Patterns of sore mouth in outpatients with cancer receiving chemotherapy.
The aims of this secondary data analysis were to (a) categorize patterns in the development, duration, intensity, and resolution of sore mouth (which can be considered a proxy for oral mucositis) severity and distress over two cycles of chemotherapy in cancer outpatients and (b) examine the relationship of demographic (age, gender, marital status, and educational level) and disease characteristics (type of cancer and type of chemotherapy) to specific patterns of sore mouth (SM). Visual graphical analysis (VGA) was applied to identify individual patterns of SM severity and distress in 51 outpatients receiving chemotherapy who provided daily reports of sore mouth using a computerized interactive voice response system. The majority were female (n = 41, 8%) with a mean age of 53 (SD = 8.35). Most had breast cancer (68%), and one third received chemotherapy with adriamycin and cyclophosphamide (AC). VGA is a technique in which graphs of individual patients' symptoms are coded for specific individual or group profiles. Seven distinct patterns were identified based on variability in onset, duration, and intensity (degree of severity or distress). Chemotherapy agents were significantly associated with patterns of SM. The AC regimen was significantly associated with late onset; however, the intensity did not last long. In contrast, patients receiving R-CHOP were significantly more likely to experience duration intensity (SM after day 15 and a score equal to or greater than a 5 on a 1-10 scale). VGA revealed symptom patterns often hidden in traditional analysis. Understanding individual variability is important to the design and implementation of future intervention research and clinical care.


Heartbeat-enhanced immersive virtual reality to treat complex regional pain syndrome.
To develop and test a new immersive digital technology for complex regional pain syndrome (CRPS) that combines principles from mirror therapy and immersive virtual reality and the latest research from multisensory body processing. In this crossover double-blind study, 24 patients with CRPS and 24 age- and sex-matched healthy controls were immersed in a virtual environment and shown a virtual depiction of their affected limb that was flashing in synchrony (or in asynchrony in the control condition) with their own online detected heartbeat (heartbeat-enhanced virtual reality [HEVR]). The primary outcome measures for pain reduction were subjective pain ratings, force strength, and heart rate variability (HRV). HEVR reduced pain ratings, improved motor limb function, and modulated a physiologic pain marker (HRV). These significant improvements were reliable and highly selective, absent in control HEVR conditions, not observed in healthy controls, and obtained without the application of tactile stimulation (or movement) of the painful limb, using a readily available biological signal (the heartbeat) that is most often not consciously perceived (thus preventing placebo effects). Next to these specific and well-controlled analgesic effects, immersive HEVR allows the application of prolonged and repeated doses of digital therapy, enables the automatized integration with existing pain treatments, and avoids application of painful bodily cues while minimizing the active involvement of the patient and therapist. This study provides Class III evidence that HEVR reduces pain and increases force strength in patients with CRPS.


The identification of novel ovarian proteases through the use of genomic and bioinformatic methodologies.
Proteolytic activities are essential for follicular growth, ovulation, as well as for luteal formation and regression. Using suppression subtractive hybridization (SSH), a novel mouse ovary-selective gene (termed protease serine 35, Prss35) was identified. Analysis of the mouse genome database using the Prss35 sequence led to the identification of a homologous protease (protease serine 23, Prss23). PRSS35 possesses general features that are characteristic of serine (Ser) proteases, but is unique in that the canonical Ser that defines this enzyme family is replaced by a threonine (Thr). In contrast, PRSS23 possesses the standard catalytic Ser typical for this family of proteases. As determined by real-time polymerase chain reaction (PCR), the Prss35 mRNA levels increased around the time of ovulation and remained elevated in the developing corpus luteum. Steroid ablation/replacement studies demonstrated progesterone-dependent regulation of Prss35 gene expression prior to follicle rupture. Prss35 gene expression was localized to the theca cells of pre-antral follicles, the theca and granulosa cells of pre-ovulatory and ovulatory follicles, as well as to the developing corpus luteum. In contrast, Prss23 mRNA levels decreased transiently after ovulation induction and again in the postovulatory period. Prss23 gene expression was noted primarily in the granulosa cells of the secondary/early antral follicles. PRSS35 and PRSS23 orthologs in the rat, human, rhesus macaque, chimpanzee, cattle, dog, and chicken were identified and found to be highly homologous to one another (75-99% homology). Collectively, these results suggest that the PRSS35 and PRSS23 genes have been conserved as critical ovarian proteases throughout the course of vertebrate evolution.


Ion Current Rectification and Long-Range Interference in Conical Silicon Micropores.
Fluidic devices exhibiting ion current rectification (ICR), or ionic diodes, are of broad interest for applications including desalination, energy harvesting, and sensing, among others. For such applications a large conductance is desirable, which can be achieved by simultaneously using thin membranes and wide pores. In this paper we demonstrate ICR in micrometer sized conical channels in a thin silicon membrane with pore diameters comparable to the membrane thickness but both much larger than the electrolyte screening length. We show that for these pores the entrance resistance is key not only to Ohmic conductance around 0 V but also for understanding ICR, both of which we measure experimentally and capture within a single analytic theoretical framework. The only fit parameter in this theory is the membrane surface potential, for which we find that it is voltage dependent and its value is excessively large compared to the literature. From this we infer that surface charge outside the pore strongly contributes to the observed Ohmic conductance and rectification by a different extent. We experimentally verify this hypothesis in a small array of pores and find that ICR vanishes due to pore-pore interactions mediated through the membrane surface, while Ohmic conductance around 0 V remains unaffected. We find that the pore-pore interaction for ICR is set by a long-ranged decay of the concentration which explains the surprising finding that the ICR vanishes for even a sparsely populated array with a pore-pore spacing as large as 7 μm.


The role of Twist1 in mutant huntingtin-induced transcriptional alterations and neurotoxicity.
Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an abnormal expansion of polyglutamine repeats in the huntingtin protein (Htt). Transcriptional dysregulation is an early event in the course of HD progression and is thought to contribute to disease pathogenesis, but how mutant Htt causes transcriptional alterations and subsequent cell death in neurons is not well understood. RNA-Seq analysis revealed that expression of a mutant Htt fragment in primary cortical neurons leads to robust gene expression changes before neuronal death. Basic helix-loop-helix transcription factor Twist1, which is essential for embryogenesis and is normally expressed at low levels in mature neurons, was substantially up-regulated in mutant Htt-expressing neurons in culture and in the brains of HD mouse models. Knockdown of Twist1 by RNAi in mutant Htt-expressing primary cortical neurons reversed the altered expression of a subset of genes involved in neuronal function and, importantly, abrogated neurotoxicity. Using brain-derived neurotrophic factor (Bdnf), which is known to be involved in HD pathogenesis, as a model gene, we found that Twist1 knockdown could reverse mutant Htt-induced DNA hypermethylation at the Bdnf regulatory region and reactivate Bdnf expression. Together, these results suggest that Twist1 is an important upstream mediator of mutant Htt-induced neuronal death and may in part operate through epigenetic mechanisms.


Robust optimization of intensity modulated proton therapy.
Intensity modulated proton therapy (IMPT) is highly sensitive to range uncertainties and uncertainties caused by setup variation. The conventional inverse treatment planning of IMPT optimized based on the planning target volume (PTV) is not often sufficient to ensure robustness of treatment plans. In this paper, a method that takes the uncertainties into account during plan optimization is used to mitigate the influence of uncertainties in IMPT. The authors use the so-called "worst-case robust optimization" to render IMPT plans robust in the face of uncertainties. For each iteration, nine different dose distributions are computed-one each for ± setup uncertainties along anteroposterior (A-P), lateral (R-L) and superior-inferior (S-I) directions, for ± range uncertainty, and the nominal dose distribution. The worst-case dose distribution is obtained by assigning the lowest dose among the nine doses to each voxel in the clinical target volume (CTV) and the highest dose to each voxel outside the CTV. Conceptually, the use of worst-case dose distribution is similar to the dose distribution achieved based on the use of PTV in traditional planning. The objective function value for a given iteration is computed using this worst-case dose distribution. The objective function used has been extended to further constrain the target dose inhomogeneity. The worst-case robust optimization method is applied to a lung case, a skull base case, and a prostate case. Compared with IMPT plans optimized using conventional methods based on the PTV, our method yields plans that are considerably less sensitive to range and setup uncertainties. An interesting finding of the work presented here is that, in addition to reducing sensitivity to uncertainties, robust optimization also leads to improved optimality of treatment plans compared to the PTV-based optimization. This is reflected in reduction in plan scores and in the lower normal tissue doses for the same coverage of the target volume when subjected to uncertainties. The authors find that the worst-case robust optimization provides robust target coverage without sacrificing, and possibly even improving, the sparing of normal tissues. Our results demonstrate the importance of robust optimization. The authors assert that all IMPT plans should be robustly optimized.


In organello formaldehyde crosslinking of proteins to mtDNA: identification of bifunctional proteins.
The segregating unit of mtDNA is a protein-DNA complex called the nucleoid. In an effort to understand how nucleoid proteins contribute to mtDNA organization and inheritance, we have developed an in organello formaldehyde crosslinking procedure to identify proteins associated with mtDNA. Using highly purified mitochondria, we observed a time-dependent crosslinking of protein to mtDNA as determined by sedimentation through isopycnic cesium chloride gradients. We detected approximately 20 proteins crosslinked to mtDNA and identified 11, mostly by mass spectrometry. Among them is Abf2p, an abundant, high-mobility group protein that is known to function in nucleoid morphology, and in mtDNA transactions. In addition to several other proteins with known DNA binding properties or that function in mtDNA maintenance, we identified other mtDNA-associated proteins that were not anticipated, such as the molecular chaperone Hsp60p and a Krebs cycle protein, Kgd2p. Genetic experiments indicate that hsp60-ts mutants have a petite-inducing phenotype at the permissive temperature and that a kgd2Delta mutation increases the petite-inducing phenotype of an abf2Delta mutation. Crosslinking and DNA gel shift experiments show that Hsp60p binds to single-stranded DNA with high specificity for the template strand of a putative origin of mtDNA replication. These data identify bifunctional proteins that participate in the stability of rho(+) mtDNA.


