Replitase: complete machinery for DNA synthesis.
Replication of nuclear DNA in eukaryotes presents a tremendous challenge, not only due to the size and complexity of the genome, but also because of the time constraint imposed by a limited duration of S phase during which the entire genome has to be duplicated accurately and only once per cell division cycle. A challenge of this magnitude can only be met by the close coupling of DNA precursor synthesis to replication. Prokaryotic systems provide evidence for multienzyme and multiprotein complexes involved in DNA precursor synthesis and DNA replication. In addition, fractionation of nuclear proteins from proliferating mammalian cells shows co-sedimentation of enzymes involved in DNA replication with those required for synthesis of deoxynucleoside triphosphates (dNTPs). Such complexes can be isolated only from cells that are in S phase, but not from cells in G(0)/G(1) phases of cell cycle. The kinetics of deoxynucleotide metabolism supporting DNA replication in intact and permeabilized cells reveals close coupling and allosteric interaction between the enzymes of dNTP synthesis and DNA replication. These interactions contribute to channeling and compartmentation of deoxynucleotides in the microvicinity of DNA replication. A multienzyme and multiprotein megacomplex with these unique properties is called "replitase." In this article, we summarize some of the relevant evidence to date that supports the concept of replitase in mammalian cells, which originated from the observations in Dr. Pardee's laboratory. In addition, we show that androgen receptor (AR), which plays a critical role in proliferation and viability of prostate cancer cells, is associated with replitase, and that identification of constituents of replitase in androgen-dependent versus androgen-independent prostate cancer cells may provide insights into androgen-regulated events that control proliferation of prostate cancer cells and potentially offer an effective strategy for the treatment of prostate cancer.


A device architecture for three-dimensional, patterned paper immunoassays.
Diagnostic assays can provide valuable information about the health status of a patient, which include detection of biomarkers that indicate the presence of an infection, the progression or regression of a disease, and the efficacy of a course of treatment. Critical healthcare decisions must often be made at the point-of-care, far from the infrastructure and diagnostic capabilities of centralized laboratories. There exists an obvious need for diagnostic tools that are designed to address the unique challenges encountered by healthcare workers in limited-resource settings. Paper, a readily-available and inexpensive commodity, is an attractive medium with which to develop diagnostic assays for use in limited-resource settings. In this article, we describe a device architecture to perform immunoassays in patterned paper. These paper-based devices use a combination of lateral and vertical flow to control the wicking of fluid in three-dimensions. We provide guidelines to aid in the design of these devices and we illustrate how patterning can be used to tune the duration and performance of the assay. We demonstrate the use of these paper-based devices by developing a sandwich immunoassay for human chorionic gonadotropin (hCG) in urine, a biomarker of pregnancy. We then directly compare the qualitative and quantitative results of these paper-based immunoassays to commercially available lateral flow tests (i.e., the home pregnancy test). Our results suggest paper-based devices may find broad utility in the development of immunoassays for use at the point-of-care.


Efficient targeted transgenesis of large donor DNA into multiple mouse genetic backgrounds using bacteriophage Bxb1 integrase.
The development of mouse models of human disease and synthetic biology research by targeted transgenesis of large DNA constructs represent a significant genetic engineering hurdle. We developed an efficient, precise, single-copy integration of large transgenes directly into zygotes using multiple mouse genetic backgrounds. We used in vivo Bxb1 mediated recombinase-mediated cassette exchange (RMCE) with a transgene "landing pad" composed of dual heterologous Bxb1 attachment (att) sites in cis, within the Gt(ROSA)26Sor safe harbor locus. RMCE of donor was achieved by microinjection of vector DNA carrying cognate attachment sites flanking the donor transgene with Bxb1-integrase mRNA. This approach achieves perfect vector-free integration of donor constructs at efficiencies > 40% with up to ~ 43 kb transgenes. Coupled with a nanopore-based Cas9-targeted sequencing (nCATS), complete verification of precise insertion sequence was achieved. As a proof-of-concept we describe the development of C57BL/6J and NSG Krt18-ACE2 models for SARS-CoV2 research with verified heterozygous N1 animals within ~ 4 months. Additionally, we created a series of mice with diverse backgrounds carrying a single att site including FVB/NJ, PWK/PhJ, NOD/ShiLtJ, CAST/EiJ and DBA/2J allowing for rapid transgene insertion. Combined, this system enables predictable, rapid development with simplified characterization of precisely targeted transgenic animals across multiple genetic backgrounds.


Cognitive play of mentally retarded preschoolers: observations in the home and school.
A within-subjects design was used to examine the cognitive play of 12 mainstreamed mentally retarded preschool boys during group free-play at school and in an independent play situation at home. Children played with available toys at school and with three designated toy sets at home. Cognitive and communicative abilities were established through administration of the Battelle Developmental Inventory. Children not only played more in the home condition, but this play was more sophisticated than that in the school condition. Increased differences between home and school performance were positively associated with expressive communicative developmental age. Peak play did not differ between the two settings. Children not only sequenced play activities more at home, but these sequences were longer and more complex than those at school.


Refractory Abdominal Pain in a Patient with Chronic Lymphocytic Leukemia: Be Wary of Acquired Angioedema due to C1 Esterase Inhibitor Deficiency.
Acquired angioedema due to C1 inhibitor deficiency (C1INH-AAE) is a rare and potentially fatal syndrome of bradykinin-mediated angioedema characterized by episodes of angioedema without urticaria. It typically manifests with nonpitting edema of the skin and edema in the gastrointestinal (GI) tract mucosa or upper airway. Edema of the upper airway and tongue may lead to life-threatening asphyxiation. C1INH-AAE is typically under-diagnosed because of its rarity and its propensity to mimic more common abdominal conditions and allergic reactions. In this article, we present the case of a 62-year-old male with a history of recently diagnosed chronic lymphocytic leukemia (CLL) who presented to our hospital with recurrent abdominal pain, initially suspected to have Clostridium difficile colitis and diverticulitis. He received a final diagnosis of acquired angioedema due to C1 esterase inhibitor deficiency due to concomitant symptoms of lip swelling, cutaneous nonpitting edema of his lower extremities, and complement level deficiencies. He received acute treatment with C1 esterase replacement and icatibant and was maintained on C1 esterase infusions. He also underwent chemotherapy for his underlying CLL and did not experience further recurrence of his angioedema.


Potential clinical impact of reporting breast arterial calcifications on screening mammograms in women without known coronary artery disease.
Cardiovascular disease remains a leading cause of death in women. 10-year likelihood for a cardiovascular event is determined by the American College of Cardiology Atherosclerotic Cardiovascular disease risk score calculator (ASVCD); however, this does not encompass risk factors unique to women. Breast arterial calcifications (BAC) detected on screening mammography may serve as a proxy for coronary atherosclerosis (CAC) in women. Our purpose was to investigate the correlation between BAC and CAC on imaging in women without a diagnosis of atherosclerosis to determine the potential clinical impact. Retrospective review was performed on a cohort of females evaluated by internists at our institution in 2019. Study patients had a screening mammogram within 1 year of a noncardiac chest CT. Clinical data were collected to determine ASCVD risk score. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of BAC in detecting CAC were determined. 222 women met inclusion criteria, ranging from 41 to 77 years of age, among which 25% (56/222) had BAC. 84% (47/56) of women with BAC had CAC on CT, yielding a sensitivity, specificity, PPV, and NPV of 51%, 93%, 84%, and 72%, respectively. Of the 47 patients who had both BAC and CAC, 66% had an unknown or low-to-borderline ASCVD score. Women with BACs have a high specificity for CAC. The reporting of BACs should prompt clinicians to risk stratify women for atherosclerotic disease. These women may otherwise be undetected by conventional risk calculators.


Working in a medicalised world: the experiences of palliative care nurse specialists and midwives.
This paper reports a study that explored birth and death care experiences from the perspectives of midwives and palliative care clinical nurse specialists (CNSs). A grounded theory approach illuminated the social processes associated with caring during birth and death. Data was collected during 2011 through in-depth semi-structured interviews with eight participants: four midwives and four CNSs from UK NHS Trusts. Four categories were identified through thematic analysis: memories, one act, advocate, and medical event. These integrated to create a core category: working to counter the pathologisation of birth and death. The participants illustrate the impact of medicalisation on the experience of birth and death and struggle with the negative effects of this. Health professionals should work toward practice that emphasises the importance of holistic care.


Investigating alternatives to traditional insecticides: effectiveness of entomopathogenic fungi and Bacillus thuringiensis against citrus thrips and avocado thrips (Thysanoptera: Thripidae).
Citrus thrips, Scirtothrips citri (Moulton) (Thysanoptera: Thripidae), is a plant-feeding pest most widely recognized for causing damage to citrus (Citrus spp. L. [Rutaceae]) and mango (Mangifera indica L. [Anacardiaceae]) fruits. This insect has recently broadened its known host range to become a significant pest of California grown blueberries. Avocado thrips, Scirtothrips. perseae Nakahara (Thysanoptera: Thripidae), is a recent, invasive pest of California avocados, Persea americana Mill. (Laurales: Lauraceae). Effective alternatives to traditional pesticides are desirable for both pests to reduce impacts on natural enemies and broaden control options in an effort to minimize pesticide resistance via rotation of control materials. We evaluated Bacillus thuringiensis (Bt) subsp. israelensis proteins (Cyt 1A and Cry 11A, activated and inactivated) and multiple strains (GHA, 1741ss, SFBb1, S44ss, NI1ss, and 3769ss) of Beauveria bassiana (Balsamo) Vuillemin against both species. Avocado thrips and citrus thrips were not susceptible to either Bt protein tested, regardless of activation status. All strains of B. bassiana were able to infect both avocado thrips and citrus thrips. However, the commercially available GHA strain was the most effective strain against both species and had a faster rate of infection then the other strains tested. Citrus thrips were more susceptible than avocado thrips to all B. bassiana strains (LC50 and LC95 of 8.6 x 10(4) and 4.8 x 10(6) conidia per ml for citrus thrips, respectively). Investigation of citrus thrips field control using the GHA strain of B. bassiana is therefore justified.


First Workshop on Metals in Medicine (2019): Translational Research in Medicinal Bioinorganic Chemistry.
On the 14-15th November 2019, the first workshop on Metals in Medicine took place in Paris at Chimie ParisTech, PSL University. Organised with the aim of having invited speakers share their experience in bringing metal-based drugs to (pre-)clinical trials, this event gathered 135 attendees from six continents to Paris. A special collection on this event has now been published in ChemBioChem, combining more than 20 articles on different topics related to metals in medicine.


