UV photolysis of perfluorooctanoic acid (PFOA) in dilute aqueous solution.
Perfluorooctanoic acid (PFOA) is very persistent in the environment and widely detected in the water environment. Only some advanced methods with extreme reaction conditions are shown to be capable of degrading the compound efficiently, and almost all the earlier investigations used very high PFOA concentrations. The compound is detected normally at very low concentrations in the water environment, while mild reaction conditions for its degradation are preferable. This article aimed to elucidate photodegradation of PFOA in dilute aqueous solutions by combined UV wavelengths (185 nm+254 nm) and 254 nm using a newly designed UV jacket. PFOA degradation was greatly enhanced with the combined wavelengths with almost one hundred percent PFOA removals in four-hour reaction. The removals were well described by the first-order reaction kinetic. The removal efficiencies and rate values significantly decreased with smaller initial PFOA concentrations. But defluorination was greatly enhanced with smaller PFOA concentrations possibly due to accelerated decomposition of fluorinated intermediates of PFOA. Formic acid and acetic acid were two tentatively identified intermediates of PFOA photolysis while the former was a major intermediate predominantly controlling solution pH during the oxidation. The results demonstrated that PFOA photolysis by the combined wavelengths with mild reaction conditions can be greatly enhanced by proper design of UV jacket and reactor system.


DNA methyltransferase 3a regulates osteoclast differentiation by coupling to an S-adenosylmethionine-producing metabolic pathway.
Metabolic reprogramming occurs in response to the cellular environment to mediate differentiation, but the fundamental mechanisms linking metabolic processes to differentiation programs remain to be elucidated. During osteoclast differentiation, a shift toward more oxidative metabolic processes occurs. In this study we identified the de novo DNA methyltransferase 3a (Dnmt3a) as a transcription factor that couples these metabolic changes to osteoclast differentiation. We also found that receptor activator of nuclear factor-κB ligand (RANKL), an essential cytokine for osteoclastogenesis, induces this metabolic shift towards oxidative metabolism, which is accompanied by an increase in S-adenosylmethionine (SAM) production. We found that SAM-mediated DNA methylation by Dnmt3a regulates osteoclastogenesis via epigenetic repression of anti-osteoclastogenic genes. The importance of Dnmt3a in bone homeostasis was underscored by the observations that Dnmt3a-deficient osteoclast precursor cells do not differentiate efficiently into osteoclasts and that mice with an osteoclast-specific deficiency in Dnmt3a have elevated bone mass due to a smaller number of osteoclasts. Furthermore, inhibition of DNA methylation by theaflavin-3,3'-digallate abrogated bone loss in models of osteoporosis. Thus, this study reveals the role of epigenetic processes in the regulation of cellular metabolism and differentiation, which may provide the molecular basis for a new therapeutic strategy for a variety of bone disorders.


Transcatheter aortic valve implantation for high-risk patients with severe aortic stenosis: A systematic review.
The present systematic review objectively assessed the safety and clinical effectiveness of transcatheter aortic valve implantation for patients at high surgical risk with severe aortic stenosis. Electronic searches were performed in 6 databases from January 2000 to March 2009. The end points included feasibility, safety, efficacy, and durability. Clinical effectiveness was synthesized through a narrative review with full tabulation of results of all included studies. The current evidence on transcatheter aortic valve implantation for aortic stenosis is limited to short-term observational studies. The overall procedural success rates ranged from 74% to 100%. The incidence of major adverse events included 30-day mortality (0%-25%), major ventricular tachyarrhythmia (0%-4%), myocardial infarction (0%-15%), cardiac tamponade (2%-10%), stroke (0%-10%), conversion to surgery (0%-8%), moderate to major paravalvular leak (4%-35%), vascular complication (8%-17%), valve-in-valve procedure (2%-12%), and aortic dissection/perforation (0%-4%). The overall 30-day major adverse cardiovascular and cerebral events ranged from 3% to 35%. The mean aortic valve area ranged from 0.5 to 0.8 cm(2) before and 1.3 to 2.0 cm(2) after transcatheter aortic valve implantation. The mean pressure gradient ranged from 34 to 58 mm Hg before and 3 to 12 mm Hg after transcatheter aortic valve implantation. There was no significant deterioration in echocardiography measurements during the assessment period. Death rate at 6 months postprocedure ranged from 18% to 48%. No studies had adequate follow-up to reliably evaluate long-term outcomes. The procedure has a potential for serious complications. Although short-term efficacy based on echocardiography measurements is good, there is little evidence on long-term outcomes. The use of transcatheter aortic valve implantation should be considered only within the boundaries of clinical trials.


Ergonomics in endourology and laparoscopy: an overview of musculoskeletal problems in urology.
This study aims to provide an overview of type and frequency of musculoskeletal complaints among urologists. In addition, the urologists' knowledge about ergonomic conditions during minimally invasive urology was assessed, and they were asked how they would prefer to gain knowledge about this topic. An online and hard copy version questionnaire was administered to urologists from different countries, mainly from Europe, performing endourology and laparoscopy. Of the 285 respondents, 245 (86.0%) urologists experienced musculoskeletal complaints in the past 12 months and 62.1% were considered to be work related. Most common areas for chronic complaints were neck, back, and shoulders. Almost 50% of the urologists experienced chronic musculoskeletal complaints, for which endourology (odds ratio [OR] 3.06; 95% confidence interval [CI] 1.37-6.80) and laparoscopy (OR 1.70; 95% CI 1.27-2.28) were significant risk factors. One third of the urologists considered their knowledge about ergonomics minimal, and 8% stated that they had no knowledge about these topics. Fifty percent of the respondents preferred to integrate information about ergonomic rules into hands-on training of urologic skills. High prevalence of experienced musculoskeletal complaints was found among urologists predominantly related to endourology and laparoscopy. Urologists indicate that they have a lack of knowledge about ergonomics in the operating room. Hence, we recommend integration of ergonomics in hands-on training programs early in the residency curriculum to gain knowledge and awareness and hopefully to offer possibilities to prevent these complaints in the future.


Predictors of Urinary Arsenic Levels among Postmenopausal Danish Women.
Arsenic is a risk factor for several noncommunicable diseases, even at low doses. Urinary arsenic (UAs) concentration is a good biomarker for internal dose, and demographic, dietary, and lifestyle factors are proposed predictors in nonoccupationally exposed populations. However, most predictor studies are limited in terms of size and number of predictors. We investigated demographic, dietary, and lifestyle determinants of UAs concentrations in 744 postmenopausal Danish women who had UAs measurements and questionnaire data on potential predictors. UAs concentrations were determined using mass spectrometry (ICP-MS), and determinants of the concentration were investigated using univariate and multivariate regression models. We used a forward selection procedure for model optimization. In all models, fish, alcohol, and poultry intake were associated with higher UAs concentration, and tap water, fruit, potato, and dairy intake with lower concentration. A forward regression model explained 35% (R²) of the variation in concentrations. Age, smoking, education, and area of residence did not predict concentration. The results were relatively robust across sensitivity analyses. The study suggested that UAs concentration in postmenopausal women was primarily determined by dietary factors, with fish consumption showing the strongest direct association. However, the majority of variation in UAs concentration in this study population is still unexplained.


Evidence for early morphological decomposition: combining masked priming with magnetoencephalography.
Are words stored as morphologically structured representations? If so, when during word recognition are morphological pieces accessed? Recent masked priming studies support models that assume early decomposition of (potentially) morphologically complex words. The electrophysiological evidence, however, is inconsistent. We combined masked morphological priming with magneto-encephalography (MEG), a technique particularly adept at indexing processes involved in lexical access. The latency of an MEG component peaking, on average, 220 msec post-onset of the target in left occipito-temporal brain regions was found to be sensitive to the morphological prime-target relationship under masked priming conditions in a visual lexical decision task. Shorter latencies for related than unrelated conditions were observed both for semantically transparent (cleaner-CLEAN) and opaque (corner-CORN) prime-target pairs, but not for prime-target pairs with only an orthographic relationship (brothel-BROTH). These effects are likely to reflect a prelexical level of processing where form-based representations of stems and affixes are represented and are in contrast to models positing no morphological structure in lexical representations. Moreover, we present data regarding the transitional probability from stem to affix in a post hoc comparison, which suggests that this factor may modulate early morphological decomposition, particularly for opaque words. The timing of a robust MEG component sensitive to the morphological relatedness of prime-target pairs can be used to further understand the neural substrates and the time course of lexical processing.


Grading fluorescein angiograms in malarial retinopathy.
Malarial retinopathy is an important finding in Plasmodium falciparum cerebral malaria, since it strengthens diagnostic accuracy, predicts clinical outcome and appears to parallel cerebral disease processes. Several angiographic features of malarial retinopathy have been described, but observations in different populations can only be reliably compared if consistent methodology is used to capture and grade retinal images. Currently no grading scheme exists for fluorescein angiographic features of malarial retinopathy. A grading scheme for fluorescein angiographic images was devised based on consensus opinion of clinicians and researchers experienced in malarial retinopathy in children and adults. Dual grading were performed with adjudication of admission fluorescein images from a large cohort of children with cerebral malaria. A grading scheme is described and standard images are provided to facilitate future grading studies. Inter-grader agreement was >70 % for most variables. Intravascular filling defects are difficult to grade and tended to have lower inter-grader agreement (>57 %) compared to other features. This grading scheme provides a consistent way to describe retinal vascular damage in paediatric cerebral malaria, and can facilitate comparisons of angiographic features of malarial retinopathy between different patient groups, and analysis against clinical outcomes. Inter-grader agreement is reasonable for the majority of angiographic signs. Dual grading with expert adjudication should be used to maximize accuracy.


