Differential phosphorylation of myelin-associated glycoprotein isoforms in cell culture.
The alternative splicing of myelin-associated glycoprotein (MAG) mRNA generates two isoforms that harbor distinct potential phosphorylation sites in their cytoplasmic tails. Here we characterize the in vivo phosphorylation of MAG isoforms in NIH 3T3 cells transfected with the cDNAs encoding the two isoforms of MAG. Our results demonstrate that the longer isoform, L-MAG, is phosphorylated constitutively mainly on serine, but also on threonine and tyrosine residues. This phosphorylation is subject to change by 12-O-tetradecanoylphorbol 13-acetate (TPA) and ammonium vanadate, but not by dibutyryl-cyclic AMP. The shorter isoform, S-MAG, is constitutively phosphorylated only on serine residues. While TPA and dibutyryl-cyclic AMP have no detectable effect, ammonium vanadate induces tyrosine and threonine phosphorylation in S-MAG. 32P labeling of v-src-transformed NIH 3T3 cells that express L-MAG also show that L-MAG is likely to be an in vivo substrate for pp60v-src tyrosine kinase activity. These results demonstrate that both MAG isoforms are phosphorylated in a heterologous cell system and that this phosphorylation is subject to pharmacological manipulation.


Hyperactive Dental Lamina in a 24-Year-old Female - A Case Report and Review of Literature.
An extra tooth to the normal formula of teeth sequence in any region of dental arch is regarded as Supernumerary teeth (ST). The reasons are still not clearly known, one of them being dichotomy of tooth bud, but the more accepted reason is the hyperactivity theory. Supernumerary teeth are present more in permanent dentition than in primary dentition and can present as a single entity or multiple, unilaterally or bilaterally, impacted or erupted, in either or both the dental arches. This article discusses the supernumerary teeth in detail with a case discussion of a non-syndromic 24-year-old girl, with six ST (bicuspids) present in all the four quadrants. In the mandible, ST's showed a classical clustered flower like presentation. The interesting feature in the presented case was the sequential orthopantomographs taken at various ages of the patient that showed continuous development of STs in all four quadrants, thus pointing to the theory of hyperactive dental lamina or atavism. An electronic search was conceded in PubMed, Cochrane Library and google scholar databases, and articles dated between December 1932 and December 2012 were selected to review the occurrence patterns of supernumerary teeth in non-syndromic cases.


High-security SCMA-OFDM multi-core fiber transmission system based on a regular hexagon chaotic codebook.
Sparse code multiple access (SCMA), a new code-domain non-orthogonal technology in the fifth-generation mobile communication (5G), can be modulated by orthogonal frequency division multiplexing (OFDM) to improve the link quality of a single user. In this paper, a high-security SCMA-OFDM multi-core fiber transmission system based on a regular hexagonal chaotic codebook is proposed for next-generation passive optical network (PON). The whole encryption process consists of a regular hexagon chaotic codebook design and frequency domain block scrambling. In designing the regular hexagon chaotic codebook, the optimization of constellation points on orthogonal resources are considered as the starting point. Firstly, the chaos factor generated by the four-dimensional Rossler chaos model is deployed to disturb the mother constellation, and then the corresponding chaotic book is formed by rotating the mother constellation and multiplying the sparse matrix. The designed codebook logically avoids the degradation of transmission performance caused by the rough scrambling of codebook constellation, to find a balance between codebook disturbance and bit error rate (BER). The security and reliability of the transmission system have been verified by performing 42 Gb/s encrypted SCMA-OFDM data transmission experiments in a 2km multi-core fiber. The key space of the encryption scheme can reach 10178, which effectively ensures the security of the transmission system. Furthermore, the performance of the transmission system with a regular hexagon chaotic codebook is improved by 2.5 dB compared with the traditional codebook when the BER is 1 × 10-3. Moreover, the SCMA-OFDM-based transmission architecture and the detection effects of different multi-user detection algorithms in the SCMA-OFDM multi-core fiber transmission system are also studied.


Hepatitis C virus upregulates Beclin1 for induction of autophagy and activates mTOR signaling.
Hepatitis C virus (HCV) induces autophagosome formation in infected human hepatocytes. We have previously reported that HCV exploits autophagic machinery in favor of virus growth and survival in host cells (S. Shrivastava et al., Hepatology 53:406-414, 2011); however, the mechanisms for autophagy induction is poorly understood. In the present study, we observed that HCV infection transcriptionally upregulates Beclin1, which forms complex with Vps34, the class III phosphatidylinositol 3-kinase, as a first step for autophagy initiation. Although Bcl-2 has an anti-autophagy effect by its association with Beclin1 in nutrient-deprived cells, our studies revealed that HCV-mediated autophagy occurs independent of Beclin1-Bcl-2 dissociation. Mammalian target of rapamycin (mTOR) is a positive regulator of cell growth and is recognized as an inhibitor of autophagy induction. Our results demonstrated that HCV infection enhances phospho-mTOR expression and its downstream target 4EBP1 activation, suggesting that mTOR is not a negative regulator of HCV-induced autophagy. On the other hand, HCV infection in autophagy-impaired cells reduced phospho-mTOR, mTOR, and phospho-4EBP1 expression. Together, these results suggested that HCV induces autophagy by upregulating Beclin1 and activates mTOR signaling pathway, which in turn may promote hepatocyte growth.


Detection of ESAT-6 by a label free miniature immuno-electrochemical biosensor as a diagnostic tool for tuberculosis.
Tuberculosis is a worldwide disease considered as a major health problem with high morbidity and mortality rates. Poor detection of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis remains a major obstacle to the global control of this disease. Here we report the development of a new test based on the detection of the major virulent factor of Mtb, namely the early secreted antigenic target 6-kDa protein or ESAT-6. A label free electrochemical immunosensor using an anti-ESAT-6 monoclonal antibody as a bio-receptor is described herein. Anti-ESAT-6 antibodies were first covalently immobilized on the surface of a gold screen-printed electrode functionalized via a self-assembled thiol monolayer. Interaction between the bio-receptor and ESAT-6 antigen was evaluated by square wave voltammetry method using [Fe(CN)6]3-/4- as redox probe. The detection limit of ESAT-6 antigen was 7ng/ml. The immunosensor has also been able to detect native ESAT-6 antigen secreted in cell culture filtrates of three pathogenic strains of Mtb (CDC1551, H37RV and H8N8). Overall, this work describes an immune-electrochemical biosensor, based on ESAT-6 antigen detection, as a useful diagnostic tool for tuberculosis.


The management of clotted angiographic catheters.
In our experience, clotted angiographic catheters pulled back to near the puncture site and severed near the skin will spontaneously clear, facilitating insertion of a guidewire and catheter exchange without repuncture or other manipulation.


The Effects of Organizational Characteristics, Individual Nurse Characteristics, and Occupational Fatigue on Missed Care at Night.
Missed care is defined as the omission or delay of necessary patient care and is internationally reported by nurses as a significant safety risk. Nurses working at night also report high levels of occupational fatigue that, coupled with inadequate staffing and practice environment support, may impede a nurse's ability to carry out the nursing process and lead to more missed care. The study's objective was to examine the interrelationships among organizational and nurse characteristics, occupational fatigue, and missed care among nurses working at night. A cross-sectional design was used. Participants included RNs who worked at night in New Jersey acute care hospitals. Multiple linear regression and simple moderation analyses were performed to examine the associations. Nurses reported missing necessary care at night. Unsupportive practice environments, high registered nurse workloads, high patient-RN ratios, high chronic fatigue levels, and low inter-shift recovery were individually associated with missed care at night. High patient-to-RN ratios and chronic fatigue were independently associated with missed care. However, patient-to-registered staffing levels had the most considerable effect on missed care at night. Nurses' years of experience and the number of hours of sleep between shifts were significant moderators of the relationship between occupational fatigue states and missed care. This study is the first to examine the interrelationship between occupational fatigue levels, organizational and nurse characteristics, and missed care at night. There is an urgent need to implement strategies in hospital organizations that foster work schedules and adequate staffing patterns that lessen nurses' occupational fatigue levels to ensure our workforce's and patients' safety.


Familial calcific band-shaped keratopathy: report of two new cases with early recurrence.
We report two siblings with the rare entity of familial calcific band-shaped keratopathy (BSK). Detailed ophthalmic and systemic investigations failed to reveal any underlying causative pathology. Topical disodium ethylenediamine-tetraacetate (EDTA) was applied for 30 min to all four eyes. In addition the right eye of the younger sibling required a superficial keratectomy. An improvement in corneal clarity was seen in the immediate postoperative period in both siblings. Histopathology of the keratectomy specimen revealed linear extracellular sub-epithelial granular calcium deposits. However, an early recurrence was noted in all four eyes at four weeks postoperatively. We report the second instance in the English literature of this entity. Band-shaped keratopathy presenting without an obvious etiology merits a complete systemic and ophthalmic workup. Patients with familial idiopathic BSK could be cases with poor prognosis for treatment with EDTA due to an early recurrence of the disease.


Zinc coordination environments in proteins as redox sensors and signal transducers.
Zinc/cysteine coordination environments in proteins are redox-active. Oxidation of the sulfur ligands mobilizes zinc, while reduction of the oxidized ligands enhances zinc binding, providing redox control over the availability of zinc ions. Some zinc proteins are redox sensors, in which zinc release is coupled to conformational changes that control varied functions such as enzymatic activity, binding interactions, and molecular chaperone activity. Whereas the released zinc ion in redox sensors has no known function, the redox signal is transduced to specific and sensitive zinc signals in redox transducers. Released zinc can bind to sites on other proteins and modulate signal transduction, generation of metabolic energy, mitochondrial function, and gene expression. The paradigm of such redox transducers is the zinc protein metallothionein, which, together with its apoprotein, thionein, functions at a central node in cellular signaling by redistributing cellular zinc, presiding over the availability of zinc, and interconverting redox and zinc signals. In this regard, the transduction of nitric oxide (NO) signals into zinc signals by metallothionein has received particular attention. It appears that redox-inert zinc has been chosen to control some aspects of cellular thiol/disulfide redox metabolism. Tight control of zinc is essential for redox homeostasis because both increases and decreases of cellular zinc elicit oxidative stress. Depending on its availability, zinc can be cytoprotective as a pro-antioxidant or cytotoxic as a pro-oxidant. Any condition with acute or chronic oxidative stress is expected to perturb zinc homeostasis.


