Effects of platelet-activating factor on the release of arachidonic acid and prostaglandins by rabbit iris smooth muscle. Inhibition by calcium channel antagonists.
Addition of physiological concentrations (10(-12)-10(-8)M) of platelet-activating factor (PAF) to rabbit iris muscle induced a rapid release (in 15s) of prostaglandin (PG)E2 and 6-oxo-PGF1 alpha, measured by radioimmunoassay and rapid release of 14C-labelled arachidonate and PGE2 in muscle prelabelled with [14C]arachidonic acid, measured by radiochromatography. These PAF actions are concentration- and time-dependent. The effect of PAF on PG release is not mediated through the cyclo-oxygenase pathway. The studies on the properties and mechanism of arachidonate release from phosphatidylinositol and other phospholipids in prelabelled irides by PAF suggest the involvement of a phospholipase A2. This conclusion is supported by the findings: (a) that both the removal of arachidonate and formation of lysophosphatidylinositol, from phosphatidylinositol, by PAF occur concomitantly in a time-dependent manner, (b) that Ca2+ is required for the agonist-induced release of arachidonate and PGE2, and (c) that in contrast to the rapid release of [3H]myo-inositol phosphates by carbachol and other Ca2+-mobilizing agonists previously reported in the iris muscle [Akhtar & Abdel-Latif (1984) Biochem. J. 224, 291-300], PAF (10(-12)-10(-8)M) did not appreciably enhance the release of [14C]myo-inositol phosphates and 32P labelling of phosphatidate and phosphatidylinositol in this tissue. Ca2+-channel antagonists, such as nifedipine, verapamil, diltiazem and manganese inhibited PAF-induced arachidonate and PGE2 release in a dose-dependent manner. K+ depolarization, which causes influx of extracellular Ca2+ in smooth muscle, did not increase the release of arachidonate and PGE2. The ability of Ca2+ antagonists to inhibit arachidonate release by PAF in this tissue probably reflects interference with PAF binding to its receptor. The PAF-induced release of arachidonate and PGE2 occur independently of the cyclo-oxygenase and lipoxygenase pathways. Whether the PAF-induced release of arachidonate and PG in the iris muscle is involved in the pathogenesis of inflammatory and/or physiological reactions in the eye, and how much the inhibitory effects of Ca2+-entry blockers on the PAF actions contribute to the therapeutic use of these drugs, remain to be established.


Prevalence and Factors Associated with Multidrug-Resistant Tuberculosis (MDR-TB) among Presumptive MDR-TB Patients in Tigray Region, Northern Ethiopia.
Tuberculosis (TB) is one of the major public health problems. There are alarming reports of increasing multidrug-resistant tuberculosis (MTR-TB) from various parts of the globe, including Ethiopia. This study was designed to determine the prevalence and factors associated with MDR-TB among presumptive MDR-TB cases in Tigray Regional State, Ethiopia. A cross-sectional study was conducted in Tigray Regional State from 2015 to 2016. Two hundred sputum samples were collected, transported, processed using 2% N-acetyl-L-cysteine-sodium hydroxide, and cultured in LJ medium. Besides, the microscopic examination was performed after ZN staining. Moreover, drug susceptibility test was done using molecular line probe assay. Descriptive statistics and binary and multivariable logistic regression were done. A statistical test was regarded as significant when the P value was <0.05. The prevalence of MDR-TB was found to be 18.5%. About one-fourth (26.5%) of the study participants had sputum smear positive for acid-fast bacilli (AFB). TB culture was positive in 37% of the samples, and rifampicin mono-resistant cases accounted for 3.5% of the presumptive MDR-TB cases. Three (1.5%) were new MDR-TB cases, while the rest had been treated previously for TB. Most (63.5%) of the MDR-TB cases were from 15 to 44 years of age. Age was associated with MDR-TB with a crude odds ratio of 1.06 (CI: 1.02-1.10) and adjusted odds ratio of 1.06 (CI: 1.00-1.11). The prevalence of MDR-TB was found to be high. Preventive measures should be taken to prevent the transmission of MDR-TB in the community.


Detection and quantification of melphalan-DNA adducts at the single cell level in hematopoietic tumor cells.
Bifunctional alkylating agents, such as melphalan, are widely used in the treatment of hematological malignancies. The effects of these drugs on particular types of hematological cells and the causes of treatment failure are poorly understood. The aim of this work was to establish an ability to measure the extent to which melphalan reacts with the DNA of individual tumor cells, thereby creating new possibilities for molecular pharmacological studies on clinical samples. A novel approach for staining drug-DNA adducts is described in which cells were embedded in agarose and then lysed. The DNA from each cell remained in an ideal state for quantitative immunofluorescent staining using a previously described monoclonal antibody. Immunofluorescence and DNA-Hoechst dye fluorescence were quantified using a cooled slow scan charge coupled device camera and image analysis procedures. Immunofluorescence of drug-treated cells from a human leukemia cell line was partially correlated with DNA content. Mean integrated immunofluorescence of 50 to 100 cells was dependent on drug concentration and was linearly related to adduct levels. In these cells and in chronic lymphocytic leukemia cells obtained from patients, there was considerable intercell heterogeneity in apparent adduct levels. This was also seen in peripheral blood mononuclear cells isolated from a patient after melphalan therapy.


SARS-CoV-2 Aerosol Transmission Indoors: A Closer Look at Viral Load, Infectivity, the Effectiveness of Preventive Measures and a Simple Approach for Practical Recommendations.
There is uncertainty about the viral loads of infectious individuals required to transmit COVID-19 via aerosol. In addition, there is a lack of both quantification of the influencing parameters on airborne transmission and simple-to-use models for assessing the risk of infection in practice, which furthermore quantify the influence of non-medical preventive measures. In this study, a dose-response model was adopted to analyze 25 documented outbreaks at infection rates of 4-100%. We show that infection was only possible if the viral load was higher than 108 viral copies/mL. Based on mathematical simplifications of our approach to predict the probable situational attack rate (PARs) of a group of persons in a room, and valid assumptions, we provide simplified equations to calculate, among others, the maximum possible number of persons and the person-related virus-free air supply flow necessary to keep the number of newly infected persons to less than one. A comparison of different preventive measures revealed that testing contributes the most to the joint protective effect, besides wearing masks and increasing ventilation. In addition, we conclude that absolute volume flow rate or person-related volume flow rate are more intuitive parameters for evaluating ventilation for infection prevention than air exchange rate.


