinical trial to test the safety and efficacy of Truvada (tenofovir disoproxil fumarate and emtricitabine) in the prevention of human immunodeficiency virus infection. Because Truvada can suppress hepatitis B virus replication, and withdrawal of Truvada can cause hepatic flares in patients with chronic hepatitis B, pre-enrollment screening included serological screening for hepatitis B virus markers. Women with chronic infections were not enrolled in the trial. Women found to be unprotected against hepatitis B were enrolled and offered three doses of hepatitis B vaccine. Reinfection and reactivation of previously resolved hepatitis B virus infections have been documented in immunosuppressed individuals but not in healthy individuals. We present the case of a participant enrolled in the FEM-PrEP clinical trial with baseline evidence of immunity against hepatitis B virus who subsequently developed acute hepatitis B. A 21-year-old Black non-pregnant woman was enrolled in the FEM-PrEP trial. She was human immunodeficiency virus-negative and a serological test for hepatitis B virus was negative. She had evidence of low levels of protection against hepatitis B virus and normal liver function. She had no hepatitis B vaccination history, thus it was concluded that she had post-infection immunity. At week 36 she presented with severely elevated liver enzyme levels that, upon further investigation, were a result of acute hepatitis B virus infection. The infection followed an asymptomatic course until full recovery of her liver enzymes a few weeks later. At study unblinding, the participant was found to be on the Truvada arm. Retrospective plasma drug level testing found low levels of study drugs from week 4. The participant remained human immunodeficiency virus-negative throughout the study. Hepatitis B virus infection reactivation or reinfection is a rare phenomenon in healthy individuals. However, reactivations have been reported in patients being treated for chronic hepatitis B with the drugs contained in Truvada, after treatment had been withdrawn. This participant may have reactivated after stopping Truvada, or she may have reactivated spontaneously owing to relatively low levels of protective antibodies against hepatitis B. Alternatively, she may have been reinfected. Clinicians should be aware that hepatitis B virus reactivation or reinfection may cause elevated transaminases even in the presence of low baseline immunity.


Dichromated polyvinyl alcohol as a real-time hologram recording material: some observations and discussions.
The real-time hologram formation in dichromated polyvinyl alcohol films has been studied in the presence of external electron donors included in the formulation. The effect of different external electron donors on the photosensitivity and real-time diffraction efficiency of volume holographic transmission gratings has been reported. The electron donors studied were found to be detrimental to both holographic characteristics, even in small concentrations. Some parameters that influence the holographic performance are discussed, and results are given. The photochemical recording mechanism in dichromated polyvinyl alcohol in the presence and absence of electron donors is briefly discussed.


Mechanical loading of mouse caudal vertebrae increases trabecular and cortical bone mass-dependence on dose and genotype.
Most in vivo studies addressing the skeletal responses of mice to mechanical loading have targeted cortical bone. To investigate trabecular bone responses also we have developed a caudal vertebral axial compression device (CVAD) that transmits mechanical loads to compress the fifth caudal vertebra via stainless steel pins inserted into the forth and sixth caudal vertebral bodies. Here, we used the CVAD in C57BL/6 (B6) and C3H/Hej (C3H) female mice (15 weeks of age) to investigate whether the effect of regular bouts of mechanical stimulation on bone modeling and bone mass was dependent on dose and genotype. A combined micro-computed tomographic and dynamic histomorphometric analysis was carried out at the end of a 4-week loading regimen (3,000 cycles, 10 Hz, 3 x week) for load amplitudes of 0N, 2N, 4N and 8N. Significant increases in trabecular bone mass of 9 and 21% for loads of 4N and 8N, respectively, were observed in B6 mice. A significant increase of 10% in trabecular bone mass occurred for a load of 8N in the C3H strain. For other loads, no significant increases were detected. Both mouse strains exhibited substantial increases in trabecular bone formation rates for all loads, B6: 111% (2N), 86% (4N), 164% (8N), C3H: 41% (2N), 38% (4N), 141% (8N). Significant decreases in osteoclast number of 146 and 93% for a load of 8N were detected in B6 and C3H mice, respectively. These findings demonstrate that the effect of loading on the structural and functional parameters of bone is dose and genotype dependent. The caudal vertebral loading model established here is proposed for further studies addressing the molecular processes involved in the skeletal responses to mechanical stimuli.


Influence of vision on adaptive postural responses following standing on an incline.
Previous studies demonstrated a leaning after-effect (LAE) following standing or walking on an inclined surface consistent with a long-lasting, somatosensory memory for body orientation relative to the surface. Here, we asked whether providing a brief visual reference during LAE resets postural orientation to the new visual reference. The results showed that subjects immediately return to upright when eyes were opened briefly during the post-incline period. However, the subjects also immediately resumed leaning after closing their eyes again following 20 s of eyes open. The duration of LAE was not influenced by 1 or 2 brief periods of vision. Also, the amplitude of the lean following the brief vision period was often larger than when subjects had their eyes closed for the entire post-incline period. These results suggest a powerful somatosensory memory contribution to postural orientation in space that is not eliminated or recalibrated with brief exposure to a visual reference.


Addition of brain and carotid imaging to the ABCD² score to identify patients at early risk of stroke after transient ischaemic attack: a multicentre observational study.
The ABCD² score improves stratification of patients with transient ischaemic attack by early stroke risk. We aimed to develop two new versions of the score: one that was based on preclinical information and one that was based on imaging and other secondary care assessments. We analysed pooled data from patients with clinically defined transient ischaemic attack who were investigated while in secondary care. Items that contribute to the ABCD² score (age, blood pressure, clinical weakness, duration, and diabetes), other clinical variables, carotid stenosis, and abnormal acute diffusion-weighted imaging (DWI) were recorded and were included in multivariate logistic regression analysis of stroke occurrence at early time intervals after onset of transient ischaemic attack. Scores based on the findings of this analysis were validated in patients with transient ischaemic attack from two independent population-based cohorts. 3886 patients were included in the study: 2654 in the derivation sample and 1232 in the validation sample. We derived the ABCD³ score (range 0-9 points) by assigning 2 points for dual transient ischaemic attack (an earlier transient ischaemic attack within 7 days of the index event). C statistics (which indicate discrimination better than chance at >0·5) for the ABCD³ score were 0·78 at 2 days, 0·80 at 7 days, 0·79 at 28 days, and 0·77 at 90 days, compared with C statistics for the ABCD² score of 0·71 at 2 days (p=0·083), 0·71 at 7 days (p=0·012), 0·71 at 28 days (p=0·021), and 0·69 at 90 days (p=0·018). We included stenosis of at least 50% on carotid imaging (2 points) and abnormal DWI (2 points) in the ABCD³-imaging (ABCD³-I) score (0-13 points). C statistics for the ABCD³-I score were 0·90 at 2 days (compared with ABCD² score p=0·035), 0·92 at 7 days (p=0·001), 0·85 at 28 days (p=0·028), and 0·79 at 90 days (p=0·073). The 90-day net reclassification improvement compared with ABCD² was 29·1% for ABCD³ (p=0·0003) and 39·4% for ABCD³-I (p=0·034). In the validation sample, the ABCD³ and ABCD³-I scores predicted early stroke at 7, 28, and 90 days. However, discrimination and net reclassification of patients with early stroke were similar with ABCD³ compared with ABCD². The ABCD³-I score can improve risk stratification after transient ischaemic attack in secondary care settings. However, use of ABCD³ cannot be recommended without further validation. Health Research Board of Ireland, Irish Heart Foundation, and Irish National Lottery.


Does the addiction in online pornography affect the behavioral pattern of undergrad private university students in Bangladesh?
Anecdotal reports from Bangladesh indicated that some young adults were becoming addicted to online pornography similar to how others become addicted to gambling, drugs, and alcohol. Such behaviors can have social, academic, and behavioral implications in this population. This study investigated the association between consumption of online pornography and sociobehavioral patterns among students from a private university in Bangladesh. In total, 299 undergraduate students (70.6% male) at the First Capital University of Bangladesh were interviewed using a structured questionnaire. The questions included sociodemographic characteristics, online-based pornography consumption habits and sociobehavioral characteristics. Chi-square test and binary logistic regression analysis were performed to examine correlations between online pornography addiction and sociobehavioral factors such as socializing habits, nature of interactions, university attendance and study focus, sleeping habits, and consumption of main meals. The use of pornography was significantly higher among students who gathered late nights with their friends (58.4%, P < 0.001). Furthermore, those who frequently argue/fight with their friends (51.0%, P = 0.001) frequently fooled around with their friends (48.4%, P < 0.001) and those who did not go to bed on time (57.7%, P < 0.001) reported greater consumption of pornography. Students who fooled around with their friends and those did not go to bed on time were more than twice as likely to watch pornography than students who did not fool around, and those went to bed on time. The study provides the first overview of online pornography consumption. A significant proportion of male students consumed erotic materials online than females. Students who did not go to bed emerged to consume online pornography. Such behaviors can have negative impacts on studies education outcomes as well as wider social and moral impacts for students and the society as a whole. In this digital era, technology has invaded every aspect of our lives, with increasing access to the internet. Therefore, it is imperative to provide specifically designed pornography addiction education programs to educate students about the adverse effects of pornography. Furthermore, targeted treatment programs for sexual addiction, sexual abuse, and pornography abuse are needed to support the individuals who are addicted to pornography.