Generating realistic in silico gene networks for performance assessment of reverse engineering methods.
Reverse engineering methods are typically first tested on simulated data from in silico networks, for systematic and efficient performance assessment, before an application to real biological networks. In this paper, we present a method for generating biologically plausible in silico networks, which allow realistic performance assessment of network inference algorithms. Instead of using random graph models, which are known to only partly capture the structural properties of biological networks, we generate network structures by extracting modules from known biological interaction networks. Using the yeast transcriptional regulatory network as a test case, we show that extracted modules have a biologically plausible connectivity because they preserve functional and structural properties of the original network. Our method was selected to generate the "gold standard" networks for the gene network reverse engineering challenge of the third DREAM conference (Dialogue on Reverse Engineering Assessment and Methods 2008, Cambridge, MA).


Gadofosveset-enhanced magnetic resonance angiography of the thoracic vasculature in the equilibrium phase: feasibility and impact of dose.
The objectives of this study were to evaluate the feasibility of gadofosveset-enhanced magnetic resonance angiography (MRA) of the thoracic vasculature in the equilibrium phase and to determine the impact of gadofosveset dose on imaging quality. Thirty healthy volunteers were randomized to receive a dose of 0.03, 0.02, or 0.01 mmol/kg of gadofosveset for MRA at 3 T in the equilibrium phase. Two radiologists assessed the central veins, the pulmonary arteries, and the thoracic aorta. Quantitative assessments were also performed. At 0.03 and 0.02 mmol/kg, all vessel segments were rated as adequate. At a dose of 0.01 mmol/kg, less than 10% of vascular segments were collectively rated as inadequate. The signal-to-noise ratio and contrast-to-noise ratio were significantly lower in all segments at 0.01 mmol/kg compared with higher doses. Gadofosveset-enhanced MRA of the thoracic vessels in the equilibrium phase in healthy volunteers resulted in adequate vessel visualization, even when dose reduction was performed.This trial was registered with clinicaltrials.gov, identifier NCT01431300.


High-resolution BOLD venographic imaging: a window into brain function.
This paper reviews the recent development of a new high-resolution magnetic resonance imaging approach to visualizing small veins in the human brain with diameters in the sub-millimeter range, which is smaller than a voxel. It briefly introduces the physical background of the underlying bulk magnetic susceptibility effects, on which this approach is based, and it demonstrates the successful application of the method for imaging different intracranial lesions, like venous anomalies, arteriovenous malformations and brain tumors. The susceptibility difference between venous blood and the surrounding tissue is used to generate contrast. Using this method it is possible to visualize draining veins in lesions better than conventional magnetic resonance imaging methods, which often require application of a contrast medium or even conventional catheter angiography. Limitations of the method are discussed. The ability to highlight deoxygenated blood with high spatial resolution yields important vascular parameters which may be helpful for improved modeling of MR signal changes during functional brain activation, it may lead to a better understanding of brain function in diseased states, or it may even offer the possibility of differentiating benign from malignant tumors non-invasively.


Regression of herpes viral infection symptoms using melatonin and SB-73: comparison with Acyclovir.
Infection with Herpes simplex virus type 1 (HSV-1) typically causes lesions of the mouth, face, skin, esophagus, or brain. Herpes simplex virus type 2 (HSV-2) usually causes infections of the genitals, rectum, skin, hands, or meninges. The herpes viruses are a major cause of blindness from keratitis. The usual drugs used for herpes are Vidarabine, Acyclovir, Penciclovir and Ganciclovir; they are associated with several complications. The aim of this study was to investigate if a formulation containing 2.5 mg melatonin and 100 mg SB-73 would help patients with herpes, and to compare the preparation with 200 mg Acyclovir. SB-73 is a mixture of magnesium, phosphate, fatty acids extracted from Aspergillus sp. which has anti-herpes virus properties. A single blind randomized study was performed in which 70 patients underwent treatment using the supplement cited above (group A) and 75 received treatment of 200 mg Acyclovir (group B). Sixty-seven patients of the group A (95.7%) reported a complete regression of symptoms after 7 days of treatment. By comparison, 64 subjects (85.3%) of the Acyclovir reported regression of symptoms in the same period. There was statiscally significant difference between the groups (P < 0.05).


Implicit theories about willpower predict self-regulation and grades in everyday life.
Laboratory research shows that when people believe that willpower is an abundant (rather than highly limited) resource they exhibit better self-control after demanding tasks. However, some have questioned whether this "nonlimited" theory leads to squandering of resources and worse outcomes in everyday life when demands on self-regulation are high. To examine this, we conducted a longitudinal study, assessing students' theories about willpower and tracking their self-regulation and academic performance. As hypothesized, a nonlimited theory predicted better self-regulation (better time management and less procrastination, unhealthy eating, and impulsive spending) for students who faced high self-regulatory demands. Moreover, among students taking a heavy course load, those with a nonlimited theory earned higher grades, which was mediated by less procrastination. These findings contradict the idea that a limited theory helps people allocate their resources more effectively; instead, it is people with the nonlimited theory who self-regulate well in the face of high demands.


Ensuring mobility-supporting environments for an aging population: critical actors and collaborations.
Successful aging takes on an array of attributes, including optimal health and community participation. Research indicates that (1) persons with disabilities, including age-related disabilities, report frequent barriers to community participation, including unsuitable building design (43%), transportation (32%), and sidewalks/curbs (31%), and (2) many seniors report an inability to cross roads safely near their homes. This paper attempts to define mobility-related elements that contribute to optimal health and quality of life, within the context of successful aging. It then examines the impacts of community design on individual mobility, delving into which traditional and nontraditional actors-including architects, urban planners, transportation engineers, occupational therapists, and housing authorities-play critical roles in ensuring that community environments serve as facilitators (rather than barriers) to mobility. As America ages, mobility challenges for seniors will only increase unless both traditional aging specialists and many nontraditional actors make a concerted effort to address the challenges.


Primary Progressive Aphasia Associated With GRN Mutations: New Insights Into the Nonamyloid Logopenic Variant.
To determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated with GRN (progranulin) mutations and to study their neuroanatomic correlates. Patients with PPA carrying GRN mutations (PPA-GRN) were selected among a national prospective research cohort of 1,696 patients with frontotemporal dementia, including 235 patients with PPA. All patients with amyloid-positive CSF biomarkers were excluded. In this cross-sectional study, speech/language and cognitive profiles were characterized with standardized evaluations, and gray matter (GM) atrophy patterns using voxel-based morphometry. Comparisons were performed with controls and patients with sporadic PPA. Among the 235 patients with PPA, 45 (19%) carried GRN mutations, and we studied 32 of these. We showed that logopenic PPA (lvPPA) was the most frequent linguistic variant (n = 13, 41%), followed by nonfluent/agrammatic (nfvPPA; n = 9, 28%) and mixed forms (n = 8, 25%). Semantic variant was rather rare (n = 2, 6%). Patients with lvPPA, qualified as nonamyloid lvPPA, presented canonical logopenic deficit. Seven of 13 had a pure form; 6 showed subtle additional linguistic deficits not fitting criteria for mixed PPA and hence were labeled as logopenic-spectrum variant. GM atrophy involved primarily left posterior temporal gyrus, mirroring neuroanatomic changes of amyloid-positive-lvPPA. Patients with nfvPPA presented agrammatism (89%) rather than apraxia of speech (11%). This study shows that the most frequent PPA variant associated with GRN mutations is nonamyloid lvPPA, preceding nfvPPA and mixed forms, and illustrates that the language network may be affected at different levels. GRN testing is indicated for patients with PPA, whether familial or sporadic. This finding is important for upcoming GRN gene-specific therapies.


Abnormal DNA Methylation in Thoracic Spinal Cord Tissue Following Transection Injury.
BACKGROUND Spinal cord injury (SCI) is a serious disease with high disability and mortality rates, with no effective therapeutic strategies available. In SCI, abnormal DNA methylation is considered to be associated with axonal regeneration and cell proliferation. However, the roles of key genes in potential molecular mechanisms of SCI are not clear. MATERIAL AND METHODS Subacute spinal cord injury models were established in Wistar rats. Histological observations and motor function assessments were performed separately. Whole-genome bisulfite sequencing (WGBS) was used to detect the methylation of genes. Gene ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed using the DAVID database. Protein-protein interaction (PPI) networks were analyzed by Cytoscape software. RESULTS After SCI, many cavities, areas of necrotic tissue, and many inflammatory cells were observed, and motor function scores were low. After the whole-genome bisulfite sequencing, approximately 96 DMGs were screened, of which 50 were hypermethylated genes and 46 were hypomethylated genes. KEGG pathway analysis highlighted the Axon Guidance pathway, Endocytosis pathway, T cell receptor signaling pathway, and Hippo signaling pathway. Expression patterns of hypermethylated genes and hypomethylated genes detected by qRT-PCR were the opposite of WGBS data, and the difference was significant. CONCLUSIONS Abnormal methylated genes and key signaling pathways involved in spinal cord injury were identified through histological observation, behavioral assessment, and bioinformatics analysis. This research can serve as a source of additional information to expand understanding of spinal cord-induced epigenetic changes.


Automatic recognition of gait patterns exhibiting patellofemoral pain syndrome using a support vector machine approach.
Patellofemoral pain syndrome (PFPS) is a common disorder that afflicts people across all age groups, and results in various degrees of knee pain. The diagnosis of PFPS is difficult since the exact biomechanical factors and the extent to which they are affected by the disorder are still unknown. Recent research has reported significant statistical differences in ground reaction forces (GRFs) and foot kinematics, which could be indicative of PFPS, but the interrelationship between many of these measures and the pathology have been absent so far. In this paper, we applied the support vector machines (SVMs) to detect PFPS gait based on 14 GRF and 16 foot kinematic features recorded from 27 subjects (14 healthy and 13 with PFPS). The influence of combined gait parameters on classification performance was investigated through the use of a feature-selection algorithm. The optimal feature set was then compared against the most statistically significant individual features (p < 0.05) found by previous study. Test results indicated that GRF features alone resulted in a higher leave-one-out (LOO) classification accuracy (85.15%) compared to 74.07% using only kinematic features. A hill-climbing feature-selection algorithm was applied to determine the subset of combined kinematic and kinetic features, which provided optimal classifier performance. This subset, which consists of six features (two from GRF and four from foot kinematic features), provided an improved LOO accuracy of 88.89% . The optimal feature set detected by the SVM, which best identified gait characteristics of PFPS, was found to be closely related to inferential statistical analysis with the added distinction that the SVM could potentially be deployed as an automated system for detecting gait changes in patients with PFPS.


