Vertical Distribution of Heterodera schachtii under Susceptible, Resistant, or Tolerant Sugar Beet Cultivars.
Heterodera schachtii is managed by rotation with non-hosts, resistant cover crops, and resistant and tolerant sugar beet cultivars. Microplots 60 cm deep and 30 cm in diameter containing steamed field soil were (i) noninfested or infested with 550 H. schachtii eggs per 100 g at (ii) 0 to 60 cm, (iii) 0 to 30 cm or (iv) 30 to 60 cm in depth. Plots were planted to susceptible, resistant, and tolerant sugar beets. Five weeks later, the sugar beet canopy was largest in condition i, smallest in condition ii, and intermediate in conditions iii and iv. White sugar yield (WSY) was highest in condition i, second in condition iv, lowest in condition ii, and intermediate in condition iii. Cultivar-specific final nematode numbers were independent of the level of infestation. In two experiments utilizing 1-m2 microplots, naturally occurring H. schachtii populations were suppressed with fosthiazate at depth layers in reverse to those infested in the first experiment, and planted to susceptible, resistant, and tolerant sugar beets. In one experiment, WSY was highest in soil treated with fosthiazate at 0 to 60 cm in depth, lowest in nontreated, unaffected in soil treated at 30 to 60 cm in depth, and somewhat lower in soil treated at 0 to 30 cm in depth. In all cultivars, early root penetration predicted canopy diameter; only in the susceptible cultivar did the canopy diameter predict WSY. Deep-occurring H. schachtii can impact productivity in sugar beet cropping.


Effect of colloid (Androcoll-Bear, Percoll, and PureSperm) selection on the freezability of brown bear (Ursus arctos) sperm.
The development of a species-specific conservation protocol that involves artificial insemination with frozen semen needs to validate an effective methodology for freezing semen. Colloid centrifugation has been suggested and widely applied as an effective tool for selecting animal spermatozoa for artificial breeding. The objective of the present study was to compare different methods of centrifugation, single layer using Androcoll-Bear and Percoll and double layer using PureSperm 100 (in two different discontinuous gradients 40%-80% and 45%-90%), for the selection of fresh brown bear sperm samples. In the before freezing group, all selected samples showed a higher progressive motility and viability (except Percoll for motility 43.0 ± 5.3 [P < 0.05]); all colloids except PureSperm 45/90% rendered samples with fewer damaged acrosomes. In the after thawing group, all tested centrifugation colloids showed a good capacity to decrease the number of damaged acrosomes. Furthermore, PureSperm treatment (45/90%) resulted in an increase in apoptotic-like changes not only immediately after thawing but also after the incubation test, leading us to suggest that this gradient could induce some kind of deleterious effects on the sperm samples. On the other hand, PureSperm treatment (40/80%) yielded a quality preservation capacity similar to Androcoll-Bear in number of damaged acrosomes, different relative to the control (control, 5.3 ± 0.6; PureSperm 80, 2.0 ± 0.3; Androcoll, 2.1 ± 0.9 [P < 0.05]) but a decrease in the number of viable spermatozoa recovered after thawing relative to the control (control, 21.2 ± 3.1; PureSperm 80, 13.7 ± 2.7 [P < 0.05]). In conclusion, Androcoll-Bear constitutes a useful tool for handling of brown bear ejaculates owing to its simple handling and procedure with a reliable sperm selection and freezability. This colloid yielded an improvement in several sperm parameters in brown bear frozen-thawed semen; the selected spermatozoa of fresh samples with this colloid showed a better resistance to freezing compared with the control sample not only for motility but also for viability.


Y-position cysteine substitution in type I collagen (alpha1(I) R888C/p.R1066C) is associated with osteogenesis imperfecta/Ehlers-Danlos syndrome phenotype.
The most common mutations in type I collagen causing types II-IV osteogenesis imperfecta (OI) result in substitution for glycine in a Gly-Xaa-Yaa triplet by another amino acid. We delineated a Y-position substitution in a small pedigree with a combined OI/Ehlers-Danlos Syndrome (EDS) phenotype, characterized by moderately decreased DEXA z-score (-1.3 to -2.6), long bone fractures, and large-joint hyperextensibility. Affected individuals have an alpha1(I)R888C (p.R1066C) substitution in one COL1A1 allele. Polyacrylamide gel electrophoresis (PAGE) of [(3)H]-proline labeled steady-state collagen reveals slight overmodification of the alpha1(I) monomer band, much less than expected for a substitution of a neighboring glycine residue, and a faint alpha1(I) dimer. Dimers form in about 10% of proband type I collagen. Dimer formation is inefficient compared to a possible 25%, probably because the SH-side chains have less proximity in this Y-position than when substituting for a glycine. Theoretical stability calculations, differential scanning calorimetry (DSC) thermograms, and thermal denaturation curves showed only weak local destabilization from the Y-position substitution in one or two chains of a collagen helix, but greater destabilization is seen in collagen containing dimers. Y-position collagen dimers cause kinking of the helix, resulting in a register shift that is propagated the full length of the helix and causes resistance to procollagen processing by N-proteinase. Collagen containing the Y-position substitution is incorporated into matrix deposited in culture, including immaturely and maturely cross-linked fractions. In vivo, proband dermal fibrils have decreased density and increased diameter compared to controls, with occasional aggregate formation. This report on Y-position substitutions in type I collagen extends the range of phenotypes caused by nonglycine substitutions and shows that, similar to X- and Y-position substitutions in types II and III collagen, the phenotypes resulting from nonglycine substitutions in type I collagen are distinct from those caused by glycine substitutions.


Mechanisms by which Astragalus membranaceus injection regulates hematopoiesis in myelosuppressed mice.
The aim of this study was to investigate the mechanism underlying the effects of Astragalus membranaceus injection (AMI) on myelopoiesis in myelosuppressed mice. At 72 h after cyclophosphamide injection (250 mg/kg), the mice were administered AMI (500 mg/kg) intraperitoneally for 6 consecutive days or an equivalent volume of saline as a control. Murine colony-forming unit-fibroblast (CFU-F) formation, production of IL-6 and GM-CSF by bone marrow stromal cells (BMSC), and bcl-2 protein and mRNA expression in BMSC were measured by CFU-F assay, ELISA, immunohistochemistry and in situ hybridization. The results indicated that AMI improved the hematopoietic microenvironment by enhancing the BMSC survival and proliferation of CFU-F, production of IL-6 as well as GM-CSF by BMSC and bcl-2 protein and mRNA expression in BMSC, which promoted myelopoiesis. The data may provide a mechanistic basis for applying this ancient Chinese herb to promote hematopoiesis as an efficacious adjuvant therapy against myelosuppression induced by anti-cancer therapy.


Evaluation of nine immunoassay kits (enzyme immunoassay and direct fluorescence) for detection of Giardia lamblia and Cryptosporidium parvum in human fecal specimens.
It is well known that Giardia lamblia and Cryptosporidium parvum can cause severe symptoms in humans, particularly those who are immunologically compromised. Immunoassay procedures offer both increased sensitivity and specificity compared to conventional staining methods. These reagents are also helpful when screening large numbers of patients, particularly in an outbreak situation or when screening patients with minimal symptoms. The data obtained by using 9 diagnostic kits were compared: direct fluorescent-antibody assay (DFA) kits (TechLab Giardia/Crypto IF kit, TechLab Crypto IF kit, and Meridian Merifluor Cryptosporidium/Giardia) and enzyme immunoassay (EIA) kits (Alexon ProSpecT Giardia EZ Microplate Assay, Alexon ProSpecT Cryptosporidium Microplate Assay, Cambridge Giardia lamblia Antigen Microwell ELISA, Meridian Premier Giardia lamblia, Meridian Premier Cryptosporidium, TechLab Giardia CELISA, Trend Giardia lamblia EIA). The test with the Meridian Merifluor Cryptosporidium/Giardia kit was used as the reference method. In various combinations, 60 specimens positive for Giardia, 60 specimens positive for Cryptosporidium, 40 specimens positive for a Giardia-Cryptosporidium mix, and 50 negative fecal specimens were tested. Different species (nine protozoa, three coccidia, one microsporidium, five nematodes, three cestodes, and one trematode) were included in the negative specimens. The sensitivity of EIA for Giardia ranged from 94% (Alexon) to 99% (Trend and Cambridge); the specificity was 100% with all EIA kits tested. The sensitivity of EIA for Cryptosporidium ranged from 98% (Alexon) to 99% (Meridian Premier); specificities were 100%. All DFA results were in agreement, with 100% sensitivity and specificity; however, the TechLab reagents resulted in fluorescence intensity that was generally one level below that seen with the reagents used in the reference method. In addition to sensitivity and specificity, factors such as cost, simplicity, ease of interpretation of results (color, intensity of fluorescence), equipment, available personnel, and number of tests ordered are also important considerations prior to kit selection.


Interaction of a type II myosin with biological membranes studied by 2H solid state NMR.
Deuterium nuclear magnetic resonance spectroscopy (2H NMR) has been employed to investigate the interaction of lung type II myosin protein with neutral bilayers containing dimyristoylphosphatidylcholine (DMPC) as the only constituent and mixed bilayers containing the negatively charged lipid dimyristoylphosphatidylglycerol (DMPG). DMPC was deuterated at its headgroup by substituting the four protons at the alpha- and beta-positions (DMPC-d4) and the nine protons at the gamma-position (DMPC-d9). DMPG was perdeuterated at its headgroup (DMPG-d5). No changes were observed in the quadrupole splittings or spin-lattice relaxation times for the deuterated DMPC headgroup segments when increasing amounts of myosin were added to liposomes, made exclusively of DMPC-d9 or of DMPC-d4. However, upon the insertion of the negatively charged lipid DMPG at 1:1 molar ratio into the DMPC bilayers, myosin was found to interact electrostatically with the liposomes, thereby affecting significantly both the quadrupole splittings and spin-lattice relaxation rates of the alpha-, beta-, and gamma-deuterons in labeled DMPC. Monitoring DMPG-d5 in mixed DMPC/DMPG bilayers revealed a direct electrostatic interaction of DMPG with the protein, where positively charged lysine residues located at the tail domain of myosin provide the necessary sites for the interaction to occur. When ATP and Mg2+ were complexed to the head domain of myosin, a reduced interaction with the negatively charged bilayers was observed. The results clearly indicate that a type II myosin can interact with membranes without the need for a specific hydrophobic domain or an anchor in the protein molecule, provided that negatively charged lipids are present in the bilayer.