Partnership, Trust and Leadership among Nursing Researchers.
Members of a nursing research cluster realized that they needed to determine whether, given their diverse philosophies, they could formulate a collective research agenda responding to an administrative recommendation. The cluster's leaders conducted an appraisal of the role and importance of trust as an element for promoting collaboration in a nursing research cluster and for building a collective social identity. The Social Exchange Theory framed the appraisal. A survey and a facilitation session about trust in research partnerships were conducted with eight female nursing researchers/faculty. Facilitation day's discussion was fully audio recorded, transcribed verbatim and the content coded using ATLAS.ti 6. Thematic analysis was employed to analyze the qualitative aspects of the recorded discussion and the survey questionnaire explanatory responses. Responses to survey closed-questions were compiled as descriptive statistics. Participants revealed that mutual support, valuing each other and working collaboratively facilitated trust in intellectual partnership. Hindering factors were an environment suppressing expression of ideas and views, lack of open dialogue and decision-making among team members and lack of a sense of belonging. This paper has the potential to contribute to the knowledge of nursing leaders who are intending to develop and sustain nursing research teams in both academic and non-academic organizations. The paper will be especially useful as they deal with issues of trust in intellectual partnership in diverse settings.


Establishing high-quality prostate brachytherapy using a phantom simulator training program.
To design and implement a unique training program that uses a phantom-based simulator to teach the process of prostate brachytherapy (PB) quality assurance and improve the quality of education. Trainees in our simulator program were practicing radiation oncologists, radiation oncology residents, and fellows of the American Brachytherapy Society. The program emphasized 6 core areas of quality assurance: patient selection, simulation, treatment planning, implant technique, treatment evaluation, and outcome assessment. Using the Iodine 125 ((125)I) preoperative treatment planning technique, trainees implanted their ultrasound phantoms with dummy seeds (ie, seeds with no activity). Pre- and postimplant dosimetric parameters were compared and correlated using regression analysis. Thirty-one trainees successfully completed the simulator program during the period under study. The mean phantom prostate size, number of seeds used, and total activity were generally consistent between trainees. All trainees met the V100 >95% objective both before and after implantation. Regardless of the initial volume of the prostate phantom, trainees' ability to cover the target volume with at least 100% of the dose (V100) was not compromised (R=0.99 pre- and postimplant). However, the V150 had lower concordance (R=0.37) and may better reflect heterogeneity control of the implant process. Analysis of implants from this phantom-based simulator shows a high degree of consistency between trainees and uniformly high-quality implants with respect to parameters used in clinical practice. This training program provides a valuable educational opportunity that improves the quality of PB training and likely accelerates the learning curve inherent in PB. Prostate phantom implantation can be a valuable first step in the acquisition of the required skills to safely perform PB.


Late-life health consequences of exposure to trauma in a general elderly population: the mediating role of reexperiencing posttraumatic symptoms.
A history of trauma is associated with poor mental and physical health, but the specific impact of posttraumatic stress disorder (PTSD) symptoms on physical health using objective indicators of health status has rarely been evaluated in elderly civilians. This study investigates the long-term consequences of a lifetime exposure to trauma on health in a French elderly general population. Data from this retrospective study were derived from a longitudinal study (the Enquête de Santé Psychologique-Risques, Incidence et Traitement [ESPRIT]) of community-dwelling participants. Psychiatric health, medical history, and clinical examination (ICD-10 criteria) were assessed in 1,662 subjects (mean [SD] age = 72.5 [5.2] years). Lifetime traumatic exposure, PTSD, and psychiatric diagnoses were obtained using the Watson PTSD Inventory and the Mini-International Neuropsychiatric Interview. The outcome measures used were the Mini-International Neuropsychiatric Interview, Center for Epidemiologic Studies Depression Scale, Mini-Mental State Examination, and measures of physical health. We observed an increase in the number and severity of health-related outcomes between groups, with nontraumatized subjects having the lowest risk and those with trauma leading to recurrent reexperiencing of events (nonresilient subjects) having the highest risk. Traumatized persons who did not report reexperiencing symptoms (resilient subjects) showed better current mental health than traumatized subjects who did and nontraumatized subjects. Nonresilient subjects were more likely to have current depressive symptoms (P = .003), current major depression (P < .0001), current anxiety disorder (P = .032), and psychiatric comorbidity (P = .002) than nontraumatized subjects. Resilient subjects differed from nontraumatized subjects in having significantly less current suicidal ideation (P = .054) and psychiatric comorbidity (P = .035). Both groups of traumatized subjects showed a higher rate of cardio-ischemic diseases, notably current angina pectoris (multivariate, adjusted OR = 2.27; 95% CI, 1.31-3.91; and OR = 2.34; 95% CI, 1.22-4.49; for resilient and nonresilient groups, respectively). Traumatized persons, specifically those nonresilient, showed a higher waist-hip ratio, higher triglyceride levels, and a greater frequency of hypertension. Our findings suggest that trauma could be associated with cardio-ischemic diseases independently of PTSD symptoms expression. However, the presence of these symptoms appears associated with additional metabolic risk factors.


The 3 prime paradigm of the miR-200 family and other microRNAs.
The number of predicted human microRNAs in Sanger miRBase currently stands at over a thousand, with each of these in turn predicted to target numerous mRNAs. However, those microRNAs for which mRNA targets have been evaluated, verified and reported in the literature are still in the minority and the bulk of microRNA/mRNA interactions are yet to be confirmed. Confirmation of microRNA interaction with predicted mRNA targets represents a considerable undertaking, made more complex by potential synergistic effects of multiple microRNAs and the three possible outcomes (translational repression, degradation or a mixture of both). In addition, contrasting results obtained when either stably expressing or transiently transfecting members of the miR-200 family illustrate limitations in the verification methods currently in use. In this article we suggest that instead of allowing computational predictions to drive investigation, it would be desirable, when possible, to systematically evaluate microRNA targets using inducible, stable, ectopic expression. The advantage of stable lines ectopically expressing microRNA(s) is that they allow an analysis of changes to both the proteome and the transcriptome. This would allow verification of targets, improve the design of prediction algorithms and greatly increase our understanding of the outcome of microRNA/mRNA interaction.


Humoral immunostimulation. IV. Role of complement.
When L cells were treated with anti-L-cell antibody in medium containing heat-inactivated fetal calf serum, nucleoside uptake and cell growth were stimulated. The response was markedly increased when fresh, unheated sera from calves, guinea pigs, humans, mice, or rabbits were also present. The factors in unheated serum responsible for the enhancement of immunostimulation were studied. Using low concentrations of sera deficient in various complement (C) components and low concentrations of antibody no augmentation of immunostimulation was seen with Clr-deficient human serum, C2-deficient human serum, C2,4-deficient human serum, C4-deficient guinea pig serum, C3-C9-depleted guinea pig serum (by administration of cobra venom factor to animals), but stimulation was observed with C5-deficient human serum, C5-deficient mouse serum, and C6-deficient rabbit serum. When the concentration of anti-serum was raised, however, augmentation was observed with C4-deficient guinea pig serum. Thus, at low concentrations of antiserum enhancement appeared to occur through the classical C pathway, whereas at high concentrations of antibody either the classical or alternate C pathways appeared to be involved. Stimulation was specifically restored by purified C2 in C2-deficient serum and by C3 in C3-C9-deficient serum. Under the usual reaction conditions consumption of guinea pig C component C4 could be demonstrated which provided direct evidence for activation of the classical C pathway under conditions leading to immunostimulation. By immunofluorescence, cells treated with antibody and normal human serum had human C3 deposited at the cell surface. Taken together these observations suggest that C activated through C3 by either the classical or alternate pathways has the potential to enhance nucleoside incorporation into DNA and cell growth of cells exposed to limiting amounts of antibody. Although the mechanism of stimulation is unknown, it is likely to involve a direct effect of C3 at the level of the cell membrane.


Transcriptomic and proteomic analyses in bone tumor cells: Deciphering parathyroid hormone-related protein regulation of the cell cycle and apoptosis.
Giant cell tumor of bone (GCT) is an aggressive skeletal tumor characterized by local bone destruction, high recurrence rates, and metastatic potential. Previous works in our laboratory, including functional assays, have shown that neutralization of parathyroid hormone-related protein (PTHrP) in the cell environment inhibits cell proliferation and induces cell death in GCT stromal cells, indicating a role for PTHrP in cell propagation and survival. The objective of this study was to investigate the global gene and protein expression patterns of GCT cells in order to identify the underlying pathways and mechanisms of neoplastic proliferation provided by PTHrP in the bone microenvironment. Primary stromal cell cultures from 10 patients with GCT were used in this study. Cells were exposed to optimized concentrations of either PTHrP peptide or anti-PTHrP neutralizing antiserum and were analyzed with both cDNA microarray and proteomic microarray assays in triplicate. Hierarchical clustering and principal component analyses confirmed that counteraction of PTHrP in GCT stromal cells results in a clear-cut gene expression pattern distinct from all other treatment groups and the control cell line human fetal osteoblast (hFOB). Multiple bioinformatics tools were used to analyze changes in gene/protein expression and identify important gene ontologies and pathways common to this anti-PTHrP-induced regulatory gene network. PTHrP neutralization interferes with multiple cell survival and apoptosis signaling pathways by triggering both death receptors and cell cycle-mediated apoptosis, particularly via the caspase pathway, TRAIL pathway, JAK-STAT signaling pathway, and cyclin E/CDK2-associated G1/S cell cycle progression. These findings indicate that PTHrP neutralization exhibits anticancer potential by regulating cell-cycle progression and apoptosis in bone tumor cells, with the corollary being that PTHrP is a pro-neoplastic factor that can be targeted in the treatment of bone tumors.


A kinetic approach to assess oxidative metabolism related features in the bivalve Mya arenaria.
Electron paramagnetic resonance uses the resonant microwave radiation absorption of paramagnetic substances to detect highly reactive and, therefore, short-lived oxygen and nitrogen centered radicals. Previously, steady state concentrations of nitric oxide, ascorbyl radical (A·) and the labile iron pool (LIP) were determined in digestive gland of freshly collected animals from the North Sea bivalve Mya arenaria. The application of a simple kinetic analysis of these data based on elemental reactions allowed us to estimate the steady state concentrations of superoxide anion, the rate of A· disappearance and the content of unsaturated lipids. This analysis applied to a marine invertebrate opens the possibility of a mechanistic understanding of the complexity of free radical and LIP interactions in a metabolically slow, cold water organism under unstressed conditions. This data can be further used as a basis to assess the cellular response to stress in a simple system as the bivalve M. arenaria that can then be compared to cells of higher organisms.