Proposed graphical system of evaluating disc-condyle displacements of the temporomandibular joint in MRI.
The aim of this preliminary study was to standardize the reading of magnetic resonance imaging (MRI) of the temporomandibular joint (TMJ). The MRI was conducted on a control group of eight subjects. In this study, the analysis of joint relationships was limited to the oblique sagittal plane, during the movement of controlled opening. The sections were analyzed by a computer-assisted quantitative method of graphical evaluation. The total surface area (TS) of the disc section was divided into an anterior surface area (AS) and a posterior area (PA), in accordance with a line joining the center of the condyle (C) to the center of the articular tubercle of the temporal bone (T). The disc-condyle relationships in the chosen plane of section were evaluated by the AS/TS ratio. If TS remains relatively constant, the AS/TS values on average decrease from 0.5 to 0.3 between the closed mouth position and the 25 mm open position. The results show good intra-observer reproducibility (p=0.26), evaluated by Wilcoxon's test. In conclusion, this protocol enables the displacement of the disc-condyle assembly during mouth opening to be described. Observed on a larger sample, the AS/TS would be able to show a range of variability in functional disc positions.


Management of iatrogenic pulmonary artery injury during pulmonary artery banding.
Pulmonary Artery banding (PAB) is limited to selected patients who cannot undergo primary repair due to complex anatomy, associated co-morbidities, as a part of staged univentricular palliation, and for preparing the left ventricle prior to an arterial switch operation. We report a catastrophic iatrogenic complication in which the pulmonary artery was injured during the PAB. We discuss its multi-pronged management.


Effect of remifentanil on intraoperative fluid balance: a retrospective statistical examination of factors contributing to fluid balance.
Postoperative fluid retention is a factor that causes delay in recovery and unexpected adverse events. It is important to prevent intraoperative fluid retention, which is putatively caused by intraoperative release of stress hormones, such as ADH (anti-diuretic hormone) or others. We hypothesized that intraoperative analgesia may prevent pathological fluid retention. We retrospectively explored the relationship between analgesics and in-out balance in surgical patients from anesthesia records. Anesthetic records of 80 patients who had undergone orthognathic surgery were checked in this study. Patients were anesthetized with either TIVA (propofol and remifentanil) or inhalational anesthesia (sevoflurane and remifentanil). During surgery, acetated Ringer's solution was infused for maintenance at a rate of 3-5 ml/kg/h at the discretion of the anesthetist. The perioperative parameters, including the amount of crystalloid and colloid infused, and the amount of urine and bleeding were checked. Furthermore, we checked the amount and administration rate of remifentanil during the surgical procedure. The correlation coefficient between the remifentanil dose and the in-out balance or the urinary output was analyzed using the Pearson correlation coefficient. The contributing factor to fluid retention, including urinary output, was statistically examined by means of multivariate logistic regression analysis. A significant positive correlation was found between remifentanil dose and urinary output. Urinary output less than 0.04 ml/kg/min was suggested to cause positive fluid balance. Although in-out balance approaches zero balance with increase in remifentanil administration rate, no contributing factor for near-zero fluid balance was statistically picked up. The remifentanil administration rate was statistically picked up as the significant factor for higher urinary output (> 0.04 ml/kg/min) (OR, 2,644; 95% CI, 3.2-2.2 × 106) among perioperative parameters. In conclusion, remifentanil contributes in maintaining the urinary output during general anesthesia. Although further prospective study is needed to confirm this hypothesis, it was suggested that fluid retention could be avoided through suppressing intraoperative stress response by means of appropriate maintenance of remifentanil infusion rate.


Expression of vimentin in gastric cancer: a possible indicator for prognosis.
Expression of vimentin in gastric cancer was immunohistologically examined in 85 surgically resected specimens and evaluated in terms of various clinicopathological features. Vimentin expression was more pronounced in gastric cancers of more advanced type and in those exhibiting a higher degree of infiltrative growth, lymph node involvement and vascular invasion. These results indicate that vimentin expression by gastric cancer might be related to the invasion and metastatic process of cancer cells and could be useful as a prognostic indicator for patients with gastric cancer.


Detection of amfepramone and its metabolite cathinone in human hair: Application to a uthentic cases of amfepramone use.
In recent years, overseas anti-obesity drugs including amfepramone have flowed into China through the internet or personal import by travelers. Amfepramone is controlled in China and is not available as a pharmaceutical product. It is obtainable either through the internet or imported by individuals across the border. The abuse of amfepramone is causing serious health problems. A method for the detection and quantification of amfepramone and its metabolite cathinone in human hair was developed and fully validated using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Approximately 10 mg of hair was weighed and pulverized with extraction solvent (a mixture of methanol: acetonitrile: 2 mM ammonium formate [pH 5.3] [25:29:46, v/v/v]). The limit of detection (LOD) and the limit of quantitation (LOQ) were 5 and 10 pg/mg, respectively. The method was linear over a concentration range from 10 to 10,000 pg/mg. The accuracy varied from -9.3% to 2.3%, with acceptable intra- and inter-day precision. The validated method was successfully applied to 17 authentic cases. The amfepramone concentrations ranged from 11.7 to 209 pg/mg, with a median of 30.2 pg/mg, and the hair cathinone concentrations ranged from 11.9 to 507 pg/mg, with a median of 54.0 pg/mg. This is the first report of amfepramone concentrations in human hair from amfepramone users. Cathinone can be incorporated into hair after amfepramone use.


Is preinfarction angina associated with better outcome after myocardial infarction?
In a clinical setting of acute myocardial infarction (MI), short-lasting and transient anginal pain, preceding the development of acute MI, is regarded as a symptom representing ischaemic preconditioning. Some experimental and clinical data suggested that preinfarction angina may favourably influence the course of acute MI. We sought to examine the hypothesis that preinfarction angina occurring within 24 hours prior to the onset of acute MI favourably influences the outcome. The study group consisted of 331 patients who were admitted to our hospital due to acute MI with ST segment elevation with a symptom duration <12 hours and received thrombolysis. Preinfarction angina within 24 hours prior to MI was present in 80 patients whereas the remaining 251 patients had no chest pain preceding acute MI. The course of the in-hospital phase of MI (mean 15 days) was analysed. In patients with preinfarction angina the in-hospital complication rate was significantly lower than in patients without angina preceding acute MI (p<0.001). Patients without preinfarction angina more frequently developed heart failure (p<0.001) or died (p<0.01) in hospital. Patients with preinfarction angina had significantly less extensive MI and had reperfusion symptoms more frequently. Multivariate analysis showed that there were three factors which independently favourably influenced survival: preinfarction angina (p=0.01), age < or =65 years (p=0.04) and duration of chest pain during acute MI < or =3h (p=0.03). Of the analysed group, 73 patients died in hospital. The independent variables predicting death included prior MI (p=0.04), history of diabetes (p=0.02), acute left bundle branch block (p=0.01) and age >65 years (p=0.03). Non-fatal re-infarction complicated the in-hospital course of MI in 27 patients. The independent variables which predicted this complication included age >65 years (p=0.03) and hypercholesterolemia (p=0.04). Patients with preinfarction angina, occurring within 24 hours of acute MI, have better in-hospital outcome and less extensive myocardial injury than patients without antecedent angina. These results may be attributed to the protective effects of ischaemic preconditioning.


Deep-Learning-Assisted Underwater 3D Tactile Tensegrity.
The growth of underwater robotic applications in ocean exploration and research has created an urgent need for effective tactile sensing. Here, we propose an underwater 3-dimensional tactile tensegrity (U3DTT) based on soft self-powered triboelectric nanogenerators and deep-learning-assisted data analytics. This device can measure and distinguish the magnitude, location, and orientation of perturbations in real time from both flow field and interaction with obstacles and provide collision protection for underwater vehicles operation. It is enabled by the structure that mimics terrestrial animals' musculoskeletal systems composed of both stiff bones and stretchable muscles. Moreover, when successfully integrated with underwater vehicles, the U3DTT shows advantages of multiple degrees of freedom in its shape modes, an ultrahigh sensitivity, and fast response times with a low cost and conformability. The real-time 3-dimensional pose of the U3DTT has been predicted with an average root-mean-square error of 0.76 in a water pool, indicating that this developed U3DTT is a promising technology in vehicles with tactile feedback.


Evaluation of cardiovascular risk factors in HIV-1 infected patients using carotid intima-media thickness measurement.
Highly active antiretroviral therapies (HAART) in HIV-infected patients are often associated with lipodystrophy syndrome and metabolic disorders. Atherogenic lipid profile could expose these patients to atheromatous cardiovascular disease. We describe carotid artery intima-media thickness (IMT), a surrogate marker of atherosclerosis, according to HIV status, antiretroviral treatment, lipodystrophy and conventional cardiovascular risk factors. In a multicenter prospective cohort study we have surveyed HIV-infected subjects with a carotid IMT measurement by B-mode ultrasonography. We collected information on lipodystrophy clinical manifestations, age, gender, body mass index (BMI), smoking habits, alcohol intake, systolic blood pressure, HIV transmission category, AIDS stage, type and duration of HAART, CD4+ cell count, plasma HIV-1 RNA, glucose, insulin, total cholesterol and homocysteine. Four hundred and twenty-three HIV-infected patients were studied. The median carotid IMT measurement was 0.54 mm (range: 0.50-0.60). Lipodystrophy syndrome was diagnosed in 161 HIV-infected patients (38.1%). In univariate linear regression, IMT was significantly higher (P<0.05) with older age, male gender, higher body mass index, higher waist-to-hip ratio, increased systolic blood pressure, total cholesterol, glucose disorders and homocysteine, regular smoking and alcohol consumption, lipodystrophy and HAART. In a multivariate analysis, the effect of lipodystrophy and HAART disappeared after adjustment for other cardiovascular risk factors. It was concluded that only conventional cardiovascular risk factors are independently associated with increased IMT in HIV-infected patients.


