Two different approaches of microbial community structure characterization in riverine epilithic biofilms under multiple stressors conditions: Developing molecular indicators.
Microbial communities are major players in the biogeochemical processes and ecosystem functioning of river networks. Despite their importance in the ecosystem, biomonitoring tools relying on prokaryotes are still lacking. Only a few studies have employed both metabarcoding and quantitative techniques such as catalysed reported deposition fluorescence in situ hybridization (CARD-FISH) to analyse prokaryotic communities of epilithic biofilms in river ecosystems. We intended to investigate the efficacy of both techniques in detecting changes in microbial community structure associated with environmental drivers. We report a significant correlation between the prokaryotic community composition and pH in rivers from two different geographical areas in Norway. Both CARD-FISH and metabarcoding data were following the pattern of the environmental variables, but the main feature distinguishing the community composition was the regional difference itself. Beta-dispersion analyses on both CARD-FISH abundance and metabarcoding data revealed higher accuracy of metabarcoding to differentiate regions and river systems. The CARD-FISH results showed high variability, even for samples within the same river, probably due to some unmeasured microscale ecological variability which we could not resolve. We also present a statistical method, which uses variation coefficient and overall prevalence of taxonomic groups, to detect possible biological indicators among prokaryotes using metabarcoding data. The development of new prokaryotic bioindicators would benefit from both techniques used in this study, but metabarcoding seems to be faster and more reliable than CARD-FISH for large scale bio-assessment.


Multiple genetic factors in the heterogeneity of thyroid hormone resistance.
Generalized resistance to thyroid hormone (GRTH), a syndrome of inherited tissue hyposensitivity to thyroid hormone, is linked to thyroid hormone receptor (TR) mutations. A typical feature of GRTH is variable severity of organ involvement among families that, surprisingly, does not correlate with the degree of T3-binding impairment of the corresponding in vitro synthesized mutant TRs. Furthermore, variations in the clinical severity among family members harboring identical TR beta mutations have been reported. We compared serum levels of thyroid hormones that maintained a normal TSH in members of a large family with GRTH divided in three groups: Group A, 8 affected subjects with a mutation replacing arginine-320 with a histidine in the T3-binding domain of TR beta; Group B, 11 first degree relatives (sibs and children of affected subjects) with no TR beta mutation; Group C, 16 controls related by marriage. TSH values were not different among the three groups. As expected, total and free T4 and T3, and rT3 levels were significantly higher in Group A vs Groups B and C. However, with the exception of T3, the same tests were also significantly higher in Group B vs Group C. The latter differences are not due to thyroid hormone transport in serum since TBG concentrations were not different. It is postulated that genetic variability of factors that contribute to the action of thyroid hormone modulate the phenotype of GRTH associated with TR beta mutations.


Root canal length determination by different methods in primary teeth: an in vivo study.
To evaluate and compare the accuracy of root canal lengths (RCLs) in primary teeth using different clinical methods. RCLs of 70 extracted human primary single-rooted teeth were estimated in vivo by a calibrated investigator using the electronic apex locator (EAL) method, radiovisiography (RVG), conventional radiography (X-ray), and tactile sensation method (TSM). The teeth were categorized into Group 1 (G1; teeth without physiological root resorption [PRR]); Group 2 (G2; teeth with one-fourth apical PRR); and Group 3 (G3; teeth with one-fourth to three-fourths lingual PRR). RCLs determined by various in vivo methods were compared with the ex vivo actual root canal length method (ARCL), as determined by stereo-microscope. Data obtained were compared using analysis of variance, Newman-Keuls test, and Student's test. In Groups 1 and 2, the mean RCL determined by EAL was closest to that of the gold standard ARCL, followed by RVG, X-ray, and TSM. In G3, the mean RCL determined by EAL was closest to ARCL, followed by TSM, RVG, and X-ray. A fifth-generation electronic apex locator was found to be useful in accurately determining root canal lengths of primary teeth with or without physiological root resorption.


Development of heparin antagonists with focused biological activity.
Heparin, a complex glycosaminoglycan, has long been used to temporarily render the blood incoagulable during extracorporeal circulation, cardiovascular surgery, and other arterial interventions. But bleeding complications are especially common when the arterial tree is violated, occurring in as many as 10-15% of cases. For cardiovascular surgery and many related interventions, protamine has long been the standard antagonist when acute and complete neutralization of heparin s anticoagulant effect is necessary. Protamine s efficacy is related in part to its total net cationic charge, but unfortunately so is its toxicity. For these reasons, there is renewed interest in developing heparin antagonists which will replace the use of protamine. At Commonwealth Biotechnologies, Inc., we have used a rationale design approach for the preparation of a family of low molecular weight helix peptides which bind heparin with high affinity. For each of the new compounds, we have assessed their ability to bind heparin using isothermal titration calorimetry and circular dichroism spectrometry and have examined potential complexes formed with the anticoagulant pentasaccharide unit of heparin using molecular modeling techniques. The biological potencies of these compounds were assessed in ex vivo experiments where their ability to compete with antithrombin for binding heparin was determined. The best of the compounds, designated HepArrestTM, is highly effective in reversing heparin-mediated and HepArrest is a safer drug than protamine because of reduced adverse hemodynamic side effects compared with those associated with protamine. HepArrest binds low molecular weight heparins and causes reversal of anticoagulation by low molecular weight heparins, as determined by activated partial thromboplastin time, thrombin time, or factor Xa neutralization assays. These highly promising preclinical results indicate that HepArrest is a novel heparin neutralizing agent that may well fill a substantial unmet need for vascular surgeons and cardiac anesthesiologists who perform coronary artery bypass grafts and several other major vascular surgeries, as well as for cardiologists and interventional radiologists.


State-of-the-art for DNA technology in newborn screening.
Just as metabolites, hormones and proteins are measured in newborn screening tests, DNA has become an analyte that is important in the screens for certain disorders. DNA confirmatory testing on the original dried blood specimen reduces the age at diagnostic confirmation and antibiotic prophylaxis initiation for neonates with sickle cell disease. Molecular genetic analysis of the initial specimens from newborns with elevated immunoreactive trypsinogen (IRT) for cystic fibrosis (CF) screening permits reduction of the IRT threshold value, improving specificity without compromising sensitivity. Because of this cost reduction, CF neonatal screening programs routinely incorporate DNA confirmatory testing into their initial CF screening algorithm. DNA analysis is also a valuable adjunct in screening programs for congenital adrenal hyperplasia (CAH), improving sensitivity and specificity. Incorporation of DNA into newborn screening programs will continue to be stimulated by development of robust, high throughput technologies for evaluation of this analyte. New paradigms for neonatal screening are evolving, including hearing screening in the newborn nursery. DNA testing, such as for mutations in the connexin 26 gene, may have a role in the evaluation of those screened positive. Newborn screening dried blood specimens are DNA databases. Therefore, there are significant ethical, legal and social issues that must be considered in the storage and utilization of neonatal screening specimens.


A preliminary study of the measurement of overload applied to the foot support of a wheelchair and a seated postural support device.
[Purpose] The mechanical strength of wheelchair and seating products is specified by standards to ensure user safety. However, some individual users are affected by severe spasticity resulting from cerebral palsy that occasionally breaks such devices. Until recently, reports of quantitative measurement of these mechanical overloads have been scarce, and the exact loads applied have been unknown. This study aimed to conduct a sampling survey prior to conducting a future full-scale study. [Subjects and Methods] Using two force plates, we measured the load on the foot support applied by three participants with cerebral palsy. The applied load was measured at a 100 Hz sampling rate, and maximum load and vertical/horizontal component forces were analyzed. [Results] The maximum load applied by participants was approximately 1.34 times their body weight. The vertical force applied on the foot support accounted for 70-80% of the total load. The horizontal force also reached about 35% at its maximum. [Conclusion] Because the horizontal load also reached 1/3 of the total load, it will be advantageous to use a three-axis force plate to measure forces in a future study with more participants.


Identification of a suitable and selective inhibitor towards aldehyde oxidase catalyzed reactions.
1. Aldehyde oxidase (AO) is a liver cytosolic molybdoflavoprotein enzyme whose importance in drug metabolism is gaining in the recent. The objective of this work is to find a potent and selective inhibitor for AO activity using phthalazine oxidation as a marker reaction. 2. Among organic solvents tested, it was identified that methanol was not a suitable choice for AO activity even at concentrations less than 0.2% v/v. Acetonitrile and DMSO did not show any effect till 0.5% v/v but thereafter activites tend to decrease. 3. For selectivity, 23 compounds were selected and evaluated for their effects on AO and nine CYP450 enzymes. Among the tested compounds chlorpromazine, estradiol, hydralazine, quetiapine and raloxifene were selected based on their potency of inhibition towards AO activity. 4. Raloxifene was found to be a non-specific inhibitor of all major tested CYP450 enzymes and was excluded as a selective inhibitor for AO. Quetiapine also showed a degree of inhibition towards the major CYP450 tested. Hydralazine used as a specific inhibitor during the past for AO activity demonstrated a stimulation of AO activity at high and low concentrations respectively and the inhibition noted to be time dependent while inhibiting other enzymes like monoamine oxidase. 5. Estradiol showed no inhibition towards the tested CYP450 enzymes and thus proved to be a selective and specific inhibitor for AO activity with an uncompetitive mode of inhibition.


Cryogenic gallium phosphide acousto-optic deflectors.
We present measurements of the acoustic intensity in a gallium phosphide acousto-optic deflector for the 0.6-1.3-GHz frequency range and the 8-295-K temperature range. The data show a significant increase in the available time aperture of this deflector as a result of cryogenic cooling.


