Cancer cell sensitivity to bortezomib is associated with survivin expression and p53 status but not cancer cell types.
Survivin is known playing a role in drug resistance. However, its role in bortezomib-mediated inhibition of growth and induction of apoptosis is unclear. There are conflicting reports for the effect of bortezomib on survivin expression, which lacks of a plausible explanation. In this study, we tested cancer cells with both p53 wild type and mutant/null background for the relationship of bortezomib resistance with survivin expression and p53 status using MTT assay, flow cytometry, DNA fragmentation, caspase activation, western blots and RNAi technology. We found that cancer cells with wild type p53 show a low level expression of survivin and are sensitive to treatment with bortezomib, while cancer cells with a mutant or null p53 show a high level expression of survivin and are resistant to bortezomib-mediated apoptosis induction. However, silencing of survivin expression utilizing survivin mRNA-specific siRNA/shRNA in p53 mutant or null cells sensitized cancer cells to bortezomib mediated apoptosis induction, suggesting a role for survivin in bortezomib resistance. We further noted that modulation of survivin expression by bortezomib is dependent on p53 status but independent of cancer cell types. In cancer cells with mutated p53 or p53 null, bortezomib appears to induce survivin expression, while in cancer cells with wild type p53, bortezomib downregulates or shows no significant effect on survivin expression, which is dependent on the drug concentration, cell line and exposure time. Our findings, for the first time, unify the current inconsistent findings for bortezomib treatment and survivin expression, and linked the effect of bortezomib on survivin expression, apoptosis induction and bortezomib resistance in the relationship with p53 status, which is independent of cancer cell types. Further mechanistic studies along with this line may impact the optimal clinical application of bortezomib in solid cancer therapeutics.


Kernel machine testing for risk prediction with stratified case cohort studies.
Large assembled cohorts with banked biospecimens offer valuable opportunities to identify novel markers for risk prediction. When the outcome of interest is rare, an effective strategy to conserve limited biological resources while maintaining reasonable statistical power is the case cohort (CCH) sampling design, in which expensive markers are measured on a subset of cases and controls. However, the CCH design introduces significant analytical complexity due to outcome-dependent, finite-population sampling. Current methods for analyzing CCH studies focus primarily on the estimation of simple survival models with linear effects; testing and estimation procedures that can efficiently capture complex non-linear marker effects for CCH data remain elusive. In this article, we propose inverse probability weighted (IPW) variance component type tests for identifying important marker sets through a Cox proportional hazards kernel machine (CoxKM) regression framework previously considered for full cohort studies (Cai et al., 2011). The optimal choice of kernel, while vitally important to attain high power, is typically unknown for a given dataset. Thus, we also develop robust testing procedures that adaptively combine information from multiple kernels. The proposed IPW test statistics have complex null distributions that cannot easily be approximated explicitly. Furthermore, due to the correlation induced by CCH sampling, standard resampling methods such as the bootstrap fail to approximate the distribution correctly. We, therefore, propose a novel perturbation resampling scheme that can effectively recover the induced correlation structure. Results from extensive simulation studies suggest that the proposed IPW CoxKM testing procedures work well in finite samples. The proposed methods are further illustrated by application to a Danish CCH study of Apolipoprotein C-III markers on the risk of coronary heart disease.


Increased dietary iron and radiation in rats promote oxidative stress, induce localized and systemic immune system responses, and alter colon mucosal environment.
Astronauts are exposed to increased body iron stores and radiation, both of which can cause oxidative damage leading to negative health effects. The purpose of this study was to investigate combined effects of high dietary iron (650 mg/kg diet) and radiation exposure (0.375 Gy cesium-137 every other day for 16 d) on markers of oxidative stress, immune system function, and colon mucosal environment in male Sprague-Dawley rats (n=8/group). Control rats consumed adequate iron (45 mg/kg diet) and were not irradiated. Combined treatments increased liver glutathione peroxidase, serum catalase, and colon myeloperoxidase while decreasing total fecal short-chain fatty acid concentrations. The high-iron diet alone increased leukocyte count. Radiation decreased the T-cell CD4:CD8 ratio. Plasma iron was negatively correlated with cytokine production in activated monocytes. Genes involved in colon microbial signaling, immune response, and injury repair were altered by radiation. Genes involved with injury repair and pathogen recognition changed with dietary iron. These data demonstrate that dietary iron and radiation, alone and combined, contribute to oxidative stress that is related to immune system alterations in circulation and the colon. The model presented may help us better understand the changes to these systems that have been identified among astronauts.


A high-throughput plasmonic tongue using an aggregation assay and nonspecific interactions: classification of taste profiles in maple syrup.
A simple colorimetric test detects off-flavour profiles of maple syrups in minutes, which are detectable by the naked eye. As flavour profiles are due to complex mixtures of molecules, the test uses nonspecific interactions for analysing the aggregation and color change of Au nanoparticles (AuNPs) induced by the different organic molecules contained in off-flavour maple syrup. The test was optimal with 13 nm citrate-capped AuNPs reacting 1 : 1 with pure maple syrup diluted 10 times. Under these conditions, normal flavour maple syrups did not react and the solution remained red, while off-flavoured maple syrups aggregated the AuNPs and the solution turned blue. Different classes of molecules were then tested to evaluate the types of compounds typically found in maple syrups reacting in the test, showing that sulfur- and amine-containing amino acids and aromatic amines caused aggregation of the AuNPs. The test was validated with 1818 maple syrup samples from the 2018 harvest in Quebec and 98% of the off-flavoured maple syrups were positively identified against the standard taste test. Preliminary tests were performed on site in maple sugar shacks to validate the applicability of the test on the production site.


Adaptive filtering methods for identifying cross-frequency couplings in human EEG.
Oscillations have been increasingly recognized as a core property of neural responses that contribute to spontaneous, induced, and evoked activities within and between individual neurons and neural ensembles. They are considered as a prominent mechanism for information processing within and communication between brain areas. More recently, it has been proposed that interactions between periodic components at different frequencies, known as cross-frequency couplings, may support the integration of neuronal oscillations at different temporal and spatial scales. The present study details methods based on an adaptive frequency tracking approach that improve the quantification and statistical analysis of oscillatory components and cross-frequency couplings. This approach allows for time-varying instantaneous frequency, which is particularly important when measuring phase interactions between components. We compared this adaptive approach to traditional band-pass filters in their measurement of phase-amplitude and phase-phase cross-frequency couplings. Evaluations were performed with synthetic signals and EEG data recorded from healthy humans performing an illusory contour discrimination task. First, the synthetic signals in conjunction with Monte Carlo simulations highlighted two desirable features of the proposed algorithm vs. classical filter-bank approaches: resilience to broad-band noise and oscillatory interference. Second, the analyses with real EEG signals revealed statistically more robust effects (i.e. improved sensitivity) when using an adaptive frequency tracking framework, particularly when identifying phase-amplitude couplings. This was further confirmed after generating surrogate signals from the real EEG data. Adaptive frequency tracking appears to improve the measurements of cross-frequency couplings through precise extraction of neuronal oscillations.


Value of follow-up examinations of children and adolescents evaluated for sexual abuse and assault.
The purpose of this study was to determine whether follow-up examinations of suspected victims of child sexual abuse influence medical diagnosis or treatment. A retrospective chart review of patients with initial and follow-up examinations (examinations 1 and 2, respectively) over a 5-year study period was conducted. Patient and abuse characteristics, interval between examinations and abuse, and examiner experience levels were collected; examination findings and test results for sexually transmitted infections (STIs) were compared for examinations 1 and 2. Among 727 patients, examination 2 resulted in a change in interpretation of trauma likelihood in 129 (17.7%) patients and identified STIs in 47 (6.5%) patients. Changes in trauma likelihood and detection of additional STIs during follow-up examinations were more likely in adolescent, female, and sexually active patients and those with a history of genital-genital contact, unknown examination 1 findings, or drug-facilitated sexual assault. Although examination 2 was less likely to affect the interpretation of trauma likelihood and STIs in preadolescent patients, a change in interpretation of trauma likelihood was noted for 49 (15.5%) of these patients, and 16 (5.1%) were diagnosed with a new STI on examination 2. The level of clinician experience during examination 1 did affect the likelihood of changes in examination findings during examination 2. Follow-up examinations by specialists affected the interpretation of trauma and detection of STIs in ∼23% of pediatric patients undergoing sexual abuse assessments.


Digital genotyping of sorghum - a diverse plant species with a large repeat-rich genome.
Rapid acquisition of accurate genotyping information is essential for all genetic marker-based studies. For species with relatively small genomes, complete genome resequencing is a feasible approach for genotyping; however, for species with large and highly repetitive genomes, the acquisition of whole genome sequences for the purpose of genotyping is still relatively inefficient and too expensive to be carried out on a high-throughput basis. Sorghum bicolor is a C4 grass with a sequenced genome size of ~730 Mb, of which ~80% is highly repetitive. We have developed a restriction enzyme targeted genome resequencing method for genetic analysis, termed Digital Genotyping (DG), to be applied to sorghum and other grass species with large repeat-rich genomes. DG templates are generated using one of three methylation sensitive restriction enzymes that recognize a nested set of 4, 6 or 8 bp GC-rich sequences, enabling varying depth of analysis and integration of results among assays. Variation in sequencing efficiency among DG markers was correlated with template GC-content and length. The expected DG allele sequence was obtained 97.3% of the time with a ratio of expected to alternative allele sequence acquisition of >20:1. A genetic map aligned to the sorghum genome sequence with an average resolution of 1.47 cM was constructed using 1,772 DG markers from 137 recombinant inbred lines. The DG map enhanced the detection of QTL for variation in plant height and precisely aligned QTL such as Dw3 to underlying genes/alleles. Higher-resolution NgoMIV-based DG haplotypes were used to trace the origin of DNA on SBI-06, spanning Ma1 and Dw2 from progenitors to BTx623 and IS3620C. DG marker analysis identified the correct location of two miss-assembled regions and located seven super contigs in the sorghum reference genome sequence. DG technology provides a cost-effective approach to rapidly generate accurate genotyping data in sorghum. Currently, data derived from DG are used for many marker-based analyses, including marker-assisted breeding, pedigree and QTL analysis, genetic map construction, map-based gene cloning and association studies. DG in combination with whole genome resequencing is dramatically accelerating all aspects of genetic analysis of sorghum, an important genetic reference for C4 grass species.