Alterations in Brain Cannabinoid Receptor Levels Are Associated with HIV-Associated Neurocognitive Disorders in the ART Era: Implications for Therapeutic Strategies Targeting the Endocannabinoid System.
HIV-associated neurocognitive disorders (HAND) persist despite the advent of antiretroviral therapy (ART), suggesting underlying systemic and central nervous system (CNS) inflammatory mechanisms. The endogenous cannabinoid receptors 1 and 2 (CB1 and CB2) modulate inflammatory gene expression and play an important role in maintaining neuronal homeostasis. Cannabis use is disproportionately high among people with HIV (PWH) and may provide a neuroprotective effect for those on ART due to its anti-inflammatory properties. However, expression profiles of CB1 and CB2 in the brains of PWH on ART with HAND have not been reported. In this study, biochemical and immunohistochemical analyses were performed to determine CB1 and CB2 expression in the brain specimens of HAND donors. Immunoblot revealed that CB1 and CB2 were differentially expressed in the frontal cortices of HAND brains compared to neurocognitively unimpaired (NUI) brains of PWH. CB1 expression levels negatively correlated with memory and information processing speed. CB1 was primarily localized to neuronal soma in HAND brains versus a more punctate distribution of neuronal processes in NUI brains. CB1 expression was increased in cells with glial morphology and showed increased colocalization with an astroglial marker. These results suggest that targeting the endocannabinoid system may be a potential therapeutic strategy for HAND.


Oral Sciences PhD Program Enrollment, Graduates, and Placement: 1994 to 2016.
For decades, dental schools in the United States have endured a significant faculty shortage. Studies have determined that the top 2 sources of dental faculty are advanced education programs and private practice. Those who have completed both DDS and PhD training are considered prime candidates for dental faculty positions. However, there is no national database to track those trainees and no evidence to indicate that they entered academia upon graduation. The objective of this study was to assess outcomes of dental school-affiliated oral sciences PhD program enrollment, graduates, and placement between 1994 and 2016. Using the American Dental Association annual survey of advanced dental education programs not accredited by the Commission on Dental Accreditation and data obtained from 22 oral sciences PhD programs, we assessed student demographics, enrollment, graduation, and placement. Based on the data provided by program directors, the average new enrollment was 33, and graduation was 26 per year. A total of 605 graduated; 39 did not complete; and 168 were still in training. Among those 605 graduates, 211 were faculty in U.S. academic institutions, and 77 were faculty in foreign institutions. Given that vacant budgeted full-time faculty positions averaged 257 per year during this period, graduates from those oral sciences PhD programs who entered academia in the United States would have filled 9 (3.6%) vacant faculty positions per year. Therefore, PhD programs have consistently generated only a small pipeline of dental school faculty. Better mentoring to retain talent in academia is necessary. Stronger support and creative funding plans are essential to sustain the PhD program. Furthermore, the oral sciences PhD program database should be established and maintained by dental professional organizations to allow assessments of training models, trends of enrollment, graduation, and placement outcomes.


The effect of genetic robustness on evolvability in digital organisms.
Recent work has revealed that many biological systems keep functioning in the face of mutations and therefore can be considered genetically robust. However, several issues related to robustness remain poorly understood, such as its implications for evolvability (the ability to produce adaptive evolutionary innovations). Here, we use the Avida digital evolution platform to explore the effects of genetic robustness on evolvability. First, we obtained digital organisms with varying levels of robustness by evolving them under combinations of mutation rates and population sizes previously shown to select for different levels of robustness. Then, we assessed the ability of these organisms to adapt to novel environments in a variety of experimental conditions. The data consistently support that, for simple environments, genetic robustness fosters long-term evolvability, whereas, in the short-term, robustness is not beneficial for evolvability but may even be a counterproductive trait. For more complex environments, however, results are less conclusive. The finding that the effect of robustness on evolvability is time-dependent is compatible with previous results obtained using RNA folding algorithms and transcriptional regulation models. A likely scenario is that, in the short-term, genetic robustness hampers evolvability because it reduces the intensity of selection, but that, in the long-term, relaxed selection facilitates the accumulation of genetic diversity and thus, promotes evolutionary innovation.


Why do some hospitals achieve better care of severely malnourished children than others? Five-year follow-up of rural hospitals in Eastern Cape, South Africa.
Staff at 11 rural hospitals in an under-resourced region of Eastern Cape Province, South Africa, participated in an intervention to improve the quality of care of severely malnourished children through training and support aimed at implementing the WHO case-management guidelines. Despite similar intervention inputs, some hospitals reduced their case-fatality rates by at least half, whereas others did not. The aim of this study was to investigate reasons for this disparity. Two successful and two poorly performing hospitals were purposively selected based on their case-fatality rates, which were <10% in the successful hospitals and >30% in those performing poorly. Comparative data were collected during June to October 2004 through structured observations of ward procedures, compilation of hospital data on case-loads and resources, and staff interviews and discussions related to attitudes, teamwork, training, supervision, managerial support and leadership. The four study hospitals had broadly similar resources, infrastructure and child:nurse ratios, and all had made changes to their clinical and dietary management following training. Case-management was broadly in line with WHO guidelines but the study revealed clear differences in institutional culture which influenced quality of care. Staff in the successful hospitals were more attentive and assiduous than staff in the poorly performing hospitals, especially in relation to rehydration procedures, feeding and the recording of vital signs. There was a strong emphasis on in-service training and induction of incoming staff in the successful hospitals and better supervision of junior staff and carers. Nurses had more positive attitudes towards malnourished children and their carers, and were less judgmental. Underlying factors were differences in leadership, teamwork, and managerial supervision and support. We conclude that unless there are supportive structures at managerial level, the potential benefits of efficacious interventions and related training programmes to improve health worker performance can be thwarted.


Peripheral nerve blocks in the management of postoperative pain: challenges and opportunities.
Peripheral nerve blocks (PNBs) are increasingly used as a component of multimodal analgesia and may be administered as a single injection (sPNB) or continuous infusion via a perineural catheter (cPNB). We undertook a qualitative review focusing on sPNB and cPNB with regard to benefits, risks, and opportunities for optimizing patient care. Meta-analyses of randomized controlled trials have shown superior pain control and reductions in opioid consumption in patients receiving PNB compared with those receiving intravenous opioids in a variety of upper and lower extremity surgical procedures. cPNB has also been associated with a reduction in time to discharge readiness compared with sPNB. Risks of PNB, regardless of technique or block location, include vascular puncture and bleeding, nerve damage, and local anesthetic systemic toxicity. Site-specific complications include quadriceps weakness in patients receiving femoral nerve block, and pleural puncture or neuraxial blockade in patients receiving interscalene block. The major limitation of sPNB is the short (12-24 hours) duration of action. cPNB may be complicated by catheter obstruction, migration, and leakage of local anesthetic as well as accidental removal of catheters. Potential infectious complications of catheters, although rare, include local inflammation and infection. Other considerations for ambulatory cPNB include appropriate patient selection, education, and need for 24/7 availability of a health care provider to address any complications. The ideal PNB technique would have a duration of action that is sufficiently long to address the most intense period of postsurgical pain; should be associated with minimal risk of infection, neurologic complications, bleeding, and local anesthetic systemic toxicity; and should be easy to perform, convenient for patients, and easy to manage in the postoperative period.


Effect of resealing on microleakage of resin composite restorations in relationship to margin design and composite type.
To determine the relationship between margin preparation design and resin-composite type on microleakage with or without re-application of surface-penetrating sealant. Class-I resin-composite restorations were completed for 128 extracted human molars. Half of the margins were beveled, the other half, butt-joint. Half of each group was restored with Filtek-Supreme (FS), the other half with Esthet-X (EX) using their respective adhesive systems. Margins were etched and sealed with a surface-penetrating sealant, Fortify. The samples were stored in water 24h, and thermocycled (5,000 cycles, 5°C-55°C). Then, samples were abraded using a toothbrush machine (6,000 strokes). Half of the restorations from each sealant group (n=16) were resealed, and the other half had no further treatment. Thermocycling and tooth brushing were repeated. The samples were sealed with nail polish, immersed in methylene-blue for 8h, sectioned, and magnified digital photographs were taken. Three examiners assessed dye penetration. A 2×2×2 multi-layered Chi-Square analysis, using Cochran-Mantel-Haenszel test was conducted for statistical analysis. No difference was observed between sealed and resealed FS and EX restorations with butt-joint margins. In beveled margins, resealing caused significantly less microleakage (P<.01). No differences were found between restorations either sealed or resealed with bevel margins. In butt-joint margins, at the leakage level deeper than 2/3 of the preparation depth, resealed FS showed less microleakage than EX resealed restorations (P<.01). Resealing reduced microleakage in bevel margins, however, in butt-joint margins resealing did not affect the leakage. A significant statistical relationship exists between and within resealing, margin preparation design, type of composite, and microleakage.


Structure of the CaMKIIdelta/calmodulin complex reveals the molecular mechanism of CaMKII kinase activation.
Long-term potentiation (LTP), a long-lasting enhancement in communication between neurons, is considered to be the major cellular mechanism underlying learning and memory. LTP triggers high-frequency calcium pulses that result in the activation of Calcium/Calmodulin (CaM)-dependent kinase II (CaMKII). CaMKII acts as a molecular switch because it remains active for a long time after the return to basal calcium levels, which is a unique property required for CaMKII function. Here we describe the crystal structure of the human CaMKIIdelta/Ca2+/CaM complex, structures of all four human CaMKII catalytic domains in their autoinhibited states, as well as structures of human CaMKII oligomerization domains in their tetradecameric and physiological dodecameric states. All four autoinhibited human CaMKIIs were monomeric in the determined crystal structures but associated weakly in solution. In the CaMKIIdelta/Ca2+/CaM complex, the inhibitory region adopted an extended conformation and interacted with an adjacent catalytic domain positioning T287 into the active site of the interacting protomer. Comparisons with autoinhibited CaMKII structures showed that binding of calmodulin leads to the rearrangement of residues in the active site to a conformation suitable for ATP binding and to the closure of the binding groove for the autoinhibitory helix by helix alphaD. The structural data, together with biophysical interaction studies, reveals the mechanism of CaMKII activation by calmodulin and explains many of the unique regulatory properties of these two essential signaling molecules. This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3-D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the Web plugin are available in Text S1.