The radiation response of androgen-refractory prostate cancer cell line C4-2 derived from androgen-sensitive cell line LNCaP.
Radiation therapy is a relatively effective therapeutic method for localized prostate cancer (PCa) patients. However, radioresistance occurs in nearly 30% of patients treated with potentially curative doses. Therapeutic synergy between radiotherapy and androgen ablation treatment provides a promising strategy for improving the clinical outcome. Accordingly, the androgen deprivation-induced signaling pathway may also mediate radiosensitivity in PCa cells. The C4-2 cell line was derived from the androgen-sensitive LNCaP parent line under androgen-depleted condition and had acquired androgen-refractory characteristics. In our study, the response to radiation was evaluated in both LNCaP and C4-2. Results showed that C4-2 cells were more likely to survive from irradiation and appeared more aggressive in their resistance to radiation treatment compared with LNCaP, as measured by clonogenic assays and cell viability and cell cycle analyses. Gene expression analyses revealed that a set of genes involved in cell cycle arrest and DNA repair were differentially regulated in LNCaP and C4-2 in response to radiation, which was also consistent with the radiation-resistant property observed in C4-2 cells. These results strongly suggested that the radiation-resistant property may develop with progression of PCa to androgen-independent status. Not only can the LNCaP and C4-2 PCa progression model be applied for investigating androgen-refractory progression, but it can also be used to explore the development of radiation resistance in PCa.


Alveolar bone height according to the anatomical relationship between the maxillary molar and sinus.
The aim of this study was to investigate the available alveolar bone height between the maxillary molars and the sinus floor according to their anatomical relationship using cone-beam computed tomographic (CBCT) images. A total of 752 maxillary first (M1) and second molars (M2) on CBCT scans of 188 patients were selected. First, each maxillary molar was categorized as type 1, 2, 3, or 4 according to the relationship of the molar root with the maxillary sinus floor. The frequency distribution of each type was analyzed. Second, the shortest vertical distance (VD) of each molar was measured from the furcation midpoints of the roots to the lowest point of the sinus floor by 2 observers. Intraclass correlation coefficients and the t-test were calculated for the VD measurements. For M1, type 3 was the most frequent, followed by type 2. For M2, type 3 was the most common, followed by type 1. The VD measurements of type 1 were 9.51±3.68 mm and 8.07±2.73 mm for M1 and M2, and those of type 3 were 3.70±1.52 mm and 4.03±1.53 mm for M1 and M2, respectively. The VD measurements of M2 were significantly higher in female patients than in male patients. Type 3 was the most frequent anatomical relationship in the maxillary molars, and showed the lowest alveolar bone height. This information will help clinicians to prevent complications related to the maxillary sinus during maxillary molar treatment and to predict the available bone height for immediate implant planning.


Integrated cardiac and peripheral vascular response to atriopeptin 24 in conscious dogs.
Little attention has been directed toward the action of atrial peptides on integrated cardiovascular function. In conscious dogs intravenous injection of atriopeptin 24 (10 micrograms/kg) reduced mean arterial pressure (11 +/- 3.2%), mean left atrial pressure (32 +/- 8.6%), left ventricular (LV) end-diastolic pressure (24 +/- 4.3%), and increased heart rate (25 +/- 6.2%). LV dP/dt and stroke volume increased 17 +/- 4.0 and 12 +/- 3.3%, respectively. Cardiac output increased 39 +/- 6.3%. These effects were only acute, lasting less than 10 min. The tachycardia and increase in LV dP/dt were abolished by combined beta-adrenergic and muscarinic cholinergic blocking agents. During an infusion of atriopeptin 24 (10 micrograms X kg-1 X min-1) blood flow, as measured with radioactive microspheres, increased to both the left (101 +/- 35%) and right kidney (122 +/- 37%) and to the spleen (140 +/- 50%). However, blood flow to the stomach, large and small intestine, pancreas, liver, and skeletal muscle did not change, indicating the selectivity of the atriopeptin. Blood flow in the right ventricle, septum, and in all layers of the left ventricle increased slightly, resulting in no change in the endocardial-to-epicardial blood flow ratio most likely due to the changes in myocardial function, i.e., heart rate and stroke volume. Thus, in conscious dogs, atriopeptins increase myocardial performance most likely indirectly secondary to baroreflex unloading after the direct hypotensive effects of atriopeptin 24. This serves to increase cardiac output at a time when renal and splenic blood flows are increased.


Advanced techniques for constrained internal coordinate molecular dynamics.
Internal coordinate molecular dynamics (ICMD) methods provide a more natural description of a protein by using bond, angle, and torsional coordinates instead of a Cartesian coordinate representation. Freezing high-frequency bonds and angles in the ICMD model gives rise to constrained ICMD (CICMD) models. There are several theoretical aspects that need to be developed to make the CICMD method robust and widely usable. In this article, we have designed a new framework for (1) initializing velocities for nonindependent CICMD coordinates, (2) efficient computation of center of mass velocity during CICMD simulations, (3) using advanced integrators such as Runge-Kutta, Lobatto, and adaptive CVODE for CICMD simulations, and (4) cancelling out the "flying ice cube effect" that sometimes arises in Nosé-Hoover dynamics. The Generalized Newton-Euler Inverse Mass Operator (GNEIMO) method is an implementation of a CICMD method that we have developed to study protein dynamics. GNEIMO allows for a hierarchy of coarse-grained simulation models based on the ability to rigidly constrain any group of atoms. In this article, we perform tests on the Lobatto and Runge-Kutta integrators to determine optimal simulation parameters. We also implement an adaptive coarse-graining tool using the GNEIMO Python interface. This tool enables the secondary structure-guided "freezing and thawing" of degrees of freedom in the molecule on the fly during molecular dynamics simulations and is shown to fold four proteins to their native topologies. With these advancements, we envision the use of the GNEIMO method in protein structure prediction, structure refinement, and in studying domain motion.


Mycoplasma genitalium: should we treat and how?
Mycoplasma genitalium is associated with acute and chronic urethritis in men. Existing data on infection in women are limited and inconsistent but suggest that M. genitalium is associated with urethritis, cervicitis, pelvic inflammatory disease, and possibly female infertility. Data are inconclusive regarding the role of M. genitalium in adverse pregnancy outcomes and ectopic pregnancy. Available data suggest that azithromycin is superior to doxycycline in treating M. genitalium infection. However, azithromycin-resistant infections have been reported in 3 continents, and the proportion of azithromycin-resistant M. genitalium infection is unknown. Moxifloxacin is the only drug that currently seems to uniformly eradicate M. genitalium. Detection of M. genitalium is hampered by the absence of a commercially available diagnostic test. Persons with persistent pelvic inflammatory disease or clinically significant persistent urethritis or cervicitis should be tested for M. genitalium, if possible. Infected persons who have not previously received azithromycin should receive that drug. Persons in whom azithromycin therapy fails should be treated with moxifloxicin.


