A cross-sectional analysis of HIV and hepatitis C clinical trials 2007 to 2010: the relationship between industry sponsorship and randomized study design.
The proportion of clinical research sponsored by industry will likely continue to expand as federal funds for academic research decreases, particularly in the fields of HIV/AIDS and hepatitis C (HCV). While HIV and HCV continue to burden the US population, insufficient data exists as to how industry sponsorship affects clinical trials involving these infectious diseases. Debate exists about whether pharmaceutical companies undertake more market-driven research practices to promote therapeutics, or instead conduct more rigorous trials than their non-industry counterparts because of increased resources and scrutiny. The ClinicalTrials.gov registry, which allows investigators to fulfill a federal mandate for public trial registration, provides an opportunity for critical evaluation of study designs for industry-sponsored trials, independent of publication status. As part of a large public policy effort, the Clinical Trials Transformation Initiative (CTTI) recently transformed the ClinicalTrials.gov registry into a searchable dataset to facilitate research on clinical trials themselves. We conducted a cross-sectional analysis of 477 HIV and HCV drug treatment trials, registered with ClinicalTrials.gov from 1 October 2007 to 27 September 2010, to study the relationship of study sponsorship with randomized study design. The likelihood of using randomization given industry (versus non-industry) sponsorship was reported with prevalence ratios (PR). PRs were estimated using crude and stratified tabular analysis and Poisson regression adjusting for presence of a data monitoring committee, enrollment size, study phase, number of study sites, inclusion of foreign study sites, exclusion of persons older than age 65, and disease condition. The crude PR was 1.17 (95% CI 0.94, 1.45). Adjusted Poisson models produced a PR of 1.13 (95% CI 0.82, 1.56). There was a trend toward mild effect measure modification by study phase, but this was not statistically significant. In stratified tabular analysis the adjusted PR was 1.14 (95% CI 0.78, 1.68) among phase 2/3 trials and 1.06 (95% CI 0.50, 2.22) among phase 4 trials. No significant relationship was found between industry sponsorship and use of randomization in trial design in this cross-sectional study. Prospective studies evaluating other aspects of trial design may shed further light on the relationship between industry sponsorship and appropriate trial methodology.


Extending the bereavement exclusion for major depression to other losses: evidence from the National Comorbidity Survey.
Symptoms of intense bereavement-related sadness may resemble those of major depressive disorder (MDD) but may not indicate a mental disorder. To avert false-positive diagnoses, DSM criteria for MDD exclude uncomplicated bereavement of brief duration and modest severity. However, the DSM does not similarly exempt depressive reactions to other losses, even when they are uncomplicated in duration and severity. To test the validity of the DSM exclusion of uncomplicated depressive symptoms only in response to bereavement but not in response to other losses. Community-based epidemiological study. From the National Comorbidity Survey (NCS) of 8098 persons aged 15 to 54 years representative of the US population, we identified individuals who met MDD symptom criteria and whose MDD episodes were triggered by either bereavement (n = 157) or other loss (n = 710). Intervention We divided the bereavement and other loss trigger groups into uncomplicated and complicated cases by applying the NCS algorithm for uncomplicated bereavement to the reactions to other losses. We then compared uncomplicated bereavement and uncomplicated reactions to other losses on a variety of disorder indicators and symptoms. Nine disorder indicators, as follows: number of symptoms, melancholic depression, suicide attempt, duration of symptoms, interference with life, recurrence, and 3 service use variables. Episodes of uncomplicated depression triggered by bereavement and by other loss have similar symptom profiles and are not significantly different for 8 of 9 disorder indicators. Moreover, uncomplicated reactions, whether triggered by bereavement or other loss, are significantly lower than complicated reactions on almost all disorder indicators. The NCS data do not support the validity of uniquely excluding uncomplicated bereavement but not uncomplicated reactions to other losses from MDD diagnosis.


Landscape movements of Anopheles gambiae malaria vector mosquitoes in rural Gambia.
For malaria control in Africa it is crucial to characterise the dispersal of its most efficient vector, Anopheles gambiae, in order to target interventions and assess their impact spatially. Our study is, we believe, the first to present a statistical model of dispersal probability against distance from breeding habitat to human settlements for this important disease vector. We undertook post-hoc analyses of mosquito catches made in The Gambia to derive statistical dispersal functions for An. gambiae sensu lato collected in 48 villages at varying distances to alluvial larval habitat along the River Gambia. The proportion dispersing declined exponentially with distance, and we estimated that 90% of movements were within 1.7 km. Although a 'heavy-tailed' distribution is considered biologically more plausible due to active dispersal by mosquitoes seeking blood meals, there was no statistical basis for choosing it over a negative exponential distribution. Using a simple random walk model with daily survival and movements previously recorded in Burkina Faso, we were able to reproduce the dispersal probabilities observed in The Gambia. Our results provide an important quantification of the probability of An. gambiae s.l. dispersal in a rural African setting typical of many parts of the continent. However, dispersal will be landscape specific and in order to generalise to other spatial configurations of habitat and hosts it will be necessary to produce tractable models of mosquito movements for operational use. We show that simple random walk models have potential. Consequently, there is a pressing need for new empirical studies of An. gambiae survival and movements in different settings to drive this development.


Neonatal amygdala or hippocampus lesions influence responsiveness to objects.
Medial temporal lobe brain structures, such as the amygdala, play an important role in the normal perception and generation of emotional behavior. Little research, however, has assessed the role of such structures across the neurodevelopmental trajectory. We assessed emotional behavioral responses of rhesus macaques that received bilateral ibotenic acid lesions of the amygdala or hippocampus at 2 weeks of age and sham-operated controls. At 9 and 18 months of age, animals interacted with novel objects that varied in visual complexity as a means of varying emotional salience. All animals behaved differently in the presence of visually simple, as compared to complex, objects, suggesting that they were sensitive to variation in emotional salience. Across both experiments, amygdala-lesioned animals appeared to be less behaviorally inhibited insofar as they explored all objects most readily. Interestingly, hippocampus-lesioned animals' propensity for exploration mirrored that of control animals in some contexts but that of amygdala-lesioned animals in other contexts. At 18 months of age, both amygdala-lesioned and hippocampus-lesioned animals were judged to be less fearful than controls during the testing procedure. Implications for understanding the neurobiology of emotional behavior are discussed.


Person-environment interactions among residents of Oxford Houses.
The continued struggle of addiction recovery support systems suggest that the paradigm of this field needs to continue its evolution, which has increasingly emphasized environments. Field Theory suggests that the products of individual and environmental characteristics be considered rather than a summation of the two. This study examined such interactions in Oxford Houses, a network of democratic, and self-governed addiction recovery homes. This study examined sobriety in experienced houses (average length of residency > six months) compared to less experienced houses (average length of residency ≤ six months) in relation to individual resident characteristics (age, length of residence in an Oxford House, and referral from the criminal justice system). Using multilevel modeling, findings indicated that older residents living in an experienced Oxford Houses were more likely to remain abstinent over time than those in inexperienced homes. Additionally, for inexperienced houses, residents who had been in the Oxford House for a longer period had a higher the probability of abstinence than those that had been in the house for a shorter period of time. Finally, legal referral was related to a lower probability of one-year abstinence but only for those in experienced homes. These types of person-environment interactions point to the need for more research to better understand how person variables interact with environmental variables in the processes of recovery and adaptation to settings, as well as for treatment professionals' consideration of both person and environment when making recovery home referrals.


Outcomes and impact of HIV prevention, ART and TB programs in Swaziland--early evidence from public health triangulation.
Swaziland's severe HIV epidemic inspired an early national response since the late 1980s, and regular reporting of program outcomes since the onset of a national antiretroviral treatment (ART) program in 2004. We assessed effectiveness outcomes and mortality trends in relation to ART, HIV testing and counseling (HTC), tuberculosis (TB) and prevention of mother to child transmission (PMTCT). Data triangulated include intervention coverage and outcomes according to program registries (2001-2010), hospital admissions and deaths disaggregated by age and sex (2001-2010) and population mortality estimates from the 1997 and 2007 censuses and the 2007 demographic and health survey. By 2010, ART reached 70% of the estimated number of people living with HIV/AIDS with CD4<350/mm(3), with progressively improving patient retention and survival. As of 2010, 88% of health facilities providing antenatal care offered comprehensive PMTCT services. The HTC program recorded a halving in the proportion of adults tested who were HIV-infected; similarly HIV infection rates among HIV-exposed babies halved from 2007 to 2010. Case fatality rates among hospital patients diagnosed with HIV/AIDS started to decrease from 2005-6 in adults and especially in children, contrasting with stable case fatality for other causes including TB. All-cause child in-patient case fatality rates started to decrease from 2005-6. TB case notifications as well as rates of HIV/TB co-infection among notified TB patients continued a steady increase through 2010, while coverage of HIV testing and CPT for co-infected patients increased to above 80%. Against a background of high, but stable HIV prevalence and decreasing HIV incidence, we documented early evidence of a mortality decline associated with the expanded national HIV response since 2004. Attribution of impact to specific interventions (versus natural epidemic dynamics) will require additional data from future household surveys, and improved routine (program, surveillance, and hospital) data at district level.


Therapeutic potential and challenges of natural killer cells in treatment of solid tumors.
Natural killer (NK) cells are innate lymphoid cells that hold tremendous potential for effective immunotherapy for a broad range of cancers. Due to the mode of NK cell killing, requiring one-to-one target engagement and site-directed release of cytolytic granules, the therapeutic potential of NK cells has been most extensively explored in hematological malignancies. However, their ability to precisely kill antibody coated cells, cancer stem cells, and genotoxically altered cells, while maintaining tolerance to healthy cells makes them appealing therapeutic effectors for all cancer forms, including metastases. Due to their release of pro-inflammatory cytokines, NK cells may potently reverse the anti-inflammatory tumor microenvironment (TME) and augment adaptive immune responses by promoting differentiation, activation, and/or recruitment of accessory immune cells to sites of malignancy. Nevertheless, integrated and coordinated mechanisms of subversion of NK cell activity against the tumor and its microenvironment exist. Although our understanding of the receptor ligand interactions that regulate NK cell functionality has evolved remarkably, the diversity of ligands and receptors is complex, as is their mechanistic foundations in regulating NK cell function. In this article, we review the literature and highlight how the TME manipulates the NK cell phenotypes, genotypes, and tropism to evade tumor recognition and elimination. We discuss counter strategies that may be adopted to augment the efficacy of NK cell anti-tumor surveillance, the clinical trials that have been undertaken so far in solid malignancies, critically weighing the challenges and opportunities with this approach.