Dynamic Duo: Vibrational Sum Frequency Scattering Investigation of pH-Switchable Carboxylic Acid/Carboxylate Surfactants on Nanodroplet Surfaces.
Surfactants containing pH-switchable, carboxylic acid moieties are utilized in a variety of environmental, industrial, and biological applications that require controlled stability of hydrophobic droplets in water. For nanoemulsions, kinetically stable oil droplets in water, surface adsorption of the anionic form of the carboxylic acid surfactant stabilizes the droplet, whereas a dominant surface presence of the neutral form leads to destabilization. Through the use of dynamic light scattering, ζ-potential, and vibrational sum frequency scattering spectroscopy (VSFSS), we investigate this mechanism and the relative surface population of the neutral and charged species as pH is adjusted. We find that the relative population of the two surfactant species at the droplet surface is distinctly different than their bulk equilibrium concentrations. The ζ-potential measurements show that the surface concentration of the charged surfactant stays nearly constant throughout the stabilizing pH range. In contrast, VSFSS shows that the neutral carboxylic acid form increasingly adsorbs to the surface with increased acidity. The spectral features of the headgroup vibrational modes confirm this behavior and go further to reveal additional molecular details of their adsorption. A significant hydrogen-bonding interaction occurs between the headgroups that, along with hydrophobic chain-chain interactions, assists in drawing more carboxylic acid surfactant to the interface. The charged surfactant provides the stabilizing force for these droplets, while the neutral surfactant introduces complexity to the interfacial structure as the pH is lowered. The results are significantly different than what has been found for the planar oil/water studies where stabilization of the interface is not a factor.


A Neutral Model for the Evolution of Diet Breadth.
Variation in diet breadth among organisms is a pervasive feature of the natural world that has resisted general explanation. In particular, trade-offs in the ability to use one resource at the expense of another have been expected but rarely detected. We explore a spatial model for the evolution of specialization, motivated by studies of plant-feeding insects. The model is neutral with respect to the causes and consequences of diet breadth: the number of hosts utilized is not constrained by trade-offs, and specialization or generalization does not confer a direct advantage with respect to the persistence of populations or the probability of diversification. We find that diet breadth evolves in ways that resemble reports from natural communities. Simulated communities are dominated by specialized species, with a predictable but less species-rich component of generalized taxa. These results raise the possibility that specialization might be a consequence of stochastic diversification dynamics acting on spatially segregated consumer-resource associations rather than a trait either favored or constrained directly by natural selection. Finally, our model generates hypotheses for global patterns of herbivore diet breadth, including a positive effect of host richness and a negative effect of evenness in host plant abundance on the number of specialized taxa.


Current practice in dietary management of diabetic children. A transatlantic comparison.
Dietary therapy practice in 18 British clinics for diabetic children is reviewed, and contrasted with Canadian and American practice. Values for dietary composition expressed as energy are presented for small groups of British and Canadian children. Fat is often the principal energy source in British diabetic children; protein intake is much higher in the Canadian. It is suggested that British practice might be improved by the adoption of a simple uniform exchange system. Reported differences in growth characteristics may reflect differences in protein intake.


Acyl chain unsaturation and vesicle curvature alter outer leaflet packing and promote poly(ethylene glycol)-mediated membrane fusion.
The poly(ethylene glycol) (PEG)-induced fusion of sonicated, unilamellar vesicles (SUV) and large, unilamellar vesicles (LUV) composed of a variety of phosphatidylcholine species was compared using two assays for the mixing and leakage of internal vesicle contents. In the first [Lentz et al. (1992) Biochemistry, 31, 2643], disodium 8-aminonaphthalene-1,3,6-trisulfonate (ANTS) fluorescence is quenched by co-encapsulated N,N'-p-xylylenebis(pyridinium bromide) (DPX). For this assay, interference by the fluorescence of impurities in PEG demands that the PEG content of the sample be reduced by dilution before measurements are taken. The second assay [Viguera et al. (1993) Biochemistry, 32, 3708] monitors the fluorescence of Tb3+ complexed with dipicolinic acid (DPA) directly in concentrated PEG solutions. The two assays gave identical fusion profiles for egg PC SUVs treated with increasing concentrations of PEG, demonstrating that fusion occurs in the dehydrated state in the presence of PEG and does not require dilution. Comparison of results obtained with lipid species of varying degrees of unsaturation incorporated into either SUV or LUV suggested that acyl chain unsaturation and high membrane curvature combine to favor fusion of pure phosphatidylcholine membranes. There was a clear correlation between the fluorescence lifetime or the order parameter of the membrane probe 1-(4-trimethylammonium)-6-phenyl-1,3,5-hexatriene (TMA-DPH) in different membranes and the concentration of PEG needed to induce fusion of these membranes. However, the ratios of TMA-DPH lifetimes measured in D2O versus H2O buffers were the same for different lipid species, indicating that probe penetration was not very different for different lipid species. The results suggest that the combined effect of high membrane curvature and extensive chain unsaturation is an enhanced rate of lipid motion in the upper region of the bilayer, reflective of decreased packing density in the outer leaflet of unsaturated SUV bilayers, probably allowing for enhanced water penetration leading to an enhanced probability of fusion.


Long-Term Outcomes and Causes of Death in Patients With Renovascular Disease Undergoing Renal Artery Stenting.
Renovascular disease (RVD) can lead to hypertension and chronic kidney disease (CKD). Patients with advanced peripheral arterial disease (PAD) have a 5-year mortality of ∼30%. Rate and causes of death in patients with significant RVD, who share similar risk factors with patients having PAD, are not well defined. We assessed consecutive patients with RVD who underwent renal artery stenting at our institution over 6 years. Specific causes of death were ascertained, and the probability of survival was estimated. Cox models were fit to identify predictors of outcomes. We identified 281 patients with RVD who underwent renal stenting. Follow-up was available for all patients (median 5.1 years). All-cause mortality was 24.2% at 5 years and 33.7% at 7 years (compounded annualized death rate: 5.5%). Of the 68 deaths, 36 (52.9%) were cardiovascular (13.2% acute myocardial infarction, 13.2% stroke, 11.8% sudden death, and 10.3% congestive heart failure) and 32 (47.1%) deaths had noncardiovascular causes. In patients with RVD undergoing stenting, cardiovascular events are the most common causes of death. Compared to patients with advanced PAD, RVD may have a lower 5-year mortality.


The pace of hospital life: A mixed methods study.
The pace-of-life hypothesis is a socio-psychological theory postulating that citizens of different cities transact the business of life at varying paces, and this pace is associated with a number of population level variables. Here we apply the pace-of-life hypothesis to a hospital context to empirically test the association between pace and patient and staff outcomes. As pressure on hospitals grow and pace increases to keep up with demand, is there empirical evidence of a trade-off between a rapid pace and poorer outcomes? We collected data from four large Australian hospitals, inviting all staff (clinical and non-clinical) to complete a survey, and conducted a series of observations of hospital staff's walking pace and transactional pace. From these data we constructed three measures of pace: staff perception of pace, transactional pace, and walking pace. Outcome measures included: hospital culture, perceived patient safety, and staff well-being outcomes of job satisfaction and burnout. Overall, participants reported experiencing a "fast-paced" "hurried" and "rapid" pace-of-life working in the Australian hospital sector. We found a significant difference in perceived pace across four hospital sites, similar to trends observed for transactional pace. This provides support that the pace-of-life hypothesis may apply to the hospital context. We tested associations between faster perceived pace, hospital culture, staff well-being and patient safety. Results revealed perceived faster pace significantly predicted negative perceptions of organizational culture, greater burnout and lower job satisfaction. However, perceived pace did not predict perceptions of patient safety. Different perceptions of hospital pace-of-life were found between different clinical settings and the type of care delivered; staff working in emergency departments reported significantly "faster-paced" work environments than staff working in palliative, aged care, or rehabilitation wards.


Malformations persist after metamorphosis of Xenopus laevis tadpoles exposed to Ni2+, Co2+, or Cd2+ in FETAX assays.
This study was performed to determine whether malformations induced in Xenopus laevis embryos by exposures to divalent nickel, cobalt, or cadmium chlorides in FETAX assays persist after the tadpoles undergo metamorphosis to juvenile frogs. Embryos were exposed for four days to EC50 concentrations of Ni2+, Co2+, or Cd2+ under the standard conditions of FETAX assays; thereafter, the exposures were discontinued and the tadpoles were kept in aquaria through metamorphosis. Controls were treated similarly, without exposure to metals. At 13 weeks of age, surviving frogs were killed and examined for malformations. Control and metal-exposed groups of Xenopus did not differ significantly in their median ages at metamorphosis, mean body weights, or survival at 13 weeks. Overall incidences of malformations found in Ni(2+)-, Co(2+)-, or Cd(2+)-exposed frogs at 13 weeks of age were 55, 40, and 51%, respectively (P < 0.01 vs. 3% in controls). The malformations of metal-exposed frogs included retinal depigmentation, diastematomyelia, scoliosis, kyphosis, phocomelia, sacro-pelvic and hind-limb deformities, and dysplasia of the heart, kidney, ovary and gut.


The utility of protein structure as a predictor of site-wise dN/dS varies widely among HIV-1 proteins.
Protein structure acts as a general constraint on the evolution of viral proteins. One widely recognized structural constraint explaining evolutionary variation among sites is the relative solvent accessibility (RSA) of residues in the folded protein. In influenza virus, the distance from functional sites has been found to explain an additional portion of the evolutionary variation in the external antigenic proteins. However, to what extent RSA and distance from a reference site in the protein can be used more generally to explain protein adaptation in other viruses and in the different proteins of any given virus remains an open question. To address this question, we have carried out an analysis of the distribution and structural predictors of site-wise dN/dS in HIV-1. Our results indicate that the distribution of dN/dS in HIV follows a smooth gamma distribution, with no special enrichment or depletion of sites with dN/dS at or above one. The variation in dN/dS can be partially explained by RSA and distance from a reference site in the protein, but these structural constraints do not act uniformly among the different HIV-1 proteins. Structural constraints are highly predictive in just one of the three enzymes and one of three structural proteins in HIV-1. For these two proteins, the protease enzyme and the gp120 structural protein, structure explains between 30 and 40% of the variation in dN/dS. Finally, for the gp120 protein of the receptor-binding complex, we also find that glycosylation sites explain just 2% of the variation in dN/dS and do not explain gp120 evolution independently of either RSA or distance from the apical surface.


Mouse 3-phosphoglycerate dehydrogenase gene: genomic organization, chromosomal localization, and promoter analysis.
d-3-Phosphoglycerate dehydrogenase (Phgdh; EC 188.8.131.52) is the first committed enzyme of l-serine biosynthesis in the phosphorylated pathway. We have recently demonstrated that, in developing and mature brain, expression of Phgdh is highly regulated in a cell lineage-specific manner, mainly in neuroepithelial stem cells, radial glia, and astrocytes (J. Neurosci. 21 (2001) 7691; Arch. Histol. Cytol. 66 (2003) 109). To gain insight into the regulatory mechanism of Phgdh expression, we have isolated a mouse genomic clone that contains the entire mouse Phgdh gene. Structural analysis demonstrated that the Phgdh gene spans approximately 27 kilobases (kb) in length and comprises 12 exons with 11 intervening introns. Using fluorescent in situ hybridization (FISH), we mapped the gene to mouse chromosome 3, region F2-F3. Analysis of a 1.8 kb fragment of the 5'-flanking region showed that the classical TATA-box motif near transcription initiation sites was absent. Instead, a GC-rich proximal region containing a potential Sp1 recognition sequence was present; this region is conserved in mouse, rat, and human counterparts. Transient transfection analysis revealed that the cis-acting elements necessary for basal transcription of Phgdh are contained within the -196/+4 proximal sequence of the promoter, in which the conserved Sp1 recognition sites play an important role for basal promoter activity.