Evaluation of the Medicolegal Process in Neurosurgical Practice with A Scenario.
The main purpose of medicine is to protect humans from diseases and its complications. Patients may be at risk in the course of diseases or during medical and surgical treatments, which can have undesirable consequences, including death. These risks, which are accepted by all medical authorities and medical literature, are called "complications." One of the responsibilities of the physicians is to detect complications on time and to manage them in accordance with the current medical standards. In the last two decades, allegations that any medical practice is "faulty" have been increasing, and these allegations are presented to the press and media regardless of whether they are justified. This situation adversely affects the medical practice, leading to defensive medical practices, affecting the public health. In this article, we presented our medical responsibilities over a neurosurgical scenario and mentioned the legal procedures to be experienced in such a situation. As physicians, we must know all the legal responsibilities of our profession and record all stages of treatments applied, to suffer the least damage from these claims and legal processes that cause pecuniary and non-pecuniary injury.


Constructive cigarette regulation.
Professor W. Kip Viscusi argues for a move away from the adversarial approach to tobacco regulation, an approach that is currently embodied in class action lawsuits and the proposed broadening of FDA regulatory power over cigarettes. In this Article, he suggests that the FDA should take a constructive role in fostering technological innovations to promote cigarette safety, in much the same way that the government currently fosters safety improvements in motor vehicles and jobs. Professor Viscusi claims that the objective of government policy should be to promote informed consumer risk taking--an approach which recognizes that adult consumers have a right to smoke and to incur the associated risks. He provides survey data demonstrating that although consumers know that smoking is a risky decision, they have little exposure to information regarding the comparative riskiness of various cigarette brands. According to Professor Viscusi, the government should assist in compiling and disseminating information regarding the comparative risks of different smoking options and the effects of certain innovative safety features for cigarettes. Making this information available would enable consumers to make more informed smoking decisions and potentially minimize the health hazards that smoking poses.


An investigation into the protonation states of the C1 domain of cardiac myosin-binding protein C.
Myosin-binding protein C (MyBP-C) is a myofibril-associated protein found in cardiac and skeletal muscle. The cardiac isoform (cMyBP-C) is subject to reversible phosphorylation and the surface-charge state of the protein is of keen interest with regard to understanding the inter-protein interactions that are implicated in its function. Diffraction data from the C1 domain of cMyBP-C were extended to 1.30 A resolution, where the <I/sigma(I)> of the diffraction data crosses 2.0, using intense synchrotron radiation. The protonation-state determinations were not above 2sigma (the best was 1.81sigma) and therefore an extrapolation is given, based on 100% data completeness and the average DPI, that a 3sigma determination could be possible if X-ray data could be measured to 1.02 A resolution. This might be possible via improved crystallization or multiple sample evaluation, e.g. using robotics or a yet more intense/collimated X-ray beam or combinations thereof. An alternative would be neutron protein crystallography at 2 A resolution, where it is estimated that for the unit-cell volume of the cMyBP-C C1 domain crystal a crystal volume of 0.10 mm3 would be needed with fully deuterated protein on LADI III. These efforts would optimally be combined in a joint X-ray and neutron model refinement.


Enhancer of seizure: a new genetic locus in Drosophila melanogaster defined by interactions with temperature-sensitive paralytic mutations.
Mutations in the enhancer of seizure (e(sei] locus have been isolated on the basis of their ability to cause temperature-induced paralysis of alleles at the seizure (sei) locus at temperatures at which these mutations ordinarily do not paralyze. This enhancer is specific to the seizure locus and is without effect on other temperature-sensitive paralytic mutants including para, nap, tip-E and shi. This suggests that the enhancer responds specifically to the mechanism of paralysis mediated by the seizure mutations. The e(sei) is a recessive mutation which maps to 39.0 on the left arm of chromosome 3. Deficiency mapping has placed it at 69A4-B5 on the salivary gland polytene chromosome map. When a new enhancer allele was isolated following P-M hybrid dysgenesis, there was a concomitant P-element insertion at 69B. In the absence of seizure mutations, the enhancer mutation causes non-temperature dependent hyperactivity when agitated and interferes with the climbing response. Electrophysiological studies examined the effects of increasing temperature on electrical activity in the adult giant fiber/flight muscle system. Neuronal hyperactivity was seen in both e(sei) and sei single mutant homozygotes, but not in wild type. The hyperactivity was more severe in the sei;e(sei) double mutants. The correlation between the physiological effects and the mutant behavior suggests that both sei and e(sei) cause membrane excitability defects. Since previous work has shown that seizure mutants affect [3H]saxitoxin binding to the voltage-sensitive sodium channel, e(sei) may code for a gene product which interacts with this channel.


Contrast MR of the brain after high-perfusion cardiopulmonary bypass.
To study the efficacy of contrast MR imaging in the evaluation of central nervous system complications in the cardiopulmonary bypass patient and attempt to explain their pathophysiology based on the MR appearance and the cardiopulmonary bypass protocol. Nineteen patients were prospectively studied with contrast MR examinations the day before and 3 to 7 days after cardiopulmonary bypass, to determine the nature, extent, and number of new postoperative MR abnormalities. Cardiopulmonary bypass parameters used in our institution included: membrane oxygenation, arterial filtration with a pore size of 25 microns, and a relatively high perfusion rate to produce a cardiac index of 2.0 to 2.5 L/min per m2. The preoperative noncontrast MR examination showed age-related changes and/or signs of ischemia in 60% of patients on the day before surgery. However, there was no abnormal enhancement or new T2 abnormalities on any postoperative MR examination to suggest hypoperfusion or emboli. None of the 19 patients developed overt neurologic deficits postoperatively. Review of the cardiopulmonary bypass protocol used indicated significant variations in technique at different institutions. Contrast MR imaging demonstrated no new abnormalities in patients after cardiopulmonary bypass performed with strict in-line arterial filtration and relatively high perfusion. MR imaging is feasible in the early postoperative period after cardiopulmonary bypass and may offer a convenient method for evaluation of the neurologic impact of technical factors associated with cardiopulmonary bypass.


Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people.
The neurobiological changes underlying the association of the apolipoprotein E (APOE) e4 allele with level of cognition are poorly understood. To test the hypothesis that amyloid load can account for (mediate) the association of the APOE e4 allele with level of cognition assessed proximate to death. There were 44 subjects with clinically diagnosed Alzheimer's disease and 50 without dementia, who had participated in the Religious Orders Study. They underwent determination of APOE allele status, had comprehensive cognitive testing in the last year of life, and brain autopsy at death. The percentage area of cortex occupied by amyloid beta and the density of tau positive neurofibrillary tangles were quantified from six brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Multiple regression analyses were used to examine whether amyloid load could account for the effect of allele status on level of cognition, controlling for age, sex, and education. Possession of at least one APOE e4 allele was associated with lower level of cognitive function proximate to death (p = 0.04). The effect of the e4 allele was reduced by nearly 60% and was no longer significant after controlling for the effect of amyloid load, whereas there was a robust inverse association between amyloid and cognition (p = 0.001). Because prior work had suggested that neurofibrillary tangles could account for the association of amyloid on cognition, we next examined whether amyloid could account for the effect of allele status on tangles. In a series of regression analyses, e4 was associated with density of tangles (p = 0.002), but the effect of the e4 allele was reduced by more than 50% and was no longer significant after controlling for the effect of amyloid load. These findings are consistent with a sequence of events whereby the e4 allele works through amyloid deposition and subsequent tangle formation to cause cognitive impairment.


Neural primacy of the dorsolateral prefrontal cortex in patients with obsessive-compulsive disorder.
The dorsolateral prefrontal cortex (DLPFC), a key structure in the executive system, has consistently emerged as a crucial element in the pathophysiology of obsessive-compulsive disorder (OCD). However, the neural primacy of the DLPFC remains elusive in this disorder. We investigated the causal interaction (measured by effective connectivity) between the DLPFC and the remaining brain areas using bivariate Granger causality analysis of resting-state fMRI collected from 88 medication-free OCD patients and 88 matched healthy controls. Additionally, we conducted seed-based functional connectivity (FC) analyses to identify network-level neural functional alterations using the bilateral DLPFC as seeds. OCD patients demonstrated reduced FC between the right DLPFC and right orbitofrontal cortex (OFC), and activity in the right OFC had an inhibitory effect on the right DLPFC. Additionally, we observed alterations in both feedforward and reciprocal influences between the inferior temporal gyrus (ITG) and the DLPFC in patients. Furthermore, activity in the cerebellum had an excitatory influence on the right DLPFC in OCD patients. These findings may help to elucidate the psychopathology of OCD by detailing the directional connectivity between the DLPFC and the rest of the brain, ultimately helping to identify regions that could serve as treatment targets in OCD.


Police peer support programs: current knowledge and practice.
This review examines the current empirical research and literature on peer assistance programs, peer support, and peer-facilitated interventions for police officers. A literature search was conducted to identify studies on police, peer support, and peer assistance programs. Studies were examined in terms of the following criteria: description of data collection methods, findings, study limitations, implications for police, workplace assistance, and peer support. Articles on peer support in the aftermath of the September 11, 2001, World Trade Center rescue and recovery efforts were also reviewed. The research studies reviewed in this article do not evaluate peer program effectiveness from the perspective of those officers receiving peer services. To better serve this invaluable population, efforts must be made to incorporate their views. Information is also needed on the effectiveness of peer assistance programs and peer-driven crisis intervention models. Finally, research is needed that specifically examines the effectiveness of programs that utilize trained peers in partnership with professional mental health practitioners.