Adult Spinal Deformity Over 70 Years of Age: A 2-Year Follow-Up Study.
Treatment of adult spinal deformity (ASD) in elderly patients remains controversial. The aim of this study was to identify the factors leading to the surgical treatment by comparing the baseline characteristics of operative versus nonoperative patients, to evaluate the safety and efficacy of surgery, and to compare operative and nonoperative management of elderly ASD patients at the end of the 2-year follow-up period. Retrospective review of a multicenter, prospective ASD database was performed. Patients over 70 years of age with ASD who were scheduled to undergo surgical treatment and who were treated and/or followed without surgical intervention participated in the study. Demographic, clinical, surgical, and radiological characteristics and health-related quality-of-life (HRQOL) (Core Outcome Measures Index [COMI], Oswestry Disability Index [ODI], Short-Form-36 Mental Component Summary [SF-36 MCS], Short-Form-36 Physical Component Summary [SF36-PCS], and Scoliosis Research Society-22 [SRS-22]) parameters of such group of patients were evaluated pre- and posttreatment. A total 90 patients (females: 71, males: 29; operative: 61, nonoperative: 29) made up the study group. The comparison between the operative and the nonoperative groups at baseline showed statistical significance for all the HRQOL parameters and the major coronal Cobb angle (P < .05). The calculated optimal cutoff values to diverge operative and nonoperative groups for COMI, ODI, SF-36 PCS, and SRS-22 were 5.7, 37.0, 37.5, and 3.2, respectively (P < .05). All operative patients were treated with posterior surgery. Overall, 135 complications (71 major, 64 minor) and 1 death were observed. Surgically treated patients were found to be improved both clinically and in HRQOL parameters 2 years after surgery for all HRQOL parameters except SF-36 MCS, even in the presence of complications (P < .05), while nonoperative patients have not changed or deteriorated at the end of 2 years. Despite a relatively high incidence of complications, the likelihood of achieving a clinically significant and relevant HRQOL improvement was superior for patients who were treated surgically in the present population.


Angiographic CT with intravenous contrast injection compared with conventional rotational angiography in the diagnostic work-up of cerebral aneurysms.
Noninvasive imaging of cerebral aneurysms is still considered inferior to conventional angiography. The purpose of this study was to evaluate the diagnostic accuracy of ivACT in the assessment of intracranial aneurysms compared with 3D-DSA. We included 13 patients with 15 incidental unruptured saccular aneurysms scheduled for diagnostic angiographic work-up in our study. In each patient, we performed an ivACT and a conventional angiography including a 3D rotational run. During postprocessing, MPR images were generated for each technique. Maximal aneurysm diameter, neck diameter, aneurysm height, maximum width, bulge height, parent artery diameter, and angle between the parent artery and aneurysm apex were measured for each aneurysm. 3D-DSA and ivACT both provided images of high quality without artificial disturbances (ie, motion artifacts). Measurements of all parameters resulted in comparable values for both modalities with a strong correlation (P ≤ .001). ivACT is feasible for the noninvasive visualization of saccular cerebral aneurysms and may provide reliable diagnostic information for the assessment of aneurysm size and geometry comparable with conventional intra-arterial 3D rotational angiography. These preliminary results might be a first promising step to replacing conventional angiography in preinterventional aneurysm imaging.


Evolution of Nanowire Transmon Qubits and Their Coherence in a Magnetic Field.
We present an experimental study of flux- and gate-tunable nanowire transmons with state-of-the-art relaxation time allowing quantitative extraction of flux and charge noise coupling to the Josephson energy. We evidence coherence sweet spots for charge, tuned by voltage on a proximal side gate, where first order sensitivity to switching two-level systems and background 1/f noise is minimized. Next, we investigate the evolution of a nanowire transmon in a parallel magnetic field up to 70 mT, the upper bound set by the closing of the induced gap. Several features observed in the field dependence of qubit energy relaxation and dephasing times are not fully understood. Using nanowires with a thinner, partially covering Al shell will enable operation of these circuits up to 0.5 T, a regime relevant for topological quantum computation and other applications.


Marine self-potential survey for exploring seafloor hydrothermal ore deposits.
We conducted a self-potential survey at an active hydrothermal field, the Izena hole in the mid-Okinawa Trough, southern Japan. This field is known to contain Kuroko-type massive sulphide deposits. This survey measured the self-potential continuously in ambient seawater using a deep-tow array, which comprises an electrode array with a 30-m-long elastic rod and a stand-alone data acquisition unit. We observed negative self-potential signals not only above active hydrothermal vents and visible sulphide mounds but also above the flat seafloor without such structures. Some signals were detectable >50 m above the seafloor. Analysis of the acquired data revealed these signals' source as below the seafloor, which suggests that the self-potential method can detect hydrothermal ore deposits effectively. The self-potential survey, an easily performed method for initial surveys, can identify individual sulphide deposits from a vast hydrothermal area.


Removal of biofilm from contact lens storage cases.
Lens case hygiene practices are important in maintaining safe contact lens wear. However, the effectiveness of various lens case cleaning practices have not been evaluated and compared. This in vitro study aimed to evaluate and compare the efficacy of cleaning practices that are most commonly carried out by lens wearers and recommended by practitioners. Pseudomonas aeruginosa 122, Serratia marcescens ATCC 13880, and Staphylococcus aureus ATCC 6538 were the challenge bacteria for biofilm formation on unused lens cases from two different manufacturers. After establishment of the biofilm, each lens case was subjected to one of the six cleaning regimens: "rinsed," "rubbed and rinsed," "air-dried," "soaked in a multipurpose contact lens solution," "tissue-wiped," and "lids recapped." The level of residual biofilm was quantified at the end of each cleaning regimen. The efficacy of each cleaning regimen was then compared. Mechanical rubbing and wiping of lens cases were the most effective cleaning regimen tested in reducing biofilm. Soaking lenses in disinfecting solution for 6 hours removed the majority of biofilm from lens cases. Rinsing lens cases alone provided only minimal efficacy in reducing biofilm. Air-drying or recapping the cases with the lid without any other additional cleaning methods were the least efficient at removing biofilm. Based on this study, digital rubbing and rinsing and/or wiping the lens cases with tissue is recommended. Air-drying or recapping the lens case lids after use without any additional cleaning methods should be discouraged with non-antimicrobial lens cases.


RHO methylation matters: a role for isoprenylcysteine carboxylmethyltransferase in cell migration and adhesion.
Numerous proteins involved in diverse aspects of cell biology undergo a process of post-translational modification termed prenylation. The prenylation pathway consists of three enzymatic steps, the final of which is methylation of the carboxyl-terminal prenylcysteine formed in the first two steps by the enzyme isoprenylcysteine carboxylmethyltransferase (Icmt). Due to the prevalence of prenylated proteins in cancer biology, and the findings that several of the proteins are involved in processes controlling cell migration and adhesion, we sought to examine the role of Icmt - mediated methylation on cell behavior associated with metastasis. We found that inhibition of methylation reduces migration of the highly metastatic MDA-MB-231 breast cancer cell line. In addition, cell adhesion and cell spreading were also impaired by Icmt inhibition. Further investigation revealed that inhibition of Icmt significantly decreased the activation of both RhoA and Rac1, which are both prenylated proteins. The data obtained were consistent with the decreased activation being due to an increase in Rho GDP-dissociation inhibitor (GDI) binding by both proteins in the absence of their methylation. Importantly, the addition of exogenous RhoA or Rac1 to cells in which Icmt was inhibited was able to partially, but selectively, rescue directed and random migration, respectively. These results establish a role for Icmt-mediated methylation in cell migration, and point to specific prenylated proteins involved in this biology. The prenylation pathway has been targeted for oncogenic therapies, but the role of methylation in cell motility had been largely unexplored until now. The finding that methylation of Rho family members impacts on a specific component of their function provides an additional avenue through which to interrogate the biology of this important class of regulatory proteins.


Bioactivity-based screening methods for antibiotics residues: a comparative study of commercial and in-house developed kits.
Two bioactivity-based screening methods for antibiotic residue analysis (FAST Antimicrobial Screening Test and PremiTest) were compared, in terms of sensitivity, with a new in-house developed tube test assay using Escherichia coli. Tests were performed using antibiotic standards, spiked samples and real incurred samples. The minimum inhibitory concentration (MIC) for several antibiotics was established and compared with maximum residue levels (MRLs) in samples. The results of all evaluated tests are compared with liquid chromatography-tandem mass spectrometry multi-residue screening tests to compare parameters such as sample preparation, cost, time of analysis and confidence in results. For all tests, values of half the maximum residue limit (0.5 × MRL) were considered as a satisfactory target for a screening method. The potential and limitations of each method are discussed to indicate more rational and effective strategies for high-throughput residue monitoring and surveillance programmes. It was concluded that bioactivity-based screening methods are a useful tool, but the best compromise between minimum performance limits, cost and selectivity must be taken into account. For laboratories equipped with mass spectrometry, multi-class screening methods provide more specific responses with high sensitivity.


Impact of baseline prepulse inhibition on nicotine-induced locomotor sensitization in rats.
The rats having high locomotor reactivity to a novel environment (LRNE) are known to be more vulnerable to develop locomotor sensitization, which reflects the initial neuroplastic changes in brain systems related to addictive behaviours. The present study aimed to investigate whether sensorimotor gating level, measured by prepulse inhibition (PPI) of acoustic startle reflex, also reflects vulnerability for nicotine sensitization. A batch of rats was assigned into three groups according to their baseline PPI values. The highest 1/3 and the lowest 1/3 proportions were selected and defined as high-inhibitory (HI) and low-inhibitory (LI) groups. LRNE was measured in the rats, then they were treated with nicotine (1 mg/kg, tartrate salt, subcutaneously) or saline and locomotor activity (LMA) was immediately recorded for 15 min. This procedure was performed daily for 5 successive days. After a 3-day drug-free period, all rats were challenged with nicotine (1 mg/kg) on 9th day and with saline on 12th day. Same sensitization protocol was applied in another batch of rats, except assigning them into the high-responder (HR) and low-responder (LR) groups according to LRNE levels. There was no significant difference between HI and LI rats in LRNE. Although the acute effect of nicotine on LMA was higher in HI rats, a locomotor sensitization developed and expressed only in LI rats. In the following experiments, nicotine stimulated LMA both in HR and LR rats, but induced and expressed locomotor sensitization only in HR rats. The present study shows that acute locomotor stimulant effect and locomotor sensitization developing effects of nicotine are associated with the baseline PPI and LRNE levels. But these two factors are independent from each other.


