Adjunctive divalproex and hostility among patients with schizophrenia receiving olanzapine or risperidone.
This study compared the specific antihostility effects of atypical antipsychotic monotherapy (olanzapine or risperidone) with that of combination treatment with divalproex sodium among patients with schizophrenia experiencing an acute psychotic episode. A total of 249 inpatients with schizophrenia were randomly assigned to receive olanzapine plus placebo, olanzapine plus divalproex, risperidone plus placebo, or risperidone plus divalproex in a double-blind, 28-day multicenter trial. The target daily dose was 15 milligrams for olanzapine, 6 milligrams for risperidone, and up to 30 milligrams per kilogram (minimum, 15 milligrams per kilogram) for divalproex. The hostility item of the Positive and Negative Syndrome Scale (PANSS) was the principal outcome measure. Covariates included the PANSS items reflecting positive symptoms of schizophrenia (delusions, suspiciousness/persecution, grandiosity, unusual thought content, conceptual disorganization, and hallucinatory behavior). Combination treatment with risperidone or olanzapine plus divalproex was associated with different scores on the hostility item of the PANSS compared with antipsychotic monotherapy. Combination therapy had a significantly greater antihostility effect at days 3 and 7 than monotherapy. This result was not seen beyond the first week of treatment, but there was a trend toward a difference in effect for the entire treatment period. The effect on hostility appears to be statistically independent of antipsychotic effect on other PANSS items reflecting delusional thinking, a formal thought disorder, or hallucinations. Divalproex sodium may be useful as an adjunctive agent in specifically reducing hostility in the first week of treatment with risperidone or olanzapine among patients with schizophrenia experiencing an acute psychotic episode.


Effect of omeprazole on intragastric bacterial counts, nitrates, nitrites, and N-nitroso compounds.
Previous studies have suggested that profound inhibition of gastric acid secretion may increase exposure to potentially carcinogenic N-nitroso compounds. The aim of this study was to find out if the proton pump inhibitor omeprazole (20 mg daily) is associated with increased concentrations of potentially carcinogenic N-nitroso compounds in gastric juice. The volume of gastric contents, number of bacteria, and concentrations of nitrates, nitrites, and N-nitroso compounds was determined in gastric aspirates obtained after an overnight fast in 14 healthy volunteers (7M:7F) after one week of treatment with placebo, and one and two weeks' treatment with omeprazole. Median bacterial concentrations were 1.0 x 10(4) (range 5.0 x 10(3)-5.0 x 10(6)) colony forming units (CFU)/ml after one weeks' treatment with placebo and increased significantly to 4.0 x 10(5) (0-3.3 x 10(7)) CFU/ml after two weeks' treatment with omeprazole (p < 0.05). A similar increase was seen in the concentration of nitrate reducing bacteria. There was no difference in the volume of gastric aspirates after treatment with omeprazole when compared with placebo (65 (29-155) ml v 42 (19-194) ml). The concentration of N-nitroso compounds was 0.13 (0-1.0) mumol/l after two weeks of omeprazole, which was not significantly different from that seen with placebo (0.15 (0-0.61) mumol/l). There was also no increase in the concentrations of nitrates or nitrites. It is concluded that omeprazole (20 mg once daily) for two weeks in healthy volunteers is associated with gastric bacterial proliferation but does not increase concentrations of N-nitroso compounds.


Ibuprofen, a Potential Cause of Acute Hemorrhagic Gastritis in Children - A Case Report.
Upper gastrointestinal bleeding is an uncommon but possible life-threatening entity in children, frequently caused by erosive gastritis. Non-steroidal anti-inflammatory drugs are one of the most common class of drugs which can cause gastrointestinal complications, including hemorrhagic gastritis. The case of a 6-year-old male, admitted for hematemesis, abdominal pain and loss of appetite. It was ascertained at the time of admission, that ibuprofen had been prescribed as the patient had a fever. This was inappropriately administered as the mother did not respect the intervals between the doses.Initial laboratory tests revealed neutrophilia, leukopenia, high levels of lactate dehydrogenase and urea. An upper digestive endoscopy revealed an increased friability of the mucosa, digested blood in the gastric corpus and fornix. No active bleeding site was detected. The histopathological examination described a reactive modification of the corporeal gastric mucosa. Intravenous treatment with proton pump inhibitors and fluid replacement were initiated, with favorable results. Ibuprofen can lead to upper digestive hemorrhage independently of the administered dose. Parents should avoid administering Ibuprofen for fever suppression without consulting their pediatrician.


Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder: Synopsis of the Kidney Disease: Improving Global Outcomes 2017 Clinical Practice Guideline Update.
The Kidney Disease: Improving Global Outcomes (KDIGO) 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) is a selective update of the prior CKD-MBD guideline published in 2009. The guideline update and the original publication are intended to assist practitioners caring for adults with CKD and those receiving long-term dialysis. Development of the guideline update followed an explicit process of evidence review and appraisal. The approach adopted by the Work Group and the evidence review team was based on systematic reviews of relevant trials, appraisal of the quality of the evidence, and rating of the strength of recommendations according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Searches of the English-language literature were conducted through September 2015 and were supplemented with targeted searches through February 2017. Final modification of the guidelines was informed by a public review process involving numerous stakeholders, including patients, subject matter experts, and industry and national organizations. The update process resulted in the revision of 15 recommendations. This synopsis focuses primarily on recommendations for diagnosis of and testing for CKD-MBD and treatment of CKD-MBD that emphasizes decreasing phosphate levels, maintaining calcium levels, and addressing elevated parathyroid hormone levels in adults with CKD stage G3a to G5 and those receiving dialysis. Key elements include basing treatment on trends in laboratory values rather than a single abnormal result and being cautious to avoid hypercalcemia when treating secondary hyperparathyroidism.


Evaluation of radiation dose to patients during abdominal embolizations.
Abdominal embolization procedures performed using digital subtraction angiography (DSA) is on the increase in the present-day scenario owing to their diagnostic and therapeutic values. These procedures involve prolonged fluoroscopy times and may tend to impart high radiation dose to patients if adequate radiation safety measures are not taken. To evaluate radiation dose imparted to patients and the work practices involved therein during abdominal embolization procedures. Forty-two patients who underwent abdominal embolizations performed using DSA equipment were included in the study. Dose area product (DAP) was measured using DAP meter and values obtained were used for calculating entrance surface dose (ESD). Work practices of personnel involved in conducting the procedure were evaluated based on the choice of field sizes, selection of appropriate fluoro-modes, and optimization techniques. The mean ESD values during hepatic embolization, renal embolization, splenic artery embolization and transarterial chemoembolization (TACE) were 1.2, 1.01, 1.19, and 1.03, respectively. No deterministic effects of radiation, such as transient or main erythema, were noticed for a few patients whose doses exceeded the threshold doses.


Making medical research clinically friendly: a communication-based conceptual framework.
It often takes a long time before the results of medical research are actually used by health care practitioners in day-to-day clinical settings. This problem, referred to as "the evidence-to-practice gap", has significant implications for patient health care. Practitioners have difficulty keeping up with the latest information in part because it is reported in hundreds of journals that may not be easily accessed and understood. This essay conceptualizes the evidence-to-practice gap as a communication problem and suggests how academic research can be translated into messages that are easier for practitioners to access, comprehend and incorporate into their medical practice. A "translation framework" shows the importance of targeting messages to specific audiences and provides a communication-based conceptual approach for summarizing research for clinicians. Targeting the results of academic research to practitioners will decrease the time it takes for patients to benefit from the latest medical evidence. Translation guidelines can help health researchers write more effectively for both academic and practitioner audiences. Since the evidence-to-practice gap is a systemic problem that begins with how we train our health researchers, educators should consider addressing this topic in the health professions classroom. The framework presented here can serve as the basis for an instructional unit on interpreting and reporting research findings. Finally, information technology can play a much larger role in the communication process because of the enormous advantages of quick access and data organization that computers and the Internet provide. Practitioner-targeted research summaries could be made available on government or not-for-profit sponsored websites as well as by journals themselves. Funding opportunities exist for research that focuses on how technology can help improve health care, and so the time is right for health researchers to investigate ways of making their studies more accessible and quickly usable via web-based distribution. The potential of medical science should not be limited by an information delivery system that we have the knowledge, expertise and resources to improve.


CD4 T cell-dependent CD8 T cell maturation.
We have investigated the contribution of CD4 T cells to the optimal priming of functionally robust memory CD8 T cell subsets. Intranasal infection of CD4 T cell-deficient (CD4(-/-)) mice with lymphocytic choriomeningitis virus resulted in the elaboration of virus-specific CD8 T cell responses that cleared the infection. However, by comparison with normal mice, the virus-specific CD8 T cells in CD4(-/-) mice were quantitatively and qualitatively different. In normal mice, lymphocytic choriomeningitis virus-specific memory CD8 T cells are CD44(high), many are CD122(high), and a majority of these cells regain expression of CD62L overtime. These cells produce IFN-gamma and TNF-alpha, and a subset also produces IL-2. In the absence of CD4 T cell help, a distinct subset of memory CD8 T cells develops that remains CD62L(low) up to 1 year after infection and exhibits a CD44(int)CD122(low) phenotype. These cells are qualitatively different from their counterparts in normal hosts, as their capacity to produce TNF-alpha and IL-2 is diminished. In addition, although CD4-independent CD8 T cells can contain the infection following secondary viral challenge, their ability to expand is impaired. These findings suggest that CD4 T cell responses not only contribute to the optimal priming of CD8 T cells in chronically infected hosts, but are also critical for the phenotypic and functional maturation of CD8 T cell responses to Ags that are more rapidly cleared. Moreover, these data imply that the development of CD62L(high) central memory CD8 T cells is arrested in the absence of CD4 T cell help.