Is there a role for bronchial thermoplasty in the treatment of asthma?
Bronchial thermoplasty is a new technique proposed to improve control of moderate to severe asthma. It delivers thermal energy to the large airways during a bronchoscopy to decrease the amount of bronchial smooth muscle. This intervention has been shown to reduce asthma exacerbations, and improve asthma control and quality of life over a three-year period without significant complications up to a five-year period. It could be considered as another option in the treatment of selected patients requiring oral and⁄or high doses of inhaled corticosteroids to control asthma. It should, however, be performed in specialized centres in patients who understand the potential benefits and side-effects of this technique. The response to this treatment varies from one patient to another. Consequently, further studies are required to better define the role of this option in the treatment of asthma.


Anticancer Properties of Asian Water Monitor Lizard (Varanus salvator), Python (Malayopython reticulatus) and Tortoise (Cuora kamaroma amboinensis).
Cancer contributes to significant morbidity and mortality despite advances in treatment and supportive care. There is a need for the identification of effective anticancer agents. Reptiles such as tortoise, python, and water monitor lizards are exposed to heavy metals, tolerate high levels of radiation, feed on rotten/germ-infested feed, thrive in unsanitary habitat and yet have prolonged lifespans. Such species are rarely reported to develop cancer, suggesting the presence of anticancer molecules/mechanisms. Here, we tested effects from sera of Asian water monitor lizard (Varanus salvator), python (Malayopython reticulatus) and tortoise (Cuora kamaroma amboinensis) against cancer cells. Sera were collected and cytotoxicity assays were performed using prostate cancer cells (PC3), Henrietta Lacks cervical adenocarcinoma cells (HeLa) and human breast adenocarcinoma cells (MCF7), as well as human keratinized skin cells (Hacat), by measuring lactate dehydrogenase release as an indicator for cell death. Growth inhibition assays were performed to determine the effects on cancer cell proliferation. Liquid chromatography mass spectrometry was performed for molecular identification. The findings revealed that reptilian sera, but not bovine serum, abolished viability of Hela, PC3 and MCF7 cells. Samples were subjected to liquid chromatography mass spectrometry, which detected 57 molecules from V. salvator, 81 molecules from Malayopython reticulatus and 33 molecules from C. kamaroma amboinensis and putatively identified 9 molecules from V. salvator, 20 molecules from Malayopython reticulatus and 9 molecules from C. kamaroma amboinensis when matched against METLIN database. Based on peptide amino acid composition, binary profile, dipeptide composition and pseudo-amino acid composition, 123 potential Anticancer Peptides (ACPs) were identified from 883 peptides from V. salvator, 306 potential ACPs from 1074 peptides from Malayopython reticulatus and 235 potential ACPs from 885 peptides from C. kamaroma amboinensis. To our knowledge, for the first time, we reported comprehensive analyses of selected reptiles' sera using liquid chromatography mass spectrometry, leading to the identification of potentially novel anticancer agents. We hope that the discovery of molecules from these animals will pave the way for the rational development of new anticancer agents.


Trajectories of Pelvic Floor Symptoms and Support After Vaginal Delivery in Primiparous Women Between Third Trimester and 1 Year Postpartum.
The objectives of this study were to describe trajectories of pelvic floor symptoms and support from the third trimester to 1 year postpartum in primiparous women after vaginal delivery and to explore factors associated with their resolution between 8 weeks postpartum and 1 year postpartum. Five hundred ninety-seven nulliparous women 18 years or older who gave birth vaginally at term completed the Epidemiology of Prolapse and Incontinence Questionnaire and the Pelvic Organ Prolapse Quantification examination at the third trimester, 8 weeks postpartum, and 1 year postpartum. At 1 year postpartum, 41%, 32%, and 23% of participants reported stress urinary incontinence, nocturia, and flatus incontinence, respectively, and 9% demonstrated maximal vaginal descent (MVD) ≥ 0 cm. For more common symptoms, incidence rates between the third trimester and 8 weeks postpartum ranged from 6% for urinary frequency to 22% for difficult bowel movements, and resolution rates between 8 weeks postpartum and 1 year postpartum ranged from 23% for stress urinary incontinence to 73% for pain. Between the third trimester and 8 weeks postpartum, 13% demonstrated de novo MVD ≥ 0 cm. For most symptoms, the presence of the same symptom before delivery decreased the probability of resolution between 8 weeks postpartum and 1 year. However, the sensitivities of predelivery vaginal bulge and MVD of 0 cm or greater for those outcomes at 1 year postpartum was overall low (10-12%). One year postpartum, urinary and bowel symptoms are common in primiparous women who gave birth vaginally. A substantial portion of this burden is represented by symptoms present before delivery, while most of the prevalence of worse anatomic support is accounted for by de novo changes after delivery.


Endogenous serotonin stimulates striatal dopamine release in conscious rats.
Serotonin (5-HT) and dopamine (DA) are established neurotransmitters in the brain. This study examined whether, in conscious, free-moving rats, increased concentrations of endogenous 5-HT in extracellular fluid of the corpus striatum affect local release of endogenous DA. Administration of the 5-HT reuptake blocker alaproclate via a microdialysis probe increased striatal dialysate levels of DA and its metabolites dihydroxyphenylacetic acid and homovanillic acid as well as levels of 5-HT and the 5-HT metabolite 5-hydroxyindoleacetic acid. Whereas DA reuptake blockade with GBR-12909 did not prevent these effects of alaproclate, serotonergic ablation by i.c.v. administration of 5,7-dihydroxytryptamine markedly decreased basal levels of 5-HT and 5-hydroxyindoleacetic acid and abolished the effects of alaproclate on dialysate levels of DA, 5-HT and their metabolites. The results are consistent with a stimulatory action of endogenous 5-HT on striatal DA release in conscious animals.


Health assessment for partners of pregnant women: a pilot study of four survey methods.
Health assessment for partners of pregnant women has not been routinely offered. Work in the area of smoking cessation suggests that a partner's health habits have a strong influence on the health habits of a pregnant woman. Smoking, alcohol abuse, depression, battering, and household firearms cab adversely affect the health of the expectant mother and the infant. Four methods of partner assessment were pilot tested: office visit with a family physician, office visit with a registered nurse, telephone survey conducted by the registered nurse, and mailed questionnaire. Written feedback and referrals were provided to all study participants, and verbal feedback and referrals were provided to those who completed in-person or telephone interviews. A chart review was conducted to determine participation bias. Thirty-five pregnant women and 25 partners participated in the study. Self-administered questionnaires and telephone interviews were preferred by study participants. The study group was healthier than the general population. Five partners reported troublesome drinking behavior, and 1 reported smoking two packs of cigarettes per day. health assessment of partners of pregnant women seems promising for uncovering health problems that would be likely to have an adverse impact on the health of the family. Further development of assessment and intervention strategies is needed.


[Mexiletine in treatment of chronic ventricular refractary arrhythmias (author's transl)].
We studied the antiarrhythmic effect of oral Mexiletine in 20 patients with stable high-frequency ventricular arrhythmias refractory to therapeutic doses of conventional antiarrhythmic therapy. Arrhythmias were classified according to modified grading system of Lown and Wolf. The efficacy of Mexiletine was assessed with use of both the arrhythmic modified classification of Lown and Wolf and count of premature ventricular beats (PVB) from 24 hours ambulatory electrocardiographic recordings. The dose of Mexiletine was 300 mg every 8 hours; 24 hours ECG recordings were obtained in each patient on days 5,15 and 20 during Mexiletine therapy. The worst of tracings before and during Mexiletine therapy was compared. Mean decrease in PVB was 57% (P less than 0.001). The decrease in PVB was more than 80% in 11 patients. Comparison of the grade of arrhythmias disclosed a favorable effect of Mexiletine in 13 patients, a worsening in 1, and no effect in 6. Classification of the most severe arrhythmia revealed a significant decrease from an average grade of 3.05 to 1.75 (P less than 0.01). Before Mexiletine therapy, 40% of our patients were in Class 0 to II and 60% were in Class III or V, whereas during Mexiletine therapy the corresponding proportions were 75% and 25% respectively. Side effects (confusion, tremors, gastro-intestinal complaints) prompted reduction of the dose in 3 patients. Three additional patients had transient minor side effects (dizziness, nystagmus and gastrointestinal disorders) that did not necessitate a change in therapy and 14 patients reported no side effects. In conclusion our data suggest that Mexiletine is an effective agent in the long-term treatment of serious ventricular arrhythmias refractory to other agents. Since Mexiletine therapy is not associated with severe long-term side effects, it should now be possible to determine its role as a first-line drug for treating ventricular arrhythmias.


Malaria and poverty.
Malaria is one of the most important challenges to global public health. African countries south of the Sahara bear today the heaviest burden of malaria. The relationship between poverty and malaria has long been recognized but its paths are multiple and complex. Recent studies suggest that causality works both ways, trapping communities in reinforcing cycles of poverty and disease. If malaria is to be controlled or eventually eliminated, the social and economic conditions that fuel malaria transmission need to be addressed. At the same time, malaria control should be seen as a poverty reduction strategy.


Irreversible Swelling Behavior and Reversible Hysteresis in Chemically Crosslinked Poly(vinyl alcohol) Gels.
We report the swelling properties of chemically crosslinked poly(vinyl alcohol) (PVA) gels with high degrees of polymerization and hydrolysis. Physical crosslinking by microcrystallites was introduced in this chemical PVA gel by a simple dehydration process. The equilibrium swelling ratio was measured in several mixed solvents, which comprised two-components: a good solvent (water or dimethyl sulfoxide (DMSO)), and a poor organic solvent for PVA. In the case of aqueous/organic solvent mixtures subjected to a multiple-sample test, the swelling ratio decreased continuously when the concentration of the organic solvent increased, reaching a collapsed state in the respective pure organic solvents. In the case of DMSO, starting from a swollen state, the swelling ratio rapidly decreased by between 15 and 50 mol % when the concentration of the organic compound increased in a single-sample test. To understand the hysteresis phenomenon, the swelling ratio was measured in a DMSO/acetone mixed solvent, starting from a collapsed state in acetone. The reversibility of swelling in response to successive concentration cycles between DMSO and acetone was examined. As a result, an irreversible swelling behavior was observed in the first cycle, and the swelling ratio in acetone after the first cycle became larger than the initial ratio. Subsequently, the swelling ratio changed reversibly, with a large hysteresis near a specific molar ratio of DMSO/acetone of 60/40. The microstructures were confirmed by Fourier transform infrared spectroscopy during the cycles. The irreversible swelling behavior and hysteresis are discussed in terms of the destruction and re-formation of additional physical crosslinking in the chemical PVA gels.