[Manifestation of malakoplakia in a urethral diverticulum in a female patient].
We report about a rare case of malakoplakia in a female urethral diverticulum. A 25-year-old patient with a long history of recurrent urinary tract infections and a plum-sized, painful swelling on the vaginal roof presented for operative treatment. In the anamnesis the patient reported about two spontaneous perforations, emptying several millilitres of pus each time. After total operative excision using a vaginal approach the histology showed malakoplakia in a urethral diverticulum. We found the typical intracytoplasmatic "Michaelis-Gutmann bodies" as well as "von Hansemann cells". Postoperatively we excluded an underlying tumour disease or a chronic infection. The further urological diagnostics (cystoscopy and MRI) were without any pathological findings. In patients with atypical cystic tumours of the urogenital tract, especially with an immune deficiency, malakoplakia should be taken in consideration. The preferred therapy is surgical management followed by long-term antibiosis as well as a close follow-up as recurrences are frequent.


Zn homeostasis in genetic models of Parkinson's disease in Caenorhabditis elegans.
While the underlying mechanisms of Parkinson's disease (PD) are still insufficiently studied, a complex interaction between genetic and environmental factors is emphasized. Nevertheless, the role of the essential trace element zinc (Zn) in this regard remains controversial. In this study we altered Zn balance within PD models of the versatile model organism Caenorhabditis elegans (C. elegans) in order to examine whether a genetic predisposition in selected genes with relevance for PD affects Zn homeostasis. Protein-bound and labile Zn species act in various areas, such as enzymatic catalysis, protein stabilization pathways and cell signaling. Therefore, total Zn and labile Zn were quantitatively determined in living nematodes as individual biomarkers of Zn uptake and bioavailability with inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) or a multi-well method using the fluorescent probe ZinPyr-1. Young and middle-aged deletion mutants of catp-6 and pdr-1, which are orthologues of mammalian ATP13A2 (PARK9) and parkin (PARK2), showed altered Zn homeostasis following Zn exposure compared to wildtype worms. Furthermore, age-specific differences in Zn uptake were observed in wildtype worms for total as well as labile Zn species. These data emphasize the importance of differentiation between Zn species as meaningful biomarkers of Zn uptake as well as the need for further studies investigating the role of dysregulated Zn homeostasis in the etiology of PD.


How I do it: Surgically inserted transversus abdominis plane (TAP) catheters for flank incisions.
Pain control following major abdominal surgery remains a significant barrier to patient comfort. Although thoracic epidurals have been used to provide analgesia for these surgeries, the transversus abdominis plane (TAP) block is gaining popularity. The TAP catheter insertion method has transformed over the past two decades from a blinded technique to one conducted primarily under ultrasound guidance by anesthesiologists. Recently, however, interest has increased on the potential for direct surgical insertion of catheters into the TAP plane following flank incisions due to anatomical considerations. Proposed advantages include a reduction in operating time, requirement of minimal expertise and increased accuracy of catheter placement. In this report, we describe the rationale and the technique of surgical insertion of TAP catheters following open nephrectomies as performed by urologists at our institution.


Active play opportunities at child care.
Physical activity (PA) is important for children's health and development, yet preschoolers are not meeting PA recommendations. The objective of this study was to examine different PA opportunities at child care and how variation in indoor versus outdoor and free versus teacher-led opportunities relate to children's PA. An observational study of 98 children (mean age 4.5 years, 49% girls) from 10 child care centers. Classrooms were observed for at least 4 full days per center (total 50 days) to categorize time into (1) not an active play opportunity (APO); (2) naptime; (3) APO, outdoor free play; (4) APO, outdoor teacher-led; (5) APO, indoor free play; and (6) APO, indoor teacher-led. Children wore accelerometers during observations. Linear regression models examined the influence of APO categories on moderate-vigorous physical activity (MVPA) and sedentary time. Children's activity was 73% sedentary, 13% light, and 14% MVPA. For 88% of time children did not have APOs, including 26% time as naptime. On average, 48 minutes per day were APOs (41% sedentary, 18% light, and 41% MVPA), 33 minutes per day were outdoors. The most frequent APO was outdoor free play (8% of time); outdoor teacher-led time was <1%. Children were more active and less sedentary outdoors versus indoors and during the child-initiated APOs (indoors and outdoors) versus teacher-led APOs. Preschoolers were presented with significantly fewer than recommended opportunities for PA at child care. More APOs are needed for children to meet recommendations, particularly those that encourage more outdoor time, more teacher-led and child-initiated active play, and flexibility in naptime for preschoolers.


The impact of swidden decline on livelihoods and ecosystem services in Southeast Asia: A review of the evidence from 1990 to 2015.
Global economic change and policy interventions are driving transitions from long-fallow swidden (LFS) systems to alternative land uses in Southeast Asia's uplands. This study presents a systematic review of how these transitions impact upon livelihoods and ecosystem services in the region. Over 17 000 studies published between 1950 and 2015 were narrowed, based on relevance and quality, to 93 studies for further analysis. Our analysis of land-use transitions from swidden to intensified cropping systems showed several outcomes: more households had increased overall income, but these benefits came at significant cost such as reductions of customary practice, socio-economic wellbeing, livelihood options, and staple yields. Examining the effects of transitions on soil properties revealed negative impacts on soil organic carbon, cation-exchange capacity, and aboveground carbon. Taken together, the proximate and underlying drivers of the transitions from LFS to alternative land uses, especially intensified perennial and annual cash cropping, led to significant declines in pre-existing livelihood security and the ecosystem services supporting this security. Our results suggest that policies imposing land-use transitions on upland farmers so as to improve livelihoods and environments have been misguided; in the context of varied land uses, swidden agriculture can support livelihoods and ecosystem services that will help buffer the impacts of climate change in Southeast Asia.


Risk environments and drug harms: a social science for harm reduction approach.
A 'risk environment' framework promotes an understanding of harm, and harm reduction, as a matter of 'contingent causation'. Harm is contingent upon social context, comprising interactions between individuals and environments. There is a momentum of interest in understanding how the relations between individuals and environments impact on the production and reduction of drug harms, and this is reflected by broader debates in the social epidemiology, political economy, and sociology of health. This essay maps some of these developments, and a number of challenges. These include: social epidemiological approaches seeking to capture the socially constructed and dynamic nature of individual-environment interactions; political-economic approaches giving sufficient attention to how risk is situated differentially in local contexts, and to the role of agency and experience; understanding how public health as well as harm reduction discourses act as sites of 'governmentality' in risk subjectivity; and focusing on the logics of everyday habits and practices as a means to understanding how structural risk environments are incorporated into experience. Overall, the challenge is to generate empirical and theoretical work which encompasses both 'determined' and 'productive' relations of risk across social structures and everyday practices. A risk environment approach brings together multiple resources and methods in social science, and helps frame a 'social science for harm reduction'.


Trunk muscle strength in eccentric and concentric lateral flexion.
The aim of this study was to investigate the position and velocity dependency of the strength (torque) output of lateral flexor muscles of the trunk. Twelve male volunteers with no history of back pain participated. Movement was constrained to the frontal plane and the velocity was controlled by an isokinetic dynamometer. The eccentric and concentric strength of lateral flexor muscles on the left side was measured in a supine position at velocities of 15, 30, 45 and 60 degrees x s(-1) and static strength at 20, 10, 0, -10 and -20 degrees of lateral trunk flexion. Average peak torque values ranged between 211 and 218 Nm (eccentric) and between 66 and 140 Nm (concentric) over all tested velocities, and the average static torque ranged between 80 and 172 Nm over all tested positions. The shape of the torque position curves was unaffected by speed and peak torque occurred at an average position of 11-15 degrees to the contralateral (right) side in both eccentric and concentric actions. In eccentric actions, torque output was significantly higher than that during concentric and static actions. Increasing the speed of contraction did not affect eccentric torque values, whereas both peak and angle-specific concentric torque decreased with increasing speed. These results are in general accordance with earlier findings from other muscle groups, such as the knee extensors. However, they are partially at variance with results obtained in studies of lateral lifting and lowering, indicating that there are other limiting factors in complex tasks that do not just involve the trunk muscles.


Sub-populations within the major European and African derived haplogroups R1b3 and E3a are differentiated by previously phylogenetically undefined Y-SNPs.
Single nucleotide polymorphisms on the Y chromosome (Y-SNPs) have been widely used in the study of human migration patterns and evolution. Potential forensic applications of Y-SNPs include their use in predicting the ethnogeographic origin of the donor of a crime scene sample, or exclusion of suspects of sexual assaults (the evidence of which often comprises male/female mixtures and may involve multiple perpetrators), paternity testing, and identification of non- and half-siblings. In this study, we used a population of 118 African- and 125 European-Americans to evaluate 12 previously phylogenetically undefined Y-SNPs for their ability to further differentiate individuals who belong to the major African (E3a)- and European (R1b3, I)-derived haplogroups. Ten of these markers define seven new sub-clades (equivalent to E3a7a, E3a8, E3a8a, E3a8a1, R1b3h, R1b3i, and R1b3i1 using the Y Chromosome Consortium nomenclature) within haplogroups E and R. Interestingly, during the course of this study we evaluated M222, a sub-R1b3 marker rarely used, and found that this sub-haplogroup in effect defines the Y-STR Irish Modal Haplotype (IMH). The new bi-allelic markers described here are expected to find application in human evolutionary studies and forensic genetics.