Self, friends, and lovers: structural relations among Beck Depression Inventory scores and perceived mate values.
We used an economic model based on evolutionary theory to guide an examination of relations among self-reported depressive symptoms and ratings of mate values of self, social, and sexual partners. This model treats assortative mating as a form of social exchange between partners of socially and sexually desirable traits. Two studies used variants of the Mate Value Inventory (MVI), a multivariate assessment of attributes desired in social or sexual partners. For study 1, 115 male and 124 female undergraduates provided self reports on four forms of the MVI-11 and on the Beck Depression Inventory (BDI); for study 2, 208 male and 277 female undergraduates provided self reports on seven forms of the MVI-7 and on the BDI-II. Both multisample structural equations models indicated that the parameters were statistically equivalent between female and male subsamples and provided an adequate fit to the data. The models revealed significant relations between the mate values ascribed to the self and those ascribed to short- and long-term partners as well as best friends. Furthermore, greater BDI scores significantly predicted lesser ratings of mate value for the self, and hence indirectly predicted lesser ratings of mate value for all types of partners evaluated. Although the data obtained from the MVI demonstrated good psychometric validity, external validity has not yet been established. The results are consistent with models predicting: (1) assortative mating by mate value, (2) differential exchange rates of mate value for different types of partners, (3) a negative relation between depressive symptoms and assessment of one's own mate value, and (4) a possibly consequential mismatch of mate values when one partner exhibits or recovers from significant depressive symptoms. The results are inconsistent with models predicting (5) a generalized negativity bias due to depression.


Catalytic asymmetric formal total syntheses of (+)- and (-)-cycloclavine.
We report an expeditious catalytic asymmetric approach to clavine alkaloids via a key Heck cyclization. This reaction sets the formation of vicinal stereocenters with excellent diastereoselectivity. Utilizing the aforementioned strategy, the formal total synthesis of cycloclavine (1) has been achieved via another key late-stage ester-aminolysis of 6.


A description of a knowledge broker role implemented as part of a randomized controlled trial evaluating three knowledge translation strategies.
A knowledge broker (KB) is a popular knowledge translation and exchange (KTE) strategy emerging in Canada to promote interaction between researchers and end users, as well as to develop capacity for evidence-informed decision making. A KB provides a link between research producers and end users by developing a mutual understanding of goals and cultures, collaborates with end users to identify issues and problems for which solutions are required, and facilitates the identification, access, assessment, interpretation, and translation of research evidence into local policy and practice. Knowledge-brokering can be carried out by individuals, groups and/or organizations, as well as entire countries. In each case, the KB is linked with a group of end users and focuses on promoting the integration of the best available evidence into policy and practice-related decisions. A KB intervention comprised one of three KTE interventions evaluated in a randomized controlled trial. KB activities were classified into the following categories: initial and ongoing needs assessments; scanning the horizon; knowledge management; KTE; network development, maintenance, and facilitation; facilitation of individual capacity development in evidence informed decision making; and g) facilitation of and support for organizational change. As the KB role developed during this study, central themes that emerged as particularly important included relationship development, ongoing support, customized approaches, and opportunities for individual and organizational capacity development. The novelty of the KB role in public health provides a unique opportunity to assess the need for and reaction to the role and its associated activities. Future research should include studies to evaluate the effectiveness of KBs in different settings and among different health care professionals, and to explore the optimal preparation and training of KBs, as well as the identification of the personality characteristics most closely associated with KB effectiveness. Studies should also seek to better understand which combination of KB activities are associated with optimal evidence-informed decision making outcomes, and whether the combination changes in different settings and among different health care decision makers.


Quantum study of mutational effect in binding of efavirenz to HIV-1 RT.
Full quantum mechanical computational study has been carried out to study binding of efavirenz (EFZ), a second generation FDA approved nonnucleoside inhibitor, to HIV-1 reverse transcriptase (RT) and its K103N and Y181C mutants using the MFCC (molecular fractionation with conjugate caps) method. The binding interaction energies between EFZ and each protein fragment are calculated using a combination of HF/3-21G, B3LYP/6-31G* and MP2/6-31G* ab initio levels. The present computation shows that Efavirenz binds to HIV-1 RT predominantly through strong electrostatic interaction with the Lys101 residue. The small loss of binding to K103N mutant by Efavirenz can be attributed to a slightly weakened attractive interaction between the drug and Lys101 due to a conformational change of mutation. The small loss of binding to Y181C mutant by efavirenz can be attributed to the Glu698 residue moving closer to EFZ due to conformational change, which results in an increase of repulsive energy relative to the wild type (WT). The binding of efavirenz-derived DPC961 to HIV-1 RT is enhanced by an additional attractive interaction to residue Hid235 and reduced repulsion to Glu698, resulting in an increase of binding energy by about 4 kcal/mol.


Polymorphisms in the SLC6A4 and HTR2A genes influence treatment outcome following antidepressant therapy.
The majority of antidepressant drugs act by increasing synaptic serotonin levels in the brain. Genetic variation in serotonin-related genes may therefore influence antidepressant efficacy. In this study, nine polymorphisms in four serotonin receptor genes (HTR1B, HTR2A, HTR5A and HTR6) and the serotonin transporter gene (SLC6A4) were analysed to investigate their influence on antidepressant response in a well-characterized unipolar depressive population (n=166) following a protocolized treatment regimen. 5-HTTLPR short-allele homozygotes were significantly associated with both remission (odds ratios (OR)=4.00, P=0.04) and response (OR=5.06, P=0.02) following second switch treatment, with a similar trend observed following initial treatment and paroxetine therapy. Following initial treatment, unipolar patients homozygous for the SLC6A4 intron 2 repeat polymorphism were significantly associated with lack of remission (OR=0.38, P=0.02) and lack of response (OR=0.42, P=0.01). Additionally, the HTR2A C(1354)T polymorphism showed an association with remission (OR=7.50, P=0.002) and response (OR=5.25, P=0.01) following paroxetine therapy. These results suggest that genetically determined variation in serotonin receptor genes makes a significant contribution to the efficacy of commonly prescribed antidepressant drugs.


Choice of clinical outcomes in randomized trials of heart failure therapies: disease-specific or overall outcomes?
There are different views regarding the appropriateness of using cause-specific events or all events as the primary outcome of clinical trials. This is a methodologic essay in which we discuss the pros and cons of the 2 approaches and provide illustrative examples. Our preference is the use of cause-specific outcomes (as long as they can be classified with reasonable reproducibility and without bias) because they are more likely to be sensitive to change, less likely to lead to spurious conclusions by random variations in categories of outcomes that are unlikely to be affected by treatment, and relatively free from confounding. Overall benefit-risk ratios can be derived by examining the impact of treatment on various categories of outcomes and then developing a general judgment. Such an approach will also allow judgments to be made regarding generalizability of results across various groups of patients who are at differing risks for an event. In general, cause-specific outcomes sensitive to the effects of a treatment are to be preferred as the principal outcome in trials of heart failure, as long as they are biologically sensible and can be classified without bias. Other outcomes, not expected to be affected, should also be reported separately.


Testosterone dose-response relationships in healthy young men.
Testosterone increases muscle mass and strength and regulates other physiological processes, but we do not know whether testosterone effects are dose dependent and whether dose requirements for maintaining various androgen-dependent processes are similar. To determine the effects of graded doses of testosterone on body composition, muscle size, strength, power, sexual and cognitive functions, prostate-specific antigen (PSA), plasma lipids, hemoglobin, and insulin-like growth factor I (IGF-I) levels, 61 eugonadal men, 18-35 yr, were randomized to one of five groups to receive monthly injections of a long-acting gonadotropin-releasing hormone (GnRH) agonist, to suppress endogenous testosterone secretion, and weekly injections of 25, 50, 125, 300, or 600 mg of testosterone enanthate for 20 wk. Energy and protein intakes were standardized. The administration of the GnRH agonist plus graded doses of testosterone resulted in mean nadir testosterone concentrations of 253, 306, 542, 1,345, and 2,370 ng/dl at the 25-, 50-, 125-, 300-, and 600-mg doses, respectively. Fat-free mass increased dose dependently in men receiving 125, 300, or 600 mg of testosterone weekly (change +3.4, 5.2, and 7.9 kg, respectively). The changes in fat-free mass were highly dependent on testosterone dose (P = 0.0001) and correlated with log testosterone concentrations (r = 0.73, P = 0.0001). Changes in leg press strength, leg power, thigh and quadriceps muscle volumes, hemoglobin, and IGF-I were positively correlated with testosterone concentrations, whereas changes in fat mass and plasma high-density lipoprotein (HDL) cholesterol were negatively correlated. Sexual function, visual-spatial cognition and mood, and PSA levels did not change significantly at any dose. We conclude that changes in circulating testosterone concentrations, induced by GnRH agonist and testosterone administration, are associated with testosterone dose- and concentration-dependent changes in fat-free mass, muscle size, strength and power, fat mass, hemoglobin, HDL cholesterol, and IGF-I levels, in conformity with a single linear dose-response relationship. However, different androgen-dependent processes have different testosterone dose-response relationships.


ΔF508 mutation screening of healthy individuals from two populations in Espírito Santo State, Brazil.
The ΔF508 mutation is the most common cause of cystic fibrosis and its prevalence varies worldwide. For instance, up to 20-fold variations in its frequency have been recorded across different areas of Brazil. This study aimed to compare the distribution of ΔF508 among healthy individuals of admixed Portuguese descent from Espírito Santo (ES), a state in Southeastern Brazil, to that in a subpopulation of Pomeranian descent, considered to be an isolated group in which the European gene pool has been preserved, living in Santa Maria do Jetibá (also in ES). We found this mutation to be present at a frequency of 0.81% among the Pomeranian group, and 0% in the general ES population. No genetic differentiation was noted between the two populations examined (FST = 0.004), and these frequencies were found to be similar to those estimated in other states of Southeastern Brazil. Although the population of Santa Maria de Jetibá has retained Pomeranian traits, such as language, fair skin, and eye color, to date, there is no evidence of inbreeding in this group (FIS = -0.004). Screening healthy individuals for the ΔF508 mutation can facilitate genetic counseling for cystic fibrosis, as well as inform evolutionary and population studies.


An object-tracking model that combines position and speed explains spatial and temporal responses in a timing task.
Many tasks require synchronizing our actions with particular moments along the path of moving targets. However, it is controversial whether we base these actions on spatial or temporal information, and whether using either can enhance our performance. We addressed these questions with a coincidence timing task. A target varying in speed and motion duration approached a goal. Participants stopped the target and were rewarded according to its proximity to the goal. Results showed larger reward for responses temporally (rather than spatially) equidistant to the goal across speeds, and this pattern was promoted by longer motion durations. We used a Kalman filter to simulate time and space-based responses, where modeled speed uncertainty depended on motion duration and positional uncertainty on target speed. The comparison between simulated and observed responses revealed that a single position-tracking mechanism could account for both spatial and temporal patterns, providing a unified computational explanation.