Formulas for fixing serum sodium: curb your enthusiasm.
A variety of formulas have been proposed to predict changes in serum sodium concentration. All are based on an experiment done over 50 years ago by Edelman, who derived a formula relating the plasma sodium concentration to isotopically measured body sodium, potassium, and water. Some of these formulas fail because they do not include urinary losses of electrolytes and water. Even those that include these essential variables are not accurate enough for clinical use because it is impractical to adjust calculations to rapid changes in urinary composition, and because the formulas do not account for changes in serum sodium caused by internal exchanges between soluble and bound sodium stores or shifts of water into or out of cells resulting from changes in intracellular organic osmolytes. Nephrologists should curb their enthusiasm for predictive formulas and rely instead on frequent measurements of the serum sodium when correcting hyponatremia and hypernatremia.


Theta activity in neurons and networks of the amygdala related to long-term fear memory.
With a combined in vitro/in vivo electrophysiological and behavioral approach, we have correlated conditioned fear behavior to electrophysiological activities in the lateral amygdala and the hippocampal formation in rodents. Data indicate that projection neurons in the lateral amygdala display a continuum of spike patterns including accommodating patterns, regular firing, and oscillatory activity at theta frequencies. The firing pattern is controlled to an important part by the intracellular cAMP system, in that an increase in intracellular cAMP concentration facilitates regular firing and theta oscillations. Oscillatory electrical activity, in turn, provides an important cellular element of synchronized theta activity at 4-8 Hz (indicating atropine-sensitive type 2 theta) occurring in amygdalo-hippocampal pathways during conditioned fear responses. This type of rhythmic network activity is associated with the retrieval of long-term fear memory following cued and contextual fear conditioning, but is not related to the expression of fear behavior per se or to short-term fear memory. Synchronization at theta frequencies is suggested to represent activity in amygdalo-hippocampal pathways associated with system consolidation of fear memory, which is supported by the cholinergic system.


Photons walking the line: a quantum walk with adjustable coin operations.
We present the first robust implementation of a coined quantum walk over five steps using only passive optical elements. By employing a fiber network loop we keep the amount of required resources constant as the walker's position Hilbert space is increased. We observed a non-Gaussian distribution of the walker's final position, thus characterizing a faster spread of the photon wave packet in comparison to the classical random walk. The walk is realized for many different coin settings and initial states, opening the way for the implementation of a quantum-walk-based search algorithm.


Enhanced shot noise in resonant tunneling via interacting localized states.
In a variety of mesoscopic systems shot noise is seen to be suppressed in comparison with its Poisson value. In this work we observe a considerable enhancement of shot noise in the case of resonant tunneling via localized states. We present a model of correlated transport through two localized states which provides both a qualitative and a quantitative description of this effect.


Influence of in-house composting of reused litter on litter quality, ammonia volatilisation and incidence of broiler foot pad dermatitis.
1. The objectives of this study were to evaluate the residual effects of two windrow composting methods for reused litter on its quality (pH, moisture, ammonia), ammonia (NH3) volatilisation and the prevalence (scores 0-4) of foot pad dermatitis (FPD) and hock burn (HB) on d 1, 7, 14 and 21 of age in broilers. Litter was allowed to compost for 8 d within a 14-d interval between flocks. 2. The composting methods studied were with or without a PVC plastic sheet. The same procedures were applied for three consecutive flocks, with litter initially having been used for 12 flocks. Data were analysed with a mixed model of repeated measures of day, with main effects and interactions of day, composting method, litter age (block) and house nested within method. 3. At d 1, litter NH3 and NH3 volatilisation were higher in the covered litter method. Litter moisture increased to 45.3% as broilers aged. The incidence of FPD also increased with age. No signs of HB were found in any bird throughout the trials. 4. There was no effect of litter composting methods on the prevalence of FPD or body weight at any age. 5. Litter moisture should be controlled to avoid NH3 volatilisation reaching critical levels. Windrow composting of litter with a PVC plastic sheet may not be required when considering the broiler housing environment.


Saliency-based gaze prediction based on head direction.
Despite decades of attempts to create a model for predicting gaze locations by using saliency maps, a highly accurate gaze prediction model for general conditions has yet to be devised. In this study, we propose a gaze prediction method based on head direction that can improve the accuracy of any model. We used a probability distribution of eye position based on head direction (static eye-head coordination) and added this information to a model of saliency-based visual attention. Using empirical data on eye and head directions while observers were viewing natural scenes, we estimated a probability distribution of eye position. We then combined the relationship between eye position and head direction with visual saliency to predict gaze locations. The model showed that information on head direction improved the prediction accuracy. Further, there was no difference in the gaze prediction accuracy between the two models using information on head direction with and without eye-head coordination. Therefore, information on head direction is useful for predicting gaze location when it is available. Furthermore, this gaze prediction model can be applied relatively easily to many daily situations such as during walking.


Pressure induced static magnetic order in superconducting FeSe1-x.
We report on a detailed investigation of the electronic phase diagram of FeSe1-x under pressures up to 1.4 GPa by means of ac magnetization and muon-spin rotation. At a pressure approximately 0.8 GPa the nonmagnetic and superconducting FeSe1-x enters a region where static magnetic order is realized above T{c} and bulk superconductivity coexists and competes on short length scales with the magnetic order below T{c}. For even higher pressures an enhancement of both the magnetic and the superconducting transition temperatures as well as of the corresponding order parameters is observed. These exceptional properties make FeSe1-x to be one of the most interesting superconducting systems investigated extensively at present.


Hyaline membrane disease and surfactant protein, SAP-35, in diabetes in pregnancy.
Surfactant-associated protein of Mr 28,000 to 35,000 (SAP-35) is an abundant glycoprotein present in the alveolus of the lung, which imparts both structural organization to surfactant phospholipids and provides regulatory information controlling surfactant phospholipid secretion and metabolism. SAP-35 expression is enhanced by 3'-5'-cyclic adenosine monophosphate and epidermal growth factor during perinatal differentiation of type II epithelial cells. Its synthesis and RNA are also controlled by a variety of inhibitory factors, which include transforming growth factor and insulin. Glucocorticoids both enhance and inhibit SAP-35 expression in fetal lung explants. There is evidence that fetal hyperinsulinemia or hyperglycemia, or both, inhibit the morphologic differentiation of the type II epithelial cell in association with decreased phospholipid surfactant synthesis or secretion. Insulin is also a potent inhibitor of SAP-35 expression in fetal lung tissue, and decreased SAP-35 was previously noted in amniotic fluid of patients with diabetes during pregnancy. Recent progress in the management of diabetes in pregnancy, characterized by more rigorous metabolic control, has decreased the risk of hyaline membrane disease for the infant of the diabetic mother and is associated with normal levels of SAP-35 in amniotic fluid. Hyaline membrane disease remains a major cause of morbidity in infants of diabetic mothers but may also reflect a higher incidence of premature delivery, cesarean section, and asphyxia at delivery as well as inhibition of pulmonary surfactant phospholipid synthesis or expression of the surfactant protein SAP-35.


Emerging drugs for the treatment of cocaine use disorder: a review of neurobiological targets and pharmacotherapy.
Cocaine use is a global public health concern of significant magnitude, negatively impacting both the individual as well as larger society. Despite numerous trials, the discovery of an effective medication for treatment of cocaine use disorder remains elusive. This article reviews the emerging pharmacotherapies for treatment of cocaine use disorder, focusing on those medications that are currently in Phase II or III human clinical trials. Articles reviewed were obtained through searches of PubMed, Ovid MEDLINE, Clinicaltrials.gov and the Pharmaprojects database. Research into cocaine pharmacotherapy must continue to show innovation. Given that medications targeting single neurotransmitter systems have demonstrated little efficacy in treatment of cocaine use disorder, the recent focus on pharmacotherapeutic agents with multiple neurobiochemical targets represents an exciting shift in trial design and approach. Additionally, consideration of pharmacogenetics may be helpful in identification of subpopulations of cocaine-dependent individuals who may preferentially respond to medications.


Domain alternation and active site remodeling are conserved structural features of ubiquitin E1.
E1 enzymes for ubiquitin (Ub) and Ub-like modifiers (Ubls) harbor two catalytic activities that are required for Ub/Ubl activation: adenylation and thioester bond formation. Structural studies of the E1 for the Ubl small ubiquitin-like modifier (SUMO) revealed a single active site that is transformed by a conformational switch that toggles its competency for catalysis of these two distinct chemical reactions. Although the mechanisms of adenylation and thioester bond formation revealed by SUMO E1 structures are thought to be conserved in Ub E1, there is currently a lack of structural data supporting this hypothesis. Here, we present a structure of Schizosaccharomyces pombe Uba1 in which the second catalytic cysteine half-domain (SCCH domain) harboring the catalytic cysteine has undergone a 106° rotation that results in a completely different network of intramolecular interactions between the SCCH and adenylation domains and translocation of the catalytic cysteine 12 Å closer to the Ub C terminus compared with previous Uba1 structures. SCCH domain alternation is accompanied by conformational changes within the Uba1 adenylation domains that effectively disassemble the adenylation active site. Importantly, the structural and biochemical data suggest that domain alternation and remodeling of the adenylation active site are interconnected and are intrinsic structural features of Uba1 and that the overall structural basis for adenylation and thioester bond formation exhibited by SUMO E1 is indeed conserved in Ub E1. Finally, the mechanistic insights provided by the novel conformational snapshot of Uba1 presented in this study may guide efforts to develop small molecule inhibitors of this critically important enzyme that is an active target for anticancer therapeutics.


Integrated approaches to reveal mechanisms by which RNA viruses reprogram the cellular environment.
RNA viruses are major threats to global society and mass outbreaks can cause long-lasting damage to international economies. RNA and related retro viruses represent a large and diverse family that contribute to the onset of human diseases such as AIDS; certain cancers like T cell lymphoma; severe acute respiratory illnesses as seen with COVID-19; and others. The hallmark of this viral family is the storage of genetic material in the form of RNA, and upon infecting host cells, their RNA genomes reprogram the cellular environment to favor productive viral replication. RNA is a multifunctional biomolecule that not only stores and transmits heritable information, but it also has the capacity to catalyze complex biochemical reactions. It is therefore no surprise that RNA viruses use this functional diversity to their advantage to sustain chronic or lifelong infections. Efforts to subvert RNA viruses therefore requires a deep understanding of the mechanisms by which these pathogens usurp cellular machinery. Here, we briefly summarize several experimental techniques that individually inform on key physicochemical features of viral RNA genomes and their interactions with proteins. Each of these techniques provide important vantage points to understand the complexities of virus-host interactions, but we attempt to make the case that by integrating these and similar methods, more vivid descriptions of how viruses reprogram the cellular environment emerges. These vivid descriptions should expedite the identification of novel therapeutic targets.