Guideline-concordant timely lung cancer care and prognosis among elderly patients in the United States: A population-based study.
Elderly carry a disproportionate burden of lung cancer in the US. Therefore, its important to ensure that these patients receive quality cancer care. Timeliness of care is an important dimension of cancer care quality but its impact on prognosis remains to be explored. This study evaluates the variations in guideline-concordant timely lung cancer care and prognosis among elderly in the US. Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (2002-2007), we identified elderly patients with lung cancer (n=48,850) and determined time to diagnosis and treatment. We categorized patients by receipt of timely care using guidelines from the British Thoracic Society and the RAND Corporation. Hierarchical generalized logistic model was constructed to identify variables associated with receipt of timely care. Kaplan-Meier analysis and Log Rank test was used for estimation and comparison of the three-year survival. Multivariable Cox proportional hazards model was constructed to estimate lung cancer mortality risk associated with receipt of delayed care. Time to diagnosis and treatment varied significantly among the elderly. However, majority of them (77.5%) received guideline-concordant timely lung cancer care. The likelihood of receiving timely care significantly decreased with NSCLC disease, early stage diagnosis, increasing age, non-white race, higher comorbidity score, and lower income. Paradoxically, survival outcomes were significantly worse among patients receiving timely care. Adjusted lung cancer mortality risk was also significantly lower among patients receiving delayed care, relative to those receiving timely care (Hazard ratio (HR)=0.68, 95% Confidence interval (CI)=(0.66-0.71); p ≤ 0.05). This study highlights the critical need to address disparities in receipt of guideline-concordant timely lung cancer care among elderly. Although timely care was not associated with better prognosis in this study, any delays in diagnosis and treatment should be avoided, as it may increase the risk of disease progression and psychological stress in patients. Furthermore, given that lung cancer diagnostic and management services are covered under the Medicare program, observed delays in care among Medicare beneficiaries is also a cause for concern.


Patterns of electronic cigarette use and user beliefs about their safety and benefits: an internet survey.
As the popularity of electronic cigarettes (e-cigarettes) increases, it is becoming important to find out more about the characteristics of e-cigarette users, why and how they use the product and whether e-cigarettes are used exclusively or in combination with conventional cigarettes. The objective of this study was to investigate patterns and effects of e-cigarette use and user beliefs about e-cigarette safety and benefits. E-cigarette users in Poland were recruited online and asked to participate in a web-based survey. The participants provided information on their smoking history, patterns of e-cigarette use, beliefs and attitudes regarding the product and information on concurrent use of conventional cigarettes. The survey was completed by 179 e-cigarette users. Almost all participants used e-cigarettes daily. E-cigarettes were primarily used to quit smoking or to reduce the harm associated with smoking (both 41%), and were successful in helping the surveyed users to achieve these goals with 66% not smoking conventional cigarettes at all and 25% smoking under five cigarettes a day. Most participants (82%) did not think that e-cigarettes were completely safe, but thought that they were less dangerous than conventional cigarettes. Sixty percent believed that e-cigarettes were addictive, but less so than conventional cigarettes. The participants primarily used e-cigarettes as a stop-smoking aid or as an alternative to conventional cigarettes, and the majority reported that they successfully stopped smoking. More data on e-cigarette safety and its efficacy in harm-reduction and smoking cessation are needed.


Two-age islet-autoantibody screening for childhood type 1 diabetes: a prospective cohort study.
Early prediction of childhood type 1 diabetes reduces ketoacidosis at diagnosis and provides opportunities for disease prevention. However, only highly efficient approaches are likely to succeed in public health settings. We sought to identify efficient strategies for initial islet autoantibody screening in children younger than 15 years. We harmonised data from five prospective cohorts from Finland (DIPP), Germany (BABYDIAB), Sweden (DiPiS), and the USA (DAISY and DEW-IT) into the Type 1 Diabetes Intelligence (T1DI) cohort. 24 662 children at high risk of diabetes enrolled before age 2 years were included and followed up for islet autoantibodies and diabetes until age 15 years, or type 1 diabetes onset, whichever occurred first. Islet autoantibodies measured included those against glutamic acid decarboxylase, insulinoma antigen 2, and insulin. Main outcomes were sensitivity and positive predictive value (PPV) of detected islet autoantibodies, tested at one or two fixed ages, for diagnosis of clinical type 1 diabetes. Of the 24 662 participants enrolled in the Type 1 Diabetes Intelligence cohort, 6722 total were followed up to age 15 years or until onset of type 1 diabetes. Type 1 diabetes developed by age 15 years in 672 children, but did not develop in 6050 children. Optimal screening ages for two measurements were 2 years and 6 years, yielding sensitivity of 82% (95% CI 79-86) and PPV of 79% (95% CI 75-80) for diabetes by age 15 years. Autoantibody positivity at the beginning of each test age was highly predictive of diagnosis in the subsequent 2-5·99 year or 6-15-year age intervals. Autoantibodies usually appeared before age 6 years even in children diagnosed with diabetes much later in childhood. Our results show that initial screening for islet autoantibodies at two ages (2 years and 6 years) is sensitive and efficient for public health translation but might require adjustment by country on the basis of population-specific disease characteristics. Juvenile Diabetes Research Foundation.


Reducing inappropriate polypharmacy: the process of deprescribing.
Inappropriate polypharmacy, especially in older people, imposes a substantial burden of adverse drug events, ill health, disability, hospitalization, and even death. The single most important predictor of inappropriate prescribing and risk of adverse drug events in older patients is the number of prescribed drugs. Deprescribing is the process of tapering or stopping drugs, aimed at minimizing polypharmacy and improving patient outcomes. Evidence of efficacy for deprescribing is emerging from randomized trials and observational studies. A deprescribing protocol is proposed comprising 5 steps: (1) ascertain all drugs the patient is currently taking and the reasons for each one; (2) consider overall risk of drug-induced harm in individual patients in determining the required intensity of deprescribing intervention; (3) assess each drug in regard to its current or future benefit potential compared with current or future harm or burden potential; (4) prioritize drugs for discontinuation that have the lowest benefit-harm ratio and lowest likelihood of adverse withdrawal reactions or disease rebound syndromes; and (5) implement a discontinuation regimen and monitor patients closely for improvement in outcomes or onset of adverse effects. Whereas patient and prescriber barriers to deprescribing exist, resources and strategies are available that facilitate deliberate yet judicious deprescribing and deserve wider application.


Stress, sense of coherence and quality of life among Norwegian nurse students after a period of clinical practice.
Background. Previous research has found that sense of coherence is significantly related to aspects of health, but studies on nurse students with a salutogenic approach are limited. Objectives. To investigate (1) if nurse students' experience of stress differs among clinical practice in nursing homes and medical/surgical wards. (2) Whether sense of coherence and stress are associated with quality of life. (3) If sense of coherence acts as a moderator in the relationship between stress and quality of life. Participants. Data were collected from 227 nurse students between January and April 2014. Methods. Questionnaires measuring stress, sense of coherence and quality of life were completed after a period of clinical practice. Linear regression analyses were used to measure associations between stress, and sense of coherence respectively, and quality of life. Results. The results showed that 33.92% of the students experienced moderate or high levels of stress, and there was significantly more stress in hospital wards compared to nursing homes (p = 0.027). Sense of coherence was positively associated with quality of life in the simple and multiple regression analyses (p < 0.01). Stress was negatively associated with quality of life in the simple regression analysis (p < 0.01), but not in the multiple analyses when sense of coherence was included. However, when we included an interaction term, stress was no longer associated with quality of life and sense of coherence appeared to be a significant moderator in the relationship between stress and quality of life (p = 0.015). Thus, a negative association was seen among students with the lowest levels of sense of coherence. Conclusion. These findings suggest that sense of coherence could be seen as a resource that nurse educators can build upon when supporting students in coping with stress.


Intestinal drug absorption enhancers: synergistic effects of combinations.
Although many absorption enhancers have been investigated, very few are used clinically. A need exists therefore for more effective absorption enhancers. The drug-absorption-enhancing effects of combinations of N-trimethyl chitosan chloride (TMC) with degrees of quaternization of 48 and 64%, dicarboxymethyl chitosan oligosaccharide, and chitosan lactate oligomer with monocaprin and melittin were compared to their individual performances using the in vitro Caco-2 cell model. Combining the absorption enhancers showed synergism in both the reduction of the transepithelial electrical resistance (TEER) and the enhancement of the transport of a macromolecular model compound across this intestinal epithelial cell layer. Lower concentrations of the absorption enhancers in the combination groups exhibited greater effects on the epithelial cells compared with the individual absorption enhancers.


Method of all-optical frequency encoded decimal to binary and binary coded decimal, binary to gray, and gray to binary data conversion using semiconductor optical amplifiers.
Conversion of optical data from decimal to binary format is very important in optical computing and optical signal processing. There are many binary code systems to represent decimal numbers, the most common being the binary coded decimal (BCD) and gray code system. There are a wide choice of BCD codes, one of which is a natural BCD having a weighted code of 8421, by means of which it is possible to represent a decimal number from 0 to 9 with a combination of 4 bit binary digits. The reflected binary code, also known as the Gray code, is a binary numeral system where two successive values differ in only 1 bit. The Gray code is very important in digital optical communication as it is used to prevent spurious output from optical switches as well as to facilitate error correction in digital communications in an optical domain. Here in this communication, the author proposes an all-optical frequency encoded method of ":decimal to binary, BCD," "binary to gray," and "gray to binary" data conversion using the high-speed switching actions of semiconductor optical amplifiers. To convert decimal numbers to a binary form, a frequency encoding technique is adopted to represent two binary bits, 0 and 1. The frequency encoding technique offers advantages over conventional encoding techniques in terms of less probability of bit errors and greater reliability. Here the author has exploited the polarization switch made of a semiconductor optical amplifier (SOA) and a property of nonlinear rotation of the state of polarization of the probe beam in SOA for frequency conversion to develop the method of frequency encoded data conversion.


Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization.
In many human cancers, the cyclin-dependent kinase inhibitor p27(Kip1) is expressed at low or undetectable levels. The decreased p27(Kip1) expression allows cyclin-dependent kinase activity to cause cells to enter into S phase and correlates with poor patient survival. Inhibition of serine/threonine kinase Akt signaling by some pharmacological agents or by PTEN induces G(1) arrest, in part by up-regulating p27(Kip1). However, the role of Akt-dependent phosphorylation in p27(Kip1) regulation is not clear. Here, we show that Akt bound directly to and phosphorylated p27(Kip1). Screening p27(Kip1) phosphorylation sites identified the COOH-terminal Thr(198) residue as a novel site. Further analysis revealed that 14-3-3 proteins bound to p27(Kip1) through Thr(198) only when it was phosphorylated by Akt. Although Akt also phosphorylated p27(Kip1) at Ser(10) and Thr(187), these two sites were not involved in the binding to 14-3-3 proteins. p27(Kip1) phosphorylated at Thr(198) exists only in the cytoplasm. Therefore, Akt promotes cell-cycle progression through the mechanisms of phosphorylation-dependent 14-3-3 binding to p27(Kip1) and cytoplasmic localization.


In vitro transcriptional activation by a metabolic intermediate: activation by Leu3 depends on alpha-isopropylmalate.
In the absence of the leucine biosynthetic precursor alpha-isopropylmalate (alpha-IPM), the yeast LEU3 protein (Leu3p) binds DNA and acts as a transcriptional repressor in an in vitro extract. Addition of alpha-IPM resulted in a dramatic increase in Leu3p-dependent transcription. The presence of alpha-IPM was also required for Leu3p to compete effectively with another transcriptional activator, GAL4/VP16, for limiting transcription factors. Therefore, the addition of alpha-IPM appears to convert a transcriptional repressor into an activator. This represents an example in eukaryotes of direct transcriptional regulation by a small effector molecule.


Variations in the structure of mitochondria.
A characteristic internal structure, consisting of a double-layered outer wall enclosing a matrix-filled space through which pass double-layered membranous folds, would appear to comprise as satisfactory a definition of mitochondria for electron microscopy as their intravital affinity for Janus green affords for light microscopy. Relying for identification upon this characteristic internal structure, mitochondria appear to be pleomorphic structures which vary in size, shape, complexity, and density. They are labile also in that their number may increase or decrease under controlled conditions. The possibility therefore exists that these organelles are constantly being formed and destroyed, perhaps by their participation in metabolic processes. The problem of the origin of mitochondria is in an unsatisfactory state. New organelles unquestionably are formed in particular physiological states. The possibility that new bodies are produced by fission of ones already present does not seem adequate. On the other hand, the possible fabrication of new mitochondria out of intracellular membranes, although an attractive hypothesis, has not been adequately substantiated.


Common responses of tumors and wounds to hypoxia.
Hypoxia is a characteristic of tumors and wounds. Hypoxic cells develop 2 common strategies to face hypoxia: the glycolytic switch and the angiogenic switch. At the onset of hypoxia, alleviation of the Pasteur effect ensures short-term cell survival. Long-term hypoxic cell survival requires a further acceleration of the glycolytic flux under the control of hypoxia-inducible factor 1 that stimulates the expression of most glycolytic transporters and enzymes, uncouples glycolysis from the TCA cycle, and rewires glycolysis to lactic fermentation. Hypoxic cells also trigger angiogenesis, a process that aims to restore normal microenvironmental conditions. Transcription factors (hypoxia-inducible factor 1, nuclear factor κB, activator protein 1) and lactate cooperate to stimulate the expression of proangiogenic agents. Cancer cells differ from normal hypoxic cells by their proliferative agenda and by a high metabolic heterogeneity. These effects in tumor account for further molecular and metabolic changes and for a persistent stimulation of angiogenesis.


Preliminary evidence of an association between an interleukin 6 promoter polymorphism and self-reported attentional function in oncology patients and their family caregivers.
Subgroups of individuals may be at greater risk of cytokine-induced changes in attentional function. The purposes of this study were to identify subgroups of individuals with distinct trajectories of attentional function and evaluate for phenotypic and genotypic (i.e., cytokine gene polymorphisms) differences among these subgroups. Self-reported attentional function was evaluated in 252 participants (167 oncology patients and 85 family caregivers) using the Attentional Function Index before radiation therapy and at six additional assessments over 6 months. Three latent classes of attentional function were identified using growth mixture modeling: moderate (36.5%), moderate-to-high (48.0%), and high (15.5%) attentional function. Participants in the moderate class were significantly younger, with more comorbidities and lower functional status, than those in the other two classes. However, only functional status remained significant in multivariable models. Included in the genetic association analyses were 92 single nucleotide polymorphisms (SNPs) among 15 candidate genes. Additive, dominant, and recessive genetic models were assessed for each SNP. Controlling for functional status, only Interleukin 6 (IL6) rs1800795 remained a significant genotypic predictor of class membership in multivariable models. Each additional copy of the rare "G" allele was associated with a 4-fold increase in the odds of belonging to the lower attentional function class (95% confidence interval: [1.78, 8.92]; p = .001). Findings provide preliminary evidence of subgroups of individuals with distinct trajectories of attentional function and of a genetic association with an IL6 promoter polymorphism.


Hypoxia facilitates epithelial-mesenchymal transition-mediated rectal cancer progress.
Rectal cancer is a commonly observed tumor in clinics, and epithelial-mesenchymal transition (EMT) is very important for tumor invasion and metastasis. We established a rectal cancer HCT-116 cell hypoxia model and detected cell proliferation, invasion, and EMT-related protein expression in this model, aiming to analyze the effect of hypoxia on rectal cancer cell EMT. Rectal cancer cell line HCT-116 was cultured in normoxic, hypoxic, or anaerobic environment, and hypoxia-inducible factor-1α (HIF-1α) mRNA expression was detected in the cells by real-time PCR. Cell proliferation was tested by MTT assay; cell invasion was determined by transwell assay, and HIF-1α, epithelial-cadherin, and Snail protein levels were evaluated by western blot analysis. HIF-1α mRNA level significantly increased in the anaerobic group compared to that in the normoxic and hypoxic groups (P < 0.05). HCT-116 cell proliferation in the anaerobic group was obviously higher than that in the other two groups, with the hypoxic group showing stronger proliferative ability than the normoxic group (P < 0.05). Compared to the normoxic group, the HCT-116 cells demonstrated enhanced cell invasion and migration in hypoxic and anaerobic groups. HIF-1α and Snail expressions were upregulated, whereas epithelial-cadherin expression had declined in the hypoxic and anaerobic groups, compared to those in the normal control (P < 0.05). Therefore, hypoxia promoted rectal cancer cell progress by increasing HIF-1α to induce EMT.


Epidemiology and Management of Depression Following Coronary Heart Disease Diagnosis in Women.
Coronary heart disease (CHD) and depression are both highly prevalent in women. Importantly, depression is associated with significantly elevated morbidity and mortality in women with CHD. There are intriguing speculations about biological mechanisms underlying this association, such as endothelial dysfunction, subclinical atherosclerosis, inflammation, and autonomic dysregulation. Social and behavioral mechanisms, such as lack of social support and physical inactivity, have also been shown to play important roles. Unfortunately, many randomized clinical trials of counseling and pharmacologic interventions for depression in patients with CHD have failed to improve cardiovascular outcomes, and in fact have raised the possibility that interventions might be harmful in women. Several recent trials of new treatment strategies, however, have been more effective in improving depressive symptoms and quality of life and deserve further investigation. In this review, we summarize recent findings with regards to the epidemiology, etiology, diagnosis, and management of depression in women diagnosed with CHD.


World Small Animal Veterinary Association Renal Pathology Initiative: Classification of Glomerular Diseases in Dogs.
Evaluation of canine renal biopsy tissue has generally relied on light microscopic (LM) evaluation of hematoxylin and eosin-stained sections ranging in thickness from 3 to 5 µm. Advanced modalities, such as transmission electron microscopy (TEM) and immunofluorescence (IF), have been used sporadically or retrospectively. Diagnostic algorithms of glomerular diseases have been extrapolated from the World Health Organization classification scheme for human glomerular disease. With the recent establishment of 2 veterinary nephropathology services that evaluate 3-µm sections with a panel of histochemical stains and routinely perform TEM and IF, a standardized objective species-specific approach for the diagnosis of canine glomerular disease was needed. Eight veterinary pathologists evaluated 114 parameters (lesions) in renal biopsy specimens from 89 dogs. Hierarchical cluster analysis of the data revealed 2 large categories of glomerular disease based on the presence or absence of immune complex deposition: The immune complex-mediated glomerulonephritis (ICGN) category included cases with histologic lesions of membranoproliferative or membranous patterns. The second category included control dogs and dogs with non-ICGN (glomerular amyloidosis or focal segmental glomerulosclerosis). Cluster analysis performed on only the LM parameters led to misdiagnosis of 22 of the 89 cases-that is, ICGN cases moved to the non-ICGN branch of the dendrogram or vice versa, thereby emphasizing the importance of advanced diagnostic modalities in the evaluation of canine glomerular disease. Salient LM, TEM, and IF features for each pattern of disease were identified, and a preliminary investigation of related clinicopathologic data was performed.


Effect of Maryland's 2011 Alcohol Sales Tax Increase on Alcohol-Positive Driving.
The 2011 Maryland alcohol sales tax increase from 6% to 9% provided an opportunity to evaluate the impact on rates of alcohol-positive drivers involved in injury crashes. Maryland police crash reports from 2001 to 2013 were analyzed using an interrupted time series design and a multivariable analysis employing generalized estimating equations models with a negative binomial distribution. Data were analyzed in 2014-2015. There was a significant gradual annual reduction of 6% in the population-based rate of all alcohol-positive drivers (p<0.03), and a 12% reduction for drivers aged 15-20 years (p<0.007), and 21-34 years (p<0.001) following the alcohol sales tax increase. There were no significant changes in rates of alcohol-positive drivers aged 35-54 years (rate ratio, 0.98; 95% CI=0.89, 1.09). Drivers aged ≥55 years had a significant immediate 10% increase in the rate of alcohol-positive drivers (rate ratio, 1.10; 95% CI=1.04, 1.16) and a gradual increase of 4.8% per year after the intervention. Models using different denominators and controlling for multiple factors including a proxy for unmeasured factors found similar results overall. The 2011 Maryland alcohol sales tax increase led to a significant reduction in the rate of all alcohol-positive drivers involved in injury crashes especially among drivers aged 15-34 years. This is the first study to examine the impact of alcohol sales taxes on crashes; previous research focused on excise tax. Increasing alcohol taxes is an important but often neglected intervention to reduce alcohol-impaired driving.