BRCA1 and CtIP promote alternative non-homologous end-joining at uncapped telomeres.
Loss of telomere protection occurs during physiological cell senescence and ageing, due to attrition of telomeric repeats and insufficient retention of the telomere-binding factor TRF2. Subsequently formed telomere fusions trigger rampant genomic instability leading to cell death or tumorigenesis. Mechanistically, telomere fusions require either the classical non-homologous end-joining (C-NHEJ) pathway dependent on Ku70/80 and LIG4, or the alternative non-homologous end-joining (A-NHEJ), which relies on PARP1 and LIG3. Here, we show that the tumour suppressor BRCA1, together with its interacting partner CtIP, both acting in end resection, also promotes end-joining of uncapped telomeres. BRCA1 and CtIP do not function in the ATM-dependent telomere damage signalling, nor in telomere overhang removal, which are critical for telomere fusions by C-NHEJ. Instead, BRCA1 and CtIP act in the same pathway as LIG3 to promote joining of de-protected telomeres by A-NHEJ. Our work therefore ascribes novel roles for BRCA1 and CtIP in end-processing and fusion reactions at uncapped telomeres, underlining the complexity of DNA repair pathways that act at chromosome ends lacking protective structures. Moreover, A-NHEJ provides a mechanism of previously unanticipated significance in telomere dysfunction-induced genome instability.


Post-illumination pupil response after blue light: Reliability of optimized melanopsin-based phototransduction assessment.
Melanopsin-containing retinal ganglion cells have recently been shown highly relevant to the non-image forming effects of light, through their direct projections on brain circuits that regulate alertness, mood and circadian rhythms. A quantitative assessment of functionality of the melanopsin-signaling pathway could be highly relevant in order to mechanistically understand individual differences in the effects of light on these regulatory systems. We here propose and validate a reliable quantification of the melanopsin-dependent Post-Illumination Pupil Response (PIPR) after blue light, and evaluated its sensitivity to dark adaptation, time of day, body posture, and light exposure history. Pupil diameter of the left eye was continuously measured during a series of light exposures to the right eye, of which the pupil was dilated using tropicamide 0.5%. The light exposure paradigm consisted of the following five consecutive blocks of five minutes: baseline dark; monochromatic red light (peak wavelength: 630 nm, luminance: 375 cd/m(2)) to maximize the effect of subsequent blue light; dark; monochromatic blue light (peak wavelength: 470 nm, luminance: 375 cd/m(2)); and post-blue dark. PIPR was quantified as the difference between baseline dark pupil diameter and post-blue dark pupil diameter (PIPR-mm). In addition, a relative PIPR was calculated by dividing PIPR by baseline pupil diameter (PIPR-%). In total 54 PIPR assessments were obtained in 25 healthy young adults (10 males, mean age ± SD: 26.9 ± 4.0 yr). From repeated measurements on two consecutive days in 15 of the 25 participants (6 males, mean age ± SD: 27.8 ± 4.3 yrs) test-retest reliability of both PIPR outcome parameters was calculated. In the presence of considerable between-subject differences, both outcome parameters had very high test-retest reliability: Cronbach's α > 0.90 and Intraclass Correlation Coefficient > 0.85. In 12 of the 25 participants (6 males, mean age ± SD: 26.5 ± 3.6 yr) we examined the potential confounding effects of dark adaptation, time of the day (morning vs. afternoon), body posture (upright vs. supine position), and 24-h environmental light history on the PIPR assessment. Mixed effect regression models were used to analyze these possible confounders. A supine position caused larger PIPR-mm (β = 0.29 mm, SE = 0.10, p = 0.01) and PIPR-% (β = 4.34%, SE = 1.69, p = 0.02), which was due to an increase in baseline dark pupil diameter; this finding is of relevance for studies requiring a supine posture, as in functional Magnetic Resonance Imaging, constant routine protocols, and bed-ridden patients. There were no effects of dark adaptation, time of day, and light history. In conclusion, the presented method provides a reliable and robust assessment of the PIPR to allow for studies on individual differences in melanopsin-based phototransduction and effects of interventions.


Identification of a long non-coding RNA-associated RNP complex regulating metastasis at the translational step.
Long non-coding RNAs (lncRNAs) are a novel class of regulatory genes that play critical roles in various processes ranging from normal development to human diseases such as cancer progression. Recent studies have shown that lncRNAs regulate the gene expression by chromatin remodelling, transcription, splicing and RNA decay control, enhancer function, and epigenetic regulation. However, little is known about translation regulation by lncRNAs. We identified a translational regulatory lncRNA (treRNA) through genome-wide computational analysis. We found that treRNA is upregulated in paired clinical breast cancer primary and lymph-node metastasis samples, and that its expression stimulates tumour invasion in vitro and metastasis in vivo. Interestingly, we found that treRNA downregulates the expression of the epithelial marker E-cadherin by suppressing the translation of its mRNA. We identified a novel ribonucleoprotein (RNP) complex, consisting of RNA-binding proteins (hnRNP K, FXR1, and FXR2), PUF60 and SF3B3, that is required for this treRNA functions. Translational suppression by treRNA is dependent on the 3'UTR of the E-cadherin mRNA. Taken together, our study indicates a novel mechanism of gene regulation by lncRNAs in cancer progression.


FISHing for gutta-percha-adhered biofilms in purulent post-treatment apical periodontitis.
This study investigated the possibility of depicting individual taxa in clinically relevant biofilms using fluorescent in situ hybridization (FISH). Gutta-percha samples were collected from the apical aspect of root canals associated with a chronic apical abscess (test samples, n = 8). Corresponding control samples were obtained from previously filled root canals with apparently normal periapical tissues (n = 3). The transport medium was investigated for detached biofilm fragments using FISH staining and conventional epifluorescence microscopy. Gutta-percha samples were stained by multiplex FISH, and inspected using confocal laser scanning microscopy. FISH of the transport medium confirmed the presence of the main species formerly identified by conventional methods in post-treatment purulent endodontic infections, most prominently Fusobacterium spp., Bacteroidetes and Prevotellaceae. Treponemes were identified in five of eight cases associated with purulent infections, but Enterococcus faecalis and Staphylococcus spp. were not identified. The biofilms on gutta-percha from root canals associated with apical periodontitis showed dense aggregates of variable composition. Control samples contained few, if any, bacteria in the transport medium, and featured no biofilms on the respective gutta-percha specimens. The current study revealed some direct, visual in situ information on the nature of biofilms associated with purulent periapical infections in man.


Effects of topical application of taurolidine on second intention healing of experimentally induced wounds in rats.
To determine the macroscopic effects of topical application of taurolidine on second intention healing of experimentally induced wounds in rats. 32 adult Sprague-Dawley female rats. In each rat, 2 skin wounds were created in the lumbar area. Groups of 7 rats were assigned to have 1 wound treated topically with hydroxycellulose gel (HDCG), 2% taurolidine in HDCG (T-HDCG), 2% taurolidine-sodium citrate solution, or bacitracin-neomycin-polymyxin B ointment; the other wound was not treated. Four control rats (8 untreated wounds) were used. Wounds were monitored for contraction, epithelialization, and complete healing at 4, 8, and 14 days after wound creation. The number of days to complete healing was also recorded for each wound. Compared with other treatments or untreated wounds, wounds treated with T-HDCG had decreased total healing at day 8 and decreased epithelialization and decreased total healing at day 14. Wounds treated with T-HDCG required approximately 3 days longer to completely heal than all other treated and untreated wounds. Application of bacitracinneomycin-polymyxin B ointment did not enhance wound healing. Mean time to complete healing of untreated wounds in all treatment and control groups was 10.00 to 10.14 days. In rats, topical application of T-HDCG to wounds had a negative effect on second intention healing by delaying the epithelialization process. In mammals, generally, wounds treated topically with taurolidine may need to be treated and monitored for a longer period than other wounds treated with other common woundhealing compounds or untreated wounds.


Arrhythmias during and after zoledronic acid infusion patients with bone metastasis.
Zoledronic acid (ZA) is one of the important bisphosphonates which is widely used in bone metastatic cancer and osteoporotic patients. In a few studies, it has been reported that treatment with bisphosphonates was associated with an increased risk of atrial fibrillation. We aimed to evaluate the arrhythmias that developed during and immediately after infusion of the ZA. Fifty-two bone metastatic patients were included in the study group. All patients had 24-h Holter monitorization during the first dose ZA infusion day. All of the patients had 4-h basal cardiac rhythm records before ZA infusion and about 19 h after infusion. A short survey including demographic data and past medical history has been completed. None of patients had clinically important arrhythmias before ZA infusion. We divided arrhythmias into two groups as supraventricular and ventricular. We evaluated arrhythmias in pre-infusion, during infusion, and post-infusion periods. ZA was administered 4 mg intravenously (IV) in 15 min. Thirty-three of patients (63.5 %) were male and 19 (36.5 %) patients were female. Mean age of the patients was 53.9 ± 11.8 years. Most frequent cancers were breast (25 %) and lung cancer (15.3 %). Twelve (23 %) patients had history of mediastinal radiotherapy. In basal records, we detected that twenty-four (46 %) of patients had supraventricular premature complexes (SVPC) or ventricular premature complexes (VPC). Fifteen (28.8 %) of patients had SVPC and fourteen (26.9 %) had VPC during infusion period. After infusion period, 48 (92.3 %) of patients had SVPC and 41 (78.8 %) had VPC. Only 3 patients had no arrhythmia after infusion. Three patients had sinus arrhythmia and two had Mobitz type 2 atrioventricular blocks after infusion. One patient, who had no history of comorbidities and had SVPC in the basal records, developed atrial fibrillation that was refractory to medical cardioversion after 10 days of seventh dose of ZA infusion. In this study, we found that both SVPC and VPC increased in cancer patients treated with ZA. Furthermore, ZA may induce clinically important arrhythmias.


