188Re-HYNIC-trastuzumab enhances the effect of apoptosis induced by trastuzumab in HER2-overexpressing breast cancer cells.
The development of radioimmunotherapy has provided an impressive alternative approach in improving trastuzumab therapy. However, the mechanisms of trastuzumab and radiation treatment combined to increase therapeutic efficacy are poorly understood. Here, we try to examine the efficacy of cytotoxicity and apoptosis induction for (188)Re-HYNIC-trastuzumab in cancer cell lines with various levels of Her2. Fluorescence flow cytometry was used to detect the alterations of apoptosis induction after (188)Re-HYNIC-trastuzumab treatment in two breast cancer cell lines with different levels of HER2 (BT-474 and MCF-7) and a colorectal carcinoma cell line (HT-29) for control. Our results indicated that (188)Re-HYNIC-trastuzumab led to cell death of breast cancer cells specifically in HER2 level-dependent and radioactivity dose-dependent fashions. In BT-474 cells, 370 kBq/ml of (188)Re-HYNIC-trastuzumab enhanced the cytotoxicity to a level nearly 100-fold that of trastuzumab-alone treatment. The results also revealed that the mitochondria-dependent pathway attenuated irradiation-induced apoptosis in HER2-expressing breast cancer cells after (188)Re-HYNIC-trastuzumab treatment. In contrast, only after 48 h of (188)Re-HYNIC-trastuzumab treatment, BT-474 cells exhibited typical apoptotic changes, including exposure of phospholipid phosphatidylserine on the cell surface, or fragmented DNA formation, in a radioactivity dose-dependent manner. Briefly, our study demonstrates that (188)Re-labeled HYNIC-trastuzumab not only enhances cell death in a radioactivity dose-dependent fashion, but may also prolong the effects of apoptosis involved with the mitochondria-dependent pathway in HER2-overexpressing breast cancer cells. It is possible that the (188)Re-HYNIC-trastuzumab treatment induced a second round of apoptosis to prolong the effects of cell kill in these cancer cells. These data revealed that (188)Re-HYNIC-trastuzumab has the potential for use as a therapeutic radiopharmaceutical agent in HER2-overexpressing breast cancer cell treatment.


Examining the evidence for an independent semantic analyzer: an ERP study in Spanish.
Recent ERP findings challenge the widespread assumption that syntactic and semantic processes are tightly coupled. Syntactically well-formed sentences that are semantically anomalous due to thematic mismatches elicit a P600, the component standardly associated with syntactic anomaly. This 'thematic P600' effect has been attributed to detection of semantically plausible thematic relations that conflict with the surface syntactic structure of the sentence, implying a processing architecture with an independent semantic analyzer. A key finding is that the P600 is selectively sensitive to the presence of plausible verb-argument relations, and that otherwise an N400 is elicited (The hearty meal was devouring … vs. The dusty tabletop was devouring …: Kim & Osterhout, 2005). The current study investigates in Spanish whether the evidence for an independent semantic analyzer is better explained by a standard architecture that rapidly integrates multiple sources of lexical, syntactic, and semantic information. The study manipulated the presence of plausible thematic relations, and varied the choice of auxiliary between passive-biased fue and active-progressive biased estaba. Results show a late positivity that appeared as soon as comprehenders detected an improbable combination of subject animacy, auxiliary bias, or verb voice morphology. This effect appeared at the lexical verb in the fue conditions and at the auxiliary in the estaba conditions. The late positivity elicited by surface thematic anomalies was the same, regardless of the presence of a plausible non-surface interpretation, and no N400 effects were elicited. These findings do not implicate an independent semantic analyzer, and are compatible with standard language processing architectures.


Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci.
We used a collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We found that the level of methylation at 71 of the 415,848 interrogated CpGs was significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validated 11 of the differentially methylated regions in an independent set of 117 subjects. Furthermore, we functionally validated these CpG associations and identified the nearby genes whose RNA expression was altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD given that we observed them in presymptomatic subjects and that six of the validated genes connect to a known AD susceptibility gene network.


Effect of temperature on post-tetanic potentiation in human dorsiflexor muscles.
The effect of temperature on post-tetanic potentiation (PTP) has been examined in the muscles of small mammals but not in human skeletal muscle. We examined PTP in the ankle dorsiflexor muscles of 10 young men by evoking twitches before and after a 7-second tetanus at 100 Hz in a control (room air approximately 21 degrees C) condition and after immersion of the lower leg in warm (45 degrees C) and cold (10 degrees C) water baths for 30 min. Exposure to cold decreased tetanus and pre-tetanus twitch peak torque, but increased rise time, half-relaxation time, and muscle action potential (M-wave) amplitude; exposure to warm water had little effect. PTP was smallest in cold exposure 5 s post-tetanus, but persisted throughout the 12 min test period, whereas PTP had subsided by 6 min post-tetanus in control and warm exposures. M-wave amplitude initially decreased after exposure to warm water, recovered, then decreased again by 11 min post-tetanus. In contrast, exposure to cold had no initial effect but did increase the M-wave amplitude during the last half of the 12 min test period, similar to that seen in the control. The greatest immediate decrease in rise time and half-relaxation time was observed in the control; however, by 12 min post-tetanus warm exposure showed the greatest increase in rise time and half-relaxation time above pre-tetanus values. The decrease in the unpotentiated twitch torque with cooling in human dorsiflexors is typical for muscles with a predominance of type I (slow) fibres. The effect of cold on PTP is similar to that seen previously in mammalian muscles with a predominance of type II (fast) fibres, although the underlying mechanism of the cooling effect appears to differ.


In vivo two-photon microscopy of the hippocampus using glass plugs.
Two-photon microscopy has been used in conjunction with micro-optics, such as GRIN lenses, to access subcortical structures in the intact mouse brain. In this study, we demonstrate the use of thick glass windows, or plugs, for high-resolution, large field-of-view two-photon imaging of the hippocampus in a live mouse. These plugs are less expensive, yield larger fields-of-view and are simpler to use than GRIN lenses while requiring less tissue removal compared to previous methods based on cortical ablation. To demonstrate the capabilities of our system, we show fluorescence images of dendritic spines in the CA1 region of the hippocampus in THY1-YFP transgenic mice.


Typical and atypical carcinoid tumors of the lung: a clinicopathological correlation of 783 cases with emphasis on histological features.
We present 783 surgical resections of typical and atypical carcinoid tumors of the lung identified in the pathology files of 20 different pathology departments. All cases were critically reviewed for clinical and pathological features and further correlated with clinical outcomes. Long-term follow-up was obtained in all the patients and statistically analyzed to determine significance of the different parameters evaluated. Of the histopathological features analyzed, the presence of mitotic activity of 4 mitoses or more per 2 mm2, necrosis, lymphatic invasion, and lymph node metastasis were identified as statistically significant. Tumors measuring 3 cm or more were also identified as statistically significant and correlated with clinical outcomes. Based on our analysis, we consider that the separation of low- and intermediate-grade neuroendocrine neoplasms of the lung needs to be readjusted in terms of mitotic count as the risk of overgrading these neoplasms exceeds 10% under the current criteria. We also consider that tumor size is an important feature to be considered in the assessment of these neoplasms and together with the histological grade of the tumor offers important features that can be correlated with clinical outcomes.


Interpretation of "negative" studies in occupational epidemiology.
Two criteria for an interpretation of noneffect are that the relative risk estimate be near unity and that the confidence interval be narrow; lack of statistical significance has no bearing on this issue. A further requirement is that the relative risk estimate not be near the null value as an effect of non-differential exposure misclassification, negative confounding, or some other systematic error. Occasionally, when results are unexpected or difficult to accept, studies are "underinterpreted" as negative or inconclusive on the basis of arguments such as "confounding," "crude exposure assessment," or "lack of a known mechanism." The present paper supports the position that these arguments are commonly invalid. Scientific standards should be used to separate causal associations from noncausal ones, but in public health decisions this practice has to be balanced by the principle that the "benefit of the doubt" should be given to the persons subject to potential risk.


Parent and adolescent perceived need for parental consent involving research with minors.
To assess parents' and adolescents' perceived need for parental consent for minor adolescents to participate in minimal risk research studies based on procedural invasiveness (anonymous surveys, interviews, and blood or urine testing) and sensitivity of the topics (sexuality, drug and alcohol use, and sexually transmitted diseases and human immunodeficiency virus [HIV]). An anonymous self-report questionnaire was administered to 100 adolescent-parent pairs at 2 clinical sites (urban and suburban) of Children's Hospital of Michigan in Detroit. By invasiveness of the research procedure, the proportions of parents and adolescents who perceived a need for parental consent were as follows: face-to-face interviews, 62% vs 48%; telephone interviews, 72% vs 46%; blood or urine testing, 77% vs 62%; and blood testing for HIV status, 78% vs 59%. These differences were only significant for telephone interviews and HIV blood testing. For anonymous surveys, a minority of parents (33%) and adolescents (26%) reported that parental consent was needed. Based on sensitivity of the research topics, the proportions of parents and adolescents who perceived a need for parental consent were as follows: sexuality, 60% vs 34%; drug and alcohol use, 56% vs 44%; contraception, 62% vs 46%; and sexually transmitted diseases and HIV testing, 56% vs 52%. These differences were only significant for sexuality. Parents with higher education believed that teens could give their own consent (P < .05). Fifty-seven percent of parents and their teens agreed that parental consent for anonymous surveys was not necessary. For more invasive procedures and more sensitive topics, the percentage of disagreement ranged from 28% to 55.5%. There is a greater perceived need for parental consent to adolescent participation in research studies among parents than among teens for more invasive procedures and more sensitive topics. These results suggest the need for sensitivity to differing adolescent and parental perceived need for parental consent for a minor adolescent to participate in such studies. Further studies with larger samples are needed to determine what factors influence diverse parent and adolescent opinions.