Fruit and vegetable intakes and subsequent changes in body weight in European populations: results from the project on Diet, Obesity, and Genes (DiOGenes).
High fruit and vegetable intakes may limit weight gain, particularly in susceptible persons, such as those who stop smoking. The objective was to assess the association of fruit and vegetable intake with subsequent weight change in a large-scale prospective study. The data used were from 89,432 men and women from 5 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). The association between fruit and vegetable intake and weight change after a mean follow-up of 6.5 y was assessed by linear regression. Polytomous logistic regression was used to evaluate whether fruit and vegetable intake relates to weight gain, weight loss, or both. Per 100-g intake of fruit and vegetables, weight change was -14 g/y (95% CI: -19, -9 g/y). In those who stopped smoking during follow-up, this value was -37 g/y (95% CI: -58, -15 g/y; P for interaction < 0.0001). When weight gain and loss were analyzed separately per 100-g intake of fruit and vegetables in a combined model, the odds ratios (95% CIs) were 0.97 (0.95, 0.98) for weight gain > or =0.5 and <1 kg/y, 0.94 (0.92, 0.96) for weight gain > or =1 kg/y, and 0.97 (0.95, 0.99) for weight loss > or =0.5 kg/y. In those who stopped smoking during follow-up, the odds ratios (95% CIs) were 0.93 (0.88, 0.99), 0.87 (0.81, 0.92), and 0.97 (0.88, 1.07), respectively (P for interaction < 0.0001). Fruit and vegetable intake relates significantly, albeit weakly inversely, to weight change. For persons who stop smoking, high fruit and vegetable intakes may be recommended to reduce the risk of weight gain.


The use of propensity score methods in psychotherapy research. A practical application.
Randomized controlled trials are considered the best scientific proof of effectiveness. There is increasing concern, though, about their feasibility in psychotherapy research. We discuss a quasi-experimental study design for situations in which a randomized controlled trial is not feasible. Here, as an alternative strategy, the propensity score (PS) method is used to correct for selection bias. We used data from a Dutch research project, SCEPTRE (Study on Cost-Effectiveness of Personality Disorder Treatment). The sample consisted of 749 psychotherapy patients with personality pathology. We tested whether the PS method was useful and applicable. We examined differences between 2 treatment groups (short vs. long treatment duration) in pretreatment characteristics before and after PS correction. This revealed the impact of the PS on outcome differences. The PS offered statistical control over observed pretreatment differences between patients in a non-randomized study. When a randomized controlled trial is not possible, this quasi-experimental design using the PS could be a feasible alternative. Its advantages and limitations are discussed. Implemented carefully, this method is promising for future effectiveness research.


The Cognitive Underpinnings of Option Generation in Everyday Life Decision-Making: A Latent Variable Analysis.
The ability to generate options for action is crucial for everyday life decision-making. In this article, we propose and test a model of the cognitive underpinnings of option generation in everyday life situations. We carried out a laboratory study using measures of a wide range of cognitive functions and asked participants (N = 157) to generate options for actions for different everyday life decision-making scenarios. The results of a latent variable analysis show that the cognitive underpinnings of option generation are consistent across different everyday life situations and, hence, option generation can be conceptualized as a general construct. Moreover, the results of a confirmatory factor analysis reveal that, when controlling for the shared variance among the cognitive processes assessed, verbal fluency, working memory capacity, ideation fluency, and processing speed predicted option generation. These findings suggest that option generation in everyday life situations can be distinguished from other cognitive constructs, such as divergent thinking (in terms of ideas' originality) and long-term memory.


Interdisciplinary management of deep vein thrombosis during rehabilitation of acute rupture of the anterior cruciate ligament: a case report.
The purpose of this case report is to describe a patient who experienced deep venous thrombosis (DVT) during pre-operative rehabilitation of an acute rupture of an anterior cruciate ligament (ACL) reconstruction graft, to increase awareness of DVT occurring in a healthy individual after periodic immobilization, and to describe the interdisciplinary management for this patient. A 30-year-old male was referred to a chiropractic clinic for presurgical treatment of a left ACL rupture and medial meniscus tear confirmed at magnetic resonance imaging. During the course of preoperative rehabilitation, the patient became limited in ambulation and presented for a routine rehabilitation visit. During this visit, he experienced increased leg swelling, pain and tenderness. The patient was assessed for DVT and was referred to the local emergency department for further evaluation where multiple DVTs were found in the left popliteal, posterior tibial, and peroneal veins. The patient was treated with a 17-week course of warfarin during which time the clinical signs and symptoms of DVT resolved. Meanwhile, the patient completed the rehabilitation treatment plan in preparation for ACL reconstruction without further complications. This case raises awareness that DVT may occur in a healthy individual after periodic immobilization. While there may be controversy regarding the appropriate application of pharmaceutical anticoagulants in patients with DVT of the leg, the most risk averse strategy is for a short duration prescription medication with compression stockings. Through interdisciplinary management, the patient experienced a successful outcome.


Tired and lack focus? Insomnia increases distractibility.
Chronic insomnia is associated with subjective daytime cognitive dysfunction, but objective corroborative data are often lacking. In this study, we use Perceptual Load Theory to objectively assess distractibility in participants with insomnia (N = 23) compared with age- and sex-matched controls (N = 23). Following overnight supervised sleep observation, all participants completed a selective attention task which varied in the level of perceptual load and distractor congruency. The insomnia group was found to be more distracted than controls, whereas their selective attention mechanism appeared to be intact, with reduced distractor processing under high load for both groups. Insomnia symptom severity was positively correlated with participant distractibility. These findings suggest that there are insomnia-related daytime cognitive impairments that are likely to arise from compromised cognitive control rather than an ineffective selective attention mechanism. This task may be clinically useful in assessing daytime impairments, and potentially treatment response, in those with insomnia.


The TAPS Project. 4: An observational study of the social life of long-stay patients.
Observations of long-stay patients in a club in a psychiatric hospital were carried out unobtrusively over several months. Much of the social activity that went on was stimulated by an economy based around the purchase and exchange of tea and cigarettes, and the borrowing and lending of small change. Most patients could be fitted into one of four social categories: helpers, friends, nuisances, and the asocial. The inter-rater reliability of the observations was found to be 0.95. A close correspondence emerged between the observations of patients' social behaviour and material reported by patients when interviewed with the Social Network Schedule.


Evaluation of CT Perfusion Biomarkers of Tumor Hypoxia.
Tumor hypoxia is associated with treatment resistance to cancer therapies. Hypoxia can be investigated by immunohistopathologic methods but such procedure is invasive. A non-invasive method to interrogate tumor hypoxia is an attractive option as such method can provide information before, during, and after treatment for personalized therapies. Our study evaluated the correlations between computed tomography (CT) perfusion parameters and immunohistopathologic measurement of tumor hypoxia. Wistar rats, 18 controls and 19 treated with stereotactic radiosurgery (SRS), implanted with the C6 glioma tumor were imaged using CT perfusion on average every five days to monitor tumor growth. A final CT perfusion scan and the brain were obtained on average 14 days (8-22 days) after tumor implantation. Tumor hypoxia was detected immunohistopathologically with pimonidazole. The tumor, necrotic, and pimonidazole-positive areas on histology samples were measured. Percent necrotic area and percent hypoxic areas were calculated. Tumor volume (TV), blood flow (BF), blood volume (BV), and permeability-surface area product (PS) were obtained from the CT perfusion studies. Correlations between CT perfusion parameters and histological parameters were assessed by Spearman's ρ correlation. A Bonferroni-corrected P value < 0.05 was considered significant. BF and BV showed significant correlations with percent hypoxic area ρ = -0.88, P < 0.001 and ρ = -0.81, P < 0.001, respectively, for control animals and ρ = -0.7, P < 0.001 and ρ = -0.6, P = 0.003, respectively, for all animals, while TV and BV were correlated (ρ = -0.64, P = 0.01 and ρ = -0.43, P = 0.043, respectively) with percent necrotic area. PS was not correlated with either percent necrotic or percent hypoxic areas. Percent hypoxic area provided significant correlations with BF and BV, suggesting that CT perfusion parameters are potential non-invasive imaging biomarkers of tumor hypoxia.


Sulforaphane inhibits constitutive and interleukin-6-induced activation of signal transducer and activator of transcription 3 in prostate cancer cells.
D,L-sulforaphane (SFN), a synthetic analogue of broccoli-derived L-isomer, inhibits viability of human prostate cancer cells and prevents development of prostate cancer and distant site metastasis in a transgenic mouse model. However, the mechanism underlying the anticancer effect of SFN is not fully understood. We now show that SFN inhibits constitutive and interleukin-6 (IL-6)-inducible activation of signal transducer and activator of transcription 3 (STAT3), which is an oncogenic transcription factor activated in many human malignancies, including prostate cancer. Growth-suppressive concentrations of SFN (20 and 40 micromol/L) decreased constitutive (DU145 cells) and IL-6-induced (DU145 and LNCaP cells) phosphorylation of STAT3 (Tyr(705)) as well as its upstream regulator Janus-activated kinase 2 (Tyr(1007/1008)). Exposure of DU145 and LNCaP cells to SFN resulted in suppression of (a) IL-6-induced transcriptional activity of STAT3 as judged by luciferase reporter assay and (b) nuclear translocation of phospho-STAT3 as revealed by immunofluorescence microscopy. Levels of many STAT3-regulated gene products, including Bcl-2, cyclin D1, and survivin, were also reduced in SFN-treated cells. The IL-6-mediated activation of STAT3 conferred partial but marked protection against SFN-induced apoptosis as evidenced by cytoplasmic histone-associated DNA fragmentation and cleavage of poly(ADP-ribose) polymerase and procaspase-3. Furthermore, knockdown of STAT3 protein using small interfering RNA resulted in a modest yet statistically significant increase in SFN-induced apoptotic DNA fragmentation in DU145 cells. Suppression of STAT3 activation was also observed in cells treated with naturally occurring analogues of SFN. In conclusion, the present study indicates that inhibition of STAT3 partially contributes to the proapoptotic effect of SFN.