Citizen Science to Communicate about Public Health Messages: The Reach of a Playful Online Survey on Sitting Time and Physical Activity.
There is a lack of research on how to communicate public health guidelines. Citizen science (CS) has been an effective way to involve the public in research. This study analyses the reach of a well-established CS experiment, launched during an annual national science event, to understand if it could be used as communication strategy for public health issues. A short playful online survey contained tailored health-related messages associated to an "animal totem" profile, based on the combination of sitting and physical activity levels (koala: high sitting, low activity; gorilla: high sitting, high activity; zebra: low sitting, low activity; bee: low sitting, high activity). Tweets, radio interviews, radio and online advertisements, press articles, and a press conference were used to promote the CS experiment. Google Analytics and Facebook Graph API (application programming interface) (use and spread of experiment) and descriptive statistics (attributes of adults completing the experiment) were used. A total of 6,246 adults completed the experiment, with a peak of views (n = 5,103) and completions (n = 1,209) a couple of days before the event. Completers were mostly female (65.8%), on average 37.5 years old, and had a healthy body mass index (23.8 kg/m2). Nearly half (46.4%) had the most beneficial profile ("bee"), 26.5% had the least healthy profile ("koala"). CS as part of a national science event is a good platform for health communication as 1 in 1,000 Flemish adults were reached. However, those completing the experiment were not representative of the general Flemish adult population and reported to be more physically active. Abbreviations: API: application programming interface; BMI: body mass index; CVD: cardiovascular disease; METs: metabolic equivalents.


Neural responses during the anticipation and receipt of olfactory reward and punishment in human.
Pleasure experience is an important part of normal healthy life and is essential for general and mental well-being. Many neuroimaging studies have investigated the underlying neural processing of verbal and visual modalities of reward. However, how the brain processes rewards in the olfactory modality is not fully understood. This study aimed to examine the neural basis of olfactory rewards in 25 healthy participants using functional magnetic resonance imaging (fMRI). We developed an Olfactory Incentive Delay (OLID) imaging task distinguishing between the anticipation and receipt of olfactory rewards and punishments. We found that the pallidum was activated during the anticipation of both olfactory rewards and punishments. The bilateral insula was activated independently from the odours' hedonic valence during the receipt phase. In addition, right caudate activation during the anticipation of unpleasant odours was correlated with self-reported anticipatory hedonic traits, whereas bilateral insular activation during the receipt of pleasant odours was correlated with self-reported consummatory hedonic traits. These findings suggest that activity in the insula and the caudate may be biomarkers of anhedonia. These findings also highlight a useful and valid paradigm to study the neural circuitry underlying reward processing in people with anhedonia.


Glucose stimulates islet beta-cell mitogenesis through GTP-binding proteins and by protein kinase C-dependent mechanisms.
Glucose is a cardinal secretory and mitogenic stimulus for the insulin-producing pancreatic beta-cell both in vitro and in vivo, but the mechanisms by which the sugar acts mitogenically remain largely elusive. In this study, the intracellular pathways that convey glucose-induced mitogenic and secretory signaling in beta-cells were investigated. For this purpose, fetal rat pancreatic islets enriched in beta-cells were cultured in 3.3 or 16.7 mmol/l glucose for 3 days. It was found that glucose stimulated beta-cell replication, insulin secretion, and cAMP content. These effects were mimicked by agonists of cAMP-dependent protein kinases but not by guanosine-3',5'-cyclic monophosphate (cGMP). Antagonists of cAMP-dependent protein kinases failed to block the glucose-induced increments in beta-cell replication and insulin secretion. Glucose is known to activate protein kinase C, and a protein kinase C-activating phorbol ester was found to promote beta-cell mitogenesis and insulin secretion. Conversely, when protein kinase C was inhibited, the mitogenic (but not secretory) response to glucose was attenuated. There were no additive or synergistic effects on beta-cell replication when cAMP and phorbol ester were combined, whereas insulin secretion was potentiated by this combination. Artificially causing Ca2+ inlet by glibenclamide or ionomycin did not result in a stimulated mitogenic response, and preventing Ca2+ influx by blocking plasma membrane Ca2+ channels did not abolish the mitogenicity of glucose, although it reduced insulin secretion. Pretreatment of islets with pertussis toxin, known to regulate transduction of signals through heterotrimeric GTP-binding proteins, completely prevented the stimulatory effect of glucose on beta-cell mitogenesis but not on insulin secretion. We conclude that specific activation of protein kinase C or cAMP synthesis is sufficient to increase beta-cell mitogenesis and insulin secretion, whereas cGMP appears not to affect these processes. However, cAMP does not seem to mediate the mitogenicity or secretory action of glucose. The results instead suggest that signaling through GTP-binding proteins and protein kinase C activation is required for transduction of the mitogenic, but not secretory, message of the sugar in the beta-cell.


Inflammatory chemokines direct and restrict leukocyte migration within live tissues as glycan-bound gradients.
Chemokines are essential in many cell migration processes, including the recruitment of leukocytes to sites of infection. In the latter context, chemokines promote leukocyte extravasation into the relevant tissue through a well-studied cascade of events. It is widely believed that chemokines further guide leukocytes within tissues via chemotaxis, the directed migration along gradients of soluble ligands. However, the basic mechanism of chemokine action within tissues has yet to be formally addressed in vivo. We identified a chemokine (zCxcl8) that recruits zebrafish neutrophils to infection loci and analyzed its function directly within interstitial tissues of living larvae. Using noninvasive imaging and a controlled cellular source of zCxcl8, we found that zCxcl8 guides neutrophils in a 2-fold manner: by biasing cell speed according to direction (orthotaxis) and by restricting cell motility near the source. We further show that zCxcl8 establishes tissue-bound gradients in vivo by binding to heparan sulfate proteoglycans (HSPGs). Inhibition of this interaction compromised both directional guidance and restriction of neutrophil motility. Thus, by interacting with extracellular HSPGs, chemokines establish robust surface-bound (haptotactic) gradients that mediate both recruitment and retention of leukocytes at sites of infection.


Chlamydia muridarum infection-induced destruction of male germ cells and sertoli cells is partially prevented by Chlamydia major outer membrane protein-specific immune CD4 cells.
Chlamydia trachomatis infections are increasingly prevalent worldwide. Male chlamydial infections are associated with urethritis, epididymitis, and orchitis; however, the role of Chlamydia in prostatitis and male factor infertility remains controversial. Using a model of Chlamydia muridarum infection in male C57BL/6 mice, we investigated the effects of chlamydial infection on spermatogenesis and determined the potential of immune T cells to prevent infection-induced outcomes. Antigen-specific CD4 T cells significantly reduced the infectious burden in the penile urethra, epididymis, and vas deferens. Infection disrupted seminiferous tubules, causing loss of germ cells at 4 and 8 wk after infection, with the most severely affected tubules containing only Sertoli cells. Increased mitotic proliferation, DNA repair, and apoptosis in spermatogonial cells and damaged germ cells were evident in atrophic tubules. Activated caspase 3 (casp3) staining revealed increased (6-fold) numbers of Sertoli cells with abnormal morphology that were casp3 positive in tubules of infected mice, indicating increased levels of apoptosis. Sperm count and motility were both decreased in infected mice, and there was a significant decrease in morphologically normal spermatozoa. Assessment of the spermatogonial stem cell population revealed a decrease in promyelocytic leukemia zinc finger (PLZF)-positive cells in the seminiferous tubules. Interestingly, adoptive transfer of antigen-specific CD4 cells, particularly T-helper 2-like cells, prior to infection prevented these effects in spermatogenesis and Sertoli cells. These data suggest that chlamydial infection adversely affects spermatogenesis and male fertility, and that vaccination can potentially prevent the spread of infection and these adverse outcomes.


A role for BDNF/TrkB signaling in behavioral and physiological consequences of social defeat stress.
Accumulating evidences underlie the importance of the interplay between environmental and genetic factors in contributing to the risk to develop mental illness. Brain-derived neurotrophic factor (BDNF) and its Tyrosine receptor kinase B (TrkB) receptor play a fundamental contribution to brain development and plastic adaptations to life events. In the present study, the potential for the BDNF/TrkB contribution in increasing vulnerability to negative social experiences was assessed by subjecting TrkB.T1 overexpressing mice to a chronic social defeat model. TrkB.T1 mice overexpress the dominant-negative truncated splice variant of TrkB receptor leading to decreased BDNF signaling. After repeated social defeat, mice were assessed in a longitudinal study for behavioral, physiological, endocrine and immune responses potentially related to psychiatric endophenotypes. TrkB.T1 overexpression corresponded to smaller changes in metabolic parameters such as body weight, food intake, feed efficiency and peripheral ghrelin levels compared with wild-type (wt) littermates following social defeat. Interestingly, 4 weeks after the last defeat, TrkB.T1 overexpressing mice exhibited more consistent social avoidance effects than what observed in wt subjects. Finally, previously unreported effects of TrkB mutations could be observed on lymphoid organ weight and on peripheral immune biomarker levels, such as interleukin-1α and regulated on activation, normal, T-cell expressed, and secreted (RANTES), thus suggesting a systemic role of BDNF signaling in immune function. In conclusion, the present data support a contribution of TrkB to stress vulnerability that, given the established role of TrkB in the response to antidepressant treatment, calls for further studies addressing the link between stress susceptibility and variability in drug efficacy.