Effect of levitra on sustenance of erection (EROS): an open-label, prospective, multicenter, single-arm study to investigate erection duration measured by stopwatch with flexible dose vardenafil administered for 8 weeks in subjects with erectile dysfunction.
To investigate the change of erection duration measured by stopwatch with flexible dose vardenafil administered for 8 weeks in subjects with erectile dysfunction (ED). Effect of levitra on sustenance of erection was an open-label, prospective, multicenter and single-arm study designed to measure the duration of erection in men with ED receiving a flexible dose of vardenafil over an 8-week treatment period. Patients were instructed to take vardenafil 10 mg 60 min before attempting the intercourse. Vardenfil could be increased to 20 mg or decreased to 5 mg concerning patients' efficacy and safety. Following the initial screening, patients entered a 4-week treatment-free run-in phase and 8-week treatment period, during which they were instructed to attempt intercourse at least four times on four separate days. A total of 95 men were enrolled in 10 centers. After the 8 weeks treatment, the mean duration of erection leading to successful intercourse was statistically superior when patients were treated with vardenafil. After an 8-week treatment, the duration of erection leading to successful intercourse was 9.39 min. There were significant benefits with vardenafil in all domains of International Index of Erectile Function. Secondary efficacy end points included success rate of penetration, maintaining erection, ejaculation and satisfaction were superior when patients were treated with vardenafil. There was a significant correlation between duration of erection with other sexual factors. Also partner's sexual satisfaction was increased with vardenafil. Most adverse events were mild or moderate in severity. Vardenafil was safe and well tolerated. Vardenafil therapy provided a statistically superior duration of erection leading to successful intercourse in men with ED with female partner.


Winners don't take all: Characterizing the competition for links on the web.
As a whole, the World Wide Web displays a striking "rich get richer" behavior, with a relatively small number of sites receiving a disproportionately large share of hyperlink references and traffic. However, hidden in this skewed global distribution, we discover a qualitatively different and considerably less biased link distribution among subcategories of pages-for example, among all university homepages or all newspaper homepages. Although the connectivity distribution over the entire web is close to a pure power law, we find that the distribution within specific categories is typically unimodal on a log scale, with the location of the mode, and thus the extent of the rich get richer phenomenon, varying across different categories. Similar distributions occur in many other naturally occurring networks, including research paper citations, movie actor collaborations, and United States power grid connections. A simple generative model, incorporating a mixture of preferential and uniform attachment, quantifies the degree to which the rich nodes grow richer, and how new (and poorly connected) nodes can compete. The model accurately accounts for the true connectivity distributions of category-specific web pages, the web as a whole, and other social networks.


Experiences of the Breast Cancer Patients Undergoing Radiotherapy at a Public Hospital Peshawar Pakistan.
This study aimed to explore the experiences of female breast cancer patients undergoing radiotherapy (RT) in a public hospital in Peshawar, Pakistan. This study employed a descriptive exploratory method. A purposive sample of 14 breast cancer women undergoing RT was selected for this study. Data were collected over the period of 5 months, using a semi-structured interview guide and conducting in-depth face-to-face interviews. These interviews were audio taped and transcribed by a bilingual transcriber. The translated version of the interview was coded, and the analysis was done manually. Four main categories emerged from data analysis, which were: feelings and perceptions of the patients, their challenges, coping strategies, and teaching and informational needs. Women undergoing RT in this culture experience more intense psychological effects, as compared to the physical effects. Keeping in mind, the magnitude of the emotional stress experienced by the participants, recommendations for policy reforms, and training for female RT staff are suggested based on findings of this research.


Summit firn caves, mount rainier, washington.
Heat and steam from the crater fumaroles have melted over 5700 feet (1737 meters) of cave passage in the ice-filled east crater of Mount Rainier. The caves are in approximate balance with the present geothermal heat release. Future changes in the thermal activity of the summit cone will cause corresponding changes in cave passage dimensions, location, and ceiling and wall ablation features.


Ignoring the elephant in the room: a neural circuit to downregulate salience.
How do we ignore stimuli that are salient but irrelevant when our task is to select a lower salient stimulus? Since bottom-up processes favor high saliency, detection of a low-salient target in the presence of highly salient distractors requires top-down attentional guidance. Previous studies have demonstrated that top-down attention can modulate perceptual processing and also that the control of attention is driven by frontoparietal regions. However, to date, there is no direct evidence on the cause and effect relationship between control regions and perceptual processing. Here, we report the first evidence demonstrating a neural circuit for the downregulation of salient distractors when a low-salient target is selected, combining brain imaging using functional magnetic resonance imaging with brain stimulation by transcranial magnetic stimulation. Using these combined techniques, we were able to identify a cause and effect relationship in the suppression of saliency, based on an interaction between the left intraparietal sulcus (IPS) and a region implicated in visual processing in our task (the left occipital pole). In particular, low-salient stimuli were selected by the left IPS suppressing early visual areas that would otherwise respond to a high-saliency distractor in the task. Apart from providing a first documentation of the neural circuit supporting selection by saliency, these data can be critical for understanding the underlying causes of problems in ignoring irrelevant salience that are found in both acquired and neurodevelopmental disorders (e.g., attention deficit/hyperactivity disorder or autism).


B7-H3×4-1BB bispecific antibody augments antitumor immunity by enhancing terminally differentiated CD8+ tumor-infiltrating lymphocytes.
Cancer immunotherapy with 4-1BB agonists has limited further clinical development because of dose-limiting toxicity. Here, we developed a bispecific antibody (bsAb; B7-H3×4-1BB), targeting human B7-H3 (hB7-H3) and mouse or human 4-1BB, to restrict the 4-1BB stimulation in tumors. B7-H3×m4-1BB elicited a 4-1BB-dependent antitumor response in hB7-H3-overexpressing tumor models without systemic toxicity. BsAb primarily targets CD8 T cells in the tumor and increases their proliferation and cytokine production. Among the CD8 T cell population in the tumor, 4-1BB is solely expressed on PD-1+Tim-3+ "terminally differentiated" subset, and bsAb potentiates these cells for eliminating the tumor. Furthermore, the combination of bsAb and PD-1 blockade synergistically inhibits tumor growth accompanied by further increasing terminally differentiated CD8 T cells. B7-H3×h4-1BB also shows antitumor activity in h4-1BB-expressing mice. Our data suggest that B7-H3×4-1BB is an effective and safe therapeutic agent against B7-H3-positive cancers as monotherapy and combination therapy with PD-1 blockade.


Coronary artery bypass grafts: ECG-gated multi-detector row CT angiography--influence of image reconstruction interval on graft visibility.
To evaluate the influence of different reconstruction intervals of retrospectively electrocardiographically (ECG)-gated multi-detector row computed tomographic (CT) angiography on image quality of different segments of various types of coronary artery bypass grafts. Twenty consecutive patients with 62 grafts underwent retrospectively ECG-gated four-channel multi-detector row CT angiography and conventional coronary angiography. Raw helical CT data were reconstructed at 0%-90% of the cardiac cycle in increments of 10%. Each graft was separated into three segments (proximal segment, graft body, and distal anastomosis). Three graft types were identified according to site of distal anastomosis. Two readers assessed image quality of segments and graft types. Effective radiation dose was calculated. Best image quality of all segments was obtained at a reconstruction interval of 50%-70% of the cardiac cycle. Image quality of the proximal segment did not vary significantly with different reconstruction intervals (analysis of variance, P =.8), whereas image quality of the graft body and distal anastomosis changed significantly with varying reconstruction intervals (P <.001). Distal anastomosis and body of types 1 and 2 grafts were best seen at 60%-70% of the cardiac cycle, whereas distal anastomosis and body of type 3 grafts were best visualized at 50%. Accuracy of CT angiography for detection of graft patency was 94% for reader 1 and 95% for reader 2. Effective dose for CT was 11.4 mSv for both men and women. Mean effective dose for angiography was 2.1 mSv for men and women. Optimal selection of reconstruction interval improves image quality of the graft body and of distal anastomosis in particular.


Complications and competing risks of death in compensated viral cirrhosis (ANRS CO12 CirVir prospective cohort).
Various critical events, liver related or not, occur in patients with compensated cirrhosis, but their respective burden remains to be prospectively assessed. The aim of this prospective cohort study involving 35 French centers was to capture the whole spectrum of complications occurring in compensated viral cirrhosis (VC) using competing risks analyses. Inclusion criteria were: histologically proven cirrhosis resulting from hepatitis C virus (HCV) or hepatitis B virus (HBV); Child-Pugh A; and no previous hepatic complications. The cohort was considered as a multistate disease model, cumulative incidences (CumIs) of events were estimated in a competing risks framework. A total of 1,654 patients were enrolled from 2006 to 2012 (HCV, 1,308; HBV, 315; HCV-HBV, 31). During a median follow-up of 34 months, at least one liver nodule was detected in 271 patients, confirmed as hepatocellular carcinoma (HCC) in 128 (4-year cumI: 10.5%) and cholangiocarcinoma in 3. HCC incidence was higher in HCV (4-year cumI: 11.4% vs. 7.4%; P = 0.05). HCC fulfilled Milan criteria in 79.3%, leading to curative treatment in 70.4%. Liver decompensation occurred more frequently in HCV patients (4-year cumI: 10.8% vs. 3.6%; P = 0.0004). Virological eradication/control was achieved in 34.1% of HCV and 88.6% of HBV patients and was associated with a marked decrease in HCC, decompensation, and bacterial infection incidences. Survival was shorter in HCV patients (4-year cumI: 91.6% vs. 97.2%; P = 0.0002). Death (n = 102; missing data: 6) was attributed to liver disease in 48 (47%; liver cancer: n = 18; miscellaneous, n = 30) and extrahepatic causes in 48 (47%; bacterial infection: n = 13; extrahepatic cancers: n = 10; cardiovascular events: n = 5; miscellaneous, n = 20). After 3 years of follow-up, extrahepatic events still explained half of deaths in patients with compensated VC. A strong decrease in complications was linked to virological eradication/control.