Genotype/phenotype relationships in HNF-4alpha/MODY1: haploinsufficiency is associated with reduced apolipoprotein (AII), apolipoprotein (CIII), lipoprotein(a), and triglyceride levels.
Hepatocyte nuclear factor (HNF)-4alpha is a transcription factor that plays an important role in regulation of gene expression in pancreatic beta-cells and in the liver. Heterozygous mutations in the HNF-4alpha gene are responsible for maturity-onset diabetes of the young 1 (MODY1), which is characterized by pancreatic beta-cell-deficient insulin secretion. HNF-4alpha is a major transcriptional regulator of many genes expressed in the liver. However, no liver defect has been identified in individuals with HNF-4alpha mutations. In this study, we have identified HNF-4alpha target genes that are mainly expressed in the liver, including alpha1-antitrypsin, alpha1-antichymotrypsin, alpha-fetal protein, ceruloplasmin, IGF binding protein 1, transferrin, apolipoprotein(AI) [apo(AI)], apo(AII), apo(B), and apo(CIII). Serum levels of these proteins and Lp(a) and triglycerides were measured in 24 members of the HNF-4alpha/MODY1 RW pedigree (Q268X mutation), including 12 diabetic patients with HNF-4alpha mutations (D-HNF4+/-), 6 nondiabetic subjects with HNF-4alpha mutations (N-HNF4+/-), 6 normal relatives (N-HNF4+/+), 6 unrelated normal matched control subjects (N-HNF4+/+), and 12 matched diabetic (non-MODY1-5) patients (D-HNF4+/+). Serum levels of apo(AII), apo(CIII), lipoprotein(a) [Lp(a)], and triglyceride were significantly reduced in HNF4+/- subjects (26.9, 19.8, 12.1, and 72.1 mg/dl, respectively) compared with HNF4+/+ subjects (37.4, 26.5, 45.2, and 124.2 mg/dl, respectively) (P = 0.00001, P = 0.01, P = 0.00006, and P = 0.000003, respectively). This reduction was not found when apo(AII), apo(CIII), Lp(a), and triglyceride levels were compared in D-HNF4+/- versus N-HNF4+/- or in D-HNF4+/+ versus N-HNF4+/+ subjects, which indicates that HNF-4alpha haploinsufficiency rather than hyperglycemia is the primary cause of decreased serum protein and triglyceride concentrations. Furthermore, we determined that genetic or environmental modifiers other than HNF-4alpha do not appear to contribute to the observed decrease of HNF-4alpha-regulated serum proteins. This study demonstrates that a heterozygous HNF-4alpha mutation leads to an HNF-4alpha-dependent hepatocyte secretory defect of liver-specific proteins.


Improvising 5-HT7R homology model for design of high affinity ligands: model validation with docking, embrace minimization, MM-GBSA, and molecular dynamic simulations.
The subtype, 5-HT7R has been implicated in neurological disorders and presents itself as a promising target for antidepressant drugs. Design of targeted selective ligands, require a sound knowledge of 3D-receptor structure. In absence of receptor structure, structure-based design of targeted ligands relies on generation of 5-HT7R homology model. In this study, the impact of template choice, alignment, and model building methods on the homology model of 5-HT7R is addressed. The compactness and model quality due to the presence of cholesterol (lipidic receptor) have also been observed. The results suggest good stereochemical quality of the final model. Ramachandran Plot Analysis indicated more than 97.5% amino acid residues in the favorable region. The overall quality factor was 91.8% using ERRAT. The Z-score for backbone confirmation and packing quality were -1.248 and -1.427, respectively, using WHATCHECK. The RMS Z-score for side chain planarity was .711. Other validation results for the final model include binding site analysis in which Asp162, Val163, Phe343, Phe344, Arg350, Arg367, and Leu370 conserved residues were found in the active site, correlation coefficient of .82 in ligand-based screening and .85 in embrace minimization. Further, the model showed good correlation for agonist and antagonist in docking ([Formula: see text] ≈ .76, [Formula: see text] ≈ .82), embrace minimization ([Formula: see text] ≈ .73, [Formula: see text] ≈ .72), and MM-GBSA ([Formula: see text] ≈ .69, [Formula: see text] ≈ .75) studies. The model was subjected to Molecular Dynamics (MD) simulation of 20 ns both in ligand-free and ligand-bound receptor (agonist and antagonist) system in order to assess its stability.


Value of imaging in disorders of the facial nerve.
Imaging of the facial nerve has proved its usefulness to physicians in the evaluation of pathological conditions of this nerve. Magnetic resonance imaging (MRI) of the facial nerve should always be obtained selectively and should include the parotid gland in case of peripheral facial nerve palsy. Gadolinium-DTPA contrast pulse sequence is the most informative MRI study for evaluation of facial nerve pathology. This article reviews the imaging anatomy of the facial nerve and describes the clinical features and MR characteristics of common disorders of the facial nerve.


Estimation of Biological Parameters of Cutaneous Ulcers Caused by Leishmaniasis in an Animal Model Using Diffuse Reflectance Spectroscopy.
Cutaneous leishmaniasis (CL) is a neglected tropical disease that requires novel tools for its understanding, diagnosis, and treatment follow-up. In the cases of other cutaneous pathologies, such as cancer or cutaneous ulcers due to diabetes, optical diffuse reflectance-based tools and methods are widely used for the investigation of those illnesses. These types of tools and methods offer the possibility to develop portable diagnosis and treatment follow-up systems. In this article, we propose the use of a three-layer diffuse reflectance model for the study of the formation of cutaneous ulcers caused by CL. The proposed model together with an inverse-modeling procedure were used in the evaluation of diffuse-reflectance spectral signatures acquired from cutaneous ulcers formed in the dorsal area of 21 golden hamsters inoculated with Leishmanisis braziliensis. As result, the quantification of the model's variables related to the main biological parameters of skin were obtained, such as: diameter and volumetric fraction of keratinocytes, collagen; volumetric fraction of hemoglobin, and oxygen saturation. Those parameters show statistically significant differences among the different stages of the CL ulcer formation. We found that these differences are coherent with histopathological manifestations reported in the literature for the main phases of CL formation.


Nonadiabatic Excited-State Molecular Dynamics for Open-Shell Systems.
Nonadiabatic Molecular Dynamics (NAMD) of excited states has been widely used in the simulation of photoinduced phenomena. However, the inability to treat bond breaking and forming processes with single-reference electronic structure methods limits their application in photochemistry for extended molecular systems. In this work, the extension of excited-state NAMD for open-shell systems is developed and implemented in the NEXMD software. We present the spin-unrestricted CIS and TD-SCF formalism for the ground and excited states, analytical derivatives, and nonadiabatic derivative couplings for the respective potential energy surfaces. This methodology is employed to study the photochemical reaction of three model molecules. The results demonstrate the advantage of the open-shell approach in modeling photochemical reactions, especially involving bond breaking processes. We find that the open-shell method lowers the reaction barrier at the bond-breaking limits resulting in larger calculated photochemical quantum yields compared to the respective closed-shell results. We also address problems related to spin contamination in the open-shell method, especially when molecular geometries are far from equilibrium.