Fever-range hyperthermia enhances L-selectin-dependent adhesion of lymphocytes to vascular endothelium.
The L-selectin leukocyte adhesion molecule plays an important role in controlling leukocyte extravasation in peripheral lymph nodes and at sites of tissue injury or infection. Although febrile responses during infection and inflammation are associated with enhanced immune activity, the contribution of fever-range temperatures to controlling lymphocyte recruitment to tissues has not been previously examined. In this report we provide evidence that direct exposure of lymphocytes to fever-range temperatures (38-41 degrees C) in vitro for 9 to 24 h resulted in a >100% increase in L-selectin-dependent adhesion of these cells to lymph node high endothelial venules (HEV). Moreover, culture of lymphocytes under hyperthermia conditions markedly enhanced the ability of these cells to traffic in an L-selectin-dependent manner to peripheral lymph nodes, mesenteric lymph nodes, and Peyer's patches. In contrast, febrile temperatures did not increase LFA-1 function as assessed by measuring lymphocyte adhesion to ICAM-1-3T3 transfectants. Fever-range hyperthermia further did not increase L-selectin surface density on lymphocytes or L-selectin-dependent recognition of soluble carbohydrate substrates; however, a marked increase in ultrastructural immunogold-labeling of L-selectin was observed in response to thermal stimuli. These results suggest that elevated temperatures enhance L-selectin adhesion and/or avidity through the regulation of L-selectin conformation or organization in the plasma membrane. Finally, the observed thermal effects on L-selectin adhesion were attributed to soluble factors in the conditioned medium of heat-treated cells. Taken together, these data provide new insight into the potential physiologic role of the febrile response in enhancing lymphocyte recruitment to tissues through the regulation of L-selectin adhesion.


Hepatitis B virus-induced calreticulin protein is involved in IFN resistance.
IFN-α is a widely used treatment for hepatitis B virus (HBV) infection, and IFN resistance caused by viral and/or host factors is currently a challenging clinical problem. A better understanding of the molecular mechanisms underlying IFN immunotherapy in the treatment of viral infection would be very beneficial clinically and is of immense clinical importance. Calreticulin (CRT) is an endoplasmic reticulum luminal calcium-binding chaperone that is involved in the regulation of calcium homoeostasis, the folding of newly synthesized proteins, and many other cellular functions. However, little is known about the role of CRT in HBV infection. In this study, we observed high levels of CRT expression in the sera and PBMCs of patients with HBV relative to those of healthy individuals. HBV upregulated the expression of CRT at the transcriptional level. Further investigation showed that HBV-induced CRT enhanced HBV replication by antagonizing the IFN pathway. CRT suppressed the production of endogenous IFN-α by reducing the nuclear translocation of IFN regulatory factor-7 but not IFN regulatory factor-3. Furthermore, CRT also suppressed the antiviral activity of IFN-α by inhibiting the phosphorylation of STAT1 and decreasing the expression of two IFN-α downstream effectors, protein kinase R and 2',5'-oligoadenylate synthetase. Our results offer new insights into the pathogenesis of HBV infection and may provide potential targets for anti-HBV therapy.


From the Foundation Up.
In 2019, The Hastings Center will celebrate its fiftieth anniversary. It is more than a bit staggering to think how far we have come since 1969. When I floated the idea of a center on bioethics to my friend and neighbor, psychiatrist Willard Gaylin, at a Christmas party in 1968-even before the word "bioethics" was used-I had only the fuzziest idea of where that would take us. Neither Will nor I had run anything, nor did we know how to raise money to support an organization. We would and did learn how, but much of what we did in those early years was made up on the fly. We not only had to invent an organization but no less to invent a field of research and education on issues still little noticed by the public or academics. Out of curiosity, I recently googled "bioethics." I was astonished at what I found and by the sheer quantity of what is going on.


CRISPR-Cas13a-Based Assay for Accurate Detection of OXA-48 and GES Carbapenemases.
Carbapenem-resistant pathogens have been recognized as a health concern as they are both difficult to treat and detect in clinical microbiology laboratories. Researchers are making great efforts to develop highly specific, sensitive, accurate, and rapid diagnostic techniques, required to prevent the spread of these microorganisms and improve the prognosis of patients. In this context, CRISPR-Cas systems are proposed as promising tools for the development of diagnostic methods due to their high specificity; the Cas13a endonuclease can discriminate single nucleotide changes and displays collateral cleavage activity against single-stranded RNA molecules when activated. This technology is usually combined with isothermal pre-amplification reactions in order to increase its sensitivity. We have developed a new LAMP-CRISPR-Cas13a-based assay for the detection of OXA-48 and GES carbapenemases in clinical samples without the need for nucleic acid purification and concentration. To evaluate the assay, we used 68 OXA-48-like-producing Klebsiella pneumoniae clinical isolates as well as 64 Enterobacter cloacae complex GES-6, 14 Pseudomonas aeruginosa GES-5, 9 Serratia marcescens GES-6, 5 P. aeruginosa GES-6, and 3 P. aeruginosa (GES-15, GES-27, and GES-40) and 1 K. pneumoniae GES-2 isolates. The assay, which takes less than 2 h and costs approximately 10 € per reaction, exhibited 100% specificity and sensitivity (99% confidence interval [CI]) for both OXA-48 and all GES carbapenemases. IMPORTANCE Carbapenems are one of the last-resort antibiotics for defense against multidrug-resistant pathogens. Multiple nucleic acid amplification methods, including multiplex PCR, multiplex loop-mediated isothermal amplification (LAMP) and multiplex RPAs, can achieve rapid, accurate, and simultaneous detection of several resistance genes to carbapenems in a single reaction. However, these assays need thermal cycling steps and specialized instruments, giving them limited application in the field. In this work, we adapted with high specificity and sensitivity values, a new LAMP CRISPR-Cas13a-based assay for the detection of OXA-48 and GES carbapenemases in clinical samples without the need for RNA extraction.


Major changes in the composition of a Southern Ocean bacterial community in response to diatom-derived dissolved organic matter.
In the Southern Ocean, natural iron fertilization in the wake of islands leads to annually occurring spring phytoplankton blooms associated with enhanced heterotrophic activity through the release of labile dissolved organic matter (DOM). The aim of this study was to investigate experimentally how diatom-derived DOM affects the composition of Southern Ocean winter water bacterial communities and to identify the most responsive taxa. A bacterial community collected in the naturally iron-fertilized region off Kerguelen Island (KEOPS2 October-November 2011) was grown onboard in continuous cultures, on winter water alone or amended with diatom-derived DOM supplied at identical DOC concentrations. 454 sequencing of 16S amplicons revealed that the two DOM sources sustained strikingly different bacterial communities, with higher relative abundances of Sulfitobacter, Colwellia and Methylophaga operational taxonomic units (OTUs) and lower relative abundances of Polaribacter, Marinobacter, NAC11-7 and SAR11 OTUs in diatom-DOM compared to winter water conditions. Using a modeling approach, we obtained growth rates for phylogenetically diverse taxa varying between 0.12 and 0.49 d-1 under carbon-limited conditions. Our results identify diatom DOM as a key factor shaping Southern Ocean winter water bacterial communities and suggest a role for niche partitioning and microbial interactions in organic matter utilization.


Differential temperature acclimatization responses in the membrane phospholipids of Posthodiplostomum minimum and its second intermediate host, Lepomis macrochirus.
The effects of temperature change on phospholipid content in metacercariae of Posthodiplostomum minimum and their second intermediate hosts, Lepomis macrochirus, were examined to gauge similarities in the homeoviscous adaptation of host and parasite membranes to environmental thermal change. Heart, liver, and muscle tissues from individual L. macrochirus responded to environmental temperature declines with a decrease in the ratio of phosphatidylethanolamine (PE) to phosphatidylcholine (PC). Increases in membrane PE concentration increase membrane fluidity, maintaining fish membrane function as environmental temperature declines. However, the metacercariae of P. minimum exhibit changes in cholesterol levels, total lipid levels, and lipid composition (PE/PC) that contrast the normal changes for homeoviscous membrane adaptation exhibited by their fish intermediate hosts. The parasites seem to rely on their hosts for homeoviscous adaptation within normal developmental temperature ranges, pooling both cholesterol and PE as energetic stores for development and ontological transitions signaled by elevated temperatures.


The effect of two consecutive dives on bubble formation and endothelial function in rats.
Gas bubble formation during and after decompression is considered to be the main initiator of decompression sickness (DCS). Compressed-air workers have been reported to acclimatise to the working environment and hence have a reduced risk of DCS, but the exact nature of the adaptation is not known. In the present study, we investigated the effect of two consecutive dives, separated by a 24-hour surface interval, on bubble formation and endothelial damage in rats. A total of 30 rats were divided into four groups, one control group and three dive groups with different dive profiles, of which two of the groups had two dives. The amount of bubbles in the pulmonary artery was estimated by ultrasound for one hour after surfacing, and tension measurements were performed in vitro on segments of the abdominal aorta following sacrifice of the animals. No significant differences between the groups were found in endothelial function or bubble grade. However, animals that died immediately after the dive, irrespective of grouping order, had lower acetylcholine-induced dilatory responses in the aorta than surviving rats. Bubble formation and endothelial function among rats were not significantly affected by exposure to consecutive dives 24 hours apart. An adaptive, protective effect of repeated dives was hence not seen in this animal model.


A Scale to Measure Impairment in Severe Dementia and Similar Conditions.
The authors describe an 11-item, 22-point scale that measures cognitive capacity in severely cognitively impaired individuals. The Severe Impairment Rating Scale (SIRS) has acceptable interrater reliability (r = 0.992; P < 0.001), test-retest reliability (r = 0.97; P < 0.0001), and internal consistency (Chronbach's alpha = 0.76). Validity is supported by correlations with the Glasgow Coma Scale (r = 0.866; P < 0.001) and Mini-Mental State Examination (r = 0.770; P < 0.001).