Thermal, Hyperspectral, and Laser Doppler Imaging: Non-Invasive Tools for Detection of The Deep Inferior Epigastric Artery Perforators-A Prospective Comparison Study.
Perforator flaps have become one of the leading procedures in microsurgical tissue transfer. Individual defects require a tailored approach to guarantee the most effective treatment. A thorough understanding of the individual vascular anatomy and the location of prominent perforators is of utmost importance and usually requires invasive angiography or at least acoustic Doppler exploration. In this study, we aimed at evaluating different non-invasive imaging modalities as possible alternatives for perforator location detection. After a cooling phase, we performed thermal, hyperspectral and Laser Doppler imaging and visually evaluated a possible detection of the perforator for a period of five minutes with an image taken every minute. We identified the most prominent perforator of the deep inferior epigastric artery by handheld acoustic Doppler in 18 patients. The detected perforator locations were then correlated. Eighteen participants were assessed with six images each per imaging method. We could show a positive match for 94.44%, 38.89%, and 0% of patients and 92.59%, 25.93%, and 0% of images for the methods respectively compared to the handheld acoustic Doppler. Sex, age, abdominal girth, and BMI showed no correlation with a possible visual detection of the perforator in the images. Therefore, thermal imaging can yield valuable supporting data in the individualized procedure planning. Future larger cohort studies are required to better assess the full potential of modern handheld thermal imaging devices.


Prevalence and prognosis of non-specific chest pain among patients hospitalized for suspected acute coronary syndrome - a systematic literature search.
The term non-specific chest pain (NSCP) is applied to hospitalized patients in order to designate that they neither have an acute coronary syndrome (ACS) nor display evidence of a coronary ischemia. The number of NSCP patients is increasing and comprehensive guidelines specifying their optimal management have not yet been introduced. The objective of this review was to explore the prevalence and prognosis of NSCP versus ACS among patients recruited in consecutive series hospitalized for chest pain suspected to be ACS. This is a systematic literature search where three databases were searched from 1990 to 14 November 2011. In addition, one database was searched for Epub ahead of print per 24 March 2012. Three inclusion criteria were applied: 1. documentation of an unselected consecutive series of patients admitted for chest pain, where this review is based upon two groups of patients defined as follows: a) 'ACS/high-risk' and b) NSCP; 2. at least 100 cases with NSCP; and 3. follow-up of hospital readmissions and mortality for at least six months. A total of 2,204 citations were screened after removal of duplicates. Out of 80 full text articles assessed for eligibility 12 studies were included, comprising 24,829 patients (inter-study range 250 to 13,762), with 11,008 (44%) categorized as NSCP and 13,821 (56%) as 'ACS/high-risk'. The mean one-year total mortality rate among patients with NSCP in nine studies was 3.2% (inter-study range 1.4% to 8.1%), with the highest mortality among patients with pre-existing coronary heart disease (CHD). The mean one-year mortality rate among 'ACS/high-risk' patients was 18.0% (inter-study range 14.0% to 19.9%) in four studies with available data. In six studies the mean one-year readmission rate for patients with NSCP was 17.5% (inter-study range 2.5% to 40%). Patients with NSCP represent a large, heterogeneous and important group. Due to co-existing CHD in nearly 40% of these patients, their prognosis is not necessarily benign. Although their average one-year mortality rate was almost six times lower than those with 'ACS/high-risk', the subset with concomitant CHD had a relatively poor prognosis when compared with NSCP patients without evidence of CHD.


Functionally Homologous Host Components Recognize Potato Virus X in Gomphrena globosa and Potato.
All known isolates of potato virus X (PVX), with the exception of a South American isolate PVXHB, induce an extreme resistance response on potato carrying the Rx gene and elicit the production of necrotic lesions on Gomphrena globosa: PVXHB establishes systemic infection on Rx genotypes of potato and infects the inoculated leaf of G. globosa without lesion formation. Previously, we have shown that the Rx-mediated resistance is affected by a feature of the coat protein that depends on the presence of a threonine residue at position 121 in the coat protein of PVXCP4 and that the resistance is an induced response expressed in protoplasts of potato with the Rx genotype. In this study, we provide evidence, based on the analysis of PVXCP4/PVXHB hybrids, that the elicitation of lesions on G. globosa also requires the presence of a threonine residue at position 121 of the viral coat protein. The lesion-forming phenotype was not associated with the ability of the viral isolate to accumulate in the infected plant. We therefore propose that there is a homologous component of both potato carrying Rx and G. globosa that interacts with a feature of the PVX coat protein and, following the interaction, activates an induced response in the plant cell.


Melatonin protects against stress-induced gastric lesions by scavenging the hydroxyl radical.
The antiulcer effect of melatonin on gastric lesions caused by restraint-cold stress or by indomethacin (IMN) was studied with the intent of determining the mechanism of action of the indole. Melatonin dose-dependently prevents both stress and IMN-induced gastric damage with around 90% inhibition at a dose of 60 mg per kg BW. When compared with already-marketed antiulcer drugs, such as ranitidine and omeprazole, melatonin was found to be more effective than ranitidine but less effective than omeprazole in preventing stress ulcer. When compared with other antioxidants, melatonin was more potent than glutathione and essentially equipotent to alpha-tocopherol in blocking stress-induced ulcer. As stress-induced gastric lesions are mainly caused by oxidative damage due to hydroxyl radicals (*OH), the effect of melatonin in scavenging the *OH generated during stress conditions, as well as in an in vitro model system, was studied. The results indicate that melatonin at the dose of 60 mg per kg BW caused an 88% reduction of endogenous *OH during stress. Melatonin was also highly effective in scavenging *OH generated in vitro by a Cu2+-ascorbate system. In this case, melatonin at 100 microM reduced *OH by 80%. Melatonin was also found to be a more potent radical scavenger than benzoate, a known *OH scavenger. The results indicate that melatonin prevents stress-induced gastric lesions by scavenging the endogenous *OH. As it also protects against IMN-induced gastric damage, it probably also offers gastroprotection by maintaining endogenous prostaglandin levels.


Lipid Biosynthetic Genes Affect Candida albicans Extracellular Vesicle Morphology, Cargo, and Immunostimulatory Properties.
Microbial secretion is integral for regulating cell homeostasis as well as releasing virulence factors during infection. The genes encoding phosphatidylserine synthase (CHO1) and phosphatidylserine decarboxylase (PSD1 and PSD2) are Candida albicans genes involved in phospholipid biosynthesis, and mutations in these genes affect mitochondrial function, cell wall thickness, and virulence in mice. We tested the roles of these genes in several agar-based secretion assays and observed that the cho1Δ/Δ and psd1Δ/Δ psd2Δ/Δ strains manifested less protease and phospholipase activity. Since extracellular vesicles (EVs) are surrounded by a lipid membrane, we investigated the effects of these mutations on EV structure, composition, and biological activity. The cho1Δ/Δ mutant releases EVs comparable in size to wild-type EVs, but EVs from the psd1Δ/Δ psd2Δ/Δ strain are much larger than those from the wild type, including a population of >100-nm EVs not observed in the EVs from the wild type. Proteomic analysis revealed that EVs from both mutants had a significantly different protein cargo than that of EVs from the wild type. EVs were tested for their ability to activate NF-κB in bone marrow-derived macrophage cells. While wild-type and psd1Δ/Δ psd2Δ/Δ mutant-derived EVs activated NF-κB, the cho1Δ/Δ mutant-derived EV did not. These studies indicate that the presence and absence of these C. albicans genes have qualitative and quantitative effects on EV size, composition, and immunostimulatory phenotypes that highlight a complex interplay between lipid metabolism and vesicle production.


Cognitive-electrophysiological indices of attentional and inhibitory processing in adults with ADHD: familial effects.
Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder that starts in childhood and frequently persists in adults. In a comparison of adults with ADHD and a matched control sample, we previously showed that abnormal inhibitory processing is typically preceded or accompanied by other processing deficits in adult ADHD. We now compare these data further to additional data from first-degree relatives (fathers) of children with ADHD to identify whether this pattern of abnormal processing shares familial influences with ADHD in adults. Using a family design, we compared 20 fathers of children with the combined subtype of ADHD with 21 adults with ADHD combined subtype and 20 controls in event-related potential indices of preparatory states and subsequent response inhibition processing as elicited by a cued continuous performance task. Fathers of children with ADHD exhibited significantly weaker orienting attention to cues and inhibitory processing than the controls but not the ADHD sample. These findings provide evidence for the familial association of attentional orienting and response inhibition processes with ADHD in adults and indicate a familial and neurobiological link between ADHD in children and adults.


Three-dimensional structure and cytokine distribution of platelet-rich fibrin.
Previous reports have revealed that several cytokines (including platelet-derived growth factor-BB, transforming growth factors-β1 and insulin-like growth factor-1) can enhance the rate of bone formation and synthesis of extracellular matrix in orthopaedics or periodontology. This study aimed to determine the concentration of cytokines within platelet-rich fibrin microstructures and investigate whether there are differences in the different portions of platelet-rich fibrin, which has implications for proper clinical use of platelet-rich fibrin gel. Whole blood was obtained from six New Zealand rabbits (male, 7 to 39 weeks old, weight 2.7-4 kg); it was then centrifuged for preparation of platelet-rich fibrin gels and harvest of plasma. The resultant platelet-rich fibrin gels were used for cytokine determination, histological analyses and scanning electron microscopy. All plasmas obtained were subject to the same cytokine determination assays for the purpose of comparison. Cytokines platelet-derived growth factor-BB and transforming growth factor-β1 formed concentration gradients from high at the red blood cell end of the platelet-rich fibrin gel (p=1.88×10-5) to low at the plasma end (p=0.19). Insulin-like growth factor-1 concentrations were similar at the red blood cell and plasma ends. The porosities of the platelet-rich fibrin samples taken in sequence from the red blood cell end to the plasma end were 6.5% ± 4.9%, 24.8% ± 7.5%, 30.3% ± 8.5%, 41.4% ± 12.3%, and 40.3% ± 11.7%, respectively, showing a gradual decrease in the compactness of the platelet-rich fibrin network. Cytokine concentrations are positively associated with platelet-rich fibrin microstructure and portion in a rabbit model. As platelet-rich fibrin is the main entity currently used in regenerative medicine, assessing cytokine concentration and the most valuable portion of PRF gels is essential and recommended to all physicians.


Interaction of cells with patterned reactors.
Surface coatings that allow externally controlled interaction with cells are of interested for diverse biomedical applications. We fabricated particle patterns and assessed the interaction of these substrates with endothelial cells and hepatocytes. The particles were turned into subcompartmentalized reactors by immobilizing glucose oxidase loaded liposomes sandwiched between polymer layers. The reactor activities depending on the number of liposome deposition steps were confirmed in solution and on patterned surfaces. Finally, reduced viability of hepatocytes adhering to the reactor patterned surfaces in the presence of glucose was observed due to the local production of hydrogen peroxide. This first report on patterned reactors in combination with cells opens up vast opportunities to assemble interactive nanobiointerfaces.