A quantitative analysis of the maturation of steroid negative feedbacks controlling gonadotropin release in the female rat: the infantile-juvenile periods, transition from an androgenic to a predominantly estrogenic control.
To determine what ovarian or adrenal steroid(s) are involved in restraining gonadotropin secretion in infantile female rats, several experiments were performed. Adrenalectomy of 10-day-old rats markedly decreased serum progesterone (P) and, to a lesser extent, serum estradiol (E2) levels. Androgen (A) levels were only transiently reduced, and serum dihydrotestosterone was not affected. Serum LH and FSH, on the other hand, increased only transiently after adrenalectomy. Ovariectomy (OVX) failed to decrease serum P and partially depressed serum E2, but resulted in a marked fall of both testosterone (T) and dihydrotestosterone. Serum LH and FSH were increased in these animals. Replacement of pre-OVX serum T levels via Silastic capsules prevented the postcastration rise in both LH and FSH, suggesting that the increase in gonadotropins that follows OVX of 10-day-old rats is, to a large extent, a consequence of the loss of ovarian T. OVX of juvenile (27 days old) rats increased serum FSH and LH 48 h later and reduced both serum T and E2 levels, with no significant change in serum P. Replacement of pre-OVX serum T levels depressed post-OVX serum FSH and LH titers only partially. In contrast, replacement of pre-OVX serum E2 levels, effectively suppressed the postcastration rise in serum gonadotropins. The results suggest that 1) during the infantile period, gonadotropin release is predominantly under ovarian androgenic inhibitory control, but this mechanism is not very effective, because basal serum gonadotropin levels, particularly FSH, are elevated; 2) the effectiveness of the A negative feedback on FSH remains unchanged during prepubertal development; and 3) the previously reported increase in E2 negative feedback effectiveness that occurs after day 15 results in an E2 inhibitory signal that surpasses that of As, so that during juvenile days, most of the ovarian steroidal inhibitory control on gonadotropin release is mediated by E2.


Cognitive Training for Post-Acute Traumatic Brain Injury: A Systematic Review and Meta-Analysis.
Objective: To quantitatively aggregate effects of cognitive training (CT) on cognitive and functional outcome measures in patients with traumatic brain injury (TBI) more than 12-months post-injury. Design: We systematically searched six databases for non-randomized and randomized controlled trials of CT in TBI patients at least 12-months post-injury reporting cognitive and/or functional outcomes. Main Measures: Efficacy was measured as standardized mean difference (Hedges' g) of post-training change. We investigated heterogeneity across studies using subgroup analyses and meta-regressions. Results: Fourteen studies encompassing 575 patients were included. The effect of CT on overall cognition was small and statistically significant (g = 0.22, 95%CI 0.05 to 0.38; p = 0.01), with low heterogeneity (I2 = 11.71%) and no evidence of publication bias. A moderate effect size was found for overall functional outcomes (g = 0.32, 95%CI 0.08 to 0.57, p = 0.01) with low heterogeneity (I2 = 14.27%) and possible publication bias. Statistically significant effects were also found only for executive function (g = 0.20, 95%CI 0.02 to 0.39, p = 0.03) and verbal memory (g = 0.32, 95%CI 0.14 to 0.50, p < 0.01). Conclusion: Despite limited studies in this field, this meta-analysis indicates that CT is modestly effective in improving cognitive and functional outcomes in patients with post-acute TBI and should therefore play a more significant role in TBI rehabilitation.


How do metal ions direct ribozyme folding?
Ribozymes, which carry out phosphoryl-transfer reactions, often require Mg(2+) ions for catalytic activity. The correct folding of the active site and ribozyme tertiary structure is also regulated by metal ions in a manner that is not fully understood. Here we employ coarse-grained molecular simulations to show that individual structural elements of the group I ribozyme from the bacterium Azoarcus form spontaneously in the unfolded ribozyme even at very low Mg(2+) concentrations, and are transiently stabilized by the coordination of Mg(2+) ions to specific nucleotides. However, competition for scarce Mg(2+) and topological constraints that arise from chain connectivity prevent the complete folding of the ribozyme. A much higher Mg(2+) concentration is required for complete folding of the ribozyme and stabilization of the active site. When Mg(2+) is replaced by Ca(2+) the ribozyme folds, but the active site remains unstable. Our results suggest that group I ribozymes utilize the same interactions with specific metal ligands for both structural stability and chemical activity.


Factors that introduce intrasubject variability into ear-canal absorbance measurements.
Wideband immittance measures can be useful in analyzing acoustic sound flow through the ear and also have diagnostic potential for the identification of conductive hearing loss as well as causes of conductive hearing loss. To interpret individual measurements, the variability in test–retest data must be described and quantified. Contributors to variability in ear-canal absorbance–based measurements are described in this article. These include assumptions related to methodologies and issues related to the probe fit within the ear and potential acoustic leaks. Evidence suggests that variations in ear-canal cross-sectional area or measurement location are small relative to variability within a population. Data are shown to suggest that the determination of the Thévenin equivalent of the ER-10C probe introduces minimal variability and is independent of the foam ear tip itself. It is suggested that acoustic leaks in the coupling of the ear tip to the ear canal lead to substantial variations and that this issue needs further work in terms of potential criteria to identify an acoustic leak. In addition, test–retest data from the literature are reviewed.


An exploratory study to test the impact on three "bolt-on" items to the EQ-5D.
Generic preference-based measures were criticized for being inappropriate in some conditions. One solution is to include "bolt-on" dimensions describing additional specific health problems. This study aimed to develop bolt-on dimensions to the EuroQol five-dimensional questionnaire (EQ-5D) and assess their impact on health state values. Bolt-on dimensions were developed for vision problems, hearing problems, and tiredness. Each bolt-on dimension had three severity levels to match the EQ-5D. Three "core" EQ-5D states across a range of severity were selected, and each level of a bolt-on item was added, resulting in nine states in each condition. Health states with and without the bolt-on dimensions were valued by 300 members of the UK general public using time trade-off in face-to-face interviews, and mean health state values were compared using t tests. Regression analysis examined the impact of the bolt-on variants and the level of the bolt-on items after controlling for sociodemographic characteristics. Bolt-on dimensions had an impact on health state values of the EQ-5D; however, the size, direction, and significance of the impact depend on the severity of the core EQ-5D state and of the bolt-on dimension. Regression analysis demonstrated that after controlling for possible differences in sociodemographic characteristics between the groups, there were no significant differences in health state values between the three bolt-on dimensions but confirmed that the impact depended on the severity of the EQ-5D health state and the levels of bolt-on dimensions. The impact of a bolt-on dimension on the EQ-5D depends on the core health state and the level of the bolt-on dimension. Further research in this area is encouraged.


The existence of the vomeronasal organ in postnatal chimpanzees and evidence for its homology with that of humans.
It is currently thought that New World monkeys, prosimians, and humans are the only primates to possess vomeronasal organs (VNOs) as adults. Recent studies of the human VNO suggest that previous investigations on Old World primates may have missed the VNO. We examined nasal septa from the chimpanzee (Pan troglodytes) grossly and histologically for comparison with nasal septa from humans, Old World monkeys (Macaca fascicularis, M. nemistrina) and prosimian primates (Microcebus murinus, Otolemur garnettii). Grossly, chimpanzees had depressions on the nasal septum similar to fossae reported anterior to the VNO openings in humans. Histologically, chimpanzees and humans had bilateral epithelial tubes which were above the superior margin of the paraseptal cartilages (vomeronasal cartilage homologue). The epithelial tubes had a homogeneous ciliated epithelium. These structures were thus positionally and structurally identical to the human VNO and unlike the well-developed prosimian VNOs which were surrounded by vomeronasal cartilage. Macaques had no structures which resembled the VNO of either the prosimians or humans. The results demonstrate that the VNO is present postnatally in the chimpanzee and is almost identical to the human VNO in its anatomical position and histological structure. This in turn suggests that the reported absence of the VNO in at least some adult Old World primates is artifactual, and that further study may provide evidence for its existence in other species.


The small nucleoid protein Fis is involved in Vibrio cholerae quorum sensing.
Quorum sensing is a process of cell-cell communication that bacteria use to relay information to one another about the cell density and species composition of the bacterial community. Quorum sensing involves the production, secretion and population-wide detection of small signalling molecules called autoinducers. This process allows bacteria to synchronize group behaviours and act as multicellular units. The human pathogen, Vibrio cholerae, uses quorum sensing to co-ordinate such complex behaviours as pathogenicity and biofilm formation. The quorum-sensing circuit of V. cholerae consists of two autoinducer/sensor systems, CAI-1/CqsS and AI-2/LuxPQ, and the VarS/A-CsrA/BCD growth-phase regulatory system. Genetic analysis suggests that an additional regulatory arm involved in quorum sensing exists in V. cholerae. All of these systems channel information into the histidine phosphotransfer protein, LuxU, and/or the response regulator, LuxO. LuxO, when phosphorylated, activates the expression of four genes encoding the Qrr (quorum regulatory RNAs) small RNAs (sRNAs). The Qrr sRNAs destabilize the hapR transcript encoding the master regulator of quorum sensing, HapR. Here we identify the nucleoid protein Fis as playing a major role in the V. cholerae quorum-sensing circuit. Fis fulfils the predictions required to be the putative additional component that inputs information into the cascade: its expression is regulated in a growth phase-dependent manner; it requires LuxO but acts independently of LuxU, and it regulates all four qrr genes and, in turn, HapR by directly binding to the qrr gene promoters and modulating their expression.