The Origins of Theory of Mind in Infant Social Cognition: Investigating Longitudinal Pathways from Intention Understanding and Joint Attention to Preschool Theory of Mind.
A growing body of literature has established longitudinal associations between key social cognitive capacities emerging in infancy and children's subsequent theory of mind. However, existing work is limited by modest sample sizes, narrow infant measures, and theory of mind assessments with restricted variability and generalizability. The current study aimed to extend this literature by (a) recruiting a large sample of participants (n = 116; 53 boys; 63 girls; all U.S. residents; 88 White, 8 Hispanic or Latino, 2 Black or African American, 14 two or more races/ethnicities, 4 unknown; median family income: $74-122,000), (b) examining multiple measures of infant social cognition (intentional action understanding, responding to joint attention, initiating joint attention) at Time 1 (8-12 months), and (c) using an ecologically valid theory of mind assessment designed to capture individual differences in preschoolers' mental state understanding (the Children's Social Understanding Scale; Tahiroglu et al., 2014) at Time 2 (37-45 months). Measured variable path analysis revealed a significant longitudinal association between infants' initiating joint attention and later theory of mind: infants who engaged in more attempts to initiate joint attention with experimenters through gaze alternation or gestures went on to show better parent-reported mental state understanding as preschoolers. Notably, the paths from infants' responding to joint attention and intentional action understanding to later theory of mind did not emerge as significant. These findings bolster and clarify existing claims about how mental state reasoning is rooted in foundational social-cognitive capacities emerging in infancy.


Reduced Prefrontal Cortex Activation in Children with Attention-Deficit/Hyperactivity Disorder during Go/No-Go Task: A Functional Near-Infrared Spectroscopy Study.
Objective: Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders in children and affects 3 to 5% of school-aged children. This study is to demonstrate whether functional near-infrared spectroscopy (fNIRS) can detect the changes in the concentration of oxygenated hemoglobin (oxy-HB) in children with ADHD and typically developing children (TD children). Method: In this study, 14 children with ADHD and 15 TD children were studied. Metabolic signals of functional blood oxygen were recorded by using fNIRS during go/no-go task. A statistic method is used to compare the fNIRS between the ADHD children and controls. Results: A significant oxy-HB increase in the left frontopolar cortex (FPC) in control subjects but not in children with ADHD during inhibitory tasks. Moreover, ADHD children showed reduced activation in left FPC relative to TD children. Conclusion: Functional brain imaging using fNIRS showed reduced activation in the left prefrontal cortex (PFC) of children with ADHD during the inhibition task. The fNIRS could be a promising tool for differentiating children with ADHD and TD children.


Expression and recombination of the EGFP and EYFP genes in lentiviral vectors carrying two heterologous promoters.
Expressing two genes in the progeny of stem and progenitor cells that are transduced with a unique viral vector is desirable in certain situations. We tested the ability of two lentiviral vectors to transduce human cells of hematopoietic origin and concomitantly express two reporter genes, either EGFP (enhanced green fluorescent protein) and DsRed2, or EGFP and EYFP (enhanced yellow fluorescent protein), from two internal promoters. The vectors were generated from the pTRIP deltaU3 EF1alpha EGFP lentiviral vector. Following transduction of hematopoietic and non-hematopoietic cell lines, we performed FACS, PCR and Southern blot analyzes to quantify transduction, integration efficiencies and size of integrated lentiviral vectors, respectively. The detection of DsRed2 fluorescence appeared unexpectedly low in human cells of hematopoietic origin. Alternatively, a modification in the flow cytometry assay allowed us to distinguish between the two overlapping fluorescence signals emitted by EGFP and EYFP, when transduced cells were excited with a 488-nm laser beam. However, the low frequency of double-positive EGFP+ EYFP+ cells, and the existence of single-positive, mostly EGFP- EYFP+, cells, prompted us to search for recombinations in the vector sequence. Southern blotting of DNA obtained from transduced cells indeed demonstrated that recombination had occurred between the two closely related EGFP and EYFP sequences. These observations suggest that recombination occurred within the EGFP and EYFP genes, which differ by only four amino acids. We conclude that the insertion of two highly homologous sequences into a lentiviral backbone can favor recombination.


Relative Risk of High-Danger Industries in China from 2004 to 2016.
Accidents in high-danger industries in China occur frequently and cause loss of life, injuries, and economic loss. One of the most important reasons causing severe safety situations is the lack of knowledge on macro industry risk in the practice and academic field in China. In order to solve this problem, the method to calculate group risk and individual risk, concerning risk aversion, is discussed, selected, and improved. The group risks and individual risks of five high-danger industries from 2004 to 2016 are calculated. Relative risk indices between five high-danger industries during the 11th and 12th Five-Year Guideline for National Economic and Social Development (FYP) are determined. The results show that there are some differences between group risk and individual risk of high-danger industries. The reasons for differences and the connections with published interventions are discussed. Through discussion, two different ways to reduce group risk and individual risk are identified, which could help supervisors inspect the actual effectiveness of safety policies, measures, and interventions and choose a better way to reduce risk and ensure work safety in industries.


Dysregulation of Immature Sertoli Cell Functions by Exposure to Acetaminophen and Genistein in Rodent Cell Models.
Sertoli cells are essential for germ cell development and function. Their disruption by endocrine disrupting chemicals (EDCs) or drugs could jeopardize spermatogenesis, contributing to male infertility. Perinatal exposure to EDCs and acetaminophen (APAP) disrupts male reproductive functions in animals and humans. Infants can be exposed simultaneously to the dietary soy phytoestrogen genistein (GEN) and APAP used for fever or pain relief. Our goal was to determine the effects of 10-100 µM APAP and GEN, alone or mixed, on immature Sertoli cells using mouse TM4 Sertoli cell line and postnatal-day 8 rat Sertoli cells, by measuring cell viability, proliferation, prostaglandins, genes and protein expression, and functional pathways. A value of 50 µM APAP decreased the viability, while 100 µM APAP and GEN decreased the proliferation. Sertoli cell and eicosanoid pathway genes were affected by GEN and mixtures, with downregulation of Sox9, Cox1, Cox2, and genes relevant for Sertoli cell function, while genes involved in inflammation were increased. RNA-seq analysis identified p53 and TNF signaling pathways as common targets of GEN and GEN mixture in both cell types. These results suggest that APAP and GEN dysregulate immature Sertoli cell function and may aid in elucidating novel EDC and drug targets contributing to the etiology of male infertility.


[Current status of the chemotherapy for lung cancer].
In the treatment of limited-stage small cell lung cancer (LD-SCLC) and unresectable locally-advanced non-small cell lung cancer, several phase III trials and meta-analysis have demonstrated the following: 1) combining chemotherapy and thoracic irradiation is better than chemotherapy alone or radiotherapy alone, 2) the concurrent use of chemoradiotherapy has been expected a better survival than the sequential use, 3) the improvement in outcome seen with a concurrent chemoradiotherapy approach may be because of spatial cooperation, enhanced radiosensitization, and/or enhanced cytotoxicity, and 4) the chemoradiotherapy is tolerable without significant morbidities, such as pneumonitis and esophagitis. However, the chemoradiotherapy is still an investigational strategy because of the absence of a definite schedule and dose on radiotherapy. Newer, more tolerable chemotherapeutic agents, molecular biologic novel approaches and newer irradiated procedures are now being investigated.


D-glucuronyl C5-epimerase acts in dorso-ventral axis formation in zebrafish.
Heparan sulfate (HS) is an ubiquitous component of the extracellular matrix that binds and modulates the activity of growth factors, cytokines and proteases. Animals with defective HS biosynthesis display major developmental abnormalities however the processes that are affected remain to be defined. D-glucuronyl-C5-epimerase (Glce) is a key HS chain modifying enzyme that catalyses the conversion of glucuronic acid into iduronic acid, a biosynthetic step that enhances HS biological activity. In this study the role of Glce during early zebrafish development has been investigated. Two Glce-like proteins (Glce-A and -B) are expressed in zebrafish at all times. They are the products of two distinct genes that, based on chromosomal mapping, are both orthologues of the same single human gene. Transcripts for both proteins were detected in fertilized zebrafish embryos prior to the onset of zygotic transcription indicating their maternal origin. At later developmental stages the epimerases are expressed widely throughout gastrulation and then become restricted to the hindbrain at 24 h post-fertilization. By monitoring the expression of well characterized marker genes during gastrulation, we have found that misexpression of Glce causes a dose-dependent expansion of the ventral structures, whereas protein knockdown using targeted antisense morpholino oligonucleotides promotes axis dorsalization. The ventralizing activity of Bmp2b is enhanced by Glce overexpression whereas Glce knockdown impairs Bmp2b activity. Glce activity is an important determinant of of dorso-ventral axis formation and patterning in zebrafish. In particular Glce acts during gastrulation by affecting Bmp-mediated cell specification. The results obtained further corroborate the concept that HS encodes information that affect morphogenesis during early vertebrate development.


Development of Assays to Measure GNE Gene Potency and Gene Replacement in Skeletal Muscle.
GNE myopathy (GNEM) is a severe muscle disease caused by mutations in the UDP-GlcNAc-2-epimerase/ManNAc-6-kinase (GNE) gene, which encodes a bifunctional enzyme required for sialic acid (Sia) biosynthesis. To develop assays to demonstrate the potency of AAV gene therapy vectors in making Sia and to define the dose required for replacement of endogenous mouse Gne gene expression with human GNE in skeletal muscles. A MyoD-inducible Gne-deficient cell line, Lec3MyoDI, and a GNE-deficient human muscle cell line, were made and tested to define the potency of various AAV vectors to increase binding of Sia-specific lectins, including MAA and SNA. qPCR and qRT-PCR methods were used to quantify AAV biodistribution and GNE gene expression after intravenous delivery of AAV vectors designed with different promoters in wild-type mice. Lec3 cells showed a strong deficit in MAA binding, while GNE-/-MB135 cells did not. Overexpressing GNE in Lec3 and Lec3MyoDI cells by AAV infection stimulated MAA binding in a dose-dependent manner. Use of a constitutive promoter, CMV, showed higher induction of MAA binding than use of muscle-specific promoters (MCK, MHCK7). rAAVrh74.CMV.GNE stimulated human GNE expression in muscles at levels equivalent to endogenous mouse Gne at a dose of 1×1013vg/kg, while AAVs with muscle-specific promoters required higher doses. AAV biodistribution in skeletal muscles trended higher when CMV was used as the promoter, and this correlated with increased sialylation of its viral capsid. Lec3 and Lec3MyoDI cells work well to assay the potency of AAV vectors in making Sia. Systemic delivery of rAAVrh74.CMV.GNE can deliver GNE gene replacement to skeletal muscles at doses that do not overwhelm non-muscle tissues, suggesting that AAV vectors that drive constitutive organ expression could be used to treat GNEM.