Women, anger, and aggression: an interpretative phenomenological analysis.
This study reports a qualitative phenomenological investigation of anger and anger-related aggression in the context of the lives of individual women. Semistructured interviews with five women are analyzed using interpretative phenomenological analysis. This inductive approach aims to capture the richness and complexity of the lived experience of emotional life. In particular, it draws attention to the context-dependent and relational dimension of angry feelings and aggressive behavior. Three analytic themes are presented here: the subjective experience of anger, which includes the perceptual confusion and bodily change felt by the women when angry, crying, and the presence of multiple emotions; the forms and contexts of aggression, paying particular attention to the range of aggressive strategies used; and anger as moral judgment, in particular perceptions of injustice and unfairness. The authors conclude by examining the analytic observations in light of phenomenological thinking.


Investigating the Effect of Cold Soak Duration on Phenolic Extraction during Cabernet Sauvignon Fermentation.
The impact of increasing cold soak (CS) duration (0, 1, 4, 7, and 10 days at 10 °C) on the extraction of phenolic compounds during the CS period and primary fermentation as well as the final composition of Cabernet Sauvignon wine was investigated. The results showed that CS duration had no effect on hydroxycinnamate and flavonol extractions. Greater amounts of gallic acid, (+)-catechin, (-)-epicatechin, and total tannins were extracted with increasing CS duration, with differences maintained during bottle aging. Anthocyanin extraction and color density increased with longer periods of CS; however, by the end of primary fermentation, as well as three months' bottle aging, there were no significant differences due to CS duration. The wines made with seven and 10 days of CS had higher seed tannin contributions and total tannin compared to the non-CS wine, which could potentially result in increased astringency.


Predictors of early progression to severe sepsis or shock among emergency department patients with nonsevere sepsis.
Progression from nonsevere sepsis-i.e., sepsis without organ failure or shock-to severe sepsis or shock among emergency department (ED) patients has been associated with significant mortality. Early recognition in the ED of those who progress to severe sepsis or shock during their hospital course may improve patient outcomes. We sought to identify clinical, demographic, and laboratory parameters that predict progression to severe sepsis, septic shock, or death within 96 h of ED triage among patients with initial presentation of nonsevere sepsis. This is a retrospective cohort of patients presenting to a single urban academic ED from November 2008 to October 2010. Patients aged 18 years or older who met criteria for sepsis and had a lactate level measured in the ED were included. Patients were excluded if they had any combination of the following: a systolic blood pressure <90 mmHg upon triage, an initial whole blood lactate level ≥4 mmol/L, or one or more of a set of predefined signs of organ dysfunction upon initial assessment. Disease progression was defined as the development of any combination of the aforementioned conditions, initiation of vasopressors, or death within 96 h of ED presentation. Data on predefined potential predictors of disease progression and outcome measures of disease progression were collected by a query of the electronic medical record and via chart review. Logistic regression was used to assess associations of potential predictor variables with a composite outcome measure of sepsis progression to organ failure, hypotension, or death. In this cohort of 582 ED patients with nonsevere sepsis, 108 (18.6 %) experienced disease progression. Initial serum albumin <3.5 mg/dL (OR 4.82; 95 % CI 2.40-9.69; p < 0.01) and a diastolic blood pressure <52 mmHg at ED triage (OR 4.59; 95 % CI 1.57-13.39; p < 0.01) were independently associated with disease progression to severe sepsis or shock within 96 h of ED presentation. There were no deaths within 96 h of ED presentation. In our patient cohort, serum albumin <3.5 g/dL and an ED triage diastolic blood pressure <52 mmHg independently predict early progression to severe sepsis or shock among ED patients with presumed sepsis.


Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1-Deficient Thoracic Cancers.
Purpose Pegylated arginine deiminase (ADI-PEG 20) depletes essential amino acid levels in argininosuccinate synthetase 1 (ASS1) -negative tumors by converting arginine to citrulline and ammonia. The main aim of this study was to determine the recommended dose, safety, and tolerability of ADI-PEG 20, cisplatin, and pemetrexed in patients with ASS1-deficient malignant pleural mesothelioma (MPM) or non-small-cell lung cancer (NSCLC). Patients and Methods Using a 3 + 3 + 3 dose-escalation study, nine chemotherapy-naïve patients (five MPM, four NSCLC) received weekly ADI-PEG 20 doses of 18 mg/m2, 27 mg/m2, or 36 mg/m2, together with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 which were given every three weeks (maximum of six cycles). Patients achieving stable disease or better could continue ADI-PEG 20 monotherapy until disease progression or withdrawal. Adverse events were assessed by Common Terminology Criteria for Adverse Events version 4.03, and pharmacodynamics and immunogenicity were also evaluated. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for NSCLC and by modified RECIST criteria for MPM. Results No dose-limiting toxicities were reported; nine of 38 reported adverse events (all grade 1 or 2) were related to ADI-PEG 20. Circulating arginine concentrations declined rapidly, and citrulline levels increased; both changes persisted at 18 weeks. Partial responses were observed in seven of nine patients (78%), including three with either sarcomatoid or biphasic MPM. Conclusion Target engagement with depletion of arginine was maintained throughout treatment with no dose-limiting toxicities. In this biomarker-selected group of patients with ASS1-deficient cancers, clinical activity was observed in patients with poor-prognosis tumors. Therefore, we recommend a dose for future studies of weekly ADI-PEG 20 36 mg/m2 plus three-weekly cisplatin 75 mg/m2 and pemetrexed 500 mg/m2.


Postoperative irradiation for rectal cancer increases the risk of small bowel obstruction after surgery.
To determine the risk of small bowel obstruction (SBO) after irradiation (RT) for rectal cancer : SBO is a frequent complication after standard resection of rectal cancer. Although the use of RT is increasing, the effect of RT on risk of SBO is unknown. We conducted a retrospective cohort study using Surveillance, Epidemiology, and End Results cancer registry data linked to Medicare claims data to determine the effect of RT on risk of SBO. Patients 65 years of age and older diagnosed with nonmetastatic invasive rectal cancer treated with standard resection from 1986 through 1999 were included. We determined whether patients had undergone RT and evaluated the effect of RT and timing of RT on the incidence of admission to hospital for SBO, adjusting for potential confounders using a proportional hazards model. We identified a total of 5606 patients who met our selection criteria: 1994 (36%) underwent RT, 74% postoperatively. Patients were followed for a mean of 3.8 years. A total of 614 patients were admitted for SBO over the study period; 15% of patients in the RT group and 9% of patients in the nonirradiated group (P < 0.001). After controlling for age, sex, race, diagnosis year, type of surgery, and stage, we found that patients who underwent postoperative RT were at higher risk of SBO, hazard ratio 1.69 (95% CI, 1.3-2.1). However, the long-term risk associated with preoperative irradiation was not statistically significant (hazard ratio, 0.89; 95% CI, 0.55-1.46). Postoperative but not preoperative RT after standard resection of rectal cancer results in an increased risk of SBO over time.


High Expression of Aldolase B Confers a Poor Prognosis for Rectal Cancer Patients Receiving Neoadjuvant Chemoradiotherapy.
Background : Colorectal cancer is the third most common cancer in both sex worldwide and it is also the fourth most common cause of cancer mortality. For rectal cancer, neoadjuvant concurrent chemoradiotherapy (CCRT) followed by radical proctectomy is gold standard treatment for patients with stage II/III rectal cancer. By data mining a documented database of rectal cancer transcriptome (GSE35452) from Gene Expression Omnibus, National Center of Biotechnology Information, we recognized that ALDOB was the most significantly up-regulated transcript among those related to glycolysis (GO: 0006096). Hence, we analyzed the clinicopathological correlation and prognostic effect of ALDOB protein (Aldolase B), which encoded by ALDOB gene. Methods : ALDOB immunostain was performed in 172 rectal adenocarcinomas treated with preoperative chemoradiotherapy followed by radical surgery, which were divided into high- and low-expression groups. Furthermore, statistical analyses were examined to correlate the relationship between ALDOB immunoreactivity and important clinical and pathological characteristics, as well as three survival indices: disease-specific survival (DSS), local recurrence-free survival (LRFS) and metastasis-free survival (MeFS). Results : ALDOB (Aldolase B) over-expression was significantly associated with pre-CCRT and post-CCRT tumor advancement, lymphovascular invasion, perineural invasion and poor response to CCRT (all P ≤ .023). In addition, ALDOB high expression was linked to adverse DSS, LRFS and MeFS in univariate analysis (P ≤ .0075) and also served as an independent prognosticator indicating dismal DSS and MeFS in multivariate analysis (hazard ratio (HR) = 3.462, 95% confidence interval (CI): 1.263-9.495; HR = 2.846, 95% CI: 1.190-6.808, respectively). Conclusion : ALDOB (Aldolase B) may play an imperative role in rectal cancer progression and responsiveness to neoadjuvant CCRT, and serve as a novel prognostic biomarker. Additional researches to clarify the molecular and biochemical pathways are essential for developing promising ALDOB-targeted therapies for patients with rectal cancers.


Articular and abarticular manifestations in type 2 diabetes mellitus.
Diabetes mellitus (DM), a worldwide high-prevalence disease, is associated with a large variety of rheumatic manifestations. It affects the connective tissues in many ways and causes alterations in the periarticular and the musculoskeletal systems. In most cases, these manifestations are associated with functional disability and pain, affecting the quality of life of the diabetic patient. The aim of our study is to review the different articular and abarticular manifestations in diabetic patients and the associated factors of these rheumatic manifestations. A cross-sectional study that includes all patients suffering from type 2 DM who present with articular or abarticular manifestations. We included 116 diabetic patients presenting with articular or abarticular manifestations. Our study showed four important findings. First, a large variety of articular and abarticular manifestations were present in patients with type 2 DM. Second, osteoarthritis (OA) of the knee was the most frequent articular manifestations. It was seen in 49% of our patients. Third, the most common manifestations in diabetic Moroccan patients were carpal tunnel syndrome (CTS), adhesive capsulitis of the shoulder, and diabetic cheiroarthropathy (29%, 23%, and 16%, respectively). Fourth, there was a significant association between vascular complications and the development of articular and abarticular manifestations. This study shows that the articular and abarticular manifestations in diabetic Moroccan patients are dominated by CTS, adhesive capsulitis of the shoulder, and diabetic cheiroarthropathy, with a significant association between vascular complications and the development of some of these manifestations.