Catalytic CO Oxidation by O2 Mediated by Noble-Metal-Free Cluster Anions Cu2 VO3-5<sup/>.
Catalytic CO oxidation by molecular O2 is an important model reaction in both the condensed phase and gas-phase studies. Available gas-phase studies indicate that noble metal is indispensable in catalytic CO oxidation by O2 under thermal collision conditions. Herein, we identified the first example of noble-metal-free heteronuclear oxide cluster catalysts, the copper-vanadium bimetallic oxide clusters Cu2 VO3-5- for CO oxidation by O2 . The reactions were characterized by mass spectrometry, photoelectron spectroscopy, and density functional calculations. The dynamic nature of the Cu-Cu unit in terms of the electron storage and release is the driving force to promote CO oxidation and O2 activation during the catalysis.


Prediction of hybridization and melting for double-stranded nucleic acids.
This article presents a general statistical mechanical approach to describe self-folding together with the hybridization between a pair of finite length DNA or RNA molecules. The model takes into account the entire ensemble of single- and double-stranded species in solution and their mole fractions at different temperatures. The folding and hybridization models deal with matched pairs, mismatches, symmetric and asymmetric interior loops, bulges, and single-base stacking that might exist at duplex ends or at the ends of helices. All possible conformations of the single- and double-stranded species are explored. Only intermolecular basepairs are considered in duplexes at this stage.In particular we focus on the role of stacking between neighboring nucleotide residues of single unfolded strands as an important source of enthalpy change on helix formation which has not been modeled computationally thus far. Changes in the states of the single strands with temperature are shown to lead to a larger heat effect at higher temperature. An important consequence of this is that predictions of enthalpies, which are based on databases of nearest-neighbor energy parameters determined for molecules or duplexes with lower melting temperatures compared with the melting temperatures of the oligos for which they are used as a predictive tool, will be underestimated.


The Role of Insulin Therapy in Correcting Hepcidin Levels in Patients with Type 2 Diabetes Mellitus.
Iron overload can cause or contribute to the pathogenesis of type 2 diabetes mellitus (T2DM), but how the major parameters of iron metabolism change in different settings of diabetes are still unclear. The aim of this study was to determine the relationship between iron, ferritin, and hepcidin levels in diabetic patients and the effect of insulin treatment. The study included 80 subjects, 60 with T2DM and 20 without (control group). Serum hepcidin, insulin, ferritin, and iron levels were determined as well as other clinical parameters. The associations between these parameters were analyzed between both groups. Hepcidin levels expressed as mean± standard deviation between groups showed no significant changes (14.4±6.7 ng/mL for the control group, and 18.4±7.9 ng/mL for patients with diabetes, p = 0.069). Parameters of iron metabolism showed modest correlation with the parameters of glucose metabolism. However, the correlation between ferritin and insulin in both groups was statistically significant (p = 0.032; ρ = 0.480 vs. p = 0.011; ρ = 0.328). Our study showed that hepcidin levels in patients with T2DM on insulin therapy do not change, which might be a result of treatment with insulin. In this context, insulin treatment can be used as a novel method for correction of hepcidin levels. By correcting hepcidin levels, we can prevent cellular iron overload and reduce the risk of diabetes.


Increased plasma norepinephrine in psoriasis.
Free plasma catecholamines were measured by means of a standardized HPLC method in 50 adult patients with psoriasis and in 18 healthy volunteers. The concentrations of circulating norepinephrine were significantly higher in the psoriasis group (p less than 0.005); by contrast only slight differences were found in the epinephrine and dopamine concentrations. The possible mechanisms leading to these changes are discussed.


Functional and prognostic implications of left ventricular contractile reserve in patients with asymptomatic severe mitral regurgitation.
To evaluate contractile reserve (CR) determined by exercise echocardiography in predicting clinical outcome and left ventricular (LV) function in asymptomatic severe mitral regurgitation (MR). Cohort study. Regional cardiac centre. LV volumes and ejection fraction (EF) were measured at rest and after stress in 71 patients with isolated MR. During follow up (mean (SD) 3 (1) years), EF and functional capacity were serially assessed and cardiac events (cardiac death, heart failure, and new atrial fibrillation) were documented. CR was present in 45 patients (CR+) and absent in 26 patients (CR-). Age, resting LV dimensions, EF, and MR severity were similar in both groups. Mitral surgery was performed in 19 of 45 (42%) CR+ patients and 22 of 26 (85%) CR- patients. In patients undergoing surgery, CR was an independent predictor of follow up EF (p = 0.006) and postoperative LV dysfunction (EF < 50%) persisted in five patients, all in the CR- group. Event-free survival was lower in surgically treated patients without CR (p = 0.03). In medically treated patients, follow up EF was preserved in those with intact CR but progressively deteriorated in patients without CR, in whom functional capacity also deteriorated. Evaluation of CR by exercise echocardiography may be useful for risk stratification and may help to optimise the timing of surgery in asymptomatic severe MR.


A Multiscale Ray-Shooting Model for Termination Detection of Tree-Like Structures in Biomedical Images.
Digital reconstruction (tracing) of tree-like structures, such as neurons, retinal blood vessels, and bronchi, from volumetric images and 2D images is very important to biomedical research. Many existing reconstruction algorithms rely on a set of good seed points. The 2D or 3D terminations are good candidates for such seed points. In this paper, we propose an automatic method to detect terminations for tree-like structures based on a multiscale ray-shooting model and a termination visual prior. The multiscale ray-shooting model detects 2D terminations by extracting and analyzing the multiscale intensity distribution features around a termination candidate. The range of scale is adaptively determined according to the local neurite diameter estimated by the Rayburst sampling algorithm in combination with the gray-weighted distance transform. The termination visual prior is based on a key observation-when observing a 3D termination from three orthogonal directions without occlusion, we can recognize it in at least two views. Using this prior with the multiscale ray-shooting model, we can detect 3D terminations with high accuracies. Experiments on 3D neuron image stacks, 2D neuron images, 3D bronchus image stacks, and 2D retinal blood vessel images exhibit average precision and recall rates of 87.50% and 90.54%. The experimental results confirm that the proposed method outperforms other the state-of-the-art termination detection methods.


Mineral uptake by the femora of older female X-linked hypophosphatemic (HYP) mice but not older male HYP mice.
X-linked hypophosphatemic (Hyp) mice are a model of human sex-linked vitamin D-resistant rickets. Young adult Hyp mice are characterized by osteomalacia and decreased bone mineral content. However, older heterozygous Hyp female mice increase in bone mineral content with age so that by one year of age the bone mass/mm femoral length equals or exceeds normal females. To test for the occurrence of this mineral accretion in Hyp male mice and in homozygous Hyp female mice, femora from all 3 Hyp genotypes as well as normal male and female mice were analyzed at various ages from one to 52 weeks of age. Compared to normal mice, all three Hyp genotypes were depressed in bone ash, femoral length, and ash/length ratio at 13 weeks of age. After that age the femora of both heterozygous and homozygous Hyp females showed a slow mineral accretion and, by 52 weeks of age, a normal ash/length ratio. However, the femora of Hyp males, as well as those of normal males, failed to increase in bone mineral content or ash/length ratio after 13 weeks of age. The differences between male and female Hyp mice could not be explained by differences in the plasma levels of calcium, phosphate, or alkaline phosphatase. Increased bone mineral content in older Hyp mice was seen in both heterozygous and homozygous females but not in hemizygous males. Thus, the basis for this increase is not incomplete dominance of the Hyp gene in females nor the Lyon hypothesis. The accretion of mineral in older female Hyp mice despite lifelong reduced plasma phosphate levels suggests that there are factors other than phosphate that also regulate mineral accretion in this bone disease.


Fall Reduction Interventions for Hospice Patients.
Despite efforts to decrease inpatient falls at a Midwestern Veterans Administration Medical Center, patients on the hospice unit continued to have higher rates of falls than patients on other units. The purpose of this article is to review the literature to determine if evidence-based, population-specific, fall prevention measures could be implemented to reduce the risk of falls for hospice patients. As a result of this literature review, an end-of-life care plan was developed and will be utilized to increase the frequency of assessment and rounding, and to encourage family involvement during this critical time frame.


Pharmacological treatment of Alzheimer's dementia: state of the art and current dilemmas.
Alzheimer's disease (AD) is one of the most frequent disorders of the central nervous system characterised by a progressive cognitive decline. The demographic changes of our aging population lead to increased numbers of patients and a need of early diagnosis and treatment of cognitive and behavioural symptoms of AD. Drugs are available for symptomatic treatment of AD. The pharmacological treatment of behavioural disturbances experienced dynamic changes in the last years. In this paper, we present the current state and future perspectives in the treatment of AD. Furthermore, we discuss current difficulties regarding AD treatment by looking for explanations for a still unsatisfying rate of state-of-the-art treatment of AD-patients.


The prevalence, clinical features, risk factors and outcome associated with cryptococcal meningitis in HIV positive patients in Kenya.
To determine the prevalence, clinical features, risk factors and outcomes associated with cryptococcal meningitis (CM) in human immunodeficiency virus (HIV) positive patients at two referral hospitals in Nairobi, Kenya. Prospective, observational study. Kenyatta National Hospital (KNH) and Mbagathi District Hospital (MDH), Nairobi, Kenya. Three hundred and forty HIV patients presenting with suspected CM. Of three hundred and forty suspected CM patients, 111 (33%) were diagnosed with CM by CrAg. Among CM patients, in-hospital mortality was 36% (38/106), median age was 35 years (range, 19-60 years) and median CD4 count was 41 cells/microL (n = 89, range 2-720 cells/microL). Common clinical manifestations among CM patients included headache 103 (93%), neck stiffness 76 (69%) and weight loss 53 (48%). Factors independently associated with CM were male sex, headache, blurred vision and previous antifungal drug use. Night sweats and current use of anti-retroviral therapy were associated with reduced risk for CM. There is a high prevalence of CM and CM-associated mortality in HIV patients at KNH and MDH despite treatment with antifungal and anti-retroviral drugs. This study demonstrates the need to address the existing inadequacies of CM patient outcomes in Kenya.