Four forward-looking guidance points.
Four key guidance points in the UNAIDS guidance document, Ethical Considerations in HIV Preventive Vaccine Research, are compared with analogous statements in three other recently issued documents dealing with international research. Those documents are: the Declaration of Helsinki, as revised in 2000; the report of the U.S. National Bioethics Advisory Commission, issued in 2001; and a current (2001) draft revision of the 1993 CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects. The four guidance points compared with statements on similar issues on the other three documents are Guidance Point 2, which deals with making available a safe and effective vaccine after trials are completed; the second half of Guidance Point 4, which requires that the desired outcome should benefit the population from which research participants are drawn; Guidance Point 11, which discusses what should be provided to a control group in a vaccine trial; and Guidance Point 16, which addresses the care and treatment to be provided for trial participants who become infected with HIV during the trial. The analysis and comparison concludes that the UNAIDS guidance points are at least as ethically sound as analogous points in these other documents, and for the most part are ethically superior in providing greater benefits to research participants and to others. Nevertheless, they are subject to the criticism that they are too 'aspirational' and not sufficiently 'pragmatic'.


Prognostic indices with brief and standard CBT for panic disorder: I. Predictors of outcome.
Although the effectiveness of cognitive behavioural therapy (CBT) in the management of panic disorder (PD) is now well established, there have been few studies of predictors of outcome with this patient group using clinical effectiveness trial data, a hypothesis-testing model, and a dependent measure of clinically significant change. The data for this study came from a randomized controlled trial of three forms of CBT delivery for PD with and without agoraphobia (two 6-week CBT programmes, one of which was computer assisted, and one therapist-directed 12-week CBT programme), comprising a total of 186 patients across two sites. Based on previous related research, five hypothesized predictors of post-treatment and follow-up outcome were identified and examined, using a series of bivariate and multivariate analyses. The results in general supported the hypotheses. Strength of blood/injury fears, age of initial onset of panic symptoms, co-morbid social anxieties and degree of agoraphobic avoidance were predictive of both measures of post-treatment outcome. Degree of residual social difficulties and the continued use of anxiolytics at post-treatment were also shown to predict poor outcome at the 6-month follow-up. However, strength of continuing dysfunctional agoraphobic cognitions by the end of active treatment did not predict outcome at follow-up for the sample as a whole. The identification of consistent predictors of outcome with CBT has many clinical and research benefits. As CBT, however, is being delivered increasingly in a variety of brief formats, further research is required to identify moderators of response to these 'non-standard' treatment formats.


The role of soils in the disposition, sequestration and decontamination of environmental contaminants.
Soil serves as both a 'source' and 'sink' for contaminants. As a source, contaminants are derived from both 'geogenic' and 'anthropogenic' origins. Typically, while some of the inorganic contaminants including potentially toxic elements are derived from geogenic origin (e.g. arsenic and selenium) through weathering of parent materials, the majority of organic (e.g. pesticides and microplastics) as well as inorganic (e.g. lead, cadmium) contaminants are derived from anthropogenic origin. As a sink, soil plays a critical role in the transformation of these contaminants and their subsequent transfer to environmental compartments, including groundwater (e.g. pesticides), surface water (phosphate and nitrate), ocean (e.g. microplastics) and atmosphere (e.g. nitrous oxide emission). A complex transformation process of contaminants in soil involving adsorption, precipitation, redox reactions and biodegradation control the mobility, bioavailability and environmental toxicity of these contaminants. Soil also plays a major role in the decontamination of contaminants, and the 'cleaning' action of soil is controlled primarily by the physico-chemical interactions of contaminants with various soil components, and the biochemical transformations facilitated by soil microorganisms. In this article, we examine the geogenic and anthropogenic sources of contaminants reaching the soil, and discuss the role of soil in the sequestration and decontamination of contaminants in relation to various physico-chemical and microbial transformation reactions of contaminants with various soil components. Finally, we propose future actions that would help to maintain the role of soils in protecting the environment from contaminants and delivering sustainable development goals. This article is part of the theme issue 'The role of soils in delivering Nature's Contributions to People'.


Gamma Knife radiosurgery for vestibular schwannomas: evaluation of tumor control and its predictors in a large patient cohort in The Netherlands.
OBJECT The authors of this study sought to assess tumor control and complication rates in a large cohort of patients who underwent Gamma Knife radiosurgery (GKRS) for vestibular schwannoma (VS) and to identify predictors of tumor control. METHODS The records of 420 patients treated with GKRS for VS with a median marginal dose of 11 Gy were retrospectively analyzed. Patients with neurofibromatosis Type 2 or who had undergone treatment for VS previously were excluded. The authors assessed tumor control and complication rates with chart review and used the Cox proportional hazards model to identify predictors of tumor control. Preservation of serviceable hearing, defined as Gardner-Robertson Class I-II, was evaluated in a subgroup of 71 patients with serviceable hearing at baseline and with available follow-up audiograms. RESULTS The median VS tumor volume was 1.4 cm(3), and the median length of follow-up was 5.1 years. Actuarial 5-and 10-year tumor control rates were 91.3% and 84.8%, respectively. Only tumor volume was a statistically significant predictor of tumor control rate. The tumor control rate decreased from 94.1% for tumors smaller than 0.5 cm(3) to 80.7% for tumors larger than 6 cm(3). Thirteen patients (3.1%) had new or increased permanent trigeminal nerve neuropathy, 4 (1.0%) had new or increased permanent facial weakness, and 5 (1.2%) exhibited new or increased hydrocephalus requiring a shunting procedure. Actuarial 3-year and 5-year hearing preservation rates were 65% and 42%, respectively. CONCLUSIONS The 5-year actuarial tumor control rate of 91.3% in this cohort of patients with VS compared slightly unfavorably with the rates reported in other large studies, but the complication and hearing preservation rates in this study were similar to those reported previously. Various factors may contribute to the observed differences in reported outcomes. These factors include variations in treatment indication and in the definition of treatment failure, as well as a lack of standardization of terminology and of evaluation of complications. Last, differences in dosimetric variables may also be an explanatory factor.


An accurate, clinically feasible multi-gene expression assay for predicting metastasis in uveal melanoma.
Uveal (ocular) melanoma is an aggressive cancer that often forms undetectable micrometastases before diagnosis of the primary tumor. These micrometastases later multiply to generate metastatic tumors that are resistant to therapy and are uniformly fatal. We have previously identified a gene expression profile derived from the primary tumor that is extremely accurate for identifying patients at high risk of metastatic disease. Development of a practical clinically feasible platform for analyzing this expression profile would benefit high-risk patients through intensified metastatic surveillance, earlier intervention for metastasis, and stratification for entry into clinical trials of adjuvant therapy. Here, we migrate the expression profile from a hybridization-based microarray platform to a robust, clinically practical, PCR-based 15-gene assay comprising 12 discriminating genes and three endogenous control genes. We analyze the technical performance of the assay in a prospective study of 609 tumor samples, including 421 samples sent from distant locations. We show that the assay can be performed accurately on fine needle aspirate biopsy samples, even when the quantity of RNA is below detectable limits. Preliminary outcome data from the prospective study affirm the prognostic accuracy of the assay. This prognostic assay provides an important addition to the armamentarium for managing patients with uveal melanoma, and it provides a proof of principle for the development of similar assays for other cancers.


The association between previous and future severe exacerbations of chronic obstructive pulmonary disease: Updating the literature using robust statistical methodology.
There is minimal evidence on the extent to which the occurrence of a severe acute exacerbation of COPD that results in hospitalization affects the subsequent disease course. Previous studies on this topic did not generate causally-interpretable estimates. Our aim was to use corrected methodology to update previously reported estimates of the associations between previous and future exacerbations in these patients. Using administrative health data in British Columbia, Canada (1997-2012), we constructed a cohort of patients with at least one severe exacerbation, defined as an episode of inpatient care with the main diagnosis of COPD based on international classification of diseases (ICD) codes. We applied a random-effects 'joint frailty' survival model that is particularly developed for the analysis of recurrent events in the presence of competing risk of death and heterogeneity among individuals in their rate of events. Previous severe exacerbations entered the model as dummy-coded time-dependent covariates, and the model was adjusted for several observable patient and disease characteristics. 35,994 individuals (mean age at baseline 73.7, 49.8% female, average follow-up 3.21 years) contributed 34,271 severe exacerbations during follow-up. The first event was associated with a hazard ratio (HR) of 1.75 (95%CI 1.69-1.82) for the risk of future severe exacerbations. This risk decreased to HR = 1.36 (95%CI 1.30-1.42) for the second event and to 1.18 (95%CI 1.12-1.25) for the third event. The first two severe exacerbations that occurred during follow-up were also significantly associated with increased risk of all-cause mortality. There was substantial heterogeneity in the individual-specific rate of severe exacerbations. Even after adjusting for observable characteristics, individuals in the 97.5th percentile of exacerbation rate had 5.6 times higher rate of severe exacerbations than those in the 2.5th percentile. Using robust statistical methodology that controlled for heterogeneity in exacerbation rates among individuals, we demonstrated potential causal associations among past and future severe exacerbations, albeit the magnitude of association was noticeably lower than previously reported. The prevention of severe exacerbations has the potential to modify the disease trajectory.