Maternal use of hormonal contraception and risk of childhood ADHD: a nationwide population-based cohort study.
Although maternal use of hormones has been suspected of increasing the risk for childhood attention-deficit/hyperactivity disorder (ADHD), no study has examined hormonal contraception use in this context. We examined the association between maternal hormonal contraception use before or during pregnancy and ADHD risk in children. This nationwide population-based cohort study included 1,056,846 children born in Denmark between 1998 and 2014. Prescriptions for hormonal contraceptives redeemed by the mother was categorized as: no use, previous use (> 3 months before pregnancy), and recent use (≤ 3 months before or during pregnancy). Children were followed for ADHD, from birth until 31 December 2015. Cox proportional hazard models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). During 9,819,565 person-years of follow-up (median: 9.2), ADHD was diagnosed or a prescription for ADHD medication redeemed for 23,380 children (2.2%). The adjusted HR for ADHD was higher in children of mothers who had previously (HR 1.23; 95% CI 1.18-1.28) or recently (HR 1.30; 95% CI 1.24-1.37) used hormonal contraception than in those of mothers with no use. The highest estimates were seen for use of non-oral progestin products with HRs of 1.90 (95% CI 1.59-2.26) for previous use, 2.23 (95% CI 1.96-2.54) for recent use, and 3.10 (95% CI 1.62-5.91) for use during pregnancy. Maternal use of hormonal contraception was associated with an increased risk for ADHD in the offspring; more pronounced for non-oral progestin-only than other products.


Taxonomy-Based Glyph Design—with a Case Study on Visualizing Workflows of Biological Experiments.
Glyph-based visualization can offer elegant and concise presentation of multivariate information while enhancing speed and ease in visual search experienced by users. As with icon designs, glyphs are usually created based on the designers' experience and intuition, often in a spontaneous manner. Such a process does not scale well with the requirements of applications where a large number of concepts are to be encoded using glyphs. To alleviate such limitations, we propose a new systematic process for glyph design by exploring the parallel between the hierarchy of concept categorization and the ordering of discriminative capacity of visual channels. We examine the feasibility of this approach in an application where there is a pressing need for an efficient and effective means to visualize workflows of biological experiments. By processing thousands of workflow records in a public archive of biological experiments, we demonstrate that a cost-effective glyph design can be obtained by following a process of formulating a taxonomy with the aid of computation, identifying visual channels hierarchically, and defining application-specific abstraction and metaphors.


Association Between the Use of Cannabis and Physical Violence in Youths: A Meta-Analytical Investigation.
The aim of this meta-analysis was to investigate the extent to which cannabis use among youths is associated with the risk of perpetrating physical violence. Searches were conducted in PubMed, PsycINFO, Web of Science, and Google Scholar for articles published from the inception of each database to July 2019. All studies that examined both cannabis use and the perpetration of physical violence in a sample of youths and young adults <30 years old were included. The meta-analysis was performed with a random-effects model. Risk of publication bias was assessed with Egger's test. Guidelines from the Meta-Analysis of Observational Studies in Epidemiology were followed. After screening 11,348 potential studies, 30 study arms were included, yielding a total of 296,815 adolescents and young adults. The odds ratio for the pooled studies was 2.11 (95% CI=1.64, 2.72). The pooled odds ratios were 2.15 (95% CI=1.58, 2.94) and 2.02 (95% CI=1.26, 3.23) for the cross-sectional and longitudinal studies, respectively. Preliminary evidence suggests that the risk of violence was higher for persistent heavy users (odds ratio=2.81, 95% CI=1.68, 4.74) compared with past-year users (odds ratio=2.05, 95% CI=1.5, 2.8) and lifetime users (odds ratio=1.94, 95% CI=1.29, 2.93). The odds ratio for unadjusted studies was 2.62 (95% CI=1.89, 3.62), and for studies using odds ratios adjusted for potential confounding factors, 2.01 (95% CI=1.57, 2.56). These results demonstrate a moderate association between cannabis use and physical violence, which remained significant regardless of study design and adjustment for confounding factors (i.e., socioeconomic factors, other substance use). Cannabis use in this population is a risk factor for violence.


The intrinsic innervation of the canine heart: a functional study.
The intrinsic innervation of the heart has been described anatomically but seldom, functionally. These experiments were designed to verify and to evaluate the influence of intrinsic neural activation on the contractility of the atria and ventricles. Nine mongrel dogs underwent total cardiac denervation using the Geis two-stage technique. Following recovery, they were placed on total cardiopulmonary bypass. Balloons were inserted into each cardiac chamber, filled with saline, and used to record atrial and ventricular isovolumic pressures in response to intracoronary drug injections. The hearts were paced to avoid rate changes. Acetylcholine (ACh) (0.05-1.0 mug) was given to assess direct effects on the myocardium; nicotine (NIC) (25-200 mug) was used to produce indirect inotropic effects. d-Tubocurare (dTC) (1.0-2.5 mg) and tetrodotoxin (TTX) (10-30 mug) were used to differentiate the direct and the indirect effects. Both ACh and NIC produced qualitatively similar negative inotropic responses in both atria and ventricles. dTC usually produced a significantly greater blockade of responses to NIC than toACh. TTX administered to 12 other denervated dogs to differentiate direct and neurally mediated responses, completely blocked NIC-induced negative inotropy but did not change responses to ACh. The data show that (1) the intrinsic cardiac innervation can exert significant negative inotropic effects on atria and ventricles (10 to greater than 30%); (2) there is no functional evidence of participation by chromaffin cells in the inotropic responses to intrinsic nerve activation; (3) the negative inotropy produced by NIC is sensitive to dTC and, especially, TTX blockade. This is consistent with the mechanism of action being intrinsic neural stimulation.


Child behavior problems and parental well-being in families of children with autism: the mediating role of mindfulness and acceptance.
Few research studies have explored how the level of a child's behavior problems leads to psychological distress in parents of children with autism. The authors explored whether psychological acceptance and mindfulness mediated this relationship between child behavior and parental distress. Seventy-one mothers and 39 fathers of children with autism participated, by reporting on their own positive and negative psychological well-being and their child's behavior problems. Psychological acceptance was found to act as a mediator variable for maternal anxiety, depression, and stress, and for paternal depression. General mindfulness and mindful parenting had significant mediation effects for maternal anxiety, depression, and stress. These results contribute to evidence that mindfulness and acceptance may be important parental psychological processes, with implications for parent support.


Summary health statistics for U.S. children: National Health Interview Survey, 2005.
This report presents both age-adjusted and unadjusted statistics from the 2005 National Health Interview Survey (NHIS) on selected health measures for children under 18 years of age, classified by sex, age, race, Hispanic origin, family structure, parent education, family income, poverty status, health insurance coverage, place of residence, region, and current health status. The topics covered are asthma, allergies, learning disability, Attention Deficit Hyperactivity Disorder (ADHD), prescription medication use, respondent-assessed health status, school-loss days, usual place of health care, time since last contact with a health care professional, selected measures of health care access and utilization, and dental care. NHIS is a multistage probability sample survey conducted annually by interviewers of the U.S. Census Bureau for the Centers for Disease Control and Prevention's National Center for Health Statistics and is representative of the civilian noninstitutionalized population of the United States. Data are collected for all family members during face-to-face interviews with adults present at the time of interview. Additional information about children is collected for one randomly selected child per family in face-to-face interviews with an adult proxy respondent familiar with the child's health. In 2005, most U.S. children under 18 years of age had excellent or very good health (82%). However, 9% of children had no health insurance coverage, and 5% of children had no usual place of health care. Thirteen percent of children had ever been diagnosed with asthma. An estimated 7% of children 3-17 years of age had a diagnosed learning disability, and an estimated 7% of children had ADHD.


In Search for Comparability: The PECUNIA Reference Unit Costs for Health and Social Care Services in Europe.
Improving the efficiency of mental healthcare service delivery by learning from international best-practice examples requires valid data, including robust unit costs, which currently often lack cross-country comparability. The European ProgrammE in Costing, resource use measurement and outcome valuation for Use in multi-sectoral National and International health economic evaluAtions (PECUNIA) aimed to harmonize the international unit cost development. This article presents the methodology and set of 36 externally validated, standardized reference unit costs (RUCs) for five health and social care services (general practitioner, dentist, help-line, day-care center, nursing home) in Austria, England, Germany, Hungary, The Netherlands, and Spain based on unambiguous service definitions using the extended DESDE PECUNIA coding framework. The resulting PECUNIA RUCs are largely comparable across countries, with any causes for deviations (e.g., country-specific scope of services) transparently documented. Even under standardized methods, notable limitations due to data-driven divergences in key costing parameters remain. Increased cross-country comparability by adopting a uniform methodology and definitions can advance the quality of evidence-based policy guidance derived from health economic evaluations. The PECUNIA RUCs are available free of charge and aim to significantly improve the quality and feasibility of future economic evaluations and their transferability across mental health systems.


Prednisolone mediated suppression of HIV-1 viral load strongly correlates with C-C chemokine CCL2: In vivo and in vitro findings.
CCL2 (MCP-1) is a proinflammatory chemokine induced in HIV-1 infection. We have previously demonstrated a significant correlation of CCL2 gene expression with HIV-1 viremia. In this study we investigated the effect of prednisolone on CCL2 gene expression and viral load in an HIV-1-infected patient receiving high-dose prednisolone for severe uveitis. We observed a >1 log reduction of HIV-1 viral load, associated with more than hundred fold reduction of CCL2 expression at day 3 of prednisolone treatment. In vitro HIV-1 infection of PBMC demonstrated reduced HIV-1 replication in the presence of prednisolone. Flow cytometric analysis revealed 50% reduction of LTR driven GFP activity by prednisolone in GHOST cells. These findings indicate that prednisolone suppresses both HIV-1 viral load and CCL2 mRNA expression, an association which might be exploited for future anti-inflammatory therapeutic strategies in HIV-1 infection.