Use of Mintzberg's model of managerial roles to evaluate academic administrators.
Quantitative and qualitative methods were used to measure the administrative activities of physician assistant (PA) department chairpersons as compared with Henry Mintzberg's model of managerial roles. The use of Mintzberg's model is unique in that it was developed from observations in the corporate setting but was applied here in an academic setting. Both PA department chairpersons (n = 77) and PA faculty (n = 94) identified Mintzberg's leader role as one that was used most by PA chairpersons and one that was viewed as most important as perceived by PA chairpersons and faculty. Both groups agreed that PA chairpersons were more concerned about functioning in the interpersonal realms of Mintzberg's managerial roles as opposed to the informational and decisional realms, and there was a great deal of unanimity about the perceived role use and importance of the roles in regard to the job of a PA chairperson. This finding was important according to Mintzberg's model because it is through leader role use that PA chairpersons can weld diverse elements into a cooperative enterprise (an important aspect of managing academic departments). Chairpersons and faculty were given the opportunity to identify other constructs not covered by Mintzberg's model in an effort to include other roles unique to PA education. Although a handful of roles were identified, when compared with Mintzberg's model, each one matched an existing role defined in the model. These data indicate that both chairpersons and faculty were in agreement with the way Mintzberg's model can describe PA chairperson roles.


Surgical management of sinonasal inverted papillomas through endoscopic approach.
We defined a standardized approach to surgery of sinonasal inverted papillomas (IP) for adequate and safe resection. A cohort of 65 patients treated from January 1995 to December 2005 at a single institution was retrospectively analyzed (mean follow-up: 28 months; range 1-132). The extension of the tumor was evaluated on clinical findings and computed tomography (CT) scan and/or resonance magnetic imaging (RMI). External and endoscopic surgical approaches were compared according to tumor extension, rate of local recurrence. Univariate analysis was used to review the impact on disease-free survival of factors related to the histopathological findings and the treatment. Endoscopic (alone or combined with transantral approach) and external surgery were used in 46 patients (71%) and 19 patients, respectively. Endoscopic approach (34/46) was performed to control IP in the nasal fossa, the ostiomeatal complex, the sphenoid sinus. It was combined with Caldwell-Luc procedure (12/46) for tumor extent into the lateral part of the maxillary sinus. The mean time for recurrences to occur was 19 months with range of 5-35 months. The rate of local recurrence was 17.6% (6/34) in endoscopic approach alone, 8.3% in endoscopic approach combined with a Caldwell-Luc procedure and 15.8% (3/19) in external approach. Tumor extension, excision with safe margins, associated malignancy or dysplasia have no significant impact on disease-free survival regardless of surgical procedure. On the basis of imaging evaluation and peroperative view of tumor extent, we propose a surgical strategy in which endoscopic approach could be used on the first attempt by trained surgeons. RMI is very useful to determine acute extent of the disease.


Regulation of apoptosis and neurite extension by FKBP38 is required for neural tube formation in the mouse.
FKBP38 (also known as FKBP8) is a transmembrane chaperone protein that inhibits apoptosis by recruiting the anti-apoptotic proteins Bcl-2 and Bcl-x(L) to mitochondria. We have now generated mice harboring a loss-of-function mutation in Fkbp38. The Fkbp38(-/-) mice die soon after birth manifesting defects in neural tube closure in the thoraco-lumbar-sacral region (spina bifida) as well as skeletal defects including scoliosis, rib deformities, club foot and curled tail. The neuroepithelium is disorganized and that formation of dorsal root ganglia is defective in Fkbp38(-/-) embryos, likely as a result of an increased frequency of apoptosis and aberrant migration of neuronal cells. Furthermore, the extension of nerve fibers in the spinal cord is abnormal in the mutant embryos. To explore the mechanisms underlying these characteristics, we screened for proteins that interact with FKBP38 in the yeast two-hybrid system and thereby identified protrudin, a protein that promotes process formation by regulating membrane trafficking. Protrudin was found to be hyperphosphorylated in the brain of Fkbp38(-/-) mice, suggesting that FKBP38 regulates protrudin-dependent membrane recycling and neurite outgrowth. Together, our findings suggest that FKBP38 is required for neuroectodermal organization during neural tube formation as a result of its anti-apoptotic activity and regulation of neurite extension.


Activated protein C.
Protein C is a vitamin K-dependent plasma protein zymogen whose genetic mild or severe deficiencies are linked with risk for venous thrombosis or neonatal purpura fulminans, respectively. Studies over past decades showed that activated protein C (APC) inactivates factors (F) Va and VIIIa to down-regulate thrombin generation. More recent basic and preclinical research on APC has characterized the direct cytoprotective effects of APC that involve gene expression profile alterations, anti-inflammatory and anti-apoptotic activities and endothelial barrier stabilization. These actions generally require endothelial cell protein C receptor (EPCR) and protease activated receptor-1. Because of these direct cytoprotective actions, APC reduces mortality in murine endotoxemia and severe sepsis models and provides neuroprotective benefits in murine ischemic stroke models. Furthermore, APC reduces mortality in patients with severe sepsis (PROWESS clinical trial). Although much remains to be clarified about mechanisms for APC's direct effects on various cell types, it is clear that APC's molecular features that determine its antithrombotic action are partially distinct from those providing cytoprotective actions because we have engineered recombinant APC variants with selective reduction or retention of either anticoagulant or cytoprotective activities. Such APC variants can provide relatively enhanced levels of either cytoprotective or anticoagulant activities for various therapeutic applications. We speculate that APC variants with reduced anticoagulant action but normal cytoprotective actions hold the promise of reducing bleeding risk because of attenuated anticoagulant activity while reducing mortality based on direct cytoprotective effects on cells.