Survival of porcelain laminate veneers with different degrees of dentin exposure: 2-year clinical results.
To evaluate the clinical performance of porcelain laminate veneers (PLVs) after 2 years. Twenty-eight patients were treated with 125 PLVs. The experimental variables were preparation design (incisal overlap [IO] and incisal bevel [IB]) and adhesion surface (enamel [E], enamel with minimal dentin exposure [MDE], and enamel with severe dentin exposure (SDE)]. Marginal adaptation, marginal discoloration, secondary caries, postoperative sensitivity, and patient satisfaction were assessed according to the modified United States Public Health Service criteria. Each restoration was examined for fractures and debonding. In addition, gingival tissue health by gingival plaque, bleeding, and recession was recorded. An experienced clinician evaluated the restorations at baseline and after 6, 12, and 24 months, and survival rates evaluating relative and absolute failures were calculated (p = 0.05). Eleven (8.8%) veneers failed, and the overall cumulative survival rate was 91.2% after 2 years of followup. IB and IO preparation designs exhibited survival rates of 94% and 85.7%, respectively, but this difference was not statistically significant (p > 0.05). PLVs bonded to SDE were more likely to fail than those bonded to E and MDE (p < 0.05). There was no significant difference between the failure rate of PLVs bonded to E and those bonded to MDE (p > 0.05). PLVs have high survival rates when bonded to enamel only, as well as to enamel with minimal dentin exposure. However, extensive dentin exposure should be avoided during the preparation.


New cerebral microbleeds in AF patients on non-vitamin K oral anticoagulants or warfarin: One-year follow-up.
Anticoagulant treatment increases the risk of intracerebral hemorrhage (ICH), but whether the treatment, more specifically non-vitamin K oral anticoagulants (NOACs), increases the risk of cerebral microbleeds (CMBs) remains uncertain. We performed this study to investigate the development of new CMBs due to NOACs or warfarin treatment in patients with atrial fibrillation (AF).We prospectively recruited AF patients before anticoagulation from June 2016 to June 2018. We performed susceptibility-weighted imaging (SWI) examinations on all enrolled AF patients and re-examined SWI 1 year later. We compared demographic features and new CMBs between the NOACs group and the warfarin group. Univariate analysis of clinical factors was performed according to the development of new CMBs; and age, a HAS-B(L)ED score, warfarin use, and the presence of baseline CMBs were then selected for inclusion in the multivariate logistic regression model.A total of 72 AF patients were recruited, 29 of whom were assigned to the NOACs group and 43 to the warfarin group. Finally, 1 patient in the NOACs group (3.4%) and 9 patients (20.9%) in the warfarin group developed new CMBs after 1 year follow-up (P = .08). Univariate analysis showed that age, a HAS-B(L)ED score ≥4, the presence of baseline CMBs were associated with the development of new CMBs (P < .05). And multivariate regression analysis showed baseline CMBs (P = .03, odds ratio = 6.37, 95% confidence interval 1.15-35.36) was independently related to the increase in new CMBs.AF patients treated with NOACs may have a decreased trend in the development of new CMBs compared with those treated with warfarin. Baseline CMBs increased the frequency of new CMBs during anticoagulant treatment. The development of new CMBs in AF patients with anticoagulation requires further longitudinal studies with longer follow-up in larger samples.


Molecular mechanisms of zika virus pathogenesis: An update.
Zika virus (ZIKV), member of the family Flaviviridae belonging to genus Flavivirus, is an arthropod-borne virus. The ZIKV is known to cause severe congenital birth defects in neonates. Due to a large number of worldwide outbreaks and associated neurological complications with ZIKV, a public health emergency was declared by the World Health Organization on February 1, 2016. The virus exhibits neurotropism and has a specific propensity towards neural precursor cells of the developing brain. In utero ZIKV infection causes massive cell death in the developing brain resulting in various motor and cognitive disabilities in newborns. The virus modulates cell machinery at several levels to replicate itself and inhibits toll like receptors-3 signalling, deregulates microRNA circuitry and induces a chronic inflammatory response in affected cells. Several significant advances have been made to understand the mechanisms of neuropathogenesis, its prevention and treatment. The current review provides an update on cellular and molecular mechanisms of ZIKV-induced alterations in the function of various brain cells.


Coincidence of selective immunoglobulin A deficiency in juvenile idiopathic arthritis - a series of three cases.
Immunoglobulin A (IgA) deficiency is the most common primary immunodeficiency in humans, with incidence depending on ethnic background and the highest frequency in Caucasians. Selective IgA deficiency may have an asymptomatic course and constitute a random laboratory finding with no clinical manifestation. There is, however, a group of patients with increased incidence of recurrent upper respiratory tract infections, allergies, asthma, atopic dermatitis and other pathologies connected with IgA deficiency. This group of patients often needs broad-spectrum antibiotic therapy with maximum doses and extended time of treatment as there is no causal treatment for IgA deficiency. An association between IgA deficiency and autoimmune diseases, such as juvenile idiopathic arthritis, has been proved before. Nonetheless, the frequency of co-occurrence of these disorders in an individual as well as the way immunodeficiency may influence the course of juvenile idiopathic arthritis is still undefined, with limited literature on this topic. This article presents case reports of three pediatric patients with confirmed co-occurrence of IgA deficiency and oligoarticular juvenile idiopathic arthritis.


Orientation of luminescent excitons in layered nanomaterials.
In nanomaterials, optical anisotropies reveal a fundamental relationship between structural and optical properties. Directional optical properties can be exploited to enhance the performance of optoelectronic devices, optomechanical actuators and metamaterials. In layered materials, optical anisotropies may result from in-plane and out-of-plane dipoles associated with intra- and interlayer excitations, respectively. Here, we resolve the orientation of luminescent excitons and isolate photoluminescence signatures arising from distinct intra- and interlayer optical transitions. Combining analytical calculations with energy- and momentum-resolved spectroscopy, we distinguish between in-plane and out-of-plane oriented excitons in materials with weak or strong interlayer coupling-MoS₂ and 3,4,9,10-perylene tetracarboxylic dianhydride (PTCDA), respectively. We demonstrate that photoluminescence from MoS₂ mono-, bi- and trilayers originates solely from in-plane excitons, whereas PTCDA supports distinct in-plane and out-of-plane exciton species with different spectra, dipole strengths and temporal dynamics. The insights provided by this work are important for understanding fundamental excitonic properties in nanomaterials and designing optical systems that efficiently excite and collect light from exciton species with different orientations.


Mechanisms of Cytotoxic Lymphocyte-Mediated Apoptosis and Relationship with the Tumor Suppressor p53.
Cytotoxic T lymphocytes and natural killer cells are key effector cells in the immune response against intracellular infection and transformed cells. These killer cells induce multiple programs of cell death to achieve their function of eliminating their targets. In this review, we summarize our current understanding of the signaling pathways involved in target cells apoptosis triggered by the cytotoxic effector cells. We also discuss the role of an important player in the field of apoptosis, the well-known p53 tumor suppressor, in the modulation of cytotoxic lymphocyte-mediated cell death.


First report of Fusarium ussurianum causing leaf spot on Hemerocallis citrina in Sichuan Basin of China.
Hemerocallis citrina is a popular vegetable crop in China, due to abundant nutrients in its edible flower buds. In March 2021, serious symptoms of leaf spot were observed on nearly 90% cultivated H. citrina seedlings in the fields of Dazhou city (31°17'56″ N, 107°31'59″ E), Sichuan, China. Symptomatic leaves were collected from 15 seedlings in five different sampling sites (3 seedlings per site). Small pieces (5 × 3 mm) of lesion margin were excised, surface disinfected in 70% ethanol for 20 s and 1% sodium hypochlorite (NaClO) for 40 s, washed, dried, placed on potato dextrose agar (PDA) amended with streptomycin sulfate (50 mg/L) and incubated in dark at 25 ℃ for two days. Finally, eight purified isolates, HHC-FL22, HHC-FL23, HHC-FL25, HHC-FL26, HHC-FL27, HHC-FL28, HHC-FL29 and HHC-FL30, showing similar morphology were obtained through transferring hyphal tips to fresh PDA plates. On PDA plates, mycelia were initially white but gradually became light yellow, and scarlet diffusible pigments were also produced with time. On carnation leaf agar, our isolates produced slightly curved macroconidia with 4 to 8 septa that measured 3.1 to 5.7 × 36.8 to 69.3 µm (n = 30). Microconidia and chlamydospores were not observed. Our isolates were initially identified as Fusarium species based on morphological features (Leslie and Summerell 2006). To further confirm accurate identity, primers EF1/EF2 (O'Donnell et al. 2010), TRI1015B/TRI1013E (Hao et al. 2017), RPB1-F5/RPB1-G2R (O'Donnell et al. 2010), and fRPB2-5F/fRPB2-11aR and RPB2-5f2/RPB2-7cr (O'Donnell et al. 2012) were used to amplify gene sequences of translation elongation factor-1 alpha (TEF1), 3-O-acetyltransferase (Tri101), and DNA-directed RNA polymerase II largest (RPB1) and second largest subunit (RPB2), respectively. Our sequences were deposited in GenBank under accession numbers OQ860946 to OQ860953 (TEF1), OR393245 to OR393252 (Tri101), OP131893 to OP131900 (RPB1), and OQ860954 to OQ860961 and OP131885 to OP131892 (RPB2), respectively. BLASTN searches of our sequences showed 99 ~ 100% identity with TEF1 (FJ240301.1), Tri101 (FJ240345.1), RPB1 (MW233297.1) and RPB2 (KM361666.1) of F. ussurianum NRRL 45681, and 99.05 ~ 100% identity with TEF1 (FJ240305.1) and Tri101 (FJ240349.1) of F. ussurianum NRRL 45833, respectively. Two independent maximum-likelihood phylogenetic trees based on different combined datasets of TEF1, Tri101, RPB1 and RPB2 of Fusarium species confirmed that our isolates were F. ussurianum. To test pathogenicity, conidial suspension from HHC-FL23 (106 conidia / mL) were sprayed to seedlings of cultivar "chuanhuanghua No.1" (n = 3) and incubated in a greenhouse (25°C under 90% relative humidity, 16/8 h light/dark cycle). Controls were treated with ddH2O. Ten days post-inoculation, natural symptoms appeared on leaves inoculated with HHC-FL23, but control group seedlings remained disease-free. This experiment was repeated three times. All re-isolated pathogens from diseased leaves were molecularly and morphologically identified using methods described above. Consequently, the re-isolated fungi were identical to these inoculated. The leaf spot disease could cause foliar damage and even drastic yield loss of flower buds under severe conditions. To our knowledge, this is the first report of F. ussurianum causing leaf spot in H. citrina worldwide. Our study will assist in monitoring causal agent diversity of leaf spot and breeding new resistant varieties in H. citrina.