[The "Nephrology outpatient Triage": an organizational model for the ambulatory care of patients with advanced renal disease].
The clinical course of outpatients with advanced chronic kidney disease requires a close monitoring by the nephrology team, in order to identify emerging clinical problems promptly and prevent subsequent complications. With the aim of improving the outpatient management in our clinic dedicated to advanced renal failure, we implemented the "Nephrology Clinic Triage" (NCT). This organizational model is coordinated by the nephrologist and supported by nurses. In case the outpatients, or their caregivers, have clinical problems or need advice, they can easily get in touch with a nephrology nurse by a dedicated telephone line. The nurse, who had been specifically trained for this purpose, interviews the patient by telephone and track his health conditions using dedicated flow-charts. The patients must be able to answer in a suitable way to the telephone interview on which NCT is based. Therefore, all patients referring to nephrology clinic are trained to record and report properly by telephone some relevant clinical parameters (i.e., blood pressure, body temperature, heart rate, body weight, urine volume) and clinical signs (dyspnea, dysuria, diarrhea, nausea, vomiting, abdominal/lumbar/chest pain). On the basis of the information obtained by means of NCT, the nurse can identify the patient's need and classify its severity and priority by means of a color-coding system. The subsequent medical intervention (telephone conversation, scheduled appointment, hospitalization) is planned accordingly. The implementation of NCT may be useful to monitor the clinical course of outpatients with advanced chronic renal failure also when they are home, thereby reducing the risk of harmful complications and hospitalization.


Bunching-induced optical nonlinearity and instability in cold atoms [Invited].
We report a new nonlinear optical process that occurs in a cloud of cold atoms at low-light-levels when the incident optical fields simultaneously polarize, cool, and spatially-organize the atoms. We observe an extremely large effective fifth-order nonlinear susceptibility of χ(⁵) = 7.6 × 10⁻¹⁵ (m/V)⁴, which results in efficient Bragg scattering via six-wave mixing, slow group velocities (∼ c/10⁵), and enhanced atomic coherence times (> 100 μs). In addition, this process is particularly sensitive to the atomic temperatures, and provides a new tool for in-situ monitoring of the atomic momentum distribution in an optical lattice. For sufficiently large light-matter couplings, we observe an optical instability for intensities as low as ∼ 1 mW/cm² in which new, intense beams of light are generated and result in the formation of controllable transverse optical patterns.


[Event-related functional magnetic resonance imaging of cerebral pain processing].
Neurofunctional magnetic resonance imaging (fMRI) offers the possibility to map cerebral activity non-invasively. The development of event-related techniques during the past years allows to study brain processes with high spatial and temporal resolution. Based on these techniques, EPI- and FLASH sequences were developed in this study, to investigate cerebral processing of experimental thermal pain stimulation. Phasic and tonic stimulation paradigms were developed with an MR-compatible contact thermode. Functional mapping of pain-relevant areas was performed with these paradigms, as well as a specification of the temporal characteristics of the activation. Further, a randomized paradigm with several stimulus intensities could differentiate graded functional responses, dependent on stimulus intensity in specific "regions-of-interest". In this design, randomizing the stimulus order reduced habituation effects, while continuous subjective magnitude estimation of the stimuli kept attention of subjects maximal.


Diversification of Hox Gene Clusters in Osteoglossomorph Fish in Comparison to Other Teleosts and the Spotted Gar Outgroup.
An ancient genome duplication (TGD or 3R) occurred in teleost fish after divergence from the lineage leading to gar. This genome duplication is shared by the three extant teleost lineages: Osteoglossomorpha (bony-tongues), Elopomorpha (eels and tarpons), and Clupeocephala (a large clade including salmon, carp, medaka, zebrafish, cichlids, pufferfish, stickleback, and ∼26,000 other species). After TGD, different clupeocephalan species retained different gene duplicates; this is seen clearly in Hox gene clusters but extends to all genes. Since divergent resolution of TGD paralogs is a potential driving force for speciation, it is possible this contributed to diversification of this clade. The extent to which divergent resolution of TGD paralogs occurred within Osteoglossomorpha has not been investigated in detail, and Hox cluster organization has been reported for just two species: Pantodon buchholzi (Pantodontidae) and Scleropages formosus (Osteoglossidae). We applied survey-scale genome sequencing and de novo assembly to three further osteoglossomorph taxa: Osteoglossum bicirrhosum (Osteoglossidae), Chitala ornata (Notopteridae), and Gnathonemus petersii (Mormyridae). We find that each retained more Hox genes than clupeocephalan taxa (excluding those that underwent additional genome duplication), but fewer than eels. Several Hox genes are missing in all teleosts, including duplicates of two Hox genes present in the slow evolving pre-TGD genome of the spotted gar. We find divergent resolution through individual gene losses, and whole cluster losses have been rampant across osteoglossomorphs, despite their extant species paucity. We suggest that reciprocal gene loss following TGD was probably insufficient to drive the exceptional diversification of teleosts.


A Multiyear Analysis of the Clinical Encounters of the ATF Tactical Medical Program.
The Bureau of Alcohol, Tobacco, Firearms and Explosives (ATF) Tactical Medical Program provides tactical medical support for ATF's tactical Special Response Teams (SRTs) and investigative National Response Teams (NRTs) through the deployment of specially trained ATF Agent-Medics. All patient care activities are centrally coordinated through ATF Headquarters. A retrospective analysis of de-identified patient care reports (PCRs) from the ATF Tactical Medical Program from 2009 to 2012 was performed. Clinical and operational data were extracted from PCRs and were entered into a database by the research team. Descriptive and summative analyses were performed to assess patient type, law enforcement incident type, chief complaint, and interventions performed. Analysis was performed on the 254 charts. Nearly half (114; 44.9%) of patients encountered during the study period were law enforcement officers. High-risk warrant service was associated with one third (85; 33.5%) of the ATF medics' clinical encounters. The most common chief complaints of patients encountered were musculoskeletal pain/injury (57; 22.4%) and wounds/lacerations (57; 22.4%), followed by heat illness (17; 6.7%). The most common intervention was wound care (61; 26.9%), followed by control of bleeding with direct pressure (43; 18.9%). The most common medications administered were ibuprofen (28; 25.2%), topical antibiotic (12; 10.8%), and acetaminophen (12;10.8%). This multiyear analysis represents an important contribution to the growing body of scientific literature surrounding tactical medicine. The results of this analysis demonstrate a continued need for expanded scope of practice training, as well as enhanced treatment protocols for tactical medics.


Headache diagnoses among Iraq and Afghanistan war veterans enrolled in VA: a gender comparison.
To examine the prevalence and correlates of headache diagnoses, by gender, among Iraq and Afghanistan War Veterans who use Department of Veterans Affairs (VA) health care. Understanding the health care needs of recent Veterans, and how these needs differ between women and men, is a priority for the VA. The potential for a large burden of headache disorders among Veterans seeking VA services exists but has not been examined in a representative sample. We conducted a historical cohort study using national VA inpatient and outpatient data from fiscal year 2011. Participants were all (n = 470,215) Iraq and Afghanistan War Veteran VA users in 2011; nearly 13% were women. We identified headache diagnoses using International Classification of Diseases (ICD-9) diagnosis codes assigned during one or more VA inpatient or outpatient encounters. Descriptive analyses included frequencies of patient characteristics, prevalence and types of headache diagnoses, and prevalence of comorbid diagnoses. Prevalence ratios (PR) with 95% confidence intervals (CI) were used to estimate associations between gender and headache diagnoses. Multivariate models adjusted for age and race. Additional models also adjusted for comorbid diagnoses. In 2011, 56,300 (11.9%) Veterans received a headache-related diagnosis. While controlling for age and race, headache diagnoses were 1.61 times more prevalent (95% CI = 1.58-1.64) among women (18%) than men (11%). Most of this difference was associated with migraine diagnoses, which were 2.66 times more prevalent (95% CI = 2.59-2.73) among women. Cluster and post-traumatic headache diagnoses were less prevalent in women than in men. These patterns remained the same when also controlling for comorbid diagnoses, which were common among both women and men with headache diagnoses. The most prevalent comorbid diagnoses examined were depression (46% of women with headache diagnoses vs 40% of men), post-traumatic stress disorder (38% vs 58%), and back pain (38% vs 46%). Results of this study have implications for the delivery of post-deployment health services to Iraq and Afghanistan War Veterans. Migraine and other headache diagnoses are common among Veterans, particularly women, and tend to occur in combination with other post-deployment health conditions for which patients are being treated.


Floral volatile alleles can contribute to pollinator-mediated reproductive isolation in monkeyflowers (Mimulus).
Pollinator-mediated reproductive isolation is a major factor in driving the diversification of flowering plants. Studies of floral traits involved in reproductive isolation have focused nearly exclusively on visual signals, such as flower color. The role of less obvious signals, such as floral scent, has been studied only recently. In particular, the genetics of floral volatiles involved in mediating differential pollinator visitation remains unknown. The bumblebee-pollinated Mimulus lewisii and hummingbird-pollinated Mimulus cardinalis are a model system for studying reproductive isolation via pollinator preference. We have shown that these two species differ in three floral terpenoid volatiles - d-limonene, β-myrcene, and E-β-ocimene - that are attractive to bumblebee pollinators. By genetic mapping and in vitro analysis of enzyme activity we demonstrate that these interspecific differences are consistent with allelic variation at two loci, LIMONENE-MYRCENE SYNTHASE (LMS) and OCIMENE SYNTHASE (OS). Mimulus lewisii LMS (MlLMS) and OS (MlOS) are expressed most strongly in floral tissue in the last stages of floral development. Mimulus cardinalis LMS (McLMS) is weakly expressed and has a nonsense mutation in exon 3. Mimulus cardinalis OS (McOS) is expressed similarly to MlOS, but the encoded McOS enzyme produces no E-β-ocimene. Recapitulating the M. cardinalis phenotype by reducing the expression of MlLMS by RNA interference in transgenic M. lewisii produces no behavioral difference in pollinating bumblebees; however, reducing MlOS expression produces a 6% decrease in visitation. Allelic variation at the OCIMENE SYNTHASE locus is likely to contribute to differential pollinator visitation, and thus promote reproductive isolation between M. lewisii and M. cardinalis. OCIMENE SYNTHASE joins a growing list of 'speciation genes' ('barrier genes') in flowering plants.