Role of material-driven fibronectin fibrillogenesis in protein remodeling.
Protein remodeling at the cell-material interface is an important phenomenon that should be incorporated into the design of advanced biomaterials for tissue engineering. In this work, we address the relationship between fibronectin (FN) activity at the material interface and remodeling, including proteolytic cascades. To do so, we studied FN adsorption on two chemically similar substrates, poly(ethyl acrylate) (PEA) and poly(methyl acrylate) (PMA), which resulted in different distribution and conformation of the protein at the material interface: FN organized spontaneously upon adsorption on PEA into physiological-like fibrils, through a process called material-driven FN fibrillogenesis. The amount of adsorbed FN and its conformation were investigated in two different coating concentrations (2 and 20 μg/mL). Since FN activity at the material interface determines the initial cellular response, we followed the formation of focal adhesions (vinculin) and subsequent cell signaling by focal adhesion kinase (FAK) expression and its phosphorylation (pFAK). More detailed studies were performed to get further insights into integrin binding by crosslinking and extraction followed by immunofluorescence, as well as protein and gene expression for α5 and αv. To correlate cell adhesion with matrix degradation, gene expression and activity (zymography) of matrix metalloproteinases (MMPs) were measured. Overall, we demonstrated that the material-driven FN fibrillogenesis triggers proteolytic activity: MMP activity was higher on the material-driven FN fibrils, as a compensatory mechanism to the inability of cells to reorganize this FN network.


An error-prone family Y DNA polymerase (DinB homolog from Sulfolobus solfataricus) uses a 'steric gate' residue for discrimination against ribonucleotides.
DNA polymerases of the A and B families, and reverse transcriptases, share a common mechanism for preventing incorporation of ribonucleotides: a highly conserved active site residue obstructing the position that would be occupied by a 2' hydroxyl group on the incoming nucleotide. In the family Y (lesion bypass) polymerases, the enzyme active site is more open, with fewer contacts to the DNA and nucleotide substrates. Nevertheless, ribonucleotide discrimination by the DinB homolog (Dbh) DNA polymerase of Sulfolobus solfataricus is as stringent as in other polymerases. A highly conserved aromatic residue (Phe12 in Dbh) occupies a position analogous to the residues responsible for excluding ribonucleotides in other DNA polymerases. The F12A mutant of Dbh incorporates ribonucleoside triphosphates almost as efficiently as deoxyribonucleoside triphosphates, and, unlike analogous mutants in other polymerase families, shows no barrier to adding multiple ribonucleotides, suggesting that Dbh can readily accommodate a DNA-RNA duplex product. Like other members of the DinB group of bypass polymerases, Dbh makes single-base deletion errors at high frequency in particular sequence contexts. When making a deletion error, ribonucleotide discrimination by wild-type and F12A Dbh is the same as in normal DNA synthesis, indicating that the geometry of nucleotide binding is similar in both circumstances.


Delusional Parasitosis: Diagnosis and Treatment.
Delusional parasitosis (DP) is a somatic type of delusional disorder, usually mono-symptomatic, in which the patients are convinced they are being infested with animal parasites while no objective evidence exists to support this belief. The complaints are usually about skin infestation, but involvement of the gastrointestinal tract has also been described. Numerous samples are brought for examination from skin, clothes, and environmental sources, while a detailed description of the "parasite" is given. In primary DP, the delusion arises spontaneously as a mono-delusional disorder, while in secondary DP, the delusional disorder arises secondary to another major medical, neurological, or psychiatric disorder. Practically all patients refuse psychiatric help. Shared psychotic disorder - folie à deux - is a known mode of presentation in delusional parasitosis. More than one member within a family may experience the same delusional state. For diagnosis and treatment of DP, a close collaboration among dermatologists, psychiatrists, and parasitologists is essential. Patients whose delusion of parasitosis is not severe can sometimes be relieved of their symptoms by establishing a reliable and meaningful therapeutic relationship. Symptomatic medication may be prescribed for the relief of pruritus, pain, and other symptoms. In more severe cases, such patients should be treated with psychopharmacological agents.


MicroRNA gene expression signatures in long-surviving malignant pleural mesothelioma patients.
Malignant pleural mesothelioma (MPM) is a tumor originating in the mesothelium, the membrane lining the thoracic cavities, and is induced by exposure to asbestos. Australia suffers one of the world's highest rates of MPM and the incidence is yet to peak. The prognosis for patients with MPM is poor and median survival following diagnosis is 4-18 months. Currently, no or few effective therapies exist for MPM. Trials of targeted agents such as antiangiogenic agents (VEGF, EGFR) or ribonuclease inhibitors (ranpirnase) largely failed to show efficacy in MPM Tsao et al. (2009) [1]. A recent study, however, showed that cisplatin/pemetrexed + bevacizumab (a recombinant humanized monoclonal antibody that inhibit VEGF) treatment has a survival benefit of 2.7 months Zalcman et al. (2016) [2]. It remains to be seen if this targeted therapy will be accepted as a new standard for MPM. Thus the unmet needs of MPM patients remain very pronounced and almost every patient will be confronted with drug resistance and recurrence of disease. We have identified unique gene signatures associated with prolonged survival in mesothelioma patients undergoing radical surgery (EPP, extrapleural pneumonectomy), as well as patients who underwent palliative surgery (pleurectomy/decortication). In addition to data published in Molecular Oncology, 2015;9:715-26 (GSE59180) Kirschner et al. (2015) , we describe here additional data using a system-based approach that support our previous observations. This data provides a resource to further explore microRNA dynamics in MPM.


ADP-ribosylation signalling and human disease.
ADP-ribosylation (ADPr) is a reversible post-translational modification of proteins, which controls major cellular and biological processes, including DNA damage repair, cell proliferation and differentiation, metabolism, stress and immune responses. In order to maintain the cellular homeostasis, diverse ADP-ribosyl transferases and hydrolases are involved in the fine-tuning of ADPr systems. The control of ADPr network is vital, and dysregulation of enzymes involved in the regulation of ADPr signalling has been linked to a number of inherited and acquired human diseases, such as several neurological disorders and in cancer. Conversely, the therapeutic manipulation of ADPr has been shown to ameliorate several disorders in both human and animal models. These include cardiovascular, inflammatory, autoimmune and neurological disorders. Herein, we summarize the recent findings in the field of ADPr, which support the impact of this modification in human pathophysiology and highlight the curative potential of targeting ADPr for translational and molecular medicine.


Prunella vulgaris Attenuates Diabetic Renal Injury by Suppressing Glomerular Fibrosis and Inflammation.
Diabetic nephropathy is both the most common complication and the leading cause of mortality associated with diabetes. Prunella vulgaris, a well-known traditional medicinal plant, is used for the cure of abscess, scrofula, hypertension and urinary diseases. This study confirmed whether an aqueous extract of Prunella vulgaris (APV) suppresses renal inflammation and fibrosis. In human mesangial cell (HMC), pretreatment of APV attenuated 25[Formula: see text]mM HG-induced suppressed TGF-[Formula: see text] and Smad-2/4 expression; it increased the expression level of Smad-7. Connective tissue growth factor (CTGF) and collagen IV, fibrosis biomarkers, were significantly decreased by APV. APV suppressed inflammatory factors such as intracellular cell adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1). APV inhibited activation and translocation of nuclear factor kappa-B (NF-[Formula: see text]B) in HG-stimulated HMCs. Moreover, APV significantly improved HG-induced ROS in a dose-dependent manner. In diabetic rat models, APV significantly decreased blood glucose, blood urea nitrogen (BUN) and ameliorated plasma creatinine (PCr). APV reduced the PAS positivity staining intensity and basement membrane thickening in glomeruli of diabetic rats. Fibrosis related proteins such as collagen IV and TGF-[Formula: see text]1 were also inhibited by APV. These results suggest that APV has a significant protective effect against diabetic renal dysfunction including inflammation and fibrosis through disruption of the TGF-[Formula: see text]/Smad signaling. Therefore, APV may be useful in potential therapies that target glomerulonephritis and glomerulosclerosis, which lead to diabetic nephropathy.


Is Caffeine Recommended Before Exercise? A Systematic Review To Investigate Its Impact On Cardiac Autonomic Control Via Heart Rate And Its Variability.
Evaluating different doses of caffeine (CAF) on heart rate (HR) variability (HRV) during and following exercise in order to assess its impact on autonomic control. We intended to evaluate the influence of CAF as a supplement before exercise on HRV through a systematic review. Manuscripts were selected based on electronic searches of MEDLINE, EMBASE and CINAHL databases from 2010 to 2019 and followed the protocol Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA). Blind randomized designs and controlled trials that reported the influence of CAF on HRV during exercise and during recovery from exercise, with strength of evidence assessed using the GRADE system; the search for the studies was organized using the PICOS strategy. A total of 1797 articles were recognized, following the screening and eligibility stages, 9 studies continued to the final sample. Six studies reported that the combination of CAF supplementation with physical exercise exhibited higher HR when compared to the placebo group during post-exercise recovery; additionally, prolonged activation of sympathetic cardiac control and delayed parasympathetic reactivation following exercise was observed. However, three studies demonstrated no CAF influence when using similar doses. This review observed equivocal results in HR and HRV recovery following exercise with the presence of CAF consumption. These findings cannot confirm the cardiac autonomic changes observed where entirely due to the influence of CAF, and further studies should be performed to better understand this relationship.KEY TEACHING POINTSCAF increased HR during exercise and throughout the recovery period.CAF prolonged post exercise sympathetic activity.CAF delayed vagal reactivation.Deviations in HRV and HR are dependent on the combination of three main factors: CAF dosage, type of exercise, and cardiorespiratory fitness.