Nuclear Targeting with an Auger Electron Emitter Potentiates the Action of a Widely Used Antineoplastic Drug.
We present the combination of the clinically well-proven chemotherapeutic agent, Doxorubicin, and (99m)Tc, an Auger and internal conversion electron emitter, into a dual-action agent for therapy. Chemical conjugation of Doxorubicin to (99m)Tc afforded a construct which autonomously ferries a radioactive payload into the cell nucleus. At this site, damage is exerted by dose deposition from Auger radiation. The (99m)Tc-conjugate exhibited a dose-dependent inhibition of survival in a selected panel of cancer cells and an in vivo study in healthy mice evidenced a biodistribution which is comparable to that of the parent drug. The homologous Rhenium conjugate was found to effectively bind to DNA, inhibited human Topoisomerase II, and exhibited cytotoxicity in vitro. The collective in vitro and in vivo data demonstrate that the presented metallo-conjugates closely mimic native Doxorubicin.


Evidence for the involvement of two areas of the zebra finch forebrain in sexual imprinting.
Sexual imprinting in male zebra finches is a two-step process, including an acquisition period early in life and a stabilization process normally occuring during the first courtship attempts of the male. During the acquisition period, a young male learns about its social environment. During stabilization, which can be delayed experimentally until day 100, it develops a preference for the appropriate object for courtship behavior on the basis of its previous and acute experience. Thereafter, this preference cannot be altered again. Exploring the physiological basis for imprinting, we have previously shown that the neurons of two forebrain areas (ANC and HAD) increase their spine density in the course of the stabilization process, while in two other areas (MNH and LNH) a decrease of spine density can be observed. With the present experiments, we tested the idea that the spine density decrease in MNH and LNH is the anatomical manifestation of the imprinting process. Previous behavioral experiments have shown that exposure to a nestbox after 100 days of age stabilizes the sexual preference of a zebra finch male as well as does exposure to a female. The present study shows that nestbox exposure also reduces the spine density in MNH and LNH, but has no effect on ANC and HAD. It has also been shown previously that treating males with an antiandrogen between days 40 and 100 affects the final preference of a male. The present experiment indicates that the same treatment affects spine growth during development in MNH and LNH and prevents the increase of spine density within HAD and ANC normally induced by exposure to a female. The results are interpreted as strong evidence for the involvement of MNH and LNH in sexual imprinting.


Retinal vessel pathologies in a rat model of periventricular leukomalacia: a new model for retinopathy of prematurity?
To characterize concurrent retinal vessel pathologies reminiscent to retinopathy of prematurity (ROP) in a rat model of periventricular leukomalacia (PVL), in order to identify uniform damage pathways in both organs, the eye and the brain. Ischemia was induced in Long Evans rat pups on postnatal day 6 (P6) with unilateral (left side) carotid ligation (UCL) followed by exposure to different oxygen concentrations. Four different groups were studied: group A, hypoxia/ischemia (UCL + 6% O2, 1 hour); group B, hyperoxia (80% O2, 24 hours); group C, hypoxia/ischemia + hyperoxia (UCL + 6% O2, 1 hour + 80% O2, 24 hours); and group D, normoxia. In groups A and C, both retinae were examined separately (left retina, group A [A-L], right retina, group A [A-R]; left retina, group C [C-L], right retina, group C [C-R]). Morphologic analysis of vessel development based on flatmounts and cryosections was performed at P11 and P21. Quantitative (q)PCR was performed at P7, P11, and P21 (VEGF-A164, HIF-1α, EpoR, TNFα, iNOS, BMP-9, and IGF-1). On flatmounts, distinct retardation in deeper vascular plexus development was observed, most prominent in A-L and C-L. Retinae of groups A-L and C-L displayed reduced capillary-free zones and an increased number of branching points at P11. Quantitative PCR analysis showed significantly different expression profiles of IGF-1 in A-L and B compared with D over the time course of the experiment. This is the first report on concurring damage to the retina that was evaluated in a rat model of white matter injury in the developing brain. The relatively mild damage to the retinal vessel system may represent the basis for a model of moderate forms of ROP and to study vascular remodeling.


Electroconvulsive therapy, depression severity and mortality: Data from the Danish National Patient Registry.
The effects of electroconvulsive therapy are usually estimated from changes in depression scales from studies with relatively small patient samples. Larger patient samples can be achieved from epidemiological registers, which provide information on other social and clinical predictors, results and risks. To examine whether depression severity predicts the use of electroconvulsive therapy, risk of re-hospitalization, suicidal behaviour and mortality following electroconvulsive therapy in patients with major depression. A cohort of 92,895 patients diagnosed with single or recurrent depression between 2005 and 2016 in the Danish National Patient Registry was followed for electroconvulsive therapy and adverse outcomes. Associations between electroconvulsive therapy and outcomes were analysed using Cox regression. A total of 5004 (5.4%) patients were treated with electroconvulsive therapy. Depression severity was the strongest predictor of electroconvulsive therapy. Electroconvulsive therapy was used more frequently above age 70, in those better educated or married, whereas comorbid alcohol abuse or history of prior stroke at study entry were associated with lower rates. Electroconvulsive therapy was associated with lower mortality. The adjusted hazard ratio for the association between electroconvulsive therapy and suicide in patients with mild depression was 6.99 (3.30-14.43), whereas it was 1.10 (0.55-2.20) in those with severe depression and psychotic symptoms. A similar pattern was seen for emergency contacts and attempted suicide. Electroconvulsive therapy was associated with lower all-cause mortality and the relative risk for re-hospitalization and attempted and committed suicide was lowest in patients with the most severe depression. Electroconvulsive therapy is an important treatment, with significant public health benefits, for patients with severe depression.


MicroRNA-208a increases myocardial fibrosis via endoglin in volume overloading heart.
MicroRNA-208a (mir-208a) is essential for cardiac hypertrophy and fibrosis. Endoglin, a co-receptor of transforming growth factor-β is also essential for cardiac fibrosis. Endoglin has been shown to be a target of mir-208a in the in vitro mechanical stress model. Volume overload can lead to heart failure and cardiac fibrosis. The role of mir-208a and endoglin in volume overload heart failure is well known. We sought to investigate the mechanism of regulation of mir-208a and endoglin in volume overload-induced heart failure. Aorta-caval (AV) shunt was performed in adult Sprague-Dawley rats to induce volume overload. Heart weight and heart weight/body weight ratio significantly increased in AV shunt animals. AV shunt significantly increased left ventricular end-diastolic dimension as compared to sham group. Mir-208a was significantly induced by AV shunt from 3 to 14 days. Endoglin, myosin heavy chain-β and brain natriuretic peptide were significantly induced by AV shunt from 3 to 14 days. Overexpression of mir-208a in the sham group without AV shunt significantly increased endoglin expression similar to the AV shunt group. Antagomir-208a attenuated the endoglin expression induced by AV shunt. Pretreatment with atorvastatin also attenuated the endoglin expression induced by AV shunt. AV shunt significantly increased myocardial fibrosis as compared to sham group. Overexpression of mir-208a in the sham group significantly increased myocardial fibrosis. Antagomir-208a and atorvastatin significantly attenuated the myocardial fibrosis induced by AV shunt. In conclusion, mir-208a increased endoglin expression to induce myocardial fibrosis in volume overloaded heart failure. Treatment with atorvastatin can attenuate the myocardial fibrosis induced by volume overload through inhibition of endoglin expression.


A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol.
This study examines the current knowledge of physiological and clinical effects of tetrahydrocannabinol (THC) and cannabidiol (CBD) and presents a rationale for their combination in pharmaceutical preparations. Cannabinoid and vanilloid receptor effects as well as non-receptor mechanisms are explored, such as the capability of THC and CBD to act as anti-inflammatory substances independent of cyclo-oxygenase (COX) inhibition. CBD is demonstrated to antagonise some undesirable effects of THC including intoxication, sedation and tachycardia, while contributing analgesic, anti-emetic, and anti-carcinogenic properties in its own right. In modern clinical trials, this has permitted the administration of higher doses of THC, providing evidence for clinical efficacy and safety for cannabis based extracts in treatment of spasticity, central pain and lower urinary tract symptoms in multiple sclerosis, as well as sleep disturbances, peripheral neuropathic pain, brachial plexus avulsion symptoms, rheumatoid arthritis and intractable cancer pain. Prospects for future application of whole cannabis extracts in neuroprotection, drug dependency, and neoplastic disorders are further examined. The hypothesis that the combination of THC and CBD increases clinical efficacy while reducing adverse events is supported.


With a little help from my friends?: racial and gender differences in the role of social support in later-life depression medication adherence.
Social support has been shown to be an important factor in improving depression symptom outcomes, yet less is known regarding its impact on antidepressant medication adherence. This study sought to evaluate the role of perceived social support on adherence to new antidepressant medication prescriptions in later-life depression. Data from two prospective observational studies of participants ≥60 years old, diagnosed with depression, and recently prescribed a new antidepressant (N = 452). Perceived social support was measured using a subscale of the Duke Social Support Index and medication adherence was assessed using a validated self-report measure. At four-month follow up, 68% of patients reported that they were adherent to antidepressant medication. Examining the overall sample, logistic regression analysis demonstrated no significant relationship between perceived social support and medication adherence. However, when stratifying the sample by social support, race, and gender, adherence significantly differed by race and gender in those with inadequate social support: Among those with low social support, African-American females were significantly less likely to adhere to depression treatment than white females (OR = 4.82, 95% CI = 1.14-20.28, p = 0.032) and white males (OR = 3.50, 95% CI = 1.03-11.92, p = 0.045). There is a significant difference in antidepressant medication adherence by race and gender in those with inadequate social support. Tailored treatment interventions for low social support should be sensitive to racial and gender differences.