Armadillidin H, a Glycine-Rich Peptide from the Terrestrial Crustacean Armadillidium vulgare, Displays an Unexpected Wide Antimicrobial Spectrum with Membranolytic Activity.
Antimicrobial peptides (AMPs) are key components of innate immunity and are widespread in nature, from bacteria to vertebrate animals. In crustaceans, there are currently 15 distinct AMP families published so far in the literature, mainly isolated from members of the Decapoda order. Up to now, armadillidin is the sole non-decapod AMP isolated from the haemocytes of Armadillidium vulgare, a crustacean isopod. Its first description demonstrated that armadillidin is a linear glycine-rich (47%) cationic peptide with an antimicrobial activity directed toward Bacillus megaterium. In the present work, we report identification of armadillidin Q, a variant of armadillidin H (earlier known as armadillidin), from crude haemocyte extracts of A. vulgare using LC-MS approach. We demonstrated that both armadillidins displayed broad spectrum antimicrobial activity against several Gram-positive and Gram-negative bacteria, fungi, but were totally inactive against yeasts. Membrane permeabilization assays, only performed with armadillidin H, showed that the peptide is membrane active against bacterial and fungal strains leading to deep changes in cell morphology. This damaging activity visualized by electronic microscopy correlates with a rapid decrease of cell viability leading to highly blebbed cells. In contrast, armadillidin H does not reveal cytotoxicity toward human erythrocytes. Furthermore, no secondary structure could be defined in this study [by circular dichroism (CD) and nuclear magnetic resonance (NMR)] even in a membrane mimicking environment. Therefore, armadillidins represent interesting candidates to gain insight into the biology of glycine-rich AMPs.


Evidence and knowledge gaps on the disease burden in sexual and gender minorities: a review of systematic reviews.
Sexual and gender minorities (SGM) include individuals with a wide range of sexual orientations, physical characteristics, and gender identities and expressions. Data suggest that people in this group face a significant and poorly understood set of additional health risks and bear a higher burden of some diseases compared to the general population. A large amount of data is available on HIV/AIDS, but far less on other health problems. In this review we aimed to synthesize the knowledge on the burden of communicable and non-communicable diseases, mental health conditions and violence experienced by SGM, based on available systematic reviews. We conducted a global review of systematic reviews, including searching the Cochrane and the Campbell Collaboration libraries, as well as PubMed, using a range of search terms describing the populations of interest, without time or language restrictions. Google Scholar was also scanned for unpublished literature, and references of all selected reviews were checked to identify further relevant articles. We found 30 systematic reviews, all originally written in English. Nine reviews provided data on HIV, 12 on other sexually transmitted infections (STIs), 4 on cancer, 4 on violence and 3 on mental health and substance use. A quantitative meta-analysis was not possible. The findings are presented in a narrative format. Our review primarily showed that there is a high burden of disease for certain subpopulations of SGM in HIV, STIs, STI-related cancers and mental health conditions, and that they also face high rates of violence. Secondly, our review revealed many knowledge gaps. Those gaps partly stem from a lack of original research, but there is an equally urgent need to conduct systematic and literature reviews to assess what we already know on the disease burden in SGM. Additional reviews are needed on the non-biological factors that could contribute to the higher disease burden. In addition, to provide universal access to health-care for all, more information is needed on the barriers that SGM face in accessing health services, including the attitudes of health-care providers. Understanding these barriers and the additional health risks they impose is crucial to improving the health status of SGM.


Development of a multidimensional measure for recurrent abdominal pain in children: population-based studies in three settings.
Recurrent abdominal pain (RAP) is a common problem in children and adolescents. Evaluation and treatment of children with RAP continue to challenge physicians because of the lack of a psychometrically sound measure for RAP. A major obstacle to progress in research on RAP has been the lack of a biological marker for RAP and the lack of a reliable and valid clinical measure for RAP. The objectives of this study were (1) to develop and test a multidimensional measure for RAP (MM-RAP) in children to serve as a primary outcome measure for clinical trials, (2) to evaluate the reliability of the measure and compare its responses across different populations, and (3) to examine the reliabilities of the measure scales in relation to the demographic variables of the studied population. We conducted 3 cross-sectional studies. Two studies were clinic-based studies that enrolled children with RAP from 1 pediatric gastroenterology clinic and 6 primary care clinics. The third study was a community-based study in which children from 1 elementary and 2 middle schools were screened for frequent episodes of abdominal pain. The 3 studies were conducted in Houston, Texas. Inclusion criteria for the clinic-based studies were (1) age of 4 to 18 years; (2) abdominal pain that had persisted for 3 or more months; (3) abdominal pain that was moderate to severe and interfered with some or all regular activities; (4) abdominal pain that may or may not be accompanied by upper-gastrointestinal symptoms; and (5) children were accompanied by a parent or guardian who was capable of giving informed consent, and children over the age of 10 years were capable of giving informed assent. The community-based study used standardized questionnaires that were offered to 1080 children/parents from the 3 participating schools; 700 completed and returned the questionnaires (65% response rate). The questionnaire was designed to elicit data concerning the history of abdominal pain or discomfort. A total of 160 children met Apley's criteria and were classified as having RAP. Inclusion criteria were identical to those criteria for the clinic-based studies. Participating children in the 3 studies received a standardized questionnaire that asked about socioeconomic variables, abdominal pain (intensity; frequency; duration; nature of abdominal pain, if present, and possible relationships with school activities; and other upper gastrointestinal symptoms). We used 4 scales for the MM-RAP: pain intensity scale (3 items), nonpain symptoms scale (12 items), disability scale (3 items), and satisfaction scale (2 items). Age 7 was used as a cutoff point for the analysis as the 7-year-olds have been shown to exhibit more sophisticated knowledge of illness than younger children. A total of 295 children who were aged 4 to 18 years participated in the study: 155 children from the pediatric gastroenterology clinics, 82 from the primary care clinics, and 58 from the schools. The interitem consistency (Cronbach's coefficient alpha) for the pain intensity items, nonpain symptoms items, disability items, and satisfaction items were 0.75, 0.81, 0.80, and 0.78, respectively, demonstrating good reliability of the measure. The internal consistencies of the 4 scales did not significantly differ between younger (< or =7 years) and older (>7 years) children. There was also no significant variation in the coefficient alpha of each of the 4 scales in relation to gender or the level of the parent's education. Reliability was identical for the pain-intensity items (0.74) among children who sought medical attention from primary care or pediatric gastroenterology clinics. The intercorrelations of factor scores among the 4 scales showed a strong relationship among the factors but not high enough that correlations would be expected to be measuring the same items. The results of the factor analysis identified 5 components instead of 4 components representing the 4 scales. The 12 items of the nonpain symptoms scale were classified into 2 components; 1 component included heartburn, burping, passing gas, bloating, problem with ingestion of milk, bad breath, and sour taste (nonpain symptoms I), and the other included nausea/vomiting, diarrhea, and constipation (nonpain symptoms II). The program ordered the 5 components on the basis of the percentage of the total variance explained by each component and consequently by the strength of each components in the following order: nonpain symptoms I, pain intensity, pain disability, satisfaction, and nonpain symptoms II. Of the 20 items that composed the MM-RAP, 17 met the inclusion criteria of having a correlation of > or =0.40 on the primary factor analyses. The 3 items that assessed pain intensity met the inclusion criteria as well as the 2 items that assessed satisfaction. Two of the 3 items that assessed disability met the inclusion criteria; however, the missed school item did not. The sleep problem and the loss of appetite items in the nonpain items also did not meet the inclusion criteria in both components of the nonpain symptoms scale. However, the loss of appetite item met the inclusion criteria in the disability scale with a correlation of 0.6. The 2 items that did not meet the inclusion criteria (missed school days and sour taste) will be eliminated in the revised measure for RAP. The MM-RAP demonstrated good reliability evidence in population samples. Children who have RAP and are seen at pediatric gastroenterology or primary care pediatric clinics have similar responses, showing that the measure performed well across several populations. Age did not affect the reliability of responses. The MM-RAP included 4 dimensions, each with several items that may identify disease-specific dimensions. In addition, dividing the nonpain symptoms scale into 2 components instead of 1 component could assist in creating a disease-specific measure. The present study focused exclusively on developing the multidimensional measure for RAP in children that could assist physicians in evaluating the efficacy of RAP treatment independent of psychological evaluations. In addition, the measure was designed for use in clinical trials that evaluate the efficacy of RAP treatment and to allow comparison between intervention studies. In conclusion, we were able to identify 4 dimensions of RAP in children (pain intensity, nonpain symptoms, pain disability, and satisfaction with health). We demonstrated that these dimensions can be measured in a reliable manner that is applicable to children who experience RAP in various settings.


Trap-controlled proton hopping: interpretation of low-temperature dielectric relaxation of ice Ih.
A microscopic model of the dielectric relaxation of ice at low temperatures is proposed. This model is based on the mechanism of proton hopping controlled by traps created by orientation defects. Using the multiple-trapping model an expression for the dielectric relaxation time is obtained, which describes the non-Arrhenius behavior of the temperature dependence of the ice relaxation time at temperatures below 155 K.


Changes in temporal flow characteristics of CSF in Chiari malformation Type I with and without syringomyelia: implications for theory of syrinx development.
The pathogenesis of syringomyelia in association with Chiari malformation Type I (CM-I) is unclear. Studies of patients with CM-I have shown alterations in the CSF velocity profile using cardiac-gated cine phase-contrast MRI, and computational simulations have demonstrated that temporal features of the CSF pulse could contribute to syrinx development or enlargement. Few studies have reported temporal characteristics of the CSF profile, and few studies have reported on CM-I patients with and without syringomyelia separately. This study was performed to determine whether specific temporal features of the CSF flow profile may underlie the development or enlargement of a syrinx in patients with CM-I. Ten healthy volunteers and 18 patients with CM-I with (8 patients) and without (10 patients) syringomyelia were studied using cardiac-gated cine phase-contrast MRI, measuring the maximum CSF velocities in the cranial and caudal directions, the timing of these maximums relative to the cardiac cycle time, the timing of caudal flow onset, timing of cranial flow onset, and the duration of caudal flow. The caudal CSF flow was significantly faster (p ≤ 0.01) and earlier (p < 0.02) in patients without syringomyelia than in healthy volunteers and patients with syringomyelia. There were no significant differences in the CSF velocities between patients with syringomyelia and healthy volunteers. Patients with CM-I who had syringomyelia had a significantly later start of caudal CSF flow (p < 0.01) and earlier maximum cranial velocity (p = 0.03) than healthy volunteers, but the relative durations of caudal and cranial flow were not significantly different between any of the groups. The significantly earlier arrival and earlier peak velocity of caudal CSF flow may underlie the development of syringomyelia in patients with CM-I, and after a syrinx develops the CSF flow profile appears to stabilize.