Vitamin D receptor attenuates renal fibrosis by suppressing the renin-angiotensin system.
Analogs of vitamin D attenuate renal injury in several models of kidney disease, but the mechanism underlying this renoprotective effect is unknown. To address the role of the vitamin D receptor (VDR) in renal fibrogenesis, we subjected VDR-null mice to unilateral ureteral obstruction for 7 days. Compared with wild-type mice, VDR-null mice developed more severe renal damage in the obstructed kidney, with marked tubular atrophy and interstitial fibrosis. Significant induction of extracellular matrix proteins (fibronectin and collagen I), profibrogenic and proinflammatory factors (TGF-beta, connective tissue growth factor, and monocyte chemoattractant protein 1), and epithelial-to-mesenchymal transition accompanied this histologic damage. Because VDR ablation activates the renin-angiotensin system and leads to accumulation of angiotensin II (AngII) in the kidney, we assessed whether elevated AngII in the VDR-null kidney promotes injury. Treatment with the angiotensin type 1 antagonist losartan eliminated the difference in obstruction-induced interstitial fibrosis between wild-type and VDR-null mice, suggesting that AngII contributes to the enhanced renal fibrosis observed in obstructed VDR-null kidneys. Taken together, these results suggest that the VDR attenuates obstructive renal injury at least in part by suppressing the renin-angiotensin system.


Development of Fish Oil-Loaded Microcapsules Containing Whey Protein Hydrolysate as Film-Forming Material for Fortification of Low-Fat Mayonnaise.
The influence of the carbohydrate-based wall matrix (glucose syrup, GS, and maltodextrin, MD21) and the storage temperature (4 °C or 25 °C) on the oxidative stability of microencapsulated fish oil was studied. The microcapsules (ca. 13 wt% oil load) were produced by spray-drying emulsions stabilized with whey protein hydrolysate (WPH), achieving high encapsulation efficiencies (>97%). Both encapsulating materials showed an increase in the oxidation rate with the storage temperature. The GS-based microcapsules presented the highest oxidative stability regardless of the storage temperature with a peroxide value (PV) of 3.49 ± 0.25 meq O2/kg oil and a content of 1-penten-3-ol of 48.06 ± 9.57 ng/g oil after six weeks of storage at 4 °C. Moreover, low-fat mayonnaise enriched with GS-based microcapsules loaded with fish oil and containing WPH as a film-forming material (M-GS) presented higher oxidative stability after one month of storage when compared to low-fat mayonnaise enriched with either a 5 wt% fish oil-in-water emulsion stabilized with WPH or neat fish oil. This was attributed to a higher protective effect of the carbohydrate wall once the microcapsules were incorporated into the mayonnaise matrix.


Correction of severe facial deformity.
A craniofacial team has been developed to corrdinate the treatment of patients with severe facial deformity and to minimize the surgical risks. Two hundred patients have been evaluated in the last 4 years and more than 100 treated by this team to correct orbital hypertelorism, oxycephaly and plagiocephaly with exophthalmos, features of Crouzon's disease and Apert's and Treacher Collins syndromes, hemifacial microsomia, and severe lower facial deformity and malocclusion. Surgical principles include extensive subperiosteal stripping of bone, osteotomy as necessary, and repositioning maintained by bone grafts. Postoperative evaluation is being maintained for 5 years or to maturity in younger children. Although many of the results are less than perfect, there has been sufficient improvement, especially psychologic and functional, to warrant continuation of the surgical program under closely controlled conditions.


Network-Pharmacology-Based Study on Active Phytochemicals and Molecular Mechanism of Cnidii Fructus in Treating Colorectal Cancer.
Cnidii Fructus (CF) is known for its antibacterial, anti-inflammatory, and antitumor properties, as well as its activities against kidney deficiency and impotence. In this study, we aimed to explore the anti-CRC cancer effect and molecular mechanism of CF via network pharmacology and in vitro antitumor experiments. Network pharmacology was used to investigate the anti-CRC mechanism of CF. First, a series of databases was used to screen the active phytochemical targets and anti-CRC core targets. Then, the GO and KEGG pathways were analyzed to predict possible mechanisms. Molecular docking analysis explore core targets-phytochemicals interactions. In vitro antitumor experiments were carried on verifying anti-CRC mechanism of CF. In this study, 20 active ingredient targets and 50 intersecting targets were analyzed by Cytoscape software 3.9.1 to obtain the core genes and phytochemicals. Then, the GO and KEGG pathways of 50 intersecting targets were analyzed to predict possible mechanisms. The results from GO and KEGG indicated that CF has significant antitumor efficacy, which involves many signaling pathways, such as PI3K/AKT and p53. The five core targets and five core phytochemicals were screened for molecular docking to show protein-ligand interactions. According to the results of molecular docking, the compound O-acetylcolumbianetin was selected for the anti- CRC functional verification in vitro. MTT assay showed that O-acetylcolumbianetin significantly inhibited the proliferation of colorectal HCT116 cells in a time- and quantity-dependent manner. O-acetylcolumbianetin can promote the expression of CASP3 protein, induce HCT116 cells apoptosis, thus exert anti-CRC effect. This study preliminarily verified the anti-CRC effect and molecular mechanism of CF and provided a reference for Traditional Chinese Medicine anti-tumor subsequent research.


Clinical trial design: the neglected problem of asymmetrical transfer in cross-over trials.
The paper illustrates drawbacks of the popular cross-over design in clinical trials in psychiatry where treatment effects become distorted by, and confounded with, the effects of their order of administration. It is argued that research workers should analyse data from cross-over trials for asymmetries due to order of treatment and seriously doubt the reliability of data if such effects are found. The problem is avoided by the use of separate-groups designs.


AcFT promotes kiwifruit in vitro flowering when overexpressed and Arabidopsis flowering when expressed in the vasculature under its own promoter.
Kiwifruit (Actinidia chinensis) has three FLOWERING LOCUS T (FT) genes, AcFT, AcFT1, and AcFT2, with differential expression and potentially divergent roles. AcFT was previously shown to be expressed in source leaves and induced in dormant buds by winter chilling. Here, we show that AcFT promotes flowering in A. chinensis, despite a short sequence insertion not present in other FT-like genes. A 3.5-kb AcFT promoter region contained all the regulatory elements required to mediate vascular expression in transgenic Arabidopsis thaliana (Arabidopsis). The promoter activation was initially confined to the veins in the distal end of the leaf, before extending to the veins in the base of the leaf, and was detected in inductive and noninductive photoperiods. The 3-kb and 2.7-kb promoter regions of AcFT1 and AcFT2, respectively, demonstrated different activation patterns in Arabidopsis, corresponding to differential expression in kiwifruit. Expression of AcFT cDNA from the AcFT promoter was capable to induce early flowering in transgenic Arabidopsis in noninductive photoperiods. Further, expression of AcFT cDNA fused to the green fluorescent protein was detected in the vasculature and was also capable to advance flowering in noninductive photoperiods. Taken together, these studies implicate AcFT in regulation of kiwifruit flowering time and as a candidate for kiwifruit florigen.


Effects of norepinephrine on transmembrane calcium transport in rat mast cells.
The effect of norepinephrine on transmembrane passage of calcium in rat peritoneal mast cells, was studied in an in vitro system. It was found the histamine release from mast cells induced by the ionophore A 23 187 in normal calcium medium and compound 48/80 in a calcium-free medium was suppressed by 10(-3) M norepinephrine but not at concentrations in the range 10(-5)-10(-4) M. When the secretory process is totally dependent on the presence of calcium in the incubation medium, i.e. calcium-depleted cells, 10(-5) M norepinephrine suppresses the histamine release induced by low concentrations of compound 48/80. The effect of norepinephrine (10(-5) M) on strontium-induced "spontaneous' histamine release was also studied. It was found that norepinephrine (10(-5) M) totally inhibits the progressive histamine release induced by strontium. It is possible to evoke secretion in a calcium-free medium, and subsequent introduction of Ca2+ will result in optimal histamine release. This demonstrates a secretory process in which we can distinguish between utilization of endogenous versus exogenous calcium. The release that is dependent on extracellular calcium is inhibited by norepinephrine (10(-5) M). These data indicate that the suppressive effect of norepinephrine (concentrations less than 10(-3) M) on histamine release from rat mast cells is due to an interference in transmembrane passage of calcium.


Heterogeneity of smooth muscle in bovine coronary arteries.
The monoclonal antibodies TT-1 against troponin T and TI-1 against troponin I of cardiac muscle, together with Western blots and immunofluorescence techniques, were used to evaluate the presence of troponin-like antigens in the smooth muscle cells of bovine coronary arteries. The walls of the left coronary artery before the bifurcation, its circumflex and descending branches, the right coronary artery, and the small branches of coronary arteries and the intramural arterial vessels were found to be homogeneously stained by the TT-1 antibody. Conversely, with the TI-1 antibody, differences were observed in the distribution of the TnI-like antigen among the smooth muscle cells of extramural and intramural vessels. Heterogeneity of the smooth muscle cells of the coronary artery was also evident in the medial layer of large vessels near the branching points, where an intimal thickening was consistently observed. Double immunofluorescence assays with anti-troponin antibodies in vivo and in vitro indicated a distinct intracellular localization of troponin T and troponin I immunoreactivities in vascular smooth muscle cells. The data are compatible with the existence of distinct troponin-like antigens in smooth muscle cells of bovine coronary arteries whose distribution is in part related to the extramural or intramural localization of blood vessels.