Quinine hydrochloride treatment delays xenoma formation and dissolution in rainbow trout challenged with Loma salmonae.
An experiment was designed to study the effect of dietary quinine hydrochloride (61 mg/kg of fish/day), on the rate of xenoma formation in the gills of Loma salmonae-infected juvenile rainbow trout maintained at a water temperature of 15 degrees C. Almost all (90.9%) control fish had developed xenomas by week 6 post-exposure (PE), but significantly fewer (18.2%) of the medicated fish were similarly affected (P < 0.0001). By week 8 PE, 100% of control fish had xenomas, but only 57.5% of quinine-treated had xenomas (P < 0.0001). However, by week 9 there was no difference between treated and control fish. Xenoma dissolution and branchitis, two crucial events in the pathogenesis of L. salmonae infection in farm-reared Pacific salmon, were present at week 10 in control fish. In contrast, comparable lesions did not develop in treated fish until week 14. These findings are of potential significance for the control of L. salmonae infection in farmed salmon.


Controlling vertical optical confinement in two-dimensional surface-emitting photonic-crystal lasers by shape of air holes.
We use the finite-difference time domain method to calculate the vertical optical confinement, which corresponds to the quality factor in the vertical direction, of two-dimensional photonic-crystal (PC) lasers as a function of the asymmetry of the shape of the air holes that form the PC. The vertical optical confinement for triangular air holes, which give the highest output power measured thus far, is decreased by two thirds when V-shaped air holes are used. In contrast, the vertical optical confinement becomes infinite for rhomboid air holes. The vertical optical confinement decreases when the air holes are deformed such that areas of opposing electric fields exist in regions of the PC with different dielectric constants. In this way, the vertical optical confinement can be controlled by changing the shape of the air holes.


Physiological characterization of the SynCardia total artificial heart in a mock circulation system.
The SynCardia total artificial heart (TAH) has emerged as an effective, life-saving biventricular replacement system for a wide variety of patients with end-stage heart failure. Although the clinical performance of the TAH is established, modern physiological characterization, in terms of elastance behavior and pressure-volume (PV) characterization has not been defined. Herein, we examine the TAH in terms of elastance using a nonejecting left ventricle, and then characterize the PV relation of the TAH by varying preload and afterload parameters using a Donovan Mock Circulatory System. We demonstrate that the TAH does not operate with time-varying elastance, differing from the human heart. Furthermore, we show that the TAH has a PV relation behavior that also differs from that of the human heart. The TAH does exhibit Starling-like behavior, with output increasing via preload-dependent mechanisms, without reliance on an alteration of inotropic state within the operating window of the TAH. Within our testing range, the TAH is insensitive to variations in afterload; however, this insensitivity has a limit, the limit being the maximum driving pressure of the pneumatic driver. Understanding the physiology of the TAH affords insight into the functional parameters that govern artificial heart behavior providing perspective on differences compared with the human heart.


CYP2C polymorphisms, phenytoin metabolism and gingival overgrowth in epileptic subjects.
Previous studies suggested that the onset of phenytoin-induced gingival overgrowth depended on serum phenytoin concentration. Cytochrome P450 2C (CYP2C) plays an important role in phenytoin metabolism. Recently, single nucleotide polymorphisms in the coding region of CYP 2C influencing phenytoin metabolism were identified. The purpose of the present study was to see if CYP 2C polymorphisms might relate to the onset and severity of phenytoin-induced gingival overgrowth. Twenty-eight epileptic patients taking phenytoin aged 15 to 75 (mean age: 42.2 years old, 20 males and 8 females) and 56 unrelated healthy subjects aged 30 to 48 (mean age: 36.8 years old, 48 males and 8 females) were examined for CYP 2C polymorphisms. All epileptic subjects were examined for the degree of gingival overgrowth, daily phenytoin dose and serum phenytoin concentration. The results indicated about 7% of the subjects including epileptic and healthy subjects examined were positive for CYP 2C9*3. However, the degree of gingival overgrowth did not directly correlate with CYP 2C polymorphisms. Nevertheless, the subjects with severer gingival overgrowth exhibited significantly higher serum phenytoin concentration, indicating that phenytoin metabolism is an important determinant for the severity of the disease. Additionally, CYP 2C9*3 carriers exhibited significantly higher serum drug concentration to drug dose. Therefore, we concluded although the gene analysis is not directly related to diagnose the disease itself, it can be utilized in estimating serum phenytoin concentration from drug dose, which in turn serves to predict the future development and clinical course of the disease.


Infiltrative Rash Secondary to Leukemic-Phase Diffuse Large B-Cell Lymphoma With t(14;18), CDKN2A and MLL Deletion.
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous and highly aggressive subtype of non-Hodgkin's lymphoma. It commonly presents as rapidly-growing, painless lymphadenopathy (LAD). DLBCL presenting in leukemic-phase is rare, with fewer than 40 cases published. Chemotherapy remains the standard approach, although selecting the correct regimen has become more perplexing in patients with CDKN2A mutations. Patients with MLL- and CDKN2A-positive DLBCL may benefit from therapy with a dose-adjusted regimen of rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-R-EPOCH) compared to traditional rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP). Herein, we report a case of leukemic-phase DLBCL presenting as a cutaneous eruption of the bilateral lower extremities, which has not been previously reported in the literature.


Noble-gas difluoride complexes of mercury(II): the syntheses and structures of Hg(OTeF5)2·1.5NgF2 (Ng = Xe, Kr) and Hg(OTeF5)2.
The synthesis of high-purity Hg(OTeF5)2 has resulted in its structural characterization in the solid state by Raman spectroscopy and single-crystal X-ray diffraction (XRD) and in solution by (19)F NMR spectroscopy. The crystal structure of Hg(OTeF5)2 (-173 °C) consists of discrete Hg(OTeF5)2 units having gauche-conformations that interact through long Hg---O and Hg---F intramolecular contacts to give a chain structure. The Lewis acidity of Hg(OTeF5)2 toward NgF2 (Ng = Xe, Kr) was investigated in SO2ClF solvent and shown to form stable coordination complexes with NgF2 at -78 °C. Both complexes were characterized by low-temperature Raman spectroscopy (-155 °C) and single-crystal XRD. The complexes are isostructural and are formulated as Hg(OTeF5)2·1.5NgF2. The Hg(OTeF5)2 units of Hg(OTeF5)2·1.5NgF2 also have gauche-conformations and are linked through bridging NgF2 molecules, also resulting in chain structures. These complexes represent the only examples of coordination compounds where NgF2 coordinates to mercury in a neutral covalent compound and the only example of mercury coordinated to KrF2. Moreover, the Hg(OTeF5)2·1.5KrF2 complex is the only KrF2 complex known to contain a bridging KrF2 ligand. Energy-minimized gas-phase geometries and vibrational frequencies for the model compounds, [Hg(OTeF5)2]3 and [Hg(OTeF5)2]3·2NgF2, were obtained and provide good approximations of the local environments of Hg(OTeF5)2 and NgF2 in the crystal structures of Hg(OTeF5)2 and Hg(OTeF5)2·1.5NgF2. Assignments of the Raman spectra of Hg(OTeF5)2 and Hg(OTeF5)2·1.5NgF2 are based on the calculated vibrational frequencies of the model compounds. Natural bond orbital analyses provided the associated bond orders, valencies, and natural population analysis charges.


Pesticides and Ostreid Herpesvirus 1 Infection in the Pacific Oyster, Crassostrea gigas.
Since 2008, mass mortality outbreaks have been reported in all French regions producing Pacific oysters, and in several Member States of the European Union. These mass mortality events of Pacific oysters are related to OsHV-1 infection. They occur during spring and summer periods leaving suspect the quality of the marine environment and the role of seasonal use of pesticides associated with the arrival of freshwater in oyster rearing areas. Pesticides have been also detected in French coastal waters, especially in areas of oyster production. Using PMA real-time PCR we showed that a mixture of 14 pesticides has no effect on the integrity of virus capsids from viral suspension in the conditions tested. A contact of oysters with this pesticide mixture was related to higher mortality rates among experimentally infected animals in comparison with control ones (no previous pesticide exposure before experimental infection). We therefore suggest that pesticides at realistic concentration can exert adverse effects on Pacific oysters and causes an increased susceptibility to the viral infection in experimental conditions.


Evolutionary Physiology and Genomics in the Highly Adaptable Killifish (Fundulus heteroclitus).
By investigating evolutionary adaptations that change physiological functions, we can enhance our understanding of how organisms work, the importance of physiological traits, and the genes that influence these traits. This approach of investigating the evolution of physiological adaptation has been used with the teleost fish Fundulus heteroclitus and has produced insights into (i) how protein polymorphisms enhance swimming and development; (ii) the role of equilibrium enzymes in modulating metabolic flux; (iii) how variation in DNA sequences and mRNA expression patterns mitigate changes in temperature, pollution, and salinity; and (iv) the importance of nuclear-mitochondrial genome interactions for energy metabolism. Fundulus heteroclitus provides so many examples of adaptive evolution because their local population sizes are large, they have significant standing genetic variation, and they experience large ranges of environmental conditions that enhance the likelihood that adaptive evolution will occur. Thus, F. heteroclitus research takes advantage of evolutionary changes associated with exposure to diverse environments, both across the North American Atlantic coast and within local habitats, to contrast neutral versus adaptive divergence. Based on evolutionary analyses contrasting neutral and adaptive evolution in F. heteroclitus populations, we conclude that adaptive evolution can occur readily and rapidly, at least in part because it depends on large amounts of standing genetic variation among many genes that can alter physiological traits. These observations of polygenic adaptation enhance our understanding of how evolution and physiological adaptation progresses, thus informing both biological and medical scientists about genotype-phenotype relationships. © 2020 American Physiological Society. Compr Physiol 10:637-671, 2020.