Invariant scattering convolution networks.
A wavelet scattering network computes a translation invariant image representation which is stable to deformations and preserves high-frequency information for classification. It cascades wavelet transform convolutions with nonlinear modulus and averaging operators. The first network layer outputs SIFT-type descriptors, whereas the next layers provide complementary invariant information that improves classification. The mathematical analysis of wavelet scattering networks explains important properties of deep convolution networks for classification. A scattering representation of stationary processes incorporates higher order moments and can thus discriminate textures having the same Fourier power spectrum. State-of-the-art classification results are obtained for handwritten digits and texture discrimination, with a Gaussian kernel SVM and a generative PCA classifier.


The regulating role of mindfulness in enacted workplace incivility: An experience sampling study.
Incivility at work poses a problem, both for individuals who are the targets of incivility and for organizations. However, relatively little is known about what drives or hinders individuals to engage in incivility, and how they respond to their own uncivil behavior. Adopting a self-regulation perspective, we link theories explaining enacted incivility as self-regulatory failure with research about the self-regulatory benefits of mindfulness. We develop and investigate a conceptual model on the role of trait mindfulness in antecedent- and consequent-based processes of enacted workplace incivility. Data from an experience-sampling study across 5 work days provided support for the majority of our hypotheses. Individuals high in trait mindfulness not only showed generally low levels of enacted incivility, but they also displayed less variability in enacted incivility over time. Specifically, while enacted incivility was entrained to the work week and systematically decreased from Monday to Friday for individuals low in mindfulness, enacted incivility remained stable over the course of the work week for individuals high in mindfulness. Furthermore, employees high in trait mindfulness reacted in a more morally mature manner and experienced guilt when having engaged in uncivil behavior compared to their low mindful counterparts. However, increases in guilt for high mindful individuals did not translate into lower levels of enacted incivility the following work day. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Learning with convex loss and indefinite kernels.
We consider a kind of kernel-based regression with general convex loss functions in a regularization scheme. The kernels used in the scheme are not necessarily symmetric and thus are not positive semidefinite; l(1)-norm of the coefficients in the kernel ensembles is taken as the regularizer. Our setting in this letter is quite different from the classical regularized regression algorithms such as regularized networks and support vector machines regression. Under an established error decomposition that consists of approximation error, hypothesis error, and sample error, we present a detailed mathematical analysis for this scheme and, in particular, its learning rate. A reweighted empirical process theory is applied to the analysis of produced learning algorithms, which plays a key role in deriving the explicit learning rate under some assumptions.


Highly elevated serum lactate dehydrogenase is associated with central nervous system relapse in patients with diffuse large B-cell lymphoma: Results of a multicenter prospective cohort study.
Central nervous system involvement remains a challenging issue in the treatment of patients with diffuse large B-cell lymphoma. We conducted a prospective cohort study with newly diagnosed diffuse large B-cell lymphoma patients receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone to identify incidence and risk factors for central nervous system involvement. Among 595 patients, 279 patients received pre-treatment central nervous system evaluation, and 14 patients had central nervous system involvement at diagnosis (2.3% out of entire patients and 5.0% out of the 279 patients). For those patients, median follow-up duration was 38.2 months and some of them achieved long-term survival. Out of 581 patients who did not have central nervous system involvement at diagnosis, 26 patients underwent secondary central nervous system relapse with a median follow-up of 35 months, and the median time to central nervous system involvement was 10.4 months (range: 3.4-29.2). Serum lactate dehydrogenase > ×3 upper limit of normal range, the Eastern Cooperative Oncology Group performance status ≥ 2, and involvement of sinonasal tract or testis, were independent risk factors for central nervous system relapse in multivariate analysis. Our study suggests that enhanced stratification of serum lactate dehydrogenase according to the National Comprehensive Cancer Network-International Prognostic Index may contribute to better prediction for central nervous system relapse in patients with diffuse large B-cell lymphoma. This trial was registered at clinicaltrials.gov identifier: 01202448.


Computerized literature searching in the ambulatory setting using PaperChase.
PaperChase, a self-service computerized literature search (SSCLS) service, was compared to conventional resources for accessing recent medical information by assessing user attitudes, search costs, and number of searches performed. The study was designed as a randomized controlled trial using survey instruments before and after the intervention. Accounting of PaperChase searches was monitored electronically, and costs of librarian searches were provided by the hospital library. Participants included 57 physicians in several specialties who were members of a group practice located in a suburban ambulatory care center. Responses were received from 67%. The experimental group received free, unlimited access to PaperChase over a one-year period, while the control group used conventional resources (manually self-performed searches and computerized MEDLINE searches performed free-of-charge by hospital librarians). The study disclosed no change in attitude of either those employing computers or SSCLS. Attitude scores in the experimental group showed statistically significant worsening in preference for SSCLS over textbook use and the estimation of SSCLS utility in the outpatient setting. The cost of PaperChase compared favorably to literature searches done by librarians. The self-reported numbers of literature searches of all types increased in the experimental group. PaperChase searches changed physicians' perceptions of patient treatment and outcome in some cases. While computerized literature searches may have a role in the outpatient setting, other resources remain important. Although only certain physicians are interested in using this method, this study shows that PaperChase can be a cost-effective alternative to MEDLINE searches performed by hospital librarians.


Thrombus Aspiration in ST-Segment-Elevation Myocardial Infarction: An Individual Patient Meta-Analysis: Thrombectomy Trialists Collaboration.
Thrombus aspiration during percutaneous coronary intervention (PCI) for the treatment of ST-segment-elevation myocardial infarction (STEMI) has been widely used; however, recent trials have questioned its value and safety. In this meta-analysis, we, the trial investigators, aimed to pool the individual patient data from these trials to determine the benefits and risks of thrombus aspiration during PCI in patients with ST-segment-elevation myocardial infarction. Included were large (n≥1000), randomized, controlled trials comparing manual thrombectomy and PCI alone in patients with ST-segment-elevation myocardial infarction. Individual patient data were provided by the leadership of each trial. The prespecified primary efficacy outcome was cardiovascular mortality within 30 days, and the primary safety outcome was stroke or transient ischemic attack within 30 days. The 3 eligible randomized trials (TAPAS [Thrombus Aspiration During Percutaneous Coronary Intervention in Acute Myocardial Infarction], TASTE [Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia], and TOTAL [Trial of Routine Aspiration Thrombectomy With PCI Versus PCI Alone in Patients With STEMI]) enrolled 19 047 patients, of whom 18 306 underwent PCI and were included in the primary analysis. Cardiovascular death at 30 days occurred in 221 of 9155 patients (2.4%) randomized to thrombus aspiration and 262 of 9151 (2.9%) randomized to PCI alone (hazard ratio, 0.84; 95% confidence interval, 0.70-1.01; P=0.06). Stroke or transient ischemic attack occurred in 66 (0.8%) randomized to thrombus aspiration and 46 (0.5%) randomized to PCI alone (odds ratio, 1.43; 95% confidence interval, 0.98-2.10; P=0.06). There were no significant differences in recurrent myocardial infarction, stent thrombosis, heart failure, or target vessel revascularization. In the subgroup with high thrombus burden (TIMI [Thrombolysis in Myocardial Infarction] thrombus grade ≥3), thrombus aspiration was associated with fewer cardiovascular deaths (170 [2.5%] versus 205 [3.1%]; hazard ratio, 0.80; 95% confidence interval, 0.65-0.98; P=0.03) and with more strokes or transient ischemic attacks (55 [0.9%] versus 34 [0.5%]; odds ratio, 1.56; 95% confidence interval, 1.02-2.42, P=0.04). However, the interaction P values were 0.32 and 0.34, respectively. Routine thrombus aspiration during PCI for ST-segment-elevation myocardial infarction did not improve clinical outcomes. In the high thrombus burden group, the trends toward reduced cardiovascular death and increased stroke or transient ischemic attack provide a rationale for future trials of improved thrombus aspiration technologies in this high-risk subgroup. URLs: http://www.ClinicalTrials.gov http://www.crd.york.ac.uk/prospero/. Unique identifiers: NCT02552407 and CRD42015025936.


Dynamics of Dark-Fly Genome Under Environmental Selections.
Environmental adaptation is one of the most fundamental features of organisms. Modern genome science has identified some genes associated with adaptive traits of organisms, and has provided insights into environmental adaptation and evolution. However, how genes contribute to adaptive traits and how traits are selected under an environment in the course of evolution remain mostly unclear. To approach these issues, we utilize "Dark-fly", a Drosophila melanogaster line maintained in constant dark conditions for more than 60 years. Our previous analysis identified 220,000 single nucleotide polymorphisms (SNPs) in the Dark-fly genome, but did not clarify which SNPs of Dark-fly are truly adaptive for living in the dark. We found here that Dark-fly dominated over the wild-type fly in a mixed population under dark conditions, and based on this domination we designed an experiment for genome reselection to identify adaptive genes of Dark-fly. For this experiment, large mixed populations of Dark-fly and the wild-type fly were maintained in light conditions or in dark conditions, and the frequencies of Dark-fly SNPs were compared between these populations across the whole genome. We thereby detected condition-dependent selections toward approximately 6% of the genome. In addition, we observed the time-course trajectory of SNP frequency in the mixed populations through generations 0, 22, and 49, which resulted in notable categorization of the selected SNPs into three types with different combinations of positive and negative selections. Our data provided a list of about 100 strong candidate genes associated with the adaptive traits of Dark-fly.


