Oxytocin modulates third-party sanctioning of selfish and generous behavior within and between groups.
Human groups function because members trust each other and reciprocate cooperative contributions, and reward others' cooperation and punish their non-cooperation. Here we examined the possibility that such third-party punishment and reward of others' trust and reciprocation is modulated by oxytocin, a neuropeptide generally involved in social bonding and in-group (but not out-group) serving behavior. Healthy males and females (N=100) self-administered a placebo or 24 IU of oxytocin in a randomized, double-blind, between-subjects design. Participants were asked to indicate (incentivized, costly) their level of reward or punishment for in-group (outgroup) investors donating generously or fairly to in-group (outgroup) trustees, who back-transferred generously, fairly or selfishly. Punishment (reward) was higher for selfish (generous) investments and back-transfers when (i) investors were in-group rather than outgroup, and (ii) trustees were in-group rather than outgroup, especially when (iii) participants received oxytocin rather than placebo. It follows, first, that oxytocin leads individuals to ignore out-groups as long as out-group behavior is not relevant to the in-group and, second, that oxytocin contributes to creating and enforcing in-group norms of cooperation and trust.


Fluoxetine for the treatment of fatigue in primary biliary cirrhosis: a randomized, double-blind controlled trial.
Fatigue is a common symptom in primary biliary cirrhosis (PBC). In animal models of cholestasis, abnormalities in serotonin neurotransmission are observed with fatigue. The role of selective serotonin reuptake inhibitors in fatigue-related PBC, however, is unknown. A double-blind, placebo-controlled study design was conducted to determine the safety and efficacy of fluoxetine for the treatment of fatigue in PBC. Patients were randomized to fluoxetine, 20 mg daily, or matched placebo for 8 weeks' duration. Fatigue was assessed by the Fisk Fatigue Impact Scale (FFIS). The primary study endpoint was a > or =50% reduction in overall FFIS score at the end of treatment. Health-related quality of life (HRQL) was assessed as a secondary endpoint. Among 220 consecutively screened patients, only 18 (9%) eligible individuals were randomized to fluoxetine (n=10) or placebo (n=8) for 8 weeks. Baseline variables including median FFIS scores (52 vs 42; P=0.21) were similar between treatment arms (P > 0.05). After 8 weeks of therapy, no statistically significant change in median FFIS score was observed in the fluoxetine group. Median FFIS score in the placebo group was reduced (42 to 28), but not statistically significant. No difference in HRQL was observed between treatment arms after 8 weeks. Fourteen (78%) patients completed therapy, while four (22%) individuals withdrew from the trial. Three of the four patients had drug-related adverse events with fluoxetine. In this study, fluoxetine did not improve fatigue in PBC and was associated with adverse events.


A general procedure for rounding m/z values in low-resolution mass spectra.
It was revealed that nominal mass spectra extracted from the same NetCDF file using different gas chromatography/mass spectrometry (GC/MS) software products are not identical. This phenomenon is caused by differences in algorithms used for rounding floating-point m/z values to integers. It was found that all programs under consideration (AMDIS, ChemStation, ChromaTOF, MS Search, OpenChrom) use different procedures. It is necessary to know how fractional parts of accurate m/z values of ions are distributed to determine which algorithm yields more robust results. We estimated the respective distribution using two databases (PubChem and NIST). As a result, we came up with a procedure that minimizes the influence of random errors on rounding to integer m/z values. The procedure we suggest is to sum intensities of all floating-point m/z values in a bin [MZ - 0.38; MZ + 0.62] and assign MZ as a nominal m/z value, where MZ is an integer m/z value.


Pulmonary vascular disorders in portal hypertension.
The wide spectrum of pulmonary vascular disorders in liver disease and portal hypertension ranges from the hepatopulmonary syndrome characterized by intrapulmonary vascular dilatations, to pulmonary hypertension (portopulmonary hypertension), in which pulmonary vascular resistance is elevated. Since hepatopulmonary syndrome and portopulmonary hypertension have been reported in patients with nonhepatic portal hypertension, the common factor that determines their development must be portal hypertension. The clinical presentations are very different, with gas exchange impairment in the hepatopulmonary syndrome and haemodynamic failure in portopulmonary hypertension. The severity of hepatopulmonary syndrome seems to parallel the severity of liver failure, whereas no simple relationship has been identified between hepatic impairment and the severity of portopulmonary hypertension. Resolution of hepatopulmonary syndrome is common after liver transplantation, which has an uncertain effect in portopulmonary hypertension. The pathophysiology of both syndromes may involve vasoactive mediators and angiogenic factors.


Marine current energy conversion: the dawn of a new era in electricity production.
Marine currents can carry large amounts of energy, largely driven by the tides, which are a consequence of the gravitational effects of the planetary motion of the Earth, the Moon and the Sun. Augmented flow velocities can be found where the underwater topography (bathymetry) in straits between islands and the mainland or in shallows around headlands plays a major role in enhancing the flow velocities, resulting in appreciable kinetic energy. At some of these sites where practical flows are more than 1 m s(-1), marine current energy conversion is considered to be economically viable. This study describes the salient issues related to the exploitation of marine currents for electricity production, resource assessment, the conversion technologies and the status of leading projects in the field. This study also summarizes important issues related to site development and some of the approaches currently being undertaken to inform device and array development. This study concludes that, given the highlighted commitments to establish favourable regulatory and incentive regimes as well as the aspiration for energy independence and combating climate change, the progress to multi-megawatt arrays will be much faster than that achieved for wind energy development.


Mineral trioxide aggregate as a pulpotomy agent in primary molars: an in vivo study.
The retention of pulpally involved deciduous tooth in a healthy state until the time of normal exfoliation remains to be one of the challenges for Pedodontists. A scientific noise has been generated about several materials some of which have been popular pulpotomy medicaments. Concerns have been raised about the toxicity and potential carcinogenicity of these materials, and alternatives have been proposed to maintain the partial pulp vitality, however to date no material has been accepted as an ideal pulpotomy agent. Mineral trioxide aggregate (MTA) is a biocompatible material which provides a biological seal. MTA has been proposed as a potential medicament for various pulpal procedures like pulp capping with reversible pulpitis, apexification, repair of root perforations, etc. Hence the present study was done to evaluate the efficacy of MTA as a pulpotomy medicament. A clinical and radiographic evaluation was done on children where MTA was used as pulpotomy medicament in primary molars for a period of 6 months and it was found to be a successful material.


DICOM for Clinical Research: PACS-Integrated Electronic Data Capture in Multi-Center Trials.
Providing surrogate endpoints in clinical trials, medical imaging has become increasingly important in human-centered research. Nowadays, electronic data capture systems (EDCS) are used but binary image data is integrated insufficiently. There exists no structured way, neither to manage digital imaging and communications in medicine (DICOM) data in EDCS nor to interconnect EDCS with picture archiving and communication systems (PACS). Manual detours in the trial workflow yield errors, delays, and costs. In this paper, requirements for a DICOM-based system interconnection of EDCS and research PACS are analysed. Several workflow architectures are compared. Optimized for multi-center trials, we propose an entirely web-based solution integrating EDCS, PACS, and DICOM viewer, which has been implemented using the open source projects OpenClinica, DCM4CHEE, and Weasis, respectively. The EDCS forms the primary access point. EDCS to PACS interchange is integrated seamlessly on the data and the context levels. DICOM data is viewed directly from the electronic case report form (eCRF), while PACS-based management is hidden from the user. Data privacy is ensured by automatic de-identification and re-labelling with study identifiers. Our concept is evaluated on a variety of 13 DICOM modalities and transfer syntaxes. We have implemented the system in an ongoing investigator-initiated trial (IIT), where five centers have recruited 24 patients so far, performing decentralized computed tomography (CT) screening. Using our system, the chief radiologist is reading DICOM data directly from the eCRF. Errors and workflow processing time are reduced. Furthermore, an imaging database is built that may support future research.


Nna1-like proteins are active metallocarboxypeptidases of a new and diverse M14 subfamily.
Nna1 has some sequence similarity to metallocarboxypeptidases, but the biochemical characterization of Nna1 has not previously been reported. In this work we performed a detailed genomic scan and found >100 Nna1 homologues in bacteria, Protista, and Animalia, including several paralogs in most eukaryotic species. Phylogenetic analysis of the Nna1-like sequences demonstrates a major divergence between Nna1-like peptidases and the previously known metallocarboxypeptidases subfamilies: M14A, M14B, and M14C. Conformational modeling of representative Nna1-like proteins from a variety of species indicates an unusually open active site, a property that might facilitate its action on a wide variety of peptide and protein substrates. To test this, we expressed a recombinant form of one of the Nna1-like peptidases from Caenorhabditis elegans and demonstrated that this protein is a fully functional metallocarboxypeptidase that cleaves a range of C-terminal amino acids from synthetic peptides. The enzymatic activity is activated by ATP/ADP and salt-inactivated, and is preferentially inhibited by Z-Glu-Tyr dipeptide, which is without precedent in metallocarboxypeptidases and resembles tubulin carboxypeptidase functioning; this hypothesis is strongly reinforced by the results depicted in Kalinina et al. published as accompanying paper in this journal. Our findings demonstrate that the M14 family of metallocarboxypeptidases is more complex and diverse than expected, and that Nna1-like peptidases are functional variants of such enzymes, representing a novel subfamily (we propose the name M14D) that contributes substantially to such diversity.


A solution processed carbon nanotube modified conducting paper sensor for cancer detection.
A solution processed poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS)-carbon nanotube (CNT) nano-composite has been utilized for the fabrication of a conducting paper (CP) via dip coating. Further, high conductivity of this paper (from ∼6.5 × 10-4 to 2.2 × 10-2 S cm-1) obtained by treating it with formic acid (CNT/FA@CP) is due to the removal of the non-conducting PSS molecules from its surface. This smart conducting platform has been used for the conjugation of the anti-carcinoembronic antigen (CEA) protein for quantitative estimation of CEA, a cancer biomarker. Transmission electron microscopy (TEM), Raman spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), electrochemical impedance spectroscopy (EIS) and amperometric techniques have been used to characterize the low cost, flexible and environmentally friendly conducting BSA/anti-CEA/CNT/FA@CP) paper electrode that is found to be highly sensitive (7.8 μA ng-1 ml cm-2) in the physiological range (2-15 ng ml-1) of CEA. The response of the paper electrode is validated using CEA concentration of serum samples of cancer patients obtained via the immunoassay technique.