Crkl is constitutively tyrosine phosphorylated in platelets from chronic myelogenous leukemia patients and inducibly phosphorylated in normal platelets stimulated by thrombopoietin.
Platelet functions such as aggregation and clot retraction are often abnormal in chronic mylogenous leukemia (CML) patients. However, the molecular mechanisms of these altered functions are unknown. As expression of the p210bcr-abl oncogene product, a constitutively active tyrosine kinase, is known to have an essential role in the pathogenesis of CML and tyrosine phosphorylation is intimately involved in various aspects of platelet activation, we examined the pattern of protein tyrosine phosphorylation in platelets from 15 CML patients by immunoblotting with a monoclonal antiphosphotyrosine antibody (4G10). Before and after stimulation with thrombin, the only consistent difference between normal and CML platelets was the presence of a tyrosine phosphorylated protein with a relative molecular weight of 39 kD. This tyrosine phosphorylated protein was identified as crid, an SH2, SH3 containing adapter protein. Thus, as previously demonstrated for neutrophils from CML patients, tyrosine phosphorylation of p39crkl persists in mature platelets. No tyrosine phosphorylation of crid was detected following stimulation with thrombin in normal platelets. However, crkl became incorporated into the Triton X-100 insoluble residue following thrombin stimulation in a manner dependent on platelet aggregation. Further, we found that crkl is an endogenous substrate for calpain, a protease that may be involved in postaggregation signaling processes. This suggests that crkl may be involved in the reorganization of the cytoskeleton during normal platelet aggregation and its tyrosine phosphorylation in CML platelets may contribute to the abnormal platelet function in CML patients. Finally, we found that thrombopoietin induces tyrosine phosphorylation of crk1 in normal platelets and FDCP cells genetically engineered to express human c-Mpl. This suggests that crk1 can be phosphorylated by a kinase other than p210bcr-abl and that crk1 may have a role in signaling by thrombopoietin.


The Renal Extraction and the Natriuretic Action of GLP-1 in Humans Depend on Interaction With the GLP-1 Receptor.
The natriuretic effect of glucagon-like peptide-1 (GLP-1) in humans is independent of changes in renal plasma flow (RPF) and glomerular filtration rate (GFR) but may involve suppression of angiotensin II (ANG II) and a significant (~45%) renal extraction of GLP-1. The current study was designed to investigate the consequences for the renal extraction and the natriuretic effect of blocking GLP-1 receptors with the specific GLP-1 receptor antagonist, Exendin 9-39 (Ex 9-39). Under fixed sodium intake for 4 days before each study day, 6 healthy male participants were recruited from our recent study where GLP-1 or vehicle was infused (1). In the present new experiments, participants were examined during a 3-hour infusion of GLP-1 (1.5 pmol/kg/min) together with a 3.5-hour infusion of Ex 9-39 (900 pmol/kg/min). Timed urine collections were conducted throughout the experiments. Renal extraction of GLP-1 as well as RPF and GFR were measured via Fick's principle after catheterization of a renal vein. Arterial plasma renin, ANG II, and aldosterone concentrations were measured. Co-infusion of Ex 9-39 significantly reduced renal extraction of GLP-1 to ~25% compared with GLP-1 infusion alone (~45%). Urinary sodium excretions remained at baseline levels during co-infusion of Ex 9-39 as well as vehicle. By contrast, GLP-1 infusion alone resulted in a 2-fold increase in natriuresis. Ex 9-39 abolished the GLP-1-induced decrease in arterial ANG II concentrations. RPF and GFR remained unchanged during all experiments. Renal extraction of GLP-1 and its effect on natriuresis are both dependent on GLP-1 receptor activation in healthy humans.


Active Microbial Communities Inhabit Sulphate-Methane Interphase in Deep Bedrock Fracture Fluids in Olkiluoto, Finland.
Active microbial communities of deep crystalline bedrock fracture water were investigated from seven different boreholes in Olkiluoto (Western Finland) using bacterial and archaeal 16S rRNA, dsrB, and mcrA gene transcript targeted 454 pyrosequencing. Over a depth range of 296-798 m below ground surface the microbial communities changed according to depth, salinity gradient, and sulphate and methane concentrations. The highest bacterial diversity was observed in the sulphate-methane mixing zone (SMMZ) at 250-350 m depth, whereas archaeal diversity was highest in the lowest boundaries of the SMMZ. Sulphide-oxidizing ε-proteobacteria (Sulfurimonas sp.) dominated in the SMMZ and γ-proteobacteria (Pseudomonas spp.) below the SMMZ. The active archaeal communities consisted mostly of ANME-2D and Thermoplasmatales groups, although Methermicoccaceae, Methanobacteriaceae, and Thermoplasmatales (SAGMEG, TMG) were more common at 415-559 m depth. Typical indicator microorganisms for sulphate-methane transition zones in marine sediments, such as ANME-1 archaea, α-, β- and δ-proteobacteria, JS1, Actinomycetes, Planctomycetes, Chloroflexi, and MBGB Crenarchaeota were detected at specific depths. DsrB genes were most numerous and most actively transcribed in the SMMZ while the mcrA gene concentration was highest in the deep methane rich groundwater. Our results demonstrate that active and highly diverse but sparse and stratified microbial communities inhabit the Fennoscandian deep bedrock ecosystems.


Regional blood flow of exercise-trained younger and older cold-exposed rats.
O2 consumption (thermogenesis) and regional blood flows (measured using radioactively labeled microspheres) were evaluated in younger (12 mo) and older (24 mo) sedentary and exercised male Fischer 344 (F-344) rats. These variables were measured at rest and during exposure to 6 degrees C. Exercise-trained rats were run on a motor-driven treadmill 5 days/wk, 1 h/day, at 20 m/min for 6 mo. Resting rates of O2 consumption did not differ with age or exercise training. However, thermogenesis during cold exposure was significantly greater in the older exercised rats than in the other three groups. This difference did not reflect a greater contribution from brown fat as indicated by the fact that total blood flow to the brown fat depots during cold exposure was not greater in the older exercised vs. the other rat groups. Neither exercise training nor age had a significant effect on specific resting blood flow (expressed as ml.min-1.g tissue mass-1) to most of the organs measured, including heart, kidney, brown fat, white fat, and skeletal muscle. The notable exception to this was in the spleen of the older sedentary animals where flow was diminished compared with that in the older exercised animals. We conclude that aging, between 12 and 24 mo of age, and/or exercise training have only a minor effect on regional blood flow of F-344 rats during rest or cold exposure and that the enhanced thermogenesis seen in cold-exposed older exercised vs. sedentary F-344 rats cannot be explained by a greater contribution from brown fat.


In vivo directed differentiation of pluripotent stem cells for skeletal regeneration.
Pluripotent cells represent a powerful tool for tissue regeneration, but their clinical utility is limited by their propensity to form teratomas. Little is known about their interaction with the surrounding niche following implantation and how this may be applied to promote survival and functional engraftment. In this study, we evaluated the ability of an osteogenic microniche consisting of a hydroxyapatite-coated, bone morphogenetic protein-2-releasing poly-L-lactic acid scaffold placed within the context of a macroenvironmental skeletal defect to guide in vivo differentiation of both embryonic and induced pluripotent stem cells. In this setting, we found de novo bone formation and participation by implanted cells in skeletal regeneration without the formation of a teratoma. This finding suggests that local cues from both the implanted scaffold/cell micro- and surrounding macroniche may act in concert to promote cellular survival and the in vivo acquisition of a terminal cell fate, thereby allowing for functional engraftment of pluripotent cells into regenerating tissue.


Nitric-oxide-mediated regulation of cardiac contractility and stretch responses.
In the heart, nitric oxide (NO) is constitutively produced by the vascular and endocardial endothelium, the cardiomyocytes and the autonomic nerves. Whereas stimulation of NO release from the vascular endothelium has consistently been shown to quicken the onset of left ventricular (LV) relaxation and cause a small reduction in peak contraction, the role of myocardial NO production in regulating cardiac function appears to be more complex and controversial. Some studies have shown that non-isoform-specific inhibition of NO synthesis with L-arginine analogues has no effect on basal contraction in LV myocytes. However, others have demonstrated that stimulation of myocardial NO production can offset the increase in contraction in response to a rise in intracellular Ca(2+). Cardiac NO production is also activated by stretch and under these conditions NO has been shown to facilitate the Frank-Starling response and to contribute to the increase in intracellular Ca(2+) transients that mediates the slow increase in contraction in response to stretch (i.e., the Anrep effect). These findings suggest that NO can mediate diverse and even contrasting actions within the myocardium, a notion that is difficult to reconcile with the early description of NO as a highly reactive and diffusible molecule possessing minimal specificity in its interactions. The purpose of this short review is to revisit some of the 'controversial' aspects of NO-mediated regulation of myocardial function, taking into account our current understanding of how mammalian cells may target and regulate the synthesis of NO in such a way that NO can serve diverse physiological functions.


Thermal effects of mobile phones on facial nerves and surrounding soft tissue.
To investigate the possible thermal effects of microwaves from mobile phones on facial nerves (FN) and surrounding soft tissue. A prospective study. We studied FN conduction rate and compound muscle action potentials (CMAP) on 12 rabbits before exposure to radiofrequency radiation (RFR) emitted from a mobile phone. Also, the temperature change in the soft tissues around the FN was investigated by a four channel Luxtron fiber optic system. A mobile phone with 1900 MHz frequency was placed over the ipsilateral ear of the rabbit for 25 minutes, and FN and surrounding tissues were exposed to a 1.5 watts pulse modulated (217 packets/s) electromagnetic field. During exposure to RFR, immediately after turning off the mobile phone, and 25 minutes after the exposure temperature change in the surrounding tissue of the FN was recorded and compared to preexposure values. Additionally, another recording regarding the FN functions was done and the data were compared to preexposure values. The average temperature of the surrounding soft tissues was 0.39 K higher than the preexposure values during the exposure and immediately after turning off the mobile phone, and decreased to normal levels 25 minutes after the exposure, which was statistically significant. The amplitudes of FN CMAP after radiofrequency radiation exposure were significantly smaller than the preexposure amplitudes and the amplitudes were normal in the 25 minute measurement. The RFR emitted from a mobile phone can cause temporary FN dysfunction that can be due to temporary temperature increase in the soft tissue around the FN.


An Exponential-Gamma Convolution Model for Background Correction of Illumina BeadArray Data.
Illumina BeadArrays are becoming an increasingly popular Microarray platform due to its high data quality and relatively low cost. One distinct feature of Illumina BeadArrays is that each array has thousands of negative control bead types containing oligonucleotide sequences that are not specific to any target genes in the genome. This design provides a way of directly estimating the distribution of the background noise. In the literature of background correction for BeadArray data, the information from negative control beads is either ignored, used in a naive way that can lead to a loss in efficiency, or the noise is assumed to be normally distributed. However, we show with real data that the noise can be skewed. In this study we propose an exponential-gamma convolution model for background correction of Illumina BeadArray data. Using both simulated and real data examples, we show that the proposed method can improve the signal estimation and detection of differentially expressed genes when the signal to noise ratio is large and the noise has a skewed distribution.