Is the southern crab Halicarcinus planatus (Fabricius, 1775) the next invader of Antarctica?
The potential for biological colonization of Antarctic shores is an increasingly important topic in the context of anthropogenic warming. Successful Antarctic invasions to date have been recorded exclusively from terrestrial habitats. While non-native marine species such as crabs, mussels and tunicates have already been reported from Antarctic coasts, none have as yet established there. Among the potential marine invaders of Antarctic shallow waters is Halicarcinus planatus (Fabricius, 1775), a crab with a circum-Subantarctic distribution and substantial larval dispersal capacity. An ovigerous female of this species was found in shallow waters of Deception Island, South Shetland Islands in 2010. A combination of physiological experiments and ecological modelling was used to assess the potential niche of H. planatus and estimate its future southward boundaries under climate change scenarios. We show that H. planatus has a minimum thermal limit of 1°C, and that its current distribution (assessed by sampling and niche modelling) is physiologically restricted to the Subantarctic region. While this species is presently unable to survive in Antarctica, future warming under both 'strong mitigation' and 'no mitigation' greenhouse gas emission scenarios will favour its niche expansion to the Western Antarctic Peninsula (WAP) by 2100. Future human activity also has potential to increase the probability of anthropogenic translocation of this species into Antarctic ecosystems.


An update on intracerebral stem cell grafts.
Primary neurological disorders are notoriously debilitating and deadly, and over the past four decades stem cell therapy has emerged as a promising treatment. Translation of stem cell therapies from the bench to the clinic requires a better understanding of delivery protocols, safety profile, and efficacy in each disease. Areas covered: In this review, benefits and risks of intracerebral stem cell transplantation are presented for consideration. Milestone discoveries in stem cell applications are reviewed to examine the efficacy and safety of intracerebral stem cell transplant therapy for disorders of the central nervous system and inform design of translatable protocols for clinically feasible stem cell-based treatments. Expert commentary: Intracerebral administration, compared to peripheral delivery, is more invasive and carries the risk of open brain surgery. However, direct cell implantation bypasses the blood-brain barrier and reduces the first-pass effect, effectively increasing the therapeutic cell deposition at its intended site of action. These benefits must be weighed with the risk of graft-versus-host immune response. Rigorous clinical trials are underway to assess the safety and efficacy of intracerebral transplants, and if successful will lead to widely available stem cell therapies for neurologic diseases in the coming years.


Analysis of household data on influenza epidemic with Bayesian hierarchical model.
Data used for modelling the household transmission of infectious diseases, such as influenza, have inherent multilevel structures and correlated property, which make the widely used conventional infectious disease transmission models (including the Greenwood model and the Reed-Frost model) not directly applicable within the context of a household (due to the crowded domestic condition or socioeconomic status of the household). Thus, at the household level, the effects resulting from individual-level factors, such as vaccination, may be confounded or modified in some way. We proposed the Bayesian hierarchical random-effects (random intercepts and random slopes) model under the context of generalised linear model to capture heterogeneity and variation on the individual, generation, and household levels. It was applied to empirical surveillance data on the influenza epidemic in Taiwan. The parameters of interest were estimated by using the Markov chain Monte Carlo method in conjunction with the Bayesian directed acyclic graphical models. Comparisons between models were made using the deviance information criterion. Based on the result of the random-slope Bayesian hierarchical method under the context of the Reed-Frost transmission model, the regression coefficient regarding the protective effect of vaccination varied statistically significantly from household to household. The result of such a heterogeneity was robust to the use of different prior distributions (including non-informative, sceptical, and enthusiastic ones). By integrating out the uncertainty of the parameters of the posterior distribution, the predictive distribution was computed to forecast the number of influenza cases allowing for random-household effect.


Glucose regulation of glutaminolysis and its role in insulin secretion.
Leucine or the nonmetabolized leucine analog +/- 2-amino-2-norbornane-carboxylic acid (BCH) (both at 10 mmol/l) induced biphasic insulin secretion in the presence of 2 mmol/l glutamine (Q2) in cultured mouse islets pretreated for 40 min without glucose but with Q2 present. The beta-cell response consisted of an initial peak of 20- to 25-fold above basal and a less marked secondary phase. However, BCH produced only a delayed response, while leucine was totally ineffective when islets were pretreated with 25 mmol/l glucose plus Q2. With Q2, 10 mmol/l BCH or leucine caused a nearly threefold increase, a twofold increase, or had no effect on cytosolic Ca2+ levels in islets pretreated for 40 min with 0, 5, or 15 mmol/l glucose, respectively. Thus, pretreatment of islets with high glucose inhibited BCH- and leucine-induced cytosolic Ca2+ changes and insulin release. Glucose decreased glutamine oxidation in cultured rat islets when BCH was present at 10 mmol/l, but not in its absence, with a lowest effective level of approximately 0.1 mmol/l, a maximum of 18-30 mmol/l, and an inhibitory concentration, 50%, of approximately 3 mmol/l. The data are consistent with the hypothesis that glucose inhibits glutaminolysis in pancreatic beta-cells in a concentration-dependent manner and hence blocks leucine-stimulated insulin secretion. We postulate that in the basal interprandial state, glutaminolysis of beta-cells is partly turned on because glutamate dehydrogenase (GDH) is activated by a decreased P-potential due to partial fuel depletion and sensitization to endogenous activators such as leucine. Additionally, it may contribute significantly to basal insulin release, which is known to be responsible for about half of the insulin released daily. The data explain "leucine-hypersensitivity" of beta-cells during hypoglycemia and contribute to the elucidation of the GDH-linked syndrome of hyperinsulinism associated with elevated serum ammonia levels. Thus, understanding the precise regulation and role of beta-cell glutaminolysis is probably central to our concept of normal blood glucose control.


Monitoring self-sorting by electrospray ionization mass spectrometry: formation intermediates and error-correction during the self-assembly of multiply threaded pseudorotaxanes.
Three binary pseudorotaxanes, which are based on two different secondary ammonium/crown ether binding motifs, have been studied by (1)H NMR and (1)H,(1)H EXSY NMR experiments with respect to their thermodynamic stabilities and their axle exchange kinetics. The stability ranking does not follow the order of axle exchange rates, and the thermodynamically most stable axle-wheel combinations assemble only slowly. On the basis of these binding motifs, a series of self-sorting systems have been studied ranging from simple four-component mixtures through sequence-specific pseudorotaxanes to multiply threaded complexes. Because of the mismatch of kinetic and thermodynamic order, wrongly assembled structures are unavoidable, which require error-correction steps to yield the final thermodynamically controlled self-sorted products. These error-correction steps can easily be monitored by electrospray mass spectrometry, when a mixed-flow microreactor is coupled to the ion source to cover second time scales. Self-assembly intermediates, wrongly assembled structures, and the final thermodynamic products can be simultaneously identified. The determination of preferred assembly pathways as well as the formation of dead-end structures provides a clear picture of a rich kinetic behavior of the self-sorting systems under study.


Habitat-specific natural selection at a flowering-time QTL is a main driver of local adaptation in two wild barley populations.
Understanding the genetic basis of local adaptation requires insight in the fitness effects of individual loci under natural field conditions. While rapid progress is made in the search for genes that control differences between plant populations, it is typically unknown whether the genes under study are in fact key targets of habitat-specific natural selection. Using a quantitative trait loci (QTL) approach, we show that a QTL associated with flowering-time variation between two locally adapted wild barley populations is an important determinant of fitness in one, but not in the other population's native habitat. The QTL mapped to the same position as a habitat-specific QTL for field fitness that affected plant reproductive output in only one of the parental habitats, indicating that the genomic region is under differential selection between the native habitats. Consistent with the QTL results, phenotypic selection of flowering time differed between the two environments, whereas other traits (growth rate and seed weight) were under selection but experienced no habitat-specific differential selection. This implies the flowering-time QTL as a driver of adaptive population divergence. Our results from phenotypic selection and QTL analysis are consistent with local adaptation without genetic trade-offs in performance across environments, i.e. without alleles or traits having opposing fitness effects in contrasting environments.


Selective Association Between Tetris Game Play and Visuospatial Working Memory: A Preliminary Investigation.
Recent experimental and clinical research has suggested that Tetris game play can disrupt maladaptive forms of mental imagery because Tetris competes for limited cognitive resources within visuospatial working memory (WM) that contribute to imagery. Whether or not Tetris performance is selectively associated with visuospatial WM remains to be tested. In this study, young adults (N = 46) completed six standardized measures indexing verbal and non-verbal reasoning, verbal and visuospatial short-term memory, and verbal and visuospatial WM. They also played Tetris. Consistent with the hypothesis that visuospatial WM resources support Tetris game play, there was a significant moderate positive relationship between Tetris scores and visuospatial WM performance but no association with other cognitive ability measures. Findings suggest that Tetris game play involves both storage and processing resources within visuospatial WM. These preliminary results can inform interventions involving computer games to disrupt the development of maladaptive visual imagery, for example, intrusive memories of trauma. © 2017 The Authors. Applied Cognitive Psychology Published by John Wiley & Sons Ltd.


MRI-based radiation-free method for navigated percutaneous radiofrequency trigeminal rhizotomy.
BACKGROUND/STUDY AIMS: Percutaneous radiofrequency trigeminal rhizotomy (RTR) is a standardized treatment for trigeminal neuralgia, yet it has been associated with serious complications related to the cannulation of the foramen ovale. Some of these complications, such as carotid injury, are potentially lethal. Neuronavigation was recently proposed as a method to increase the procedure's safety. All of the techniques described so far rely on pre- or intraoperative computed tomography scanning. Here we present a simple method based on magnetic resonance imaging (MRI) (radiation free) used to target the foramen ovale under navigation guidance. We retrospectively analyzed nine patients who had undergone navigated percutaneous RTR based solely on preoperative MRI and compared them with 35 patients who underwent conventional RTR guided by fluoroscopy. We analyzed immediate and late outcome and categorized the results into pain free, > 70% pain reduction, and persistent pain. We also compared groups in terms of the duration of the procedure and the complication rates. Here we describe the navigation method in detail and review the anatomical landmarks for target definition. The duration of the surgical procedure was similar in both groups (32.1 in the standard technique versus 34.5 minutes with navigation; p = 0.5157). There was no significant difference between groups regarding pain reduction at the immediate (p = 1.0) or late follow-up (p = 0.6284) time points. Furthermore, no serious complications were observed in the navigated group. We present a simple radiation-free method for neuronavigation-assisted percutaneous RTR. This method proved to be safe and effective, and it is especially recommended for young, inexperienced neurosurgeons.