The sole LSm complex in Cyanidioschyzon merolae associates with pre-mRNA splicing and mRNA degradation factors.
Proteins of the Sm and Sm-like (LSm) families, referred to collectively as (L)Sm proteins, are found in all three domains of life and are known to promote a variety of RNA processes such as base-pair formation, unwinding, RNA degradation, and RNA stabilization. In eukaryotes, (L)Sm proteins have been studied, inter alia, for their role in pre-mRNA splicing. In many organisms, the LSm proteins form two distinct complexes, one consisting of LSm1-7 that is involved in mRNA degradation in the cytoplasm, and the other consisting of LSm2-8 that binds spliceosomal U6 snRNA in the nucleus. We recently characterized the splicing proteins from the red alga Cyanidioschyzon merolae and found that it has only seven LSm proteins. The identities of CmLSm2-CmLSm7 were unambiguous, but the seventh protein was similar to LSm1 and LSm8. Here, we use in vitro binding measurements, microscopy, and affinity purification-mass spectrometry to demonstrate a canonical splicing function for the C. merolae LSm complex and experimentally validate our bioinformatic predictions of a reduced spliceosome in this organism. Copurification of Pat1 and its associated mRNA degradation proteins with the LSm proteins, along with evidence of a cytoplasmic fraction of CmLSm complexes, argues that this complex is involved in both splicing and cytoplasmic mRNA degradation. Intriguingly, the Pat1 complex also copurifies with all four snRNAs, suggesting the possibility of a spliceosome-associated pre-mRNA degradation complex in the nucleus.


The cost of infertility diagnosis and treatment in Canada in 1995.
The objectives of this study were to estimate the direct cost of infertility management, including diagnosis and treatment, in Canada during 1995, and the relative cost per live birth by treatment category. The analysis was based on the following estimates: the prevalence of infertility in Canada in 1995; the volume and distribution of infertility services; and the effectiveness and cost of specific infertility treatments. In 1995 there were approximately 330,000 couples experiencing infertility in Canada. It is estimated that <50% (150,000) sought medical advice or treatment during that year. A total of 13 diagnostic and treatment categories account for nearly all of the treatments received, and these categories form the treatment model. The cost of treatment per live birth ranges from Cdn$650 for clomiphene treatment of unexplained infertility to Cdn$41,000 for in-vitro fertilization. For a hypothetical group of 100 couples, the annual cost of diagnosis and treatment would be Cdn$77,000 and Cdn$200,000 respectively for a total of Cdn$277,000, or an average of Cdn$2770 per couple. After 1 year of treatment, it is expected that 26 of these 100 couples would achieve a live birth. The total annual cost of infertility management in Canada, estimated to be approximately Cdn$415 million, is 0.6% of the annual cost of health care.


Novel role of microtubules in thrombin-induced endothelial barrier dysfunction.
Disturbances in endothelial cell (EC) barrier regulation are critically dependent upon rearrangements of EC actin cytoskeleton. However, the role of microtubule (MT) network in the regulation of EC permeability is not well understood. We examined involvement of MT remodeling in thrombin-induced EC permeability and explored MT regulation by heterotrimeric G12/13 proteins and by small GTPase Rho. Thrombin induced phosphorylation of MT regulatory protein tau at Ser409 and Ser262 and peripheral MT disassembly, which was linked to increased EC permeability. MT stabilization by taxol attenuated thrombin-induced permeability, actin remodeling, and paracellular gap formation and diminished thrombin-induced activation of Rho and Rho-kinase. Expression of activated Galpha12/13 subunits involved in thrombin-mediated signaling or their effector p115RhoGEF involved in Rho activation caused MT disassembly, whereas p115RhoGEF-specific negative regulator RGS preserved MT from thrombin-induced disassembly. Consistent with these results, expression of activated RhoA and Rho-kinase induced MT disassembly. Conversely, thrombin-induced disassembly of peripheral MT network was attenuated by expression of dominant negative RhoA and Rho-kinase mutants or by pharmacological inhibition of Rho-kinase. Collectively, our data demonstrate for the first time a critical involvement of MT disassembly in thrombin-induced EC barrier dysfunction and indicate G-protein-dependent mechanisms of thrombin-induced MT alteration.


Ribosomal DNA variation and population differentiation in Salicornia L.
Analysis of nuclear rDNA variation within and between populations of Salicornia from the salt marsh at Stiffkey, Norfolk has detected new patterns of genetic differentiation. Individual plants may have alternative 10.5 and 12 kb repeat units. A strong association between the frequency of particular genetic variants and the environmental gradient of tidal inundation was evident. Salicornia dolichostachya Moss from sandy flats on the lowest parts of the marsh, near to the seaward edge, and S. fragilis Ball & Tutin from deep creeks were both monomorphic for the 12 kb variant; in contrast, S. pusilla J. Woods, characteristic of the highest parts of the tidal range, was monomorphic for the 10-5 kb variant. The more phenotypically variable S. europaea L. and S. ramosissima J. Woods populations that are found in large areas of lower and upper marsh, respectively, were heterogeneous for rDNA variant type. Nevertheless, the frequency of the 12 kb variant was significantly higher in plants from the lower marsh than in those from upper marsh, and in plants from low-lying pans than in those from raised interfluves; the 10.5 kb variant had the converse distribution. Variation in rDNA was not obviously associated with variation in morphology, or with variations in isozyme frequency established previously. Comparison of these results with those for populations from an extensive study, ranging from Anglesey (N. Wales) to S.W. Spain and the Gulf coast of Saudi Arabia, suggested that the rDNA variation and its association with environmental variation are complex and site-dependent. Plants from Anglesey had 10.5 and 11.5 kb variants, whereas only a 10-75 kb variant was detected in material from Spain and Saudi Arabia. rDNA variants were used as genetic markers in order to test the hypothesis that Salicornia is predominantly an inbreeder; conventional breeding experiments have been hampered by its highly specialized morphology and this represents the first direct, sensitive test of an idea that has been suggested mainly on morphological and phenological grounds. Analysis of rDNA in 38 maternal plants from Stiffkey and 2112 of their progeny provided no evidence for out-crossing.


Nutritional Control of Chronological Aging and Heterochromatin in Saccharomyces cerevisiae.
Calorie restriction extends life span in organisms as diverse as yeast and mammals through incompletely understood mechanisms.The role of NAD+-dependent deacetylases known as Sirtuins in this process, particularly in the yeast Saccharomyces cerevisiae, is controversial. We measured chronological life span of wild-type and sir2Δ strains over a higher glucose range than typically used for studying yeast calorie restriction. sir2Δ extended life span in high glucose complete minimal medium and had little effect in low glucose medium, revealing a partial role for Sir2 in the calorie-restriction response under these conditions. Experiments performed on cells grown in rich medium with a newly developed genetic strategy revealed that sir2Δ shortened life span in low glucose while having little effect in high glucose, again revealing a partial role for Sir2 In complete minimal media, Sir2 shortened life span as glucose levels increased; whereas in rich media, Sir2 extended life span as glucose levels decreased. Using a genetic strategy to measure the strength of gene silencing at HML, we determined increasing glucose stabilized Sir2-based silencing during growth on complete minimal media. Conversely, increasing glucose destabilized Sir-based silencing during growth on rich media, specifically during late cell divisions. In rich medium, silencing was far less stable in high glucose than in low glucose during stationary phase. Therefore, Sir2 was involved in a response to nutrient cues including glucose that regulates chronological aging, possibly through Sir2-dependent modification of chromatin or deacetylation of a nonhistone protein.


Engineered split in Pfu DNA polymerase fingers domain improves incorporation of nucleotide gamma-phosphate derivative.
Using compartmentalized self-replication (CSR), we evolved a version of Pyrococcus furiosus (Pfu) DNA polymerase that tolerates modification of the γ-phosphate of an incoming nucleotide. A Q484R mutation in α-helix P of the fingers domain, coupled with an unintended translational termination-reinitiation (split) near the finger tip, dramatically improve incorporation of a bulky γ-phosphate-O-linker-dabcyl substituent. Whether synthesized by coupled translation from a bicistronic (-1 frameshift) clone, or reconstituted from separately expressed and purified fragments, split Pfu mutant behaves identically to wild-type DNA polymerase with respect to chromatographic behavior, steady-state kinetic parameters (for dCTP), and PCR performance. Although naturally-occurring splits have been identified previously in the finger tip region of T4 gp43 variants, this is the first time a split (in combination with a point mutation) has been shown to broaden substrate utilization. Moreover, this latest example of a split hyperthermophilic archaeal DNA polymerase further illustrates the modular nature of the Family B DNA polymerase structure.


Transcriptional Orchestration of the Global Cellular Response of a Model Pennate Diatom to Diel Light Cycling under Iron Limitation.
Environmental fluctuations affect distribution, growth and abundance of diatoms in nature, with iron (Fe) availability playing a central role. Studies on the response of diatoms to low Fe have either utilized continuous (24 hr) illumination or sampled a single time of day, missing any temporal dynamics. We profiled the physiology, metabolite composition, and global transcripts of the pennate diatom Phaeodactylum tricornutum during steady-state growth at low, intermediate, and high levels of dissolved Fe over light:dark cycles, to better understand fundamental aspects of genetic control of physiological acclimation to growth under Fe-limitation. We greatly expand the catalog of genes involved in the low Fe response, highlighting the importance of intracellular trafficking in Fe-limited diatoms. P. tricornutum exhibited transcriptomic hallmarks of slowed growth leading to prolonged periods of cell division/silica deposition, which could impact biogeochemical carbon sequestration in Fe-limited regions. Light harvesting and ribosome biogenesis transcripts were generally reduced under low Fe while transcript levels for genes putatively involved in the acquisition and recycling of Fe were increased. We also noted shifts in expression towards increased synthesis and catabolism of branched chain amino acids in P. tricornutum grown at low Fe whereas expression of genes involved in central core metabolism were relatively unaffected, indicating that essential cellular function is protected. Beyond the response of P. tricornutum to low Fe, we observed major coordinated shifts in transcript control of primary and intermediate metabolism over light:dark cycles which contribute to a new view of the significance of distinctive diatom pathways, such as mitochondrial glycolysis and the ornithine-urea cycle. This study provides new insight into transcriptional modulation of diatom physiology and metabolism across light:dark cycles in response to Fe availability, providing mechanistic understanding for the ability of diatoms to remain metabolically poised to respond quickly to Fe input and revealing strategies underlying their ecological success.