A latent class analysis of stigmatizing attitudes and knowledge of HIV risk among youth in South Africa.
The current study aims to investigate how the ability to accurately gauge risk factors associated with contracting HIV while taking into consideration various individual and community level socio-demographic characteristics (e.g., race and poverty) predicts the nature of stigmatizing attitudes toward persons with HIV. Data from a sample of 1,347 Cape Town area youth who participated in the Cape Area Panel Study (CAPS) Wave 2a were used. Latent Class Analysis was conducted to ascertain whether response patterns regarding knowledge of HIV contraction suggest the presence of subgroups within the sample. Findings indicate that there are four latent classes representing unique response pattern profiles regarding knowledge of HIV contraction. Additionally, our results suggest that those in South Africa who are classified as "white," live in more affluent communities, and have more phobic perceptions of HIV risk are also more likely to have the most stigmatizing attitudes toward those who are HIV positive. Implications of these findings include extending HIV knowledge, education, and awareness programs to those who are not traditionally targeted in an attempt to increase levels of knowledge about HIV and, consequently, decrease stigma.


Genetic loci for Epstein-Barr virus nuclear antigen-1 are associated with risk of multiple sclerosis.
Infection with the Epstein-Barr virus (EBV) is associated with an increased risk of multiple sclerosis (MS). We sought genetic loci influencing EBV nuclear antigen-1 (EBNA-1) IgG titers and hypothesized that they may play a role in MS risk. We performed a genome-wide association study (GWAS) of anti-EBNA-1 IgG titers in 3599 individuals from an unselected twin family cohort, followed by a meta-analysis with data from an independent EBNA-1 GWAS. We then examined the shared polygenic risk between the EBNA-1 GWAS (effective sample size (Neff) = 5555) and a large MS GWAS (Neff = 15,231). We identified one locus of strong association within the human leukocyte antigen (HLA) region, of which the most significantly associated genotyped single nucleotide polymorphism (SNP) was rs2516049 (p = 4.11 × 10-9). A meta-analysis including data from another EBNA-1 GWAS in a cohort of Mexican-American families confirmed that rs2516049 remained the most significantly associated SNP (p = 3.32 × 10-20). By examining the shared polygenic risk, we show that the genetic risk for elevated anti-EBNA-1 titers is positively correlated with the development of MS, and that elevated EBNA-1 titers are not an epiphenomena secondary to MS. In the joint meta-analysis of EBNA-1 titers and MS, loci at 1p22.1, 3p24.1, 3q13.33, and 10p15.1 reached genome-wide significance (p < 5 × 10-8). Our results suggest that apart from the confirmed HLA region, the association of anti-EBNA-1 IgG titer with MS risk is also mediated through non-HLA genes, and that studies aimed at identifying genetic loci influencing EBNA immune response provides a novel opportunity to identify new and characterize existing genetic risk factors for MS.


Nonlinear optical processing with Fabry-Perot interferometers containing phase recording media.
New techniques in nonlinear optical processing are explored, based on the operation of intensity level selection as performed by a Fabry-Perot interferometer containing a phase object. The image being processed is recorded on a medium between the mirrors as a spatially varying phase shift less than 7r. The interferometer only transmits light through those portions of the object that correspond to a single value of the phase and hence to a single intensity level in the input. More complicated operations such as thresholding and analog-to-digital conversion are performed by modulating the light source as the different levels are selected. Photoresist and lithium niobate have been used as phase objects, and experimental data for both are presented. Three kinds of Fabry-Perot interferometers have been used to demonstrate nonlinear processing using coherent and incoherent light. Color images have been produced with black and white inputs and white light illumination.


Endoscopic transaxillary subpectoral augmentation mammaplasty: a safe and predictable procedure.
During the last decades breast augmentation has gained worldwide acceptance. In addition to the inframammary and periareolar approach for augmentation mammaplasty, the transaxillary route provides an elegant means of retaining the integrity of the breast mound by avoiding visible scars. Due to concerns as to the safety of this technique we analysed 47 patients who underwent endoscopy-assisted transaxillary submuscular augmentation mammaplasty in our department from 1999 to 2004. The inclusion criteria were aesthetic breast augmentation due to breast hypoplasia. Patients with a history of breast cancer, other malignancies, or previously performed mastectomy were excluded. Procedures for tuberous breast deformity as well as concomitantly performed mastopexy were also excluded. No complications were observed impairing final outcome or requiring early operative intervention, such as infection or haematoma. This technique is suitable for patients who prefer a hidden incision at a distant site, and provides predictability of aesthetic outcome and is safe.


Quantitative promoter hypermethylation analysis of cancer-related genes in salivary gland carcinomas: comparison with methylation-specific PCR technique and clinical significance.
To compare the methylation status of tumor-associated genes by quantitative pyrosequencing and qualitative methylation-specific PCR (MSP) techniques and to correlate the results with clinicopathologic features and patients outcome to determine which method might have greater clinical utility. The hypermethylation status of the retinoid acid receptor beta2 (RARbeta2), RAS association domain family 1A (RASSF1A), O(6)-methylguanine-DNA methyltransferase (MGMT), and E-cadherin genes was analyzed in five salivary carcinoma cell lines and 69 human salivary gland carcinoma specimens by pyrosequencing and MSP techniques. The two datasets were compared by linear regression. Correlations between methods and with clinicopathologic characteristics were assessed by Pearson's chi(2) test or the two-tailed Fisher exact test, as applicable, using cutoff points determined from the regression curves and empirical fitting. We also investigated the effect of demethylating agents on methylated genes in cell lines to assess their effect on the expression of these genes. Overall, regression analysis indicated high degrees of correlation of the two methods for measurement of methylation for the RARb2, RASSF1A, and MGMT genes (adjusted R(2) = 0.319, 0.835, and 0.178; P < 0.001, <0.001, and 0.0002, respectively) among the 69 tumors tested. However, the pyrosequencing technique yielded four more instances of methylation above background levels than MSP for RARbeta2 and three more for RASSF1. Methylation of either RARbeta2 and RASSF1A alone or both by pyrosequencing were correlated with tumor type (P = 0.027, 0.014, and 0.012, respectively). Methylation of RARbeta2 alone and in combination with RASSF1A by pyrosequencing were also significantly correlated with tumor grade (P = 0.014 and 0.011, respectively) and 3-year survival (P = 0.002 and 0.004, respectively). The survival curves of patients who had hypermethylation at both RARbeta2 and RASSF1A were significantly lower than those of patients who had hypermethylation at neither or just for the RASSF1A (P = 0.008 and 0.007, respectively). 5-Azadeoxycytidine treatment of methylated cell lines led to the reactivation of RARbeta2 expression in only one of the five cell lines. (a) Although the methylation status of RARb2, RASSF1A, and MGMT genes by both techniques were significantly correlated, pyrosequencing is generally more sensitive and its results correlate better with the clinical variables than those of MSP. (b) The methylation level of the RARbeta2 and/or RASSF1A by pyrosequencing is significantly associated with aggressive tumor phenotypes and patients survival.


Clinical failure with and without empiric atypical bacteria coverage in hospitalized adults with community-acquired pneumonia: a systematic review and meta-analysis.
Both typical and atypical bacteria can cause community-acquired pneumonia (CAP); however, the need for empiric atypical coverage remains controversial. Our objective was to evaluate the impact of antibiotic regimens with atypical coverage (a fluoroquinolone or combination of a macrolide/doxycycline with a β-lactam) to a regimen without atypical antibiotic coverage (β-lactam monotherapy) on rates of clinical failure (primary endpoint), mortality, bacteriologic failure, and adverse events, (secondary endpoints). We searched the PubMed, EMBASE and Cochrane Library databases for relevant RCTs of hospitalized CAP adults. We estimated risk ratios (RRs) with 95% confidence intervals (CIs) using a fixed-effect model, but used a random-effects model if significant heterogeneity (I 2 ) was observed. Five RCTs with a total of 2011 patients were retained. A statistically significant lower clinical failure rate was observed with empiric atypical coverage (RR, 0.851 [95% CI, 0.732-0.99; P = 0.037]; I 2 = 0%). The secondary outcomes did not differ between the two study groups: mortality (RR = 0.549 [95% CI, 0.259-1.165, P = 0.118], I 2 = 61.434%) bacteriologic failure (RR = 0.816 [95% CI, 0.523-1.272, P = 0.369], I 2 = 0%), diarrhea (RR = 0.746 [95% CI, 0.311-1.790, P = 0.512], I 2 = 65.048%), and adverse events requiring antibiotic discontinuation (RR = 0.83 [95% CI, 0.542-1.270, P = 0.39], I 2 = 0%). Empiric atypical coverage was associated with a significant reduction in clinical failure in hospitalized adults with CAP. Reduction in mortality, bacterial failure, diarrhea, and discontinuation due to adverse effects were not significantly different between groups, but all estimates favored atypical coverage. Our findings provide support for the current guidelines recommendations to include empiric atypical coverage.


Importance of Plasmonic Heating on Visible Light Driven Photocatalysis of Gold Nanoparticle Decorated Zinc Oxide Nanorods.
Herein we explore the role of localized plasmonic heat generated by resonantly excited gold (Au) NPs on visible light driven photocatalysis process. Au NPs are deposited on the surface of vertically aligned zinc oxide nanorods (ZnO NRs). The localized heat generated by Au NPs under 532 nm continuous laser excitation (SPR excitation) was experimentally probed using Raman spectroscopy by following the phonon modes of ZnO. Under the resonant excitation the temperature at the surface of the Au-ZnO NRs reaches up to about 300 °C, resulting in almost 6 times higher apparent quantum yield (AQY) for photocatalytic degradation of methylene blue (MB) compared to the bare ZnO NRs. Under solar light irradiation the Au-ZnO NRs demonstrated visible light photocatalytic activity twice that of what was achieved with bare ZnO NRs, while significantly reduced the activation energy required for the photocatalytic reactions allowing the reactions to occur at a faster rate.


A review of return to play issues and sports-related concussion.
Mild traumatic brain injury in sports has become a significant public health concern which has not only received the general public's attention through multiple news media stories involving athletic concussions, but has also resulted in local, state, and national legislative efforts to improve recognition and management. The purpose of this article is to review the current literature for return to play (RTP) guidelines. State, regional, national, and professional legislation on sport-related concussion RTP management issues will be reviewed. This article will be helpful in developing a generalized systematic approach to concussion management and highlight specific RTP guidelines. The article will also touch upon specific contraindications to RTP, the role of neuropsychological testing in RTP, and other considerations and complications that affect an athlete's ability to return to competition. Finally, considerations for terminating an athlete's competitive season or ending a career after sustaining a concussion resulting in prolonged and protracted symptomatology or repeated concussions will be reviewed. PubMed and Google were searched using the key terms mentioned below. In addition, the author's library of concussion-related articles was reviewed for the relevant literature.