Recovery of benthic megafauna from anthropogenic disturbance at a hydrocarbon drilling well (380 m depth in the Norwegian Sea).
Recovery from disturbance in deep water is poorly understood, but as anthropogenic impacts increase in deeper water it is important to quantify the process. Exploratory hydrocarbon drilling causes physical disturbance, smothering the seabed near the well. Video transects obtained by remotely operated vehicles were used to assess the change in invertebrate megafaunal density and diversity caused by drilling a well at 380 m depth in the Norwegian Sea in 2006. Transects were carried out one day before drilling commenced and 27 days, 76 days, and three years later. A background survey, further from the well, was also carried out in 2009. Porifera (45% of observations) and Cnidaria (40%) dominated the megafauna. Porifera accounted for 94% of hard-substratum organisms and cnidarians (Pennatulacea) dominated on the soft sediment (78%). Twenty seven and 76 days after drilling commenced, drill cuttings were visible, extending over 100 m from the well. In this area there were low invertebrate megafaunal densities (0.08 and 0.10 individuals m(-2)) in comparison to pre-drill conditions (0.21 individuals m(-2)). Three years later the visible extent of the cuttings had reduced, reaching 60 m from the well. Within this area the megafaunal density (0.05 individuals m(-2)) was lower than pre-drill and reference transects (0.23 individuals m(-2)). There was a significant increase in total megafaunal invertebrate densities with both distance from drilling and time since drilling although no significant interaction. Beyond the visible disturbance there were similar megafaunal densities (0.14 individuals m(-2)) to pre-drilling and background surveys. Species richness, Shannon-Weiner diversity and multivariate techniques showed similar patterns to density. At this site the effects of exploratory drilling on megafaunal invertebrate density and diversity seem confined to the extent of the visible cuttings pile. However, elevated Barium concentration and reduced sediment grain size suggest persistence of disturbance for three years, with unclear consequences for other components of the benthic fauna.


Colony-forming progenitor cells in the postnatal mouse liver and pancreas give rise to morphologically distinct insulin-expressing colonies in 3D cultures.
In our previous studies, colony-forming progenitor cells isolated from murine embryonic stem cell-derived cultures were differentiated into morphologically distinct insulin-expressing colonies. These colonies were small and not light-reflective when observed by phase-contrast microscopy (therefore termed "Dark" colonies). A single progenitor cell capable of giving rise to a Dark colony was termed a Dark colony-forming unit (CFU-Dark). The goal of the current study was to test whether endogenous pancreas, and its developmentally related liver, harbored CFU-Dark. Here we show that dissociated single cells from liver and pancreas of one-week-old mice give rise to Dark colonies in methylcellulose-based semisolid culture media containing either Matrigel or laminin hydrogel (an artificial extracellular matrix protein). CFU-Dark comprise approximately 0.1% and 0.03% of the postnatal hepatic and pancreatic cells, respectively. Adult liver also contains CFU-Dark, but at a much lower frequency (~0.003%). Microfluidic qRT-PCR, immunostaining, and electron microscopy analyses of individually handpicked colonies reveal the expression of insulin in many, but not all, Dark colonies. Most pancreatic insulin-positive Dark colonies also express glucagon, whereas liver colonies do not. Liver CFU-Dark require Matrigel, but not laminin hydrogel, to become insulin-positive. In contrast, laminin hydrogel is sufficient to support the development of pancreatic Dark colonies that express insulin. Postnatal liver CFU-Dark display a cell surface marker CD133⁺CD49f(low)CD107b(low) phenotype, while pancreatic CFU-Dark are CD133⁻. Together, these results demonstrate that specific progenitor cells in the postnatal liver and pancreas are capable of developing into insulin-expressing colonies, but they differ in frequency, marker expression, and matrix protein requirements for growth.


How does music aid 5 km of running?
This research investigated the effects of music and its time of application on a 5-km run. Fifteen well-trained male long-distance runners (24.87 ± 2.47 years; 78.87 ± 10.57 kg; 178 ± 07 cm) participated in this study. Five randomized experimental conditions during a 5-km run on an official track were tested (PM: motivational songs, applied before 5 km of running; SM: slow motivational songs, applied during 5 km of running; FM: fast and motivational songs, applied during 5 km of running; CS: calm songs, applied after 5 km of running; CO: control condition). Psychophysiological assessments were performed before (functional near-infrared spectroscopy, heart rate variability [HRV], valence, and arousal), during (performance time, heart rate, and rate of perceived exertion [RPE]), and after (mood, RPE, and HRV) tests. The chosen songs were considered pleasurable and capable of activating. Furthermore, they activated the 3 assessed prefrontal cortex (PFC) areas (medial, right dorsolateral, and left dorsolateral) similarly, generating positive emotional consequences by autonomous system analysis. The first 800 m was accomplished faster for SM and FM compared with other conditions (p ≤ 0.05); moreover, there was a high probability of improving running performance when music was applied (SM: 89%; FM: 85%; PM: 39%). Finally, music was capable of accelerating vagal tonus after 5 km of running with CS (p ≤ 0.05). In conclusion, music was able to activate the PFC area, minimize perceptions, improve performance, and accelerate recovery during 5 km of running.


RNAi microarray analysis in cultured mammalian cells.
RNA interference (RNAi) mediated by small interfering RNAs (siRNAs) is a powerful new tool for analyzing gene knockdown phenotypes in living mammalian cells. To facilitate large-scale, high-throughput functional genomics studies using RNAi, we have developed a microarray-based technology for highly parallel analysis. Specifically, siRNAs in a transfection matrix were first arrayed on glass slides, overlaid with a monolayer of adherent cells, incubated to allow reverse transfection, and assessed for the effects of gene silencing by digital image analysis at a single cell level. Validation experiments with HeLa cells stably expressing GFP showed spatially confined, sequence-specific, time- and dose-dependent inhibition of green fluorescence for those cells growing directly on microspots containing siRNA targeting the GFP sequence. Microarray-based siRNA transfections analyzed with a custom-made quantitative image analysis system produced results that were identical to those from traditional well-based transfection, quantified by flow cytometry. Finally, to integrate experimental details, image analysis, data display, and data archiving, we developed a prototype information management system for high-throughput cell-based analyses. In summary, this RNAi microarray platform, together with ongoing efforts to develop large-scale human siRNA libraries, should facilitate genomic-scale cell-based analyses of gene function.


EEG oscillations reflect visual short-term memory processes for the change detection in human faces.
People often fail to notice a large change in the visual scene when the change occurs during a brief interruption of the viewing. Since the change is well above perceptual threshold in continuous viewing, the failure (termed change blindness) has been attributed to abnormal visual short-term memory (VSTM). However, it is still unclear where the abnormality lies among the phases in VSTM, namely, encoding, maintenance, and retrieval-comparison. EEG oscillations, especially the gamma activity, have been suggested as neural signatures of VSTM, but have not been examined in the context of change blindness. Thus, we asked in the present study whether change detection or failure is correlated with EEG oscillatory activities and, if so, whether the timing and the spatial distribution of the oscillations could pin-point the abnormal phase of VSTM in change blindness. While on EEG recording, subjects watched morphed pictures of human faces in trials which consisted of a 200-ms initial image display, a 500-ms blank period, and a 200-ms comparison image display. The two images were either the same or clearly different above threshold. Trials with different images were classified as hit or missed, based on subjects' responses, and EEG data were compared between the two types of trials. Enhanced gamma activity was observed in the right temporal-parietal region during all periods in the hit trials compared to the missed ones. Frontal theta activity was increased during initial image encoding, whereas beta activity was decreased during maintenance and retrieval-comparison in the hit trials. These results point to weak encoding of initial images as the culprit for a later failure in change detection, while abnormal processing in subsequent phases of VSTM may result from the weak encoding and also contribute to change blindness.


Modelling the co-evolution of indirect genetic effects and inherited variability.
When individuals interact, their phenotypes may be affected not only by their own genes but also by genes in their social partners. This phenomenon is known as Indirect Genetic Effects (IGEs). In aquaculture species and some plants, however, competition not only affects trait levels of individuals, but also inflates variability of trait values among individuals. In the field of quantitative genetics, the variability of trait values has been studied as a quantitative trait in itself, and is often referred to as inherited variability. Such studies, however, consider only the genetic effect of the focal individual on trait variability and do not make a connection to competition. Although the observed phenotypic relationship between competition and variability suggests an underlying genetic relationship, the current quantitative genetic models of IGE and inherited variability do not allow for such a relationship. The lack of quantitative genetic models that connect IGEs to inherited variability limits our understanding of the potential of variability to respond to selection, both in nature and agriculture. Models of trait levels, for example, show that IGEs may considerably change heritable variation in trait values. Currently, we lack the tools to investigate whether this result extends to variability of trait values. Here we present a model that integrates IGEs and inherited variability. In this model, the target phenotype, say growth rate, is a function of the genetic and environmental effects of the focal individual and of the difference in trait value between the social partner and the focal individual, multiplied by a regression coefficient. The regression coefficient is a genetic trait, which is a measure of cooperation; a negative value indicates competition, a positive value cooperation, and an increasing value due to selection indicates the evolution of cooperation. In contrast to the existing quantitative genetic models, our model allows for co-evolution of IGEs and variability, as the regression coefficient can respond to selection. Our simulations show that the model results in increased variability of body weight with increasing competition. When competition decreases, i.e., cooperation evolves, variability becomes significantly smaller. Hence, our model facilitates quantitative genetic studies on the relationship between IGEs and inherited variability. Moreover, our findings suggest that we may have been overlooking an entire level of genetic variation in variability, the one due to IGEs.


Security analysis of a double-image encryption technique based on an asymmetric algorithm.
In this paper, we evaluate the security of a double-image encryption technique based on an asymmetric algorithm. Compared with traditional cryptosystems based on a phase-truncated Fourier transform, the technique is able to improve the security of the encryption by combining a joint transform correlator; consequently, the encryption scheme is immune to some common attacks. We propose a special attack based on a phase retrieval algorithm with median filtering and normalization operation to break the cryptosystem. Low key sensitivity of a position parameter set has been found and an additional constraint is utilized to improve the attack to simplify the process and further decrease the computational time. Numerical simulation results show that the cryptosystem is vulnerable to the proposed special attack.