Use of Chinese herbal medicines by rheumatoid arthritis patients was associated with lower risk of stroke: A retrospective cohort study.
Rheumatoid arthritis (RA) patients have increased risk of developing stroke. The use Chinese herbal medicines (CHMs) is increasing, but whether they can reduce the risk of developing stroke remains unclear. We conducted a longitudinal cohort study to compare the effect of CHMs use on the subsequent stroke risk in RA individuals. Using claims data from the National Health Insurance of Taiwan, we identified 7925 newly-diagnosed RA patients with no history of previous stroke who were 20 years of age or older between 1998 and 2010. From this sample, we enrolled 3134 CHMs users and 3134 non-CHMs users, randomly selected using propensity scores matching from the remaining cases. They were followed until the end of 2012 to record stroke incidence. A Cox proportional hazards regression model was used to compute the hazard ratio of stroke with regard to CHMs use. During the follow-up, 299 CHMs users and 395 non-CHMs users developed stroke, representing incidence rates of 10.94 and 16.69, respectively, per 1000 person-years. CHMs use was associated with 38% (adjusted HR: 0.62; 95% confidence interval: 0.54-0.73) lower subsequent risk of stroke. The most prominent effect was observed in those receiving CHMs for over two years. The following seven commonly-prescribed CHMs were found to lessen the stroke risk: Dan-Shen, Tian-Hua-Feng, Fu-Zi, Shao-Yao-Gan-Cao-Tang, Jia-Wei-Xiao-Yao-San, Ge-Gen-Tang, and Gui-Zhi-Shao-Yao-Zhi-Mu-Tang. The CHMs use was associated with lower risk of stroke for RA patients, suggesting that it could be integrated into conventional therapy to prevent subsequent stroke incident.


Continuous separation of breast cancer cells from blood samples using multi-orifice flow fractionation (MOFF) and dielectrophoresis (DEP).
Circulating tumor cells (CTCs) are highly correlated with the invasive behavior of cancer, so their isolations and quantifications are important for biomedical applications such as cancer prognosis and measuring the responses to drug treatments. In this paper, we present the development of a microfluidic device for the separation of CTCs from blood cells based on the physical properties of cells. For use as a CTC model, we successfully separated human breast cancer cells (MCF-7) from a spiked blood cell sample by combining multi-orifice flow fractionation (MOFF) and dielectrophoretic (DEP) cell separation technique. Hydrodynamic separation takes advantage of the massive and high-throughput filtration of blood cells as it can accommodate a very high flow rate. DEP separation plays a role in precise post-processing to enhance the efficiency of the separation. The serial combination of these two different sorting techniques enabled high-speed continuous flow-through separation without labeling. We observed up to a 162-fold increase in MCF-7 cells at a 126 µL min(-1) flow rate. Red and white blood cells were efficiently removed with separation efficiencies of 99.24% and 94.23% respectively. Therefore, we suggest that our system could be used for separation and detection of CTCs from blood cells for biomedical applications.


Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic stenosis.
Mutations in the Notch pathway ligand Jagged1 (JAG1) cause Alagille syndrome (AGS), as well as cardiac defects in seemingly nonsyndromic individuals. To estimate the frequency of JAG1 mutations in cases with right-sided cardiac defects not otherwise diagnosed with AGS, we screened 94 cases with tetralogy of Fallot (TOF) and 50 with pulmonic stenosis/peripheral pulmonary stenosis (PS/PPS) or pulmonary valve atresia with intact ventricular septum (PA) for mutations. Sequence changes were identified in three TOF and three PS/PPS/PA patients, that were not present in 100 controls. We identified one frameshift and two missense mutations in the TOF cases, and one frameshift and two missense mutations in cases with PS/PPS/PA. The four missense mutations were assayed for their effect on protein localization, posttranslational modification, and ability to activate Notch signaling. The missense mutants displayed heterogeneous behavior in these assays, some with complete haploinsufficiency, suggesting that there are additional modifiers leading to organ specific features. We identified functionally significant mutations in 2% (2/94) of TOF patients and 4% (2/50) of PS/PPS/PA patients. Patients with right-sided cardiac defects should be carefully screened for features of AGS or a family history of cardiac defects that might suggest the presence of a JAG1 mutation.


Surgical therapy of prostatitis: a systematic review.
The clinical term "prostatitis" refers to a clinical syndrome defined by the following 4 distinct entities: acute bacterial prostatitis (category 1), chronic bacterial prostatitis (category 2), chronic prostatitis/chronic pelvic pain syndrome (category 3), and asymptomatic prostatitis (category 4) The etiology of the chronic forms is still not fully understood and choice of therapy is often debated. The objective of this systematic review is to collect evidence on the surgical treatment of the chronic form of prostatitis and to evaluate its clinical implication. We performed a systematic literature search and identified 6683 relevant publications, of which 16 were included in the review. Transurethral prostate resection was performed in 110 patients; 78 patients (70%) were reported as "cured", 16 patients (15%) as improved, and 16 patients (15%) as unchanged. Radical prostatectomy was performed in 21 patients; a full resolution of prostatitis related symptoms was reported for 20 patients (95%). No increased rates of complications or unusual complications were noted. Surgical therapy of chronic bacterial prostatitis or chronic pelvic pain syndrome might be a viable option; however, since little evidence is currently available and no randomized controlled trials have been conducted, the presently available data does not provide a base for clinical decisions.


Interaction of Shiga toxin 2 with complement regulators of the factor H protein family.
Shiga toxin 2 (Stx2) is believed to be a major virulence factor of enterohemorrhagic Escherichia coli (EHEC) contributing to hemolytic uremic syndrome (HUS). The complement system has recently been found to be involved in the pathogenesis of EHEC-associated HUS. Stx2 was shown to activate complement via the alternative pathway, to bind factor H (FH) at short consensus repeats (SCRs) 6-8 and 18-20 and to delay and reduce FH cofactor activity on the cell surface. We now show that complement factor H-related protein 1 (FHR-1) and factor H-like protein 1 (FHL-1), proteins of the FH protein family that show amino acid sequence and regulatory function similarities with FH, also bind to Stx2. The FHR-1 binding site for Stx2 was located at SCRs 3-5 and the binding capacity of FHR-1*A allotype was higher than that of FHR-1*B. FHR-1 and FHL-1 competed with FH for Stx2 binding, and in the case of FHR-1 this competition resulted in a reduction of FH cofactor activity. FHL-1 retained its cofactor activity in the fluid phase when bound to Stx2. In conclusion, multiple interactions of key complement inhibitors FH, FHR-1 and FHL-1 with Stx2 corroborate our hypothesis of a direct role of complement in EHEC-associated HUS.


Prevalence and Persistence of Varicella Antibodies in Previously Immunized Children and Youth With Perinatal HIV-1 Infection.
Two doses of live-attenuated varicella-zoster vaccine are recommended for human immunodeficiency virus 1 (HIV-1)-infected children with CD4% ≥ 15%. We determined the prevalence and persistence of antibody in immunized children with perinatal HIV (PHIV) and their association with number of vaccinations, combination antiretroviral therapy (cART), and HIV status. The Adolescent Master Protocol is an observational study of children with PHIV and perinatally HIV-exposed but uninfected (PHEU) children conducted at 15 US sites. In a cross-sectional analysis, we tested participants' most recent stored sera for varicella antibody using whole-cell and glycoprotein enzyme-linked immunosorbent assay. Seropositivity predictors were identified using multivariable logistic regression models and C statistics. Samples were available for 432 children with PHIV and 221 PHEU children; 82% of children with PHIV and 97% of PHEU children were seropositive (P < .001). Seropositivity after 1 vaccine dose among children with PHIV and PHEU children was 100% at <3 years (both), 73% and 100% at 3-<7 years (P < .05), and 77% and 97% at ≥ 7 years (P < .01), respectively. Seropositivity among recipients of 2 vaccine doses was >94% at all intervals. Independent predictors of seropositivity among children with PHIV were receipt of 2 vaccine doses, receipt of 1 dose while on ≥ 3 months of cART, compared with none (adjusted odds ratio [aOR]: 14.0 and 2.8, respectively; P < .001 for overall dose effect), and in those vaccinated ≥ 3 years previously, duration of cART (aOR: 1.29 per year increase, P = .02). Humoral immune responses to varicella vaccine are best achieved when children with PHIV receive their first dose ≥ 3 months after cART initiation and maintained by completion of the 2-dose series and long-term cART use.


Convective and radiative heat transfer coefficients for individual human body segments.
Human thermal physiological and comfort models will soon be able to simulate both transient and spatial inhomogeneities in the thermal environment. With this increasing detail comes the need for anatomically specific convective and radiative heat transfer coefficients for the human body. The present study used an articulated thermal manikin with 16 body segments (head, chest, back, upper arms, forearms, hands, pelvis, upper legs, lower legs, feet) to generate radiative heat transfer coefficients as well as natural- and forced-mode convective coefficients. The tests were conducted across a range of wind speeds from still air to 5.0 m/s, representing atmospheric conditions typical of both indoors and outdoors. Both standing and seated postures were investigated, as were eight different wind azimuth angles. The radiative heat transfer coefficient measured for the whole-body was 4.5 W/m2 per K for both the seated and standing cases, closely matching the generally accepted whole-body value of 4.7 W/m2 per K. Similarly, the whole-body natural convection coefficient for the manikin fell within the mid-range of previously published values at 3.4 and 3.3 W/m2 per K when standing and seated respectively. In the forced convective regime, heat transfer coefficients were higher for hands, feet and peripheral limbs compared to the central torso region. Wind direction had little effect on convective heat transfers from individual body segments. A general-purpose forced convection equation suitable for application to both seated and standing postures indoors was hc = 10.3v0.6 for the whole-body. Similar equations were generated for individual body segments in both seated and standing postures.