Structural and functional characterization of IdiA/FutA (Tery_3377), an iron-binding protein from the ocean diazotroph Trichodesmium erythraeum.
Atmospheric nitrogen fixation by photosynthetic cyanobacteria (diazotrophs) strongly influences oceanic primary production and in turn affects global biogeochemical cycles. Species of the genus Trichodesmium are major contributors to marine diazotrophy, accounting for a significant proportion of the fixed nitrogen in tropical and subtropical oceans. However, Trichodesmium spp. are metabolically constrained by the availability of iron, an essential element for both the photosynthetic apparatus and the nitrogenase enzyme. Survival strategies in low-iron environments are typically poorly characterized at the molecular level, because these bacteria are recalcitrant to genetic manipulation. Here, we studied a homolog of the iron deficiency-induced A (IdiA)/ferric uptake transporter A (FutA) protein, Tery_3377, which has been used as an in situ iron-stress biomarker. IdiA/FutA has an ambiguous function in cyanobacteria, with its homologs hypothesized to be involved in distinct processes depending on their cellular localization. Using signal sequence fusions to GFP and heterologous expression in the model cyanobacterium Synechocystis sp. PCC 6803, we show that Tery_3377 is targeted to the periplasm by the twin-arginine translocase and can complement the deletion of the native Synechocystis ferric-iron ABC transporter periplasmic binding protein (FutA2). EPR spectroscopy revealed that purified recombinant Tery_3377 has specificity for iron in the Fe3+ state, and an X-ray crystallography-determined structure uncovered a functional iron substrate-binding domain, with Fe3+ pentacoordinated by protein and buffer ligands. Our results support assignment of Tery_3377 as a functional FutA subunit of an Fe3+ ABC transporter but do not rule out dual IdiA function.


[Surgical options of metastatic spine tumors].
Spinal metastases are a common concomitant phenomenon of advanced tumor disease. Beside the lung and liver, the spine is the third most common localization of manifestation. Apart from chronic and increasing pain, spinal metastases lead to neurological deficits due to destruction of the vertebral body and subsequent epidural growth expansion. The aim of a surgical treatment is the reduction of pain and the maintenance of neurological function as well as spine stability. The indication for surgery should be determined individually in an interdisciplinary consultation. The purpose of this article was to provide a brief overview regarding diagnostics and therapy of metastatic spine tumors.


Point-of-care ultrasound in primary care: a systematic review of generalist performed point-of-care ultrasound in unselected populations.
Both the interest and actual extent of use of point-of-care ultrasound, PoCUS, among general practitioners or family physicians are increasing and training is also increasingly implemented in residency programs. However, the amount of research within the field is still rather limited compared to what is seen within other specialties in which it has become more established, such as in the specialty of emergency medicine. An assumption is made that what is relevant for emergency medicine physicians and their populations is also relevant to the general practitioner, as both groups are generalists working in unselected populations. This systematic review aims to examine the extent of use and to identify clinical studies on the use of PoCUS by either general practitioners or emergency physicians on indications that are relevant for the former, both in their daily practice and in out-of-hours services. Systematic searches were done in PubMed/MEDLINE using terms related to general practice, emergency medicine, and ultrasound. On the extent of use, we identified 19 articles, as well as 26 meta-analyses and 168 primary studies on the clinical use of PoCUS. We found variable, but generally low, use among general practitioners, while it seems to be thoroughly established in emergency medicine in North America, and increasingly also in the rest of the world. In terms of clinical studies, most were on diagnostic accuracy, and most organ systems were studied; the heart, lungs/thorax, vessels, abdominal and pelvic organs, obstetric ultrasound, the eye, soft tissue, and the musculoskeletal system. The studies found in general either high sensitivity or high specificity for the particular test studied, and in some cases high total accuracy and superiority to other established diagnostic imaging modalities. PoCUS also showed faster time to diagnosis and change in management in some studies. Our review shows that generalists can, given a certain level of pre-test probability, safely use PoCUS in a wide range of clinical settings to aid diagnosis and better the care of their patients.


Human hippocampal and parahippocampal theta during goal-directed spatial navigation predicts performance on a virtual Morris water maze.
The hippocampus and parahippocampal cortices exhibit theta oscillations during spatial navigation in animals and humans, and in the former are thought to mediate spatial memory formation. Functional specificity of human hippocampal theta, however, is unclear. Neuromagnetic activity was recorded with a whole-head 275-channel magnetoencephalographic (MEG) system as healthy participants navigated to a hidden platform in a virtual reality Morris water maze. MEG data were analyzed for underlying oscillatory sources in the 4-8 Hz band using a spatial filtering technique (i.e., synthetic aperture magnetometry). Source analyses revealed greater theta activity in the left anterior hippocampus and parahippocampal cortices during goal-directed navigation relative to aimless movements in a sensorimotor control condition. Additional analyses showed that left anterior hippocampal activity was predominantly observed during the first one-half of training, pointing to a role for this region in early learning. Moreover, posterior hippocampal theta was highly correlated with navigation performance, with the former accounting for 76% of the variance of the latter. Our findings suggest human spatial learning is dependent on hippocampal and parahippocampal theta oscillations, extending to humans a significant body of research demonstrating such a pivotal role for hippocampal theta in animal navigation.


Prevalence of ethanol and illicit drugs in road traffic accidents in the centre of Portugal: An eighteen-year update.
This study presents the prevalence of ethanol and illicit drugs in fatal road traffic accident victims in the Centre of Portugal between January 1990 and December 2007. Among the violent deaths, road traffic accidents presented the highest percentage (around 35%; n=3095), but decreasing throughout the years. Accidents were preponderant in males (about 80%; n=2402), between 21 and 30 years-old. Accidents involving drivers (55%; n=1310) were of the most common, being the car the main vehicle (45%), followed by the motorcycle (40%). An alcohol analysis request was present in 50% of the cases (n=1687), but increasing each year. Ethanol concentrations >1.2g/L, the legal limit in Portugal, were found in 55% (n=283) of the cases. Concerning drugs of abuse requests, only 4.4% (n=137) and 17.3% (58 cases) of the cases included the analysis at the Forensic Pathology Department (FPD) and at the Medico-Legal Office (MLO), respectively. Among the road accident cases analysed, 18 were positive, mainly in men (84%), between 21 and 30 years-old; opiates (47.1%; n=8) and cannabinoids (50%; n=4) were the most found, at the FPD and at the MLO, respectively. In conclusion, ethanol was identified as a key factor to traffic accidents, which explains the definition of specific legislation and methods of enforcement to prohibit this form of impairing. Nevertheless, ethanol still remains the psychoactive substance most frequently identified in the blood of divers killed in road-traffic crashes, recommending additional actions of supervision and control.


Prestimulus Alpha Oscillations and the Temporal Sequencing of Audiovisual Events.
Perceiving the temporal order of sensory events typically depends on participants' attentional state, thus likely on the endogenous fluctuations of brain activity. Using magnetoencephalography, we sought to determine whether spontaneous brain oscillations could disambiguate the perceived order of auditory and visual events presented in close temporal proximity, that is, at the individual's perceptual order threshold (Point of Subjective Simultaneity [PSS]). Two neural responses were found to index an individual's temporal order perception when contrasting brain activity as a function of perceived order (i.e., perceiving the sound first vs. perceiving the visual event first) given the same physical audiovisual sequence. First, average differences in prestimulus auditory alpha power indicated perceiving the correct ordering of audiovisual events irrespective of which sensory modality came first: a relatively low alpha power indicated perceiving auditory or visual first as a function of the actual sequence order. Additionally, the relative changes in the amplitude of the auditory (but not visual) evoked responses were correlated with participant's correct performance. Crucially, the sign of the magnitude difference in prestimulus alpha power and evoked responses between perceived audiovisual orders correlated with an individual's PSS. Taken together, our results suggest that spontaneous oscillatory activity cannot disambiguate subjective temporal order without prior knowledge of the individual's bias toward perceiving one or the other sensory modality first. Altogether, our results suggest that, under high perceptual uncertainty, the magnitude of prestimulus alpha (de)synchronization indicates the amount of compensation needed to overcome an individual's prior in the serial ordering and temporal sequencing of information.


Complete Genome of the Starch-Degrading Myxobacteria Sandaracinus amylolyticus DSM 53668T.
Myxobacteria are members of δ-proteobacteria and are typified by large genomes, well-coordinated social behavior, gliding motility, and starvation-induced fruiting body formation. Here, we report the 10.33 Mb whole genome of a starch-degrading myxobacterium Sandaracinus amylolyticus DSM 53668(T) that encodes 8,962 proteins, 56 tRNA, and two rRNA operons. Phylogenetic analysis, in silico DNA-DNA hybridization and average nucleotide identity reveal its divergence from other myxobacterial species and support its taxonomic characterization into a separate family Sandaracinaceae, within the suborder Sorangiineae. Sequence similarity searches using the Carbohydrate-active enzymes (CAZyme) database help identify the enzyme repertoire of S. amylolyticus involved in starch, agar, chitin, and cellulose degradation. We identified 16 α-amylases and two γ-amylases in the S. amylolyticus genome that likely play a role in starch degradation. While many of the amylases are seen conserved in other δ-proteobacteria, we notice several novel amylases acquired via horizontal transfer from members belonging to phylum Deinococcus-Thermus, Acidobacteria, and Cyanobacteria. No agar degrading enzyme(s) were identified in the S. amylolyticus genome. Interestingly, several putative β-glucosidases and endoglucanases proteins involved in cellulose degradation were identified. However, the absence of cellobiohydrolases/exoglucanases corroborates with the lack of cellulose degradation by this bacteria.