Development of "Imprint-and-Report" Dynamic Combinatorial Libraries for Differential Sensing Applications.
Sensor arrays using synthetic receptors have found great utility in analyte detection, resulting from their ability to distinguish analytes based on differential signals via indicator displacement. However, synthesis and characterization of receptors for an array remain a bottleneck in the field. Receptor discovery has been streamlined using dynamic combinatorial libraries (DCLs), but the resulting receptors have primarily been utilized in isolation rather than as part of the entire library, with only a few examples that make use of the complexity of a library of receptors. Herein, we demonstrate a unique sensor array approach using "imprint-and-report" DCLs that obviates the need for receptor synthesis and isolation. This strategy leverages information stored in DCLs in the form of differential library speciation to provide a high-throughput method for both developing a sensor array and analyzing data for analyte differentiation. First, each DCL is templated with analyte to give an imprinted library, followed by in situ fluorescent indicator displacement analysis. We further demonstrate that the reverse strategy, imprinting with the fluorescent reporter followed by displacement with each analyte, provides a more sensitive method for differentiating analytes. We describe the development of this differential sensing system using the methylated Arg and Lys post-translational modifications (PTMs). Altogether, 19 combinations of 3-5 DCL data sets that discriminate all 7 PTMs were identified. Thus, a comparable sensor array workflow results in a larger payoff due to the immense information stored within multiple noncovalent networks.


Adaptation and sensitization to proteotoxic stress.
Although severe stress can elicit toxicity, mild stress often elicits adaptations. Here we review the literature on stress-induced adaptations versus stress sensitization in models of neurodegenerative diseases. We also describe our recent findings that chronic proteotoxic stress can elicit adaptations if the dose is low but that high-dose proteotoxic stress sensitizes cells to subsequent challenges. In these experiments, long-term, low-dose proteasome inhibition elicited protection in a superoxide dismutase-dependent manner. In contrast, acute, high-dose proteotoxic stress sensitized cells to subsequent proteotoxic challenges by eliciting catastrophic loss of glutathione. However, even in the latter model of synergistic toxicity, several defensive proteins were upregulated by severe proteotoxicity. This led us to wonder whether high-dose proteotoxic stress can elicit protection against subsequent challenges in astrocytes, a cell type well known for their resilience. In support of this new hypothesis, we found that the astrocytes that survived severe proteotoxicity became harder to kill. The adaptive mechanism was glutathione dependent. If these findings can be generalized to the human brain, similar endogenous adaptations may help explain why neurodegenerative diseases are so delayed in appearance and so slow to progress. In contrast, sensitization to severe stress may explain why defenses eventually collapse in vulnerable neurons.


Strain distribution pattern of susceptibility to immune-mediated nephritis.
The genetic basis of immune-mediated nephritis is poorly understood. Recent studies have demonstrated that the NZW mouse strain is more prone to immune-mediated nephritis compared with C57BL/6 and BALB/c strains. The present study extends these findings by challenging 12 additional inbred strains of mice with rabbit anti-mouse glomerular basement membrane (GBM) reactive sera. Compared with control sera-injected mice and anti-GBM-injected A/J, AKR/J, C3H/HeJ, DBA/2J, MRL/MpJ, NOD/LtJ, P/J, SJL/J, and SWR/J mice, the anti-GBM-injected BUB/BnJ, DBA/1J, and 129/svJ mice developed severe proteinuria and azotemia. Their kidneys exhibited pronounced glomerulonephritis, with crescent formation, as well as tubulointerstitial disease, with these phenotypes being particularly profound in 129/svJ mice. However, these strains did not appear to differ in the nature of their xenogeneic immune response to the administered rabbit sera, either quantitatively or qualitatively. Collectively, these findings allude to the presence of genetic elements in the BUB/BnJ, DBA/1J, and 129/svJ genomes that may potentially confer susceptibility to immune-mediated nephritis. Detailed studies to dissect out the immunological and genetic basis of renal disease in these three strains are clearly warranted.


Hakenmethode.
The experimental technique and the general theory of the hakenmethode (hook method or dispersion method) is reviewed. The review presents the basic experimental arrangement for the formation of hooks in a crossed interferometer-spectrometer system and the experimental parameters of importance of an f-value measurement by the hakenmethode. The significance of the complex index of refraction of a dispersive and dissipative medium and its relation to the hakenmethode technique, as applied to single- and multiple-line spectra is described in some detail. Penkin's total absorption method for measuring absolute f values by combining the hakenmethode with absorption measurements is reviewed. A method (similar to a Voigt profile analysis) is introduced for studying the formation of hooks about spectral lines whose absorption widths may be an appreciable fraction of the hook separation.


Medication for attention deficit-hyperactivity disorder and criminality.
Attention deficit-hyperactivity disorder (ADHD) is a common disorder that has been associated with criminal behavior in some studies. Pharmacologic treatment is available for ADHD and may reduce the risk of criminality. Using Swedish national registers, we gathered information on 25,656 patients with a diagnosis of ADHD, their pharmacologic treatment, and subsequent criminal convictions in Sweden from 2006 through 2009. We used stratified Cox regression analyses to compare the rate of criminality while the patients were receiving ADHD medication, as compared with the rate for the same patients while not receiving medication. As compared with nonmedication periods, among patients receiving ADHD medication, there was a significant reduction of 32% in the criminality rate for men (adjusted hazard ratio, 0.68; 95% confidence interval [CI], 0.63 to 0.73) and 41% for women (hazard ratio, 0.59; 95% CI, 0.50 to 0.70). The rate reduction remained between 17% and 46% in sensitivity analyses among men, with factors that included different types of drugs (e.g., stimulant vs. nonstimulant) and outcomes (e.g., type of crime). Among patients with ADHD, rates of criminality were lower during periods when they were receiving ADHD medication. These findings raise the possibility that the use of medication reduces the risk of criminality among patients with ADHD. (Funded by the Swedish Research Council and others.).


Thymic stromal lymphopoietin-mediated epicutaneous inflammation promotes acute diarrhea and anaphylaxis.
Atopic dermatitis (AD) and food allergy are closely linked; however, the mechanisms that guide the progression of AD to allergic inflammatory responses at other mucosal surfaces, including the gastrointestinal tract, are not well understood. Here, we determined that exposure of mice that have been epicutaneously sensitized with thymic stromal lymphopoietin (TSLP) and antigen to repeated oral doses of the same antigen induced acute diarrhea and anaphylaxis. In this model, loss of TSLP signaling specifically in DCs led to loss of induced allergic diarrhea through lack of sensitization. While TSLP responses were not required during oral allergen challenge, CD4(+) T cells were required and transferred disease when introduced into naive hosts. In addition, oral exposure to the antigen prior to skin sensitization blocked development of allergic disease. Finally, mice lacking the receptor for IL-25 failed to develop acute diarrhea and anaphylaxis, highlighting a role for IL-25 in the initiation of type 2 immunity in the intestine. These results demonstrate a role for TSLP and IL-25 in the atopic march from skin sensitization to food allergic responses and provide a model system for the generation of potential therapeutic interventions.


Health benefits of fruits and vegetables.
Fruits and vegetables are universally promoted as healthy. The Dietary Guidelines for Americans 2010 recommend you make one-half of your plate fruits and vegetables. Myplate.gov also supports that one-half the plate should be fruits and vegetables. Fruits and vegetables include a diverse group of plant foods that vary greatly in content of energy and nutrients. Additionally, fruits and vegetables supply dietary fiber, and fiber intake is linked to lower incidence of cardiovascular disease and obesity. Fruits and vegetables also supply vitamins and minerals to the diet and are sources of phytochemicals that function as antioxidants, phytoestrogens, and antiinflammatory agents and through other protective mechanisms. In this review, we describe the existing dietary guidance on intake of fruits and vegetables. We also review attempts to characterize fruits and vegetables into groups based on similar chemical structures and functions. Differences among fruits and vegetables in nutrient composition are detailed. We summarize the epidemiological and clinical studies on the health benefits of fruits and vegetables. Finally, we discuss the role of fiber in fruits and vegetables in disease prevention.


Life Cycle Greenhouse Gas Emissions for Last-Mile Parcel Delivery by Automated Vehicles and Robots.
Increased E-commerce and demand for contactless delivery during the COVID-19 pandemic have fueled interest in robotic package delivery. We evaluate life cycle greenhouse gas (GHG) emissions for automated suburban ground delivery systems consisting of a vehicle (last-mile) and a robot (final-50-feet). Small and large cargo vans (125 and 350 cubic feet; V125 and V350) with an internal combustion engine (ICEV) and battery electric (BEV) powertrains were assessed for three delivery scenarios: (i) conventional, human-driven vehicle with human delivery; (ii) partially automated, human-driven vehicle with robot delivery; and (iii) fully automated, connected automated vehicle (CAV) with robot delivery. The robot's contribution to life cycle GHG emissions is small (2-6%). Compared to the conventional scenario, full automation results in similar GHG emissions for the V350-ICEV but 10% higher for the V125-BEV. Conventional delivery with a V125-BEV provides the lowest GHG emissions, 167 g CO2e/package, while partially automated delivery with a V350-ICEV generates the most at 486 g CO2e/package. Fuel economy and delivery density are key parameters, and electrification of the vehicle and carbon intensity of the electricity have a large impact. CAV power requirements and efficiency benefits largely offset each other, and automation has a moderate impact on life cycle GHG emissions.


Adjusting family relatedness in data-driven burden test of rare variants.
Family data represent a rich resource for detecting association between rare variants (RVs) and human traits. However, most RV association analysis methods developed in recent years are data-driven burden tests which can adaptively learn weights from data but require permutation to evaluate significance, thus are not readily applicable to family data, because random permutation will destroy family structure. Direct application of these methods to family data may result in a significant inflation of false positives. To overcome this issue, we have developed a generalized, weighted sum mixed model (WSMM), and corresponding computational techniques that can incorporate family information into data-driven burden tests, and allow adaptive and efficient permutation test in family data. Using simulated and real datasets, we demonstrate that the WSMM method can be used to appropriately adjust for genetic relatedness among family members and has a good control for the inflation of false positives. We compare WSMM with a nondata-driven, family-based Sequence Kernel Association Test (famSKAT), showing that WSMM has significantly higher power in some cases. WSMM provides a generalized, flexible framework for adapting different data-driven burden tests to analyze data with any family structures, and it can be extended to binary and time-to-onset traits, with or without covariates.