International collaboration, funding and association with burden of disease in randomized controlled trials in Africa.
This study aimed to assess whether randomized controlled trials conducted in Africa with collaborators from outside Africa were more closely associated with health conditions that have a burden of disease that is of specific importance to Africa than with conditions of more general global importance or with conditions important to developed countries. We also assessed whether the source of funding influenced a study's relevance to Africa. We compared randomized controlled trials performed in Africa that looked at diseases specifically relevant to Africa (as determined by burden of disease criteria) with trials classified as looking at diseases of global importance or diseases important to developed countries in order to assess differences in collaboration and funding. Of 520 trials assessed, 347 studied diseases that are specifically important to Africa; 99 studied globally important diseases and 74 studied diseases that are important to developed countries. The strongest independent predictor of whether a study was of specifically African or global importance was the corresponding author's country of origin: African importance was negatively associated with a corresponding author being from South Africa (odds ratio (OR) = 0.04; 95% confidence interval (CI) = 0.02-0.10) but there was little difference between corresponding authors from other African countries and corresponding authors from countries outside Africa. The importance of a study to Africa was independently associated with having more non-African authors (OR per author = 1.31; 95% CI = 1.08-1.58), fewer trial sites (OR per site = 0.69; 95% CI = 0.50-0.96), and reporting of funding (OR = 2.14; 95% CI = 1.15-4.00). Similar patterns were present in the comparisons of trials studying diseases important to Africa versus those studying diseases important to developed countries with stronger associations overall. When funding was reported, private industry funding was negatively associated with African importance compared with global importance (OR = 0.31, P= 0.008 for African importance and OR = 0.51, P= 0.57 for importance for developed countries). The relevance to Africa of trials conducted in Africa was not adversely affected by collaboration with non-African researchers but funding from private industry was associated with a decreased emphasis on diseases relevant to Africa.


5-HT modulates noncholinergic contraction in guinea pig airways in vitro by prejunctional 5-HT1-like receptor.
5-Hydroxytryptamine (5-HT) has been demonstrated to cause both constriction and relaxation of guinea pig airways, partly through direct action on airway smooth muscle and partly through postganglionic facilitation of cholinergic neurotransmission. We performed an in vitro study to investigate whether 5-HT can modulate the noncholinergic contraction in guinea pig airways due to release of neuropeptides from airway sensory nerves. In the presence of atropine (1 microM), ketanserin (10 microM), and indomethacin (10 microM), 5-HT (0.1-100 microM) produced concentration-dependent inhibition of electrical field stimulation-induced noncholinergic contraction with maximal inhibition of approximately 72 +/- 4%. Tropisetron (ICS-205-930, 1 microM), a 5-HT3 and 5-HT4 receptor antagonist, was unable to prevent the inhibition produced by 5-HT. Methiothepin (1-100 nM), a 5-HT1 and 5-HT2 receptor antagonist, produced a concentration-dependent inhibition of the effect of 5-HT (1 microM) with a 50% inhibition concentration value of 66 nM. 5-HT (100 microM) had no effect on the cumulative concentration-response relationship to exogenous substance P (10 nM-10 microM). The concentration of agonist causing 35% inhibition of the noncholinergic contraction (EC35) was calculated, and a rank order of potency was established: 5-carboxamidotryptamine (EC35 = 0.24 microM) > 5-HT (EC35 = 0.77 microM) > 8-hydroxy-2-(dipropylamino)tetralin (EC35 = 8.1 microM) > sumatriptan (EC35 = 18 microM). We conclude that 5-HT concentration dependently modulates noncholinergic contraction in guinea pig airways in vitro by a prejunctional mechanism. This effect is probably mediated through a 5-HT1-like receptor; however, the exact subtype remains to be elucidated.


The independent effects of eicosapentaenoic acid and docosahexaenoic acid on cardiovascular risk factors in humans.
This review details the independent effects of purified eicosapentaenoic acid and docosahexaenoic acid on cardiovascular risk factors in humans. We report data from the recent literature and our own controlled clinical trials which compared the independent effects of these fatty acids in individuals at increased risk of cardiovascular disease, namely overweight hyperlipidaemic men and treated-hypertensive, type 2 diabetic men and women. We discuss the biological effects of these fatty acids and the potential mechanisms through which they may affect cardiovascular disease risk factors. A cardioprotective effect for omega3 fatty acids is supported by prospective studies demonstrating an inverse association between fish intake and coronary heart disease mortality. Data from secondary prevention trials support a reduction in ventricular fibrillation as a primary mechanism for the decreased incidence of myocardial infarction. Clinical trials and experimental studies have shown that omega3 fatty acids have many other potentially important antiatherogenic and antithrombotic effects. Omega-3 fatty acids lower blood pressure and heart rate, improve dyslipidaemia, reduce inflammation, and improve vascular and platelet function. These favourable effects have until recently been primarily attributed to the omega3 fatty acid eicosapentaenoic acid, which is present in large amounts in fish oil. Controlled studies in humans now demonstrate that docosahexaenoic acid, although often present in lower quantities, has equally important anti-arrhythmic, anti-thrombotic and anti-atherogenic effects. Available evidence strongly suggests that eicosapentaenoic acid and docosahexaenoic acid have differing haemodynamic and anti-atherogenic properties. The effects of the two fatty acids may also differ depending on the target population.


Parasites of the shore crab Carcinus maenas (L.): implications for reproductive potential and invasion success.
The European shore crab, Carcinus maenas, is one of the most successful marine invasive species. Its success has been in part attributed to the loss of parasites, rekindling an interest in host-parasite interactions and impacts on host fitness in this crab. In the present study, we investigated C. maenas populations from Europe, South Africa and Australia for parasites, and assessed their impact on the fitness of male crabs. For the shore crab, testes weight along with success in mating competition is traded off against other life-history traits. We therefore used this parameter as an indicator both for reproductive fitness and a possible resource trade-off in response to parasite infestation. In the native range, crabs infested with Sacculina carcini showed significantly lower testes weight than uninfected crabs. However, helminth parasites did not generally cause reduced testes weights. Crab populations from South Africa and Australia were either parasitized at very low prevalences, or were completely parasite free. However, no population level effect of this parasite release was reflected in testes weight. These findings do not support a severe fitness impact of helminth parasites on C. maenas, which questions the role of parasites on its population dynamics, both in the native area and for invasive success.


Can ageing-related degenerative diseases be ameliorated through administration of vitamin C at pharmacological levels?
Man, with other primates, lost the ability to synthesize vitamin C through an inactivating mutation of the gene encoding gulonolactone oxidase (GULO) millions of years ago. Though the consequences of this prehistoric loss must have been favorable (and thus selected for) at the population level, the inability to produce vitamin C may have serious health implications for modern humans, especially for those conditions in which antioxidants (like vitamin C) have been implicated as potential therapeutic agents. Two general types of recent findings regarding vitamin C have made re-evaluation of this important nutrient imperative. First, vitamin C is now known to be involved in several novel physiological phenomena including stem cell differentiation and respiratory development, which likely require pharmacological levels of vitamin C. Secondly, the growing recognition that many ageing-related diseases, including heart disease, neural degeneration and cancer, may have a contributing oxidative damage factor that might be reduced by dietary antioxidants such as vitamin C. In this paper, we hypothesize that high serum-level vitamin C provides important, broad-ranging therapeutic benefits in treating ageing-related degenerative diseases. This hypothesis can be readily tested using traditional and newly-developed genetically-engineered animal models.


Effective Feedback to Improve Primary Care Prescribing Safety (EFIPPS) a pragmatic three-arm cluster randomised trial: designing the intervention (ClinicalTrials.gov registration NCT01602705).
High-risk prescribing in primary care is common and causes considerable harm. Feedback interventions have small/moderate effects on clinical practice, but few trials explicitly compare different forms of feedback. There is growing recognition that intervention development should be theory-informed, and that comprehensive reporting of intervention design is required by potential users of trial findings. The paper describes intervention development for the Effective Feedback to Improve Primary Care Prescribing Safety (EFIPPS) study, a pragmatic three-arm cluster randomised trial in 262 Scottish general practices. The NHS chose to implement a feedback intervention to utilise a new resource, new Prescribing Information System (newPIS). The development phase required selection of high-risk prescribing outcome measures and design of intervention components: (1) educational material (the usual care comparison), (2) feedback of practice rates of high-risk prescribing received by both intervention arms and (3) a theory-informed behaviour change component to be received by one intervention arm. Outcome measures, educational material and feedback design, were developed with a National Health Service Advisory Group. The behaviour change component was informed by the Theory of Planned Behaviour and the Health Action Process Approach. A focus group elicitation study and an email Delphi study with general practitioners (GPs) identified key attitudes and barriers of responding to the prescribing feedback. Behaviour change techniques were mapped to the psychological constructs, and the content was informed by the results of the elicitation and Delphi study. Six high-risk prescribing measures were selected in a consensus process based on importance and feasibility. Educational material and feedback design were based on current NHS Scotland practice and Advisory Group recommendations. The behaviour change component was resource constrained in development, mirroring what is feasible in an NHS context. Four behaviour change interventions were developed and embedded in five quarterly rounds of feedback targeting attitudes, subjective norms, perceived behavioural control and action planning (2×). The paper describes a process which is feasible to use in the resource-constrained environment of NHS-led intervention development and documents the intervention to make its design and implementation explicit to potential users of the trial findings. ClinicalTrials.gov: NCT01602705.


Gestational, pathologic and biochemical differences between very long-chain acyl-CoA dehydrogenase deficiency and long-chain acyl-CoA dehydrogenase deficiency in the mouse.
Although many patients have been found to have very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, none have been documented with long-chain acyl-CoA dehydrogenase (LCAD) deficiency. In order to understand the metabolic pathogenesis of long-chain fatty acid oxidation disorders, we generated mice with VLCAD deficiency (VLCAD(-/-)) and compared their pathologic and biochemical phenotypes of mice with LCAD deficiency (LCAD(-/-)) and wild-type mice. VLCAD(-/-) mice had milder fatty change in liver and heart. Dehydrogenation of various acyl-CoA substrates by liver, heart and skeletal muscle mitochondria differed among the three genotypes. The results for liver were most informative as VLCAD(-/-) mice had a reduction in activity toward palmitoyl-CoA and oleoyl-CoA (58 and 64% of wild-type, respectively), whereas LCAD(-/-) mice showed a more profoundly reduced activity toward these substrates (35 and 32% of wild-type, respectively), with a significant reduction of activity toward the branched chain substrate 2,6-dimethylheptanoyl-CoA. C(16) and C(18) acylcarnitines were elevated in bile, blood and serum of fasted VLCAD(-/-) mice, whereas abnormally elevated C(12) and C(14) acylcarnitines were prominent in LCAD(-/-) mice. Progeny with the combined LCAD(+/+)//VLCAD(+/-) genotype were over-represented in offspring from sires and dams heterozygous for both LCAD and VLCAD mutations. In contrast, no live mice with a compound LCAD(-/-)//VLCAD(-/-) genotype were detected.