Relationships between sensory stimuli and autonomic nervous regulation during real and virtual exercises.
Application of virtual environment (VE) technology to motor rehabilitation increases the number of possible rehabilitation tasks and/or exercises. However, enhancing a specific sensory stimulus sometimes causes unpleasant sensations or fatigue, which would in turn decrease motivation for continuous rehabilitation. To select appropriate tasks and/or exercises for individuals, evaluation of physical activity during recovery is necessary, particularly the changes in the relationship between autonomic nervous activity (ANA) and sensory stimuli. We estimated the ANA from the R-R interval time series of electrocardiogram and incoming sensory stimuli that would activate the ANA. For experiments in real exercise, we measured vehicle data and electromyogram signals during cycling exercise. For experiments in virtual exercise, we measured eye movement in relation to image motion vectors while the subject was viewing a mountain-bike video image from a first-person viewpoint. For the real cycling exercise, the results were categorized into four groups by evaluating muscle fatigue in relation to the ANA. They suggested that fatigue should be evaluated on the basis of not only muscle activity but also autonomic nervous regulation after exercise. For the virtual exercise, the ANA-related conditions revealed a remarkable time distribution of trigger points that would change eye movement and evoke unpleasant sensations. For expanding the options of motor rehabilitation using VE technology, approaches need to be developed for simultaneously monitoring and separately evaluating the activation of autonomic nervous regulation in relation to neuromuscular and sensory systems with different time scales.


Observation of a Goos-Hänchen-like Phase Shift for Magnetostatic Spin Waves.
In optics, a light beam experiences a spatial shift in the beam plane upon total internal reflection. This shift is usually referred to as the Goos-Hänchen shift. When dealing with plane waves, it manifests itself as a phase shift between an incoming and reflected wave that depends on the wave vector component along the interface. In the experiments presented here, plane spin waves are excited in a 60-nm-thick Permalloy film and propagate towards the edge of the film. By means of time-resolved scanning Kerr microscopy, we are able to directly detect a phase shift between the incoming and reflected wave. With the help of a numerical model, we show that this phase shift naturally occurs for spin waves in the dipolar regime.


An Innovative Prone Position Using a Body-Shape Plaster Bed and Skull Traction for Posterior Cervical Spine Fracture Surgeries.
An innovative prone cervical spine surgical position using a body-shape plaster bed with skull traction (BSPST) was compared with the traditional prone surgical position with horseshoe headrests. A total of 47 patients, undergoing posterior cervical spine surgery for cervical spine fracture, were retrospectively classified into two groups, the BSPST group (n = 24) and the traditional group (n = 23), and underwent a posterior instrumented fusion with or without decompression. Multiple indicators were used to evaluate the advantages of the BSPST compared with the traditional position. All the operations went smoothly. The mean recovery rate was 56.30% in the BSPST group and 48.55% in the traditional group (p = 0.454), with no significant difference. The intraoperative blood loss (177.5 ml vs. 439.1 ml, p = 0.003) and the total incidence of complications (8.3 vs. 47.8%, p = 0.004) were significantly less in the BSPST group than in the traditional group. In addition, the BSPST position provided a greater comfort level for the operators and allowed convenient intraoperative radiography. This is the first study to describe a combined body-shape plaster bed and skull traction as an innovative cervical spine-prone surgical position that is simple, safe, and stable, intraoperative traction direction adjustable, reproducible, and economical for posterior cervical spine fracture surgery, and potentially other cervical and upper dorsal spine surgeries in the prone position. Additionally, this position provides the surgeons with a comfortable surgical field and can be easily achieved in most orthopedic operation rooms.


Sexual Orientation and Age at Menarche in Three U.S. Longitudinal Cohorts.
The aim of this study is to examine age at menarche across sexual orientation groups. Data were obtained from 131,090 female participants, born 1947-2001, in 3 longitudinal studies-the Growing Up Today Study and Nurses' Health Study 2 and 3. We estimated the association between sexual orientation and age at menarche using regression models adjusted for age, race/ethnicity, birthweight, height, and body mass index. Compared to heterosexual participants, sexual minorities were younger at menarche. Sexual minorities were more likely to have early menarche (≤11 years) and less likely to have late menarche (≥14 years) compared to heterosexual girls. As an example of this pattern, Nurses' Health Study 3 bisexual participants were >30% more likely than heterosexuals to have early versus average menarche (odds ratio 1.37, 95% confidence interval 1.09-1.72). Sexual minority girls have a younger age at menarche than heterosexual girls and may benefit from screening for adverse outcomes associated with early menarche.


Economic burden of advanced lung cancer patients treated by gefitinib alone and combined with chemotherapy in two regions of China.
To assess the economic burden of different chemotherapies for lung cancer patients and influencing factors in China. The economic burden of lung cancer, including direct, indirect and intangible costs was measured within three months after diagnosis and treatment. Direct cost included the cost of hospitalization, outpatient visits, out-of-pocket drug purchases, costs of transportation, accommodation and meal expenses while seeking treatments in hospitals. Cost information was attained from questionnaire and patients' medical record. Indirect cost was measured by the patients' and their caregivers' productive days lost due to outpatient visits and hospitalization for lung cancer treatment. Intangible cost was obtained through the willingness-to-pay method from a questionnaire completed by the patient. Among the total cost of CNY71,401.92, direct cost, indirect cost and intangible cost constituted 89.02%, 4.29%, and 6.69% respectively. Educational level, occupation, family income, lung cancer classification, and the city of residence significantly influenced the total cost. Limitations in our study included: First, our follow-up period of three months was relatively short compared to the whole survival period of lung cancer patients. Second, the sample size of the chemotherapy combined with targeted therapy group was not large enough, and the cost data obtained would need confirmation in future studies. Third, participants came from only two localities, which may somewhat limit the representativeness of the study results for the whole of China. The economic burden of lung cancer treatment mainly came from the cost of the drugs. Patients taking chemotherapy had significantly higher cost compared to patients using targeted therapy. The cost was generally higher for those with higher educational level, those with higher family income, and those living in an economically more developed city. Patients with NSCLC had higher cost compared to patients with SCLC.


Crystallization Behavior of Amorphous Si3N4 and Particle Size Control of the Crystallized α-Si3N4.
Amorphous silicon nitride powder prepared by low-temperature vapor-phase reaction was heat treated at various temperatures for different periods of time to examine the crystallization behavior. The effects of the heat-treatment temperature and duration on the degree of crystallization were investigated along with the effect of the heat-up rate on the particle size, and its distribution, of the crystallized α-phase silicon nitride powder. A phase transition from amorphous to α-phase occurred at a temperature above 1400 degrees C. The crystallization. process was completed after heat treatment at 1500 degrees C for 3 h or at 1550 degrees C for 1 h. The crystallization process starts at the surface of the amorphous particle: while the outer regions of the particle become crystalline, the inner part remains amorphous. The re-arrangement of the Si and N atoms on the surface of the amorphous particle leads to the formation of hexagonal crystals that are separated from the host amorphous particle. The particle size and size distribution can be controlled by varying the heat-treatment profile (namely, the heat-treatment temperature, heating rate, and heating duration at the specified temperature), which can be used to control the relative extent of the nucleation and growth. The completion of most of the nucleation process by lowering the heat-up rate can be used to achieve a singlet particle size distribution. Bimodal particle size distribution can be achieved by fast heat-up during the crystallization process.


Chest dual-energy CT to assess the effects of steroids on lung function in severe COVID-19 patients.
Steroids have been shown to reduce inflammation, hypoxic pulmonary vasoconstriction (HPV) and lung edema. Based on evidence from clinical trials, steroids are widely used in severe COVID-19. However, the effects of steroids on pulmonary gas volume and blood volume in this group of patients are unexplored. Profiting by dual-energy computed tomography (DECT), we investigated the relationship between the use of steroids in COVID-19 and distribution of blood volume as an index of impaired HPV. We also investigated whether the use of steroids influences lung weight, as index of lung edema, and how it affects gas distribution. Severe COVID-19 patients included in a single-center prospective observational study at the intensive care unit at Uppsala University Hospital who had undergone DECT were enrolled in the current study. Patients' cohort was divided into two groups depending on the administration of steroids. From each patient's DECT, 20 gas volume maps and the corresponding 20 blood volume maps, evenly distributed along the cranial-caudal axis, were analyzed. As a proxy for HPV, pulmonary blood volume distribution was analyzed in both the whole lung and the hypoinflated areas. Total lung weight, index of lung edema, was estimated. Sixty patients were analyzed, whereof 43 received steroids. Patients not exposed to steroids showed a more extensive non-perfused area (19% vs 13%, p < 0.01) and less homogeneous pulmonary blood volume of hypoinflated areas (kurtosis: 1.91 vs 2.69, p < 0.01), suggesting a preserved HPV compared to patients treated with steroids. Moreover, patients exposed to steroids showed a significantly lower lung weight (953 gr vs 1140 gr, p = 0.01). A reduction in alveolar-arterial difference of oxygen followed the treatment with steroids (322 ± 106 mmHg at admission vs 267 ± 99 mmHg at DECT, p = 0.04). The use of steroids might cause impaired HPV and might reduce lung edema in severe COVID-19. This is consistent with previous findings in other diseases. Moreover, a reduced lung weight, as index of decreased lung edema, and a more homogeneous distribution of gas within the lung were shown in patients treated with steroids. Clinical Trials ID: NCT04316884, Registered March 13, 2020.


Adult attachment, emotion dysregulation, and symptoms of depression and generalized anxiety disorder.
Differences in attachment style have been linked to both emotion regulation and psychological functioning, but the emotion regulatory mechanism through which attachment style might impact symptoms of depression and anxiety is unclear. The present study examined the explanatory role of emotion dysregulation in the relation between adult attachment style and symptoms of depression and generalized anxiety disorder (GAD) in a sample of 284 adults. Secure attachment was associated with lower depression and GAD symptoms and lower emotion dysregulation, whereas insecure attachment styles were generally associated with higher depression and GAD scores and higher emotion dysregulation. Perceived inability to generate effective emotion regulation strategies mediated the relation between insecure attachment and both depression and GAD symptoms. Nonacceptance of negative emotions and inability to control impulsive behaviors emerged as additional mediators of the relation between insecure attachment styles and GAD symptoms. The differential contribution of attachment style and emotion regulation to the prediction of depression and GAD symptoms may reflect differences in vulnerability to depression and GAD.


Development of an Economical Method to Reduce the Extractable Latex Protein Levels in Finished Dipped Rubber Products.
Natural rubber latex (NRL) allergy is caused by the extractable latex proteins in dipped rubber products. It is a major concern for the consumers who are sensitive to the allergenic extractable proteins (EP) in products such as NRL gloves. Objective of this research was to develop an economical method to reduce the EP in finished dipped NRL products. In order to reduce the EP levels, two natural proteases, bromelain from pineapple and papain from papaya, were extracted and partially purified using (NH4)2SO4. According to the newly developed method, different glove samples were treated with a 5% solution of each partially purified enzyme, for 2 hours at 60°C. Residual amounts of in treated samples were quantified using the modified Lowry assay (ASTM D5712-10). Bromelain displayed a 54 (±11)% reduction of the EP from the dipped rubber products, whereas it was 58 (±8)% with papain. These results clearly indicate that the selected natural proteases, bromelain, and papain contribute significantly towards the reduction of the total EP in finished NRL products. Application of bromelain enzyme for the aforementioned purpose has not been reported up to date, whereas papain has been used to treat raw NRL towards reducing the EP.