[Magnesium in the treatment and prevention of cerebrovascular disease].
To date, the amount of evidences for the role of magnesium in determining the energy potential of the cells increases, which is critical in the pathogenesis of stroke, as well as in the survival and recovery of brain cells. Energy donor in cellular processes is adenosine triphosphate (ATP) as a complex of Mg2+- ATP [1]. In acute and chronic cerebral ischemia deficit Mg2+ is the basis of hypoxia cells, which leads to their subsequent death. [2]. Severe deficiency of selenium, when there is an issue of life and death of the patient, requires a massive correction of magnesium homeostasis. It is an integral component of intensive care in neurology, cardiology, obstetrics. However, in daily practice neurologist frequently has patients with chronic cerebrovascular disease, accompanied by magnesium deficiency. This proves necessitate of the use of magnesium containing drugs with neuroprotective and neurotrophic properties in the treatment and prevention of cerebrovascular disease.


Strategic patient education program to prevent catheter-related bloodstream infection.
Central venous catheters (CVCs) are used commonly for venous access during treatment, and catheter-related bloodstream infection (CRBSI) is a frequent, yet highly preventable, hospital-acquired infection. One of the performance elements of the Joint Commission's 2012 National Patient Safety Goals addresses the education of patients and family members on CVC care and management, as well as CRBSI prevention before a central catheter is inserted. This article presents the history and roles of the Infusion Therapy Team at the University of Texas MD Anderson Cancer Center in CVC care and describes an organized patient education program that plays a key part in the institution's strategy to reduce and prevent CRBSI. Institutional standard policies and procedures for patient care should be in compliance with guidelines of the Centers for Disease Control and Prevention and the Joint Commission before any patient educational initiative is implemented. Such standards will serve as a guide to set up, organize, and implement an effective program.


Radiation-induced second malignancies.
The number of patients with second malignancies is growing and they represent about one in six out of all new cancers. Second malignancies can be categorized into three major groups according to the predominant etiological factor(s): (i) treatment-related, (ii) part of a syndrome and (iii) those due to shared etiologic exposures. This article focuses on radiation-induced malignancies with illustrative cases of thyroid, rectal cancer and sarcoma. The detection and management of radiation-induced malignancies of some case scenarios are presented. Second malignancies are detected within previous radiation field and the time intervals from previous tumor vary from 8 to 21 years. Clinicians should aim to reduce radiation-induced malignancies by careful selection of patients and radiation techniques before radiotherapy. Subsequent vigilant follow-up and investigations can detect these radiation-induced malignancies early and, hence, result in successful treatment.


Aging-related changes in the iron status of skeletal muscle.
The rise in non-heme iron (NHI) concentration observed in skeletal muscle of aging rodents is thought to contribute to the development of sarcopenia. The source of the NHI has not been identified, nor have the physiological ramifications of elevated iron status in aged muscle been directly examined. Therefore, we assessed plantaris NHI and heme iron (HI) levels in addition to expression of proteins involved in iron uptake (transferrin receptor-1; TfR1), storage (ferritin), export (ferroportin; FPN), and regulation (iron regulatory protein-1 (IRP1) and -2 (IRP2)) of male F344xBN F1 rats (n=10/group) of various ages (8, 18, 28, 32, and 36 months) to further understand iron regulation in aging muscle. In a separate experiment, iron chelator (pyridoxal isonicotinoyl hydrazone; PIH) or vehicle was administered to male F344xBN F1 rats (n=8/group) beginning at 30 months of age to assess the impact on plantaris muscle mass and function at ~36 months of age. Principle findings revealed the increased NHI concentration in old age was consistent with concentrating effects of muscle atrophy and reduction in HI levels, with no change in the total iron content of the muscle. The greatest increase in muscle iron content occurred during the period of animal growth and was associated with downregulation of TfR1 and IRP2 expression. Ferritin upregulation did not occur until senescence and the protein remained undetectable during the period of muscle iron content elevation. Lastly, administration of PIH did not significantly (p>0.05) impact NHI or measures of muscle atrophy or contractile function. In summary, this study confirms that the elevated NHI concentration in old age is largely due to the loss in muscle mass. The increased muscle iron content during aging does not appear to associate with cytosolic ferritin storage, but the functional consequences of elevated iron status in old age remains to be determined.


HIV-I infection in perinatally exposed siblings and twins. The Italian Register for HIV Infection in Children.
In a multicentre study on perinatal HIV-I infection including 1493 children born from 1471 pregnancies to 1415 infected mothers, 22 twin pairs and 56 sibships (115 children) were recorded. The frequency of twin pregnancies was 1.5 (22/1471) and 3.9% (56/1415) seropositive women had more than one at risk pregnancy. In 18 twin pairs with a known infection status nine of the 36 children (25%) were infected. Discordance in infection status was present in only one (5.5%) dizygous pair. A high relative risk of infection (23.1) in a twin was observed when the other was infected. Infection was unrelated to gestational age, mode of delivery, or birth weight. Infection status was defined in 41 sibships (84 children including one first born twin pair and one third born child). When the first born was infected, 11/26 (42.3%) second born children were also infected, whereas this happened in only 2/16 (12.5%) second or third born children when the first born was uninfected. Two out of nine first born (22.2%) and 5/21 (23.8%) second born children prospectively followed up from birth acquired the infection. Results of this study demonstrate that neither twin nor second pregnancies are at increased risk of mother to child HIV-I transmission. Overall data suggest that non-casual factors in mother and/or child influence perinatal infection.


Advances in nucleophilic phosphine catalysis of alkenes, allenes, alkynes, and MBHADs.
In nucleophilic phosphine catalysis, tertiary phosphines undergo conjugate additions to activated carbon-carbon multiple bonds to form β-phosphonium enolates, β-phosphonium dienolates, β-phosphonium enoates, and vinyl phosphonium ylides as intermediates. When these reactive zwitterionic species react with nucleophiles and electrophiles, they may generate carbo- and heterocycles with multifarious molecular architectures. This article describes the reactivities of these phosphonium zwitterions, the applications of phosphine catalysis in the syntheses of biologically active compounds and natural products, and recent developments in the enantioselective phosphine catalysis.


Determinants of impaired growth among hospitalized children: a case-control study.
Protein energy malnutrition constitutes a public health problem, especially in less affluent countries. The identification of amenable predictive risk factors is of major importance for policy makers to plan interventions to reduce infant malnutrition. To identify risk factors for protein energy malnutrition among hospitalized low-income children aged 6 to 24 months. Case-control study. Two public hospitals in Recife, Brazil. The cases were 124 infants with length-for-age below the 10th percentile of the National Center for Health Statistics curve and the controls were 241 infants with length-for-age equal to or above the 10th percentile who were recruited in the same infirmary. Cases and controls were compared in relation to a variety of sociodemographic, environmental and reproductive factors, and their healthcare, previous feeding practice and morbidity. Logistic regression analysis was used to investigate the net effect of risk factors on infant malnutrition, after adjusting for potential confounding variables. The mother's age, possession of a TV set, type of water supply, family size and location of the home were significantly associated with child malnutrition in the bivariate analysis. However, these associations lost their significance after adjusting for other explanatory variables in the hierarchical logistic regression analysis. This analysis showed that low birth weight contributed the largest risk for impaired growth. Increased risks of infant malnutrition were also significantly associated with households that had no toilet facilities or refrigerator, high parity for the mother, no breastfeeding of the infant, inadequate vaccination coverage and previous hospitalization for diarrhea and pneumonia. The literature shows that chronic malnutrition, as assessed by low length-for-age indexes, is often related to low income. However, this was not the case in this study, in which other variables had greater impact on child growth. In view of the multiple causes of malnutrition, the interrelationship among its determinants should be taken into account when adopting strategies for its reduction and prevention.


Plasmodium possesses dynein light chain classes that are unique and conserved across species.
Plasmodium belongs to the phylum Apicomplexa. Within the Apicomplexa, Plasmodium, Toxoplasma and Cryptosporidium are parasites of considerable medical importance while Theileria and Eimeria are animal pathogens. P. falciparum is particularly important as it causes malaria, resulting in more than 1 million deaths each year. The malaria parasite actively invades the host cell in which it propagates and several proteins associated with the apical organelles have been implicated to be crucial in the invasion process. The biogenesis of the apical organelles is not well understood, but several studies indicate that microtubule-based vesicular transport is involved. Vesicular transport proteins are also present in Plasmodium and are presumed to be involved in transcellular transport in infected erythrocytes. Dynein is a multi-subunit motor protein involved in microtubule-based vesicular transport. In this study, we analyzed the cytoplasmic dynein light chains (Dlcs) of P. falciparum since they provide adaptor surface to the cargoes and are likely to be involved in differential transport. Dlcs consist of three different families: TcTex1/2, LC8 and LC7/roadblock. The data presented demonstrate that P. falciparum Dlcs sequences and functional domains show high sequence similarity within the species, but that only the Dlc group 1 (LC8) has a high similarity to human orthologues. TcTex1 and LC7/roadblock have low similarity to human orthologues. This sequence variation could be targeted for vaccine or drug development.


Increased risk of co-morbid eye disease in patients with chronic renal failure: a population-based study.
A large-scale population-based study on ophthalmic disorders among patients suffering from chronic renal failure (CRF) is lacking in the literature. This study examined the prevalence and risk of selected ocular co-morbidities (including retinal disorders, uveitis, glaucoma, cataract, and dry eye) in patients with CRF. Data were sourced from the Taiwan Longitudinal Health Insurance Database. 9,149 patients with CRF were included in the study group, and 27,447 matched patients in the comparison group (age 40-98 years). We calculated the prevalence of retinal disorders, uveitis, glaucoma, cataract, and dry eye for patients with and without CRF. Conditional logistic regression analyses were also performed to compare the risk of ophthalmic disorders for patients with and without CRF, after taking into consideration sex, age group, diabetes, hypertension, monthly income, geographic region, and level of urbanization of the patient's community. In this study, patients with CRF had significantly higher prevalence of retinal disorders (16.62% vs. 9.70%), uveitis (1.38% vs. 0.95%), glaucoma (7.56% vs. 5.70%), and cataract (33.08% vs. 28.90%) than patients without CRF (all p < 0.001). However, no significant difference was observed in the prevalence of dry eye between these two groups. After adjusting for potential confounders, patients with CRF had higher odds of retinal disorder (odds ratio, OR, 1.84, 95% confidence interval, CI, 1.72-1.98), uveitis (OR 1.33, 95% CI 1.07-1.66), glaucoma (OR 1.35, 95% CI 1.23-1.48), and cataract (OR 1.24, 95% CI 1.18-1.31) than patients without CRF. We conclude that patients with CRF had a significantly higher prevalence of retinal disorders, uveitis, glaucoma, and cataract compared with patients without CRF.