Dose-dependent visible effect on mice Langerhans cell membrane markers.
Ultraviolet B and psoralen plus UVA treatment induce antigenic and enzymatic changes in Langerhans cells (LC). The aim of this study was to investigate the visible (VIS) effect on mice LC surface markers. As visible source, a slide projector equipped with a 150-W tungsten lamp, emitting between 400 and 740 nm (maximum at 580 nm) was used. Mice (BALB/c and C3H) were divided into groups, each irradiated with visible single fixed doses (ranging from 10 to 1000 J/cm2). The mice backs were shaved before irradiation. Skin biopsies obtained immediately after irradiation were processed for immunofluorescence and electron microscopy. Immunofluorescent studies showed: 1) a complete depletion of LC membrane markers at a dose of 700 J/cm2; 2) no effect at visible doses ranging between 0 and 75 J/cm2; 3) a dose-dependent effect with doses between 100 and 700 J/cm2. Electron microscopy revealed no cellular damage of LC at the visible doses administered.


Estimated and Measured GFR Associate Differently with Retinal Vasculopathy in the General Population.
Estimated glomerular filtration rate (eGFR) is used extensively in epidemiological research. Validations of eGFR have demonstrated acceptable performance, but the dependence of creatinine and cystatin C on non-GFR factors could confound associations with disease. Few studies have investigated this issue in direct comparison with measured GFR (mGFR). We compared the associations between eGFR and mGFR and retinal vasculopathy, a marker of systemic microvasculopathy. Iohexol clearance and retinal photography were examined in the Renal Iohexol Clearance Survey in Tromsø 6, which consists of a representative sample of middle-aged persons from the general population. A total of 1,553 persons without self-reported kidney disease, cardiovascular disease or diabetes were investigated. Three eGFR equations based on creatinine and/or cystatin C from the Chronic Kidney Disease Epidemiology Collaboration were studied. Differences between eGFR and mGFR were analyzed with seemingly unrelated regression methods. mGFR in the lowest quartile was associated with an increased multivariable-adjusted odds ratio of retinopathy (OR 1.86, 95% CI 1.16-2.97), but not with retinal artery or vein diameters. eGFR based on cystatin C (eGFRcys) was consistently biased relative to mGFR in its associations with retinal vessel diameters across different models. eGFR based on creatinine (eGFRcrea) and eGFR based on both creatinine and cystatin C were also biased in several of these models (p < 0.05). For retinopathy, the differences between the 3 eGFR and mGFR measurements were not statistically significant. Low mGFR is associated with retinopathy in the general population. eGFR based on creatinine and/or cystatin C are not valid substitutes for mGFR in studies of the relationship between the retina and kidney function in healthy persons.


Global elimination of leprosy by 2020: are we on track?
Every year more than 200,000 new leprosy cases are registered globally. This number has been fairly stable over the past 8 years. WHO has set a target to interrupt the transmission of leprosy globally by 2020. The aim of this study is to investigate whether this target, interpreted as global elimination, is feasible given the current control strategy. We focus on the three most important endemic countries, India, Brazil and Indonesia, which together account for more than 80 % of all newly registered leprosy cases. We used the existing individual-based model SIMCOLEP to predict future trends of leprosy incidence given the current control strategy in each country. SIMCOLEP simulates the spread of M. leprae in a population that is structured in households. Current control consists of passive and active case detection, and multidrug therapy (MDT). Predictions of leprosy incidence were made for each country as well as for one high-endemic region within each country: Chhattisgarh (India), Pará State (Brazil) and Madura (Indonesia). Data for model quantification came from: National Leprosy Elimination Program (India), SINAN database (Brazil), and Netherlands Leprosy Relief (Indonesia). Our projections of future leprosy incidence all show a downward trend. In 2020, the country-level leprosy incidence has decreased to 6.2, 6.1 and 3.3 per 100,000 in India, Brazil and Indonesia, respectively, meeting the elimination target of less than 10 per 100,000. However, elimination may not be achieved in time for the high-endemic regions. The leprosy incidence in 2020 is predicted to be 16.2, 21.1 and 19.3 per 100,000 in Chhattisgarh, Pará and Madura, respectively, and the target may only be achieved in another 5 to 10 years. Our predictions show that although country-level elimination is reached by 2020, leprosy is likely to remain a problem in the high-endemic regions (i.e. states, districts and provinces with multimillion populations), which account for most of the cases in a country.


Modeling Vehicle Collision Angle in Traffic Crashes Based on Three-Dimensional Laser Scanning Data.
In road traffic accidents, the analysis of a vehicle's collision angle plays a key role in identifying a traffic accident's form and cause. However, because accurate estimation of vehicle collision angle involves many factors, it is difficult to accurately determine it in cases in which less physical evidence is available and there is a lack of monitoring. This paper establishes the mathematical relation model between collision angle, deformation, and normal vector in the collision region according to the equations of particle deformation and force in Hooke's law of classical mechanics. At the same time, the surface reconstruction method suitable for a normal vector solution is studied. Finally, the estimation model of vehicle collision angle is presented. In order to verify the correctness of the model, verification of multi-angle collision experiments and sensitivity analysis of laser scanning precision for the angle have been carried out using three-dimensional (3D) data obtained by a 3D laser scanner in the collision deformation zone. Under the conditions with which the model has been defined, validation results show that the collision angle is a result of the weighted synthesis of the normal vector of the collision point and the weight value is the deformation of the collision point corresponding to normal vectors. These conclusions prove the applicability of the model. The collision angle model proposed in this paper can be used as the theoretical basis for traffic accident identification and cause analysis. It can also be used as a theoretical reference for the study of the impact deformation of elastic materials.


No Increased Risk of Posttransplant Lymphoproliferative Disorder Following Alemtuzumab Induction in Kidney Transplant.
Posttransplant lymphoproliferative disorder is a known complication of solid-organ transplant. The use of depleting induction agents has demonstrated varying associations with incidence of posttransplant lymphoproliferative disorder. Alemtuzumab, a depleting induction agent for kidney transplant patients, has shown promising results in reducing the risk of acute rejection and graft loss in the first year. Its unique mechanism of depleting both T-cell and B-cell populations may be beneficial in preventing the occurrence of posttransplant lymphoproliferative disorder. We examined the known risk factors for posttransplant lymphoproliferative disorder in the setting of alemtuzumab induction to determine whether incidence increases with this induction agent. We reviewed medical records of all alemtuzumab-induced kidney transplants from March 2006 to November 2015. Of the 675 transplant patients who received alemtuzumab induction, 10 developed posttransplant lymphoproliferative disorder, with a cumulative incidence rate of 1.5%. All diagnosed patients had several known risk factors associated with posttransplant lymphoproliferative disorder: 7 with advanced age over 60 years, 5 being cytomegalovirus-negative recipients, and all 10 donor kidneys being male patients and Epstein-Barr virus positive before transplant. The incidence rate seen in our patient population was within the range of the average in the United States but far lower than the incidence rates associated with other induction agents. Alemtuzumab is associated with a lower cumulative incidence rate of posttransplant lymphoproliferative disorder compared with published reports of other induction treatments.


Two brothers with identical variants of the CLCN5 gene-one developing Dent's disease.
Dent's disease is characterized by manifestations of proximal tubule dysfunction including hypercalciuria, kidney stones, proteinuria, rickets and progressively declining kidney function. The diagnosis is based on the presence of low-molecular-weight proteinuria, hypercalciuria and at least one of the following: nephrocalcinosis, kidney stones, haematuria, hypophosphataemia or renal insufficiency. Dent's disease is a hereditary condition that is caused by variants in the CLCN5 gene or the OCRL1 gene and affects only males. Herein, we report on two brothers who were found to have a previously reported disease-causing variant in the CLCN5 gene. One sibling had nephrocalcinosis, proteinuria and hypercalciuria, whereas the other sibling was asymptomatic and had normal laboratory findings.


Patient reported outcomes six months following surgical treatment of end stage hallux rigidus in a community based podiatric surgery service.
End stage hallux rigidus can be treated surgically by arthrodesis, excisional arthroplasty and implant arthroplasty. Evaluation of these techniques has focused on clinical indicators such as radiographic, complications and subjective examination. Little attention has been given to health related quality of life and the use of patient reported outcome measures is still infrequent. An evaluation was undertaken in a community based podiatric surgery service. utilising the PASCOM-10 online database. Patient reported outcomes were captured on the day of surgery and six months' post operation in the form of the Manchester Oxford Foot Questionnaire (MOXFQ) and the PASCOM PSQ-10 patient satisfaction questionnaire. Between 1st November 2011 and 31st October 2014, there were 157 admissions for treatment of end-stage hallux rigidus; 61 implant arthroplasties, 53 Keller's arthroplasties and 43 arthrodeses. The age range was 45-89, 72% female. MOXFQ scores improved across all domains for all procedures, the score change exceeded the minimal clinically important change threshold of 13 points and large effect sizes were achieved (range 1.10-3.179). Patient satisfaction was good for all procedures with mean PSQ-10 scores of 81.89 for arthrodesis; 82.36 for implants and 81.89 for Keller's. Few serious complications were encountered though the overall incidence of complications was high for the implant group. This evaluation found all three procedures are clinically effective with high levels of patient satisfaction and improved quality of life. Although the implant arthroplasty is associated with a higher incidence of complications, this is not reflected in the outcomes achieved.