Rorschach Aggressive Content (AgC) variable: a study of criterion validity.
This study adds to the existing literature on the clinical utility of the Aggressive Content (AgC) variable proposed by Gacono and Meloy (1994). Criterion validity is evaluated by examining the relation between AgC and behavior. Rorschach and clinical chart material taken from psychological assessments were examined for 94 patients in Exner's (1993) psychiatric reference groups. An Aggression Chart Rating Scale (ACRS) was created to score the level of aggressiveness of each patient's diagnostic report. Analyses revealed good interrater reliability (intraclass correlation coefficient = .73) for ACRS scores and Aggressive Movement (AG; kappa = .73) and excellent reliability for AgC (kappa =.88) and Morbid Content (MOR: kappa = .79). Pearson's correlation revealed significant relations between AgC and both AG and MOR. All 3 Rorschach variables were significantly related to scores on the ACRS. A stepwise regression analysis utilizing these 3 variables resulted in AgC being the only nonredundant predictor of scores on the ACRS. This suggests that AgC was more strongly related to more aggressive ACRS scores than either AG or MOR. The continued support for the clinical utility of AgC as well as recommendations for the addition of the AgC variable to Exner's (1993) Comprehensive System's list of Special Scores are discussed.


Model for hepatitis C virus transmissions.
Hepatitis C virus (HCV) is a leading cause of chronic liver disease. This paper presents a deterministic model for HCV infection transmission and uses the model to assess the potential impact of antiviral therapy. The model is based on the susceptible-infective-removed-susceptible (SIRS) compartmental structure with chronic primary infection and possibility of reinfection. Important epidemiologic thresholds such as the basic and control reproduction numbers and a measure of treatment impact are derived. We find that if the control reproduction number is greater than unity, there is a locally unstable infection-free equilibrium and a unique, globally asymptotically stable endemic equilibrium. If the control reproduction number is less than unity, the infection-free equilibrium is globally asymptotically stable, and HCV will be eliminated. Numerical simulations suggest that, besides the parameters that determine the basic reproduction number, reinfection plays an important role in HCV transmissions and magnitude of the public health impact of antiviral therapy. Further, treatment regimens with better efficacy holds great promise for lowering the public health burden of HCV disease.


Neuropsychological profiles of patients with 2q37.3 deletion associated with developmental dyspraxia.
Patients with 2q37 deletions manifest brachydactyly mental retardation syndrome (BDMR). Recent advances in human molecular research have revealed that alterations in the histone deacetylase 4 gene (HDAC4) are responsible for the clinical manifestations of BDMR. Here, we report two male patients with 2q37.3 deletions. One of the patients showed a typical BDMR phenotype, and HDAC4 was included in the deletion region. HDAC4 was preserved in the other patient, and he showed a normal intelligence level with the delayed learning of complex motor skills. Detailed neuropsychological examinations revealed similar neuropsychological profiles in these two patients (visuo-spatial dyspraxia) that suggested developmental dyspraxia. These observations suggested that some other candidate genes for neuronal development exist in the telomeric region of HDAC4.


Promoting nutrition in older people in nursing and residential homes.
Malnutrition and dehydration are serious and common problems among older people in nursing and residential care homes. The situation is exacerbated because staff may not be trained to recognize the signs and symptoms of malnutrition and dehydration and hence opportunities for early intervention are missed. A nutrition assessment should form part of the admission process to identify whether an individual has, or is at risk of developing, malnutrition and dehydration. This article suggests key questions that should be asked to assist this process. The individual and organizational risk factors that affect nutrition and health status are discussed, and practical suggestions given to help address any problems recognized. The causes and consequences of dehydration are explained and practices that place an individual at risk of dehydration considered. Suggestions are given to help identify when a person is not drinking sufficiently so that early rapid intervention can be initiated. Helping an older person to eat and drink independently is a practical activity that is often undervalued. Its importance needs to be recognized in all nursing and residential care settings.


Antiplatelet and anticoagulant therapy.
Antiplatelet therapy is clearly indicated for long-term secondary prevention after transient ischemic attack and ischemic stroke. In stroke-free patients with atrial fibrillation, oral anticoagulants reduce the risk of stroke, and antiplatelet agents may be a lower risk alternative. For the early treatment of the acute phase of ischemic stroke, the role of antiplatelet and anticoagulant therapy is unclear, but is being evaluated in large clinical trials.


Mangrove microniches determine the structural and functional diversity of enriched petroleum hydrocarbon-degrading consortia.
In this study, the combination of culture enrichments and molecular tools was used to identify bacterial guilds, plasmids and functional genes potentially important in the process of petroleum hydrocarbon (PH) decontamination in mangrove microniches (rhizospheres and bulk sediment). In addition, we aimed to recover PH-degrading consortia (PHDC) for future use in remediation strategies. The PHDC were enriched with petroleum from rhizosphere and bulk sediment samples taken from a mangrove chronically polluted with oil hydrocarbons. Southern blot hybridization (SBH) assays of PCR amplicons from environmental DNA before enrichments resulted in weak positive signals for the functional gene types targeted, suggesting that PH-degrading genotypes and plasmids were in low abundance in the rhizosphere and bulk sediments. However, after enrichment, these genes were detected and strong microniche-dependent differences in the abundance and composition of hydrocarbonoclastic bacterial populations, plasmids (IncP-1α, IncP-1β, IncP-7 and IncP-9) and functional genes (naphthalene, extradiol and intradiol dioxygenases) were revealed by in-depth molecular analyses [PCR-denaturing gradient gel electrophoresis and hybridization (SBH and microarray)]. Our results suggest that, despite the low abundance of PH-degrading genes and plasmids in the environmental samples, the original bacterial composition of the mangrove microniches determined the structural and functional diversity of the PHDC enriched.


T cell receptor V beta expression in human intestine: regional variation in postnatal intestine and biased usage in fetal gut.
A panel of T cell receptor V beta specific monoclonal antibodies was used to analyse V beta gene usage at different sites in human postnatal and fetal intestine. In normal small intestine, at a single site, different patients showed expansion of T cells expressing individual V beta s. Lamina propria and epithelial T cells from the same patient showed overlapping but not identical V beta dominance. V beta dominance was also shown in the T cells of the colonic lamina propria. Analysis of two separate regions of intestine from the same patient (5-100 cm apart) showed that T cells expressing a dominant V beta region were often present at both sites. In most patients, however, major biases in T cell V beta usage (two to 12-fold variation) were also apparent between the two sites. Analysis of V beta expression in human fetal intestine also showed considerable skewing, although the most common dominant V beta in postnatal intestine (V beta 22) was never predominant in fetal intestine. Patchy local variation in the expression of individual V beta s therefore occurs against a background of V beta dominance over large regions of the human gut. Furthermore the results from fetal gut show that factors other than luminal antigen control V beta expression in the gut.


Possibility of heat sterilization of liposomes.
Several kinds of liposomes were sterilized at 121 degrees C for 20 min. They tended to aggregate after heat sterilization (HS) in saline, while no aggregation was observed in an isotonized sugar or polyol solution. The dispersions containing egg phosphatidylcholine (EggPC) with a high peroxide value (POV) turned slightly yellowish after HS. This color change was prevented by using EggPC with a low POV, hydrogenated EggPC (H-EggPC) or dipalmitoylphosphatidylcholine (DPPC). Nitrogen gas bubbling at neutral pH also prevented the color change, but vitamin E did not. The particle size of the EggPC liposomes extruded through a 0.4 micron membrane filter did not change significantly after HS, whereas the H-EggPC or DPPC liposomes extruded through a 0.8 micron membrane filter tended to be reduced in size. On this change the type of medium had a considerable influence. The anionic 6-carboxyfluorescein leaked from the negatively charged liposomes (EggPC/cholesterol (Chol)/egg phosphatidylglycerol) during HS, while no leakage was observed from the positively charged liposomes (EggPC/Chol/stearylamine) not only during HS but also during a long period of storage. It was suggested that sterilization of liposomes by heating was practicable as well as that by filtration, if the liposomes were prepared as follows: the charged liposomes made of lipids with low POV's were dispersed in a sugar or polyol solution adjusted to nearly pH 6.5, where the amount of dissolved oxygen was minimized. An ionic water-soluble drug had to be encapsulated in the oppositely charged liposomes.


Investigation of solar noise impact on the performance of underwater wireless optical communication links.
We investigate the effect of environmental noise, caused by solar radiations under water, on the performance of underwater wireless optical communication (UWOC) systems. Presenting an analytical and generic model for this noise, we examine its impact on the link performance in terms of the bit error rate (BER). This study is conducted for different photo-detector types in the aim of highlighting practical limitations of establishing UWOC links in the presence of subsea solar noise. We show how the solar noise can impact the performance of UWOC links for relatively low operation depths. The results we present provide valuable insight for the design of UWOC links, which are likely to be established at relatively low depths. They can be exploited not only for the purpose of practical UWOC system deployment but also for in-pool experimental set-ups, since they elucidate the effect of ambient light on the measurements.


The neonatal behavioral assessment scale as a biomarker of the effects of environmental agents on the newborn.
The organization of the newborn's brain and the nature of the effects of toxins and pollutants conspire to produce complex and difficult problems for the assessment of the behavioral effects of environmental agents. The newborn's brain can be characterized as relatively undifferentiated, and more vulnerable to, but potentially more capable of recovery from, the effects of environmental agents specific to this time period than it will be later in development. Environmental agents tend to have nonspecific, possibly subtle, effects that invade many areas of newborn functioning. These characteristics of the newborn and the behavioral effects of teratogens make assessment at this point in development difficult. Further exacerbating this difficulty is the nature of development. Development is critically dependent on the care the newborn receives. Distortions of a newborn's behavior can produce disturbances in the caretaking environment, and these caretaking disturbances can amplify the original behavioral distortion and produce other distortions. Attention to these types of effects must be built into an assessment. These considerations lead to the conclusion that an apical assessment of newborn behavior is required. The most standardized, valid, and reliable instrument currently available is the Neonatal Behavioral Assessment Scale developed by Brazelton. It assesses the integrated actions of the infant that function to regulate simultaneously the infant's internal state and exchanges with the animate (caretaking) and inanimate environment. The scale uses a set of reflex and behavioral items to assess the critical domains of infant functioning (e.g., the infant's ability to control his states of consciousness).(ABSTRACT TRUNCATED AT 250 WORDS)


Fcgamma receptor IIa (CD32) polymorphism is associated with protection of infants against high-density Plasmodium falciparum infection. VII. Asembo Bay Cohort Project.
In vitro studies have shown that inhibition of Plasmodium falciparum blood-stage parasite growth by antibody-dependent cellular inhibition is mediated by cooperation between malaria-specific IgG1 and IgG3, but not IgG2, and monocytes via the Fcgamma receptor II (FcgammaRII). A single amino acid substitution at position 131 in FcgammaRIIa is critical in the binding of human IgG subclasses. The hypothesis that the FcgammaRIIa-Arg/Arg131 genotype, which does not bind to IgG2, is a host genetic factor for protection against high-density P. falciparum infection was tested. One hundred eighty-two infants from a large community-based birth cohort study in western Kenya were selected for an unmatched case-control study. Results showed that the infants with the FcgammaRIIa-Arg/Arg131 genotype were significantly less likely to be at risk for high-density falciparum infection, compared with infants with the FcgammaRIIa-His/Arg131 genotype (adjusted odds ratio, 0.278; 95% confidence interval, 0.123-0.627; P=.0021). This finding supports the hypothesis.