Hepatotoxic botanicals - an evidence-based systematic review.
Herbal medicines have been increasingly used worldwide. However, the potential harms of these herbs have been noticed most recently following hepatotoxicity with ingestion of herbal remedies. The aim of this review is to evaluate the evidence of hepatotoxic effects linked to use of herbal preparations. Electronic search was performed by searching several databases: PubMed, HerbMed, Google Scholar, Scopus, Cochrane Database of Systematic Reviews and Cochrane Library using both Latin and common names of several herbs. Language was restricted to English and articles were selected for relevance reporting incidence of hepatotoxicity associated with use of herbal products in human. From a total of 565 relevant reviews and articles, 254 met our inclusion criteria and were analyzed. Serious hepatotoxic events associated with various herbal products alone or in combination with other drugs have been reported. Linking to herbal constituents the spectrum of liver toxicity includes elevated liver enzymes, acute or chronic hepatitis, cholestasis, hepatic necrosis, fibrosis, and cirrhosis, as well as acute liver failure and hepatic veno-occlusive disease. The hepatotoxicity of herbs was extensively acknowledged. As the use of natural medicine increases, the risk of liver toxicity and drug interaction increase as well. Accordingly, herbal remedies have been known as hepatotoxins causing several liver damages. Further scientific studies with high and good quality are needed to identify toxic compounds and understand the exact mechanism of hepatotoxicity-induced by herbs. The adverse effects of herbal products must be fully reported as well as extensive education of healthcare providers must be provided in order to reduce danger of alternative medicines.


[Resistant mutant prevention concentration of fluoroquinolones in clinical isolates of extended spectrum beta-lactamase (ESBL) producing and non-producing strains of Escherichia coli].
The aim of this job is to study the capacity of ciprofloxacin and levofloxacin in restricting the development of resistant mutants in strains of Escherichia coli by determining the mutant prevention concentration (MPC). Ninety-nine isolates of E. coli with different fluoroquinolone susceptibilities were studied and divided into ESBL-producing (n = 60) and non-ESBL producing (n = 36) groups. MPC values were determined using an inoculum of 1010 cfu/ml on Mueller-Hinton plates with serial dilutions of the antibiotics. No significative differences were detected in MIC of ESBL-producing and non-ESBL producing strains of E. coli. Ciprofloxacin susceptible ESBL-producing strains exhibit higher MPC for ciprofloxacin and levofloxacin than non-ESBL producing strains. Our study helps to explain the frequent fluoroquinolone resistance found in ESBL-producing strains. In this context, doubts emerge about the advisability of using fluoroquinolones to treat infections caused by ESBL-producing strains.


Taking into Account Patient Preferences: A Consensus Study on the Assessment of Psychological Dimensions Within Patient Preference Studies.
Patient preferences are gaining recognition among key stakeholders involved in benefit-risk decision-making along the medical product lifecycle. However, one of the main challenges of integrating patient preferences in benefit-risk decision-making is understanding differences in patient preference, which may be attributable to clinical characteristics (eg age, medical history) or psychosocial factors. Measuring the latter may provide valuable information to decision-makers but there is limited guidance regarding which psychological dimensions may influence patient preferences and which psychological instruments should be considered for inclusion in patient preference studies. This paper aims to provide such guidance by advancing evidence and consensus-based recommendations and considerations. Findings of a recent systematic review on psychological constructs having an impact on patients' preferences and health-related decisions were expanded with input from an expert group (n = 11). These data were then used as the basis for final recommendations developed through two rounds of formal evaluation via an online Delphi consensus process involving international experts in the field of psychology, medical decision-making, and risk communication (n = 27). Three classes of recommendations emerged. Eleven psychological constructs reached consensus to be recommended for inclusion with the strongest consensus existing for health literacy, numeracy, illness perception and treatment-related beliefs. We also proposed a set of descriptive and checklist criteria to appraise available psychological measures to assist researchers and other stakeholders in including psychological assessment when planning patient preference studies. These recommendations can guide researchers and other stakeholders when designing and interpreting patient preference studies with a potential high impact in clinical practice and medical product benefit-risk decision-making processes.


The role of imaging in malignant pleural mesothelioma.
Imaging plays an essential role in the diagnosis, staging, and follow-up of patients with malignant pleural mesothelioma (MPM). The diagnosis is often suggested by a unilateral pleural mass with a moderate to large pleural effusion seen on chest radiographs, but computerized tomography (CT) is the most frequently used technique for evaluation of the lungs in patients with MPM. CT not only suggests pulmonary metastases typically manifested as nodules or masses, but also can demonstrate underlying lung disease often caused by prior asbestos exposure. Magnetic resonance (MR) imaging may be helpful in selected patients with potentially resectable disease to further examine the local extent of tumor. Imaging with positron emission tomography (PET) using the radionuclide imaging agent (18)F fluoro-deoxyglucose (FDG) takes advantage of a basic property of tumor cells, increased glucose metabolism to identify malignant lesions. PET provides not only anatomic information, especially regarding mediastinal node metastasis, but also biochemical information about the lesion. These imaging modalities help triage patients to the most appropriate diagnostic and treatment options. Following patients after therapy usually relies on chest radiographs, although CT can more accurately describe response to therapy. This review will focus on radiologic evaluation in diagnosing, staging, and follow-up patients with MPM.


A kinetic and thermodynamic study of the unexpected comproportionation reaction between cis-[Os(VIII)O4(OH)2](2-) and trans-[Os(VI)O2(OH)4](2-) to form a postulated [Os(VII)O3(OH)3](2-) complex anion.
A kinetic study of [OsO(4)] reduction by aliphatic alcohols (MeOH and EtOH) was performed in a 2.0 M NaOH matrix at 298.1 K. The rate model that best fitted the UV-VIS data supports a one-step, two electron reduction of Os(VIII) (present as both the [Os(VIII)O(4)(OH)](-) and cis-[Os(VIII)O(4)(OH)(2)](2-) species in a ratio of 0.34:0.66) to form the trans-[Os(VI)O(2)(OH)(4)](2-) species. The formed trans-[Os(VI)O(2)(OH)(4)](2-) species subsequently reacts relatively rapidly with the cis-[Os(VIII)O(4)(OH)(2)](2-) complex anion to form a postulated [Os(VII)O(3)(OH)(3)](2-) species according to: cis-[Os(VIII)O(4)(OH)(2)](2-) + trans-[Os(VI)O(2)(OH)(4)](2-) (k+2) <−> (k-2) 2[Os(VII)O(3)(OH)(3)](2-). The calculated forward, k(+2), and reverse, k(-2), reaction rate constants of this comproportionation reaction are 620.9 ± 14.6 M(-1) s(-1) and 65.7 ± 1.2 M(-1) s(-1) respectively. Interestingly, it was found that the postulated [Os(VII)O(3)(OH)(3)](2-) complex anion does not oxidize MeOH or EtOH. Furthermore, the reduction of Os(VIII) with MeOH or EtOH is first order with respect to the aliphatic alcohol concentration. In order to corroborate the formation of the [Os(VII)O(3)(OH)(3)](2-) species predicted with the rate model simulations, several Os(VIII)/Os(VI) mole fraction and mole ratio titrations were conducted in a 2.0 M NaOH matrix at 298.1 K under equilibrium conditions. These titrations confirmed that the cis-[Os(VIII)O(4)(OH)(2)](2-) and trans-[Os(VI)O(2)(OH)(4)](2-) species react in a 1:1 ratio with a calculated equilibrium constant, K(COM), of 9.3 ± 0.4. The ratio of rate constants k(+2) and k(-2) agrees quantitatively with K(COM), satisfying the principle of detailed balance. In addition, for the first time, the molar extinction coefficient spectrum of the postulated [Os(VII)O(3)(OH)(3)](2-) complex anion is reported.


Adaptive adjustment of the randomization ratio using historical control data.
Prospective trial design often occurs in the presence of 'acceptable' historical control data. Typically, these data are only utilized for treatment comparison in a posteriori retrospective analysis to estimate population-averaged effects in a random-effects meta-analysis. We propose and investigate an adaptive trial design in the context of an actual randomized controlled colorectal cancer trial. This trial, originally reported by Goldberg et al., succeeded a similar trial reported by Saltz et al., and used a control therapy identical to that tested (and found beneficial) in the Saltz trial. The proposed trial implements an adaptive randomization procedure for allocating patients aimed at balancing total information (concurrent and historical) among the study arms. This is accomplished by assigning more patients to receive the novel therapy in the absence of strong evidence for heterogeneity among the concurrent and historical controls. Allocation probabilities adapt as a function of the effective historical sample size (EHSS), characterizing relative informativeness defined in the context of a piecewise exponential model for evaluating time to disease progression. Commensurate priors are utilized to assess historical and concurrent heterogeneity at interim analyses and to borrow strength from the historical data in the final analysis. The adaptive trial's frequentist properties are simulated using the actual patient-level historical control data from the Saltz trial and the actual enrollment dates for patients enrolled into the Goldberg trial. Assessing concurrent and historical heterogeneity at interim analyses and balancing total information with the adaptive randomization procedure lead to trials that on average assign more new patients to the novel treatment when the historical controls are unbiased or slightly biased compared to the concurrent controls. Large magnitudes of bias lead to approximately equal allocation of patients among the treatment arms. Using the proposed commensurate prior model to borrow strength from the historical data, after balancing total information with the adaptive randomization procedure, provides admissible estimators of the novel treatment effect with desirable bias-variance trade-offs. Adaptive randomization methods in general are sensitive to population drift and more suitable for trials that initiate with gradual enrollment. Balancing information among study arms in time-to-event analyses is difficult in the presence of informative right-censoring. The proposed design could prove important in trials that follow recent evaluations of a control therapy. Efficient use of the historical controls is especially important in contexts where reliance on preexisting information is unavoidable because the control therapy is exceptionally hazardous, expensive, or the disease is rare.