Effect of frequency chirp on soliton spectral sidebands in fiber lasers.
Fiber lasers emit soliton pulses that exhibit discrete spectral sidebands generated through dispersive-wave resonances. The position of these soliton sidebands is shown to be affected by the amount of chirp acquired by the pulse, and the degree of chirp is determined by total cavity losses and gain dispersion. Our results show that the soliton chirp shifts the sideband frequencies and that sidebands can be generated even in the case of normal dispersion. The long- and short-cavity cases are discussed separately so that our results are applicable to all laser configurations.


The Notch pathway helps to pattern the tips of the Drosophila tracheal branches by selecting cell fates.
The Drosophila tracheal system consists of a stereotyped network of epithelial tubes formed by several tracheal cell types. By the end of embryogenesis, when the general branching pattern is established, some specialised tracheal cells then mediate branch fusion while others extend fine terminal branches. Here evidence is presented that the Notch signalling pathway acts directly in the tracheal cells to distinguish individual fates within groups of equivalent cells. Notch helps to single out those tracheal cells that mediate branch fusion by blocking their neighbours from adopting the same fate. This function of Notch would require the restricted activation of the pathway in specific cells. In addition, and probably later, Notch also acts in the selection of those tracheal cells that extend the terminal branches. Both the localised expression and the mutant phenotypes of Delta, a known ligand for Notch, suggest that Delta may activate Notch to specify cell fates at the tips of the developing tracheal branches.


Dietary selenium protects adiponectin knockout mice against chronic inflammation induced colon cancer.
Selenium (Se) is an essential dietary micronutrient that has been examined for protection against different types of cancers including colon cancer. Despite an established inverse association between Se and chronic inflammation induced colon cancer (CICC), the mechanistic understanding of Se's protective effects requires additional in-vivo studies using preclinical animal models of CICC. Adiponectin (APN) is an adipocytokine that is protective against CICC as well. However, its role in the anti-mutagenic effects of the Se-diet remains unknown. To address this knowledge gap, here we examine the ability of dietary Se in reducing CICC in APN knockout mice (KO) and its wild-type C57BL/6. CICC was induced with the colon cancer agent 1,2 dimethyl hydrazine (DMH) along with dextran sodium sulfate (DSS). Se-enhanced diet increased selenoproteins, Gpx-1 and Gpx-2, in the colon tissues, thereby reducing oxidative stress. Se-mediated reduction of CICC was evident from the histopathological studies in both mouse models. In both mice, reduction in inflammation and tumorigenesis associated well with reduced p65 phosphorylation and elevated 53 phosphorylation. Finally, we show that in both models Se-administration promotes goblet cell differentiation with a concomitant increase in the levels of associated proteins, Muc-2 and Math-1. Our findings suggest that Se's protection against CICC involves both colonic epithelial protection and anti-tumor effects that are independent of APN.


PI3K signalling is required for a TGFβ-induced epithelial-mesenchymal-like transition (EMT-like) in human melanoma cells.
Epithelial to mesenchymal transition (EMT) is a programme defined in epithelial cells and recognized as playing a critical role in cancer progression. Although melanoma is not a cancer of epithelial cells, hallmarks of EMT have been described to play a critical role in melanoma progression. Here, we demonstrate that long-term TGFβ exposure can induce a dedifferentiated EMT-like state resembling a previously described invasive phenotype (EMT-like). TGFβ-induced EMT-like is marked by the downregulation of melanocyte differentiation markers, such as MITF, and the upregulation of mesenchymal markers, such as N-cadherin, and an increase in melanoma cell migration and cell invasion. Pharmacological interference shows the dependency of TGFβ-induced EMT-like on the activation of the PDGF signalling pathway and the subsequent activation of PI3K in human melanoma cells. Together, the data provide novel insights into the transcriptional plasticity of melanoma cells that might contribute to tumor progression in patients and propose avenues to therapeutic interventions.


Synthesis of retinyl phosphate mannose in vitro. Non-enzymic breakdown and reversibility.
Hamster liver microsomal membranes catalyse the synthesis of retinyl phosphate mannose (Ret-P-Man) from GDP-mannose and exogenous retinyl phosphate (Ret-P). We have previously shown that maximal Ret-P-Man synthesis occurs in vitro at 20-30 min, followed by a subsequent loss of mannose from Ret-P-Man, suggestive of an intermediary function of Ret-P-Man and/or Ret-P-Man breakdown [Shidoji, Silverman-Jones & De Luca (1982) Biochem. J. 208, 865-868; Creek, Morre, Silverman-Jones, Shidoji & De Luca (1983) Biochem. J. 210, 541-547). To monitor Ret-P-Man synthesis and breakdown carefully, we developed a chromatographic system in which mannose, Ret-P-Man, mannose phosphate and GDP-mannose are separated in a single analysis on a Mono Q column eluted with a gradient of NaCl. Using this chromatographic system, we have determined that 80-90% of the Ret-P-Man made in vitro by hamster liver membranes in 30 min is recovered with the membranes upon centrifugation. Subsequent incubation of Ret-P-Man-loaded membranes at 37 degrees C results in a non-enzymic breakdown of Ret-P-Man to beta-mannopyranosyl phosphate and anhydroretinol. However, incubation of the Ret-P-Man-loaded hamster liver membranes with GDP, but not GMP, ADP, CDP or UDP, results in a loss of mannose from Ret-P-Man and the formation of GDP-mannose and Ret-P. These results demonstrate that Ret-P-Man synthesized in vitro is subject to non-enzymic breakdown to beta-mannopyranosyl phosphate and anhydroretinol and that the GDP-mannose:retinyl phosphate mannosyltransferase reaction is reversible.


The transcription factor Nrf2 as a new therapeutic target in Parkinson's disease.
In recent years, it has been accepted that oxidative stress is critically involved in the etiopathology of Parkinson's disease (PD) and as a result new therapeutic targets for reduction of oxidant injury and neuroprotection can be defined. Here we discuss the potential use of the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2), as a pharmacological target for neuroprotective therapy in PD. Data generated by various groups indicate that Nrf2 induces the expression of a group of cytoprotective, antixenobiotic and antioxidant enzymes that include heme oxygenase-1, NAD(P)H:quinone oxidoreductase and enzymes of glutathione (GSH) metabolism such as gamma-glutamyl cysteine ligase, GSH transferases and so on. Two strategies are known to increase Nrf2 transcriptional activity in PD: i) use of certain catechol-derived quinones for selective inhibition of the Nrf2 repressor Kelch-like ECH-associated protein to increase of Nrf2 protein levels; and ii) use of glycogen synthase kinase 3beta inhibitors to maintain high protein and activity levels of Nrf2 in the nucleus. This review provides a rationale for drug design of appropriate molecules that might endorse a neuroprotective strategy to PD on the basis of attenuation of oxidative stress.


Nitric oxide metabolites induced in Anopheles stephensi control malaria parasite infection.
Malaria parasite infection in anopheline mosquitoes is limited by inflammatory levels of nitric oxide metabolites. To assess the mechanisms of parasite stasis or toxicity, we investigated the biochemistry of these metabolites within the blood-filled mosquito midgut. Our data indicate that nitrates, but not nitrites, are elevated in the Plasmodium-infected midgut. Although levels of S-nitrosothiols do not change with infection, blood proteins are S-nitrosylated after ingestion by the mosquito. In addition, photolyzable nitric oxide, which can be attributed to metal nitrosyls, is elevated after infection and, based on the abundance of hemoglobin, likely includes heme iron nitrosyl. The persistence of oxyhemoglobin throughout blood digestion and changes in hemoglobin conformation in response to infection suggest that hemoglobin catalyzes the synthesis of nitric oxide metabolites in a reducing environment. Provision of urate, a potent reductant and scavenger of oxidants and nitrating agents, as a dietary supplement to mosquitoes increased parasite infection levels relative to allantoin-fed controls, suggesting that nitrosative and/or oxidative stresses negatively impact developing parasites. Collectively, our results reveal a unique role for nitric oxide in an oxyhemoglobin-rich environment. In contrast to facilitating oxygen delivery by hemoglobin in the mammalian vasculature, nitric oxide synthesis in the blood-filled mosquito midgut drives the formation of toxic metabolites that limit parasite development.