Effect of Lactobacillus Plantarum TWK10 on Improving Endurance Performance in Humans.
Microbiota is currently an important issue in disease and health and many studies have revealed it to play an important role in physiological homeostasis and health promotion. Lactobacillus plantarum (L. plantarum), isolated from Taiwan pickled vegetables, is a well-known probiotic microorganism. In a recent animal study, it was shown that supplementation of mice with L. plantarum TWK10 (TWK10) could increase muscle mass, improve exercise performance and exert anti-fatigue effects. In order to examine the ergogenic effect of TWK10 supplementation on endurance performance in humans, we conducted a human double-blind placebo-controlled clinical study. A total of sixteen adult subjects over 20 years of age were recruited and randomly allocated to the placebo or TWK10 group (n = 8 each). The TWK10 group received 6 weeks of supplementation. Physiological assessments were conducted by exhaustive treadmill exercise measurements and related biochemical indexes. After 6 weeks of supplementation, levels of lactic acid, blood ammonia, blood glucose, free fatty acid (FFA) and creatine kinase (CK) were evaluated during exhaustive exercise. We were able to show that the TWK10 group had significantly higher endurance performance and glucose content in a maximal treadmill running test compared to the placebo group (P < 0.05), suggesting that TWK10 supplementation may be beneficial to energy harvest. Taken together, our results suggest that TWK10 has the potential to be an aerobic exercise supplement for physiological adaptation or an ergogenic supplement with health benefits for amateur runners.


Embryonic transcription is controlled by maternally defined chromatin state.
Histone-modifying enzymes are required for cell identity and lineage commitment, however little is known about the regulatory origins of the epigenome during embryonic development. Here we generate a comprehensive set of epigenome reference maps, which we use to determine the extent to which maternal factors shape chromatin state in Xenopus embryos. Using α-amanitin to inhibit zygotic transcription, we find that the majority of H3K4me3- and H3K27me3-enriched regions form a maternally defined epigenetic regulatory space with an underlying logic of hypomethylated islands. This maternal regulatory space extends to a substantial proportion of neurula stage-activated promoters. In contrast, p300 recruitment to distal regulatory regions requires embryonic transcription at most loci. The results show that H3K4me3 and H3K27me3 are part of a regulatory space that exerts an extended maternal control well into post-gastrulation development, and highlight the combinatorial action of maternal and zygotic factors through proximal and distal regulatory sequences.


Multielement analysis of lunar soil and rocks.
Results for multielement analysis of lunar soil and of seven rocks returned by Apollo 11 are presented. Sixty-six elements were determined with spark source mass spectrography and neutron activation. U. S. Geological Survey standard W-1 was used as a comparative stanadard. Results indicate an apparent uniformity of composition among the samples. Comparison with solar, meteoritic, and terrestrial abundances reveals depletiozt of volatile elements and enrichment of the rare earths titaniunm, zirconium, yttriuntm, and hafnium. Althouglh there is an overall similarity of the lunar material to basaltic achondrites amid basalts, the differences suggest detailed geochemical processes to the history of this material.


Chronic mild stress paradigm as a rat model of depression: facts, artifacts, and future perspectives.
The chronic mild stress (CMS) paradigm was first described almost 40 years ago and has become a widely used model in the search for antidepressant drugs for major depression disorder (MDD). It has resulted in the publication of almost 1700 studies in rats alone. Under the original CMS procedure, the expression of an anhedonic response, a key symptom of depression, was seen as an essential feature of both the model and a depressive state. The prolonged exposure of rodents to unpredictable/uncontrollable mild stressors leads to a reduction in the intake of palatable liquids, behavioral despair, locomotor inhibition, anxiety-like changes, and vegetative (somatic) abnormalities. Many of the CMS studies do not report these patterns of behaviors, and they often fail to include consistent molecular, neuroanatomical, and physiological phenotypes of CMS-exposed animals. To critically review the CMS studies in rats so that conceptual and methodological flaws can be avoided in future studies. Analysis of the literature supports the validity of the CMS model and its impact on the field. However, further improvements could be achieved by (i) the stratification of animals into 'resilient' and 'susceptible' cohorts within the CMS animals, (ii) the use of more refined protocols in the sucrose test to mitigate physiological and physical artifacts, and (iii) the systematic evaluation of the non-specific effects of CMS and implementation of appropriate adjustments within the behavioral tests. We propose methodological revisions and the use of more advanced behavioral tests to refine the rat CMS paradigm, which offers a valuable tool for developing new antidepressant medications.


"Every shut eye, ain't sleep": The role of racism-related vigilance in racial/ethnic disparities in sleep difficulty.
Although racial/ethnic disparities in health have been well-characterized in biomedical, public health, and social science research, the determinants of these disparities are still not well-understood. Chronic psychosocial stress related specifically to the American experience of institutional and interpersonal racial discrimination may be an important determinant of these disparities, as a growing literature in separate scientific disciplines documents the adverse health effects of stress and the greater levels of stress experienced by non-White compared to White Americans. However, the empirical literature on the importance of stress for health and health disparities specifically due to racial discrimination, using population-representative data, is still small and mixed. In this paper, we explore the association between a novel measure of racially-salient chronic stress - "racism-related vigilance" - and sleep difficulty. We found that, compared to the White adults in our sample, Black (but not Hispanic) adults reported greater levels of vigilance. This vigilance was positively associated with sleep difficulty to similar degrees for all racial/ethnic groups in our sample (White, Black, Hispanic). Black adults reported greater levels of sleep difficulty compared to White adults. This disparity was slightly attenuated after adjustment for education and income. However, this disparity was completely attenuated after adjustment for racism-related vigilance. We found similar patterns of results for Hispanic compared to White adults, however, the disparities in sleep difficulty were smaller and not statistically significant. Because of the importance of sleep quality to health, our results suggest that the anticipation of and perseveration about racial discrimination is an important determinant of racial disparities in health.


[Influence of occlusion on head posture, during periods of continuous intermaxillary pressure].
The influence of divergent splint-adjusted maximum intercuspation on head posture during prolonged phases of clenching was studied in five subjects. During clenching in maximum intercuspation profound changes of head posture were observed, if intercuspation was not harmonized with an upright posture of head and body. Since the interrelation between occlusion and head posture is established a comprehensive approach of orthopedic, physiotherapeutic, and dental measures, in particular for the therapy of myoarthropathy patients with cervical spine symptoms seems appropriate. Occlusal corrections and determination of occlusal relations must always be made or at least checked in the upright relaxed patient with the head straight.


FAD mutations in amyloid precursor protein do not directly perturb intracellular calcium homeostasis.
Disturbances in intracellular calcium homeostasis are likely prominent and causative factors leading to neuronal cell death in Alzheimer's disease (AD). Familial AD (FAD) is early-onset and exhibits autosomal dominant inheritance. FAD-linked mutations have been found in the genes encoding the presenilins and amyloid precursor protein (APP). Several studies have shown that mutated presenilin proteins can directly affect calcium release from intracellular stores independently of Abeta production. Although less well established, there is also evidence that APP may directly modulate intracellular calcium homeostasis. Here, we directly examined whether overexpression of FAD-linked APP mutants alters intracellular calcium dynamics. In contrast to previous studies, we found that overexpression of mutant APP has no effects on basal cytosolic calcium, ER calcium store size or agonist-induced calcium release and subsequent entry. Thus, we conclude that mutated APP associated with FAD has no direct effect on intracellular calcium homeostasis independently of Abeta production.


Molecular xenomonitoring using mosquitoes to map lymphatic filariasis after mass drug administration in American Samoa.
Mass drug administration (MDA) programs have dramatically reduced lymphatic filariasis (LF) incidence in many areas around the globe, including American Samoa. As infection rates decline and MDA programs end, efficient and sensitive methods for detecting infections are needed to monitor for recrudescence. Molecular methods, collectively termed 'molecular xenomonitoring,' can identify parasite DNA or RNA in human blood-feeding mosquitoes. We tested mosquitoes trapped throughout the inhabited islands of American Samoa to identify areas of possible continuing LF transmission after completion of MDA. Mosquitoes were collected using BG Sentinel traps from most of the villages on American Samoa's largest island, Tutuila, and all major villages on the smaller islands of Aunu'u, Ofu, Olosega, and Ta'u. Real-time PCR was used to detect Wuchereria bancrofti DNA in pools of ≤ 20 mosquitoes, and PoolScreen software was used to infer territory-wide prevalences of W. bancrofti DNA in the mosquitoes. Wuchereria bancrofti DNA was found in mosquitoes from 16 out of the 27 village areas sampled on Tutuila and Aunu'u islands but none of the five villages on the Manu'a islands of Ofu, Olosega, and Ta'u. The overall 95% confidence interval estimate for W. bancrofti DNA prevalence in the LF vector Ae. polynesiensis was 0.20-0.39%, and parasite DNA was also detected in pools of Culex quinquefasciatus, Aedes aegypti, and Aedes (Finlaya) spp. Our results suggest low but widespread prevalence of LF on Tutuila and Aunu'u where 98% of the population resides, but not Ofu, Olosega, and Ta'u islands. Molecular xenomonitoring can help identify areas of possible LF transmission, but its use in the LF elimination program in American Samoa is limited by the need for more efficient mosquito collection methods and a better understanding of the relationship between prevalence of W. bancrofti DNA in mosquitoes and infection and transmission rates in humans.


Guanine crystals regulated by chitin-based honeycomb frameworks for tunable structural colors of sapphirinid copepod, Sapphirina nigromaculata.
Sapphirinid copepods, which are marine zooplankton, exhibit tunable structural colors originating from a layered structure of guanine crystal plates. In the present study, the coloring portion of adult male of a sapphirinid copepod, Sapphirina nigromaculata, under the dorsal body surface was characterized to clarify the regulation and actuation mechanism of the layered guanine crystals for spectral control. The coloring portions are separated into small domains 70-100 µm wide consisting of an ordered array of stacked hexagonal plates ~1.5 µm wide and ~80 nm thick. We found the presence of chitin-based honeycomb frameworks that are composed of flat compartments regulating the guanine crystal plates. The structural color is deduced to be tuned from blue to achromatic via yellow and purple by changing the interplate distance according to vital observation and optical simulation using a photonic array model. The framework structures are essential for the organization and actuation of the particular photonic arrays for the exhibition of the tunable structural color.


Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation.
Hutchinson-Gilford progeria syndrome (HGPS), a progeroid syndrome in children, is caused by mutations in LMNA (the gene for prelamin A and lamin C) that result in the deletion of 50 aa within prelamin A. In normal cells, prelamin A is a "CAAX protein" that is farnesylated and then processed further to generate mature lamin A, which is a structural protein of the nuclear lamina. The mutant prelamin A in HGPS, which is commonly called progerin, retains the CAAX motif that triggers farnesylation, but the 50-aa deletion prevents the subsequent processing to mature lamin A. The presence of progerin adversely affects the integrity of the nuclear lamina, resulting in misshapen nuclei and nuclear blebs. We hypothesized that interfering with protein farnesylation would block the targeting of progerin to the nuclear envelope, and we further hypothesized that the mislocalization of progerin away from the nuclear envelope would improve the nuclear blebbing phenotype. To approach this hypothesis, we created a gene-targeted mouse model of HGPS, generated genetically identical primary mouse embryonic fibroblasts, and we then examined the effect of a farnesyltransferase inhibitor on nuclear blebbing. The farnesyltransferase inhibitor mislocalized progerin away from the nuclear envelope to the nucleoplasm, as determined by immunofluoresence microscopy, and resulted in a striking improvement in nuclear blebbing (P < 0.0001 by chi2 statistic). These studies suggest a possible treatment strategy for HGPS.


Functional brain abnormalities are related to clinical recovery and time to return-to-play in athletes.
The relationship between athlete reports of symptoms, neurophysiological activation, and neuropsychological functioning is investigated in a sample of high school athletes. All athletes were evaluated using functional magnetic resonance imaging (fMRI), a computer-based battery of neurocognitive tests, and a subjective symptom scale. Athletes were evaluated within approximately 1 week of injury and again after clinical recovery using all assessment modalities. This study found that abnormal fMRI results during the first week of recovery predicted clinical recovery. As a group, athletes who demonstrated hyperactivation on fMRI scans at the time of their first fMRI scan demonstrated a more prolonged clinical recovery than athletes who did not demonstrate hyperactivation at the time of their first fMRI scan. These results demonstrate the relationship between neurophysiological, neuropsychological, and subjective symptom data in a relatively large sample composed primarily of concussed high school athletes. fMRI represents an important evolving technology for the understanding of brain recovery after concussion and may help shape return-to-play guidelines in the future.


Multisensory stimulation improves functional recovery and resting-state functional connectivity in the mouse brain after stroke.
Stroke causes direct structural damage to local brain networks and indirect functional damage to distant brain regions. Neuroplasticity after stroke involves molecular changes within perilesional tissue that can be influenced by regions functionally connected to the site of injury. Spontaneous functional recovery can be enhanced by rehabilitative strategies, which provides experience-driven cell signaling in the brain that enhances plasticity. Functional neuroimaging in humans and rodents has shown that spontaneous recovery of sensorimotor function after stroke is associated with changes in resting-state functional connectivity (RS-FC) within and across brain networks. At the molecular level, GABAergic inhibitory interneurons can modulate brain plasticity in peri-infarct and remote brain regions. Among this cell-type, a decrease in parvalbumin (PV)-immunoreactivity has been associated with improved behavioral outcome. Subjecting rodents to multisensory stimulation through exposure to an enriched environment (EE) enhances brain plasticity and recovery of function after stroke. Yet, how multisensory stimulation relates to RS-FC has not been determined. In this study, we investigated the effect of EE on recovery of RS-FC and behavior in mice after stroke, and if EE-related changes in RS-FC were associated with levels of PV-expressing neurons. Photothrombotic stroke was induced in the sensorimotor cortex. Beginning 2 days after stroke, mice were housed in either standard environment (STD) or EE for 12 days. Housing in EE significantly improved lost tactile-proprioceptive function compared to mice housed in STD environment. RS-FC in the mouse was measured by optical intrinsic signal imaging 14 days after stroke or sham surgery. Stroke induced a marked reduction in RS-FC within several perilesional and remote brain regions. EE partially restored interhemispheric homotopic RS-FC between spared motor regions, particularly posterior secondary motor. Compared to mice housed in STD cages, EE exposure lead to increased RS-FC between posterior secondary motor regions and contralesional posterior parietal and retrosplenial regions. The increased regional RS-FC observed in EE mice after stroke was significantly correlated with decreased PV-immunoreactivity in the contralesional posterior motor region. In conclusion, experimental stroke and subsequent housing in EE induces dynamic changes in RS-FC in the mouse brain. Multisensory stimulation associated with EE enhances RS-FC among distinct brain regions relevant for recovery of sensorimotor function and controlled movements that may involve PV/GABA interneurons. Our results indicate that targeting neural circuitry involving spared motor regions across hemispheres by neuromodulation and multimodal sensory stimulation could improve rehabilitation after stroke.


The Effects of the Korean Medicine Health Care Program on Stroke-Related Factors and Self-Care Enhancement.
This study was performed to examine the effects of the Korean medicine healthcare program on stroke-related factors and self-care enhancement. This study was a quasi-experimental, pretest-posttest nonequivalent control group design study (N = 58 participants), with 28 in the treatment group (Korean medicine health care program) and 30 in the control group (no intervention). The program was conducted twice a week for 2 hours, for a total of 12 weeks. There were statistically significant differences in systolic (p = 0.005) and diastolic blood pressure (p = 0.006), cholesterol (p < 0.001), blood glucose (p < 0.001), self-esteem (p = 0.001), self-efficacy (p < 0.001), health perception (p < 0.001), and the health behavior (p < 0.001) between the experimental group and the control group. Thus, the Korean medicine healthcare program was effective in managing stroke-related factors and enhancing self-care, and should be actively used to develop community health promotion strategies to prevent strokes and prepare long-term measures.


Immunofluorescence detection of clustered gamma-H2AX foci induced by HZE-particle radiation.
We studied the spatial and temporal distributions of foci of the phosphorylated form of the histone protein H2AX (gamma-H2AX), which is known to be activated by double-strand breaks after irradiation of human fibroblast cells with high-energy silicon (54 keV/microm) and iron (176 keV/microm) ions. Here we present data obtained with the ion path parallel to a monolayer of human fibroblast cells that leads to gamma-H2AX aggregates in the shape of streaks stretching over several micrometers in an x/y plane, thus enabling the analysis of the fluorescence distributions along the ion trajectories. Qualitative analyses of these distributions provide insights into DNA damage processing kinetics for high charge and energy (HZE) ions, including evidence of increased clustering of DNA damage and slower processing with increasing LET.


DNA cross-linking by dehydromonocrotaline lacks apparent base sequence preference.
Pyrrolizidine alkaloids (PAs) are ubiquitous plant toxins, many of which, upon oxidation by hepatic mixed-function oxidases, become reactive bifunctional pyrrolic electrophiles that form DNA-DNA and DNA-protein cross-links. The anti-mitotic, toxic, and carcinogenic action of PAs is thought to be caused, at least in part, by these cross-links. We wished to determine whether the activated PA pyrrole dehydromonocrotaline (DHMO) exhibits base sequence preferences when cross-linked to a set of model duplex poly A-T 14-mer oligonucleotides with varying internal and/or end 5'-d(CG), 5'-d(GC), 5'-d(TA), 5'-d(CGCG), or 5'-d(GCGC) sequences. DHMO-DNA cross-links were assessed by electrophoretic mobility shift assay (EMSA) of 32P endlabeled oligonucleotides and by HPLC analysis of cross-linked DNAs enzymatically digested to their constituent deoxynucleosides. The degree of DNA cross-links depended upon the concentration of the pyrrole, but not on the base sequence of the oligonucleotide target. Likewise, HPLC chromatograms of cross-linked and digested DNAs showed no discernible sequence preference for any nucleotide. Added glutathione, tyrosine, cysteine, and aspartic acid, but not phenylalanine, threonine, serine, lysine, or methionine competed with DNA as alternate nucleophiles for cross-linking by DHMO. From these data it appears that DHMO exhibits no strong base preference when forming cross-links with DNA, and that some cellular nucleophiles can inhibit DNA cross-link formation.


"Seeing a doctor is just like having a date": a qualitative study on doctor shopping among overactive bladder patients in Hong Kong.
Although having a regular primary care provider is noted to be beneficial to health, doctor shopping has been documented as a common treatment seeking behavior among chronically ill patients in different countries. However, little research has been conducted into the reasons behind doctor shopping behavior among patients with overactive bladder, and even less into how this behavior relates to these patients' illness and social experiences, perceptions, and cultural practices. Therefore, this study examines overactive bladder patients to investigate the reasons behind doctor shopping behavior. My study takes a qualitative approach, conducting 30 semi-structured individual interviews, with 30 overactive bladder patients in Hong Kong. My study found six primary themes that influenced doctor shopping behavior: lack of perceived need, convenience, work-provided medical insurance, unpleasant experiences with doctors, searching for a match doctor, and switching between biomedicine and traditional Chinese medicine. Besides the perceptual factors, participants' social environment, illness experiences, personal cultural preference, and cultural beliefs also intertwined to generate their doctor shopping behavior. Due to the low perceived need for a regular personal primary care physician, environmental factors such as time, locational convenience, and work-provided medical insurance became decisive in doctor shopping behavior. Patients' unpleasant illness experiences, stemming from a lack of understanding among many primary care doctors about overactive bladder, contributed to participants' sense of mismatch with these doctors, which induced them to shop for another doctor. Overactive bladder is a chronic bladder condition with very limited treatment outcome. Although patients with overactive bladder often require specialty urology treatment, it is usually beneficial for the patients to receive continuous, coordinated, comprehensive, and patient-centered support from their primary care providers. Primary care doctors' understanding on patients with overactive bladder with empathetic attitudes is important to reduce the motivations of doctor shopping behavior among these patients.