Scavenging of As from acid mine drainage by schwertmannite and ferrihydrite: a comparison with synthetic analogues.
Ochreous precipitates containing 5.5-69.8 g/kg As were isolated from mine drainage in Finland and were composed of schwertmannite, ferrihydrite, and goethite. Schwertmannite formation was favored at pH 3-4, but its structure was degraded at high As levels. A series of coprecipitates were therefore prepared from mixed iron arsenate/sulfate solutions to define the limits of schwertmannite stability. Schwertmannite was replaced as the dominant phase by a poorly crystalline ironIII hydroxy arsenate (FeOHAs) when As/Fe mole ratios exceeded 0.15. The FeOHAs gave an X-ray diffraction pattern similar to that obtained from an "amorphous" ironIII arsenate (As/Fe = 1.0) with broad peaks at 0.30 and 0.16 nm. The FeOHAs possessed a magnetic hyperfinefield of 41.9T at 4.2 K that was intermediate to those of schwertmannite (46.1 T) and the ironIII arsenate (24.8 T). These data indicate a strong disruptive effect of arsenate on magnetic ordering and structure development in schwertmannite. Equilibration of 0.01 M arsenate solutions with freshly prepared schwertmannite and 2-line ferrihydrite at pH 3.0 for up to 60 d gave sorbed As contents of 175 and 210 g/kg, respectively. Arsenate sorption degraded the host schwertmannite and ferrihydrite, perhaps due to the formation of an FeOHAs surface phase.


Is recombinant activated factor VII effective in the treatment of excessive bleeding after paediatric cardiac surgery?
A best evidence topic in paediatric cardiac surgery was written according to a structured protocol. The question addressed was whether recombinant activated factor VII was effective for the treatment of excessive bleeding after paediatric cardiac surgery. Altogether 150 papers were found using the reported search; 13 papers were identified that provided the best evidence to answer the question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these studies were tabulated. A total of 311 children experienced excessive bleeding following cardiac surgery that was refractory to the conventional methods of achieving haemostasis. One hundred and ninety-two patients received the rFVIIa while 116 were in control arm from five studies. The primary end-point was on chest tube drainage, the plasma prothrombin time, the activated partial thromboplastin time after the administration of rFVIIa and the secondary end-point was reduction of blood products transfusion. Thrombosis was a complication in 8 patients (4.2%); three deaths (1.6%) but not attributable to thromboembolic events following the use of rFVIIa. Most of the studies failed to clearly state the doses but the extracted doses ranged between 30 and 180 µg/kg/dose, the interval between doses ranged between 15 and 120 min with a maximum of four doses. However, most of the patients had 180 µg/kg/dose with interval between dose of 2 h and maximum of two doses with dosage moderated with respect to weight, prior coagulopathy and responsiveness. There were two randomized studies with good sample size. One showed no significant differences in the secondary end points between the two arms and noted no adverse complications. However, the rFVIIa was used prophylactically. The other observed that there were no increase in thromboembolic events rather rFVIIa was effective in decreasing excessive bleeding that may complicate cardiac surgery in children. In conclusion, the studies were in support of the notion that the use of rFVIIa was effective in decreasing excessive bleeding which may complicate paediatric cardiac surgery, and care should be exercised when using it in the children on ECMO circuit.


Aquatic toxicology: past, present, and prospects.
Aquatic organisms have played important roles as early warning and monitoring systems for pollutant burdens in our environment. However, they have significant potential to do even more, just as they have in basic biology where preparations like the squid axon have been essential tools in establishing physiological and biochemical mechanisms. This review provides a brief summary of the history of aquatic toxicology, focusing on the nature of aquatic contaminants, the levels of contamination in our waters, and the origins of these agents. It considers the features of the aquatic environment that determine the availability of xenobiotics to aquatic life and the fate of foreign chemicals within the organism. Finally, toxic effects are considered with primary emphasis on the potential of aquatic models to facilitate identification of the underlying mechanisms of toxicity.


Detection of unknown ototoxic adverse drug reactions: an electronic healthcare record-based longitudinal nationwide cohort analysis.
Ototoxic medications can lead to significant morbidity. Thus, pre-marketing clinical trials have assessed new drugs that have ototoxic potential. Nevertheless, several ototoxic side effects of drugs may remain undetected. Hence, we sought to retrospectively investigate the potential risk of ototoxic adverse drug reactions among commonly used drugs via a longitudinal cohort study. An electronic health records-based data analysis with a propensity-matched comparator group was carried out. This study was conducted using the MetaNurse algorithm for standard nursing statements on electronic healthcare records and the National Sample Cohort obtained from the South Korea National Health Insurance Service. Five target drugs capable of causing ototoxic adverse drug reactions were identified using MetaNurse; two drugs were excluded after database-based analysis because of the absence of bilateral hearing loss events in patients. Survival analysis, log-rank test, and Cox proportional hazards regression models were used to calculate the incidence, survival rate, and hazard ratio of bilateral hearing loss among patients who were prescribed candidate ototoxic drugs. The adjusted hazard ratio of bilateral hearing loss was 1.31 (1.03-1.68), 2.20 (1.05-4.60), and 2.26 (1.18-4.33) in cimetidine, hydroxyzine, and sucralfate users, respectively. Our results indicated that hydroxyzine and sucralfate may cause ototoxic adverse drug reactions in patients. Thus, clinicians should consider avoiding co-administration of these drugs with other well-confirmed ototoxic drugs should be emphasized.


Discovery and Optimization of Chromeno[2,3-c]pyrrol-9(2H)-ones as Novel Selective and Orally Bioavailable Phosphodiesterase 5 Inhibitors for the Treatment of Pulmonary Arterial Hypertension.
Phosphodiesterase 5 (PDE5) inhibitors have been used as clinical agents to treat erectile dysfunction and pulmonary arterial hypertension (PAH). Herein, we detail the discovery of a novel series of chromeno[2,3-c]pyrrol-9(2H)-one derivatives as selective and orally bioavailable inhibitors against phosphodiesterase 5. Medicinal chemistry optimization resulted in 2, which exhibits a desirable inhibitory potency of 5.6 nM with remarkable selectivity as well as excellent pharmacokinetic properties and an oral bioavailability of 63.4%. In addition, oral administration of 2 at a dose of 5.0 mg/kg caused better pharmacodynamics effects on both mPAP (mean pulmonary artery pressure) and RVHI (index of right ventricle hypertrophy) than sildenafil citrate at a dose of 10.0 mg/kg. These activities along with its reasonable druglike properties, such as human liver microsomal stability, cytochrome inhibition, hERG inhibition, and pharmacological safety, indicate that 2 is a potential candidate for the treatment of PAH.


Outcome and failure patterns of localized sinonasal lymphoma in cats treated with first-line single-modality radiation therapy: A retrospective study.
Failure rate and site are not well defined in localized sinonasal lymphoma in cats treated with radiotherapy. In this study, we describe (a) failure pattern, (b) outcome, (c) influence of previously reported prognostic variables on the outcome in cats with suspected localized sinonasal lymphoma. In this multi-institutional retrospective study, we included 51 cats treated with single-modality radiotherapy. Cats were irradiated using 10x4.2Gy (n = 32), 12x3Gy (n = 11) or 5x6Gy (n = 8). Regional lymph nodes were prophylactically irradiated in 24/51 cats (47.1%). Twenty-five cats (49.0%) developed progressive disease: progression was local (nasal) in five (9.8%), locoregional (nodal) in two (3.9%), local and locoregional in three (5.9%), systemic in nine (17.6%) and both local and systemic in six cats (11.8%). No cat receiving prophylactic nodal irradiation had progression in the locoregional lymph nodes. The median time to progression was 974 days (95%CI: 283;1666), with 58% and 53% of cats free of progression at 1 and 2 years, respectively. Median overall survival was 922 days (95%CI: 66;1779) with 61% and 49% alive at 1 and 2 years, respectively. Half of the cats that died of relapse/progression (13/26) died within 6 months of treatment, suggesting possible shortcomings of staging, rapid dissemination of disease or sequential lymphomagenesis. None of the prognostic factors evaluated were predictive of outcome (prednisolone use, anaemia, nasopharyngeal involvement, modified canine Adams tumour stage, protocol, total dose). Radiotherapy is an effective treatment for localized sinonasal lymphoma with a long time to progression. However, in one-third of the cats, systemic disease progression occurs soon after radiotherapy.


Threshold perimetry and the diagnosis of glaucoma.
Visual field examinations are one of the commonest, presumably most sensitive practical indices of optic nerve dysfunction in glaucoma. Given the difficulties in training and retaining good technicians, and presumed vagaries of the Goldmann-type isopter examination technique, interest has turned to computer-controlled automated suprathreshold and threshold static perimetry. Despite the enthusiasm for these approaches, we lack rigorous tests of their value, criteria of abnormality and progressive deterioration, and even normal standards. These important issues are now being addressed. In the interim ophthalmologists must be cautious in their use and interpretation.


Anterolateral Thigh Flap for Low-Voltage Fourth-Degree Electrical Burn Injury With Immediate Radial Nerve Palsy at the Elbow: A Case Report.
While high-voltage electrical injuries usually cause severe burn wounds and axonal polyneuropathy, low-voltage electrical injuries cause limited cutaneous wounds and demyelinating mononeuropathy, of which the median and ulnar nerves are the most commonly involved. We present the case of a 42-year-old man who suffered a 480-voltage electrical injury at his right elbow, resulting in a 24 × 10 cm fourth-degree burn wound and immediate radial nerve palsy. The burn wound was debrided with confirmation and preservation of radial nerve continuity. The wound was covered with a free anterolateral thigh flap and it healed uneventfully. The Tinel's sign continued to advance at follow-up, and electrodiagnostic studies showed progressive reinnervation. His radial nerve function recovered completely in 9 months. This is a rare case of low-voltage electrical injury with a fourth-degree burn wound and immediate radial nerve palsy. We treated the wound aggressively with early debridement and prompt flap coverage, but conservatively treated the radial nerve injury. The nerve recovery course indicates that it had a "shocked-cooked" injury and served itself as a well-placed nerve graft for the subsequent regeneration. We believe that our successful outcome in this case can provide more insights into the management of such injuries.