Treatment of the calcific tendinopathy of the rotator cuff by ultrasound-guided percutaneous needle lavage. Two years prospective study.
to evaluate the short and long term effectiveness of ultrasonography (US)-guided percutaneous needle lavage in calcific tendinopathy of the rotator cuff. To study the evolution of the size of calcifications and pain in the two years after treatment. A 2 year longitudinal prospective study is carried out after applying the UGPL technique on a number of patients diagnosed with calcific tendinitis of the rotator cuff. Clinical, ultrasound and radiology follow-up controls were performed, 3 months, 6 months, one year and two years after the treatment. The Visual Analog Scale (VAS) was used to assess the pain. The degree and point of pain is selected on a 10 cm line, arranged horizontally or vertically. The "0" represents no pain and "10" represents worst pain. The population studied was made up of 121 patients that required our service as a result of suffering from a painful shoulder. the pain (VAS) and the size of the calcification significantly decreased with the application of the technique (p< 0,001 in both cases) and regardless of the sex (p: 0.384 for pain and p: 0.578 for the size of the calcification). This occurred from the first check-up (3 months) and was maintained for two year. we consider this technique to be a valid alternative as a first-choice treatment of calcific tendinitis of the shoulder. The intervention is simple, cost-effective, does not require hospitalization, involves no complications, rehabilitation treatment is not required and it shows very few side effects without sequelae, significantly reducing the size of the calcification and pain in the majority of patients.


Variation in the effects of three different breakfast meals on subjective satiety and subsequent intake of energy at lunch and evening meal.
To determine the relative impact of three iso-caloric breakfast meals, of variable composition, on satiety, hunger and subsequent intake of energy. In a three-way, crossover design, 30 healthy men (age of 21.7 ± 1.2 years; BMI, 23.1 ± 2.7 kg/m²) were randomised to one of three test breakfasts, on three separate occasions, separated by 1 week. The breakfasts consisted of eggs on toast, cereal (cornflakes) with milk and toast, or a croissant and orange juice. Subjective ratings of satiety, hunger, fullness and desire to eat were recorded at 30-min intervals by electronic visual analogue scales (VAS). Energy intake was assessed by weighed food intake at an ad libitum lunch and evening meal. Participants showed increased satiety, less hunger and a lower desire to eat after the breakfast containing eggs relative to the cereal (p < 0.02), and croissant-based meals (p < 0.0001). The egg breakfast was also accompanied by a significantly lower intake of energy relative to the croissant- and cereal-based breakfasts at the buffet lunch and evening meal, respectively, 1,284 ± 464 (egg) versus 1,442 ± 426 kcal (croissant), p = 0.03, 1,407 ± 379 (cereal) at lunch and 1,899 ± 729 (egg) versus 2,214 ± 620 kcal (cereal), p = 0.02, 2,047 ± 712 (croissant) at evening meal. The breakfast meal with the greatest effect on satiety and subsequent intake of energy was distinct in having the highest protein and lowest carbohydrate content relative to the other two breakfasts. These findings provide evidence to support the importance of food choice at breakfast as a means of increasing satiety in the morning and reducing energy intake at lunch.


Incremental Value of Left Atrial Global Longitudinal Strain for Prediction of Post Stroke Atrial Fibrillation in Patients with Acute Ischemic Stroke.
Atrial fibrillation (AF) is a well-established risk factor for stroke. Interestingly, ischemic stroke increases risk of incident AF in patients without prior diagnosed AF. For better risk stratification for post-stroke AF, we studied left atrial (LA) size and mechanical function using two-dimensional (2D) speckle tracking imaging in patients with acute ischemic stroke. A total of 227 patients (132 males, age 67 ± 12) with acute ischemic stroke without a history of AF underwent 2D transthoracic echocardiography and speckle tracking imaging for the assessment of LA volume index and global LA longitudinal strain (LALS). From clinical variables, the CHA2DS2-VASc score and National Institute of Health Stroke Scale (NIHSS) were calculated in each patient. Post-stroke AF was defined as newly diagnosed AF during the course after ischemic stroke. Post-stroke AF occurred in 25 patients (11%). Patients with post-stroke AF were older and showed a higher tendency of CHA2DS2-VASc score, significantly higher log NIHSS, larger LA volume index and lower global LALS than those without. In multivariate analysis, global LALS was an independent predictor for post-stroke AF (hazard ratio 0.90, 95% confidence interval 0.83.0.97, p < 0.01) after controlling for confounding factors. Furthermore, global LALS provided incremental predictive value for post-stroke AF over the CHA2DS2-VASc score, NIHSS, and LA volume index. The global LALS < 14.5% better distinguished post-stroke AF (area under the curve 0.837, sensitivity 60%, specificity 95%, p < 0.01) than CHA2DS2-VASc score. Global LALS as a marker of LA mechanical function has incremental predictive value for post-stroke AF in patients with acute ischemic stroke.


The Intrinsic Geometric Structure of Protein-Protein Interaction Networks for Protein Interaction Prediction.
Recent developments in high-throughput technologies for measuring protein-protein interaction (PPI) have profoundly advanced our ability to systematically infer protein function and regulation. However, inherently high false positive and false negative rates in measurement have posed great challenges in computational approaches for the prediction of PPI. A good PPI predictor should be 1) resistant to high rate of missing and spurious PPIs, and 2) robust against incompleteness of observed PPI networks. To predict PPI in a network, we developed an intrinsic geometry structure (IGS) for network, which exploits the intrinsic and hidden relationship among proteins in network through a heat diffusion process. In this process, all explicit PPIs participate simultaneously to glue local infinitesimal and noisy experimental interaction data to generate a global macroscopic descriptions about relationships among proteins. The revealed implicit relationship can be interpreted as the probability of two proteins interacting with each other. The revealed relationship is intrinsic and robust against individual, local and explicit protein interactions in the original network. We apply our approach to publicly available PPI network data for the evaluation of the performance of PPI prediction. Experimental results indicate that, under different levels of the missing and spurious PPIs, IGS is able to robustly exploit the intrinsic and hidden relationship for PPI prediction with a higher sensitivity and specificity compared to that of recently proposed methods.


KnotProt: a database of proteins with knots and slipknots.
The protein topology database KnotProt, http://knotprot.cent.uw.edu.pl/, collects information about protein structures with open polypeptide chains forming knots or slipknots. The knotting complexity of the cataloged proteins is presented in the form of a matrix diagram that shows users the knot type of the entire polypeptide chain and of each of its subchains. The pattern visible in the matrix gives the knotting fingerprint of a given protein and permits users to determine, for example, the minimal length of the knotted regions (knot's core size) or the depth of a knot, i.e. how many amino acids can be removed from either end of the cataloged protein structure before converting it from a knot to a different type of knot. In addition, the database presents extensive information about the biological functions, families and fold types of proteins with non-trivial knotting. As an additional feature, the KnotProt database enables users to submit protein or polymer chains and generate their knotting fingerprints.


Development and evaluation of a secondary reference panel for BCR-ABL1 quantification on the International Scale.
Molecular monitoring of chronic myeloid leukemia patients using robust BCR-ABL1 tests standardized to the International Scale (IS) is key to proper disease management, especially when treatment cessation is considered. Most laboratories currently use a time-consuming sample exchange process with reference laboratories for IS calibration. A World Health Organization (WHO) BCR-ABL1 reference panel was developed (MR(1)-MR(4)), but access to the material is limited. In this study, we describe the development of the first cell-based secondary reference panel that is traceable to and faithfully replicates the WHO panel, with an additional MR(4.5) level. The secondary panel was calibrated to IS using digital PCR with ABL1, BCR and GUSB as reference genes and evaluated by 44 laboratories worldwide. Interestingly, we found that >40% of BCR-ABL1 assays showed signs of inadequate optimization such as poor linearity and suboptimal PCR efficiency. Nonetheless, when optimized sample inputs were used, >60% demonstrated satisfactory IS accuracy, precision and/or MR(4.5) sensitivity, and 58% obtained IS conversion factors from the secondary reference concordant with their current values. Correlation analysis indicated no significant alterations in %BCR-ABL1 results caused by different assay configurations. More assays achieved good precision and/or sensitivity than IS accuracy, indicating the need for better IS calibration mechanisms.


Chronic Immune Activation in Systemic Lupus Erythematosus and the Autoimmune PTPN22 Trp620 Risk Allele Drive the Expansion of FOXP3+ Regulatory T Cells and PD-1 Expression.
In systemic lupus erythematosus (SLE), perturbed immunoregulation underpins a pathogenic imbalance between regulatory and effector CD4+ T-cell activity. However, to date, the characterization of the CD4+ regulatory T cell (Treg) compartment in SLE has yielded conflicting results. Here we show that patients have an increased frequency of CD4+FOXP3+ cells in circulation owing to a specific expansion of thymically-derived FOXP3+HELIOS+ Tregs with a demethylated FOXP3 Treg-specific demethylated region. We found that the Treg expansion was strongly associated with markers of recent immune activation, including PD-1, plasma concentrations of IL-2 and the type I interferon biomarker soluble SIGLEC-1. Since the expression of the negative T-cell signaling molecule PTPN22 is increased and a marker of poor prognosis in SLE, we tested the influence of its missense risk allele Trp620 (rs2476601C>T) on Treg frequency. Trp620 was reproducibly associated with increased frequencies of thymically-derived Tregs in blood, and increased PD-1 expression on both Tregs and effector T cells (Teffs). Our results support the hypothesis that FOXP3+ Tregs are increased in SLE patients as a consequence of a compensatory mechanism in an attempt to regulate pathogenic autoreactive Teff activity. We suggest that restoration of IL-2-mediated homeostatic regulation of FOXP3+ Tregs by IL-2 administration could prevent disease flares rather than treating at the height of a disease flare. Moreover, stimulation of PD-1 with specific agonists, perhaps in combination with low-dose IL-2, could be an effective therapeutic strategy in autoimmune disease and in other immune disorders.