Model selection for factorial Gaussian graphical models with an application to dynamic regulatory networks.
Factorial Gaussian graphical Models (fGGMs) have recently been proposed for inferring dynamic gene regulatory networks from genomic high-throughput data. In the search for true regulatory relationships amongst the vast space of possible networks, these models allow the imposition of certain restrictions on the dynamic nature of these relationships, such as Markov dependencies of low order - some entries of the precision matrix are a priori zeros - or equal dependency strengths across time lags - some entries of the precision matrix are assumed to be equal. The precision matrix is then estimated by l1-penalized maximum likelihood, imposing a further constraint on the absolute value of its entries, which results in sparse networks. Selecting the optimal sparsity level is a major challenge for this type of approaches. In this paper, we evaluate the performance of a number of model selection criteria for fGGMs by means of two simulated regulatory networks from realistic biological processes. The analysis reveals a good performance of fGGMs in comparison with other methods for inferring dynamic networks and of the KLCV criterion in particular for model selection. Finally, we present an application on a high-resolution time-course microarray data from the Neisseria meningitidis bacterium, a causative agent of life-threatening infections such as meningitis. The methodology described in this paper is implemented in the R package sglasso, freely available at CRAN, http://CRAN.R-project.org/package=sglasso.


Effectiveness of DIAGNOdent in Detecting Root Caries Without Dental Scaling Among Community-dwelling Elderly.
The purpose of this clinical research was to analyze the effectiveness of DIAGNOdent in detecting root caries without dental scaling. The status of 750 exposed, unfilled root surfaces was assessed by visual-tactile examination and DIAGNOdent before and after root scaling. The sensitivity and specificity of different cut-off DIAGNOdent values in diagnosing root caries with reference to visual-tactile criteria were evaluated on those root surfaces without visible plaque/calculus. The DIAGNOdent values from sound and carious root surfaces were compared using the nonparametric Mann-Whitney U-test. The level of statistical significance was set at 0.05. On root surfaces without plaque/calculus, significantly different (p < 0.05) DIAGNOdent readings were obtained from sound root surfaces (12.2 ± 11.1), active carious root surfaces (37.6 ± 31.7) and inactive carious root surfaces (20.9 ± 10.5) before scaling. On root surfaces with visible plaque, DIAGNOdent readings obtained from active carious root surfaces (29.6 ± 20.8) and inactive carious root surfaces (27.0 ± 7.2) were not statistically significantly different (p > 0.05). Furthermore, on root surfaces with visible calculus, all DIAGNOdent readings obtained from sound root surfaces were > 50, which might be misinterpreted as carious. After scaling, the DIAGNOdent readings obtained from sound root surfaces (8.1 ± 11.3), active carious root surfaces (37.9 ± 31.9) and inactive carious root surfaces (24.9 ± 11.5) presented significant differences (p < 0.05). A cut-off value between 10 and 15 yielded the highest combined sensitivity and specificity in detecting root caries on root surfaces without visible plaque/calculus before scaling, but the combined sensitivity and specificity are both around 70%. These findings suggest that on exposed, unfilled root surfaces without visible plaque/calculus, DIAGNOdent can be used as an adjunct to the visual-tactile criteria in detecting root-surface status without pre-treatment by dental scaling.


Sox2 gene amplification significantly impacts overall survival in serous epithelial ovarian cancer.
Epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer. Recently, the existence of ovarian cancer stem cells has been reported. Sox2, Nanog and Oct4 are key markers of "stemness". The objective of this study was to determine whether Sox2, Nanog, and Oct4 are associated with EOC and poor outcome. The expression of these markers was assessed by immunofluorescence staining and real-time RT-PCR in human EOC cell lines MDAH-2774 and SKOV-3, while the cancer genome atlas (TCGA) dataset was analyzed for associations with survival. Sox2, Nanog and Oct4 (POU5F1) were all detected by immunofluorescence staining and these results were confirmed by real-time RT-PCR. The TCGA dataset revealed a 26%, 9%, and 6% amplification of Sox2, Nanog and POU5F1, respectively. Additionally, K-M survival analyses showed a significant median overall survival difference (41 versus 48.3 months, P = .01) for Sox2 amplification, but not for Nanog (44.1 versus 36.2 months, P > .05) and POU5F1 (43.5 versus 45.0 months, P > .05). Our results suggest that Sox2 gene amplification significantly influences overall survival.


Intervention planning for a digital intervention for self-management of hypertension: a theory-, evidence- and person-based approach.
This paper describes the intervention planning process for the Home and Online Management and Evaluation of Blood Pressure (HOME BP), a digital intervention to promote hypertension self-management. It illustrates how a Person-Based Approach can be integrated with theory- and evidence-based approaches. The Person-Based Approach to intervention development emphasises the use of qualitative research to ensure that the intervention is acceptable, persuasive, engaging and easy to implement. Our intervention planning process comprised two parallel, integrated work streams, which combined theory-, evidence- and person-based elements. The first work stream involved collating evidence from a mixed methods feasibility study, a systematic review and a synthesis of qualitative research. This evidence was analysed to identify likely barriers and facilitators to uptake and implementation as well as design features that should be incorporated in the HOME BP intervention. The second work stream used three complementary approaches to theoretical modelling: developing brief guiding principles for intervention design, causal modelling to map behaviour change techniques in the intervention onto the Behaviour Change Wheel and Normalisation Process Theory frameworks, and developing a logic model. The different elements of our integrated approach to intervention planning yielded important, complementary insights into how to design the intervention to maximise acceptability and ease of implementation by both patients and health professionals. From the primary and secondary evidence, we identified key barriers to overcome (such as patient and health professional concerns about side effects of escalating medication) and effective intervention ingredients (such as providing in-person support for making healthy behaviour changes). Our guiding principles highlighted unique design features that could address these issues (such as online reassurance and procedures for managing concerns). Causal modelling ensured that all relevant behavioural determinants had been addressed, and provided a complete description of the intervention. Our logic model linked the hypothesised mechanisms of action of our intervention to existing psychological theory. Our integrated approach to intervention development, combining theory-, evidence- and person-based approaches, increased the clarity, comprehensiveness and confidence of our theoretical modelling and enabled us to ground our intervention in an in-depth understanding of the barriers and facilitators most relevant to this specific intervention and user population.


Neural networks as mechanisms to regulate division of labor.
In social insects, workers perform a multitude of tasks, such as foraging, nest construction, and brood rearing, without central control of how work is allocated among individuals. It has been suggested that workers choose a task by responding to stimuli gathered from the environment. Response-threshold models assume that individuals in a colony vary in the stimulus intensity (response threshold) at which they begin to perform the corresponding task. Here we highlight the limitations of these models with respect to colony performance in task allocation. First, we show with analysis and quantitative simulations that the deterministic response-threshold model constrains the workers' behavioral flexibility under some stimulus conditions. Next, we show that the probabilistic response-threshold model fails to explain precise colony responses to varying stimuli. Both of these limitations would be detrimental to colony performance when dynamic and precise task allocation is needed. To address these problems, we propose extensions of the response-threshold model by adding variables that weigh stimuli. We test the extended response-threshold model in a foraging scenario and show in simulations that it results in an efficient task allocation. Finally, we show that response-threshold models can be formulated as artificial neural networks, which consequently provide a comprehensive framework for modeling task allocation in social insects.


The locus of microRNA-10b: a critical target for breast cancer insurgence and dissemination.
Contemporary microRNA research has led to significant advances in our understanding of the process of tumorigenesis. MicroRNAs participate in different events of a cancer cell's life, through their ability to target hundreds of putative transcripts involved in almost every cellular function, including cell cycle, apoptosis, and differentiation. The relevance of these small molecules is even more evident in light of the emerging linkage between their expression and both prognosis and clinical outcome of many types of human cancers. This identifies microRNAs as potential therapeutic modifiers of cancer phenotypes. From this perspective, we overview here the miR-10b locus and its involvement in cancer, focusing on its role in the establishment (miR-10b*) and spreading (miR-10b) of breast cancer. We conclude that targeting the locus of microRNA 10b holds great potential for cancer treatment.


High rates of aggression do not predict rates of trauma in captive groups of macaques.
Socially inflicted traumas are a major concern for the management of captive groups of rhesus macaques. Rhesus macaques are the most commonly used nonhuman primate in biomedical research, and social housing is optimal for promoting psychological well-being. However, trauma is frequent due to a strong reliance on aggression to establish and maintain hierarchical relationships. We studied six captive groups of rhesus macaques (Macaca mulatta) that underwent a variety of social perturbations and explored whether rates of aggression mapped onto rates of trauma using a fine-grained analysis that divided both aggression and trauma variables into specific, behaviorally-relevant categories (e.g., severe aggression by adult males relative to lacerations). Results did not show the expected positive relationship between aggression variables and trauma variables. Instead, rates of trauma (i.e., lacerations, moderate-severe trauma, total trauma) were negatively associated with the rate of impartial interventions (i.e., an intervention directed at both targets during an ongoing conflict) during baseline periods. Additionally, rates of trauma (i.e., lacerations, punctures, moderate-severe trauma, total trauma) were negatively associated with rates of total aggression following temporary knockouts of the individuals who commonly intervene impartially (i.e., conflict policers), and punctures and moderate-severe trauma were negatively associated with rates of severe aggression by adult males following permanent knockout of a high-ranked natal male. These results suggest that under homeostatic conditions, impartial interventions serve as a mechanism to reduce socially inflicted trauma but, following social manipulations of high-ranking males, an imbalance emerges. Our results underscore the importance of developing management strategies for rhesus macaque groups that promote internal social mechanisms of social stability such as maintaining conflict policing individuals (i.e., adult males) in social groups.


Regulatory and ethical considerations for linking clinical and administrative databases.
Clinical data registries are valuable tools that support evidence development, performance assessment, comparative effectiveness studies, and the adoption of new treatments into routine clinical practice. Although these registries do not have important information on long-term therapies or clinical events, administrative claims databases offer a potentially valuable complement. This article focuses on the regulatory and ethical considerations that arise from the use of registry data for research, including linkage of clinical and administrative data sets. (1) Are such activities primarily designed for quality assessment and improvement, research, or both, as this determines the appropriate ethical and regulatory standards? (2) Does the submission of data to a central registry, which may subsequently be linked to other data sources, require review by the institutional review board (IRB) of each participating organization? (3) What levels and mechanisms of IRB oversight are appropriate for the existence of a linked central data repository and the specific studies that may subsequently be developed using it? (4) Under what circumstances are waivers of informed consent and Health Insurance Portability and Accountability Act authorization required? (5) What are the requirements for a limited data set that would qualify a research activity as not involving human subjects and thus not subject to further IRB review? The approaches outlined in this article represent a local interpretation of the regulations in the context of several clinical data registry projects and focuses on a specific case study of the Society of Thoracic Surgeons National Database.