The effects of a relaxation program featuring aquatic therapy and autogenic training among people with cervical dystonia (a pilot study).
Classic physical interventions for cervical dystonia (CD) have focused on treating motor components or, on motor components and relaxation programs. However, no CD treatment study has focused on a relaxation program alone. We developed a pilot study to assess whether a therapy completely based on a relaxation program could improve the physical and mental symptomatologies of patients with CD. Fifteen persons were included in the experimental group, which received individual sessions of aquatic (Watsu) therapy (WT) and autogenic training (AT). In addition, 12 persons were included in passive control group. We administered different questionnaires related to quality of life (SF-36), pain (Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and Visual Analog Scale (VAS)) and mood (Beck Depression Inventory (BDI-II) and State-Trait Anxiety Inventory (STAI)). A significant interaction was observed between treatment and time with regard to the SF-36, VAS, and TWSTRS within the experimental group (p < 0.01). The BDI-II showed depression decrease as a simple effect (p < 0.05), and the STAI did not change. No effects were found with regard to the control group. In this exploratory study, we found that a therapy based on whole body relaxation improved the symptoms of patients with CD. This knowledge enables a disease-management strategy that uses a holistic perspective and moves beyond the dystonic focus.


Melatonin blocks the stimulatory effects of prolactin on human breast cancer cell growth in culture.
Melatonin (aMT) appears to be a potentially important oncostatic substance that can block the mitogenic effects of tumour-promoting hormones and growth factors such as oestradiol and epidermal growth factor, in vitro. In the present study, we examined the possibility that aMT would also inhibit the stimulatory effects of the tumour-promoter prolactin (PRL) on MCF-7 and ZR75-1 human breast cancer cell (HBC) growth under 5% charcoal-stripped fetal bovine serum culture conditions. Human PRL (10-100 ng ml-1) stimulated the rate of MCF-7 and ZR-75-1 HBC growth up to 2-fold above that of untreated controls. Melatonin, at concentrations between 10(-12) M and 10(-5)M, diminished and at physiological levels completely abolished PRL's mitogenic activity, but had no effect on growth in the absence of PRL. The mitogenic effects of human growth hormone (hGH), a PRL-related hormone, and also of several monoclonal antibodies (MAbs) against the PRL receptor (PRLR), were also abrogated by physiological concentrations of aMT. Additionally, aMT blocked the enhancement of MAb mitogenic activity induced by a second 'cross-linking' antibody (CLA). These findings indicate that aMT interrupts the PRLR-mediated growth signal in HBC and suggest that the oncostatic activity of aMT may also be linked with an antagonism of PRL's actions.


Estradiol modulates the pulsatile secretion of biologically active luteinizing hormone in man.
We investigated the effects of estradiol on bioactive luteinizing hormone (LH) release in normal men using two complementary strategies: (i) steady state intravenous infusions of estradiol at its endogenous production rate, and (ii) oral administration of the antiestrogen, tamoxifen HCl. Immunoreactive and biologically active LH were monitored by radioimmunoassay and the rat interstitial cell testosterone bioassay, respectively. Estradiol infusions significantly suppressed mean plasma bioactive LH concentrations and decreased the bio/immuno LH ratio. Conversely, antiestrogen treatment enhanced spontaneous bioactive LH pulse frequency, increased bioactive LH pulse amplitude, and augmented plasma intrapulse and interpulse bio/immuno LH ratios. Low-dose pulsed injections of exogenous gonadotropin-releasing hormone (GnRH) also increased plasma bio/immuno LH ratios. However, tamoxifen attenuated the ability of exogenous GnRH to further enhance the bio/immuno LH ratio, which suggests that endogenous LH release was already maximally enriched in LH bioactivity during antiestrogen administration. We conclude that estradiol modulates the pulsatile secretion of LH molecules enriched in biological activity in man.


Incorporation of Cl into sequentially deposited lead halide perovskite films for highly efficient mesoporous solar cells.
Organic-inorganic lead halide perovskites have been widely used as absorbers on mesoporous TiO2 films as well as thin films in planar heterojunction solar cells, yielding very high photovoltaic conversion efficiencies. Both the addition of chloride and sequential deposition methods were successfully employed to enhance the photovoltaic performance. Here, both approaches are combined in a sequential method by spincoating PbCl2 + PbI2 on a mesoporous TiO2 film followed by the perovskite transformation. The role of Cl in determining the optical, electrical, structural and morphological properties is correlated with the photovoltaic performance. The highest photovoltaic efficiency of 14.15% with the V(oc), FF and J(sc) being 1.09 V, 0.65 and 19.91 mA cm(-2) respectively was achieved with 10 mol% of PbCl2 addition due to an increase of the film conductivity induced by a better perovskite morphology. This is linked to an improvement of the hysteresis and reproducibility of the solar cells.


Haem oxygenase shows pro-oxidant activity in microsomal and cellular systems: implications for the release of low-molecular-mass iron.
Haem oxygenase-1 (HO-1) is a highly inducible stress protein that removes haem from cells with the release of biliverdin, carbon monoxide and low-molecular-mass iron (LMrFe). Several antioxidant functions have been ascribed to HO; its induction is considered to be a protective event. However, LMrFe produced during haem catabolism might elicit a pro-oxidant response, with deleterious consequences. We therefore investigated the delicate balance between pro-oxidant and antioxidant events with the use of a microsomal lipid peroxidation (LPO) system. By using microsomal-bound HO in an NADPH-dependent LPO system, we assessed the pro-oxidant nature of the released LMrFe and the antioxidant effect of the released bilirubin. Hb, a biologically relevant substrate for HO, was included with the microsomes to supplement the source of haem iron and to promote LPO. We found significant increases in microsomal LPO, by using the thiobarbituric acid (TBA) test, after incubation with Hb. This Hb-stimulated peroxidation was inhibited by HO inhibitors and by iron chelators, suggesting a HO-driven, iron-dependent mechanism. GLC-MS was employed to measure the specific LPO product 4-hydroxy-2-nonenal and to confirm our TBA test results. A HO inhibitor attenuated an increase in intracellular LMrFe that occurred after treatment of rat pulmonary artery smooth-muscle cells with Hb. Additionally, exogenously added bilirubin at an equimolar concentration to the LMrFe present in both microsomal and liposomal systems was unable to prevent the pro-oxidant effect of the iron. Under certain circumstances HO can act as a pro-oxidant and seems to have a role in stimulating microsomal LPO.


A meta-analysis of the effect of neuromuscular training on the prevention of the anterior cruciate ligament injury in female athletes.
Female athletes are more prone to anterior cruciate ligament (ACL) injury than their male counterparts, presumably because of anatomical, hormonal, and neuromuscular differences. Of these three, only the neuromuscular component can be modified by preventive exercise. We aimed to evaluate the effect of a neuromuscular protocol on the prevention of ACL injury by performing meta-analysis, and to identify essential factors by subgroup analysis. An extensive literature review was conducted to identify relevant studies, and eventually, only seven randomized controlled trials or prospective cohort studies were included in the analysis. The odds ratios (OR) and the confidence interval (CI) for the overall effects of training and of potentially contributory factors were estimated. The OR and the 95% CI for the overall effect of the preventive training were 0.40 and [0.27, 0.60], respectively. Subgroup analysis revealed that an age under 18, soccer rather than handball, pre- and in-season training rather than either pre- or in-season training, and the plyometrics and strengthening components rather than balancing were significant. Meta-analysis showed that pre- and in-season neuromuscular training with an emphasis on plyometrics and strengthening exercises was effective at preventing ACL injury in female athletes, especially in those under 18 years of age. Further study is required to develop a relevant training program protocol of appropriate intensity.


Influence of chance, history, and adaptation on digital evolution.
We evolved multiple clones of populations of digital organisms to study the effects of chance, history, and adaptation in evolution. We show that clones adapted to a specific environment can adapt to new environments quickly and efficiently, although their history remains a significant factor in their fitness. Adaptation is most significant (and the effects of history less so) if the old and new environments are dissimilar. For more similar environments, adaptation is slower while history is more prominent. For both similar and dissimilar transfer environments, populations quickly lose the ability to perform computations (the analogue of beneficial chemical reactions) that are no longer rewarded in the new environment. Populations that developed few computational "genes" in their original environment were unable to acquire them in the new environment.


The importance of incorporating smoking cessation into lung cancer screening.
Lung cancer is the leading cause of cancer-related death in the United States (U.S.) and is the second most common non-skin cancer among men and women, accounting for about 30% of cancer-related deaths. There is clear and accumulating evidence that continued tobacco use has multiple adverse effects on cancer treatment outcomes, including greater probability of recurrence, second primary malignancies, reduced survival, greater symptom burden, and poorer quality of life (QOL). Recent findings suggest an avenue to significantly mitigate the impact of smoking on lung cancer mortality rates through the use of low-dose computed tomography (LDCT) lung cancer screening. Based on the reviewed evidence (type B), the U.S. Preventive Services Task Force (USPSTF) guidelines of 2015 recommend screening combined with smoking cessation interventions for high-risk heavy smokers and recent quitters. These practice changes offer opportunities to develop novel smoking cessation strategies tailored to highly specific settings that aim to amplify the survivorship gains expected from screening alone. However, there is a paucity of research and data that speaks to the feasibility and efficacy of providing smoking cessation treatment specifically within the context of the LDCT lung cancer screening environment. While some studies have attempted to characterize the parameters within which smoking cessation interventions should be implemented in this context, further research is needed to explore relevant factors such as the format, components, and timing of interventions, as well as the influence of risk perceptions and results of the screening itself on motivation and ability to quit smoking.