Millennium Development Goal 5 and adolescents: looking back, moving forward.
Since the Millennium Declaration in 2000, unprecedented progress has been made in the reduction of global maternal mortality. Millennium Development Goal 5 (MDG 5; improving maternal health) includes two primary targets, 5A and 5B. Target 5A aimed for a 75% reduction in the global maternal mortality ratio (MMR), and 5B aimed to achieve universal access to reproductive health. Globally, maternal mortality since 1990 has nearly halved and access to reproductive health services in developing countries has substantially improved. In setting goals and targets for the post-MDG era, the global maternal health community has recognised that ultimate goal of ending preventable maternal mortality is now within reach. The new target of a global MMR of <70 deaths per 100 000 live births by 2030 is ambitious, yet achievable and to reach this target a significantly increased effort to promote and ensure universal, equitable access to reproductive, maternal and newborn services for all women and adolescents will be required. In this article, as we reflect on patterns, trends and determinants of maternal mortality, morbidity and other key MDG5 indicators among adolescents, we aim to highlight the importance of promoting and protecting the sexual and reproductive health and rights of adolescents as part of renewed global efforts to end preventable maternal mortality.


IL-6 production by monocytes is associated with graft function decline in patients with borderline changes suspicious for acute T-cell-mediated rejection: a pilot study.
Although borderline changes (BL) suspicious for acute T-cell-mediated rejection represent a diagnostic category, its clinical relevance is questioned leading to heterogeneous therapeutic management. We hypothesized that measuring IL-6 secretion by peripheral blood mononuclear cells identifies patients with ongoing graft damage. We examined the association between secreted IL-6 and the change in estimated glomerular filtration rate at 6 months after the biopsy (ΔeGFR). We then conducted phenotypic and functional studies on patient and mouse innate immune cells in the blood and the kidney. In a training set, ΔeGFR was strongly associated with IL-6 levels, showing a clinically meaningful decline of 4.6 ± 1.5 ml/min per increase in log10 IL-6 (P = 0.001). These results were consistent after adjustment and were reproduced in a validation cohort. Phenotyping of peripheral blood cells revealed that the main source of IL-6 was CD14+ CD16- CCR2+ HLA-DR+ CD86+ CD11c+ inflammatory monocytes. There was a significant correlation between IL-6 secretion and interstitial dendritic cell density in the biopsy. Finally, characterization of mouse kidney dendritic cells revealed that they share features with macrophages and function as effector cells secreting IL-6. In conclusion, measuring IL-6 secreted by peripheral blood cells can be useful in the management of patients with BL in the absence of a concurrent inflammatory condition.


Incorporation of glycoproteins into peripheral nerve myelin.
Peripheral nerve myelin contains a dominant low molecular weight glycoprotein called Po. To study the metabolism of this glycoprotein, tritiated fucose was injected into the peripheral nerves of adult mice and developing rats, and the temporal distribution of label was examined by autoradiography and gel electrophoresis. Mice and rat pups, injected with fucose, were sacrificed from 1 h to 98 days later. Series of autoradiographs were prepared. At the shortest labeling periods, newly formed product was confined to juxtanuclear Schwann cell cytoplasm, in association with regions rich in Golgi apparatus. After longer labeling periods, silver grain levels in Schwann cell cytoplasm decreased; concomitantly, there was an increase of silver grains associated with myelin. In adult animals, label associated with myelin was concentrated over outer layers of thickly myelinated fibers. Even at the longest time intervals examined (72 and 98 days), this distribution of label was largely retained. In contrast, in developing animals, label became associated with inner layers of the thicker sheaths. At no time was label observed over axons. Gel electrophoresis revealed that tritiated fucose was a suitable precursor for the faster migrating peripheral nerve glycoprotein(s). At all times examined, there was a single major peak of radioactivity that co-migrated on sodium dodecyl sulfate (SDS) acrylamide gels with the Po protein. Sometimes, a faster migrating shoulder of radioactivity was noted. With increased labeling periods, there was an enrichment of radioactivity associated with Po, indicative of a relatively slow turnover rate.


An integrative somatic mutation analysis to identify pathways linked with survival outcomes across 19 cancer types.
Identification of altered pathways that are clinically relevant across human cancers is a key challenge in cancer genomics. Precise identification and understanding of these altered pathways may provide novel insights into patient stratification, therapeutic strategies and the development of new drugs. However, a challenge remains in accurately identifying pathways altered by somatic mutations across human cancers, due to the diverse mutation spectrum. We developed an innovative approach to integrate somatic mutation data with gene networks and pathways, in order to identify pathways altered by somatic mutations across cancers. We applied our approach to The Cancer Genome Atlas (TCGA) dataset of somatic mutations in 4790 cancer patients with 19 different types of tumors. Our analysis identified cancer-type-specific altered pathways enriched with known cancer-relevant genes and targets of currently available drugs. To investigate the clinical significance of these altered pathways, we performed consensus clustering for patient stratification using member genes in the altered pathways coupled with gene expression datasets from 4870 patients from TCGA, and multiple independent cohorts confirmed that the altered pathways could be used to stratify patients into subgroups with significantly different clinical outcomes. Of particular significance, certain patient subpopulations with poor prognosis were identified because they had specific altered pathways for which there are available targeted therapies. These findings could be used to tailor and intensify therapy in these patients, for whom current therapy is suboptimal. The code is available at: http://www.taehyunlab.org firstname.lastname@example.com or firstname.lastname@example.com or firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


Insulin/IGF and target of rapamycin signaling: a TOR de force in growth control.
'They come in all sizes.' Apart from its origin and use in the clothing industry, this saying reflects the fact that the size of organisms spans an enormous range. Whether destined to be large or small, species grow in an organized fashion to reach their final specified size. For growth to proceed, food must be metabolized to liberate energy in the form of adenosine triphosphate (ATP) and protein building blocks in the form of amino acids. One major orchestrator of this complex growth process in diverse metazoan species is the insulin/insulin-like growth factor (IGF) system. This review summarizes current studies primarily from Drosophila regarding the function of the insulin/IGF system in the control of growth.


Elevated Plasma microRNA-206 Levels Predict Cognitive Decline and Progression to Dementia from Mild Cognitive Impairment.
The need for practical biomarkers for early diagnosis of Alzheimer's disease (AD) remains largely unmet. Here we investigated the use of blood-based microRNAs as prognostic biomarkers for AD and their application in a novel electrochemical microfluidic device for microRNA detection. MicroRNA transcriptome was profiled in plasma from patients with mild cognitive impairment (MCI) and AD. MicroRNAs Let-7b and microRNA-206 were validated at elevated levels in MCI and AD, respectively. MicroRNA-206 displayed a strong correlation with cognitive decline and memory deficits. Longitudinal follow-ups over five years identified microRNA-206 increases preceding the onset of dementia. MicroRNA-206 was increased in unprocessed plasma of AD and MCI subjects, detected by our microfluidic device. While increased Let-7b levels in plasma may be used to identify patients with MCI, changes in plasma levels of microRNA-206 may be used to predict cognitive decline and progression towards dementia at an MCI stage. MicroRNA quantification via a microfluidic device could provide a practical cost-effective tool for the stratification of patients with MCI according to risk of developing AD.


[Ethics guidelines for the creation and use of registries for biomedical research purposes].
The clinical information stored in registries and records of different types is a fundamental tool for biomedical research. Up until just a few years ago, hardly any limitations existed on the creation and use of epidemiological registries or the use of information from pre-existing records for research purposes. This situation has changed substantially due mainly to the growing importance current laws place upon the safeguarding of the privacy and confidentiality of personal data. Although the legal framework is already quite explicit, a certain degree of leeway exists for ethical debate and prudence advice for the purpose of conducting valid, useful research with this information which will also respect the rights of the subjects and the laws in force. These guidelines deal with those aspects which have been considered relevant from an ethical standpoint in the handling of records and registries for research-related purposes, including not only the use but also the creation proper of the registries. A total of twenty-four recommendations are provided, grouped into ten sections: warranting of the creation of registry, organization and definition of responsibilities, scientific validity of the research project, ethical requirements of the collections of anonymous and anonymized data, ethical requirements of the registries including personal data, uses of medical records for research purposes, use of historical records of deceased individuals, contact with the research subjects, notification of results and review by a Research Ethics Committee.


The Dynamic Ebbinghaus: motion dynamics greatly enhance the classic contextual size illusion.
The Ebbinghaus illusion is a classic example of the influence of a contextual surround on the perceived size of an object. Here, we introduce a novel variant of this illusion called the Dynamic Ebbinghaus illusion in which the size and eccentricity of the surrounding inducers modulates dynamically over time. Under these conditions, the size of the central circle is perceived to change in opposition with the size of the inducers. Interestingly, this illusory effect is relatively weak when participants are fixating a stationary central target, less than half the magnitude of the classic static illusion. However, when the entire stimulus translates in space requiring a smooth pursuit eye movement to track the target, the illusory effect is greatly enhanced, almost twice the magnitude of the classic static illusion. A variety of manipulations including target motion, peripheral viewing, and smooth pursuit eye movements all lead to dramatic illusory effects, with the largest effect nearly four times the strength of the classic static illusion. We interpret these results in light of the fact that motion-related manipulations lead to uncertainty in the image size representation of the target, specifically due to added noise at the level of the retinal input. We propose that the neural circuits integrating visual cues for size perception, such as retinal image size, perceived distance, and various contextual factors, weight each cue according to the level of noise or uncertainty in their neural representation. Thus, more weight is given to the influence of contextual information in deriving perceived size in the presence of stimulus and eye motion. Biologically plausible models of size perception should be able to account for the reweighting of different visual cues under varying levels of certainty.