The crystal structure of the L1 metallo-beta-lactamase from Stenotrophomonas maltophilia at 1.7 A resolution.
The structure of the L1 metallo-beta-lactamase from the opportunistic pathogen Stenotrophomonas maltophilia has been determined at 1.7 A resolution by the multiwavelength anomalous dispersion (MAD) approach exploiting both the intrinsic binuclear zinc centre and incorporated selenomethionine residues. L1 is unique amongst all known beta-lactamases in that it exists as a tetramer. The protein exhibits the alphabeta/betaalpha fold found only in the metallo-beta-lactamases and displays several unique features not previously observed in these enzymes. These include a disulphide bridge and two substantially elongated loops connected to the active site of the enzyme. Two closely spaced zinc ions are bound at the active site with tetrahedral (Zn1) and trigonal bipyramidal (Zn2) co-ordination, respectively; these are bridged by a water molecule which we propose acts as the nucleophile in the hydrolytic reaction. Ligation of the second zinc ion involves both residues and geometry which have not been previously observed in the metallo-beta-lactamases. Simulated binding of the substrates ampicillin, ceftazidime and imipenem suggests that the substrate is able to bind to the enzyme in a variety of different conformations whose common features are direct interactions of the beta-lactam carbonyl oxygen and nitrogen with the zinc ions and of the beta-lactam carboxylate with Ser187. We describe a catalytic mechanism whose principal features are a nucleophilic attack of the bridging water on the beta-lactam carbonyl carbon, electrostatic stabilisation of a negatively charged tetrahedral transition state and protonation of the beta-lactam nitrogen by a second water molecule co-ordinated by Zn2. Further, we propose that direct metal:substrate interactions provide a substantial contribution to substrate binding and that this may explain the lack of specificity which is a feature of this class of enzyme.


Neuraminidase inhibitors for preventing and treating influenza in children.
During epidemic years, influenza attack rates in children exceed 40%. Options for prevention and treatment include the neuraminidase inhibitors: zanamivir and oseltamivir. To assess the efficacy, safety and tolerability of neuraminidase inhibitors in the treatment and prevention of influenza infection in children. We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2005); MEDLINE (1966 to April 2005); EMBASE (January 1980 to December 2004); the on-line GlaxoSmithKline Clinical Trials Register; the on-line Roche Clinical Trial Protocol Registry and Clinical Trial Results Database (August 2005); and reference lists of articles. We also scrutinised web sites of European and US regulatory bodies and contacted manufacturers and authors. Double-blind, randomised, controlled trials comparing neuraminidase inhibitors with placebo or other antiviral drugs in children less than 12 years of age. Additional safety and tolerability data from other sources were also included. Four authors applied the inclusion criteria to the retrieved studies, assessed trial quality and extracted data. Data were analysed separately for oseltamivir and zanamivir. Three trials involving 1500 children with a clinical case definition of influenza were included, of whom 977 had laboratory-confirmed influenza. Overall, trial quality was good. Oseltamivir reduced the median duration of illness by 26% (36 hours) in healthy children with laboratory-confirmed influenza (P value less than 0.0001). The reduction was only 7.7% (10 hours) in 'at risk' (asthmatic) children, and this did not reach statistical significance (P value = 0.54). Zanamivir reduced the median duration of illness by 24% (1.25 days) in healthy children with laboratory-confirmed influenza (P value less than 0.001). No data in 'at risk' children were available. Only oseltamivir produced a significant reduction in the complications of influenza (particularly otitis media), although there was a trend to benefit for zanamivir. We identified one randomised, controlled trial of oseltamivir for the prevention of influenza transmission in households, reporting data from 222 paediatric contacts. Where index cases had laboratory-confirmed influenza, a protective efficacy of 55% was observed, but this did not reach statistical significance (P value = 0.089). The adverse events profile of zanamivir was no worse than placebo, but vomiting was more common in children treated with oseltamivir. Neuraminidase inhibitors are effective in shortening illness duration in healthy children with influenza, but efficacy in 'at risk' children remains to be proven. Oseltamivir is also effective in reducing the incidence of secondary complications, and may be effective for influenza prophylaxis.


Low dose detection of γ radiation via solvent assisted fluorescence quenching.
Development of low cost, easy-to-use chemical sensor systems for low dose detection of γ radiation remains highly desired for medical radiation therapy and nuclear security monitoring. We report herein on a new fluorescence sensor molecule, 4,4'-di(1H-phenanthro[9,10-d]imidazol-2-yl)biphenyl (DPI-BP), which can be dissolved into halogenated solvents (e.g., CHCl3, CH2Cl2) to enable instant detection of γ radiation down to the 0.01 Gy level. The sensing mechanism is primarily based on radiation induced fluorescence quenching of DPI-BP. Pristine DPI-BP is strongly fluorescent in halogenated solvents. When exposed to γ radiation, the halogenated solvents decompose into various radicals, including hydrogen and chlorine, which then combine to produce hydrochloric acid (HCl). This strong acid interacts with the imidazole group of DPI-BP to convert it into a DPI-BP/HCl adduct. The DPI-BP/HCl adduct possesses a more planar configuration than DPI-BP, enhancing the π-π stacking and thus molecular aggregation. The strong molecular fluorescence of DPI-BP gets quenched upon aggregation, due to the π-π stacking interaction (forming forbidden low-energy excitonic transition). Interestingly the quenched fluorescence can be recovered simply by adding base (e.g., NaOH) into the solution to dissociate the DPI-BP/HCl adduct. Such sensing mechanism was supported by systematic investigations based on HCl titration and dynamic light scattering measurements. To further confirm that the aggregation caused fluorescence quenching, a half size analogue of DPI-BP, 2-phenyl-1H-phenanthro[9,10-d]imidazole (PI-Ph), was synthesized and investigated in comparison with the observations of DPI-BP. PI-Ph shares the same imidazole conjugation structure with DPI-BP and is expected to bind the same way with HCl. However, PI-Ph did not show fluorescence quenching upon binding with HCl likely due to the smaller π-conjugation structure, which can hardly enforce the π-π stacking assembly. Combining the low detection limit, fast and reversible fluorescence quenching response, and low cost of halogenated solvent composites, the sensor system presented may lead to the development of new, simple chemical dosimetry for low dose detection of γ radiation.


Factors influencing women's decisions regarding birth planning in a rural setting in Kenya and their implications for family planning programmes.
Evidence suggests that socio-cultural barriers that limit the ability of women in sub-Saharan Africa to make decisions regarding contraceptive use and childbearing contribute to the slow uptake of contraception in this region. This paper explores factors influencing women's decisions regarding contraceptive uptake, switching and discontinuation, and the implications of those decisions for family planning programmes. Data were from in-depth interviews that were conducted in 2018 with 42 women who participated in a longitudinal research project implemented in Homa Bay County of Kenya. Participants comprised women who were aged 15-39 years at the time of recruitment into the study and who discontinued using injectables or implants between the first and second rounds of data collection. Data were analysed using an exploratory inductive content analytic approach. The findings show that uptake of contraception was largely driven by concerns about the negative consequences of frequent childbirth on individual health and household socioeconomic well-being. Most women discontinued methods because of dissatisfaction but, instead of abandoning contraception altogether, switched to alternative methods, albeit sometimes less-effective ones. However, some women had difficulties in identifying an appropriate new method after experiencing side-effects, contraceptive failure or stock-out of their current method. Securing the cooperation of sexual partners was an additional problem especially for women whose partners did not support contraception. The findings suggest that concerns about the negative consequences of frequent childbirth outweigh challenges associated with contraceptive use. This presents an opportunity for family planning programmes to improve contraceptive uptake and continuation by addressing the health system challenges related to commodity stock-out and poor quality of care, as well as the concerns of men.


RFT1 deficiency in three novel CDG patients.
The medical significance of N-glycosylation is underlined by a group of inherited human disorders called Congenital Disorders of Glycosylation (CDG). One key step in the biosynthesis of the Glc(3)Man(9)GlcNAc(2)-PP-dolichol precursor, essential for N-glycosylation, is the translocation of Man(5)GlcNAc(2)-PP-dolichol across the endoplasmic reticulum membrane. This step is facilitated by the RFT1 protein. Recently, the first RFT1-deficient CDG (RFT1-CDG) patient was identified and presented a severe N-glycosylation disorder. In the present study, we describe three novel CDG patients with an RFT1 deficiency. The first patient was homozygous for the earlier reported RFT1 missense mutation (c.199C>T; p.R67C), whereas the two other patients were homozygous for the missense mutation c.454A>G (p.K152E) and c.892G>A (p.E298 K), respectively. The pathogenic character of the novel mutations was illustrated by the accumulation of Man(5)GlcNAc(2)-PP-dolichol and by reduced recombinant DNase 1 secretion. Both the glycosylation pattern and recombinant DNase 1 secretion could be normalized by expression of normal RFT1 cDNA in the patients' fibroblasts. The clinical phenotype of these patients comprised typical CDG symptoms in addition to sensorineural deafness, rarely reported in CDG patients. The identification of additional RFT1-deficient patients allowed to delineate the main clinical picture of RFT1-CDG and confirmed the crucial role of RFT1 in Man(5)GlcNAc(2)-PP-dolichol translocation.


Automated Vulnerability Discovery and Exploitation in the Internet of Things.
Recently, automated software vulnerability detection and exploitation in Internet of Things (IoT) has attracted more and more attention, due to IoT's fast adoption and high social impact. However, the task is challenging and the solutions are non-trivial: the existing methods have limited effectiveness at discovering vulnerabilities capable of compromising IoT systems. To address this, we propose an Automated Vulnerability Discovery and Exploitation framework with a Scheduling strategy, AutoDES that aims to improve the efficiency and effectiveness of vulnerability discovery and exploitation. In the vulnerability discovery stage, we use our Anti-Driller technique to mitigate the "path explosion" problem. This approach first generates a specific input proceeding from symbolic execution based on a Control Flow Graph (CFG). It then leverages a mutation-based fuzzer to find vulnerabilities while avoiding invalid mutations. In the vulnerability exploitation stage, we analyze the characteristics of vulnerabilities and then propose to generate exploits, via the use of several proposed attack techniques that can produce a shell based on the detected vulnerabilities. We also propose a genetic algorithm (GA)-based scheduling strategy (AutoS) that helps with assigning the computing resources dynamically and efficiently. The extensive experimental results on the RHG 2018 challenge dataset and the BCTF-RHG 2019 challenge dataset clearly demonstrate the effectiveness and efficiency of the proposed framework.