Large differences in neonatal drug use between NICUs are common practice: time for consensus?
Evidence for drug use in newborns is sparse, which may cause large differences in drug prescriptions. We aimed to investigate the differences between neonatal intensive care units (NICUs) in the Netherlands in currently prescribed drugs. This multicentre study included neonates admitted during 12 months to four different NICUs. Drugs were classified in accordance with the Anatomical Therapeutic Chemical (ATC) classification system and assessed for on/off-label status in relation to neonatal age. The treatment protocols for four common indications for drug use were compared: pain, intubation, convulsions and hypotension. A total of 1491 neonates (GA range 23+6 -42+2 weeks) were included with a total of 32 182 patient days, 181 different drugs and 10 895 prescriptions of which 23% was off-label in relation to neonatal age. Overall, anti-infective drugs were most frequently used with a total of 3161 prescriptions, of which 4% was off-label in relation to neonatal age. Nervous system drugs included 2500 prescriptions of which 31% was off-label in relation to neonatal age. Nervous system drugs, blood and blood forming organs, and cardiovascular drugs showed the largest differences between NICUs with ranges of 919-2278, 554-1465, and 238-952 total prescriptions per 1000 patients per ATC class, respectively. We showed that drug use varies widely in neonatal clinical practice. The drug classes with the highest proportion of off-label drugs in relation to neonatal age showed the largest differences between NICUs, i.e. cardiovascular and nervous system drugs. Drug research in neonates should receive high priority to guarantee safe and appropriate medicines and optimal treatment.


Oxidative stability of marine phospholipids in the liposomal form and their applications.
Marine phospholipids (MPL) have attracted a great deal of attention recently as they are considered to have a better bioavailability, a better resistance towards oxidation and a higher content of eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) than oily triglycerides (fish oil) from the same source. Due to their tight intermolecular packing conformation at the sn-2 position and their synergism with α-tocopherol present in MPL extracts, they can form stable liposomes which are attractive ingredients for food or feed applications. However, MPL are still susceptible to oxidation as they contain large amounts polyunsaturated fatty acids and application of MPL in food and aquaculture industries is therefore a great challenge for researchers. Hence, knowledge on the oxidative stability of MPL and the behavior of MPL in food and feed systems is an important issue. For this reason, this review was undertaken to provide the industry and academia with an overview of (1) the stability of MPL in different forms and their potential as liposomal material, and (2) the current applications and future prospects of MPL in both food and aquaculture industries with special emphasis on MPL in the liposomal form.


Sonographic assessment of carotid atherosclerosis: preferred risk indicator for future cardiovascular events?
Carotid ultrasound allows rapid and reliable quantification of atherosclerosis in humans. Although the definition of carotid plaque is not uniform, intimal thickening of at least 1.5 mm is currently defined as plaque. Plaque can be easily quantified by tracing the plaque area, a software-independent low-cost technique. More sophisticated quantifications involve 3D volume acquisitions, which is software-dependent and not widely available. Carotid plaque has a higher prognostic impact than intimal thickening, and carotid plaque volume showed comparable prognostic power to coronary calcifications. According to the latest European Joint ESC guidelines, carotid artery scanning should be considered for adjusting the level of risk especially in intermediate-risk subjects. There are various methods to incorporate results from imaging into clinical decision making, such as using arterial age instead of chronological age in risk equations or post-test risk calculations using the sensitivity and the specificity of the results from a given carotid plaque burden. In subjects with low or intermediate cardiovascular risk, the search for atherosclerosis may be appropriate and ultrasound of the carotid or the femoral arteries could be the primary method applied (depending on local expertise). Assessment of carotid total plaque presence, progression, stability and regression over time may be a valuable clinical tool for optimising the intensity of preventive therapies.


Is central obesity, hyperinsulinemia and dyslipidemia associated with high-grade prostate cancer? A descriptive cross-sectional study.
The association of central obesity, hyperinsulinemia, and dyslipidemia with higher grade advanced prostate cancer as determined by Gleason grading is not well understood. We evaluated the effect of central obesity waist hip ratio (WHR ≥ 0.9) and biochemical parameters associated with central obesity on Gleason grading in North Indian patients of prostate cancer presenting at advanced stages. A cross-sectional study was conducted among 50 nondiabetic patients having clinical stages III and IV prostate cancer. Gleason grading on core biopsy samples by histopathology was done and patients were divided in two groups-group1, Gleason score ≥8; group 2, Gleason score <8. WHR along with serum levels of prostate-specific antigen (PSA), testosterone, insulin, and lipid profile was done in each patient. The two groups are similar in Age (67.54 years); range (50-80 years). Group 1 men had statistically higher mean WHR (0.96 vs 0.90; P ≤ 0.001), higher mean triglyceride level (201.34 vs 150.52 mg/dL; P=0.0006), higher mean very low-density lipoprotein (VLDL) (40.27 vs 30.10 mg/dL; P =0.0006), higher mean insulin (19.49 vs 15.04 μIU/mL; P = 0.0024), and lower mean high-density lipoprotein (HDL) levels (32.39 vs 36.82 mg/dL; P = 0.034) than men in group 2. Serum levels of cholesterol, LDL, and testosterone did not show statistically significant differences between the two groups. This pilot study involving small number of patients indicates that central obesity, dyslipidemia, and hyperinsulinemia could be associated with high-grade prostate cancer.


Prevention of relapse after quitting smoking: a systematic review of trials.
After initially successful quit attempts, many people return to smoking within a year, reducing the public health benefits of investment in smoking cessation. We aimed to assess whether interventions designed to prevent relapse after a successful quit attempt reduce the proportion of recent quitters who return to smoking. We searched the Cochrane Tobacco Addiction Review Group trials' register. We selected randomized or quasi-randomized controlled trials of relapse prevention interventions with a minimum follow-up of 6 months. We included people who quit on their own, underwent enforced abstinence, or were in treatment programs. We included trials comparing relapse prevention interventions with no intervention or cessation plus relapse prevention with cessation intervention alone. Two of us independently extracted data from each report, with disagreements referred to a third author. Forty-two studies met the inclusion criteria. The most common interventions were skills training to identify and resolve tempting situations and extended treatment contact. A few studies tested pharmacotherapy. We separately analyzed studies that randomized abstainers and those that randomized participants before their quit date. Within subgroups of trials, pooled odds ratios ranged from 0.86 to 1.30, and in most analyses, 95% confidence intervals included 1. Most studies had limited power to detect moderate differences between interventions. The evidence to date does not support the adoption of skills training or other specific interventions to help individuals who have successfully quit smoking to avoid relapse, but this is an important area for future study.


Family History of Breast Cancer, Breast Density, and Breast Cancer Risk in a U.S. Breast Cancer Screening Population.
Background: The utility of incorporating detailed family history into breast cancer risk prediction hinges on its independent contribution to breast cancer risk. We evaluated associations between detailed family history and breast cancer risk while accounting for breast density.Methods: We followed 222,019 participants ages 35 to 74 in the Breast Cancer Surveillance Consortium, of whom 2,456 developed invasive breast cancer. We calculated standardized breast cancer risks within joint strata of breast density and simple (1st-degree female relative) or detailed (first-degree, second-degree, or first- and second-degree female relative) breast cancer family history. We fit log-binomial models to estimate age-specific breast cancer associations for simple and detailed family history, accounting for breast density.Results: Simple first-degree family history was associated with increased breast cancer risk compared with no first-degree history [Risk ratio (RR), 1.5; 95% confidence interval (CI), 1.0-2.1 at age 40; RR, 1.5; 95% CI, 1.3-1.7 at age 50; RR, 1.4; 95% CI, 1.2-1.6 at age 60; RR, 1.3; 95% CI, 1.1-1.5 at age 70). Breast cancer associations with detailed family history were strongest for women with first- and second-degree family history compared with no history (RR, 1.9; 95% CI, 1.1-3.2 at age 40); this association weakened in higher age groups (RR, 1.2; 95% CI, 0.88-1.5 at age 70). Associations did not change substantially when adjusted for breast density.Conclusions: Even with adjustment for breast density, a history of breast cancer in both first- and second-degree relatives is more strongly associated with breast cancer than simple first-degree family history.Impact: Future efforts to improve breast cancer risk prediction models should evaluate detailed family history as a risk factor. Cancer Epidemiol Biomarkers Prev; 26(6); 938-44. ©2017 AACR.


Neuroprotective properties of RT10, a fraction isolated from Parawixia bistriata spider venom, against excitotoxicity injury in neuron-glia cultures.
L-Glutamate (L-Glu), the major excitatory neurotransmitter in the mammalian Central Nervous System (CNS), is essential to cognitive functions. However, when L-Glu is accumulated in large concentrations at the synaptic cleft, it can induce excitotoxicity that results in secondary damage implicated in many neurological disorders. Current therapies for the treatment of neurological disorders are ineffective and have side effects associated with their use; therefore, there is a need to develop novel treatments. In this regard, previous studies have shown that neuroactive compounds obtained from the venom of the spider Parawixia bistriata have neuroprotective effects in vitro and in vivo. In this sense, this work aimed to evaluate potential neuroprotective effects of fraction RT10, obtained from this spider venom, on primary cultures of neuron and glial cells subjected to glutamate excitotoxicity insults. Primary cultures of neurons and glia were obtained from the cerebral tissue of 1-day-old postnatal Wistar rats. After 7 days in vitro (DIV), the cultures were incubated with fraction RT10 (0.002; 0.02; 0.2 and 2 µg/µL) or riluzole (100 µM) for 3-hours before application of 5 mM L-Glu. After 12 hours, the resazurin sodium salt (RSS) test was applied to measure metabolic activity and proliferation of living cells, whereas immunocytochemistry for MAP2 was performed to measure neuronal survival. In addition, the cells were immunolabeled with NeuN and GFAP in baseline conditions. In the RSS tests, we observed that pre-incubation with RT10 before the excitotoxic insults from L-Glu resulted in neuroprotection, shown by a 10% reduction in the cell death level. RT10 was more effective than riluzole, which resulted in a cell-death reduction of 5%. Moreover, qualitative analysis of neuronal morphology (by MAP2 staining, expressed as fluorescence intensity (FI), an indirect measure of neuronal survival) indicate that RT10 reduced the toxic effects of L-Glu, as shown by a 38 % increase in MAP2 fluorescence when compared to L-Glu insult. On the other hand, the riluzole treatment resulted in 17% increase of MAP2 fluorescence; therefore, the neuroprotection from RT10 was more efficacious. RT10 fraction exhibits neuroprotective effects against L-Glu excitotoxicity in neuron-glia cultured in vitro.