Chromosomal localization of nucleic acid-binding proteins by affinity mapping: assignment of the IRE-binding protein gene to human chromosome 9.
Three human mRNAs are regulated post-transcriptionally by iron via iron-responsive elements (IREs) contained in each mRNA. A cytoplasmic protein (IRE-BP) binds to these cis-acting elements and mediates the translational regulation of ferritin H- and L-chain mRNA and the iron-dependent stability of transferrin receptor (TfR) mRNA. We have taken advantage of the different mobilities of the human and rodent IRE/IRE-BP complexes on non-denaturing polyacrylamide gels to determine the chromosomal localization of the gene encoding the IRE-BP. Utilizing a panel of 34 different human/rodent hybrid cell lines we have assigned the IRE-BP gene to human chromosome 9. This new technique based on nucleic acid/protein interaction may allow determination of the chromosomal localization of other RNA- or DNA-binding proteins.


Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients.
Elevated plasma lipopolysaccharide (LPS), an indicator of microbial translocation from the gut, is a likely cause of systemic immune activation in chronic HIV infection. LPS induces monocyte activation and trafficking into brain, which are key mechanisms in the pathogenesis of HIV-associated dementia (HAD). To determine whether high LPS levels are associated with increased monocyte activation and HAD, we obtained peripheral blood samples from AIDS patients and examined plasma LPS by Limulus amebocyte lysate (LAL) assay, peripheral blood monocytes by FACS, and soluble markers of monocyte activation by ELISA. Purified monocytes were isolated by FACS sorting, and HIV DNA and RNA levels were quantified by real time PCR. Circulating monocytes expressed high levels of the activation markers CD69 and HLA-DR, and harbored low levels of HIV compared to CD4(+) T-cells. High plasma LPS levels were associated with increased plasma sCD14 and LPS-binding protein (LBP) levels, and low endotoxin core antibody levels. LPS levels were higher in HAD patients compared to control groups, and were associated with HAD independently of plasma viral load and CD4 counts. LPS levels were higher in AIDS patients using intravenous heroin and/or ethanol, or with Hepatitis C virus (HCV) co-infection, compared to control groups. These results suggest a role for elevated LPS levels in driving monocyte activation in AIDS, thereby contributing to the pathogenesis of HAD, and provide evidence that cofactors linked to substance abuse and HCV co-infection influence these processes.


[Prevalence and susceptibility pattern of bacteria isolated from infected chronic wounds in adult patients].
Chronic wounds are considered a public health problem that may be complicated by bacterial infections, mainly caused by resistant strains. To study the bacteria prevalence and antimicrobial susceptibility in samples from adult patients with chronic wounds. Patients treated at National Institute of Wounds Foundation between May and July 2014, with chronic ulcers in lower extremities with clinical inflammatory signs were recluted. Samples were cultured in aerobic and anaerobic atmosphere and species identification was performed by API (Biomerieux) galleries. The in vitro susceptibility was evaluated according to the Kirby Bauer method. From 73 patients, 46 had infected wounds most of them were venous ulcers (33) with prevalence in polymicrobial infections and 10 with foot-diabetes ulcers with prevalence in monomicrobial infections (p ≤ 0.05). Sixty-eight strains were isolated and Enterobacteriaceae were predominant in monomicrobial infection (p ≤ 0.05) and the other groups were slightly higher in polymicrobial infection. The main species were Staphylococcus aureus (24%) followed by P. aeruginosa (18%). Fifty strains (77%) were resistant or multi-resistance. We emphasize resistance of S. aureus to ciprofloxacin (50%) and cefoxitin (37.5%), thus identifying resistance to methicillin in the community (CA-SAMR), all of which are sensitive to cotrimoxazole. Enterobacteria showed sensitivity to amikacin (95.5%), P. aeruginosa showed resistance to ciprofloxacin (33.3%) with high sensitivity to gentamicin (91.7%) and amikacin (83.3%), while Acinetobacter spp showed resistance to ciprofloxacin and ceftazidime in 60%, with 100% sensitivity to imipenem. 50% Streptococcus β hemolytic showed resistance to clindamycin and penicillin. These data provide epidemiological information on chronic wound infections, representing support for diagnosis, treatment and management of this pathology.


Long-term studies of hantavirus reservoir populations in the southwestern United States: a synthesis.
A series of intensive, longitudinal, mark-recapture studies of hantavirus infection dynamics in reservoir populations in the southwestern United States indicates consistent patterns as well as important differences among sites and host-virus associations. All studies found a higher prevalence of infection in older (particularly male) mice; one study associated wounds with seropositivity. These findings are consistent with horizontal transmission and transmission through fighting between adult male rodents. Despite very low rodent densities at some sites, low-level hantavirus infection continued, perhaps because of persistent infection in a few long-lived rodents or periodic reintroduction of virus from neighboring populations. Prevalence of hantavirus antibody showed seasonal and multiyear patterns that suggested a delayed density-dependent relationship between prevalence and population density. Clear differences in population dynamics and patterns of infection among sites, sampling periods, and host species underscore the importance of replication and continuity of long-term reservoir studies. Nevertheless, the measurable associations between environmental variables, reservoir population density, rates of virus transmission, and prevalence of infection in host populations may improve our capacity to model processes influencing infection and predict increased risk for hantavirus transmission to humans.


Anti-tumor necrosis factor therapies.
Recently published studies confirm that the long-term use of biologicals targeting tumor necrosis factor-alpha (TNF-alpha) in therapy for rheumatoid arthritis (RA) gives rise to sustained improvement in symptoms and signs of disease provided the anti-TNF agent is efficacious and of low immunogenicity. The current regimens for infliximab 3 or 10 mg/kg infusion in combination with weekly oral methotrexate, or of etanercept 25 mg subcutaneously twice per week, appear to fulfill these criteria. D2E7, a "human" antibody produced by phage display, has also been used for over a year. It has recently emerged that anti-TNF therapy protects joints from structural damage. The 1-year data for infliximab and methotrexate combination therapy suggest that this regimen reduces disability. In early RA, etanercept acts more rapidly than methotrexate to decrease symptoms and retard the progression of erosions. In conclusion, for patients with established and early RA, anti-TNF therapies set a new standard for symptom control and joint protection.


Validity of self-reported substance use: research setting versus primary health care setting.
Self-reported substance use is more likely to be influenced by underreporting bias compared to the biological markers. Underreporting bias or validity of self-reported substance use depends on the study population and cannot be generalized to the entire population. This study aimed to compare the validity of self-reported substance use between research setting and primary health care setting from the same source population. The population in this study included from Rafsanjan Youth Cohort Study (RYCS) and from primary care health centers. The sample from RYCS is made up 607 participants, 113 (18.62%) women and 494 (81.38%) men and sample from PHC centers is made up 522 individuals including 252 (48.28%) women and 270 (51.72%) men. We compared two groups in respect of prevalence estimates based on self-reported substance use and urine test. Then for evaluating validity of self-reported substance use in both group, the results of reference standard, urine tests, were compared with the results of self-reported drug use using measures of concordance. The prevalence of substance use based on urine test was significantly higher in both settings compared to self-reported substance use over the past 72 h. The sensitivity of self-report substance use over the past 72 h in research setting was 39.4, 20, 10% and zero for opium, methadone, cannabis and amphetamine, respectively and in primary health care setting was 50, 20.7, 12.5% and zero for opium, methadone, cannabis and amphetamine, respectively. The level of agreement between self-reported substance use over the past 72 h and urine test indicated fair and moderate agreement for opium in both research and primary health care settings, respectively and also slight agreement for methadone and cannabis in both settings were reported. There was no significant difference between the two groups in terms of self-reported substance use. For all substances, the level of agreement increased with longer recall periods. The specificity of self-report for all substances in both groups was more than 99%. Individuals in primary health care setting were more likely to self-reported substance use than in research setting, but setting did not have a statistically significant effect in terms of self-reported substance use. Programs that rely on self-reported substance use may not estimate the exact prevalence of substance use in both research and primary health care settings, especially for substances that have a higher social stigma. Therefore, it is recommended that self-report and biological indicators be used for more accurate evaluation in substance use studies. It is also suggested that future epidemiological studies be performed to reduce bias of social desirability and find a method providing the highest level of privacy.


Flux balance analysis of primary metabolism in Chlamydomonas reinhardtii.
Photosynthetic organisms convert atmospheric carbon dioxide into numerous metabolites along the pathways to make new biomass. Aquatic photosynthetic organisms, which fix almost half of global inorganic carbon, have great potential: as a carbon dioxide fixation method, for the economical production of chemicals, or as a source for lipids and starch which can then be converted to biofuels. To harness this potential through metabolic engineering and to maximize production, a more thorough understanding of photosynthetic metabolism must first be achieved. A model algal species, C. reinhardtii, was chosen and the metabolic network reconstructed. Intracellular fluxes were then calculated using flux balance analysis (FBA). The metabolic network of primary metabolism for a green alga, C. reinhardtii, was reconstructed using genomic and biochemical information. The reconstructed network accounts for the intracellular localization of enzymes to three compartments and includes 484 metabolic reactions and 458 intracellular metabolites. Based on BLAST searches, one newly annotated enzyme (fructose-1,6-bisphosphatase) was added to the Chlamydomonas reinhardtii database. FBA was used to predict metabolic fluxes under three growth conditions, autotrophic, heterotrophic and mixotrophic growth. Biomass yields ranged from 28.9 g per mole C for autotrophic growth to 15 g per mole C for heterotrophic growth. The flux balance analysis model of central and intermediary metabolism in C. reinhardtii is the first such model for algae and the first model to include three metabolically active compartments. In addition to providing estimates of intracellular fluxes, metabolic reconstruction and modelling efforts also provide a comprehensive method for annotation of genome databases. As a result of our reconstruction, one new enzyme was annotated in the database and several others were found to be missing; implying new pathways or non-conserved enzymes. The use of FBA to estimate intracellular fluxes also provides flux values that can be used as a starting point for rational engineering of C. reinhardtii. From these initial estimates, it is clear that aerobic heterotrophic growth on acetate has a low yield on carbon, while mixotrophically and autotrophically grown cells are significantly more carbon efficient.