Trait-demography relationships underlying small mammal population fluctuations.
Large-scale fluctuations in abundance are a common feature of small mammal populations and have been the subject of extensive research. These demographic fluctuations are often associated with concurrent changes in the average body mass of individuals, sometimes referred to as the 'Chitty effect'. Despite the long-standing recognition of this phenomenon, an empirical investigation of the underlying coupled dynamics of body mass and population growth has been lacking. Using long-term life-history data combined with a trait-based demographic approach, we examined the relationship between body mass and demography in a small mammal population that exhibits non-cyclic, large-scale fluctuations in abundance. We used data from the male segment of a 25-year study of the monogamous prairie vole, Microtus ochrogaster, in Illinois, USA. Specifically, we investigated how trait-demography relationships and trait distributions changed between different phases of population fluctuations, and the consequences of these changes for both trait and population dynamics. We observed phase-specific changes in male adult body mass distribution in this population of prairie voles. Our analyses revealed that these changes were driven by variation in ontogenetic growth, rather than selection acting on the trait. The resulting changes in body mass influenced most life-history processes, and these effects varied among phases of population fluctuation. However, these changes did not propagate to affect the population growth rate due to the small effect of body mass on vital rates, compared to the overall differences in vital rates between phases. The increase phase of the fluctuations was initiated by enhanced survival, particularly of juveniles and fecundity, whereas the decline phase was driven by an overall reduction in fecundity, survival and maturation rates. Our study provides empirical support, as well as a potential mechanism, underlying the observed trait changes accompanying population fluctuations. Body size dynamics and population fluctuations resulted from different life-history processes. Therefore, we conclude that body size dynamics in our population do not drive the observed population dynamics. This more in-depth understanding of different components of small mammal population fluctuations will help us to better identify the mechanistic drivers of this interesting phenomenon.


Potential and capabilities of hydroxynitrile lyases as biocatalysts in the chemical industry.
The application of hydroxynitrile lyases (HNLs) as catalysts for the stereoselective condensation of HCN with carbonyl compounds has been reported as early as 1908. This enzymatic C-C bond coupling reaction furnishes enantiopure cyanohydrins which serve as versatile bifunctional building blocks for chemical synthesis. Screening of natural sources led to the discovery of both (R)- and (S)-selective HNLs, and several distinctly different classes of these enzymes with substantial differences concerning sequence, structure, and mechanism have been found. Especially during the last two centuries, HNLs have been developed into valuable biocatalysts, which can be produced in recombinant form by overexpression in microbial hosts, resulting in the implementation of industrial processes utilizing these enzymes. Recently, protein engineering in combination with in silico methods gave rise to the development of a tailor-made HNL for large-scale manufacturing of a specific target cyanohydrin.


Clustering of nicotinic acetylcholine receptors: from the neuromuscular junction to interneuronal synapses.
Fast and accurate synaptic transmission requires high-density accumulation of neurotransmitter receptors in the postsynaptic membrane. During development of the neuromuscular junction, clustering of acetylcholine receptors (AChR) is one of the first signs of postsynaptic specialization and is induced by nerve-released agrin. Recent studies have revealed that different mechanisms regulate assembly vs stabilization of AChR clusters and of the postsynaptic apparatus. MuSK, a receptor tyrosine kinase and component of the agrin receptor, and rapsyn, an AChR-associated anchoring protein, play crucial roles in the postsynaptic assembly. Once formed, AChR clusters and the postsynaptic membrane are stabilized by components of the dystrophin/utrophin glycoprotein complex, some of which also direct aspects of synaptic maturation such as formation of postjunctional folds. Nicotinic receptors are also expressed across the peripheral and central nervous system (PNS/CNS). These receptors are localized not only at the pre- but also at the postsynaptic sites where they carry out major synaptic transmission. In neurons, they are found as clusters at synaptic or extrasynaptic sites, suggesting that different mechanisms might underlie this specific localization of nicotinic receptors. This review summarizes the current knowledge about formation and stabilization of the postsynaptic apparatus at the neuromuscular junction and extends this to explore the synaptic structures of interneuronal cholinergic synapses.


A single-center retrospective analysis of 3- or 4-level anterior cervical discectomy and fusion: surgical outcomes in 66 patients.
Anterior cervical discectomy and fusion (ACDF) is a safe and effective intervention to treat cervical spine pathology. Although these were originally performed as single-level procedures, multilevel ACDF has been performed for patients with extensive degenerative disc disease. To date, there is a paucity of data regarding outcomes related to ACDFs of 3 or more levels. The purpose of this study was to compare surgical outcomes of 3- and 4-level ACDF procedures. The authors performed a retrospective chart review of patients who underwent 3- and 4-level ACDF at the University of Virginia Health System between January 2010 and December 2017. In patients meeting the inclusion/exclusion criteria, demographics, fusion rates, time to fusion, and reoperation rates were evaluated. Fusion was determined by < 1 mm of change in interspinous distance between individual fused vertebrae on lateral flexion/extension radiographs and lack of radiolucency between the grafts and vertebral bodies. Any procedure requiring a surgical revision was considered a failure. Sixty-six patients (47 with 3-level and 19 with 4-level ACDFs) met the inclusion/exclusion criteria of having at least one lateral flexion/extension radiograph series ≥ 12 months after surgery. Seventy percent of 3-level patients and 68% of 4-level patients had ≥ 24 months of follow-up. Ninety-four percent of 3-level patients and 100% of 4-level patients achieved radiographic fusion for at least 1 surgical level. Eighty-eight percent and 82% of 3- and 4-level patients achieved fusion at C3-4; 85% and 89% of 3- and 4-level patients achieved fusion at C4-5; 68% and 89% of 3- and 4-level patients achieved fusion at C5-6; 44% and 42% of 3- and 4-level patients achieved fusion at C6-7; and no patients achieved fusion at C7-T1. Time to fusion was not significantly different between levels. Revision was required in 6.4% of patients with 3-level and in 16% of patients with 4-level ACDF. The mean time to revision was 46.2 and 45.4 months for 3- and 4-level ACDF, respectively. The most common reason for revision was worsening of initial symptoms. The authors' experience with long-segment anterior cervical fusions shows their fusion rates exceeding most of the reported fusion rates for similar procedures in the literature, with rates similar to those reported for short-segment ACDFs. Three-level and 4-level ACDF procedures are viable options for cervical spine pathology, and the authors' analysis demonstrates an equivalent rate of fusion and time to fusion between 3- and 4-level surgeries.


Expression of the Vibrio cholerae gene encoding aldehyde dehydrogenase is under control of ToxR, the cholera toxin transcriptional activator.
The toxR gene of Vibrio cholerae encodes a transcriptional activator required for the expression of the cholera toxin genes (ctxAB) and more than 15 other genes encoding secreted or membrane proteins. The latter group includes virulence genes involved in the biogenesis of the TCP pilus, the accessory colonization factor, and such ToxR-activated genes as tagA, mutations in which cause no detectable virulence defect in the suckling mouse model. To analyze the regulation of expression and the structure of tagA, we have cloned and sequenced about 2 kb of DNA upstream from a tagA::TnphoA fusion. While the portion of the tagA gene product examined presented no extensive similarity to any known protein, the amino acid sequence deduced from an open reading frame (designated aldA) located upstream from and in opposite orientation to tagA was highly similar to the sequences of eukaryotic aldehyde dehydrogenases. An assay of aldehyde dehydrogenase activity in extracts of a wild-type V. cholerae strainand an aldA mutant confirmed that aldA encodes an aldehyde dehydrogenase. Expression of the aldA gene was studied together with that of tagA in both V. cholerae and Escherichia coli. The expression of both tagA and aldA was environmentally regulated and dependent on a functional toxR gene in V. cholerae, but neither promoter was activated by ToxR in E. coli, suggesting that expression of tagA and aldA requires an additional transcriptional activator besides ToxR. The aldA gene is the first example of a gene encoding a cytoplasmic protein that is under the control of ToxR, and this suggests that metabolic enzymes may constitute novel members of virulence regulons in bacteria.


A Multicenter Retrospective Analysis Stressing the Importance of Long-Term Follow-Up after Hematopoietic Cell Transplantation for β-Thalassemia.
Allogeneic hematopoietic cell transplantation (HCT) is curative in patients with β-thalassemia major. However, most reports on HCT outcomes lack long-term follow-up data with the exception of single-center reports. An international multicenter retrospective data collection and analysis was conducted in 176 β-thalassemia patients who were 1 year or beyond after first HCT to evaluate follow-up methods and outcomes at 7 centers. Median age at HCT was 5.5 years (range, .6 to 18.5), and median follow-up was 7 years (range, 1 to 20). HCT was predominantly from HLA-matched related donors (91%) with bone marrow as stem cell source (91%) and myeloablative conditioning regimens (88%). Late mortality or persistent chronic graft-versus-host disease (GVHD) was rare (<2%). Graft rejection was reported in 23% (24% of these occurred beyond 1 year) post-HCT. Of 119 patients with donor chimerism results available for ≥4 years post-HCT, 50% had >95%, 22% had 50% to 95%, 7% had 20% to 50% and 25 (21%) had <20% donor chimerism. Organ dysfunction was identified in 10% pre-HCT and in 20% post-HCT even without complete clinical details on all patients. Hypogonadism and elevated creatinine for age were most commonly reported and significantly higher in recipients ≥ 7 years at the time of HCT (P = .007) and in those with pre-existing morbidity before HCT (P = .02). Outcomes were unaffected by pre-HCT ferritin or GVHD. Mean z scores for height and weight were low at baseline and remained low post-HCT (79%), confirming that growth impairment from disease lacked recovery post-HCT during this follow-up period. HCT for β-thalassemia has a high rate of cure and low mortality, especially in the young and from HLA-matched related donors. Half of the number of recipients live with mixed chimerism that requires continued follow-up because of a risk of late graft rejection (14%). Organ function after HCT when <7 years of age was generally preserved. Hypogonadism, renal dysfunction, and growth impairment that failed to correct were late complications identified most frequently in older transplant recipients. Systematic follow-up of individual organs such as lung and heart were inadequate but important. These data support the development of simple measures of uniformly tracking long-term HCT outcomes and organ functions in children and adolescents who undergo HCT for thalassemia, allowing for systematic identification and implementation of standardized surveillance strategies and interventions.