Formulation and delivery of microbicides.
The development of pre-exposure prophylactics or microbicide products for the reduction or elimination of the sexual transmission of HIV has numerous challenges or barriers to success. Historically traditional dosage forms such as gels have been developed in the field but more recently controlled release dosage forms such as vaginal rings and novel dosage forms such as polymeric thin films have been studied. Studies have begun to incorporate scientific strategies into the formulation design of microbicide products in order to develop safer and more effective products. In addition advanced drug delivery strategies to overcome barriers to delivery and specific drug targeting methods are being employed. In the present review, a comprehensive discussion of formulation efforts and novel delivery strategies in the field of microbicide product development is presented.


Transcatheter closure of atrial septal defects with the STARFlex device: early results and follow-up.
The STARFlex (SF) device is a CardioSEAL (CS) double-umbrella device that has been modified by the addition of a self-centering mechanism comprised of nitinol springs connected between the two umbrellas and a flexible core wire with a pin-pivoting connection. This paper compares the results of atrial septal defect (ASD) closure with CardioSEAL and STARFlex devices. Between December 1996 and March 2000, 117 patients underwent ASD closure with CardioSEAL (n = 79) and STARFlex (n = 38). The mean age (17 years), weight (49 kg), and ASD size (15 mm) were similar in the two groups. The procedures were performed under general anesthesia with both fluoroscopic and transesophageal echocardiographic monitoring. The devices were successfully implanted in all patients. Ten patients had multiple ASDs. A single device was used in four patients (CardioSEAL in three, STARFlex in one), while a simultaneous placement of two CardioSEAL (one patient) or two STARFlex (five patients) were performed in six patients. The results are summarized as follows: [table: see text] Follow-Up Results: On follow-up clinical exam, electrocardiograms, chest X-rays, and echocardiograms were obtained at 1, 6, and 12 months. [table: see text] During follow-up there were no deaths, endocarditis, rhythm disturbances, or other complications. Arm fractures were observed almost exclusively with large CardioSEAL devices (40 mm, less frequently with 33 mm), and only in one 33-mm STARFlex device. There were no clinical complications related to fractures. The STARFlex device seems to offer better results than the CardioSEAL, with significantly lower rates of residual shunts and arm fractures.


Synaptic Activity Protects Neurons Against Calcium-Mediated Oxidation and Contraction of Mitochondria During Excitotoxicity.
Excitotoxicity triggered by extrasynaptic N-methyl-d-aspartate-type glutamate receptors has been implicated in many neurodegenerative conditions, including Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and stroke. Mitochondrial calcium overload leading to mitochondrial dysfunction represents an early event in excitotoxicity. Neurons are rendered resistant to excitotoxicity by previous periods of synaptic activity that activates a nuclear calcium-driven neuroprotective gene program. This process, termed acquired neuroprotection, involves transcriptional repression of the mitochondrial calcium uniporter leading to a reduction in excitotoxcity-associated mitochondrial calcium load. As mitochondrial calcium and the production of reactive oxygen species may be linked, we monitored excitotoxicity-associated changes in the mitochondrial redox status using the ratiometric glutathione redox potential indicator, glutaredoxin 1 (GRX1)-redox-sensitive green fluorescent protein (roGFP)2, targeted to the mitochondrial matrix. Aim of this study was to investigate if suppression of oxidative stress underlies mitoprotection afforded by synaptic activity. We found that synaptic activity protects primary rat hippocampal neurons against acute excitotoxicity-induced mitochondrial oxidative stress and mitochondrial contraction associated with it. Downregulation of the mitochondrial uniporter by genetic means mimics the protective effect of synaptic activity on mitochondrial redox status. These findings indicate that oxidative stress acts downstream of mitochondrial calcium overload in excitotoxicity. Innovation and Conclusion: We established mito-GRX1-roGFP2 as a reliable and sensitive tool to monitor rapid redox changes in mitochondria during excitotoxicity. Our results highlight the importance of developing means of blocking mitochondrial calcium overload for therapeutic targeting of oxidative stress and mitochondrial dysfunction in neurodegenerative diseases. Antioxid. Redox. Signal. 29, 1109-1124.


Lorcaserin for Dravet Syndrome: A Potential Advance Over Fenfluramine?
Lorcaserin, a selective serotonin 5-HT2C receptor agonist, was developed as an appetite suppressant with the rationale of minimizing the risk of cardiovascular toxicity associated with non-selective serotoninergic agents such as fenfluramine. Eight years after FDA approval, however, it was withdrawn from the market, when a large safety study suggested a potential cancer risk. Following in the fenfluramine footsteps and utilizing the repurposing approach coupled with the regulatory orphan drug designation, lorcaserin is currently in clinical development for the treatment of epilepsy. This potential novel indication builds on the evidence that 5-HT2C receptor stimulation can protect against seizures, and accounts at least in part for fenfluramine's antiseizure effects in Dravet syndrome models. In animal models, lorcaserin shows a narrower range of antiseizure activity than fenfluramine. In particular, lorcaserin is inactive in classical acute seizure tests such as maximal electroshock and subcutaneous pentylenetetrazole in mice and rats, and the 6-Hz stimulation model in mice. However, it is active in the GAERS absence seizure model, and in mutant zebrafish models of Dravet syndrome. Preliminary uncontrolled studies in patients with Dravet syndrome have yielded promising results, and a phase III, double-blind, placebo-controlled, parallel group trial is currently ongoing to assess its efficacy and safety in children and adults with Dravet syndrome.


Insights into an unusual nonribosomal peptide synthetase biosynthesis: identification and characterization of the GE81112 biosynthetic gene cluster.
The GE81112 tetrapeptides (1-3) represent a structurally unique class of antibiotics, acting as specific inhibitors of prokaryotic protein synthesis. Here we report the cloning and sequencing of the GE81112 biosynthetic gene cluster from Streptomyces sp. L-49973 and the development of a genetic manipulation system for Streptomyces sp. L-49973. The biosynthetic gene cluster for the tetrapeptide antibiotic GE81112 (getA-N) was identified within a 61.7-kb region comprising 29 open reading frames (open reading frames), 14 of which were assigned to the biosynthetic gene cluster. Sequence analysis revealed the GE81112 cluster to consist of six nonribosomal peptide synthetase (NRPS) genes encoding incomplete di-domain NRPS modules and a single free standing NRPS domain as well as genes encoding other biosynthetic and modifying proteins. The involvement of the cloned gene cluster in GE81112 biosynthesis was confirmed by inactivating the NRPS gene getE resulting in a GE81112 production abolished mutant. In addition, we characterized the NRPS A-domains from the pathway by expression in Escherichia coli and in vitro enzymatic assays. The previously unknown stereochemistry of most chiral centers in GE81112 was established from a combined chemical and biosynthetic approach. Taken together, these findings have allowed us to propose a rational model for GE81112 biosynthesis. The results further open the door to developing new derivatives of these promising antibiotic compounds by genetic engineering.


Obesity-induced miR-15b is linked causally to the development of insulin resistance through the repression of the insulin receptor in hepatocytes.
Obesity increases intracellular lipid accumulation in key tissues or organs, which often leads to metabolic dysfunction and insulin resistance. Diets rich in saturated fatty acid (SFA) exacerbate obesity and hepatic steatosis, which accentuate the risk of insulin resistance and type 2 diabetes (T2DM). Although microRNAs (miRNAs) play a critical role in the regulation of gene expression, the implication of obesity-induced miRNAs in metabolic disorders particularly in the development of insulin resistance is largely unknown. Here, we investigated the implication of miR-15b, which is induced by SFA palmitate or obesity, in hepatic insulin resistance. Diet-induced obesity (DIO) in mice developed hyperglycemia and insulin resistance, accompanying with a reduction of insulin receptor (INSR) expression. Palmitate impaired insulin signaling as well as a decrease of INSR in hepatocytes. The expression of miR-15b was upregulated by DIO or palmitate in hepatocytes. Furthermore, the overexpression of miR-15b suppressed the protein expression of INSR through targeting INSR 3' untranslated region directly, resulting in an impairment of the insulin signaling and glycogen synthesis in hepatocytes. These results unveil a novel mechanism whereby miR-15b is linked causally to the pathogenesis of hepatic insulin resistance in SFA-induced obesity.


Evaluation of Serum Metal Ion Levels in Dental Implant Patients: A Prospective Study.
Titanium is the most commonly used bio-inert implant material. Nevertheless, there is a possibility of systemic release of metal ions, which could have clinical implications like implant failure and toxicity. This prospective study focuses on the evaluation of serum metal ion levels in patients receiving dental implants. The aim of the study is to evaluate the release of titanium, aluminium, and vanadium from dental implants by comparing the preoperative and postoperative serum levels of these ions. Serum samples were collected from 30 patients undergoing dental implant placement preoperatively and postoperatively at intervals of 6 weeks, 3, 6, and 12 months. These samples were analyzed for titanium, aluminium, and vanadium levels using Inductively Coupled Plasma Optical Emission Spectrometry. The difference in preoperative and postoperative serum levels was measured and statistically analyzed using the paired t-test. There was a slight difference in the postoperative levels of titanium and aluminium (2.30 and 4.07 mg/dl) as compared to the preoperative levels (2.28 and 2.30 mg/dl), which was statistically insignificant (P > 0.5). The serum levels of vanadium were too insignificant to be detected by the instrument (<0.0088 mg/dl). Mild increase in the titanium and aluminium levels in blood serum was noted. These metallic ion levels might increase significantly due to which further clinical research with larger sample sizes and a long-term follow-up period is required to evaluate the clinical effects of metallic ion release from dental implants. There is no significant difference in the serum metal ion levels before and after the implant placement, although a little increase is observed in the aluminium ion levels after the implant placement.