Characterization of hybrid organo-silica monoliths for possible application in the gradient elution of peptides.
We characterized thermally polymerized organo-silica hybrid monolithic capillaries to test their applicability in the gradient elution of peptides. We have used a single-pot approach utilizing 3-(methacryloyloxy)propyltrimethoxysilane (MPTMS), ethylene dimethacrylate (EDMA), and n-octadecyl methacrylate (ODM) as functional monomers. The organo-silica monolith containing MPTMS and EDMA was compared with the stationary phase prepared by adding ODM to the original polymerization mixture. Column prepared using a three-monomer system provided a lower accessible volume of flow-through pores, a higher proportion of mesopores, and higher efficiency. We utilized isocratic and gradient elution data to predict peak widths in gradient elution. Both protocols provided comparable results and can be used for peptide peak width prediction. However, applying gradient elution data for peak width prediction seems simpler. Finally, we tested the effect of gradient time on achievable peak capacity in the gradient elution of peptides with a column prepared with a three-monomer system providing a higher peak capacity. However, the performance of hybrid organo-silica monolithic stationary phases in gradient elution of peptides must be improved compared to other monolithic stationary phases. The limiting factor is column efficiency in highly aqueous mobile phases, which needs to be focused on.


The periodontal health of adult Nepalese.
There exists meagre information on the prevalence of periodontal conditions among adults in Nepal. Therefore, appropriate data on periodontal conditions are needed to facilitate planning, monitoring and evaluation of oral health programmes. The objective of the present study was to determine the prevalence of periodontal conditions among adults aged between 33 and 97 years in Nepal and also to elucidate any possible risk predictors of periodontal problems. The total subjects included in the present study were 1210 (33 to 49 years [n = 596] and 50 to 97 years [n = 614]). Community Periodontal Index scores were used to assess the periodontal status of the selected subjects. Self-reported data were used to ascertain oral health behaviour. Logistic regression analyses showed the following observations for the age group 33 to 49 years: (1) bleeding was more likely found among those subjects who resided in rural areas and upper hill terrain, and among those who used non-fluoridated dentifrice; (2) bleeding was, however, less likely to be observed among those with primary or unfinished secondary school education (PSE); (3) calculus deposits were accentuated in illiterates, whereas less calculus formation was experienced by alcohol users; (4) periodontal pocket 4 to 5 mm was predominantly seen among illiterates and those with PSE, smokers and those who used non-fluoridated dentifrice; (5) periodontal pocket v 6 mm was observed among illiterates and those with PSE and those who used non-fluoridated dentifrice. With regard to 50 years old and above, the following observations were noticed: (1) bleeding was associated with the use of non-fluoridated dentifrice; (2) chewing betel nut showed a protective effect with regard to calculus formation; (3) being illiterate increased the likelihood of having periodontal pockets 6 mm or more in depth. Several findings of the present study are in concordance with empirical evidence. However, the protective effect of alcohol and betel nut against calculus formation needs to be investigated further.


A genomic island, termed high-pathogenicity island, is present in certain non-O157 Shiga toxin-producing Escherichia coli clonal lineages.
Shiga toxin-producing Escherichia coli (STEC) strains cause a wide spectrum of diseases in humans. In this study, we tested 206 STEC strains isolated from patients for potential virulence genes including stx, eae, and enterohemorrhagic E. coli hly. In addition, all strains were examined for the presence of another genetic element, the high-pathogenicity island (HPI). The HPI was first described in pathogenic Yersinia species and encodes the pesticin receptor FyuA and the siderophore yersiniabactin. The HPI was found in the genome of distinct clonal lineages of STEC, including all 31 eae-positive O26:H11/H(-) strains and 7 of 12 eae-negative O128:H2/H(-) strains. In total, the HPI was found in 56 (27.2%) of 206 STEC strains. However, it was absent from the genome of all 37 O157:H7/H(-), 14 O111:H(-), 13 O103:H2, and 13 O145:H(-) STEC isolates, all of which were positive for eae. Polypeptides encoded by the fyuA gene located on the HPI could be detected by using immunoblot analysis in most of the HPI-positive STEC strains, suggesting the presence of a functional yersiniabactin system. The HPI in STEC was located next to the tRNA gene asnT. In contrast to the HPI of other pathogenic enterobacteria, the HPI of O26 STEC strains shows a deletion at its left junction, leading to a truncated integrase gene int. We conclude from this study that the Yersinia HPI is disseminated among certain clonal subgroups of STEC strains. The hypothesis that the HPI in STEC contributes to the fitness of the strains in certain ecological niches rather than to their pathogenic potential is discussed.


Longitudinal analysis of the associations between antiretroviral therapy, viraemia and immunosuppression with lipid levels: the D:A:D study.
Antiretroviral (ART) drugs have been associated with higher triglycerides (TG), higher total cholesterol (TC) and lower high-density lipoprotein cholesterol (HDL-C) levels. Associations between lipid levels with HIV viraemia and immunosuppression in the presence of ART remain unclear. Participants from the D:A:D study with at least one TG/TC/HDL-C measurement were included. Linear mixed effect models were used to determine the association of ART, viral load (VL), nadir and current CD4+ T-cell count and previous AIDS diagnosis with lipids. Of 49,717 participants, 90%, 92% and 80% contributed at least one TG/TC/HDL-C measurement (median follow-up 6.8, 6.8 and 5.0 years, respectively). Predicted mean (95% CI) baseline levels for TG, TC and HDL-C (mmol/l), were 2.10 (2.05, 2.14), 4.94 (4.91, 4.98) and 1.08 (1.07, 1.10), respectively. Lopinavir was associated with the worst TG profile, (27.2% higher levels compared to atazanavir; 95% CI 25.2%, 29.2%), and darunavir had a similar profile as atazanavir. The nucleoside pair lamivudine/tenofovir was associated with the most favourable TG profile (-2.8%; -3.5%, -2.0%) compared with emtricitabine/tenofovir, whereas lamivudine/abacavir (+10.2%; +9.3%, +11.2%) and lamivudine/stavudine (+8.0%; +6.9%, +9.0%), were associated with the worst. Raltegravir was associated with lower TG (-5.2%; -6.4%, -3.9%), and nevirapine had a more favourable HDL-C profile (+11.3%; +10.8%, +11.7%) than efavirenz (+5.3%; 5.0%, 5.7%), compared to atazanavir. Higher VLs were associated with lower TG/TC/HDL-C, whereas higher CD4+ T-cell counts were associated with higher TG/TC/HDL-C. TG, TC and HDL-C levels, which generally improved over time, are dependent on ART, viraemia and, to a lesser extent, immunosuppression.


[Mycobacterium genavense infection in 2 HIV seropositive patients in Amsterdam].
Two patients with an HIV-I infection, a man aged 47 with confusion, aphasia and diarrhoea, and a man aged 32 with dysphagia, a non-productive cough and diarrhoea, were diagnosed as having a disseminated Mycobacterium genavense infection. Both had low counts of CD4+ T lymphocytes. They responded to antimycobacterial treatment. M. genavense was recognized in Geneva in the early nineties as a causative agent of disseminated mycobacterial infections in HIV-seropositive patients with poor cellular immunity. The clinical picture resembles that of a generalized infection with M. avium-intracellulare. M. genavense is a slowly growing mycobacterium which can be isolated and identified using enriched nutrient media and molecular-biological techniques. The infection probably begins in the gastrointestinal tract after oral contamination. DNA of M. genavense can be demonstrated in 25% of the intestinal biopsy samples of non-HIV-seropositive patients.