The Warwick patellofemoral arthroplasty trial: a randomised clinical trial of total knee arthroplasty versus patellofemoral arthroplasty in patients with severe arthritis of the patellofemoral joint.
Severe arthritis of the knee is a disabling condition, with over 50,000 knee replacements performed each year in the UK. Isolated patellofemoral joint arthritis occurs in over 10% of these patients with the treatment options being patellofemoral arthroplasty or total knee arthroplasty. Whilst many surgeons believe total knee arthroplasty is the 'gold standard' treatment for severe knee arthritis, patellofemoral arthroplasty has certain potential advantages. Primarily, because this operation allows the patient to keep the majority of their own knee joint; preserving bone-stock and the patients' own ligaments. Patellofemoral arthroplasty has also been recognised as a less 'invasive' operation than primary total knee arthroplasty, facilitating a more rapid recovery. There are currently no published results of randomised clinical trials comparing the two arthroplasty techniques. The primary objective of the current study is to assess whether there is a difference in functional knee scores and quality of life outcome assessments at one year post-operation between patellofemoral arthroplasty and total knee arthroplasty. The secondary objective is to assess the complication rates for both procedures. Patients who are deemed suitable, by an Orthopaedic Consultant, for patellofemoral arthroplasty and medically fit for surgery are eligible to take part in this trial. The consenting patients will be randomised in a 1:1 allocation to a total knee or patellofemoral arthroplasty. The randomisation sequence will be computer generated and administered by a central independent randomisation service. Following consent, all participants will have their knee function, quality of life and physical activity level assessed through questionnaires. The assigned surgery will then be performed using the preferred technique and implant of the operating surgeon. The first post-operative assessments will take place at six weeks, followed by further assessments at 3, 6 and 12 months. At each assessment time point all complications will be recorded. In addition, community and social care services usage will be collected using a patient questionnaire at 3, 6 & 12 months. The patients will then be sent an annual postal questionnaire. The questionnaire will ask about any problems, knee pain and function following their knee arthroplasty to monitor long-term function and failure rates. This trial is expected to deliver results in early 2013. ISRCTN: ISRCTN34863373UKCRN portfolio ID 6847.


The Zinc Finger Antiviral Protein ZAP Restricts Human Cytomegalovirus and Selectively Binds and Destabilizes Viral UL4/UL5 Transcripts.
Interferon-stimulated gene products (ISGs) play a crucial role in early infection control. The ISG zinc finger CCCH-type antiviral protein 1 (ZAP/ZC3HAV1) antagonizes several RNA viruses by binding to CG-rich RNA sequences, whereas its effect on DNA viruses is less well understood. Here, we decipher the role of ZAP in the context of human cytomegalovirus (HCMV) infection, a β-herpesvirus that is associated with high morbidity in immunosuppressed individuals and newborns. We show that expression of the two major isoforms of ZAP, ZAP-S and ZAP-L, is induced during HCMV infection and that both negatively affect HCMV replication. Transcriptome and proteome analyses demonstrated that the expression of ZAP results in reduced viral mRNA and protein levels and decelerates the progression of HCMV infection. Metabolic RNA labeling combined with high-throughput sequencing (SLAM-seq) revealed that most of the gene expression changes late in infection result from the general attenuation of HCMV. Furthermore, at early stages of infection, ZAP restricts HCMV by destabilizing a distinct subset of viral mRNAs, particularly those from the previously uncharacterized UL4-UL6 HCMV gene locus. Through enhanced cross-linking immunoprecipitation and sequencing analysis (eCLIP-seq), we identified the transcripts expressed from this HCMV locus as the direct targets of ZAP. Moreover, our data show that ZAP preferentially recognizes not only CG, but also other cytosine-rich sequences, thereby expanding its target specificity. In summary, this report is the first to reveal direct targets of ZAP during HCMV infection, which strongly indicates that transcripts from the UL4-UL6 locus may play an important role for HCMV replication.IMPORTANCE Viral infections have a large impact on society, leading to major human and economic losses and even global instability. So far, many viral infections, including human cytomegalovirus (HCMV) infection, are treated with a small repertoire of drugs, often accompanied by the occurrence of resistant mutants. There is no licensed HCMV vaccine in sight to protect those most at risk, particularly immunocompromised individuals or pregnant women who might otherwise transmit the virus to the fetus. Thus, the identification of novel intervention strategies is urgently required. In this study, we show that ZAP decelerates the viral gene expression cascade, presumably by selectively handpicking a distinct set of viral transcripts for degradation. Our study illustrates the potent role of ZAP as an HCMV restriction factor and sheds light on a possible role for UL4 and/or UL5 early during infection, paving a new avenue for the exploration of potential targets for novel therapies.


Spatial variation in the relationship between performance and metabolic rate in wild juvenile Atlantic salmon.
Maintenance of metabolic rate (MR, the energy cost of self-maintenance) is linked to behavioural traits and fitness and varies substantially within populations. Despite having received much attention, the causes and consequences of this variation remain obscure. Theoretically, such within-population variation in fitness-related traits can be maintained by environmental heterogeneity in selection patterns, but for MR, this has rarely been tested in nature. Here, we experimentally test whether the relationship between MR and performance can vary spatially by assessing survival, growth rate and movement of Atlantic salmon (Salmo salar L.) juveniles from 10 family groups differing in MR (measured as egg metabolism) that were stocked in parallel across 10 tributaries of a single watershed. The relationship between MR and relative survival and growth rate varied significantly among tributaries. Specifically, the effect of MR ranged from negative to positive for relative survival, whereas it was negative for growth rate. The association between MR and movement was positive and did not vary significantly among tributaries. These results are consistent with a fitness cost of traits associated with behavioural dominance that varies across relatively small spatial scales (within a single watershed). More generally, our results support the hypothesis that spatial heterogeneity in environmental conditions contributes to maintain within-population variation in fitness-related traits, such as MR.


Fibrinolytic Enzyme Cotherapy Improves Tumor Perfusion and Therapeutic Efficacy of Anticancer Nanomedicine.
Elevated interstitial fluid pressure and solid stress within tumors contribute to poor intratumoral distribution of nanomedicine. In this study, we hypothesized that the presence of fibrin in tumor extracellular matrix contributes to hindered intratumoral distribution of nanocarriers and that this can be overcome through the use of a fibrinolytic enzyme such as tissue plasminogen activator (tPA). Analysis of fibrin expression in human tumor biopsies showed significant fibrin staining in nearly all tumor types evaluated. However, staining was heterogeneous across and within tumor types. We determined the effect of fibrin on the diffusion, intratumoral distribution, and therapeutic efficacy of nanocarriers. Diffusivity of nanocarriers in fibrin matrices was limited and could be improved significantly by coincubation with tPA. In vivo, coadministration of tPA improved the anticancer efficacy of nanoparticle-encapsulated paclitaxel in subcutaneous syngeneic mouse melanoma and orthotopic xenograft lung cancer models. Furthermore, treatment with tPA led to decompression of blood vessels and improved tumor perfusion. Cotreatment with tPA resulted in greater intratumoral penetration of a model nanocarrier (Doxil), leading to enhanced availability of the drug in the tumor core. Fibrinolytics such as tPA are already approved for other indications. Fibrinolytic cotherapy is therefore a rapidly translatable strategy for improving therapeutic effectiveness of anticancer nanomedicine. Cancer Res; 77(6); 1465-75. ©2017 AACR.


Association between television, movie, and video game exposure and school performance.
The relationship between media exposure and school performance has not been studied extensively in adolescents. The purpose of this work was to test the relative effects of television, movie, and video game screen time and content on adolescent school performance. We conducted a population-based cross-sectional survey of middle school students (grades 5-8) in the Northeastern United States. We looked at weekday television and video game screen time, weekend television and video game screen time, cable movie channel availability, parental R-rated movie restriction, and television content restriction. The main outcome was self-report of school performance (excellent, good, average, or below average). We used ordinal logistic-regression analysis to test the independent effects of each variable, adjusting for demographics, child personality, and parenting style. There were 4508 students who participated in the study; gender was equally represented, and 95% were white. In multivariate analyses, after adjusting for other covariates, the odds of poorer school performance increased with increasing weekday television screen time and cable movie channel availability and decreased with parental restriction of television content restriction. As compared with children whose parents never allowed them to watch R-rated movies, children who watched R-rated movies once in a while, sometimes, or all of the time had significantly increased cumulative odds of poorer school performance. Weekend screen time and video game use were not associated with school performance. We found that both content exposure and screen time had independent detrimental associations with school performance. These findings support parental enforcement of American Academy of Pediatrics guidelines for media time (particularly weekdays) and content limits to enhance school success.


Addition of radiotherapy to surgery and chemotherapy improves survival in localized malignant pleural mesothelioma: A Surveillance, Epidemiology, and End Results (SEER) study.
Malignant pleural mesothelioma (MPM) is a devastating disease with poor survival outcomes for most patients. Optimizing therapeutic approaches is thus vital, but has been hampered by a dearth of randomized trials to guide decision making. We used a population-level database to evaluate the impact of radiotherapy as a component of trimodality therapy on overall survival (OS) in MPM. We retrospectively reviewed the SEER Radiation/Chemotherapy database for patients with MPM who received surgery and chemotherapy, with or without radiotherapy. A propensity score-matched analysis with inverse probability of treatment weighting (IPTW) was performed. Weight-adjusted univariate KM analysis was performed and doubly robust, IPTW-adjusted multivariable cox proportional hazards regression modeling was also performed to quantify the effect of radiotherapy on OS in trimodality therapy for MPM. 1015 patients were identified. 678 patients received surgery and chemotherapy, and 337 patients received trimodality therapy. For patients with localized disease, OS was significantly improved with trimodality therapy (HR 0.56, CI 0.4 - 0.8, p = 0.001), which persisted with IPTW adjustment (HR 0.65, CI 0.49 - 0.95, p = 0.0248). No significant benefit was seen for patients with regional or distant disease. On multivariate analysis, positive predictors of survival after IPTW adjustment were female sex, diagnosis after 2005, and left-sided disease. These findings support a significant benefit to OS by incorporating radiotherapy as a component of trimodality therapy for patients with localized MPM compared to only surgery and chemotherapy. It does not provide a significant overall survival benefit for patients with regional or metastatic disease.