Vaccinal antibodies: Fc antibody engineering to improve the antiviral antibody response and induce vaccine-like effects.
The coronavirus disease 2019 (COVID-19) pandemic highlights the urgent clinical need for efficient virus therapies and vaccines. Although the functional importance of antibodies is indisputable in viral infections, there are still significant unmet needs that require vast improvements in antibody-based therapeutics. The IgG Fc domain can be engineered to produce antibodies with tailored and potent responses that will meet these clinical demands. Engaging Fc receptors (FcRs) to perform effector functions as cytotoxicity, phagocytosis, complement activation, intracellular neutralization and controlling antibody persistence. Furthermore, it produces vaccine-like effects by activating signals to stimulate T-cell responses, have proven to be required for protection, as neutralization alone does not off the full protection capacity of antibodies. This review highlights antiviral Fc functions and FcRs' contributions in linking innate and adaptive immunity against viral threats. Moreover, it provides the latest Fc engineering strategies to improve the safety and efficacy of human antiviral antibodies and vaccines.


Acupuncture in diabetic peripheral neuropathy-protocol for the randomized, multicenter ACUDPN trial.
Acupuncture is used to treat patients with diabetic peripheral neuropathy; however, the evidence is unclear. We present the design and methodology of the ACUDPN (ACUpuncture in Diabetic Peripheral Neuropathy) trial, which investigates the effectiveness of acupuncture for the treatment of diabetic peripheral neuropathy (DPN) symptoms. The aim of this study is to investigate whether acupuncture is effective for the treatment of DPN symptoms. This study is a two-armed, randomized, controlled, parallel group, open-label, confirmatory, multicenter trial (8-week intervention period plus 16 weeks of follow-up). Physicians in outpatient units in Germany who specialize in acupuncture treatment will treat 110 diabetes type II patients with clinical symptoms of peripheral neuropathy in the feet and legs with signs of neuropathy according to nerve conduction testing. The patients will be randomized in a 1:1 ratio to one of the following two groups: (a) semi-standardized acupuncture plus routine care or (b) routine care alone. Acupuncture will consist of 12 treatments per patient over 8 weeks. The primary outcome will be the overall DPN-related complaints in the extremities after 8 weeks as measured by the Visual Analog Scale (VAS). Further outcome measures will include DPN-related pain, the Neuropathic Pain Symptom Inventory (NPSI), Diabetic Peripheral Neuropathic Pain Impact (DPNPI) scores, and nerve conduction parameters of the sural nerve at weeks 8, 16, and 24. The results of this trial will be available in 2021 and will help clarify whether acupuncture can be considered effective for the treatment of DPN with regard to the subdimensions of the neuropathic clinical picture. ClinicalTrials.gov NCT03755960 . Registered on 11 August 2018.


Holographic Photopolymer Material with High Dynamic Range (Δn) via Thiol-Ene Click Chemistry.
A high-performance holographic recording medium was developed based on a unique combination of photoinitiated thiol-ene click chemistry and functional, linear polymers used as binders. Allyl reactive sites were incorporated along the backbone of the linear polymer binder to enable facile film casting and to facilitate cross-linking by photopolymerization of the thiol-ene monomers that also serve as the writing monomers in this distinctive approach to holographic materials. The allyl content and the ratio of the linear polymer to the writing monomers were varied to maximize and control the refractive index contrast. A blade-coating-based film preparation method was developed to form films from the mixture of linear polymer and the thiol-ene monomers. This approach results in a holographic material with a peak to mean index contrast (Δn) that reaches 0.04. The refractive index contrast was stable for at least two weeks. Haze in holograms with a high writing monomer loading was significantly reduced when a higher allyl content was incorporated into the binder, resulting in the lowest haze around 0.2%. Finally, the media exhibit high resolution as demonstrated by the ability to record reflection holograms with 140 nm pitch and diffraction efficiency in excess of 90%.


Generation of 21.3 Gbaud 8PSK signal using an SOA-based all-optical phase modulator.
We describe a novel SOA-based all-optical pure-phase modulator, and show how deleterious cross-gain modulation from the SOAs can be suppressed by utilizing an integrated interferometer structure. We experimentally demonstrate the use of the optical gate as a π/4 phase modulator producing 21.3 Gbaud 8PSK from 21.3 Gbit/s OOK and 21.3 Gbaud QPSK inputs. The modulator produces 3 dB of gain and coherent detection-based bit error rate measurements indicate a 2.4 dB excess penalty.


A new enzyme immunoassay for the detection of antibody to hepatitis E virus.
The purpose of the present study was to develop enzyme immunoassay (EIA) for the detection of IgG anti-hepatitis E virus (HEV) activity using two new recombinant proteins as antigenic targets, and to evaluate these EIA with the aid of statistical methods. Two proteins, a mosaic protein and pB166 containing region 452-617 aa of the ORF2 of the HEV Burma strain, were used to develop the new HEV EIA. This EIA was evaluated using several panels of serum specimens obtained from: (i) acutely HEV-infected patients; (ii) patients with non-A, non-C hepatitis; (iii) normal blood donors (NBD) from non-endemic countries; and (iv) experimentally infected chimpanzees. A new HEV EIA was developed using two new recombinant proteins. This assay was able to detect anti-HEV activity in all specimens from acutely HEV-infected patients. When NBD were tested, more than 15% of specimens were found to be IgG anti-HEV positive. All NBD anti-HEV-positive specimens were tested with overlapping synthetic peptides spanning the entire HEV ORF2-encoded protein. More than 90% of the anti-HEV-positive NBD specimens immunoreacted with an average of 15 synthetic peptides derived from different regions of the HEV ORF2 protein. These data suggest that the HEV EIA is at least 90% specific in detecting remote HEV infections. The new HEV EIA developed in the present study is a highly specific diagnostic assay for the detection of anti-HEV activity in serum specimens obtained from different epidemiologic settings.


Role of BDNF in central motor structures and motor diseases.
Brain-derived neurotrophic factor (BDNF), belonging to the neurotrophic family of growth factors, has a widespread distribution in the central and peripheral nervous systems. In central motor structures including the motor cortex, cerebellum, basal ganglia, and spinal cord, BDNF exerts both neurotrophic and direct electrophysiological effects via a high-affinity tyrosine receptor kinase B receptor and a common low-affinity p75 neurotrophin receptor. The underlying signaling pathways mainly involve mitogen-activated protein kinase cascades, phosphatidylinositol 3-kinase pathway, and phospholipase C-γ pathway. The loss of BDNF usually leads to neurodegeneration in these motor centers and eventually results in several severe motor diseases, such as amyotrophic lateral sclerosis, spinocerebellar ataxias, Parkinson's disease, Huntington's disease, as well as vestibular syndrome. In this review, we summarize the recent understanding of functions of BDNF in motor structures and suggest that BDNF may be a potent candidate for the treatment of these neurodegenerative motor diseases.


Design of a Blockchain-Enabled Traceability System Framework for Food Supply Chains.
Tracing food products along the entire supply chain is important for achieving better management of food products. Traditionally, centralized traceability systems have been developed for such purposes. One major drawback of this approach is that different users of the supply chain have their own systems with their own complexities and distinct features; thus, the interaction among them creates challenges when implementing a single centralized system. Therefore, a decentralized traceability system is favorable for tracing food products along the supply chain. In this study, we develop a supply chain traceability system framework based on blockchain and radio frequency identification (RFID) technology. The system consists of a decentralized blockchain-enabled data storage platform for data management and an RFID system at the packaging level for data collection and storage. We applied a consortium blockchain to the application. Fabric 2.0 in Hyperledger was chosen as the development platform. The proposed blockchain-enabled platform can provide decentralized data management and its underlying algorithm can guarantee data security. The system includes a creatively designed blockchain-enabled data structure in the RFID tag. When people scan the tag, the relevant information is written in the tag as a block linked to the previous blocks; simultaneously, the information is transmitted to the blockchain platform and recorded on the platform. No battery is required and the system works when there is an RFID reader nearby. The usage conditions included shipment, stocking, and storage. The RFID tag can be directly attached to paper packaging. This approach embeds the blockchain technique into the RFID tag and develops a corresponding system. The new traceability system has the potential to simplify the tracking of products and can be scaled for industrial use.


Feasibility studies of robot-assisted stroke rehabilitation at clinic and home settings using RUPERT.
Task based repetitive therapy has been proposed to help stroke survivors to regain functional control of arm movement. We developed a wearable exoskeleton rehabilitation robot with associated control algorithm and safety protection mechanisms, and a graphic user interface that is easy to use and intuitive to patients and therapists, as the framework for automated and customizable robot-assisted rehabilitation system for clinic and home based therapy. The system was tested in two feasibility studies. The first study involved 6 patients to receive therapeutic training during three time weekly clinic visits for 4 weeks. The second study set up the robot-assisted rehabilitation system at patient's house, where the therapeutic training was practiced on a daily base. Two patients were recruited for the home application study. Patients' performances were assessed using clinical evaluation tools, including Wolf Motor Function Test and Fugl Meyer Assessment (FMA), both before and after the training. The performances of patients during the training weeks were also objectively evaluated by using the robot sensory data.


Rapid transition from drinking to alcohol dependence among adolescent and young-adult newly incident drinkers in the United States, 2002-2013.
To study male-female and age differences in estimates of rapid transition from first full drink to alcohol dependence among youthful newly incident drinkers in the United States (US). The study population included 12-to-25-year-old non-institutionalized US civilian residents, sampled for US National Surveys on Drug Use and Health 2002-2013, with assessments via confidential computer assisted self-interviews. Newly incident drinkers are those who had their first full drink soon before the assessment (n=32,562 12-to-25-year- olds). Alcohol dependence (AD) criteria are from DSM-IV. For 12-to-25-year-old females, the peak risk for making a rapid transition from first full drink to alcohol dependence is seen during adolescence, followed by declining estimates (meta-analysis summary=3% at 12-17 years of age, 95% CI=2%, 3%). Among males, corresponding estimates fluctuate around 2%, with no appreciable differences across age strata. Among 12-to-17-year-old newly incident drinkers, there is a female excess in the rapid transition to alcohol dependence; a male excess is observed among young adult newly incident drinkers. Evaluated cohort-wise, using an epidemiological mutoscope view, individual cohorts show a congruent pattern, with age at first drink held constant. Studying multiple replication samples of young newly incident drinkers, we discovered a clear female excess in the risk of a rapid transition from first full drink to alcohol dependence among adolescents, with age patterns differing across males and females.