Young Aboriginal people's sexual health risk reduction strategies: a qualitative study in remote Australia.
Background Surveillance data indicate that Aboriginal and Torres Strait Islander young people are more likely than their non-Indigenous counterparts to experience sexually transmissible infections (STIs) and teenage pregnancy. Despite increasing emphasis on the need for strengths-based approaches to Aboriginal sexual health, limited published data document how young Aboriginal people reduce sexual health risks encountered in their everyday lives. In-depth interviews with 35 young Aboriginal women and men aged 16-21 years in two remote Australian settings were conducted; inductive thematic analysis examining sexual health risk reduction practices was also conducted. Participants reported individual and collective STI and pregnancy risk reduction strategies. Individual practices included accessing and carrying condoms; having a regular casual sexual partner; being in a long-term trusting relationship; using long-acting reversible contraception; having fewer sexual partners; abstaining from sex; accessing STI testing. More collective strategies included: refusing sex without a condom; accompanied health clinic visits with a trusted individual; encouraging friends to use condoms and go for STI testing; providing friends with condoms. Findings broaden understanding of young Aboriginal people's sexual health risk reduction strategies in remote Aboriginal communities. Findings signal the need for multisectoral STI prevention and sexual health programs driven by young people's existing harm minimisation strategies and cultural models of collective support. Specific strategies to enhance young people's sexual health include: peer condom distribution; accompanied health service visits; peer-led health promotion; continued community-based condom distribution; enhanced access to a fuller range of available contraception in primary care settings; engaging health service-experienced young people as 'youth health workers'.


Actin polymerization and pseudopod extension during amoeboid chemotaxis.
Amoebae of the cellular slime mold Dictyostelium discoideum are an excellent model system for the study of amoeboid chemotaxis. These cells can be studied as a homogeneous population whose response to chemotactic stimulation is sufficiently synchronous to permit the correlation of the changes in cell shape and biochemical events during chemotaxis. Having demonstrated this synchrony of response, we show that actin polymerization occurs in two stages during stimulation with chemoattractants. The assembly of F-actin that peaks between 40 and 60 sec after the onset of stimulation is temporally correlated with the growth of new pseudopods. F-actin, which is assembled by 60 sec after stimulation begins, is localized in the new pseudopods that are extended at this time. Both stages of actin polymerization during chemotactic stimulation involve polymerization at the barbed ends of actin filaments based on the cytochalasin sensitivity of this response. We present a hypothesis in which actin polymerization is one of the major driving forces for pseudopod extension during chemotaxis. The predictions of this model, that localized regulation of actin nucleation activity and actin filament cross-linking must occur, are discussed in the context of current models for signal transduction and of recent information regarding the types of actin-binding proteins that are present in the cell cortex.


Awareness and knowledge of cervical cancer and its prevention among the nursing staff of a tertiary health institute in Ahmedabad, Gujarat, India.
Carcinoma of the cervix is the second most common cancer in women worldwide, while it is the commonest cancer among Indian women. Awareness regarding cervical cancer and its prevention is quite low amongst Indian women. The Pap test is a simple and cost effective technique for early diagnosis of cervical cancer. It is necessary to make nursing staff aware of cervical cancer, so that they can impart knowledge regarding cervical cancer and its prevention to the general public. (1) To assess the knowledge level regarding symptoms, risk factors, prevention and screening of cervical carcinoma among nursing staff. (2) To find out the behaviour of respondents regarding prevention and screening of cervical carcinoma. A cross-sectional interview-based survey regarding knowledge levels about cervical carcinoma was conducted among the nursing staff from one of the tertiary health institutes of Ahmedabad, India. A structured questionnaire with multiple choices was used for data collection. Provision for open-ended responses was also made in the questionnaire. Department-wise stratification was carried out, and thereafter 15% of the total nursing staff from all departments were selected randomly so as to include a total of 100 nurses in the current study. Data entry was done in Microsoft Excel. SPSS statistical software was used to generate statistical parameters like proportion, mean, standard deviation, etc. The Z test was used as a test of significance, and a P value of <0.05 was considered as the level of significance.


PROSPECT guideline for hallux valgus repair surgery: a systematic review and procedure-specific postoperative pain management recommendations.
Hallux valgus repair is associated with moderate-to-severe postoperative pain. The aim of this systematic review was to assess the available literature and develop recommendations for optimal pain management after hallux valgus repair. A systematic review using PROcedure SPECific Postoperative Pain ManagemenT (PROSPECT) methodology was undertaken. Randomized controlled trials (RCTs) published in the English language from inception of database to December 2019 assessing postoperative pain using analgesic, anesthetic, and surgical interventions were identified from MEDLINE, EMBASE, and Cochrane Database, among others. Of the 836 RCTs identified, 55 RCTs and 1 systematic review met our inclusion criteria. Interventions that improved postoperative pain relief included paracetamol and non-steroidal anti-inflammatory drugs or cyclo-oxygenase-2 selective inhibitors, systemic steroids, ankle block, and local anesthetic wound infiltration. Insufficient evidence was found for the use of gabapentinoids or wound infiltration with extended release bupivacaine or dexamethasone. Conflicting evidence was found for percutaneous chevron osteotomy. No evidence was found for homeopathic preparation, continuous local anesthetic wound infusion, clonidine and fentanyl as sciatic perineural adjuncts, bioabsorbable magnesium screws, and plaster slippers. No studies of sciatic nerve block met the inclusion criteria for PROSPECT methodology due to a wider scope of included surgical procedures or the lack of a control (no block) group. The analgesic regimen for hallux valgus repair should include, in the absence of contraindication, paracetamol and a non-steroidal anti-inflammatory drug or cyclo-oxygenase-2 selective inhibitor administered preoperatively or intraoperatively and continued postoperatively, along with systemic steroids, and postoperative opioids for rescue analgesia.


Conservation of whole body nitric oxide metabolism in human alcoholic liver disease: implications for nitric oxide production.
Patients with advanced liver diseases tend to develop a hyperdynamic circulation which complicates cirrhosis. Impairment of nitric oxide (NO) metabolism has been implicated in the pathogenesis of portal hypertension. The aim of this study was to determine nitric oxide synthase (NOS)-dependent whole body NO production in patients with decompensated liver cirrhosis and portal hypertension. Ten patients with decompensated alcoholic liver disease and portal hypertension (Child-Pugh Classifications B and C with no signs of infection) and 10 age- and gender-matched control subjects received an intravenous infusion of L-[15N]2-arginine (50 micromol/min for 30 min). Urine and serum nitrite and nitrate concentrations were determined using ion chromatography-mass spectrometry. NOS-dependent whole body NO synthesis was estimated by the conversion of [15N]guanidino nitrogen of arginine to urine 15N-nitrite and 15N-nitrate. The amount of 15N-nitrite and 15N-nitrate in the urine of patients and control subjects was significantly correlated with the amount of urine nitrite and nitrate over 36 h (r=0.91 and 0.77, respectively, p<0.0001). However, neither a median of 12 h 15N-nitrite and 15N-nitrate nor nitrite and nitrate excretion in the urine was different between patients and control subjects, 46.4 (9.4-152.2) versus 98.7 (29.9-146.5) nmol/mmol creatinine and 20.6 (2.1-69.0) versus 40.0 (27.0-70.1) micromol/mmol creatinine, respectively. No differences were found in serum nitrite and nitrate concentrations and glomerular filtration rates between patients and control subjects, 111.4 (73.2-158.8) versus 109.3 (83.5-176.4) micromol/l. Our results contraindicate a greater basal NOS-dependent whole body NO production in patients with decompensated liver disease and portal hypertension.


Carla Task Force on Sarcopenia: propositions for clinical trials.
In the presence of an aging population, public health priorities need to evolve. As the populations gets older, the already existing pathologies have become commonplace with specific geriatric clinical syndromes like frailty, mobility disability, or cognitive impairment, among others. Sarcopenia is a good example for which geriatricians, neurologists, physiologists, nutritionists and epidemiologists need to find a consensual definition and diagnostic tool as well as guidelines for the management of clinical trials and possible treatments. The Carla Sarcopenia Task Force, which met in the south of France (Toulouse) for an expert consensus meeting called "Les Entretiens du Carla", have addressed a series of existing issues to place Sarcopenia into a nosological context: a definition which should be a composite of a change in muscle mass and a change in strength/function depending on either a progressive and chronic wasting process or an acute onset of loss of muscle mass; a recommendation for DXA and the Short Physical Performance Battery as a clinical pragmatic approach of Sarcopenia; a differentiated approach for clinical studies according to prevention or treatment objectives and depending on the sub-groups and target populations; and finally, a summary of therapeutic strategies currently recommended. The aim of "Les Entretiens du Carla", based on an expert meeting panel, was to address a series of unsolved issues in the field of Sarcopenia by combining the expert opinion with a revision of the existing literature on the topic. Through this report, the reader will appreciate the determination to find conclusions on the various issues and further studies to be developed to determine the best multidisciplinary approach needed.


Arterial-venous network formation during brain vascularization involves hemodynamic regulation of chemokine signaling.
During angiogenic sprouting, newly forming blood vessels need to connect to the existing vasculature in order to establish a functional circulatory loop. Previous studies have implicated genetic pathways, such as VEGF and Notch signaling, in controlling angiogenesis. We show here that both pathways similarly act during vascularization of the zebrafish central nervous system. In addition, we find that chemokine signaling specifically controls arterial-venous network formation in the brain. Zebrafish mutants for the chemokine receptor cxcr4a or its ligand cxcl12b establish a decreased number of arterial-venous connections, leading to the formation of an unperfused and interconnected blood vessel network. We further find that expression of cxcr4a in newly forming brain capillaries is negatively regulated by blood flow. Accordingly, unperfused vessels continue to express cxcr4a, whereas connection of these vessels to the arterial circulation leads to rapid downregulation of cxcr4a expression and loss of angiogenic characteristics in endothelial cells, such as filopodia formation. Together, our findings indicate that hemodynamics, in addition to genetic pathways, influence vascular morphogenesis by regulating the expression of a proangiogenic factor that is necessary for the correct pathfinding of sprouting brain capillaries.