Nitrogen-Rich Copper(II) Bromate Complexes: an Exotic Class of Primary Explosives †.
Because of the ongoing very challenging search for potential replacements of the currently used toxic lead-based primary explosives, new synthetic strategies have to be developed. In particular, the smart concept of energetic coordination compounds (ECC) has proven to hold great potential to solve this difficult and complex problem. The herein-described approach combines the exotic and neglected class of copper(II) bromate ECC with different environmentally friendly nitrogen-rich heterocycles, which exhibit the energetic properties of powerful primary explosives. The concept is the simple adjustment of the energetic properties of the complexes through alteration of the corresponding azoles. Six new copper(II) bromate complexes with reasonable sensitivities are featured in this study, which were synthesized in a practical and straightforward fashion, assured through easy access to copper(II) bromate obtained by metathesis reaction. Obtained compounds were comprehensively characterized through various analytical methods such as low-temperature X-ray diffraction, IR spectroscopy, and elemental analysis. Their sensitivities toward impact and friction were assessed through BAM standard techniques, together with their sensitivity against electrostatic discharge. Evaluation of the energetic properties of the newly synthesized compounds included examination of the respective thermal stabilities by differential thermal analysis. Furthermore, the complexes were tested regarding their behavior toward laser irradiation. Additionally, to receive insight into a possible correlation between the laser-investigated compounds' optical absorption and their ability to ignite by exposure to laser irradiation, UV-vis-near-IR spectra were recorded.


Data Collection on Sensitive Topics with Adolescents Using Interactive Voice Response Technology.
We describe the development and implementation of a survey administered using interactive voice response (IVR) technology to collect information on sensitive topics in a US national sample of adolescents age 12-17. Respondents were participants in the Panel Study of Income Dynamics 2014 Child Development Supplement (N=1,098). We review questionnaire design, fieldwork protocols, data quality and completeness, and respondent burden. We find that in the context of research on sensitive topics with adolescents, IVR is a cost-efficient and flexible method of data collection that yields high survey response rates and low item nonresponse rates with distributions on key variables that are comparable to other national studies.


Genome-Wide Single Nucleotide Polymorphism Analysis Elucidates the Evolution of Prunus takesimensis in Ulleung Island: The Genetic Consequences of Anagenetic Speciation.
Of the two major speciation modes of endemic plants on oceanic islands, cladogenesis and anagenesis, the latter has been recently emphasized as an effective mechanism for increasing plant diversity in isolated, ecologically homogeneous insular settings. As the only flowering cherry occurring on Ulleung Island in the East Sea (concurrently known as Sea of Japan), Prunus takesimensis Nakai has been presumed to be derived through anagenetic speciation on the island. Based on morphological similarities, P. sargentii Rehder distributed in adjacent continental areas and islands has been suggested as a purported continental progenitor. However, the overall genetic complexity and resultant non-monophyly of closely related flowering cherries have hindered the determination of their phylogenetic relationships as well as the establishment of concrete continental progenitors and insular derivative relationships. Based on extensive sampling of wild flowering cherries, including P. takesimensis and P. sargentii from Ulleung Island and its adjacent areas, the current study revealed the origin and evolution of P. takesimensis using multiple molecular markers. The results of phylogenetic reconstruction and population genetic structure analyses based on single nucleotide polymorphisms detected by multiplexed inter-simple sequence repeat genotyping by sequencing (MIG-seq) and complementary cpDNA haplotypes provided evidence for (1) the monophyly of P. takesimensis; (2) clear genetic differentiation between P. takesimensis (insular derivative) and P. sargentii (continental progenitor); (3) uncertain geographic origin of P. takesimensis, but highly likely via single colonization from the source population of P. sargentii in the Korean Peninsula; (4) no significant reduction in genetic diversity in anagenetically derived insular species, i.e., P. takesimensis, compared to its continental progenitor P. sargentii; (5) no strong population genetic structuring or geographical patterns in the insular derivative species; and (6) MIG-seq method as an effective tool to elucidate the complex evolutionary history of plant groups.


Apnea, sudden infant death syndrome, and home monitoring.
More than 25 years have elapsed since continuous cardiorespiratory monitoring at home was suggested to decrease the risk of sudden infant death syndrome (SIDS). In the ensuing interval, multiple studies have been unable to establish the alleged efficacy of its use. In this statement, the most recent research information concerning extreme limits for a prolonged course of apnea of prematurity is reviewed. Recommendations regarding the appropriate use of home cardiorespiratory monitoring after hospital discharge emphasize limiting use to specific clinical indications for a predetermined period, using only monitors equipped with an event recorder, and counseling parents that monitor use does not prevent sudden, unexpected death in all circumstances. The continued implementation of proven SIDS prevention measures is encouraged.


Understanding methods of wound debridement.
Autolytic debridement describes the body's natural method of wound-bed cleansing, helping it to prepare the wound bed for healing. In acute wounds, autolytic debridement occurs automatically and often does not require intervention, as during the inflammatory stage of a wound, neutrophils and macrophages digest and removes devitalised tissue, cell debris and contaminants, clearing the wound of any cellular barriers to healing. In chronic wounds, by contrast, healing is often delayed, frequently because of inadequate debridement. The autolytic process becomes overwhelmed by high levels of endotoxins released from damaged tissue (Broadus, 2013). Therefore wound debridement becomes an integral part of chronic-wound management and practitioners involved in wound care must be fully competent at wound-bed assessment and have an awareness of the options available for debridement. This article will review wound-bed assessment, highlighting variations in devitalised tissue, and explore options available for wound debridement, taking into consideration patients' pain and quality of life.