Effect of UV-B radiation on morphology, phenolic compound production, gene expression, and subsequent drought stress responses in chili pepper (Capsicum annuum L.).
It has been suggested that accumulation of flavonoids could be a key step in development of plant tolerance to different environmental stresses. Moreover, it has been recognized that abiotic stresses such as drought and UV-B radiation (280-315 nm) induce phenolic compound accumulation, suggesting a role for these compounds in drought tolerance. The aim of the present study was to evaluate the effect of UV-B exposure on chili pepper (Capsicum annuum, cv. 'Coronel') plant performance, phenolic compound production, and gene expression associated with response to subsequent drought stress. Additionally, the phenotypic response to drought stress of these plants was studied. UV-B induced a reduction both in stem length, stem dry weight and number of floral primordia. The largest reduction in these variables was observed when combining UV-B and drought. UV-B-treated well-watered plants displayed fructification approximately 1 week earlier than non-UV-B-treated controls. Flavonoids measured epidermally in leaves significantly increased during UV-B treatment. Specifically, UV-B radiation significantly increased chlorogenic acid and apigenin 8-C-hexoside levels in leaves and a synergistic increase of luteolin 6-C-pentoside-8-C-hexoside was obtained by UV-B and subsequent drought stress. Gene expression of phenylalanine ammonia lyase (PAL) and chalcone synthase (CHS) genes also increased during UV-B treatments. On the other hand, expression of genes related to an oxidative response, such as mitochondrial Mn-superoxide dismutase (Mn-SOD) and peroxidase (POD) was not induced by UV-B. Drought stress in UV-B-treated plants induced mitochondrial Mn-SOD gene expression. Taken together, the UV-B treatment did not induce significant tolerance in plants towards drought stress under the conditions used.


DNMT1: an emerging target in the treatment of invasive urinary bladder cancer.
More than 14,000 people die from invasive urothelial carcinoma (iUC) of the urinary bladder each year in the USA, and more effective therapies are needed. Naturally occurring canine iUC very closely resembles the disease in humans and serves as a highly relevant translational model for novel therapy of human iUC. Work was undertaken to identify new targets for anticancer therapy in dogs with the goal of translating successful therapeutic strategies into humans with iUC. Microarray expression analyses were conducted on mRNA extracted from canine normal bladder (n = 4) and iUC tissues (n = 4) using Genome Array 1.0 and analyzed by GeneSpring GX 11, with the stringency of P < 0.02 and a ≥ 2-fold change. The genes thus identified were further analyzed for functional and pathway analysis using Protein ANalysis THrough Evolutionary Relationships (PANTHER) Classification System. In selecting genes for further study, consideration was given for evidence of a role of the gene in human iUC. From these analyses, DNA methyltransferase 1 (DNMT1) was selected for further study. Immunohistochemistry (IHC) of canine normal bladder and iUC tissues was performed to confirm the microarray expression analyses. The effects of targeting DNMT1 in vitro was assessed through MTT assay and Western blot of canine iUC cells treated with 5-azacitidine (5-azaC) and trichostatin A (TSA). DNMT1 was expressed in 0 of 6 normal canine bladder samples and in 10 of 22 (45%) canine iUC samples. The proliferation of canine iUC cells was inhibited by 5-azaC (at concentrations ≥ 5 μm) and by TSA (at concentrations ≥ 0.1 μm). Western blot results were supportive of DNMT1-related effects having a role in the antiproliferative activity. Microarray expression analyses on canine tissues identified DNMT1 as a potentially "targetable" gene. Expression of DNMT1 in canine iUC was confirmed by IHC, and in vitro studies confirmed that drugs that inhibit DNMT1 have antiproliferative effects. These findings are similar to those recently reported in human iUC and are also in line with results of a preclinical (prehuman) trial of 5-azaC in dogs with naturally occurring iUC. DNMT1 has excellent potential as a target for iUC therapy in humans.


Malaria control under the Taliban regime: insecticide-treated net purchasing, coverage, and usage among men and women in eastern Afghanistan.
Scaling up insecticide-treated mosquito net (ITN) coverage is a key malaria control strategy even in conflict-affected countries 12. Socio-economic factors influence access to ITNs whether subsidized or provided free to users. This study examines reported ITN purchasing, coverage, and usage in eastern Afghanistan and explores women's access to health information during the Taliban regime (1996-2001). This strengthens the knowledge base on household-level health choices in complex-emergency settings. Fifteen focus group discussions (FGDs) and thirty in-depth interviews were conducted with men and women from ITN-owning and non-owning households. FGDs included rank ordering, pile sorting and focused discussion of malaria knowledge and ITN purchasing. Interviews explored general health issues, prevention and treatment practices, and women's malaria knowledge and concerns. Seven key informant interviews with health-related workers and a concurrent survey of 200 ITN-owning and 214 non-owning households were used to clarify or quantify findings. Malaria knowledge was similar among men and women and ITN owners and non-owners. Women reported obtaining health information through a variety of sources including clinic staff, their husbands who had easier access to information, and particularly female peers. Most participants considered ITNs very desirable, though not usually household necessities. ITN owners reported more household assets than non-owners. Male ITN owners and non-owners ranked rugs and ITNs as most desired, while women ranked personal assets such as jewellery highest. While men were primarily responsible for household decision-making and purchasing, older women exerted considerable influence. Widow-led and landless households reported most difficulties purchasing ITNs. Most participants wanted to buy ITNs only if they could cover all household members. When not possible, preferential usage was given to women and children. Despite restricted access to health facilities and formal education, Afghan women were surprisingly knowledgeable about the causes of malaria and the value of ITNs in prevention. Inequities in ITN usage were noted between rather than within households, with some unable to afford even one ITN and others not wanting ITNs unless all household members could be protected. Malaria knowledge thus appears a lesser barrier to ITN purchasing and coverage in eastern Afghanistan than are pricing and distribution strategies.


Accuracy of commercial geocoding: assessment and implications.
Published studies of geocoding accuracy often focus on a single geographic area, address source or vendor, do not adjust accuracy measures for address characteristics, and do not examine effects of inaccuracy on exposure measures. We addressed these issues in a Women's Health Initiative ancillary study, the Environmental Epidemiology of Arrhythmogenesis in WHI. Addresses in 49 U.S. states (n = 3,615) with established coordinates were geocoded by four vendors (A-D). There were important differences among vendors in address match rate (98%; 82%; 81%; 30%), concordance between established and vendor-assigned census tracts (85%; 88%; 87%; 98%) and distance between established and vendor-assigned coordinates (mean rho [meters]: 1809; 748; 704; 228). Mean rho was lowest among street-matched, complete, zip-coded, unedited and urban addresses, and addresses with North American Datum of 1983 or World Geodetic System of 1984 coordinates. In mixed models restricted to vendors with minimally acceptable match rates (A-C) and adjusted for address characteristics, within-address correlation, and among-vendor heteroscedasticity of rho, differences in mean rho were small for street-type matches (280; 268; 275), i.e. likely to bias results relying on them about equally for most applications. In contrast, differences between centroid-type matches were substantial in some vendor contrasts, but not others (5497; 4303; 4210) p(interaction) < 10(-4), i.e. more likely to bias results differently in many applications. The adjusted odds of an address match was higher for vendor A versus C (odds ratio = 66, 95% confidence interval: 47, 93), but not B versus C (OR = 1.1, 95% CI: 0.9, 1.3). That of census tract concordance was no higher for vendor A versus C (OR = 1.0, 95% CI: 0.9, 1.2) or B versus C (OR = 1.1, 95% CI: 0.9, 1.3). Misclassification of a related exposure measure--distance to the nearest highway--increased with mean rho and in the absence of confounding, non-differential misclassification of this distance biased its hypothetical association with coronary heart disease mortality toward the null. Geocoding error depends on measures used to evaluate it, address characteristics and vendor. Vendor selection presents a trade-off between potential for missing data and error in estimating spatially defined attributes. Informed selection is needed to control the trade-off and adjust analyses for its effects.


Federalism Complicates the Response to the COVID-19 Health and Economic Crisis: What Can Be Done?
Federalism has complicated the US response to the novel coronavirus. States' actions to address the pandemic have varied widely, and federal and state officials have provided conflicting messages. This fragmented approach has surely cost time and lives. Federalism will shape the long-term health and economic impacts of COVID-19, including plans for the future, for at least two reasons: First, federalism exacerbates inequities, as some states have a history of underinvesting in social programs, especially in certain communities. Second, many of the states with the deepest needs are poorly equipped to respond to emergencies due to low taxes and distrust of government, leading to inadequate infrastructure. These dynamics are not new, but they have been laid bare by this crisis. What can policy makers do to address the inequities in health and economic outcomes that federalism intensifies? The first section of this article offers a case study of the Mississippi Delta to illustrate the role of federalism in perpetuating the connection between place, health, and economics. The second section examines challenges that safety net programs will face when moving beyond the acute phase of COVID-19. The final section explores near-, middle-, and long-term policy options to mitigate federalism's harmful side effects.