An efficient RNA-cleaving DNA enzyme that synchronizes catalysis with fluorescence signaling.
DNA enzymes are single-stranded DNA molecules with catalytic capabilities that are isolated from random-sequence DNA libraries by "in vitro selection". This new class of catalytic biomolecules has the potential of being used as unique molecular tools in a variety of innovative applications. Here we describe the creation and characterization of an RNA-cleaving autocatalytic DNA, DEC22-18, that uniquely links chemical catalysis with real-time fluorescence signaling capability in the same molecule. A trans-acting DNA molecule, DET22-18, was also developed from DEC22-18 that behaves as a true enzyme with a k(cat) of approximately 7 min(-1)-a rate constant that is the second largest ever reported for a DNA enzyme. It cleaves a chimeric RNA/DNA substrate at the lone RNA linkage surrounded by a closely spaced fluorophore-quencher pair-a unique structure that permits the synchronization of the chemical cleavage with fluorescence signaling. DET22-18 has a stem-loop structure and can be conjugated with DNA aptamers to form allosteric deoxyribozyme biosensors.


Performance indicators for public mental healthcare: a systematic international inventory.
The development and use of performance indicators (PI) in the field of public mental health care (PMHC) has increased rapidly in the last decade. To gain insight in the current state of PI for PMHC in nations and regions around the world, we conducted a structured review of publications in scientific peer-reviewed journals supplemented by a systematic inventory of PI published in policy documents by (non-) governmental organizations. Publications on PI for PMHC were identified through database- and internet searches. Final selection was based on review of the full content of the publications. Publications were ordered by nation or region and chronologically. Individual PI were classified by development method, assessment level, care domain, performance dimension, diagnostic focus, and data source. Finally, the evidence on feasibility, data reliability, and content-, criterion-, and construct validity of the PI was evaluated. A total of 106 publications were included in the sample. The majority of the publications (n = 65) were peer-reviewed journal articles and 66 publications specifically dealt with performance of PMHC in the United States. The objectives of performance measurement vary widely from internal quality improvement to increasing transparency and accountability. The characteristics of 1480 unique PI were assessed. The majority of PI is based on stakeholder opinion, assesses care processes, is not specific to any diagnostic group, and utilizes administrative data sources. The targeted quality dimensions varied widely across and within nations depending on local professional or political definitions and interests. For all PI some evidence for the content validity and feasibility has been established. Data reliability, criterion- and construct validity have rarely been assessed. Only 18 publications on criterion validity were included. These show significant associations in the expected direction on the majority of PI, but mixed results on a noteworthy number of others. PI have been developed for a broad range of care levels, domains, and quality dimensions of PMHC. To ensure their usefulness for the measurement of PMHC performance and advancement of transparency, accountability and quality improvement in PMHC, future research should focus on assessment of the psychometric properties of PI.


Association of Bartter's syndrome and empty sella.
Bartter's syndrome is characterized by hypochloremia, hypokalemia, metabolic alkalosis associated with renal potassium leakage, and normal blood pressure despite increased plasma renin activity. Although association of empty sella with Gitelman syndrome has been reported, no association has been reported with Bartter's syndrome. Here we report a patient with Bartter's syndrome and empty sella. A 12 month-old male patient presented with a history of nausea, vomiting, abdominal distension, constipation, and edema in the lower extremities that had begun in the early postnatal period. The patient was born at 32 weeks gestation by operative delivery for polyhydramnios. Blood pressure was normal. Serum sodium, potassium, calcium, phosphate, chloride, albumin and alkaline phosphatase levels were 129 mEq/l, 2.5 mEq/l, 9 mg/dl, 3.8 mg/dl, 72 mg/dl, 4.2 g/dl and 1285 IU/l, respectively. Serum magnesium level was normal. Arterial blood gas levels revealed pH 7.55 (normal, 7.35-7.45), PCO2 33.6 mm/Hg (36-46), base excess +7.1 (+/- 2.3), and total CO2 33.6 mmol/l (23-27). Renin and aldosterone levels were elevated. Urine had pH 8.0 and specific gravity 1.010. Urinary calcium excretion was 22.8 kg/day (urine calcium/creatinine ratio 0.46). Urinary potassium and chloride levels were elevated. MRI of the brain was normal except for partially empty sella. We present the first pediatric patient with the association of Bartter's syndrome and empty sella.


Water privatization and public health in Latin America.
This study had two objectives: (1) to determine what the public health and development literature has found regarding the public health outcomes of water privatization in Latin America and (2) to evaluate whether the benefits of water privatization, if any, outweigh the equity and justice concerns that privatization raises. Using a standard set of terms to search several databases, the authors identified and reviewed articles and other materials from public health and development sources that were published between 1995 and 2005 and that evaluated the public health effects of water privatizations in Latin America from 1989 to 2000, based on (1) access to water by the poor and/or (2) improvements in public health. Next, the authors examined the experiences of three cities in Bolivia (Cochabamba, El Alto, and La Paz) in order to illuminate further the challenges of water privatization. Finally, the authors considered the equity and justice issues raised by the privatization of water. The literature review raised persistent concerns regarding access to water by the poor under privatization. The review also suggested that the public sector could deliver public health outcomes comparable to those of the private sector, as measured by access rates and decreasing child mortality rates. In terms of social equity and justice, privatization marked a troubling shift away from the conception of water as a "social good" and toward the conception of water--and water management services--as commodities. Our results indicated there is no compelling case for privatizing existing public water utilities based on public health grounds. From the perspective of equity and justice, water privatization may encourage a minimalist conception of social responsibility for public health that may hinder the development of public health capacities in the long run.


A challenging case of hypercapnic respiratory failure during pregnancy.
We describe a 40-year-old female who presented with progressive breathlessness and hypercapnic respiratory failure during pregnancy secondary to undiagnosed muscle-specific kinase myasthenia gravis. Her presentation was progressive and protracted, having over five contacts with healthcare professionals over nine months, many of these predating her pregnancy. Her atypical presentation for myasthenia with minimal limb weakness led to consideration of other causes of hypercapnic respiratory failure. Once diagnosed, she was treated with intravenous immunoglobulin and non-invasive ventilation. She gave birth to a pre-term infant by planned caesarean section. Her insidious presentation and the progressive nature of her breathlessness were unusual and our report highlights the predominant involvement of respiratory muscles in muscle-specific kinase myasthenia. Her pregnancy may have further delayed her diagnosis due the attribution of some symptoms to normal pregnancy. Early recognition and treatment of myasthenia gravis are important to prevent life-threatening complications.


Formation of long and thin polymer fiber using nondiffracting beam.
We present a unique method that utilizes high intensity core of the zero-order nondiffracting beam (NDB) to fabricate a homogeneous polymer fiber as narrow as 2 mum and as long as centimeters. The constant diameter of the fiber along all its length is done by the propagation invariant properties of the NDB. The length of the fiber is determined by the maximum propagation distance of the NDB which is much longer than the classical Gaussian beam of comparable width. Moreover, we also proved that the self-writing waveguide mechanism prolongs the length of the developed fibers. Circular movement of the NDB creates hollow fiber, several co-axial, or overlapping fibers.


Why do some voluntary patients feel coerced into hospitalisation? A mixed-methods study.
This study aimed to investigate factors linked to perceived coercion at admission and during treatment among voluntary inpatients. Quantitative and qualitative methods were used. Two hundred seventy patients were screened for perceived coercion at admission. Those who felt coerced into admission rated their perceived coercion during treatment a month after admission. Patient characteristics and experiences were tested as predictors of coercion. In-depth interviews on experiences leading to perceived coercion were conducted with 36 participants and analysed thematically. Thirty-four percent of patients felt coerced into admission and half of those still felt coerced a month later. No patient characteristics were associated with perceived coercion. Those whose satisfaction with treatment increased more markedly between baseline and a month later were less likely to feel coerced a month after admission. In the qualitative interviews three themes leading to perceived coercion were identified: viewing the hospital as ineffective and other treatments as more appropriate, not participating in the admission and treatment and not feeling respected. Involving patients in the decision-making and treating them with respect may reduce perceived coercion.


Thioredoxin regulates multiple hydrogen peroxide-induced signaling pathways in Candida albicans.
The ability of the major systemic fungal pathogen of humans, Candida albicans, to sense and respond to reactive oxygen species (ROS), such as H(2)O(2) generated by the host immune system, is required for survival in the host. However, the intracellular signaling mechanisms underlying such responses are poorly understood. Here, we show that thioredoxin (Trx1), in addition to its antioxidant activity, plays a central role in coordinating the response of C. albicans to ROS by regulating multiple pathways. In particular, Trx1 function is important for H(2)O(2)-induced phosphorylation of the Hog1 stress-activated protein kinase and to reverse H(2)O(2)-induced oxidation and activation of the AP-1 like transcription factor Cap1. Furthermore, Trx1 regulates H(2)O(2)-induced hyperpolarized bud growth in a mechanism that involves activation of the Rad53 checkpoint kinase. Consistent with its key roles in responses to ROS, cells lacking Trx1 displayed significantly attenuated virulence in a murine model of C. albicans systemic infection. Collectively, our data indicate that Trx1 has a multifaceted role in H(2)O(2) signaling and promotes C. albicans survival in the host.