The application of PCR-ELISA to the detection of Trypanosoma brucei and T. vivax infections in livestock.
Teneral tsetse flies infected with either Trypanosoma brucei or T. vivax were fed on healthy cattle. Blood samples collected daily from the cattle were examined by microscopy for the presence of trypanosomes, in thick smear, thin smear and in the buffy coat (BC). All the cattle fed upon by infected tsetse developed a fluctuating parasitaemia. DNA was extracted from the blood of these cattle and subjected to polymerase chain reaction (PCR) using oligonucleotide primers specific for T. brucei or T. vivax. The PCR products unique to either T. brucei or T. vivax were identified following amplification of DNA from the blood samples of infected cattle, whereas none was detectable in the DNA from the blood of the cattle exposed to non-infected teneral tsetse. In a concurrent set of experiments, one of the oligonucleotide primers in each pair was biotinylated for use in PCR-ELISA to examine all the blood samples with this assay. Both the PCR and the PCR-ELISA revealed trypanosome DNA in 85% of blood samples serially collected from the cattle experimentally infected with T. brucei. In contrast, the parasitological assays showed trypanosomes in only 21% of the samples. In the blood samples from cattle experimentally infected with T. vivax, PCR and PCR-ELISA revealed trypanosome DNA in 93 and 94%, respectively. Microscopy revealed parasites in only 63% of the BCs prepared from these cattle. Neither PCR nor PCR-ELISA detected any trypanosome DNA in blood samples collected from the animals in the trypanosome-free areas. However, both assays revealed the presence of trypanosome DNA in a number of blood samples from cattle in trypanosomosis-endemic areas.


Association of Anorexia Nervosa With Risk of Cancer: A Systematic Review and Meta-analysis.
Anorexia nervosa is recognized as an important cause of morbidity in young people. However, the risk of cancer in people with anorexia nervosa remains uncertain. To evaluate the association of anorexia nervosa with the risk of developing or dying of cancer. MEDLINE, Scopus, Embase, and Web of Science from database inception to January 9, 2019. Published observational studies in humans examining the risk of cancer in people with anorexia nervosa compared with the general population or those without anorexia nervosa. Studies needed to report incidence or mortality rate ratios (RRs). Screening, data extraction, and methodological quality assessment were performed by at least 2 researchers independently. A random-effects model was used to synthesize individual studies. Heterogeneity (I2) was assessed and 95% prediction intervals (PIs) were calculated. All cancer incidence and cancer mortality associated with anorexia nervosa. Secondary outcomes were site-specific cancer incidence and mortality. Seven cohort studies published in 10 articles (42 602 participants with anorexia nervosa) were included. Anorexia nervosa was not associated with risk of developing any cancer (4 studies in women; RR, 0.97; 95% CI, 0.89-1.06; P = .53; I2, 0%; 95% PI, 0.80-1.18; moderate confidence). Anorexia nervosa was associated with decreased breast cancer incidence (5 studies in women; RR, 0.60; 95% CI, 0.50-0.80; P < .001; I2, 0%; 95% PI, 0.44-0.83; high confidence). Conversely, anorexia nervosa was associated with increased risk of developing lung cancer (3 studies in women; RR, 1.50; 95% CI, 1.06-2.12; P = .001; I2, 0%; 95% PI, 0.19-16.46; low confidence) and esophageal cancer (2 studies in women; RR, 6.10; 95% CI, 2.30-16.18; P < .001; I2, 0%; low confidence). Among people with anorexia nervosa, risk of developing cancer did not differ compared with the general population, but a significantly reduced risk of breast cancer was observed. Understanding the mechanisms underlying these associations could have important preventive potential.


Internal jugular vein morphology and hemodynamics in patients with multiple sclerosis.
The aim of this study is to compare the hemodynamics and the morphology of the internal jugular veins using colour-Doppler and B-mode sonongraphy in multiple sclerosis patients (MS) and in controls. The internal jugular veins of 25 MS patients and 25 controls were examined using colour Doppler and B-mode ultrasound in sitting and supine positions, recording the changes in hemodynamics and the presence or absence of morphological changes. The presence of at least two of the extracranial Zamboni criteria in the same individual was considered positive for evidence of chronic cerebrospinal venous insufficiency (CCSVI). According to the described criteria, 92% of the MS patients showed abnormal findings and 84% of them showed evidence of CCSVI, however; only 24% of controls showed abnormal findings, but none of them showed evidence of CCSVI (OR=7.25, 95% CI 2.92-18.01, P<0.0001). Hemodynamic abnormalities and morphological changes involving the internal jugular vein are strongly associated with MS. These findings can be demonstrated by a non-invasive, cost effective Doppler ultrasound criteria.


Covalent adduction of human serum albumin by 4-hydroxy-2-nonenal: kinetic analysis of competing alkylation reactions.
The electrophilic lipid oxidation product 4-hydroxy-2-nonenal (HNE) reacts with proteins to form covalent adducts, and this damage has been implicated in pathologies associated with oxidative stress. HNE adduction of blood proteins, such as human serum albumin (HSA), yields adducts that may serve as markers of oxidative stress in vivo. We used liquid chromatography-tandem mass spectrometry (LC-MS-MS) and the P-Mod algorithm to map the sites of 10 adducts formed by reaction of HNE with HSA in vitro. The detected adducts included Michael adducts formed at histidine and lysine residues. The selectivity of HNE in competing adduction reactions was evaluated by analysis of kinetics for HNE Michael adduction at six targeted HSA histidine residues. Reaction kinetics were analyzed by selected reaction monitoring in LC-MS-MS using stable isotope tagging with phenyl isocyanate. Rate constants ranged over 4 orders of magnitude, with the order of reactivity being H242 > H510 > H67 > H367 > H247 approximately K233. The most reactive target, H242, is located in a fatty acid- and drug binding cavity in subdomain IIa of HSA and appears to be a hot-spot for HNE modification. Analysis of adduction kinetics together with HSA structure and target residue pK(a) values suggest that location in the hydrophobic binding cavity and low predicted pK(a) of H242 account for its high reactivity toward HNE. H242 adducts may be preferred products of adduction by lipophilic electrophiles and may comprise a family of biomarkers for oxidative stress.


Penalized weighted least-squares approach to sinogram noise reduction and image reconstruction for low-dose X-ray computed tomography.
Reconstructing low-dose X-ray computed tomography (CT) images is a noise problem. This work investigated a penalized weighted least-squares (PWLS) approach to address this problem in two dimensions, where the WLS considers first- and second-order noise moments and the penalty models signal spatial correlations. Three different implementations were studied for the PWLS minimization. One utilizes a Markov random field (MRF) Gibbs functional to consider spatial correlations among nearby detector bins and projection views in sinogram space and minimizes the PWLS cost function by iterative Gauss-Seidel algorithm. Another employs Karhunen-Loève (KL) transform to de-correlate data signals among nearby views and minimizes the PWLS adaptively to each KL component by analytical calculation, where the spatial correlation among nearby bins is modeled by the same Gibbs functional. The third one models the spatial correlations among image pixels in image domain also by a MRF Gibbs functional and minimizes the PWLS by iterative successive over-relaxation algorithm. In these three implementations, a quadratic functional regularization was chosen for the MRF model. Phantom experiments showed a comparable performance of these three PWLS-based methods in terms of suppressing noise-induced streak artifacts and preserving resolution in the reconstructed images. Computer simulations concurred with the phantom experiments in terms of noise-resolution tradeoff and detectability in low contrast environment. The KL-PWLS implementation may have the advantage in terms of computation for high-resolution dynamic low-dose CT imaging.


Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities.
The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.


Elucidating drug targets and mechanisms of action by genetic screens in mammalian cells.
Phenotypic screening is a powerful approach to discover small molecules with desired effects on biological systems, which can then be developed into therapeutic drugs. The identification of the target and mechanism of action of compounds discovered in phenotypic screens remains a major challenge. This feature article describes the use of genetic tools to reveal drug targets and mechanisms in mammalian cells. Until recently, RNA interference was the method of choice for such studies. Here, we highlight very recent additions to the genetic toolkit in mammalian cells, including CRISPR, CRISPR interference, and CRISPR activation, and illustrate their usefulness for drug target identification.


A case for the use of aminopterin in treatment of patients with leukemia based on metabolic studies of blasts in vitro.
Clinical and laboratory investigations during the past four decades have resulted in numerous schedules, doses, and routes of delivery for methotrexate (MTX). It remains as an important drug for the treatment of children with acute lymphoblastic leukemia (ALL). Aminopterin (AMT) was the initial antifolate showing promise as an anticancer drug. It is more potent than MTX and also is known to be accumulated more efficiently than MTX in model systems. Because Whitehead et al. (Blood, 76: 44-49, 1990) have shown that MTX accumulation by blasts at diagnosis is of prognostic significance in children with ALL, we reasoned that if accumulation of a "stoichiometric inhibitor" of dihydrofolate reductase by leukemic blasts was of prognostic importance, then whether it was AMT or MTX may be relevant only with respect to the absolute dose. To compare MTX and AMT metabolism, we incubated lymphoblasts with 1 microM radiolabeled drug in vitro. MTX and AMT accumulation by ALL cells (n = 24) was 0.7 +/- 0.7 and 1.47 +/- 0.9 pmol/10(6) cells, respectively. Based on the data of Whitehead et al., this predicts pharmacological success in 59 and 84% of the MTX and AMT groups, respectively. Moreover, 5 of 10 patients considered poor risks based on MTX accumulation would be "cures" based on AMT uptake. Even at only 0.1 microM AMT, a concentration at which there is little accumulation of MTX, 5 of 11 patients studied would be "pharmacological cures" based on AMT uptake. Accumulation of AMT by blasts from 11 patients with T-cell-lineage ALL and 5 patients with acute myelogenous leukemia was also found to be twice the uptake of MTX. These data allow the suggestion that AMT, despite increased potential for toxicity, may be useful in children who are identified as poor risks with respect to MTX uptake.