[Ethics of care and new profiles of the woman].
In health professions listening represents an essential condition for any cure relation. Learning to listen is thus neither easy nor granted. It requires the ability to put oneself in somebody else's place, maintaining self-possession of judgement and the ability of evaluating events. In health professions women have always occupied a privileged position for their sensitiveness and their ability of giving meaning even to everyday life. Empathy is the privileged way women have of getting to know, understand and take care of people. They follow a feminine style which accepts and welcomes other people even if they are not able to explain their intimate contradictions, their anxieties, their difficulties, their pain and weakness. Women know how to be near people, even if they understand they are not up to the situation, not expecting to solve pain: neither personal nor other people's. They act in a different way from men who instead are attached to a reductionism that assumes a theoretical scheme to understand the issue. Man's need to dominate the problem with knowledge makes him sacrifice the complexity of reality in which he lives. Men's simplicity, their tendency to generalize processes and easily find guidelines to proceed with no useless wastes, often sacrifices elements which find no place into the chosen standards. For women this way of behaving, apparently reassuring, is not possible because they are aware that such aspects while escaping their understanding express the personality of the people involved in this process, their uniqueness which does not accept generalisations. Behind interpretative schemes, behind apparently definitive diagnosis, women perceive vagueness and interpretative inadequacy. Female rationality is inclined to live with one's own and other's contradictions just because it is strongly attached to a reality which avoids simplification of understanding. It refuses interpretative schemes, theories which try to offer themselves as exhaustive models which can explain all events, lessening the value or even denying elements which do not fall within the interpretation model assumed. Women appear contradictory because they do not refuse confrontation with life contradictions and its perennial changes.


A rare case of a juvenile polyp of patient with Peutz-Jeghers syndrome, complicated with intussusception of the small intestine.
We report a rare case of Peutz-Jeghers syndrome (PJS) in a 35-year-old female. The patient was diagnosed with PJS when she was 11 years old. She has remained under observation since then. We strongly believe that PJS is a very rare diagnosis. However, it can have serious complications such as the intussusception we observed in our patient. Her condition (recurrent abdominal pain and vomiting) in childhood required further diagnostic procedures. Although the diagnosis of PJS was made, among many resected polyps, one of them appeared to be a juvenile polyp. The diagnosis was confirmed in the histopathology report, which was incredibly unique. Genetic testing revealed LKB1/STK11 gene mutation. Clinicians should be aware of the malignant potential in the course of PJS. Hence, these patients require tailor-made management, long-term follow-up, and our particular attention.


Trends of abortion complications in a transition of abortion law revisions in Ethiopia.
Evidence from developed countries has shown that abortion-related mortality and morbidity has decreased with the liberalization of the abortion law. This study aimed to assess the trend of hospital-based abortion complications during the transition of legalization in Ethiopia in May 2005. Medical records of women with abortion complications from 2003 to 2007 were reviewed (n = 773). Abortion and its complications with regard to legalization were described by rates and ratios, and predictors of fatal outcomes were analyzed by logistic regression. The overall and abortion-related maternal mortality ratios (AMMRs) showed a non-statistically significant downward trend over the 5-year period. However, the case fatality rate of abortion increased from 1.1% in 2003 to 3.6% in 2007. Late gestational age, history of interference and presenting after new abortion legislation passed have been found to be significant predictors of mortality. Decreased trends of abortion ratio and the AMMR were identified, but the severity of abortion complications and the case fatality rate increased during the transition of legal revision.


Spectroscopic Investigation of Catalyst Inks and Thin Films Toward the Development of Ionomer Quality Control.
As the production of polymer electrolyte fuel cells expands, novel quality control methods must be invented or adapted in order to support expected rates of production. Ensuring the quality of deposited catalyst layers is an essential step in the fuel cell manufacturing process, as the efficiency of a fuel cell is reliant on the catalyst layer being uniform at both the target platinum loading and the target ionomer content. Implementing a quality control method that is sensitive to these aspects is imperative, as wasting precious metals and other catalyst materials is expensive, and represents a potential barrier to entry into the field for manufacturers experimenting with novel deposition processes. In this work, we analyzed catalyst inks to determine if their ionomer content could be quantized spectroscopically. Attenuated total reflection (ATR) Fourier transform infrared spectroscopic technique was investigated producing a signal proportional to the ionomer content. ATR spectroscopy was able to quantitatively differentiate samples in which the ionomer to carbon mass ratio (I/C) varied between 0.9 and 3.0. The I/C ratio was correlated to the measured ATR signal near the CF2 vibrational bands located between 1100 cm-1 and 1400 cm-1. The experimental results obtained constitute a step toward the development of novel quality control methodologies for catalyst inks utilized by the fuel cell industry.


[Imaging features of posterior polymorphous corneal dystrophy observed by in vivo confocal microscopy].
Objective: To identify and analyze imaging features of posterior polymorphous corneal dystrophy (PPCD) by in vivo confocal microscopy (IVCM). Methods: This retrospective case series enrolled 27 eyes of 18 patients (including 10 males and 8 females) who were diagnosed with PPCD at the Department of Ophthalmology in Peking University Third Hospital between January 2013 and December 2019. The mean age was (23.61±14.81) years. There were 9 monocular and 9 binocular cases. All patients were examined by slit-lamp biomicroscopy and IVCM. The visual acuity, the mean endothelial cell density, and the images of IVCM were analyzed in all cases. Results: The mean best-corrected visual acuity was 0.76±0.33, and the mean endothelial cell density was (1 723.6±698.3) cells/mm2. The IVCM images of type 1 PPCD (vesicular lesions) showed hyperreflective, placoid or homocentric lesions at the level of the Descemet's membrane, hyporeflective, oval or round lesions at the level of the Descemet's membrane, and hyporeflective, crater-like lesions at the level of the endothelial cell layer. The IVCM images of type 2 PPCD (band lesions) displayed hyperreflective, band lesions and a fibrous strand structure at the level of the Descemet's membrane, hyporeflective, vesicular lesions at the level of the Descemet's membrane, and hyporeflective, trough-and ridge-like lesions at the level of the endothelial cell layer. The IVCM images of type 3 PPCD (geographic placoid opacities) showed loss of the hexagonal features of endothelial cells and epithelial-like cell transformation. Conclusions: PPCD primarily affects the endothelium and Descemet's membrane. IVCM could highlight the special characteristics of PPCD including hyperreflective lesions at the level of the Descemet's membrane, hyporeflective lesions at the level of the endothelial cell layer, and epithelial-like cell transformation of endothelial cells. IVCM is an invaluable tool for clinical diagnosis and dynamic monitoring of PPCD.


Structure of viruses: a short history.
This review is a partially personal account of the discovery of virus structure and its implication for virus function. Although I have endeavored to cover all aspects of structural virology and to acknowledge relevant individuals, I know that I have favored taking examples from my own experience in telling this story. I am anxious to apologize to all those who I might have unintentionally offended by omitting their work. The first knowledge of virus structure was a result of Stanley's studies of tobacco mosaic virus (TMV) and the subsequent X-ray fiber diffraction analysis by Bernal and Fankuchen in the 1930s. At about the same time it became apparent that crystals of small RNA plant and animal viruses could diffract X-rays, demonstrating that viruses must have distinct and unique structures. More advances were made in the 1950s with the realization by Watson and Crick that viruses might have icosahedral symmetry. With the improvement of experimental and computational techniques in the 1970s, it became possible to determine the three-dimensional, near-atomic resolution structures of some small icosahedral plant and animal RNA viruses. It was a great surprise that the protecting capsids of the first virus structures to be determined had the same architecture. The capsid proteins of these viruses all had a 'jelly-roll' fold and, furthermore, the organization of the capsid protein in the virus were similar, suggesting a common ancestral virus from which many of today's viruses have evolved. By this time a more detailed structure of TMV had also been established, but both the architecture and capsid protein fold were quite different to that of the icosahedral viruses. The small icosahedral RNA virus structures were also informative of how and where cellular receptors, anti-viral compounds, and neutralizing antibodies bound to these viruses. However, larger lipid membrane enveloped viruses did not form sufficiently ordered crystals to obtain good X-ray diffraction. Starting in the 1990s, these enveloped viruses were studied by combining cryo-electron microscopy of the whole virus with X-ray crystallography of their protein components. These structures gave information on virus assembly, virus neutralization by antibodies, and virus fusion with and entry into the host cell. The same techniques were also employed in the study of complex bacteriophages that were too large to crystallize. Nevertheless, there still remained many pleomorphic, highly pathogenic viruses that lacked the icosahedral symmetry and homogeneity that had made the earlier structural investigations possible. Currently some of these viruses are starting to be studied by combining X-ray crystallography with cryo-electron tomography.


Next-Generation Sequencing Whole-Genome Analysis for Targeted Treatment Approach of Metastatic Bartholin Gland Adenocarcinoma: An Emblematic Case Report and Review of the Literature.
Bartholin gland adenocarcinoma (BGA) is extremely rare and is characterized by high rates of lymph-node recurrence and distant metastases. No effective palliative treatments are available for metastatic BGA; therefore, advanced BGA remains a challenge for gynecologic oncologists. Considering the rarity of this disease and the lack of a standardized approach, the present study aims to discuss the available literature on current therapies for BGA and to describe an emblematic case treated with a novel tailored approach. A postmenopausal woman with advanced BGA was referred to our department for an adequate evaluation, staging and treatment. Notably, we used PET/CT as a fundamental imaging technique for staging and follow-up. The patient underwent primary surgery followed by standard chemotherapy and pelvic radiotherapy. Three months later, she relapsed, with the appearance of multiple metastatic sites. Considering the evident chemoresistance to standard chemotherapy and the absence of valid therapeutic alternatives for this rare cancer, she was treated with a combination of repeated minimally invasive surgical procedures for all the resectable metastatic lesions and innovative approaches comprising, firstly, chemoimmunotherapy with Nivolumab combined with metronomic vinorelbine, which resulted in a clinical response for approximately 7 months. Upon disease progression, we used a targeted systemic approach based on the whole genomic profile of the primary tumor, which showed PTEN loss, which is predictive of a benefit from an mTOR inhibitor, and a CCND1 amplification, which predicts sensitivity to CDK4/6 inhibitors. Therefore, she received Everolimus, resulting in a significant metabolic response that lasted 12 months. Thereafter, upon further progression of the disease, the patient started Palbociclib treatment, which is currently ongoing, with evidence of a metabolic response. The patient has survived for 54 months from diagnosis, with a good performance status. In conclusion, the present paper confirms the lack of efficacy of conventional therapeutic regimens in the context of advanced, recurrent or metastatic adenocarcinomas of the Bartholin gland. The case report shows how a personalized multidisciplinary approach based on repeated minimally invasive surgery and tailored anticancer treatment based on whole-genome sequencing analysis could be effective and associated with prolonged survival in this rare gynecological cancer.