What do your eyes reveal about your foreign language? Reading emotional sentences in a native and foreign language.
Foreign languages are often learned in emotionally neutral academic environments which differ greatly from the familiar context where native languages are acquired. This difference in learning contexts has been argued to lead to reduced emotional resonance when confronted with a foreign language. In the current study, we investigated whether the reactivity of the sympathetic nervous system in response to emotionally-charged stimuli is reduced in a foreign language. To this end, pupil sizes were recorded while reading aloud emotional sentences in the native or foreign language. Additionally, subjective ratings of emotional impact were provided after reading each sentence, allowing us to further investigate foreign language effects on explicit emotional understanding. Pupillary responses showed a larger effect of emotion in the native than in the foreign language. However, such a difference was not present for explicit ratings of emotionality. These results reveal that the sympathetic nervous system reacts differently depending on the language context, which in turns suggests a deeper emotional processing when reading in a native compared to a foreign language.


Cell adhesive peptides functionalized on CoCr alloy stimulate endothelialization and prevent thrombogenesis and restenosis.
Immobilization of bioactive peptide sequences on CoCr surfaces is an effective route to improve endothelialization, which is of great interest for cardiovascular stents. In this work, we explored the effect of physical and covalent immoblization of RGDS, YIGSR and their equimolar combination peptides on endothelial cells (EC) and smooth muscle cell (SMC) adhesion and on thrombogenicity. We extensively investigated using RT-qPCR, the expression by ECs cultured on functionalised CoCr surfaces of different genes. Genes relevant for adhesion (ICAM-1 and VCAM-1), vascularization (VEGFA, VEGFR-1 and VEGFR-2) and anti-thrombogenicity (tPA and eNOS) were over-expressed in the ECs grown to covalently functionalized CoCr surfaces compared to physisorbed and control surfaces. Pro-thrombogenic genes expression (PAI-1 and vWF) decreased over time. Cell co-cultures of ECs/SMCs found that functionalization increased the amount of adhered ECs onto modified surfaces compared to plain CoCr, independently of the used peptide and the strategy of immobilization. SMCs adhered less compared to ECs in all surfaces. All studied peptides showed a lower platelet cell adhesion compared to TCPS. Covalent functionalization of CoCr surfaces with an equimolar combination of RGDS and YIGSR represented prevailing strategy to enhance the early stages of ECs adhesion and proliferation, while preventing SMCs and platelet adhesion. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 973-983, 2017.


Angiogenic factor-driven inflammation promotes extravasation of human proangiogenic monocytes to tumours.
Recruitment of circulating monocytes is critical for tumour angiogenesis. However, how human monocyte subpopulations extravasate to tumours is unclear. Here we show mechanisms of extravasation of human CD14dimCD16+ patrolling and CD14+CD16+ intermediate proangiogenic monocytes (HPMo), using human tumour xenograft models and live imaging of transmigration. IFNγ promotes an increase of the chemokine CX3CL1 on vessel lumen, imposing continuous crawling to HPMo and making these monocytes insensitive to chemokines required for their extravasation. Expression of the angiogenic factor VEGF and the inflammatory cytokine TNF by tumour cells enables HPMo extravasation by inducing GATA3-mediated repression of CX3CL1 expression. Recruited HPMo boosts angiogenesis by secreting MMP9 leading to release of matrix-bound VEGF-A, which amplifies the entry of more HPMo into tumours. Uncovering the extravasation cascade of HPMo sets the stage for future tumour therapies.


Sustained loss of a neoplastic phenotype by brief inactivation of MYC.
Pharmacological inactivation of oncogenes is being investigated as a possible therapeutic strategy for cancer. One potential drawback is that cessation of such therapy may allow reactivation of the oncogene and tumor regrowth. We used a conditional transgenic mouse model for MYC-induced tumorigenesis to demonstrate that brief inactivation of MYC results in the sustained regression of tumors and the differentiation of osteogenic sarcoma cells into mature osteocytes. Subsequent reactivation of MYC did not restore the cells' malignant properties but instead induced apoptosis. Thus, brief MYC inactivation appears to cause epigenetic changes in tumor cells that render them insensitive to MYC-induced tumorigenesis. These results raise the possibility that transient inactivation of MYC may be an effective therapy for certain cancers.


The origin and diversity of the HIV-1 pandemic.
This review examines the enormous progress that has been made in the past decade in understanding the origin of HIV, HIV genetic variability, and the impact of global HIV diversity on the pandemic. Multiple zoonotic transmissions of simian immunodeficiency virus (SIV) have resulted in different HIV lineages in humans. In addition, the high mutation and recombination rates during viral replication result in a great genetic variability of HIV within individuals, as well as within populations, upon which evolutionary selection pressures act. The global HIV pandemic is examined in the context of HIV evolution, and the global diversity of HIV subtypes and recombinants is discussed in detail. Finally, the impact of HIV diversity on pathogenesis, transmission, diagnosis, treatment, the immune response, and vaccine development is reviewed.


Effects of in vivo single and multiple isoproterenol injections on subsequently explanted submandibular glands.
The present study reports on the effects of in vivo single and multiple isoproterenol (ISP) injections on the proliferative response of subsequently explanted mouse submandibular glands. Explants were cultured in Waymouth's medium supplemented with 10% fetal bovine serum, and were harvested after 1,2,4 or 6 days in culture. 24 h prior to harvest, the explants were fed medium containing [3H] thymidine. At the time of harvest, the explants were fixed in situ and processed for light-microscopic radioautography. The number of labeled nuclei and the total number of nuclei were counted, and labeling indices were calculated for the control and ISP-treated explant sectons. The results show that the ISP-treated explants had more cells actively synthesizing DNA than did the corresponding control explants after 1 day in culture. In addition, after 2 days in culture, the explants from mice that had received a single dose of ISP incorporated more [3H] thymidine than the corresponding control explants. These results suggest that the in vivo ISP stimulus initiated a hyperplastic response in vivo that was completed during the 1st or 2nd day in vitro.


Abnormal muscle coactivation patterns during isometric torque generation at the elbow and shoulder in hemiparetic subjects.
To study abnormal spatial patterns of muscle activation in hemiparetic stroke, we compared EMG activity in paretic and contralateral elbow and shoulder muscles of 10 hemiparetic subjects during 1.5-s voluntary isometric contractions, against five to eight different loads. Isometric forces were generated in eight directions, referenced to a plane orthogonal to the long axis of the forearm, and were recorded by a three degrees of freedom load cell, mounted at the wrist. Surface and intramuscular EMGs of six elbow and six shoulder muscles were recorded from both impaired and contralateral upper extremities of each subject. The spatial characteristics of EMG activation of individual muscles were summarized using two measures. The first, called the 'net resultant EMG vector' is a new measure which calculated the vector sum of EMG magnitudes for each of the eight directions, and the second, index of EMG focus, is a measure of the range of EMG activation recorded for each load level. Use of these measures permitted us to describe spatial EMG characteristics quantitatively, which has not been done previously. We observed consistent and statistically significant shifts in the resultant EMG vector directions in the impaired limb, especially in shoulder and other proximal muscles. Significant increases in the angular range of EMG activity were also identified and were most evident at the elbow. Correlation analysis techniques were used to assess the degree of coactivation of different muscle pairs. There were consistent EMG coactivation patterns observed across all subjects (both normal and hemiparetic). However, in spasticparetic limbs, additional novel coactivational relationships were also recorded, especially between elbow flexors/shoulder abductors and elbow extensors/shoulder adductors. These novel coactivation patterns represent a reduction in the number of possible muscle combinations, or in the number of possible 'synergies' in the paretic limb of the stroke subject. This reduction in number of 'synergies' could result from a loss of descending command options; from an increased reliance on residual, descending brainstem pathways (such as the reticulospinal and vestibulospinal projections); from changes in spinal interneuronal excitability; or from a combination of several of these factors. The relative merits of these hypotheses are addressed.


The relationship between apathy and impulsivity in large population samples.
Apathy and impulsivity are debilitating conditions associated with many neuropsychiatric conditions, and expressed to variable degrees in healthy people. While some theories suggest that they lie at different ends of a continuum, others suggest their possible co-existence. Surprisingly little is known, however, about their empirical association in the general population. Here, gathering data from six large studies ([Formula: see text]), we investigated the relationship between measures of apathy and impulsivity in young adults. The questionnaires included commonly used self-assessment tools-Apathy Evaluation Scale, Barratt Impulsiveness Scale (BIS-11) and UPPS-P Scale-as well as a more recent addition, the Apathy Motivation Index (AMI). Remarkably, across datasets and assessment tools, global measures of apathy and impulsivity correlated positively. However, analysis of sub-scale scores revealed a more complex relationship. Although most dimensions correlated positively with one another, there were two important exceptions revealed using the AMI scale. Social apathy was mostly negatively correlated with impulsive behaviour, and emotional apathy was orthogonal to all other sub-domains. These results suggest that at a global level, apathy and impulsivity do not exist at distinct ends of a continuum. Instead, paradoxically, they most often co-exist in young adults. Processes underlying social and emotional apathy, however, appear to be different and dissociable from behavioural apathy and impulsivity.


Select and Cluster: A Method for Finding Functional Networks of Clustered Voxels in fMRI.
Extracting functional connectivity patterns among cortical regions in fMRI datasets is a challenge stimulating the development of effective data-driven or model based techniques. Here, we present a novel data-driven method for the extraction of significantly connected functional ROIs directly from the preprocessed fMRI data without relying on a priori knowledge of the expected activations. This method finds spatially compact groups of voxels which show a homogeneous pattern of significant connectivity with other regions in the brain. The method, called Select and Cluster (S&C), consists of two steps: first, a dimensionality reduction step based on a blind multiresolution pairwise correlation by which the subset of all cortical voxels with significant mutual correlation is selected and the second step in which the selected voxels are grouped into spatially compact and functionally homogeneous ROIs by means of a Support Vector Clustering (SVC) algorithm. The S&C method is described in detail. Its performance assessed on simulated and experimental fMRI data is compared to other methods commonly used in functional connectivity analyses, such as Independent Component Analysis (ICA) or clustering. S&C method simplifies the extraction of functional networks in fMRI by identifying automatically spatially compact groups of voxels (ROIs) involved in whole brain scale activation networks.