Adolescent Major Depressive Disorder: Neuroimaging Evidence of Sex Difference during an Affective Go/No-Go Task.
Compared to female major depressive disorder (MDD), male MDD often receives less attention. However, research is warranted since there are significant sex differences in the clinical presentation of MDD and a higher rate of suicide in depressed men. To the best of our knowledge, this is the first functional magnetic resonance imaging (fMRI) study with a large sample addressing putative sex differences in MDD during adolescence, a period when one of the most robust findings in psychiatric epidemiology emerges; that females are twice as likely to suffer from MDD than males. Twenty-four depressed and 10 healthy male adolescents, together with 82 depressed and 24 healthy female adolescents, aged 11-18 years, undertook an affective go/no-go task during fMRI acquisition. In response to sad relative to neutral distractors, significant sex differences (in the supramarginal gyrus) and group-by-sex interactions (in the supramarginal gyrus and the posterior cingulate cortex) were found. Furthermore, in contrast to the healthy male adolescents, depressed male adolescents showed decreased activation in the cerebellum with a significant group-by-age interaction in connectivity. Future research may consider altered developmental trajectories and the possible implications of sex-specific treatment and prevention strategies for MDD.


Poly(A)-binding protein is differentially required for translation mediated by viral internal ribosome entry sites.
The 3' poly(A) tail present on the majority of mature eukaryotic mRNAs is an important regulator of protein synthesis and mRNA stability. The poly(A) tail improves the efficiency of translation initiation through recruitment of PABP, enabling its interaction with eIF4F located at the mRNA 5'-end. Recent evidence has also implicated a possible role for PABP and the poly(A) tract in translation control at steps beyond the initiation phase. Similar to conventional mRNAs, plus-strand RNA virus genomes that utilize internal ribosome entry sites (IRESes) to promote cap-independent translation are influenced by PABP and poly(A) status. However, the relative contribution of these factors to translation initiation mediated by distinct IRESes is unclear. We have investigated cis- and trans-acting effects of poly(A) and PABP, respectively, on RNAs harboring IRESes from three diverse viruses: encephalomyocarditis virus (EMCV), hepatitis C virus (HCV), and coxsackievirus B3 (CBV3). A 3' poly(A) tract enhanced translation of both capped and IRES-containing reporter RNAs. However, only CBV3 and capped transcripts were stabilized as a result of polyadenylation. Correspondingly, translation of polyadenylated CBV3 and capped RNAs displayed heightened sensitivity to the PABP inhibitor Paip2 compared with EMCV and HCV. Sucrose density gradient analyses suggested a stimulatory role for PABP and 3' poly(A) in the CBV3 initiation phase, while assembly of HCV and EMCV RNAs into ribosomal complexes was little affected by either factor. Collectively, the observed differential effects of PABP and poly(A) on translation imply mechanistic differences between viral IRES elements and suggest modulating roles for PABP and the poly(A) tail at multiple phases of translation.


Direct evidence for ligand-induced internalization of the yeast alpha-factor pheromone receptor.
When Saccharomyces cerevisiae a cells bind alpha-factor pheromone, the ligand is internalized and its binding sites are lost from the cell surface in a time-, energy-, and temperature-dependent manner. This report presents direct evidence for alpha-factor-induced internalization of cell surface receptors. First, membrane fractionation on Renografin density gradients indicated that the alpha-factor receptors were predominantly found in the plasma membrane peak before alpha-factor treatment and then appeared in membranes of lesser buoyant density after alpha-factor exposure. Second, receptors were susceptible to cleavage by extracellular proteases before alpha-factor treatment and then became resistant to proteolysis after exposure to pheromone, consistent with the transit of receptors from the cell surface to an internal compartment. The median transit time in both assays was approximately 8 min. The ultimate target of the internalized receptors was identified as the vacuole, since the membranes containing internalized receptors cofractionated with vacuolar membranes, since the turnover of receptors was stimulated by alpha-factor exposure, and since receptor degradation was blocked in a pep4 mutant that is deficient for vacuolar proteases. The carboxy-terminal domain of the receptor that is required for ligand internalization was also found to be essential for endocytosis of the receptor. A receptor mutant, ste2-L236H, which is defective for pheromone response but capable of ligand internalization, was found to be proficient for receptor endocytosis. Hence, separate structural features of the receptor appear to specify its signal transduction and internalization activities.


Pain and analgesic use associated with skeletal-related events in patients with advanced cancer and bone metastases.
Bone metastases secondary to solid tumors increase the risk of skeletal-related events (SREs), including the occurrence of pathological fracture (PF), radiation to bone (RB), surgery to bone (SB), and spinal cord compression (SCC). The aim of this study was to evaluate the impact of SREs on patients' pain, analgesic use, and pain interference with daily functioning. Data were combined from patients with solid tumors and bone metastases who received denosumab or zoledronic acid across three identically designed phase 3 trials (N = 5543). Pain severity (worst pain) and pain interference were assessed using the Brief Pain Inventory at baseline and each monthly visit. Analgesic use was quantified using the Analgesic Quantification Algorithm. The proportion of patients with moderate/severe pain and strong opioid use generally increased in the 6 months preceding an SRE and remained elevated, while they remained relatively consistent over time in patients without an SRE. Regression analysis indicated that all SRE types were significantly associated with an increased risk of progression to moderate/severe pain and strong opioid use. PF, RB, and SCC were associated with significantly greater risk of pain interference overall. Results were similar for pain interference with emotional well-being. All SRE types were associated with significantly greater risk of pain interference with physical function. SREs are associated with increased pain and analgesic use in patients with bone metastases. Treatments that prevent SREs may decrease pain and the need for opioid analgesics and reduce the impact of pain on daily functioning.


The structure of spatial networks and communities in bicycle sharing systems.
Bicycle sharing systems exist in hundreds of cities around the world, with the aim of providing a form of public transport with the associated health and environmental benefits of cycling without the burden of private ownership and maintenance. Five cities have provided research data on the journeys (start and end time and location) taking place in their bicycle sharing system. In this paper, we employ visualization, descriptive statistics and spatial and network analysis tools to explore system usage in these cities, using techniques to investigate features specific to the unique geographies of each, and uncovering similarities between different systems. Journey displacement analysis demonstrates similar journey distances across the cities sampled, and the (out)strength rank curve for the top 50 stands in each city displays a similar scaling law for each. Community detection in the derived network can identify local pockets of use, and spatial network corrections provide the opportunity for insight above and beyond proximity/popularity correlations predicted by simple spatial interaction models.


Photoswitching of Green mEos2 by Intense 561 nm Light Perturbs Efficient Green-to-Red Photoconversion in Localization Microscopy.
Green-to-red photoconvertible fluorescent proteins (PCFPs) such as mEos2 and its derivatives are widely used in PhotoActivated Localization Microscopy (PALM). However, the complex photophysics of these genetically encoded markers complicates the quantitative analysis of PALM data. Here, we show that intense 561 nm light (∼1 kW/cm2) typically used to localize single red molecules considerably affects the green-state photophysics of mEos2 by populating at least two reversible dark states. These dark states retard green-to-red photoconversion through a shelving effect, although one of them is rapidly depopulated by 405 nm light illumination. Multiple mEos2 switching and irreversible photobleaching is thus induced by yellow/green and violet photons before green-to-red photoconversion occurs, contributing to explain the apparent limited signaling efficiency of this PCFP. Our data reveals that the photophysics of PCFPs of anthozoan origin is substantially more complex than previously thought, and suggests that intense 561 nm laser light should be used with care, notably for quantitative or fast PALM approaches.


Mercury speciation in seawater by liquid chromatography-inductively coupled plasma-mass spectrometry following solid phase extraction pre-concentration by using an ionic imprinted polymer based on methyl-mercury-phenobarbital interaction.
Trace levels of inorganic mercury, methyl-mercury and ethyl-mercury have been assessed in seawater by high performance liquid chromatography (HPLC) hyphenated with inductively coupled plasma-mass spectrometry (ICP-MS) after solid phase extraction (SPE) pre-concentration with a novel synthesized ionic imprinted polymer. The adsorbent material was prepared by trapping a non-vinylated chelating ligand (phenobarbital) via imprinting of a ternary mixed ligand complex of the non-vinylated chelating agent, the template (methyl-mercury), and the vinyl ligand (metacrylic acid, MAA). Ethylene dimetacrylate (EDMA) and 2,2'-azobisisobutyronitrile (AIBN) were used as cross-linker and initiator reagents, respectively; and the precipitation polymerization technique was used in a porogen of acetonitrile/water (4:1). The best retention properties for methyl-mercury, inorganic mercury and ethyl-mercury species from seawater were obtained when loading 200 mL of sample adjusted to pH 8.0 and at a flow rate of 2.0 mL min(-1) on a column-packed with 200mg of the material. Quantitative mercury species recoveries were obtained using 4 mL of an eluting solution consisting of 0.8% (v/v) 2-mercaptoethanol and 20% (v/v) methanol (pH adjusted to 4.5) pumped at a flow rate of 2.0 mL min(-1). Mercury species separation was achieved on a Kinetex C18 column working under isocratic conditions (0.4% (v/v) 2-mercaptoethanol, 10% (v/v) methanol, pH 2.5, flow rate 0.7 mL min(-1)). ICP-MS detection was performed by monitoring the mercury mass to charge ratio of 202. The limits of quantification of the method were 11, 6.7, and 12 ng L(-1), for inorganic mercury, methyl-mercury and ethyl-mercury, respectively (pre-concentration factor of 50); whereas, analytical recoveries ranged from 96 to 106%. The developed method was successfully applied to several seawater samples from unpolluted areas.