Biosynthesis of poly(3-hydroxybutyrate- co-3-hydroxyalkanoates) by metabolically engineered Escherichia coli strains.
Biosynthesis of polyhydroxyalkanoates (PHAs) consisting of 3-hydroxy-alkanoates (3HAs) of 4 to 10 carbon atoms was examined in metabolically engineered Escherichia coli strains. When the fadA and/or fadB mutant E. coli strains harboring the plasmid containing the Pseudomonas sp. 61-3 phaC2 gene and the Ralstonia eutropha phaAB genes were cultured in Luria-Bertani (LB) medium supplemented with 2 g/L of sodium decanoate, all the recombinant E. coli strains synthesized PHAs consisting of C4, C6, C8, and C10 monomer units. The monomer composition of PHA was dependent on the E. coli strain used. When the fadA mutant E. coli was employed, PHA containing up to 63 mol% of 3-hydroyhexanoate was produced. In fadB and fadAB mutant E. coli strains, 3-hydroxybutyrate (3HB) was efficiently incorporated into PHA up to 86 mol%. Cultivation of recombinant fadA and/or fadB mutant E. coli strains in LB medium containing 10 g/L of sodium gluconate and 2 g/L of sodium decanoate resulted in the production of PHA copolymer containing a very high fraction of 3HB up to 95 mol%. Since the material properties of PHA copolymer consisting of a large fraction of 3HB and a small fraction of medium-chain-length 3HA are similar to those of low-density polyethylene, recombinant E. coli strains constructed in this study should be useful for the production of PHAs suitable for various commercial applications.


Direct and self-reported measures of physical activity and sedentary behaviours by weight status in school-aged children: results from ISCOLE-Kenya.
Previous work has shown little association between self-report and directly measured physical activity. The objective of this study was to investigate the relationships between self-reported and directly assessed measures of physical activity and sedentary time by weight status in Kenyan children. Direct assessment of body weight, physical activity and sedentary time of 563 children was collected through anthropometry and accelerometry, while self-reported assessment was achieved by administering a questionnaire. Under/healthy weight children had significantly higher directly measured mean daily minutes of moderate-to-vigorous physical activity (MVPA) compared to overweight/obese children (39 vs 20 minutes); had lower mean weekend-day minutes of sedentary time (346 vs 365 minutes); had a higher proportion who met accepted physical activity guidelines (15.3% vs 2.6%); and a higher number reported using active transportation to/from school (49.2% vs 32.4%). Self-reported time spent outside before and after school and active transport to/from school were significantly associated with mean weekday minutes of MVPA (r-value range = 0.12-0.36), but only for the under/healthy weight children. The results of this study found a number of differences in the accumulation of MVPA and sedentary time by weight status and weak-to-moderate correlations between self-report and direct measures of weekday and weekend-day physical activity among the under/healthy weight children.


Location of biomarkers and reagents within agarose beads of a programmable bio-nano-chip.
The slow development of cost-effective medical microdevices with strong analytical performance characteristics is due to a lack of selective and efficient analyte capture and signaling. The recently developed programmable bio-nano-chip (PBNC) is a flexible detection device with analytical behavior rivaling established macroscopic methods. The PBNC system employs ≈300 μm-diameter bead sensors composed of agarose "nanonets" that populate a microelectromechanical support structure with integrated microfluidic elements. The beads are an efficient and selective protein-capture medium suitable for the analysis of complex fluid samples. Microscopy and computational studies probe the 3D interior of the beads. The relative contributions that the capture and detection of moieties, analyte size, and bead porosity make to signal distribution and intensity are reported. Agarose pore sizes ranging from 45 to 620 nm are examined and those near 140 nm provide optimal transport characteristics for rapid (<15 min) tests. The system exhibits efficient (99.5%) detection of bead-bound analyte along with low (≈2%) nonspecific immobilization of the detection probe for carcinoembryonic antigen assay. Furthermore, the role analyte dimensions play in signal distribution is explored, and enhanced methods for assay building that consider the unique features of biomarker size are offered.


Fiber lasers with loop reflectors.
The theory of homogeneously broadened four level fiber lasers, which use fiber loops as distributed reflective elements, is examined. Such cavities can be made entirely from rare earth doped fiber. The amplifying characteristics of doped fiber loops are examined. The threshold pump power and the loop reflectivity necessary to optimize the lasing output power from an oscillator formed from two loops in series are predicted.


Search for trilepton nucleon decay via p→e+νν and p→μ+νν in the Super-Kamiokande experiment.
The trilepton nucleon decay modes p→e+νν and p→μ+νν violate |Δ(B-L)| by two units. Using data from a 273.4 kt yr exposure of Super-Kamiokande a search for these decays yields a fit consistent with no signal. Accordingly, lower limits on the partial lifetimes of τp→e+νν>1.7×10(32) years and τp→μ+νν>2.2×10(32) years at a 90% confidence level are obtained. These limits can constrain Grand Unified Theories which allow for such processes.


What's the story? The tale of reading fluency told at speed.
Fluent readers process written text rapidly and accurately, and comprehend what they read. Historically, reading fluency has been modeled as the product of discrete skills such as single word decoding. More recent conceptualizations emphasize that fluent reading is the product of competency in, and the coordination of, multiple cognitive sub-skills (a multi-componential view). In this study, we examined how the pattern of activation in core reading regions changes as the ability to read fluently is manipulated through reading speed. We evaluated 13 right-handed adults with a novel fMRI task assessing fluent sentence reading and lower-order letter reading at each participant's normal fluent reading speed, as well as constrained (slowed) and accelerated reading speeds. Comparing fluent reading conditions with rest revealed regions including bilateral occipito-fusiform, left middle temporal, and inferior frontal gyral clusters across reading speeds. The selectivity of these regions' responses to fluent sentence reading was shown by comparison with the letter reading task. Region of interest analyses showed that at constrained and accelerated speeds these regions responded significantly more to fluent sentence reading. Critically, as reading speed increased, activation increased in a single reading-related region: occipital/fusiform cortex (left > right). These results demonstrate that while brain regions engaged in reading respond selectively during fluent reading, these regions respond differently as the ability to read fluently is manipulated. Implications for our understanding of reading fluency, reading development, and reading disorders are discussed.


Is the post-disturbance composition of a plant population determined by selection for outcrossed seedlings or by the composition of the seedbank?
Seedbanks are expected to buffer populations against disturbances, such as fire, that could alter the genetic composition of smaller, ephemeral adult populations. However, seedling genotypes may be influenced by the spatially heterogeneous nature of both the seedbank and the disturbance (for example, germination may vary with local disturbance) and also by selection acting on germination and post-germination performance. We used microsatellite-DNA surveys of seedlings emerging from the soil-stored seedbanks of Grevillea macleayana after wildfire to compare diversity and spatial structure in seedlings and adults, and through resampling of the seedling data set, to determine whether the resultant adult population reflected the effects of selection or random seedling mortality. The large post-fire seedling cohorts captured the full allelic diversity of the pre-fire adult population. However, we found a mismatch in the genotypic structure of adults and seedlings. Seedlings displayed larger heterozygous deficits than adults; however, over the ensuing 11 years, seedling heterozygosity eventually matched values for the pre-fire adults. Increasing heterozygosity among adults has generally been attributed to heterosis and/or reduction in Wahlund effects via self-thinning. Resampling of early post-fire seedlings to generate samples of equivalent size to survivors at 11 years showed that increases in heterozygosity must be driven by selection favouring outcrossed seed. This finding is important in an evolutionary context but also has implications for the restoration of natural or managed populations where a seedbank is a viable source of recruits.


Sustained spinal cord compression: part I: time-dependent effect on long-term pathophysiology.
The objective of this study is to determine whether there is a relationship between the duration of sustained spinal cord compression and the extent of spinal cord injury and the capacity for functional recovery after decompression. Sixteen dogs underwent sustained spinal cord compression for thirty or 180 minutes. The cords were compressed with use of a loading device with a hydraulic piston. A pressure transducer was attached to the surface of the piston, which transmitted real-time spinal cord interface pressures to a data-acquisition system. Somatosensory evoked potentials were monitored during a sixty-minute recovery period as well as at twenty-eight days after the injury. Functional motor recovery was judged throughout a twenty-six-day period after the injury with use of a battery of motor tasks. The volume of the lesion and damage to the tissue were assessed with both magnetic resonance imaging and histological analysis. Sustained spinal cord compression was associated with a gradual decline in interface pressure. Despite this, there was continuous decline in the amplitude of the somatosensory evoked potentials, which did not return until the cord was decompressed. Within one hour after the decompression, the dogs in the thirty-minute-compression group had recovery of somatosensory evoked potentials, but no animal had such recovery in the 180-minute group. Recovery of the somatosensory evoked potentials in the thirty-minute group was sustained over the twenty-eight days after the injury. Motor tests demonstrated rapid recovery of hindlimb motor function in the thirty-minute group, but there was considerable impairment in the 180-minute group. Within two weeks after the injury, balance, cadence, stair-climbing, and the ability to walk up an inclined plane were significantly better in the thirty-minute group than in the 180-minute group. The longer duration of compression produced lesions of significantly greater volume, which corresponded to the long-term functional outcome. The relatively rapid viscoelastic relaxation of the spinal cord during the early phase of sustained cord compression suggests that there are mechanisms of secondary injury that are linked to tissue displacement. Longer periods of displacement allow propagation of the secondary injury process, resulting in a lack of recovery of somatosensory evoked potentials, limited functional recovery, and more extensive tissue damage.