Estimation of fish and ω-3 fatty acid intake in pediatric nonalcoholic fatty liver disease.
Fish and ω-3 fatty acids are reported to be beneficial in pediatric nonalcoholic fatty liver disease (NAFLD), but no studies have assessed their relation to histological severity. The objectives of this study were to evaluate the dietary intake of fish and ω-3 fatty acids in children with biopsy-proven NAFLD, and examine their association with serological and histological indicators of disease. This was a cross-sectional analysis of 223 children (6-18 years) who participated in the Treatment of Nonalcoholic Fatty Liver Disease in Children trial or the NAFLD Database study conducted by the Nonalcoholic Steatohepatitis Clinical Research Network. The distribution of fish and ω-3 fatty acid intake was determined from responses to the Block Brief 2000 Food Frequency Questionnaire, and analyzed for associations with serum alanine aminotransferase, histological features of fatty liver disease, and diagnosis of steatohepatitis after adjusting for demographic, anthropometric, and dietary variables. The minority of subjects consumed the recommended 8 ounces of fish per week (22/223 [10%]) and 200 mg of long-chain ω-3 fatty acids per day (12/223 [5%]). Lack of fish and long-chain ω-3 fatty acid intake was associated with greater portal (P = 0.03 and P = 0.10, respectively) and lobular inflammation (P = 0.09 and P = 0.004, respectively) after controlling for potential confounders. Fish and ω-3 fatty acid intake was insufficient in children with NAFLD, which may increase susceptibility to hepatic inflammation. Patients with pediatric NAFLD should be encouraged to consume the recommended amount of fish per week.


Lymphatic drainage function and its immunological implications: from dendritic cell homing to vaccine design.
The slow interstitial flow that drains fluid from the blood capillaries into the lymphatic capillaries provides transport of macromolecular nutrients to cells in the interstitium. We discuss herein how this flow also provides continuous access to immune cells residing in the lymph nodes of antigens from self or from pathogens residing in the interstitium. We also address mechanisms by which dendritic cells in the periphery sense interstitial flow to home efficiently into the lymphatics after activation, and how lymphatic endothelium can be activated by this flow, including how it can act as a lymphatic morphoregulator. Further, we present concepts on how interstitial flow can be exploited with biomaterial systems to deliver antigen and adjuvant molecules directly into the lymphatics, to target dendritic cells residing in the lymph nodes rather than in the peripheral tissues, using particles that are small enough to be carried along by flow through the network structure of the interstitium. Finally, we present recent work on lymphatic and lymphoid tissue engineering, including how interstitial flow can be used as a design principle. Thus, an understanding of the physiological processes that govern transport in the interstitium guides new understanding of both immune cell interactions with the lymphatics as well as therapeutic interventions exploiting the lymphatics as a target.


Precision health: treating the individual patient with chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is defined based on a reduced ratio of forced expiratory volume in one second (FEV1 ) to forced vital capacity (FVC) on spirometry. However, within this definition, there is significant heterogeneity of pathophysiological processes that lead to airflow obstruction and variation in phenotypic manifestations across patients. Current pharmacological treatments are based on large randomised clinical trials that apply to an "average" patient. Precision health enables tailoring of treatment for each individual patient by taking into account their unique characteristics. The number needed to treat (NNT) metric is often used to define implementation of precision health for specific interventions, with common endpoints requiring an NNT ≤ 5 to achieve precision therapy. Higher NNTs may be acceptable for rare but important endpoints such as mortality. Long-acting muscarinic antagonists and inhaled corticosteroids, which are commonly used in COPD, have 1-year treatment NNTs between 15 and 20 for exacerbation prevention in unselected patients with COPD. Subgroup identification using biomarkers or clinical traits may enable precision health. For example, NNT for inhaled corticosteroids is 9 in patients with a blood eosinophil count ≥ 300 cells/μL and 8 for long-acting muscarinic antagonists in patients with a body mass index ≤ 20 kg/m2 . Lung volume reduction surgery is associated with an NNT of 6 for survival over 5 years in patients with upper lobe-predominant disease and low exercise capacity (whereas the NNT is 245 when no bioimaging or exercise markers are used). Continuous domiciliary oxygen therapy (for at least 15 hours/day) has an NNT of 5 for survival over 5 years in patients with resting hypoxemia (PaO2 < 60 mmHg on room air). Emerging areas of precision health in COPD with potential for low NNTs in specific circumstances include anti-interleukin-5 therapy for eosinophilic COPD, and immunoglobulin replacement therapy for patients with severe immunoglobulin deficiency.


Quality of life instruments in studies of menorrhagia: a systematic review.
The use of quality of life (QoL) instruments in menorrhagia research is increasing but there is concern that not enough emphasis is placed on patient-focus in these measurements, i.e. on issues which are of importance to patients and reflect their experiences and concerns (clinical face validity). The objective was to assess the quality of QoL instruments in studies of menorrhagia. A systematic review of published research. Papers were identified through MEDLINE (1966-April 2000), EMBASE (1980-April 2000), Science Citation Index (1981-April 2000), Social Science Citation Index (1981-April 2000), CINAHL (1982-1999) and PsychLIT (1966-1999), and by manual searching of bibliographies of known primary and review articles. Studies were selected if they assessed women with menorrhagia for life quality, either developing QoL instruments or applying them as an outcome measure. Selected studies were assessed for quality of their QoL instruments, using a 17 items checklist including 10 items for clinical face validity (issues of relevance to patients' expectations and concerns) and 7 items for measurement properties (such as reliability, responsiveness, etc.). A total of 19 articles, 8 on instrument development and 11 on application, were included in the review. The generic Short Form 36 Health Survey Questionnaire (SF36) was used in 12/19 (63%) studies. Only two studies developed new specific QoL instruments for menorrhagia but they complied with 7/17 (41%) and 10/17 (59%) of the quality criteria. Quality assessment showed that only 7/19 (37%) studies complied with more than half the criteria for face validity whereas 17/19 (90%) studies complied with more than half of the criteria for measurement properties (P = 0.0001). Among existing QoL instruments, there is good compliance with the quality criteria for measurement properties but not with those for clinical face validity. There is a need to develop methodologically sound disease specific QoL instruments in menorrhagia focussing both on face validity and measurement properties.


Novel mutations target distinct subgroups of medulloblastoma.
Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.


Design of a superconducting volume coil for magnetic resonance microscopy of the mouse brain.
We present the design process of a superconducting volume coil for magnetic resonance microscopy of the mouse brain at 9.4T. The yttrium barium copper oxide coil has been designed through an iterative process of three-dimensional finite-element simulations and validation against room temperature copper coils. Compared to previous designs, the Helmholtz pair provides substantially higher B(1) homogeneity over an extended volume of interest sufficiently large to image biologically relevant specimens. A custom-built cryogenic cooling system maintains the superconducting probe at 60+/-0.1K. Specimen loading and probe retuning can be carried out interactively with the coil at operating temperature, enabling much higher through-put. The operation of the probe is a routine, consistent procedure. Signal-to-noise ratio in a mouse brain increased by a factor ranging from 1.1 to 2.9 as compared to a room-temperature solenoid coil optimized for mouse brain microscopy. We demonstrate images encoded at 10x10x20mum for an entire mouse brain specimen with signal-to-noise ratio of 18 and a total acquisition time of 16.5h, revealing neuroanatomy unseen at lower resolution. Phantom measurements show an effective spatial resolution better than 20mum.


A TrkB small molecule partial agonist rescues TrkB phosphorylation deficits and improves respiratory function in a mouse model of Rett syndrome.
Rett syndrome (RTT) results from loss-of-function mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2) and is characterized by abnormal motor, respiratory and autonomic control, cognitive impairment, autistic-like behaviors and increased risk of seizures. RTT patients and Mecp2-null mice exhibit reduced expression of brain-derived neurotrophic factor (BDNF), which has been linked in mice to increased respiratory frequency, a hallmark of RTT. The present study was undertaken to test the hypotheses that BDNF deficits in Mecp2 mutants are associated with reduced activation of the BDNF receptor, TrkB, and that pharmacologic activation of TrkB would improve respiratory function. We characterized BDNF protein expression, TrkB activation and respiration in heterozygous female Mecp2 mutant mice (Het), a model that recapitulates the somatic mosaicism for mutant MECP2 found in typical RTT patients, and evaluated the ability of a small molecule TrkB agonist, LM22A-4, to ameliorate biochemical and functional abnormalities in these animals. We found that Het mice exhibit (1) reduced BDNF expression and TrkB activation in the medulla and pons and (2) breathing dysfunction, characterized by increased frequency due to periods of tachypnea, and increased apneas, as in RTT patients. Treatment of Het mice with LM22A-4 for 4 weeks rescued wild-type levels of TrkB phosphorylation in the medulla and pons and restored wild-type breathing frequency. These data provide new insight into the role of BDNF signaling deficits in the pathophysiology of RTT and highlight TrkB as a possible therapeutic target in this disease.


Metabolic fate of isoleucine in a rat model of hepatic encephalopathy and in cultured neural cells exposed to ammonia.
Hepatic encephalopathy is a severe neuropathological condition arising secondary to liver failure. The pathogenesis is not well understood; however, hyperammonemia is considered to be one causative factor. Hyperammonemia has been suggested to inhibit tricarboxylic acid (TCA) cycle activity, thus affecting energy metabolism. Furthermore, it has been suggested that catabolism of the branched-chain amino acid isoleucine may help curb the effect of hyperammonemia by by-passing the TCA cycle block as well as providing the carbon skeleton for glutamate and glutamine synthesis thus fixating ammonia. Here we present novel results describing [U-(13)C]isoleucine metabolism in muscle and brain analyzed by mass spectrometry in bile duct ligated rats, a model of chronic hepatic encephalopathy, and discuss them in relation to previously published results from neural cell cultures. The metabolism of [U-(13)C]isoleucine in muscle tissue was about five times higher than that in the brain which, in turn, was lower than in corresponding cell cultures. However, synthesis of glutamate and glutamine was supported by catabolism of isoleucine. In rat brain, differential labeling patterns in glutamate and glutamine suggest that isoleucine may primarily be metabolized in the astrocytic compartment which is in accordance with previous findings in neural cell cultures. Lastly, in rat brain the labeling patterns of glutamate, aspartate and GABA do not suggest any significant inhibition by ammonia of TCA cycle activity which corresponds well to findings in neural cell cultures. Branched-chain amino acids including isoleucine are used for treating hepatic encephalopathy and the present findings shed light on the possible mechanism involved. The low turn-over of isoleucine in rat brain suggests that this amino acid does not serve the role of providing metabolites pertinent to TCA cycle function and hence energy formation as well as the necessary carbon skeleton for subsequent ammonia fixation in hyperammonemia. The higher metabolism of isoleucine in muscle could, however, contribute to ammonia fixation and thus likely be of value in the treatment of hepatic encephalopathy.