Phenylmethimazole and a thiazole derivative of phenylmethimazole inhibit IL-6 expression by triple negative breast cancer cells.
Inhibition of interleukin-6 (IL-6) holds significant promise as a therapeutic approach for triple negative breast cancer (TNBC). We previously reported that phenylmethimazole (C10) reduces IL-6 expression in several cancer cell lines. We have identified a more potent derivative of C10 termed COB-141. In the present work, we tested the hypothesis that C10 and COB-141 inhibit TNBC cell expressed IL-6 and investigated the potential for classical IL-6 pathway induced signaling within TNBC cells. A panel of TNBC cell lines (MDA-MB-231, Hs578T, MDA-MB-468) was used. Enzyme linked immunosorbent assays (ELISA) revealed that C10 and COB-141 inhibit MDA-MB-231 cell IL-6 secretion, with COB-141 being ~6.5 times more potent than C10. Therefore, the remainder of the study focused on COB-141 which inhibited IL-6 secretion, and was found, via quantitative real time polymerase chain reaction (QRT-PCR), to inhibit IL-6 mRNA in the TNBC panel. COB-141 had little, if any, effect on metabolic activity indicating that the IL-6 inhibition is not via a toxic effect. Flow cytometric analysis and QRT-PCR revealed that the TNBC cell lines do not express the IL-6 receptor (IL-6Rα). Trans-AM assays suggested that COB-141 exerts its inhibitory effect, at least in part, by reducing NF-κB (p65/p50) DNA binding. In summary, COB-141 is a potent inhibitor of TNBC cell expressed IL-6 and the inhibition does not appear to be due to non-specific toxicity. The TNBC cell lines do not have an intact classical IL-6 signaling pathway. COB-141's inhibitory effect may be due, at least in part, to reducing NF-κB (p65/p50) DNA binding.


Antiretroviral neuropenetration scores better correlate with cognitive performance of HIV-infected patients after accounting for drug susceptibility.
The aim of the study was to explore how viral resistance and antiretroviral central nervous system (CNS) penetration could impact on cognitive performance of HIV-infected patients. We performed a multicentre cross-sectional study enrolling HIV-infected patients undergoing neuropsychological testing, with a previous genotypic resistance test on plasma samples. CNS penetration-effectiveness (CPE) scores and genotypic susceptibility scores (GSS) were calculated for each regimen. A composite score (CPE-GSS) was then constructed. Factors associated with cognitive impairment were investigated by logistic regression analysis. A total of 215 patients were included. Mean CPE was 7.1 (95% CI 6.9, 7.3) with 206 (95.8%) patients showing a CPE≥6. GSS correction decreased the CPE value in 21.4% (mean 6.5, 95% CI 6.3, 6.7), 26.5% (mean 6.4, 95% CI 6.1, 6.6) and 24.2% (mean 6.4, 95% CI 6.2, 6.6) of subjects using ANRS, HIVDB and REGA rules, respectively. Overall, 66 (30.7%) patients were considered cognitively impaired. No significant association could be demonstrated between CPE and cognitive impairment. However, higher GSS-CPE was associated with a lower risk of cognitive impairment (CPE-GSSANRS odds ratio 0.75, P=0.022; CPE-GSSHIVDB odds ratio 0.77, P=0.038; CPE-GSSREGA odds ratio 0.78, P=0.038). Overall, a cutoff of CPE-GSS≥5 seemed the most discriminatory according to each different interpretation system. GSS-corrected CPE score showed a better correlation with neurocognitive performance than the standard CPE score. These results suggest that antiretroviral drug susceptibility, besides drug CNS penetration, can play a role in the control of HIV-associated neurocognitive disorders.


Transient Small-Bowel Intussusception Unmasking Adult Celiac Disease.
Celiac disease (CD) is a chronic immune-mediated small-intestinal disorder. The tissue transglutaminase (TTG) antibodies test is the initial step in the diagnosis of CD. Intussusception is a process where one segment of the bowel invaginates into the lumen of an adjacent segment. Despite that, the association between adult intussusception and CD has been descried previously, and it is still not widely recognized. We report a case of adult intussusception as the first manifestation of CD. A 28-year-old nonalcoholic and nonsmoker, previously healthy man, presented to the emergency department with a 1-week history of progressive diffuse abdominal pain associated with abdominal distension, nausea, vomiting, diarrhea, and 7 kg weight loss. The physical exam was remarkable for thin body habitus with no lymphadenopathy. Laboratory testing was significant for hypochromic microcytic anemia, AST 214 IU/L, ALT 217 IU/L, alkaline phosphatase 183 IU/L, and INR 2.9. An abdominal radiograph showed distended gas-filled small- and large-bowel loops. An abdominal computed tomography scan with contrast was done and demonstrated a telescoping of the small bowel in at least 3 areas with a target sign appearance with no signs of obstruction that suggested small-bowel intussusception. Following this imaging result, the patient was admitted under general surgery and kept nothing by mouth. The surgical team approached the gastroenterology team for push enteroscopy with biopsy which the patient refused. Further investigation included TTG antibodies; IgA and IgG were significantly elevated, 4,965.5 CU and 431.9 CU, respectively (reference: <19.9 CU). The diagnosis of CD leading to adult intussusception was made. The patient was advised to start a gluten-free diet. During the hospital stay, the patient had complete resolution of his symptoms and was discharged home. In summary, this case highlights the potential link between adult intussusception and CD. Adult intussusception is a rare condition that its underlying etiology should be meticulously investigated to expedite treatment and prevent unnecessary surgical intervention.


Elevated soluble interleukin-2 receptor in childhood hemophagocytic histiocytic syndromes.
The serum of children with untreated hemophagocytic syndromes contains elevated levels (23,600 to 75,200 U/mL) of soluble interleukin-2 receptor (SIL2R) that returns toward normal with clinical improvement. These levels are in excess of levels previously reported for benign conditions. They are as high as levels reported for HTLV-1-associated adult T-cell leukemia (HATL) and hairy cell leukemia (HCL) in adults and some children with poor-prognosis non-T, non-B, acute lymphoblastic leukemia (ALL). Serum SIL-2R is a marker of disease activity that has the potential to identify infants at risk for the inherited form of the disease before the disease is clinically expressed.


Correlation between sperm penetration assay and acrosome reaction in sperm treated with human follicular fluid.
In this study, we determined whether there was a correlation between sperm penetration assay (SPA) and acrosome reaction (AR) in sperm after being treated with human follicular fluid (hFF). Sperm specimens were obtained from 13 men participating in our in vitro fertilization program. After washing and preincubation, aliquots of sperm samples were treated with either hFF or Ham's F-10 medium (control). Approximately 1.0 x 10(6) motile sperm from the control and hFF-treated samples were coincubated individually with zona-free hamster eggs for SPA. Sperm remaining in the suspension after coincubation with eggs were taken to determine the incidence of AR by a triple-stain technique. The data revealed that an increased SPA score in hFF-treated samples was related to a higher incidence of acrosome-reacted sperm.


The acoustics of three-way lateral and nasal palatalisation contrasts in Scottish Gaelic.
This paper presents an acoustic description of laterals and nasals in an endangered minority language, Scottish Gaelic (known as "Gaelic"). Gaelic sonorants are reported to take part in a typologically unusual three-way palatalisation contrast. Here, the acoustic evidence for this contrast is considered, comparing lateral and nasal consonants in both word-initial and word-final position. Previous acoustic work has considered lateral consonants, but nasals are much less well-described. An acoustic analysis of twelve Gaelic-dominant speakers resident in a traditionally Gaelic-speaking community is reported. Sonorant quality is quantified via measurements of F2-F1 and F3-F2 and observation of the whole spectrum. Additionally, we quantify extensive devoicing in word-final laterals that has not been previously reported. Mixed-effects regression modelling suggests robust three-way acoustic differences in lateral consonants in all relevant vowel contexts. Nasal consonants, however, display lesser evidence of the three-way contrast in formant values and across the spectrum. Potential reasons for lesser evidence of contrast in the nasal system are discussed, including the nature of nasal acoustics, evidence from historical changes, and comparison to other Goidelic dialects. In doing so, contributions are made to accounts of the acoustics of the Celtic languages, and to typologies of contrastive palatalisation in the world's languages.


Metabolic epidemiology of prostatic cancer.
A review of the epidemiological evidence indicates that dietary fat very likely has an etiologic role in the development of prostatic carcinoma. While this effect may be mediated by way of altered hormonal action on the prostate, there is little supporting evidence from assays of plasma or urinary hormones in case-control studies or the investigation of high-risk and low-risk groups. The application of metabolic epidemiology to this problem is most likely to succeed by direct studies of the prostate gland, and the performance of relevant assays on prostatic fluid. Estradiol and estrone levels were found to be higher in prostatic fluid than in serum, whereas for prolactin the reverse was true. Testosterone concentrations were very low in prostatic fluid, perhaps because of the high degree of plasma protein binding. Preliminary data indicated that prostatic fluid estradiol and prolactin levels are elevated in some prostate cancer patients; estrone levels appear to be normal.


[National project for the clinical management of healthcare processes. The surgical treatment of cholelithiasis. Development of a clinical pathway].
Because surgical treatment of gallstones is highly prevalent, this topic is particularly suitable for a national study aimed at determining the most important indicators and developing a clinical pathway. To analyze the results obtained during the hospital phase of the process. To define the key indicators of the process. To design a clinical pathway for laparoscopic cholecystectomy. A multicenter, prospective, cross-sectional, descriptive study was performed of patients who consecutively underwent surgery for gallstones in 2002. The sample size calculated with data provided by the National Institute of Statistics was 304 patients, which was increased by 45% to compensate for possible losses. Inclusion criteria consisted of elective cholecystectomy for gallstones, without preoperative findings suggestive of common duct stones. A database was designed (Microsoft Access 2000) with 76 variables analyzed in each patient. Completed questionnaires were obtained from 37 hospitals with 426 patients. The mean age was 55.69 years, with a predominance of women (68.3%). The most frequent symptom was biliary colic (23%). A total of 20.3% of the patient had prior episodes of cholecystitis and 18% had a history of mild pancreatitis. Diagnosis was given by ultrasonography in 93.2% of the patients. Informed consent was provided by 93.2%. The intervention was performed on an inpatient basis in 96.1% and in the ambulatory setting in the remainder. Antibiotic and antithrombotic prophylaxis was administered in 78.9% and 75.1% of the patients respectively. The laparoscopic approach was used in 84.6%, with a conversion rate of 4.9%. Intraoperative cholangiography was performed in 17.8% of the patients and common duct stones were found in 7 patients. The most frequent complication was surgical wound infection (1.1%). Possible accidental lesion of the biliary tract occurred in 0.7% of the patients and was described as biliary fistula. There were four reinterventions: biliary fistula (1), hemoperitoneum (2) and cause unknown (1). The mean surgical time was 73.17 minutes, with a median of 60 minutes. Postoperative length of stay was 4.75 days in open surgery and 2.67 days in laparoscopic surgery. Ninety-nine percent of the patients were satisfied or highly satisfied with the healthcare received. Analysis of the process and review of the literature identified a series of areas requiring improvement, which were gathered in the clinical pathway developed. These areas consisted of increasing the number of patients with correctly indicated antibiotic and antithrombotic prophylaxis, increasing the percentage of patients providing informed consent and undergoing adequate preoperative tests, limiting intraoperative cholangiography to selected patients, and reducing the number of patients with an overall stay of 3 days.