Predictors of acute kidney injury in septic shock patients: an observational cohort study.
Acute kidney injury (AKI) is a frequent complication in critically ill patients and sepsis is the most common contributing factor. We aimed to determine the risk factors associated with AKI development in patients with septic shock. Observational cohort study consisted of consecutive adults with septic shock admitted to a medical intensive care unit (ICU) of a tertiary care academic hospital from July 2005 to September 2007. AKI was defined according to RIFLE criteria (urine output and creatinine criteria). Demographic, clinical, and treatment variables were reviewed. Main outcomes measured were AKI occurrence, all-cause hospital mortality, and hospital and ICU length of stay. Three hundred ninety patients met inclusion criteria, of which 237 (61%) developed AKI. AKI development was independently associated with delay to initiation of adequate antibiotics, intra-abdominal sepsis, blood product transfusion, use of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker, and body mass index (kg/m²). Higher baseline GFR and successful early goal directed resuscitation were associated with a decreased risk of AKI. Hospital mortality was significantly greater in patients who developed AKI (49 versus 34%). In a contemporary cohort of patients with septic shock, both patient and health care delivery risk factors seemed to be important for AKI development.


Interactions between the PI3K and Raf signaling pathways can result in the transformation of hematopoietic cells.
The PI3K/Akt and Raf/MEK/ERK signal transduction cascades are pivotal in transmitting signals from membrane receptors to downstream targets that regulate apoptosis, gene expression, and cell growth. The abilities of activated PI3K, Akt, Raf, and MEK proteins to abrogate the cytokine dependence of three different hematopoietic cell lines were determined. Activated PI3K or Akt expression by themselves did not efficiently annul cytokine dependence. Raf and MEK could abrogate the cytokine dependence of murine FDC-PI and human TF-1 cells; however, the frequency of transformation was dependent on the particular oncogene examined, as more factor-independent cells were isolated after infection with activated retroviruses encoding A-Raf or Raf-1 than were with MEK1 or B-Raf. Cytokine-independent deltaRaf-1-infected cells formed tumors on injection into immunocompromised mice, whereas cytokine-dependent cell lines did not, demonstrating the oncogenic effects of activation of the Raf/MEK/ERK pathway. Overexpression of the antiapoptotic Bcl-2 protein synergized with activation of the Raf/MEK/ERK cascade and increased the efficiency of transformation of FDC-PI and TF-1 cells. In contrast to the results observed with FDC-P1 and TF-I cells, the activated Raf genes did not relieve the cytokine dependence of murine FL5.12 cells. The abilities of the Raf and PI3K pathways to interact and annul the cytokine dependence of FL5.12 cells were determined. The combination of Raf and either PI3K or Akt expression relieved cytokine dependence of some FL5.12 cells, and the efficiency of transformation could be enhanced further by Bcl-2 or Bcl-XL overexpression. Thus, the antiapoptotic PI3K/Akt and Bcl-2/Bcl-XL proteins can interact with the growth-promoting Raf/MEK/ERK pathway and annul the cytokine dependence of certain hematopoietic cells.


PANOGA: a web server for identification of SNP-targeted pathways from genome-wide association study data.
Genome-wide association studies (GWAS) have revolutionized the search for the variants underlying human complex diseases. However, in a typical GWAS, only a minority of the single-nucleotide polymorphisms (SNPs) with the strongest evidence of association is explained. One possible reason of complex diseases is the alterations in the activity of several biological pathways. Here we present a web server called Pathway and Network-Oriented GWAS Analysis to devise functionally important pathways through the identification of SNP-targeted genes within these pathways. The strength of our methodology stems from its multidimensional perspective, where we combine evidence from the following five resources: (i) genetic association information obtained through GWAS, (ii) SNP functional information, (iii) protein-protein interaction network, (iv) linkage disequilibrium and (v) biochemical pathways.


Horizontal saccade disconjugacy in strabismic monkeys.
Previous studies have shown that binocular coordination during saccadic eye movement is affected in humans with large strabismus. The purpose of this study was to examine the conjugacy of saccadic eye movements in monkeys with sensory strabismus. The authors recorded binocular eye movements in four strabismic monkeys and one unaffected monkey. Strabismus was induced by first occluding one eye for 24 hours, switching the occluder to the fellow eye for the next 24 hours, and repeating this pattern of daily alternating monocular occlusion for the first 4 to 6 months of life. Horizontal saccades were measured during monocular viewing when the animals were 2 to 3 years of age. Horizontal saccade testing during monocular viewing showed that the amplitude of saccades in the nonviewing eye was usually different from that in the viewing eye (saccade disconjugacy). The amount of saccade disconjugacy varied among animals as a function of the degree of ocular misalignment as measured in primary gaze. Saccade disconjugacy also increased with eccentric orbital positions of the nonviewing eye. If the saccade disconjugacy was large, there was an immediate postsaccadic drift for less than 200 ms. The control animal showed none of these effects. As do humans with large strabismus, strabismic monkey display disconjugate saccadic eye movements. Saccade disconjugacy varies with orbital position and increases as a function of ocular misalignment as measured in primary gaze. This type of sensory-induced strabismus serves as a useful animal model to investigate the neural or mechanical factors responsible for saccade disconjugacy observed in humans with strabismus.


Identification and glycerol-induced correction of misfolding mutations in the X-linked mental retardation gene CASK.
The overwhelming amount of available genomic sequence variation information demands a streamlined approach to examine known pathogenic mutations of any given protein. Here we seek to outline a strategy to easily classify pathogenic missense mutations that cause protein misfolding and are thus good candidates for chaperone-based therapeutic strategies, using previously identified mutations in the gene CASK. We applied a battery of bioinformatics algorithms designed to predict potential impact on protein structure to five pathogenic missense mutations in the protein CASK that have been shown to underlie pathologies ranging from X-linked mental retardation to autism spectrum disorder. A successful classification of the mutations as damaging was not consistently achieved despite the known pathogenicity. In addition to the bioinformatics analyses, we performed molecular modeling and phylogenetic comparisons. Finally, we developed a simple high-throughput imaging assay to measure the misfolding propensity of the CASK mutants in situ. Our data suggests that a phylogenetic analysis may be a robust method for predicting structurally damaging mutations in CASK. Mutations in two evolutionarily invariant residues (Y728C and W919R) exhibited a strong propensity to misfold and form visible aggregates in the cytosolic milieu. The remaining mutations (R28L, Y268H, and P396S) showed no evidence of aggregation and maintained their interactions with known CASK binding partners liprin-α3 Mint-1, and Veli, indicating an intact structure. Intriguingly, the protein aggregation caused by the Y728C and W919R mutations was reversed by treating the cells with a chemical chaperone (glycerol), providing a possible therapeutic strategy for treating structural mutations in CASK in the future.


Spontaneous kidney tumors in the frog: rate of occurrence in isolated adults.
Kidney tumors in the frog are thought to be virus-caused and naturally transmitted. The present report indicates that natural transmission between mature adults is not a factor in spontaneous tumor development and implies primary infection at earlier stages if a virus is indeed involved. Parasitism and nutritional state appear to be of little significance.


Posterolateral rotatory instability of the elbow.
Recurrent posterolateral rotatory instability of the elbow is an apparently undescribed clinical condition that is difficult to diagnose. We treated five patients, ranging in age from five to forty years, who had such a lesion and in whom the instability could be demonstrated only by what we call the posterolateral rotatory-instability test. This test involves supination of the forearm and application of a valgus moment and an axial compression force to the elbow while it is flexed from full extension. The elbow is reduced in full extension and must be subluxated as it is flexed in order to obtain a positive test result (a sudden reduction of the subluxation). Flexion of more than about 40 degrees produces a sudden palpable and visible reduction of the radiohumeral joint. The elbow does not subluxate without provocation. The cause for this condition, we think, is laxity of the ulnar part of the lateral collateral ligament, which allows a transient rotatory subluxation of the ulnohumeral joint and a secondary dislocation of the radiohumeral joint. The annular ligament remains intact, so the radio-ulnar joint does not dislocate. Operative repair of the lax ulnar part of the lateral collateral ligament eliminated the posterolateral rotatory instability, as revealed intraoperatively in our five patients.


DNA replication and transcription programs respond to the same chromatin cues.
DNA replication is a dynamic process that occurs in a temporal order along each of the chromosomes. A consequence of the temporally coordinated activation of replication origins is the establishment of broad domains (>100 kb) that replicate either early or late in S phase. This partitioning of the genome into early and late replication domains is important for maintaining genome stability, gene dosage, and epigenetic inheritance; however, the molecular mechanisms that define and establish these domains are poorly understood. The modENCODE Project provided an opportunity to investigate the chromatin features that define the Drosophila replication timing program in multiple cell lines. The majority of early and late replicating domains in the Drosophila genome were static across all cell lines; however, a small subset of domains was dynamic and exhibited differences in replication timing between the cell lines. Both origin selection and activation contribute to defining the DNA replication program. Our results suggest that static early and late replicating domains were defined at the level of origin selection (ORC binding) and likely mediated by chromatin accessibility. In contrast, dynamic domains exhibited low ORC densities in both cell types, suggesting that origin activation and not origin selection governs the plasticity of the DNA replication program. Finally, we show that the male-specific early replication of the X chromosome is dependent on the dosage compensation complex (DCC), suggesting that the transcription and replication programs respond to the same chromatin cues. Specifically, MOF-mediated hyperacetylation of H4K16 on the X chromosome promotes both the up-regulation of male-specific transcription and origin activation.