Hepatitis syndrome in infancy--an epidemiological survey with 10 year follow up.
Fifty four infants with hepatobiliary disease and conjugated hyperbilirubinaemia of more than two weeks' duration were identified in a defined area of south east England in a prospective study between January 1971 and December 1973. The overall incidence was one case per 2500 live births. The cases were regularly reviewed and all survivors except one were assessed at age 10 years. Nine of 11 with extrahepatic biliary atresia died from liver disease by 2 years of age, one died at 5 years, and the survivor has cirrhosis with portal hypertension. Four out of seven with alpha 1 antitrypsin deficiency died aged 1 to 3 years from liver disease and one of the survivors has cirrhosis. All three infants with intrauterine infection and one with chromosomal abnormality died in infancy. Three children with other associated factors, choledochal cyst, galactosaemia, and rhesus isoimmunisation, recovered completely with no persisting liver disease. Two of 29 with cryptogenic hepatitis died, but only a further two have signs of persisting liver disease. Perinatal complications were more common in this group. Four of the 27 children surviving to the age of 10 years are educationally subnormal. Prognosis for infants with intrahepatic liver disease in the absence of known associated factors is good and every effort should be made to minimise the short term effects of cholestasis.


Dynamic causal modelling of effective connectivity from fMRI: are results reproducible and sensitive to Parkinson's disease and its treatment?
Dynamic causal modelling (DCM) of functional magnetic resonance imaging (fMRI) data offers new insights into the pathophysiology of neurological disease and mechanisms of effective therapies. Current applications can be used both to identify the most likely functional brain network underlying observed data and estimate the networks' connectivity parameters. We examined the reproducibility of DCM in healthy subjects (young 18-48 years, n=27; old 50-80 years, n=15) in the context of action selection. We then examined the effects of Parkinson's disease (50-78 years, Hoehn and Yahr stage 1-2.5, n=16) and dopaminergic therapy. Forty-eight models were compared, for each of 90 sessions from 58 subjects. Model-evidences clustered according to sets of structurally similar models, with high correlations over two sessions in healthy older subjects. The same model was identified as most likely in healthy controls on both sessions and in medicated patients. In this most likely network model, the selection of action was associated with enhanced coupling between prefrontal cortex and the pre-supplementary motor area. However, the parameters for intrinsic connectivity and contextual modulation in this model were poorly correlated across sessions. A different model was identified in patients with Parkinson's disease after medication withdrawal. In "off" patients, action selection was associated with enhanced connectivity from prefrontal to lateral premotor cortex. This accords with independent evidence of a dopamine-dependent functional disconnection of the SMA in Parkinson's disease. Together, these results suggest that DCM model selection is robust and sensitive enough to study clinical populations and their pharmacological treatment. For critical inferences, model selection may be sufficient. However, caution is required when comparing groups or drug effects in terms of the connectivity parameter estimates, if there are significant posterior covariances among parameters.


Antibody-drug conjugates plus Janus kinase inhibitors enable MHC-mismatched allogeneic hematopoietic stem cell transplantation.
Despite the curative potential of hematopoietic stem cell transplantation (HSCT), conditioning-associated toxicities preclude broader clinical application. Antibody-drug conjugates (ADCs) provide an attractive approach to HSCT conditioning that minimizes toxicity while retaining efficacy. Initial studies of ADC conditioning have largely focused on syngeneic HSCT. However, to treat acute leukemias or induce tolerance for solid organ transplantation, this approach must be expanded to allogeneic HSCT (allo-HSCT). Using murine allo-HSCT models, we show that pharmacologic Janus kinase 1/2 (JAK1/2) inhibition combined with CD45- or cKit-targeted ADCs enables robust multilineage alloengraftment. Strikingly, myeloid lineage donor chimerism exceeding 99% was achievable in fully MHC-mismatched HSCT using this approach. Mechanistic studies using the JAK1/2 inhibitor baricitinib revealed marked impairment of T and NK cell survival, proliferation, and effector function. NK cells were exquisitely sensitive to JAK1/2 inhibition due to interference with IL-15 signaling. Unlike irradiated mice, ADC-conditioned mice did not develop pathogenic graft-versus-host alloreactivity when challenged with mismatched T cells. Finally, the combination of ADCs and baricitinib balanced graft-versus-host disease and graft-versus-leukemia responses in delayed donor lymphocyte infusion models. Our allo-HSCT conditioning strategy exemplifies the promise of immunotherapy to improve the safety of HSCT for treating hematologic diseases.


Anticholinergic Drug Exposure and the Risk of Dementia: There Is Modest Evidence for an Association but Not for Causality.
Many observational studies published during the past 15 years have found an association between anticholinergic drug exposure and the risk of incident dementia. Animal data suggest plausible causal mechanisms for this finding. The results of a recent, large, and well-conducted study on the subject were widely disseminated by the lay and scientific media. This study addressed protopathic bias by examining anticholinergic drug exposure in time windows 1-11, 3-13, and 5-20 years before the identification of dementia. In brief, the study found that, pooling anticholinergic drug exposure across 11 drug categories, exposure in smallest to largest cumulative dosing groups was significantly associated with incident dementia risk, with an apparently dose-dependent relationship in unadjusted as well as adjusted analyses in all time windows prior to dementia identification. Whereas these findings appear compelling, there are at least 4 elephants in the room. First, only 3 of 11 anticholinergic drug categories were consistently associated with an increased risk of dementia; this suggests that anticholinergic activity may be an irrelevant common denominator. Second, for 2 of these 3 categories (antidepressant and antipsychotic drugs), confounding by indication seemed a distinct possibility. Third, in many analyses it seemed that exposure for as little as the equivalent of 1-90 days sufficed to increase the risk of dementia at a time interval of up to 20 years later; a causal mechanism here would need to have strong neurotoxic effects to result in the widespread brain changes that characterize dementia. Finally, the associations were almost uniformly stronger for vascular dementia than for Alzheimer's disease, making the identification of a causal mechanism even more challenging. Deprescribing anticholinergics to reduce state-dependent cognitive impairment, or to reduce the risk of delirium in vulnerable demographic and medical populations, is reasonable. Deprescribing anticholinergics to reduce the risk of future dementia is presently unwarranted.


Identification of putative c-Myc-responsive genes: characterization of rcl, a novel growth-related gene.
The c-Myc protein is a helix-loop-helix leucine zipper oncogenic transcription factor that participates in the regulation of cell proliferation, differentiation, and apoptosis. The biochemical function of c-Myc has been well described, yet the identities of downstream effectors are just beginning to emerge. We describe the identification of a set of c-Myc-responsive genes in the Rat1a fibroblast through the application of cDNA representational difference analysis (RDA) to cDNAs isolated from nonadherent Rat1a and Rat1a-myc cells. In this system, c-Myc overexpression is sufficient to induce the transformed phenotype of anchorage-independent growth. We identified 20 differentially expressed cDNAs, several of which represent novel cDNA sequences. We further characterized one of the novel cDNAs identified in this screen, termed rcl. rcl expression is (i) directly stimulated by c-Myc; (ii) stimulated in the in vivo growth system of regenerating rat liver, as is c-myc; and (iii) elevated in human lymphoid cells that overexpress c-myc. By using an anti-Rcl antibody, immunoblot analysis, and immunofluorescence microscopy, the Rcl protein was found to be a 23-kDa nuclear protein. Ectopic expression of the protein encoded by the rcl cDNA induces anchorage-independent growth in Rat1a fibroblasts, albeit to a diminished extent compared to ectopic c-Myc expression. These data suggest a role for rcl during cellular proliferation and c-Myc-mediated transformation.


Applying Criteria of Active Surveillance to Low-Risk Papillary Thyroid Cancer Over a Decade: How Many Surgeries and Complications Can Be Avoided?
The 2015 American Thyroid Association guidelines acknowledged that "an active surveillance management approach can be considered as an alternative to immediate surgery" in patients with low-risk papillary thyroid carcinoma (PTC). The aim of this study was to determine the proportion of PTC that would meet the criteria for active surveillance and the surgeries and complications that could have been avoided. A total of 681 patients with thyroid cancer who underwent thyroid surgery from 2003 to 2012 were retrospectively reviewed. A decision-making framework for active surveillance was applied to patients with PTC in nodules measuring ≤1.5 cm on ultrasound. Patients were identified as suitable for active surveillance based on imaging and patient characteristics. These patients were reviewed for management and outcomes. PTC was diagnosed based on fine-needle aspiration histology of Bethesda V or VI in thyroid nodules in 243 patients. Of these, 77 patients had nodules measuring ≤1.5 cm on ultrasound, and 56/77 (23%) patients met the criteria for surveillance: 15/243 (6%) patients met the criteria with a ≤1 cm size threshold, and 41/243 (17%) met the criteria with a 1.1-1.5 cm threshold. Of the 56 patients who met the criteria for active surveillance, 52 underwent total thyroidectomy, and four had a lobectomy. Forty-five (80%) patients had elective central nodal dissection, and 14 had nodal metastases on pathology (all <4 mm). Three patients had permanent complications from surgery, including vocal cord paralysis, hypoparathyroidism, and a chipped tooth from intubation. No patients died or had recurrent disease. Future programs in the United States should consider increasing the size threshold for active surveillance of PTC to 1.5 cm, since this will allow up to one quarter of patients to be eligible instead of only 6% with a 1 cm size threshold. Without an active surveillance program, the majority of patients with low-risk cancers have thyroidectomy and carry a small risk of permanent complications.