Turning Symbolic: The Representation of Motion Direction in Working Memory.
What happens to the representation of a moving stimulus when it is no longer present and its motion direction has to be maintained in working memory (WM)? Is the initial, sensorial representation maintained during the delay period or is there another representation, at a higher level of abstraction? It is also feasible that multiple representations may co-exist in WM, manifesting different facets of sensory and more abstract features. To that end, we investigated the mnemonic representation of motion direction in a series of three psychophysical experiments, using a delayed motion-discrimination task (relative clockwise∖counter-clockwise judgment). First, we show that a change in the dots' contrast polarity does not hamper performance. Next, we demonstrate that performance is unaffected by relocation of the Test stimulus in either retinotopic or spatiotopic coordinate frames. Finally, we show that an arrow-shaped cue presented during the delay interval between the Sample and Test stimulus, strongly biases performance toward the direction of the arrow, although the cue itself is non-informative (it has no predictive value of the correct answer). These results indicate that the representation of motion direction in WM could be independent of the physical features of the stimulus (polarity or position) and has non-sensorial abstract qualities. It is plausible that an abstract mnemonic trace might be activated alongside a more basic, analog representation of the stimulus. We speculate that the specific sensitivity of the mnemonic representation to the arrow-shaped symbol may stem from the long term learned association between direction and the hour in the clock.


Facebook-augmented partner notification in a cluster of syphilis cases in Milwaukee.
Public health professionals face many challenges in infectious disease cluster case identification and partner notification (PN), especially in populations using social media as a primary communication venue. We present a method using Facebook and social network diagram illustration to identify, link, and notify individuals in a cluster of syphilis cases in young black men who have sex with men (MSM). Use of Facebook was crucial in identifying two of 55 individuals with syphilis, and the cooperation of socially connected individuals with traditional PN methods yielded a high number of contacts per case. Integration of PN services for HIV and sexually transmitted diseases, as well as collaboration between the city and state information systems, assisted in the cluster investigation. Given that rates of syphilis and HIV infection are increasing significantly in young African American MSM, the use of social media can provide an additional avenue to facilitate case identification and notification.


Mastering Your Fellowship: Part 4, 2022.
The 'Mastering Your Fellowship' series provides examples of the question format encountered in the written and clinical examinations, Part A of the Fellowship of the College of Family Physicians of South Africa examination. The series is aimed at helping family medicine registrars prepare for this examination.


Oral steroid-sparing effect of high-dose inhaled corticosteroids in asthma.
The proportion of the efficacy of high-dose inhaled corticosteroids (ICS) in oral corticosteroid-dependent asthma that is due to systemic effects is uncertain. This study aimed to estimate the ICS dose-response relationship for oral corticosteroid-sparing effects in oral corticosteroid-dependent asthma, and to determine the proportion of oral corticosteroid-sparing effects due to their systemic effects, based on the comparative dose-response relationship of ICS versus oral corticosteroids on adrenal suppression. Systematic review and meta-analysis of randomised controlled trials reporting oral corticosteroid-sparing effects of high-dose ICS in oral corticosteroid-dependent asthma. In addition, reports of oral corticosteroid to ICS dose-equivalence in terms of adrenal suppression were retrieved. The primary outcome was the proportion of the oral corticosteroid-sparing effect of ICS that could be attributed to systemic absorption, per 1000 µg increase of ICS, expressed as a ratio. This ratio estimates the oral corticosteroid sparing effect of ICS due to systemic effects. 11 studies including 1283 participants reporting oral corticosteroid-sparing effects of ICS were identified. The prednisone dose decrease per 1000 µg increase in ICS varied from 2.1 mg to 4.9 mg, depending on the type of ICS. The ratio of the prednisone-sparing effect due to the systemic effects per 1000 µg of fluticasone propionate was 1.02 (95% CI 0.68-2.08) and for budesonide was 0.93 (95% CI 0.63-1.89). In patients with oral corticosteroid-dependent asthma, the limited available evidence suggests that the majority of the oral corticosteroid-sparing effect of high-dose ICS is likely to be due to systemic effects.


Consensus on guidelines for stereotactic neurosurgery for psychiatric disorders.
For patients with psychiatric illnesses remaining refractory to 'standard' therapies, neurosurgical procedures may be considered. Guidelines for safe and ethical conduct of such procedures have previously and independently been proposed by various local and regional expert groups. To expand on these earlier documents, representative members of continental and international psychiatric and neurosurgical societies, joined efforts to further elaborate and adopt a pragmatic worldwide set of guidelines. These are intended to address a broad range of neuropsychiatric disorders, brain targets and neurosurgical techniques, taking into account cultural and social heterogeneities of healthcare environments. The proposed consensus document highlights that, while stereotactic ablative procedures such as cingulotomy and capsulotomy for depression and obsessive-compulsive disorder are considered 'established' in some countries, they still lack level I evidence. Further, it is noted that deep brain stimulation in any brain target hitherto tried, and for any psychiatric or behavioural disorder, still remains at an investigational stage. Researchers are encouraged to design randomised controlled trials, based on scientific and data-driven rationales for disease and brain target selection. Experienced multidisciplinary teams are a mandatory requirement for the safe and ethical conduct of any psychiatric neurosurgery, ensuring documented refractoriness of patients, proper consent procedures that respect patient's capacity and autonomy, multifaceted preoperative as well as postoperative long-term follow-up evaluation, and reporting of effects and side effects for all patients. This consensus document on ethical and scientific conduct of psychiatric surgery worldwide is designed to enhance patient safety.


Integration of MicroRNA, mRNA, and Protein Expression Data for the Identification of Cancer-Related MicroRNAs.
MicroRNAs (miRNAs) are responsible for the regulation of target genes involved in various biological processes, and may play oncogenic or tumor suppressive roles. Many studies have investigated the relationships between miRNAs and their target genes, using mRNA and miRNA expression data. However, mRNA expression levels do not necessarily represent the exact gene expression profiles, since protein translation may be regulated in several different ways. Despite this, large-scale protein expression data have been integrated rarely when predicting gene-miRNA relationships. This study explores two approaches for the investigation of gene-miRNA relationships by integrating mRNA expression and protein expression data. First, miRNAs were ranked according to their effects on cancer development. We calculated influence scores for each miRNA, based on the number of significant mRNA-miRNA and protein-miRNA correlations. Furthermore, we constructed modules containing mRNAs, proteins, and miRNAs, in which these three molecular types are highly correlated. The regulatory interactions between miRNA and genes in these modules have been validated based on the direct regulations, indirect regulations, and co-regulations through transcription factors. We applied our approaches to glioblastomas (GBMs), ranked miRNAs depending on their effects on GBM, and obtained 52 GBM-related modules. Compared with the miRNA rankings and modules constructed using only mRNA expression data, the rankings and modules constructed using mRNA and protein expression data were shown to have better performance. Additionally, we experimentally verified that miR-504, highly ranked and included in the identified modules, plays a suppressive role in GBM development. We demonstrated that the integration of both expression profiles allows a more precise analysis of gene-miRNA interactions and the identification of a higher number of cancer-related miRNAs and regulatory mechanisms.


Applying the Behavior Change Technique Taxonomy to Four Multicomponent Childhood Obesity Interventions.
Applying the Behavior Change Technique Taxonomy has the potential to facilitate identification of effective childhood obesity intervention components. This article evaluates the feasibility of coding Childhood Obesity Prevention and Treatment Consortium interventions and compares reliability between external taxonomy-familiar coders and internal intervention-familiar coders. After training, coder pairs independently coded prespecified portions of intervention materials. An adjudication process was used to explore coding discrepancies. Reliability between internal and external coders was moderate (prevalence and bias-adjusted kappa .38 to .55). Reliability for specific target behaviors varied with substantial agreement for physical activity (.63 to .76) and moderate for dietary intake (.44 to .63). Applying the taxonomy to these interventions was feasible, but agreement was modest. Coding discrepancies highlight the importance of refining coding to capture the complexities of childhood obesity interventions, which often engage multiple recipients (e.g., parents and/or children) and address multiple behaviors (e.g., diet, physical activity, screen time).