LORE1, an active low-copy-number TY3-gypsy retrotransposon family in the model legume Lotus japonicus.
We have identified a low-copy-number retrotransposon family present in nine to 10 copies in the Lotus japonicus model legume genome, and characterized its activity. LORE1 (Lotus retrotransposon 1) belongs to the Ty3-gypsy group of elements, and is a long terminal repeat (LTR) retrotransposon. Genetic mapping located LORE1 elements in gene-rich regions of Lotus chromosomes, and analysis of native as well as new insertion sites revealed integration outside the highly repetitive sequences of centromeres and telomeres. Sequencing of individual LORE1 family members identified several intact elements, and analysis of new insertions showed that at least one member is active and reinserts into functional genes, creating gene-disruption mutations. Southern blot analysis and SSAP on a selection of symbiotic mutants revealed up to 12 new insertion sites in individual mutant lines and a Mendelian segregation of new inserts. Expression analysis showed that LORE1 elements are transcribed in all organs analysed and, in contrast to other active retrotransposons, LORE1 appears not to be transcriptionally upregulated during in vitro tissue culture. Activity of LORE1 in callus and whole plants suggests that a simple insertion mutagenesis based on endogenous LORE1 elements can be established for Lotus.


Exploring the Functions of 9-Lipoxygenase (DkLOX3) in Ultrastructural Changes and Hormonal Stress Response during Persimmon Fruit Storage.
Lipoxygenase (LOX) initiates the hydroperoxidation of polyunsaturated fatty acids and is involved in multiple physiological processes. In this study, investigation of various microscopic techniques showed that the fruit peel cellular microstructure of the two persimmon cultivars differed after 12 days of storage, resulting in fruit weight loss and an increased number and depth of microcracks. Analysis of subcellular localization revealed that greater amounts of DkLOX3-immunolabelled gold particles accumulated in "Fupingjianshi" than in "Ganmaokui" during storage. In addition, the expression of DkLOX3 was positively up-regulated by abscisic acid (ABA), concomitant with the promotion of ethylene synthesis and loss of firmness, and was suppressed by salicylic acid (SA), concomitant with the maintenance of fruit firmness, inhibition of ethylene production and weight loss. In particular, the expression of DkLOX3 differed from the ethylene trajectory after methyl jasmonate (MeJA) treatment. Furthermore, we isolated a 1105 bp 5' flanking region of DkLOX3 and the activity of promoter deletion derivatives was induced through various hormonal treatments. Promoter sequence cis-regulatory elements were analysed, and two conserved hormone-responsive elements were found to be essential for responsiveness to hormonal stress. Overall, these results will provide us with new clues for exploring the functions of DkLOX3 in fruit ripening and hormonal stress response.


Investigation of the catalytic and structural roles of conserved histidines of human coproporphyrinogen oxidase using site-directed mutagenesis.
The catalytic contribution of four conserved histidines of human coproporphyrinogen oxidase (CPO) has been investigated using site-directed mutagenesis to change histidine (H) into alanine (A). The wild-type and mutant enzyme forms were analyzed for their ability to utilize coproporphyrinogen-III, mesoporphyrinogen-VI, and harderoporphyrinogen as substrates. Wild-type CPO had specific activities of 4.9+/-0.9 nmole product/min/mg for coproporphyrinogen-III, 1.7+/-0.7 nmole product/min/mg for mesoporphyrinogen-VI, and 5.1+/-1.8 nmole product/min/mg for harderoporphyrinogen. The four mutant enzymes were catalytically competent with all three substrates, but to varying degrees. The most affected mutant was the H158A enzyme which exhibited approximately 50-fold lower activity than wild-type recombinant CPO. Thus, His158 of human CPO may have a role in the active site, but none of the conserved histidine residues of human coproporphyrinogen oxidase is essential for catalytic activity although changes in histidines have been implicated in the disease state hereditary coproporphyria.


Fabrication of silicon-based template-assisted nanoelectrode arrays and ohmic contact properties investigation.
A convenient fabrication technology for large-area, highly-ordered nanoelectrode arrays on silicon substrate has been described here, using porous anodic alumina (PAA) as a template. The ultrathin PAA membranes were anodic oxidized utilizing a two-step anodization method, from Al film evaporated on substrate. The purposes for the use of two-step anodization were, first, improving the regularity of the porous structures, and second reducing the thickness of the membranes to 100-200 nm we desired. Then the nanoelectrode arrays were obtained by electroless depositing Ni-W alloy into the through pores of PAA membranes, making the alloy isolated by the insulating pore walls and contacting with the silicon substrates at the bottoms of pores. The Ni-W alloy was also electroless deposited at the back surface of silicon to form back electrode. Then ohmic contact properties between silicon and Ni-W alloy were investigated after rapid thermal annealing. Scanning electron microscopy (SEM) observations showed the structure characteristics, and the influence factors of fabrication effect were discussed. The current-voltage (I-V) curves revealed the contact properties. After annealing in N2 at 700 degrees C, good linear property was shown with contact resistance of 33 omega, which confirmed ohmic contacts between silicon and electrodes. These results presented significant application potential of this technology in nanosize current-injection devices in optoelectronics, microelectronics and bio-medical fields.


Cirrhosis and hyperdynamic circulatory state due to a dysplasic giantism of the hepatic artery.
The authors here refer about the clinical case of a patient suffering from cirrhosis and hyperdynamic circulatory state due to a giantism of the hepatic artery. The surgical ligature of the main hepatic artery determined the complete regression of the abdominal pain and melena: the high output cardiac failure also disappeared with surgical correction.


Fiber-optic interferometer fringe projection using integrating bucket modulation.
A new fiber-optic interferometer fringe projection with the integrating bucket method is presented. This method is based on the sinusoidal phase-modulating technique and makes use of Mach-Zehnder interferometer structure and Young's double pinhole interference principle to achieve interference fringe projection. Here, we consider the modulated signal with the modulation intensity of laser (companion amplitude modulation) m in the calculation directly, adjust the optimal value of z to accommodate different m, and calculate the initial phase with phase generated carrier technology at the same time. Preliminary results from the optimum phase modulation z and initial phase φ(0) are discussed.


Erythema elevatum diutinum arising in the setting of dermatitis herpetiformis.
Dermatitis herpetiformis is an autoimmune blistering disease characterized by granular deposits of immunoglobulin A (IgA) in dermal papillae. Erythema elevatum diutinum is a chronic form of vasculitis associated with IgA paraproteinemia. We report a patient with dermatitis herpetiformis who developed characteristic erythema elevatum diutinum lesions on the elbows and knees despite sulfone therapy. We speculate that the different patterns of IgA deposition in the skin account for the clinical manifestation of these 2 uncommon disorders.


Clinical NECR in 18F-FDG PET scans: optimization of injected activity and variable acquisition time. Relationship with SNR.
The injected activity and the acquisition time per bed position for 18F-FDG PET scans are usually optimized by using metrics obtained from phantom experiments. However, optimal activity and time duration can significantly vary from a phantom set-up and from patient to patient. An approach using a patient-specific noise equivalent count rate (NECR) modelling has been previously proposed for optimizing clinical scanning protocols. We propose using the clinical NECR on a large population as a function of the body mass index (BMI) for deriving the optimal injected activity and acquisition duration per bed position. The relationship between the NEC and the signal-to-noise ratio (SNR) was assessed both in a phantom and in a clinical setting. 491 consecutive patients were retrospectively evaluated and divided into 4 BMI subgroups. Two criteria were used to optimize the injected activity and the time per bed position was adjusted using the NECR value while keeping the total acquisition time constant. Finally, the relationship between NEC and SNR was investigated using an anthropomorphic phantom and a population of 507 other patients. While the first dose regimen suggested a unique injected activity (665 MBq) regardless of the BMI, the second dose regimen proposed a variable activity and a total acquisition time according to the BMI. The NEC improvement was around 35% as compared with the local current injection rule. Variable time per bed position was derived according to BMI and anatomical region. NEC and number of true events were found to be highly correlated with SNR for the phantom set-up and partially confirmed in the patient study for the BMI subgroup under 28 kg m(-2) suggesting that for the scanner, the nonlinear reconstruction algorithm used in this study and BMI < 28 kg m(-2), NEC, or the number of true events linearly correlated with SNR(2).


[The value of heparin-dihydergot in the prevention of thromboembolic complications].
57 papers dealing with the prevention of postoperative thromboembolic complications have been analyzed. They comprise 28 prospective, randomized, comparative studies using objective diagnostic techniques. 2 X 5000 IU daily of heparin-DHE lowers the incidence of deep vein thrombosis in general surgery, thoracic surgery and gynecology significantly better than 2 X 5000 IU heparin alone. In hip surgery 3 X 5000 IU heparin-DHE is more effective than the same amount of heparin alone. In the entire field of orthopedic surgery, heparin-DHE, in a dosage of 2 X 5000 IU, lowers the incidence of fatal pulmonary emboli just as well as dextran 70. With regard to prevention of deep vein thrombosis in general surgery, there is no statistically significant difference between prevention with 2 X 2500 IU heparin-DHE and 2 X 5000 IU heparin. 2 X 2500 IU heparin-DHE significantly lowers the incidence of bleeding complications in general surgery, as evaluated in double-blind studies and compared to 2 X 5000 IU heparin alone.


Effects of oral therapy with calcium and vitamin D in primary osteoporosis.
Eighteen patients (17 women and 1 man) with primary osteoporosis were divided into two groups of 9 patients each. Group A received 2.0 to 2.5 g of calcium and 400 units of vitamin D per day orally and was studied before and after short-term (3 to 4 months) treatment; group B received 1.5 to 2.0 g of calcium per day and 50,000 units of vitamin D twice weekly and was studied before, after short-term, and after long-term (1 year) treatment. In group A there was a decrease (P is less than 0.01) in bone-resorbing surfaces (microradiography of bone biopsy samples) after short-term treatment. In group B there was a decrease (P is less than 0.01) in bone-forming and bone-resorbing surfaces after both short-tern and long-term treatment. Fasting-state (morning) serum immunoreactive parathyroid hormone (iPTH) concentrations decreased after short-term treatment (combined data of groups A and B) and after long-term treatment (group B). We conclude that the principal effect of the oral calcium and vitamin D therapy in primary osteoporosis is to decrease bone turnover. The most probable mechanism for this effect on bone is a partial inhibition of PTH secretion.