Comparative evaluation of antitumor effects of TNF superfamily costimulatory ligands delivered by mesenchymal stem cells.
Stimulation of costimulatory receptors serves as an alternative immunotherapeutic strategy other than checkpoint inhibition. However, systemic administration of the agonistic antibodies is associated with severe toxicities, which is one of the major obstacles for their clinical application. This study aimed to develop a mesenchymal stem cell (MSC)-based system for tumor-targeted delivery of TNF superfamily ligands and assess their potential in enhancing antitumor immunity. Here we established an MSC-based system for tumor-targeted delivery of TNF superfamily ligands, including TNFSF4, 9 and 18. The TNFSF receptors (TNFRSFs) were evaluated in mouse models and patient samples for lung and colorectal cancers. TNFRSFs were all expressed at various levels on tumor-infiltrated lymphocytes, with TNFRSF18 being the most prevalent receptor. Human umbilical cord-derived MSCs expressing these costimulatory ligands (MSC-TNFSFs) effectively activated lymphocytes in vitro and elicited antitumor immunity in mice. TNFSF4 showed the least antitumor efficacy in both LLC1 and CT26 tumor models. MSC-TNFSF9 showed the most potent tumor-inhibiting effect in the LLC1 tumor model, while MSCs expressing TNFSF18 in combination with CXCL9 most significantly repressed CT26 tumor growth. Overall, TNFSF9 and TNFSF18 exhibited stronger lymphocyte-stimulating and antitumor activities than TNFSF4. Our study provides evidence that antitumor effects of agonism of different costimulatory receptors may vary in different tumor types and presents a promising approach for targeted delivery of TNF superfamily costimulatory ligands to avoid the systemic toxicities and side effects associated with immune agonist antibodies.


Projection of current and future distribution of adaptive genetic units in an alpine ungulate.
Climate projections predict major changes in alpine environments by the end of the 21st century. To avoid climate-induced maladaptation and extinction, many animal populations will either need to move to more suitable habitats or adapt in situ to novel conditions. Since populations of a species exhibit genetic variation related to local adaptation, it is important to incorporate this variation into predictive models to help assess the ability of the species to survive climate change. Here, we evaluate how the adaptive genetic variation of a mountain ungulate-the Northern chamois (Rupicapra rupicapra)-could be impacted by future global warming. Based on genotype-environment association analyses of 429 chamois using a ddRAD sequencing approach, we identified genetic variation associated with climatic gradients across the European Alps. We then delineated adaptive genetic units and projected the optimal distribution of these adaptive groups in the future. Our results suggest the presence of local adaptation to climate in Northern chamois with similar genetic adaptive responses in geographically distant but climatically similar populations. Furthermore, our results predict that future climatic changes will modify the Northern chamois adaptive landscape considerably, with various degrees of maladaptation risk.


Von Hippel-Lindau disease: clinical and pathological manifestations in nine families with 50 affected members.
Fifty individuals in nine families had von Hippel-Lindau disease. Nearly all of the morbidity and mortality of the entity is associated with six of its manifestations, each of which can be successfully treated. Retinal angiomatosis, which occurs in more than half of those affected, can produce blindness if not treated. Cerebellar hemangioblastoma, which is observed in one third of patients, is the most common source of initial symptoms and caused more than half of the deaths in the series. Medullary and spinal hemangioblastomas occur infrequently. Pheochromocytoma is common in certain families and is usually bilateral. Renal cell carcinoma, which generally arises at a later age, may befall the patient who is successfully treated for the tumors that occurred earlier. However, this tumor can be treated also, if there is early detection.


Effects of insulin and prior exercise on prostaglandin release from perfused rat muscle. Evidence that prostaglandins do not mediate changes in glucose uptake.
Prostaglandin generation and its inter-relation to the metabolic effects of insulin and prior exercise were examined in perfused muscle of fed rats. During a 60 min perfusion of the rat hindquarter, a substantial release of the prostaglandins PGF2 alpha, PGE2 and 6-oxoPGF1 alpha was observed. Blood cells present in the perfusate released these substances in negligible amounts indicating the prostaglandins were produced by the hindquarter. Addition of insulin to the perfusate increased both glucose uptake and the generation of PGE2 and 6-oxoPGF1 alpha. At 30 min after intense treadmill exercise, glucose and alpha-aminoisobutyric acid (AIB) uptake by the hindquarter were increased in the absence of added insulin, but prostaglandin release was not increased. Insulin further increased glucose and AIB uptake; however, in contrast with its effects in non-exercised rats, insulin no longer stimulated prostaglandin generation. Indomethacin (10 microM) added to the perfusate inhibited the release of PGF2 alpha and PGE2 by 90% and the release of 6-oxoPGF1 alpha by 54%. It had no effect on the stimulation of glucose uptake by either insulin or prior exercise. The data indicate that insulin increases prostaglandin synthesis by perfused rat muscle, and that prior exercise blocks this effect. They suggest that under the conditions studied prostaglandins do not mediate the effects of insulin or prior exercise on glucose uptake.


Large arteries haemodynamics: conduit versus cushioning function.
Arterial system has two distinct interrelated functions: to deliver an adequate supply of blood to organs and tissues--the conduit function, and to smooth the pressure and flow pulsation resulting from intermittent ventricular ejection in order to transform oscillatory hemodynamics into a steady flow and pressure--the cushioning function. The conduit function depends principally on low resistance of conduit arteries, i.e. on the radius of the vessel. Atherosclerotic plaques causing more or less important reduction in the caliber of arteries are the principal cause of altered conduit function. The efficiency of cushioning function depend on geometric and viscoelastic properties of arterial system described in terms of compliance or stiffness. Stiffening of the arteries induces principally an increase in left ventricular hypertrophy and alterations in coronary flow distribution. Arteriosclerosis characterised by diffuse fibroelastic thickening is the principal cause altering cushioning function. Arteriosclerosis is a physiological aging phenomenon which is accelerated in several conditions including principally those characterised by increased blood pressure.


Path Smoothing Techniques in Robot Navigation: State-of-the-Art, Current and Future Challenges.
Robot navigation is an indispensable component of any mobile service robot. Many path planning algorithms generate a path which has many sharp or angular turns. Such paths are not fit for mobile robot as it has to slow down at these sharp turns. These robots could be carrying delicate, dangerous, or precious items and executing these sharp turns may not be feasible kinematically. On the contrary, smooth trajectories are often desired for robot motion and must be generated while considering the static and dynamic obstacles and other constraints like feasible curvature, robot and lane dimensions, and speed. The aim of this paper is to succinctly summarize and review the path smoothing techniques in robot navigation and discuss the challenges and future trends. Both autonomous mobile robots and autonomous vehicles (outdoor robots or self-driving cars) are discussed. The state-of-the-art algorithms are broadly classified into different categories and each approach is introduced briefly with necessary background, merits, and drawbacks. Finally, the paper discusses the current and future challenges in optimal trajectory generation and smoothing research.