Chamomile (Matricaria chamomilla L.): An overview.
Chamomile (Matricaria chamomilla L.) is a well-known medicinal plant species from the Asteraceae family often referred to as the "star among medicinal species." Nowadays it is a highly favored and much used medicinal plant in folk and traditional medicine. Its multitherapeutic, cosmetic, and nutritional values have been established through years of traditional and scientific use and research. Chamomile has an established domestic (Indian) and international market, which is increasing day by day. The plant available in the market many a times is adulterated and substituted by close relatives of chamomile. This article briefly reviews the medicinal uses along with botany and cultivation techniques. Since chamomile is a rich source of natural products, details on chemical constituents of essential oil and plant parts as well as their pharmacological properties are included. Furthermore, particular emphasis is given to the biochemistry, biotechnology, market demand, and trade of the plant. This is an attempt to compile and document information on different aspects of chamomile and highlight the need for research and development.


Maternal Influences on Access to and Use of Infant ARVs and HIV Health Services in Uganda.
Vertical transmission of HIV is responsible for about 14 % of new HIV cases reported each year in sub-Saharan Africa. Barriers that prevent women from accessing and using antiretroviral medications (ARVs) for themselves and their infants perpetuate the epidemic. To identify influences on access to and use of infant HIV health services, specifically nevirapine administration, we conducted a mixed methods study among HIV-positive women in Uganda. This included a cross-sectional survey (n = 384) and focus group discussions (n = 6, 5-9 participants each). Of the 384 women, 80 % gave nevirapine to their infants within 72 h of birth. Factors independently associated with nevirapine administration were lack of maternal adherence to ARVs (AOR 3.55, 95 % CI 1.36-9.26) and attending a support group (AOR 2.50, 95 % CI 1.06-5.83). Non-health facility births were inversely related to nevirapine use (AOR 0.02, 95 % CI 0.003-0.09). Focus group discussions identified four themes impacting access and use: attending a support group, health care worker attitudes, lack of partner support, and poor health messaging regarding ARVs. Improving health care worker messaging regarding ARVs and providing women with needed support to access and use infant ARV prophylaxis is critical to overcoming access barriers. Eliminating these barriers may prevent numerous HIV infections each year saving the lives of many HIV-exposed infants.


Interventions for preventing hamstring injuries.
Some sports, such as football, have a high incidence of hamstring injuries. Various interventions targeting the prevention of such injuries are in common use. To assess the effects (primarily, on the incidence of hamstring injuries) of interventions used for preventing hamstring injuries in physically active individuals. We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (to December 2008), the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2008, Issue 4), MEDLINE and other databases (to December 2008), reference lists and clinical trials registers. Randomised or quasi-randomised trials of interventions for preventing hamstring injuries were included; as were trials testing interventions for the prevention of lower-limb injuries, provided that hamstring injuries were reported. Secondary outcomes included compliance, severity and the occurrence of other leg injuries. Two authors independently screened search results, assessed methodological quality and extracted data. Risk ratios (RR) and 95% confidence intervals (95% CI) were calculated for dichotomous variables and are reported for individual and pooled data. Seven randomised controlled trials involving 1919 participants were included. All trials involved people, predominantly young adults, participating in regular sporting activities. Some trials were compromised by poor methodology, including lack of blinding and incomplete outcome data.Four trials, including 287 participants, examined interventions directly targeted at preventing hamstring injuries. Three of these trials, which tested hamstring strengthening protocols, had contradictory findings, with one small trial showing benefit (although the control rate of mainly minor hamstring injury was unusually high). The other two trials found no benefit, with a greater incidence of hamstring injury in the intervention group. One unpublished and underpowered trial provided some evidence that manual therapy may prevent lower-limb muscle strain (RR 0.13, 95% CI 0.02 to 0.97), although the finding for hamstring injury did not reach statistical significance (RR 0.21, 95% CI 0.03 to 1.66).Three trials testing interventions for preventing lower limb injuries for which data for hamstring injury were available found no statistically significant effect for hamstring injury for either proprioceptive protocols (two cluster randomised trials) or a warm up/cool down and stretching protocol (one trial). There is insufficient evidence from randomised controlled trials to draw conclusions on the effectiveness of interventions used to prevent hamstring injuries in people participating in football or other high risk activities for these injuries. The findings for manual therapy need confirmation.


Global burden of disease (GBD) for hepatitis C.
Hepatitis C virus (HCV) infection is now a global public health issue. However, the global burden of disease attributable to HCV infection is unknown. The objectives of this WHO informal consultation included the following: (1) defining a strategy to estimate the global burden of disease (GBD) associated with HCV infection in terms of morbidity and mortality, (2) describing the natural history of HCV infection in terms of morbidity and mortality, and (3) identifying areas for which more research is needed. The GBD project is an attempt to examine all causes of morbidity and mortality using an approach common to all conditions. The World Health Organization (WHO) already has estimated the burden of disease associated with hepatitis B virus (HBV) infection and is now about to conduct the same analysis for HCV infection. A review has been conducted to estimate the prevalence of HCV infection by age, gender, and region. These figures can be used to estimate incidence, although there are a number of areas of uncertainty. Combined with natural history parameters, incidence estimates could be used to estimate the future burden due to current infections. However, the present model is not validated and requires calibration before it can be used. A consensus was reached over the strategies to be used to (1) estimate the current burden due to past infections and (2) estimate the future burden due to current infections. Provisional expert consensus was reached over natural history parameters and cofactors that influence them. However, systematic literature reviews and meta-analysis are preferable for obtaining estimates to be included in models. Areas deserving future research include (1) obtaining a better estimate of HCV infection prevalence by age groups, (2) characterizing the various morbidity states associated with HCV infection and their disability weights, (3) understanding the long-term natural history of HCV infection beyond 20 years after infection, and (4) estimating the prevalence (and numbers of) of HCV infection among the drug-using population worldwide. A working group was created to address unmet needs and to assist the WHO in estimating the GBD associated with HCV infection.


Bacteria survive multiple puncturings of their cell walls.
A bacterial cell wall is a highly dynamic multilayer structure interfacing the cytoplasm to the outside environment. It supports a multitude of chemical and biological processes necessary for life. It is therefore postulated that damage to the structure of bacterial cell wall would threaten cell integrity and result in cell death. We tested this hypothesis by repeatedly puncturing the cell wall of a live Gram negative bacterium Salmonella typhimurium at different locations using a sharp atomic force microscope nanotip and conducting multiple viability tests. Our study demonstrated that a S. typhimurium survives repeated puncturings of its cell wall and retains its integrity, viability, and ability to divide. The results are explained on the basis of the concept of the self-repairing of lipid bilayers and the peptidoglycan layer.


A phospholipase A2-related snake venom (from Crotalus durissus terrificus) stimulates neuroendocrine and immune functions: determination of different sites of action.
Immune neuroendocrine interactions are vital for the individual's survival in certain physiopathological conditions, such as sepsis and tissular injury. It is known that several animal venoms, such as those from different snakes, are potent neurotoxic compounds and that their main component is a specific phospholipase A type 2 (PLA2). It has been described recently that the venom from Crotalus durissus terrificus [snake venom (SV), in the present study] possesses some cytotoxic effect in different in vitro and in vivo animal models. In the present study, we investigated whether SV and its main component, PLA2 (obtained from the same source), are able to stimulate both immune and neuroendocrine functions in mice, thus characterizing this type of neurotoxic shock. For this purpose, several in vivo and in vitro designs were used to further determine the sites of action of SV-PLA2 on the hypothalamo-pituitary-adrenal (HPA) axis function and on the release of the pathognomonic cytokine, tumor necrosis factor alpha (TNF alpha), of different types of inflammatory stress. Our results indicate that SV (25 microg/animal) and PLA2 (5 microg/animal), from the same origin, stimulate the HPA and immune axes when administered (i.p.) to adult mice; both preparations were able to enhance plasma glucose, ACTH, corticosterone (B), and TNF alpha plasma levels in a time-related fashion. SV was found to activate CRH- and arginine vasopressin-ergic functions in vivo and, in vitro, SV and PLA2 induced a concentration-related (0.05-10 microg/ml) effect on the release of both neuropeptides. SV also was effective in changing anterior pituitary ACTH and adrenal B contents, also in a time-dependent fashion. Direct effects of SV and PLA2 on anterior pituitary ACTH secretion also were found to function in a concentration-related fashion (0.001-1 microg/ml), and the direct corticotropin-releasing activity of PLA2 was additive to those of CRH and arginine vasopressin; the corticotropin-releasing activity of both SV and PLA2 were partially reversed by the specific PLA2 inhibitor, manoalide. On the other hand, neither preparation was able to directly modify spontaneous and ACTH-stimulated adrenal B output. The stimulatory effect of SV and PLA2 on in vivo TNF alpha release was confirmed by in vitro experiments on peripheral mononuclear cells; in fact, both PLA2 (0.001-1 microg/ml) and SV (0.1-10 microg/ml), as well as concavalin A (1-100 microg/ml), were able to stimulate TNF alpha output in the incubation medium. Our results clearly indicate that PLA2-dependent mechanisms are responsible for several symptoms of inflammatory stress induced during neurotoxemia. In fact, we found that this particular PLA2-related SV is able to stimulate both HPA axis and immune functions during the acute phase response of the inflammatory processes.


Systematic review and meta-analyses of studies analysing instructions to authors from 1987 to 2017.
To gain insight into changes of scholarly journals' recommendations, we conducted a systematic review of studies that analysed journals' Instructions to Authors (ItAs). We summarised results of 153 studies, and meta-analysed how often ItAs addressed: 1) authorship, 2) conflicts of interest, 3) data sharing, 4) ethics approval, 5) funding disclosure, and 6) International Committee of Medical Journal Editors' Uniform Requirements for Manuscripts. For each topic we found large between-study heterogeneity. Here, we show six factors that explained most of that heterogeneity: 1) time (addressing of topics generally increased over time), 2) country (large differences found between countries), 3) database indexation (large differences found between databases), 4) impact factor (topics were more often addressed in highest than in lowest impact factor journals), 5) discipline (topics were more often addressed in Health Sciences than in other disciplines), and 6) sub-discipline (topics were more often addressed in general than in sub-disciplinary journals).