Role of scintigraphy in congenital thyroid anomalies.
Thyroid scintigraphy using Tc-99m pertechnetate is a frequently performed procedure in routine nuclear medicine practice. The indications for thyroid scintigraphy are investigation of hyperthyroidism, nodularity of the gland, cause of thyroid stimulating hormone elevation and localization of an ectopic thyroid gland. In the pediatric population, the most common request is for the evaluation of neonatal hypothyroidism. This imaging procedure is helpful in the identification of the underlying cause as well as in making a differential diagnosis. Early diagnosis is essential for appropriate therapy planning in this age group, and thyroid scintigraphy provides important diagnostic data. This article is written to review the scintigraphic findings in various congenital thyroid anomalies and to underline its use in the differential diagnosis.


Signal peptide peptidase cleavage of GB virus B core protein is required for productive infection in vivo.
Chronic infection by hepatitis C virus (HCV) is a leading cause of liver disease for which better therapies are urgently needed. Because a clearer understanding of the viral life cycle may suggest novel anti-viral approaches, we studied the role of host signal peptide peptidase (SPP) in viral infection. This intramembrane protease cleaves within a C-terminal signal sequence in the viral core protein, but the molecular determinants of cleavage and whether it is required for infection in vivo are unknown. To answer these questions, we studied SPP processing in GB virus B (GBV-B) infection. GBV-B is the closest phylogenetic relative of HCV and offers an accurate surrogate model for HCV infection. We demonstrate that SPP also processes GBV-B core protein and that a serine residue in the hydrophobic region of the signal sequence (present also in HCV) is critical for efficient SPP cleavage. The small size of the serine side chain combined with its ability to form intra- and interhelical hydrogen bonds likely contributes to recognition of the signal sequence as a substrate for SPP. By introducing mutations with differing effects on SPP processing into an infectious GBV-B molecular clone, we demonstrate that SPP processing of the core protein is required for productive infection in primates. These results broaden our understanding of the mechanism and requirements for SPP cleavage and reveal a functional role in vivo for intramembrane proteolysis in host-pathogen interactions. Moreover, they identify SPP as a potential therapeutic target for reducing the impact of HCV infection.


Physiotherapy: How to work with evidence in daily practice.
The concept of evidence-based health care has gained increasing currency over the past decades; however, questions persist regarding how to overcome the gap between research and health care practice. The question arises whether this gap derives from a true knowledge deficit or from physiotherapists' perception of working with evidence. The aim of the current study was to illuminate changes to the meaning of working with evidence experienced by a cohort of physiotherapists following an education program. A phenomenological hermeneutic design with open-ended group interviews was carried out with physiotherapists who had participated in an education program about evidence and how to implement evidence-based practice (EBP) in day-to-day practice. The interviews provided descriptions of working with evidence according to three major themes: "Confidence with the concept of evidence in relation to a way of working"; "Experience of EBP as a duty to seek evidence for individual patients"; and "EBP experienced as an integrated and patient-oriented activity". The physiotherapists' lived experiences demonstrated that the participants' perception of the concept of evidence mainly concerned a broadening of the definition of evidence, and this altered perception of evidence could interpreted as the physiotherapists viewing EBP as a more integrated and patient-oriented activity than before.


High-fidelity meshes from tissue samples for diffusion MRI simulations.
This paper presents a method for constructing detailed geometric models of tissue microstructure for synthesizing realistic diffusion MRI data. We construct three-dimensional mesh models from confocal microscopy image stacks using the marching cubes algorithm. Random-walk simulations within the resulting meshes provide synthetic diffusion MRI measurements. Experiments optimise simulation parameters and complexity of the meshes to achieve accuracy and reproducibility while minimizing computation time. Finally we assess the quality of the synthesized data from the mesh models by comparison with scanner data as well as synthetic data from simple geometric models and simplified meshes that vary only in two dimensions. The results support the extra complexity of the three-dimensional mesh compared to simpler models although sensitivity to the mesh resolution is quite robust.


Ethnic Identity predicts loss-to-follow-up in a health promotion trial.
Higher rates of attrition in health research have been reported for African Americans (AAs). However, little is known about which AAs are more prone to drop out and why. One potential predictor that has not been explored is Ethnic Identity (EI). This study examined the association between EI and loss-to-follow-up among AAs enrolled in a health promotion intervention to increase fruit and vegetable intake. Five hundred and sixty AA adults from two integrated health care delivery systems in Atlanta and Detroit were enrolled into a randomized intervention trial. At baseline, all participants were classified into six EI core groups: Afrocentric, Black American, Bicultural, Multicultural, Assimilated, and High Cultural Mistrust. We examined loss-to-follow-up rates by these EI type. Overall, 92 participants (16%) were lost to follow up. Loss-to-follow-up rates were higher among those classified as Afrocentric (24%) than those without an Afrocentric identity (13%). After adjustment for covariates, Afrocentric participants were 1.9 times (CI: 1.1-3.6) more likely to be lost to follow up than participants without this identity type. Assessing EI of AAs in research studies may help identify groups at risk for dropout and/or non-response.


Catecholamine-induced desensitization of turkey erythrocyte adenylate cyclase is associated with phosphorylation of the beta-adrenergic receptor.
Preincubation of turkey erythrocytes with catecholamines desensitizes the beta-adrenergic receptor-adenylate cyclase complex in the plasma membranes of these cells. Photoaffinity labeling of the beta-adrenergic receptors with 125I-labeled p-azidobenzylcarazolol (125I-pABC) and subsequent analysis by NaDodSO4/polyacrylamide gel electrophoresis demonstrates an altered mobility of receptor peptides from desensitized cells compared to controls [Stadel, J.M., Nambi, P., Lavin, T.N., Heald, S.L., Caron, M.G. & Lefkowitz, R.J. (1982) J. Biol. Chem. 257, 9242-9245]. The time course of alteration in beta-adrenergic receptor mobility correlates with that for desensitization of isoproterenol-stimulated adenylate cyclase activity. The altered mobility of the receptor peptides from desensitized cells is also observed if the receptors are first purified and then photoaffinity labeled with 125I-pABC. The cyclic nucleotide analog 8-bromoadenosine 3',5'-cyclic monophosphate partially mimics catecholamines in promoting desensitization of the adenylate cyclase and modification of the receptor. Phosphorylation of the beta-adrenergic receptor in intact turkey erythrocytes was assessed by preincubating the cells with [32P]orthophosphate, desensitizing them with catecholamine, purifying the receptors, and then subjecting them to NaDodSO4/polyacrylamide gel electrophoresis. Desensitization is associated with a 2- to 3-fold increase in 32P incorporation into the receptor, which also demonstrates the characteristic alterations in mobility. These effects are blocked by the beta-adrenergic antagonist propranolol. Purified turkey erythrocyte beta-adrenergic receptors could be phosphorylated by incubation with [gamma-32P]ATP and the catalytic subunit of cAMP-dependent protein kinase. The mobility of the phosphorylated receptor peptides on NaDodSO4/polyacrylamide gel electrophoresis appears to correspond to that of the desensitized receptors. These data show that catecholamine-induced desensitization of adenylate cyclase in turkey erythrocytes correlates with a stable modification of the beta-adrenergic receptor and is associated with agonist-promoted phosphorylation of beta-receptor peptides.


Clofarabine in the treatment of poor risk acute myeloid leukaemia.
Clofarabine is a second generation nucleoside analogue. It inhibits DNA repair and activates the mitochondrial apoptotic pathway leading to cell death. In vitro clofarabine has demonstrated synergy with daunorubicin and Ara-C and in phase II clinical trials has shown promising activity in poor risk Acute myeloid leukaemia (AML) patients. In our institution over a 24 month period 22 AML patients (11 M, 11 F) with poor risk features, deemed unsuitable for standard therapy, were treated with clofarabine, alone (eight patients) or in combination (14 patients) for up to three cycles of treatment. The median age was 67.5 years (24-76) with 16 patients > 60 years. At the time of treatment 18 patients had active AML. Four patients intolerant of standard induction received clofarabine as consolidation. The overall response rate (ORR) for the 18 patients with active AML was 61%, nine patients (50%) achieving a complete response (CR). Induction and consolidation were well tolerated with no unexpected toxicities. Predictably, all patients developed grade 4 neutropenia but the median duration was only 20 days (17-120). Induction mortality was acceptable at 17%. In conclusion, clofarabine (alone or in combination) is active in poor risk AML with an acceptable safety profile and should be considered a potential option in poor risk AML patients.


Intracompartmental and intercompartmental transcriptional networks coordinate the expression of genes for organellar functions.
Genes for mitochondrial and chloroplast proteins are distributed between the nuclear and organellar genomes. Organelle biogenesis and metabolism, therefore, require appropriate coordination of gene expression in the different compartments to ensure efficient synthesis of essential multiprotein complexes of mixed genetic origin. Whereas organelle-to-nucleus signaling influences nuclear gene expression at the transcriptional level, organellar gene expression (OGE) is thought to be primarily regulated posttranscriptionally. Here, we show that intracompartmental and intercompartmental transcriptional networks coordinate the expression of genes for organellar functions. Nearly 1,300 ATH1 microarray-based transcriptional profiles of nuclear and organellar genes for mitochondrial and chloroplast proteins in the model plant Arabidopsis (Arabidopsis thaliana) were analyzed. The activity of genes involved in organellar energy production (OEP) or OGE in each of the organelles and in the nucleus is highly coordinated. Intracompartmental networks that link the OEP and OGE gene sets serve to synchronize the expression of nucleus- and organelle-encoded proteins. At a higher regulatory level, coexpression of organellar and nuclear OEP/OGE genes typically modulates chloroplast functions but affects mitochondria only when chloroplast functions are perturbed. Under conditions that induce energy shortage, the intercompartmental coregulation of photosynthesis genes can even override intracompartmental networks. We conclude that dynamic intracompartmental and intercompartmental transcriptional networks for OEP and OGE genes adjust the activity of organelles in response to the cellular energy state and environmental stresses, and we identify candidate cis-elements involved in the transcriptional coregulation of nuclear genes. Regarding the transcriptional regulation of chloroplast genes, novel tentative target genes of σ factors are identified.