The ambiguous relation between aging and adverse drug reactions.
To examine the evidence for a relation between advancing patient age and the risk for adverse drug reactions. A computer-assisted search of the English-language literature (MEDLINE, 1966 to 1990) followed by selective review of all pertinent articles. Studies that stratified data on adverse drug reactions by patient age were screened for review. Article selection was not limited by study design; the relation between age and the occurrence of adverse drug reactions did not have to be a primary focus of the study. Pertinent data were abstracted from the results of case-control and cohort studies and from clinical trials. The methodologic strengths and weaknesses of these studies are discussed with particular reference to gerontologic issues. Most studies have neglected the issue of whether the increased frequency of adverse drug reactions in the elderly is attributable to age alone or to the fact that older patients are more likely to have coexisting illnesses and to be taking several medications. Studies that combine all drug exposures for each patient and report the risk for any adverse effect provide little useful information about the risks associated with specific drug therapies in the elderly. The association between age and the risk for adverse drug reactions is best examined for individual pharmacologic agents. However, the exclusion of elderly subjects from clinical trials makes the determination of age effects impossible in many studies. Where subjects do represent an adequate age range, most studies fail to control for important clinical differences among subjects of different ages to distinguish the independent effects of chronologic age. Conventional clinical wisdom suggests that the risk for adverse drug reactions increases with advancing age, but available data do not confirm this "truism" of geriatric medicine. The inter-individual variability of the aging process, including the non-uniform nature of the pharmacokinetic and pharmacodynamic changes that occur with aging, indicates that clinical reality is far more complex. Patient-specific physiologic and functional characteristics are probably more important than any chronologic measure in predicting both adverse and beneficial outcomes associated with specific drug therapies.


Independent influences of verbalization and race on the configural and featural processing of faces: a behavioral and eye movement study.
Describing a face in words can either hinder or help subsequent face recognition. Here, the authors examined the relationship between the benefit from verbally describing a series of faces and the same-race advantage (SRA) whereby people are better at recognizing unfamiliar faces from their own race as compared with those from other races. Verbalization and the SRA influenced face recognition independently, as evident on both behavioral (Experiment 1) and eye movement measures (Experiment 2). The findings indicate that verbalization and the SRA each recruit different types of configural processing, with verbalization modulating face learning and the SRA modulating both face learning and recognition. Eye movement patterns demonstrated greater feature sampling for describing as compared with not describing faces and for other-race as compared with same-race faces. In both cases, sampling of the eyes, nose, and mouth played a major role in performance. The findings support a single process account whereby verbalization can influence perceptual processing in a flexible and yet fundamental way through shifting one's processing orientation.


Oxidative metabolism of astrocytes is not reduced in hepatic encephalopathy: a PET study with [(11)C]acetate in humans.
In patients with impaired liver function and hepatic encephalopathy (HE), consistent elevations of blood ammonia concentration suggest a crucial role in the pathogenesis of HE. Ammonia and acetate are metabolized in brain both primarily in astrocytes. Here, we used dynamic [(11)C]acetate PET of the brain to measure the contribution of astrocytes to the previously observed reduction of brain oxidative metabolism in patients with liver cirrhosis and HE, compared to patients with cirrhosis without HE, and to healthy subjects. We used a new kinetic model to estimate uptake from blood to astrocytes and astrocyte metabolism of [(11)C]acetate. No significant differences of the rate constant of oxidation of [(11)C]acetate (k 3) were found among the three groups of subjects. The net metabolic clearance of [(11)C]acetate from blood was lower in the group of patients with cirrhosis and HE than in the group of healthy subjects (P < 0.05), which we interpret to be an effect of reduced cerebral blood flow rather than a reflection of low [(11)C]acetate metabolism. We conclude that the characteristic decline of whole-brain oxidative metabolism in patients with cirrhosis with HE is not due to malfunction of oxidative metabolism in astrocytes. Thus, the observed decline of brain oxidative metabolism implicates changes of neurons and their energy turnover in patients with HE.


Cardiorespiratory fitness and long-term survival in "low-risk" adults.
We sought to establish whether cardiorespiratory fitness had important implications for long-term cardiovascular risk among individuals classified as low risk by the Framingham Risk Score (10-year coronary heart disease risk <10%). Prognostic factors of long-term cardiovascular risk are needed for low-risk subjects who make up the largest percentage of the US population. The study population was composed of men and women, 30 to 50 years of age, who had a baseline medical exam at the Cooper Clinic, Dallas, TX, between 1970 and 1983. Eligible individuals were defined as at low risk for coronary heart disease by Framingham Risk Score at the time of study entry and had no history of diabetes (n=11 190). Cardiorespiratory fitness was determined by maximum graded exercise treadmill tests. Over an average 27±2-year period, 15% of low-fit (quintile 1) compared to 6% of high-fit (quintile 5) individuals died (P<0.001). A 1-metabolic equivalent level increase in baseline fitness was associated with an 11% reduction in all-cause deaths and an 18% reduction in deaths due to cardiovascular disease (CVD) after adjustment for age, sex, body mass index, systolic blood pressure, total cholesterol, blood glucose levels, smoking, and early family history of coronary disease. There was an incremental decrease in CVD risk with increasing fitness quintile, such that the high fit had the lowest adjusted 30-year CVD mortality rate (hazard ratio 0.29, 95% CI: 0.16-0.51) compared to the low fit. Cardiorespiratory fitness is associated with a significant reduction in long-term CVD among individuals identified as low risk by Framingham Risk Score. These data suggest that preventive lifestyle interventions geared to optimize cardiorespiratory fitness, even among a "low-risk" subset, should be considered to improve CVD-free survival. (J Am Heart Assoc. 2012;1:e001354 doi: 10.1161/JAHA.112.001354.).


Parametric four-wave mixing using a single cw laser.
Four-wave mixing can be used to generate coherent output beams, with frequencies difficult to acquire in commercial lasers. Here, a single narrow external cavity diode laser locked to the two photon 5s-5d transition in rubidium is combined with a tapered amplifier system to produce a high power cw beam at 778 nm and used to generate coherent light at 420 nm through parametric four-wave mixing. This process is analyzed in terms of the intensity and frequency of the incoming beam as well as the atomic density of the sample. The efficiency of the process is currently limited when on resonance due to the absorption of the 420 nm beam, and modifications should allow a significant increase in output power.


Crystal structure of autotaxin and insight into GPCR activation by lipid mediators.
Autotaxin (ATX, also known as Enpp2) is a secreted lysophospholipase D that hydrolyzes lysophosphatidylcholine to generate lysophosphatidic acid (LPA), a lipid mediator that activates G protein-coupled receptors to evoke various cellular responses. Here, we report the crystal structures of mouse ATX alone and in complex with LPAs with different acyl-chain lengths and saturations. These structures reveal that the multidomain architecture helps to maintain the structural rigidity of the lipid-binding pocket, which accommodates the respective LPA molecules in distinct conformations. They indicate that a loop region in the catalytic domain is a major determinant for the substrate specificity of the Enpp family enzymes. Furthermore, along with biochemical and biological data, these structures suggest that the produced LPAs are delivered from the active site to cognate G protein-coupled receptors through a hydrophobic channel.


Old materials with new tricks: multifunctional open-framework materials.
The literature on open-framework materials has shown numerous examples of porous solids with additional structural, chemical, or physical properties. These materials show promise for applications ranging from sensing, catalysis and separation to multifunctional materials. This critical review provides an up-to-date survey to this new generation of multifunctional open-framework solids. For this, a detailed revision of the different examples so far reported will be presented, classified into five different sections: magnetic, chiral, conducting, optical, and labile open-frameworks for sensing applications. (413 references.)


Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor 4 (vIRF4) targets expression of cellular IRF4 and the Myc gene to facilitate lytic replication.
Besides an essential transcriptional factor for B cell development and function, cellular interferon regulatory factor 4 (c-IRF4) directly regulates expression of the c-Myc gene, which is not only associated with various B cell lymphomas but also required for herpesvirus latency and pathogenesis. Kaposi's sarcoma-associated herpesvirus (KSHV), the etiological agent of Kaposi's sarcoma and primary effusion lymphoma, has developed a unique mechanism to deregulate host antiviral innate immunity and growth control by incorporating four viral homologs (vIRF1 to -4) of cellular IRFs into its genome. Previous studies have shown that several KSHV latent proteins, including vIRF3, vFLIP, and LANA, target the expression, function, and stability of c-Myc to establish and maintain viral latency. Here we report that the KSHV vIRF4 lytic protein robustly suppresses expression of c-IRF4 and c-Myc, reshaping host gene expression profiles to facilitate viral lytic replication. Genomewide gene expression analysis revealed that KSHV vIRF4 grossly affects host gene expression by upregulating and downregulating 118 genes and 166 genes, respectively, by at least 2-fold. Remarkably, vIRF4 suppressed c-Myc expression by 11-fold, which was directed primarily by the deregulation of c-IRF4 expression. Real-time quantitative PCR (RT-qPCR), single-molecule in situ hybridization, and chromatin immunoprecipitation assays showed that vIRF4 not only reduces c-IRF4 expression but also competes with c-IRF4 for binding to the specific promoter region of the c-Myc gene, resulting in drastic suppression of c-Myc expression. Consequently, the loss of vIRF4 function in the suppression of c-IRF4 and c-Myc expression ultimately led to a reduction of KSHV lytic replication capacity. These results indicate that the KSHV vIRF4 lytic protein comprehensively targets the expression and function of c-IRF4 to downregulate c-Myc expression, generating a favorable environment for viral lytic replication. Finally, this study further reinforces the important role of the c-Myc gene in KSHV lytic replication and latency.


Depletion of cutaneous macrophages and dendritic cells promotes growth of basal cell carcinoma in mice.
Basal cell carcinoma (BCC) belongs to the group of non-melanoma skin tumors and is the most common tumor in the western world. BCC arises due to mutations in the tumor suppressor gene Patched1 (Ptch). Analysis of the conditional Ptch knockout mouse model for BCC reveals that macrophages and dendritic cells (DC) of the skin play an important role in BCC growth restraining processes. This is based on the observation that a clodronate-liposome mediated depletion of these cells in the tumor-bearing skin results in significant BCC enlargement. The depletion of these cells does not modulate Ki67 or K10 expression, but is accompanied by a decrease in collagen-producing cells in the tumor stroma. Together, the data suggest that cutaneous macrophages and DC in the tumor microenvironment exert an antitumor effect on BCC.