Targeting the Immune Microenvironment in Acute Myeloid Leukemia: A Focus on T Cell Immunity.
Immunotherapies, such as chimeric antigen receptor T cells, bispecific antibodies, and immune checkpoint inhibitors, have emerged as promising modalities in multiple hematologic malignancies. Despite the excitement surrounding immunotherapy, it is currently not possible to predict which patients will respond. Within solid tumors, the status of the immune microenvironment provides valuable insight regarding potential responses to immune therapies. Much less is known about the immune microenvironment within hematologic malignancies but the characteristics of this environment are likely to serve a similar predictive role. Acute myeloid leukemia (AML) is the most common hematologic malignancy in adults, and only 25% of patients are alive 5 years following their diagnosis. There is evidence that manipulation of the immune microenvironment by leukemia cells may play a role in promoting therapy resistance and disease relapse. In addition, it has long been documented that through modulation of the immune system following allogeneic bone marrow transplant, AML can be cured, even in patients with the highest risk disease. These concepts, along with the poor prognosis associated with this disease, have encouraged many groups to start exploring the utility of novel immune therapies in AML. While the implementation of these therapies into clinical trials for AML has been supported by preclinical rationale, many questions still exist surrounding their efficacy, tolerability, and the overall optimal approach. In this review, we discuss what is known about the immune microenvironment within AML with a specific focus on T cells and checkpoints, along with their implications for immune therapies.


Microstructure, length, and connection of limbic tracts in normal human brain development.
The cingulum and fornix play an important role in memory, attention, spatial orientation, and feeling functions. Both microstructure and length of these limbic tracts can be affected by mental disorders such as Alzheimer's disease, depression, autism, anxiety, and schizophrenia. To date, there has been little systematic characterization of their microstructure, length, and functional connectivity in normally developing brains. In this study, diffusion tensor imaging (DTI) and resting state functional MRI (rs-fMRI) data from 65 normally developing right-handed subjects from birth to young adulthood was acquired. After cingulate gyrus part of the cingulum (cgc), hippocampal part of the cingulum (cgh) and fornix (fx) were traced with DTI tractography, absolute and normalized tract lengths and DTI-derived metrics including fractional anisotropy, mean, axial, and radial diffusivity were measured for traced limbic tracts. Free water elimination (FWE) algorithm was adopted to improve accuracy of the measurements of DTI-derived metrics. The role of these limbic tracts in the functional network at birth and adulthood was explored. We found a logarithmic age-dependent trajectory for FWE-corrected DTI metric changes with fast increase of microstructural integrity from birth to 2 years old followed by a slow increase to 25 years old. Normalized tract length of cgc increases with age, while no significant relationship with age was found for normalized tract lengths of cgh and fx. Stronger microstructural integrity on the left side compared to that of the right side was found. With integrated DTI and rs-fMRI, the key connectional role of cgc and cgh in the default mode network was confirmed as early as birth. Systematic characterization of length and DTI metrics after FWE correction of limbic tracts offers insight into their morphological and microstructural developmental trajectories. These trajectories may serve as a normal reference for pediatric patients with mental disorders.


Heterogeneity of brain lesions in pediatric traumatic brain injury.
Magnetic resonance imaging (MRI) provides a method to identify and quantify abnormalities resulting from traumatic brain injury (TBI). MRI abnormalities in children with TBI have not been fully characterized according to the frequency, location, and quantitative measurement of a range of pathologies critical for studies of neuropsychological outcome. Here, we report MRI findings from a large, multicenter study of childhood TBI, the Social Outcomes of Brain Injury in Kids (SOBIK) study, which compared qualitative and quantitative neuroimaging findings in 72 children with complicated mild-to-severe TBI to 52 children with orthopedic injury (OI). Qualitative analyses of MRI scans coded white matter hyperintensities (WMHs), hemosiderin deposits reflecting prior hemorrhagic lesions, regions of encephalomalacia and/or atrophy, and corpus callosum atrophy and traumatic shear lesions. Two automated quantitative analyses were conducted: (a) FreeSurfer methods computed volumes for total brain, white matter (WM), gray matter (GM), corpus callosum, ventricles, amygdala, hippocampus, basal ganglia, and thalamus along with a ventricle-to-brain ratio (VBR); and (b) voxel-based morphometry (VBM) to identify WM, GM, and cerebrospinal fluid. We also examined performance on the Processing Speed Index (PSI) from the Wechsler Intelligence Scale for Children, Fourth Edition, in relation to the above-mentioned neuroimaging variables. WMHs, hemosiderin deposits, and focal areas of encephalomalacia or atrophy were common in children with TBI, were related to injury severity, and were mostly observed within a frontotemporal distribution. Quantitative analyses showed volumetric changes related to injury severity, especially ventricular enlargement and reduced corpus callosum volume. VBM demonstrated similar findings, but, in addition, GM reductions in the inferior frontal, basal forebrain region, especially in the severe TBI group. The complicated mild TBI group showed few differences from the OI group. PSI was significantly associated with global atrophy, as measured by VBR. MRI findings after childhood TBI are diverse and particularly influenced by injury severity, and they involve common features, group heterogeneity, and individual variability.


The sole and combined effect of simvastatin and platelet rich fibrin as a filling material in induced bone defect in tibia of albino rats.
Statins like simvastatin (SIM) have demonstrated to have pleiotropic actions other than their conventional use as antilipidemic drugs. Also, nowadays natural scaffolds like platelets rich fibrin (PRF) showed promising results on bone regeneration. Aim This study compare the regenerative power of SIM and PRF added locally each as a sole filling material on induced bone defect and evaluate the combined effect using PRF loaded with SIM. MATERIALS AND METHODS: A critical size bone defect was induced in 48 male albino rats of average weight 150-200 g and were divided into 4 groups according to the filling material. Control, PRF, SIM, and SIM/PRF group. Each group was subdivided according to the sacrificing period into two subgroups (one and two-months postoperatively). Tibial specimens were evaluated histologically using masson trichrome (MT) special stain to detect areas of new bone formation, immunohistochemically using anti- BMP2 and anti-VEGF, serum levels of Osteoprotegerin (OPG), RANKL, osteocalcin and alkaline phosphatase enzyme (ALP) were measured one and two months postoperatively using ELISA, Finally bone mineral density (BMD) at the bone defect area was analyzed using digital X-ray one and two-months postoperatively. RESULTS: The percentage of newly formed bone increased significantly in the three groups vs the control group with the highest significant increase (p < 0.001) in the SIM/PRF group one month postoperatively. Also, SIM/PRF group was the only group which showed significant bone maturation two-months postoperatively compared to the other groups. Immunohistochemical analysis showed significant increase in positively stained BMP-2 and VEGF expression (p < 0.001) in the three groups vs the control group with the highest significant increase (p < 0.001) in the SIM/PRF group. Serum bone anabolic markers increased significantly in the SIM and SIM/PRF groups. In contrast, RANKL serum level decreased significantly in the SIM and SIM/PRF group one month postoperatively with no significant decrease in the PRF group vs the control group. Digital X-ray results revealed the highest BMD percent change was found in the SIM/PRF group and showed complete bone healing two-months postoperatively.


Temperature profiling by Rayleigh-scattering lidar.
A lidar with high spectral resolution can be used to measure atmospheric temperature profiles according to conservative performance calculations. The technique analyzed relies on determining the temperature-dependent Rayleigh-scattering linewidth with two stabilized Michelson interferometers in parallel. From ratios of four integrated flux values from two photomultipliers, one can determine temperature profiles within a 1 K standard deviation to 5 km with 50-m height resolution in 1(1/4) min using a laser of 1-W average power and a telescope of 30-cm diam.


Longitudinal association of biomarkers of pesticide exposure with cardiovascular disease risk factors in youth with diabetes.
Cardiovascular disease (CVD) is the leading cause of death among individuals with diabetes, but little is known about the role of exposures to environmental chemicals such as pesticides in the early development of CVD risk in this population. To describe changes over time in concentrations of pesticide biomarkers among youth with diabetes in the United States and to estimate the longitudinal association between these concentrations and established risk factors for CVD. Pesticide biomarkers were quantified in urine and serum samples from 87 youth with diabetes participating in the multi-center SEARCH cohort study. Samples were obtained around the time of diagnosis (baseline visit, between 2006 and 2010) and, on average, 5.4 years later (follow-up visit, between 2012 and 2015). We calculated geometric mean (95% CI) pesticide biomarker concentrations. Eight CVD risk factors were measured at these two time points: body mass index (BMI) z-score, HbA1c, insulin sensitivity, fasting C-peptide (FCP), LDL cholesterol, HDL cholesterol, total cholesterol, and triglycerides. Linear regression models were used to estimate the associations between each pesticide biomarker at baseline and each CVD risk factor at follow-up, adjusting for baseline health outcome, elapsed time between baseline and follow up, sex, age, race/ethnicity, and diabetes type. Participants were, on average, 14.2 years old at their baseline visit, and most were diagnosed with type 1 diabetes (57.5%). 4-nitrophenol, 3-phenoxybenzoic acid, 2,4-dichlorophenoxyacetic acid (2,4-D), 3,5,6-trichloro-2-pyridinol, 2,2-bis(4-chlorophenyl)-1,1-dichloroethene, and hexachlorobenzene were detected in a majority of participants at both time points. Participants in the highest quartile of 2,4-D and 4-nitrophenol at baseline had HbA1c levels at follow-up that were 1.05 percentage points (95% CI: -0.40, 2.51) and 1.27 percentage points (0.22, 2.75) higher, respectively, than participants in the lowest quartile of these pesticide biomarkers at baseline. These participants also had lower log FCP levels (indicating reduced beta-cell function) compared to participants in the lowest quartile at baseline: beta (95% CI) for log FCP of -0.64 (-1.17, -0.11) for 2,4-D and -0.39 (-0.96, 0.18) for 4-nitrophenol. In other words, participants in the highest quartile of 2,4-D had a 47.3% lower FCP level compared to participants in the lowest quartile, and those in the highest quartile of 4-nitrophenol had a 32.3% lower FCP level than those in the lowest quartile. Participants with trans-nonachlor concentrations in the highest quartile at baseline had HbA1c levels that were 1.45 percentage points (-0.11, 3.01) higher and log FCP levels that were -0.28 (-0.84, 0.28) lower than participants in the lowest quartile at baseline, that is to say, participants in the highest quartile of trans-nonachlor had a 24.4% lower FCP level than those in the lowest quartile. While not all of these results were statistically significant, potentially due to the small same size, clinically, there appears to be quantitative differences. No associations were observed between any pesticide biomarker at baseline with BMI z-score or insulin sensitivity at follow-up. Exposure to select pesticides may be associated with impaired beta-cell function and poorer glycemic control among youth with diabetes.