Two stage penile reconstruction with free prefabricated sensate radial forearm osteocutaneous flap.
Penile reconstructive surgeries are performed mainly as radical treatment for conditions associated with congenital abnormalities of the urethra or penis, after penile trauma, penile cancer, short penis, corporal fibrosis and in cases of gender reassignment. We present here a method of penile reconstruction with a pre fabricated radial forearm free flap incorporating the segment of the radius for structural support.


Tumor PO(2) changes during photodynamic therapy depend upon photosensitizer type and time after injection.
In this study, the vascular and tissue oxygen changes induced by photodynamic therapy in the RIF-1 tumor were examined, using electron paramagnetic resonance (EPR) oximetry. Two photosensitizers, including verteporfin (BPD-MA in a lipid-based formulation) and aminolevulinic acid-induced protoporphyrin IX (ALA-PPIX), were investigated with optical irradiation, sufficient to induce sub-curative damage in the tumor tissue, and the transient changes in PO(2) and vascular perfusion were examined. A large increase in tissue oxygenation (from 3 up to 9.5 mmHg) was observed when treated with ALA-PPIX based photodynamic therapy, which lasted during the treatment and a small residual increase that returned back to baseline levels by 48 h after treatment. With verteporfin-based photodynamic therapy, one group of animals was irradiated 15 min after injection and exhibited a small decrease in oxygenation relative to pre-irradiation levels. The second group was irradiated at 3 h after injection and exhibited a large increase in the average PO(2), (from 3 to 15 mmHg) by the end of the treatment. These observations indicate that photodynamic therapy significantly increases tissue PO(2) under certain treatment conditions, with the potential cause being either increased local blood flow or decreased local oxygen metabolic consumption due to cellular damage.


Risk of primary lung cancer after breast cancer radiotherapy: a systematic review and meta-analysis.
Epidemiological studies have shown that the risk of secondary malignancies may increase by radiotherapy. Lung cancer is the most important long-term complication of breast cancer radiotherapy. Major electronic databases including Scopus, Web of Science, and MEDLINE were searched. All cohort studies that investigated the association between radiotherapy for breast cancer and risk of primary lung, bronchus, and trachea cancers conducted until March 2021 were included. The study participants were evaluated regardless of their age and ethnicity. The Newcastle-Ottawa Scale was used to assess the quality of the studies. The designated effects were risk ratio (RR). The random-effects model was used to estimate the average effects. Fifteen studies including 1,640,247 women with primary breast cancer were identified of which 937,151 had not received radiotherapy and 703,096 subjects had received radiotherapy. In general, there was no significant association between breast cancer radiotherapy and lung cancer based on 10 studies (RR = 0.95, 95% CI 0.87-1.02, P = 0.15), There was no association between breast cancer radiotherapy and lung, bronchus, and trachea cancers either based on 5 studies (RR = 0.98, 95% CI 0.93-1.02, P = 0.32). Radiotherapy for breast cancer is not associated with an excess risk of lung cancer. Due to the limited number of studies, lack of data regarding smoking status, and substantial variation in exposure of the lungs in breast cancer radiotherapy worldwide, further investigations based on randomized controlled trials are suggested to address the potential risk of lung cancer after breast cancer radiotherapy.


3-D portal image analysis in clinical practice: an evaluation of 2-D and 3-D analysis techniques as applied to 30 prostate cancer patients.
To investigate the clinical importance and feasibility of a 3-D portal image analysis method in comparison with a standard 2-D portal image analysis method for pelvic irradiation techniques. In this study, images of 30 patients who were treated for prostate cancer were used. A total of 837 imaged fields were analyzed by a single technologist, using automatic 2-D and 3-D techniques independently. Standard deviations (SDs) of the random, systematic, and overall variations, and the overall mean were calculated for the resulting data sets (2-D and 3-D), in the three principal directions (left-right [L-R], cranial-caudal [C-C], anterior-posterior [A-P]). The 3-D analysis included rotations as well. For the translational differences between the three data sets, the overall SD and overall mean were computed. The influence of out-of-plane rotations on the 2-D registration accuracy was determined by analyzing the difference between the 2-D and 3-D translation data as function of rotations. To assess the reliability of the 2-D and 3-D methods, the number of times the automatic match was manually adjusted was counted. Finally, an estimate of the workload was made. The SDs of the random and systematic components of the rotations around the three orthogonal axes were 1. 1 (L-R), 0.6 (C-C), 0.5 (A-P) and 0.9 (L-R), 0.6 (C-C), 0.8 (A-P) degrees, respectively. The overall mean rotation around the L-R axis was 0.7 degrees, which deviated significantly from zero. Translational setup errors were comparable for 2-D and 3-D analysis (ranging from 1.4 to 2.2 mm SD and from 1.5 to 2.5 mm SD, respectively). The variation of the difference between the 2-D and 3-D translation data increased from 1.1 mm (SD) for zero rotations to 2.7 mm (SD) for out-of-plane rotations of 3 degrees, due to a reduced 2-D registration accuracy for large rotations. The number of times the analysis was not considered acceptable and was manually adjusted was 44% for the 2-D analysis, and 6% for the 3-D analysis. True 3-D analysis of setup errors for a group of 30 patients with prostate cancer demonstrated that setup rotations are rather small. The deformation of the projected anatomy in portal images caused by out-of-plane rotations leads to a reduced 2-D registration accuracy. For rotations larger than 3 degrees this effect can be quite pronounced, making 3-D registration the preferred method. Furthermore, the automatic 3-D registration has a higher success rate, most likely because this technique uses more information compared to the 2-D method.


Senescence-induced loss in photosynthesis enhances cell wall beta-glucosidase activity.
A link between senescence-induced decline in photosynthesis and activity of beta-glucosidase is examined in the leaves of Arabidopsis. The enzyme is purified and characterized. The molecular weight of the enzyme is 58 kDa. It shows maximum activity at pH 5.5 and at temperature of 50 degrees C. Photosynthetic measurements and activity of the enzyme are conducted at different developmental stages including senescence of leaves. Senescence causes a significant loss in total chlorophyll, stomatal conductance, rate of evaporation and in the ability of the leaves for carbon dioxide fixation. The process also brings about a decline in oxygen evolution, quantum yield of photosystem II (PS II) and quantum efficiency of PS II photochemistry of thylakoid membrane. The loss in photosynthesis is accompanied by a significant increase in the activity of the cell wall-bound beta-glucosidase that breaks down polysaccharides to soluble sugars. The loss in photosynthesis as a signal for the enhancement in the activity of the enzyme is confirmed from the observation that incubation of excised mature leaves in continuous dark or in light with a photosynthesis inhibitor 3-(3,4-dichlorophenyl)-1, 1-dimethylurea (DCMU) that leads to sugar starvation enhances the activity of the enzyme. The work suggests that in the background of photosynthetic decline, the polysaccharides bound to cell wall that remains intact even during late phase of senescence may be the last target of senescing leaves for a possible source of sugar for remobilization and completion of the energy-dependent senescence program.


Exponential localization of singular vectors in spatiotemporal chaos.
In a dynamical system the singular vector (SV) indicates which perturbation will exhibit maximal growth after a time interval tau . We show that in systems with spatiotemporal chaos the SV exponentially localizes in space. Under a suitable transformation, the SV can be described in terms of the Kardar-Parisi-Zhang equation with periodic noise. A scaling argument allows us to deduce a universal power law tau(-gamma) for the localization of the SV. Moreover the same exponent gamma characterizes the finite- tau deviation of the Lyapunov exponent in excellent agreement with simulations. Our results may help improve existing forecasting techniques.


Determination of irbesartan in the presence of hydrochlorothiazide by derivative spectrophotometry.
A first-derivative spectrophotometric method for the determination of irbesartan (IRB) alone and in the presence of hydrochlorothiazide (HCT) is described. Measurements are made at the zero-crossing wavelength at 263.0 nm for IRB. The calibration graph was linear over the range 1.0-12.0 mg l(-1) of IRB, detection limit was 0.15 mg l(-1). HCT, in the presence of IRB was determined by direct spectrophotometric method at 317 nm. The calibration graph was linear over the range 2.0-50.0 mg l(-1) of HCT, detection limit was 0.25 mg l(-1). The proposed methods were successfully applied to the determinations of IRB and HCT in combined tablets.


Cross-sectional geometry of the sacral ala for safe insertion of iliosacral lag screws: a computed tomography model.
To measure the dimensions of the narrowest portion of the sacral ala for safe insertion of iliosacral lag screws. Computed tomography (CT) model. Level One trauma center. Thirteen adult patients underwent pelvic CT imaging. Axial CT scans of intact pelves were reformatted in the sagittal plane at three-millimeter intervals from the first sacral body (S1 body) to the sacroiliac (SI) joint. Computer analysis and measurements of sacral geometry were used to determine the narrowest portion of the bony sacral ala. The maximum height, maximum width, and slope of the sacral ala through its geometric center in cross-section were measured. The narrowest portion of the sacral ala in all patients was consistently located at the junction between the sacral body and the alar wings, termed the sacral pedicle, directly cephalad to the first sacral foramen. The average slope of the sacral ala at the sacral pedicle was 45.08 degrees (range 25 to 65 degrees). The average maximum height at the geometric center in cross-section was 27.76 millimeters, and the average width was 28.05 millimeters. However, outside the geometric center there was a sharp decrease in height and width of the sacral ala that was in large part determined by its relative slope. Although the cross-sectional geometry of the sacral ala is highly variable among patients, there is ample space for iliosacral screws. To ensure safe insertion, iliosacral lag screws must be positioned in the geometric center of the sacral ala to avoid extraosseous placement.