Impairment of cerebral blood flow regulation in astronauts with orthostatic intolerance after flight.
We investigated cerebral blood flow regulation in astronauts before and after flights. We hypothesized that autoregulation would be different before flight and after flight between nonfinishers and the finishers of a stand test. Twenty-seven astronauts from shuttle missions lasting 8 to 16 days underwent a 10-minute stand test: 10 days before flight, 1 to 2 hours and 3 days after landing. Mean blood flow velocity of the middle cerebral artery (MCA) was measured using transcranial Doppler; Mean arterial pressure was measured using a Finapres (Ohmeda, Englewood, CO) and was adjusted to the level of the MCA (BP(MCA)). Cross-spectral power, gain, phase, and coherence were determined for the relation between BP(MCA) and the cerebrovascular resistance index mean blood flow velocity/BP(MCA). BP(MCA) was reduced with stand (P<0.001). Differences between finishers and nonfinishers (P=0.011) and over test days (P=0.004) were observed. Cerebrovascular conductance was affected by stand (P<0.001), by group (P<0.001) with a group by stand, and test day interaction (P<0.01). Preflight data suggest that the nonfinishers were operating at a higher cerebral vasodilation than finishers for a given BP(MCA), and on landing day the nonfinishers had a greater decrease in mean blood flow velocity as a function of BP(MCA) with standing compared to finishers and preflight. There was a significant interaction effect of gender over the test days and from supine to stand (P=0.035). Our results indicate that the cause of presyncope in astronauts may be related to a mismatch of cerebral blood flow with blood pressure. Astronaut gender may also play a role in susceptibility to orthostatic intolerance after flight.


Spectral analysis of sleep electroencephalography in rotating three-shift work.
Fourteen male rotating three-shift workers were subjected to 24-h ambulatory polysomnographic recording in connection with morning, afternoon, and night shift work (at home and at work). Total sleep time, stage 2, rapid-eye-movement sleep, and slow-wave sleep (stages 3 + 4) were significantly reduced during sleep in connection with the night and morning shifts. Other visually scored sleep parameters and slow-wave energy (spectral power density integrated across sleep) were not affected. The content of the sleep cycles did not differ between shifts. The sleep before the morning shift was characterized by subjectively increased difficulties of sleep initiation and sleep termination, as well as by insufficient recuperation. The night shift was characterized by increased subjective difficulties of maintaining sleep, but also by increased ease of sleep initiation. It was concluded that both morning and evening shifts interfered with sleep, although no effects of sleep deprivation were found.


Is Intravenous Thrombolysis Safe and Effective in Central Retinal Artery Occlusion? A Critically Appraised Topic.
Central retinal artery occlusion (CRAO) is a neurological and ophthalmologic emergency associated with poor visual recovery. There is a dilemma regarding the appropriate treatment, as formal guidelines are lacking. Despite being considered an ocular equivalent of cerebral infarction, the time window of intravenous (IV) thrombolysis administration for maximum efficacy and safety in CRAO remains uncertain. To critically assess the current evidence regarding the safety and effectiveness of IV thrombolysis in the treatment of patients with CRAO. The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, and content experts in the fields of vascular neurology and ophthalmology. A recent patient-level meta-analysis was selected for critical appraisal. The study compared the visual recovery rates after IV thrombolysis in CRAO against the natural history of this illness and conservative therapies (ocular massage, anterior chamber paracentesis, and/or hemodilution). Time to thrombolytic therapy administration had a significant impact on visual recovery in CRAO (P<0.001). IV thrombolysis within the first 4.5 hours after symptom onset resulted in recovery of vision in 50.0% of the patients [95% confidence interval (CI), 32.4%-67.6%]. The rate of visual recovery was nearly 3 times higher than in the natural history cohort [odds ratio, 4.7 (95% CI, 2.3-9.6); P<0.001], with a 32.3% absolute risk reduction and a number needed to treat of 4.0 (95% CI, 2.6-6.6). There was no significant difference in the recovery rate after thrombolysis compared with the natural history cohort for those patients treated after 4.5 hours. No major hemorrhages occurred after alteplase administration in this meta-analysis. IV thrombolysis in CRAO seems to be safe and effective within the first 4.5 hours of symptom onset. A clinical decision based on this meta-analysis alone cannot be made due to several limitations. A randomized controlled clinical trial of early IV alteplase administration in CRAO is necessary to provide evidence-based therapeutic guidance.


History and symptoms of depression among smokers during a self-initiated quit attempt.
History of depression in smokers has been associated with an inability to quit smoking and with an increased likelihood of smoking relapse. This study prospectively tracked nicotine withdrawal symptoms, symptoms of depression, and ability to quit smoking between smokers with and without a probable history of major depression who were trying to quit smoking with minimal assistance. Results indicated that prior to quitting, smokers with a history of depression smoked to reduce negative affect, in response to craving, and in social situations. Additionally, positive history smokers scored higher on the Center for Epidemiological Studies Depression Scale (CES-D) than did smokers without such a history. Following a quit attempt, positive history smokers were somewhat more likely to experience greater symptoms of nicotine withdrawal than negative history smokers. However, among the positive history smokers, depressive symptoms as measured by the CES-D increased significantly 4 weeks after trying to quit, compared to a decline among negative history smokers. Positive and negative history smokers did not significantly differ on ability to quit smoking within the 30-day follow-up period. History of depression appears to be associated with a delayed increase in symptoms of depression following a quit attempt. However, it remains to be demonstrated whether such an increase in depressive symptoms may influence later probability of relapse.


Magnetic resonance imaging of placenta accreta.
Placenta accreta (PA) is a severe pregnancy complication which occurs when the chorionic villi (CV) invade the myometrium abnormally. Optimal management requires accurate prenatal diagnosis. Ultrasonography (USG) and magnetic resonance imaging (MRI) are the modalities for prenatal diagnosis of PA, although USG remains the primary investigation of choice. MRI is a complementary technique and reserved for further characterization when USG is inconclusive or incomplete. Breath-hold T2-weighted half-Fourier rapid acquisition with relaxation enhancement (RARE) and balanced steady-state free precession imaging in the three orthogonal planes is the key MRI technique. Markedly heterogeneous placenta, thick intraplacental dark bands on half-Fourier acquisition single-shot turbo spin-echo (HASTE), and disorganized abnormal intraplacental vascularity are the cardinal MRI features of PA. MRI is less reliable in differentiating between different degrees of placental invasion, especially between accreta vera and increta.


Selected persistent organic pollutants (POPs) in water of River Niger: occurrence and distribution.
This study assessed the levels and distribution of selected persistent organic pollutants (POPs) in water of River Niger. The selected POPs of interest were organochlorine pesticides (OCPs). Fifteen representative sites along River Niger: three each from Gurara River (tributary) in Niger State, Lokoja (confluence) in Kogi State, Onitsha in Anambra State, Brass and Nicolas Rivers (tributaries) in Bayelsa State were selected for sampling quarterly over a 24-month period. A total of 240 surface and bottom water samples were collected using Van Dorn water sampler in the eight quarters of 2008-2009. At the Delta locations where tidal effects take place, high- and low-tide water samples were taken as compared to surface and bottom at the River Niger locations. For sample extraction, EPA method 3510c was employed with slight modifications. Certified reference standards from Accustandards USA was used for the instrument calibration and quantification of OCPs. The extracted samples were subjected to gas chromatography (GC/ECD) for identification/quantification. And Shimadzu GCMS QP2010 was used for confirmation. Chlordane, endosulfan, endrin and DDT metabolites were very prominent in the water samples, compared to HCH, dieldrin, and isomers which occurred at lower concentrations. The sequence in the concentration of the organochlorine pesticides were ∑chlordane > ∑DDT > ∑endosulfan > ∑endrine > ∑dieldrin > ∑HCH. The highest concentration of ∑OCPs in water samples of River Niger, 1138.0 ± 246.7 ng/L, with range 560.8-1629 ng/L was detected at Onitsha location, while the lowest concentration, 292.6 ± 74.9, with range 181-443.0 ng/L was detected at Nicolas River. Levels of OCPs in a larger percentage of the samples exceeded guidelines and therefore hold potential harmful effects on benthic fauna, fish, and man. Abstraction of water from the River for drinking water treatment should be discouraged. Because of the potential danger, this presents, continuous monitoring of the water body and if possible remediation, determination of the sources of the POPs is therefore very necessary.


Phase transition dynamics of single optically trapped aqueous potassium carbonate particles.
Fast dynamics (down to 10 ms) during exposure to changing relative humidity of single optically trapped K2CO3 particles were observed in the submicron to micron size range with time-resolved broadband light scattering and Raman spectroscopy. The study shows that complex multiple processes accompany efflorescence and deliquescence of unsupported aerosol particles. Efflorescence can occur in a single process in less than 10 ms (prompt) or proceed via multiple successive processes (multistep) that can last up to more than 10 seconds. The efflorescence relative humidity lies in the range of 9 to 25%. Raman spectra of the effloresced particles reveal that the final state of the particle is independent of the pathway. Deliquescence cycles start with an initial uptake of water followed by multiple complex processes which end at the deliquescence relative humidity (44-50%). The study reveals that complex multiple processes during phase transitions are not limited to deposited particles where heterogeneous processes may occur or large particles in the upper micrometer size range as previously observed.