Diabetes, its duration, and the long-term risk of abdominal aortic aneurysm: The Atherosclerosis Risk in Communities (ARIC) Study.
We aimed at comprehensively evaluate the independent association of diabetes and its duration with incident abdominal aortic aneurysm (AAA) and aortic diameter. We prospectively studied incident AAA according to baseline glycemic status (diabetes, prediabetes, normal glycemia) in 13,116 ARIC participants (1990-1992) and the time-varying exposure of duration post incident diabetes in 11,675 participants (1987-1989) using Cox models. Additionally, we cross-sectionally explored ultrasound-based abdominal aortic diameter by glycemic status and cumulative duration of diabetes in 4710 participants (2011-2013) using linear regression models. Over ~20 years of follow-up, diabetes (vs. normal glycemia) at baseline was independently associated with lower AAA risk (489 cases) (hazard ratio: 0.71 [95%CI 0.51-0.99]), especially after 10 years (hazard ratio: 0.58 [0.38-0.87]). Prediabetes did not demonstrate an independent association. The inverse association was more evident with longer duration of diabetes (p for trend = 0.045), with 30-50% lower risk in eight years after diabetes diagnosis. The cross-sectional analysis demonstrated smaller aortic diameters with longer duration of diabetes (e.g., -0.76 mm [-1.24, -0.28] in diabetes with 8-12 years) compared to non-diabetes, whereas prediabetes consistently showed nominally greater diameter. Diabetes, especially with longer duration, but not prediabetes, was independently associated with lower risk of AAA and smaller aortic diameter. Our findings suggest that long lasting clinical hyperglycemia plays an important role in the reduced AAA risk, and the reduced aortic diameter may be a structural mechanism behind this paradoxical association.


Self-refocusing 270 degrees Gaussian pulses for slice selection without gradient reversal in magnetic resonance imaging.
It is demonstrated, on the grounds of simulations, how 270 degrees Gaussian pulses can be used for slice selection in nuclear magnetic resonance imaging experiments. It is shown that the usual gradient reversal procedure can be omitted if the selective 90 degrees pulse normally used is replaced by a self-refocusing 270 degrees pulse with a Gaussian time-domain amplitude profile, and some of the properties which are specific to this type of pulse are explored.


Combination Platinum-based and DNA Damage Response-targeting Cancer Therapy: Evolution and Future Directions.
Maintenance of genomic stability is a critical determinant of cell survival and is necessary for growth and progression of malignant cells. Interstrand crosslinking (ICL) agents, including platinum-based agents, are first-line chemotherapy treatment for many solid human cancers. In malignant cells, ICL triggers the DNA damage response (DDR). When the damage burden is high and lesions cannot be repaired, malignant cells are unable to divide and ultimately undergo cell death either through mitotic catastrophe or apoptosis. The activities of ICL agents, in particular platinum-based therapies, establish a "molecular landscape," i.e., a pattern of DNA damage that can potentially be further exploited therapeutically with DDR-targeting agents. If the molecular landscape created by platinum-based agents could be better defined at the molecular level, a systematic, mechanistic rationale(s) could be developed for the use of DDR-targeting therapies in combination/maintenance protocols for specific, clinically advanced malignancies. New therapeutic drugs such as poly(ADP-ribose) polymerase (PARP) inhibitors are examples of DDR-targeting therapies that could potentially increase the DNA damage and replication stress imposed by platinum-based agents in tumor cells and provide therapeutic benefit for patients with advanced malignancies. Recent studies have shown that the use of PARP inhibitors together with platinum-based agents is a promising therapy strategy for ovarian cancer patients with "BRCAness", i.e., a phenotypic characteristic of tumors that not only can involve loss-of-function mutations in either BRCA1 or BRCA2, but also encompasses the molecular features of BRCA-mutant tumors. On the basis of these promising results, additional mechanism-based studies focused on the use of various DDR-targeting therapies in combination with platinum-based agents should be considered. This review discusses, in general, (1) ICL agents, primarily platinum-based agents, that establish a molecular landscape that can be further exploited therapeutically; (2) multiple points of potential intervention after ICL agent-induced crosslinking that further predispose to cell death and can be incorporated into a systematic, therapeutic rationale for combination/ maintenance therapy using DDR-targeting agents; and (3) available agents that can be considered for use in combination/maintenance clinical protocols with platinum-based agents for patients with advanced malignancies.


Anti-HIV activity of olive leaf extract (OLE) and modulation of host cell gene expression by HIV-1 infection and OLE treatment.
We investigated the antiviral activity of olive leaf extract (OLE) preparations standardized by liquid chromatography-coupled mass spectrometry (LC-MS) against HIV-1 infection and replication. We find that OLE inhibits acute infection and cell-to-cell transmission of HIV-1 as assayed by syncytia formation using uninfected MT2 cells co-cultured with HIV-1-infected H9 T lymphocytes. OLE also inhibits HIV-1 replication as assayed by p24 expression in infected H9 cells. These anti-HIV effects of OLE are dose dependent, with EC(50)s of around 0.2 microg/ml. In the effective dose range, no cytotoxicity on uninfected target cells was detected. The therapeutic index of OLE is above 5000. To identify viral and host targets for OLE, we characterized gene expression profiles associated with HIV-1 infection and OLE treatment using cDNA microarrays. HIV-1 infection modulates the expression patterns of cellular genes involved in apoptosis, stress, cytokine, protein kinase C, and hedgehog signaling. HIV-1 infection up-regulates the expression of the heat-shock proteins hsp27 and hsp90, the DNA damage inducible transcript 1 gadd45, the p53-binding protein mdm2, and the hedgehog signal protein patched 1, while it down-regulates the expression of the anti-apoptotic BCL2-associated X protein Bax. Treatment with OLE reverses many of these HIV-1 infection-associated changes. Treatment of HIV-1-infected cells with OLE also up-regulates the expression of the apoptosis inhibitor proteins IAP1 and 2, as well as the calcium and protein kinase C pathway signaling molecules IL-2, IL-2Ralpha, and ornithine decarboxylase ODC1.


Temporal lobe epilepsy due to hippocampal sclerosis in pediatric candidates for epilepsy surgery.
To characterize the clinical, EEG, MRI, and histopathologic features and explore seizure outcome in pediatric candidates for epilepsy surgery who have temporal lobe epilepsy (TLE) caused by hippocampal sclerosis (HS). The authors studied 17 children (4 to 12 years of age) and 17 adolescents (13 to 20 years of age) who had anteromesial temporal resection between 1990 and 1998. All patients had seizures characterized by decreased awareness and responsiveness. Automatisms were typically mild to moderate in children and moderate to marked in adolescents. Among adolescents, interictal spikes were almost exclusively unilateral anterior temporal, as opposed to children in whom anterior temporal spikes were associated with mid/posterior temporal, bilateral temporal, extratemporal, or generalized spikes in 60% of cases. MRI showed hippocampal sclerosis on the side of EEG seizure onset in all patients. Fifty-four percent of children and 56% of adolescents had significant asymmetry of total hippocampal volumes, whereas the remaining patients had only focal atrophy of the hippocampal head or body. Subtle MRI abnormalities of ipsilateral temporal neocortex were seen in all children and 60% of adolescents studied with FLAIR images. On histopathology, there was an unexpectedly high frequency of dual pathology with mild to moderate cortical dysplasia as well as HS, seen in 79% of children and adolescents. Seventy-eight percent of patients were free of seizures at follow-up (mean, 2.6 years). A tendency for lower seizure-free outcome was observed in patients with bilateral temporal interictal sharp waves or bilateral HS on MRI. The presence of dual pathology did not portend poor postsurgical outcome. TLE caused by HS similar to those in adults were seen in children as young as 4 years of age. Focal hippocampal atrophy seen on MRI often was not reflected in total hippocampal volumetry. Children may have an especially high frequency of dual pathology, with mild to moderate cortical dysplasia as well as HS, and MRI usually, but not always, predicts this finding. Postsurgical seizure outcome is similar to that in adult series.