The neuroprotective effect of methanol extract of gagamjungjihwan and fructus euodiae on ischemia-induced neuronal and cognitive impairment in the rat.
Gagamjungjihwan (GJ), a decoction consisting of five herbs including ginseng, Acori Graminei Rhizoma, Uncariae Ramulus et Uncus, Polygalae Radic and Frustus Euodiae (FE), has been widely used as herbal treatment for ischemia. In order to investigate the neuroprotective action of this novel prescription, we examined the influence of GJ and FE on learning and memory using the Morris water maze and studied their affects on the central cholinergic system in the hippocampus with neuronal and cognitive impairment. After middle cerebral artery occlusion was applied for 2 h, rats were administered GJ (200 mg kg(-1), p.o.) or FE (200 mg kg(-1), p.o.) daily for 2 weeks, followed by training and performance of the Morris water maze tasks. Rats with ischemic insults showed impaired learning and memory of the tasks. Pre-treatment with GJ and FE produced improvement in the escape latency to find the platform. Pre-treatments with GJ and FE also reduced the loss of cholinergic immunoreactivity in the hippocampus. The results demonstrated that GJ and FE have a protective effect against ischemia-induced neuronal and cognitive impairment. Our results suggest that GJ and FE might be useful in the treatment of vascular dementia.


Localization of Thy-1-positive cells in the perichondrium during endochondral ossification.
We elucidated the localization of Thy-1-positive cells in the perichondrium of fetal rat limb bones to clarify the distribution of osteogenic cells in the process of endochondral ossification. We also examined the formation of calcified bone-like matrices by isolated perichondrial cells in vitro. At embryonic day (E) 15.5, when the cartilage primodia were formed, immunoreactivity for Thy-1 was detected in cells of the perichondrium adjacent to the zone of hypertrophic chondrocytes. At E17.5, when the bone collar formation and the vascular invasion were initiated, fibroblast-like cells at the sites of vascular invasion, as well as in the perichondrium, showed Thy-1 labeling. Double immunostaining for Thy-1 and osterix revealed that Thy-1 was not expressed in the osterix-positive osteoblasts. Electron microscopic analysis revealed that Thy-1-positive cells in the zone of hypertrophic chondrocytes came in contact with blood vessels. Perichondrial cells isolated from limb bones showed alkaline phosphatase activity and formed calcified bone-like matrices after 4 weeks in osteogenic medium. RT-PCR demonstrated that Thy-1 expression decreased as calcified nodules formed. Conversely, the expression of osteogenic marker genes Runx2, osterix, and osteocalcin increased. These results indicate that Thy-1 is a good marker for characterizing osteoprogenitor cells.


Polio Legacy in Action: Using the Polio Eradication Infrastructure for Measles Elimination in Nigeria-The National Stop Transmission of Polio Program.
From 2012 to date, Nigeria has been the focus of intensified polio eradication efforts. Large investments made by multiple partner organizations and the federal Ministry of Health to support strategies and resources, including personnel, for increasing vaccination coverage and improved performance monitoring paid off, as the number of wild poliovirus (WPV) cases detected in Nigeria were reduced significantly, from 122 in 2012 to 6 in 2014. No WPV cases were detected in Nigeria in 2015 and as at March 2017, only 4 WPV cases had been detected. Given the momentum gained toward polio eradication, these resources seem well positioned to help advance other priority health agendas in Nigeria, particularly the control of vaccine-preventable diseases, such as measles. Despite implementation of mass measles vaccination campaigns, measles outbreaks continue to occur regularly in Nigeria, leading to high morbidity and mortality rates for children <5 years of age. The National Stop Transmission of Polio (NSTOP) program was collaboratively established in 2012 to create a network of staff working at national, state, and district levels in areas deemed high risk for vaccine-preventable disease outbreaks. As an example of how the polio legacy can create long-lasting improvements to public health beyond polio, the Centers for Disease Control and Prevention will transition >180 NSTOP officers to provide technical experience to improve measles surveillance, routine vaccination coverage, and outbreak investigation and response in high-risk areas.


Mouse H6 Homeobox 1 (Hmx1) mutations cause cranial abnormalities and reduced body mass.
The H6 homeobox genes Hmx1, Hmx2, and Hmx3 (also known as Nkx5-3; Nkx5-2 and Nkx5-1, respectively), compose a family within the NKL subclass of the ANTP class of homeobox genes. Hmx gene family expression is mostly limited to sensory organs, branchial (pharyngeal) arches, and the rostral part of the central nervous system. Targeted mutation of either Hmx2 or Hmx3 in mice disrupts the vestibular system. These tandemly duplicated genes have functional overlap as indicated by the loss of the entire vestibular system in double mutants. Mutants have not been described for Hmx1, the most divergent of the family. Dumbo (dmbo) is a semi-lethal mouse mutation that was recovered in a forward genetic mutagenesis screen. Mutants exhibit enlarged ear pinnae with a distinctive ventrolateral shift. Here, we report on the basis of this phenotype and other abnormalities in the mutant, and identify the causative mutation as being an allele of Hmx1. Examination of dumbo skulls revealed only subtle changes in cranial bone morphology, namely hyperplasia of the gonial bone and irregularities along the caudal border of the squamous temporal bone. Other nearby otic structures were unaffected. The semilethality of dmbo/dmbo mice was found to be ~40%, occured perinatally, and was associated with exencephaly. Surviving mutants of both sexes exhibited reduced body mass from ~3 days postpartum onwards. Most dumbo adults were microphthalmic. Recombinant animals and specific deletion-bearing mice were used to map the dumbo mutation to a 1.8 Mb region on Chromosome 5. DNA sequencing of genes in this region revealed a nonsense mutation in the first exon of H6 Homeobox 1 (Hmx1; also Nkx5-3). An independent spontaneous allele called misplaced ears (mpe) was also identified, confirming Hmx1 as the responsible mutant gene. The divergence of Hmx1 from its paralogs is reflected by different and diverse developmental roles exclusive of vestibular involvement. Additionally, these mutant Hmx1 alleles represent the first mouse models of a recently-discovered Oculo-Auricular syndrome caused by mutation of the orthologous human gene.


An autoinhibitory mechanism modulates MAVS activity in antiviral innate immune response.
In response to virus infection, RIG-I senses viral RNA and activates the adaptor protein MAVS, which then forms prion-like filaments and stimulates a specific signalling pathway leading to type I interferon production to restrict virus proliferation. However, the mechanisms by which MAVS activity is regulated remain elusive. Here we identify distinct regions of MAVS responsible for activation of transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). These IRF3- and NF-κB-stimulating regions recruit preferential TNF receptor-associated factors (TRAFs) for downstream signalling. Strikingly, these regions' activities are inhibited by their respective adjacent regions in quiescent MAVS. Our data thus show that an autoinhibitory mechanism modulates MAVS activity in unstimulated cells and, on viral infection, individual regions of MAVS are released following MAVS filament formation to activate antiviral signalling cascades.


Two new chemical constituents from the leaves of Illicium dunnianum.
One new phenolic glycoside (1) and one new benzofuran derivative (2) were isolated from the leaves of Illicium dunnianum. The structures of these compounds were established by using comprehensive spectroscopic data analysis, including the 1D and 2D NMR, IR, HR-ESI-MS, electronic circular dichroism and comparison with literature data. All isolates were evaluated for the inhibition against the production of NO by LPS-stimulated RAW 264.7 macrophages.


Assessment of antihypertensive efficacy of perindopril: results of double-blind multicenter studies versus reference drugs.
Perindopril (4 mg) was compared to atenolol (50 mg), captopril (25 mg b.i.d.), or a diuretic (hydrochlorothiazide 50 mg and amiloride 5 mg) in three studies involving a total of 503 hypertensive patients with diastolic blood pressure (DBP) of 95-125 mm Hg. A 4-week single-blind placebo period preceded 12 weeks of active treatment. Dose titration was at weeks 4 and 8 if the supine DBP was greater than 90 mm Hg. The dose was doubled and, if necessary, a diuretic was added in atenolol or captopril comparison and atenolol added in the diuretic study. The fall in supine blood pressure (BP) was 27/17 mm Hg with perindopril and 21/16 mm Hg for atenolol. Fifty-five percent on perindopril and 48% on atenolol were controlled on monotherapy, increasing to 78 and 58% with addition of hydrochlorothiazide. Captopril caused a BP fall of 19/12 mm Hg compared to 27/18 mm Hg for perindopril with 49% of both groups being controlled on monotherapy. Diuretic addition produced a greater antihypertensive effect with perindopril 75% compared to 57% of the captopril patients achieving control. Perindopril caused a comparable fall in supine BP to the diuretic combination 27/19 mm Hg and 31/18 mm Hg but the fall in erect systolic BP was significantly greater for the diuretic. At 3 months, 84% of the diuretic and 78% of the perindopril group achieved the target BP. There were no adverse effects on the blood count or blood chemistry with a low incidence of side effects and withdrawals from treatment. These studies show that perindopril compares favorably with the standard antihypertensive drugs.


Levels of circulating microparticles in lung cancer patients and possible prognostic value.
Endothelial-derived microparticles (EDMPs) and platelet-derived microparticles (PDMPs) have been reported to be increasing in various diseases including malignant diseases. Here, we investigated whether these MPs may be useful biomarkers for predicting lung cancer (LC) disease status, cell type, or metastasis. One hundred and thirty LC patients were prospectively enrolled into the study between April 2011 and February 2012. Flow cytometric analysis demonstrated that the circulating levels of platelet-derived activated MPs (PDAc-MPs), platelet-derived apoptotic MPs (PDAp-MPs), endothelial-derived activated MPs (EDAc-MPs), and endothelial-derived apoptotic MPs (EDAp-MPs) were significantly higher in LC patients than in 30 age- and gender-matched normal control subjects (all P < 0.05). Additionally, circulating level of PDAc-MPs was significantly lower (P = 0.031), whereas the circulating levels of the other three biomarkers did not differ (all P > 0.1) in early stage versus late stage LC patients. Furthermore, the circulating levels of the four types of MPs did not differ among patients with different disease statuses (i.e., disease controlled, disease progression, and disease without treatment, i.e., fresh case) (all P > 0.2) or between patients with or without LC metastasis (all P > 0.5). Moreover, only the circulating level of EDAp-MPs was significantly associated with the different cell types (i.e., squamous cell carcinoma, adenocarcinoma, and small cell carcinoma) of LC (P = 0.045). Circulating MP levels are significantly increased in LC patients as compared with normal subjects. Among the MPs, only an increased level of EDAp-MPs was significantly associated with different LC cell types.