Effects of cross-pollination among non-Bt and pyramided Bt corn expressing cry proteins in seed mixtures on resistance development of dual-gene resistant Helicoverpa zea.
Seed mixture strategy can guarantee the compliance of planting non-Bt crops to host the susceptible insects for resistance management. However, pollen movement between Bt and non-Bt corn in the mixed plantings could reduce the efficacy of this strategy for ear-feeding insects. Few studies have evaluated the effects of cross-pollination among non-Bt and pyramided Bt corn in seed mixtures on the resistance development of insects possessing multiple resistances. Here, we provided the first study to investigate whether cross-pollination in mixed plantings of pyramided Bt corn producing Cry1A.105 and Cry2Ab2 would increase the dominance of resistance of dual-gene resistant populations of Helicoverpa zea, a target of pyramided Bt corn and cotton in the USA. We compared the survival and development of susceptible, dual-gene resistant (resistance to both Cry1 and Cry2 proteins) and heterozygous genotypes of H. zea in the laboratory on non-Bt and pyramided Bt corn ears collected from mixed plantings and structured plantings in the field. We found higher fitness for F1 heterozygous insects than for the susceptible insects of H. zea on both pyramided Bt corn and non-Bt corn in the mixed plantings. These results suggest that cross-pollination in mixed plantings will significantly increase the dominance of resistance by supporting survival of heterozygous insects for dual-gene resistant populations of H. zea, and therefore accelerate evolution of resistance to pyramided Bt crops. © 2022 Society of Chemical Industry.


Botulinum toxins for the prevention of migraine in adults.
Migraine occurs in around 15% of adults and is ranked as the seventh most disabling disease amongst all diseases globally. Despite the available treatments many people suffer prolonged and frequent attacks which have a major impact on their quality of life. Chronic migraine is defined as 15 or more days of headache per month, at least eight of those days being migraine. People with episodic migraine have fewer than 15 headache days per month. Botulinum toxin type A has been licensed in some countries for chronic migraine treatment, due to the results of just two trials. To assess the effects of botulinum toxins versus placebo or active treatment for the prevention or reduction in frequency of chronic or episodic migraine in adults. We searched CENTRAL, MEDLINE & MEDLINE in Process, Embase, ClinicalTrials.gov and World Health Organization International Clinical Trials Registry (to December 2017). We examined reference lists and carried out citation searches on key publications. We sent correspondence to major manufacturers of botulinum toxin. Randomised, double-blind, controlled trials of botulinum toxin (any sero-type) injections into the head and neck for prophylaxis of chronic or episodic migraine in adults. Eligible comparators were placebo, alternative prophylactic agent or different dose of botulinum toxin. Two review authors independently selected trials and extracted data. For continuous outcomes we used mean change data when available. For dichotomous data we calculated risk ratios (RRs). We used data from the 12-week post-treatment follow-up time point. We assessed the evidence using GRADE and created two 'Summary of findings' tables. Description of trialsWe found 90 articles describing 28 trials (4190 participants), which were eligible for inclusion. The longest treatment duration was three rounds of injections with three months between treatments, so we could not analyse long-term effects. For the primary analyses, we pooled data from both chronic and episodic participant populations. Where possible, we also separated data into chronic migraine, episodic migraine and 'mixed group' classification subgroups. Most trials (21 out of 28) were small (fewer than 50 participants per trial arm). The risk of bias for included trials was low or unclear across most domains, with some trials reporting a high risk of bias for incomplete outcome data and selective outcome reporting.Botulinum toxin versus placeboTwenty-three trials compared botulinum toxin with placebo. Botulinum toxin may reduce the number of migraine days per month in the chronic migraine population by 3.1 days (95% confidence interval (CI) -4.7 to -1.4, 4 trials, 1497 participants, low-quality evidence). This was reduced to -2 days (95% CI -2.8 to -1.1, 2 trials, 1384 participants; moderate-quality evidence) when we removed small trials.A single trial of people with episodic migraine (N = 418) showed no difference between groups for this outcome measure (P = 0.49).In the chronic migraine population, botulinum toxin reduces the number of headache days per month by 1.9 days (95% CI -2.7 to -1.0, 2 trials, 1384 participants, high-quality evidence). We did not find evidence of a difference in the number of migraine attacks for both chronic and episodic migraine participants (6 trials, N = 2004, P = 0.30, low-quality evidence). For the population of both chronic and episodic migraine participants a reduction in severity of migraine rated during clinical visits, on a 10 cm visual analogue scale (VAS) of 3.3 cm (95% CI -4.2 to -2.5, very low-quality evidence) in favour of botulinum toxin treatment came from four small trials (N = 209); better reporting of this outcome measure from the additional eight trials that recorded it may have improved our confidence in the pooled estimate. Global assessment and quality-of-life measures were poorly reported and it was not possible to carry out statistical analysis of these outcome measures. Analysis of adverse events showed an increase in the risk ratio with treatment with botulinum toxin over placebo 30% (RR 1.28, 95% CI 1.12 to 1.47, moderate-quality evidence). For every 100 participants 60 experienced an adverse event in the botulinum toxin group compared with 47 in the placebo group.Botulinum toxin versus other prophylactic agentThree trials studied comparisons with alternative oral prophylactic medications. Meta-analyses were not possible for number of migraine days, number of headache days or number of migraine attacks due to insufficient data, but individually trials reported no differences between groups for a variety of efficacy measures in the population of both chronic and episodic migraine participants. The global impression of disease measured using Migraine Disability Assessment (MIDAS) scores were reported from two trials that showed no difference between groups. Compared with oral treatments, botulinum toxin showed no between-group difference in the risk of adverse events (2 trials, N = 114, very low-quality evidence). The relative risk reduction (RRR) for withdrawing from botulinum toxin due to adverse events compared with the alternative prophylactic agent was 72% (P = 0.02, 2 trials, N = 119).Dosing trialsThere were insufficient data available for the comparison of different doses.Quality of the evidenceThe quality of the evidence assessed using GRADE methods was varied but mostly very low; the quality of the evidence for the placebo and active control comparisons was low and very low, respectively for the primary outcome measure. Small trial size, high risk of bias and unexplained heterogeneity were common reasons for downgrading the quality of the evidence. In chronic migraine, botulinum toxin type A may reduce the number of migraine days per month by 2 days compared with placebo treatment. Non-serious adverse events were probably experienced by 60/100 participants in the treated group compared with 47/100 in the placebo group. For people with episodic migraine, we remain uncertain whether or not this treatment is effective because the quality of this limited evidence is very low. Better reporting of outcome measures in published trials would provide a more complete evidence base on which to draw conclusions.


Dynamic Patterns of Clonal Evolution in Tumor Vasculature Underlie Alterations in Lymphocyte-Endothelial Recognition to Foster Tumor Immune Escape.
Although tumor blood vessels have been a major therapeutic target for cancer chemotherapy, little is known regarding the stepwise development of the tumor microenvironment. Here, we use a multicolor Cre-dependent marker system to trace clonality within the tumor microenvironment to show that tumor blood vessels follow a pattern of dynamic clonal evolution. In an advanced melanoma tumor microenvironment, the vast majority of tumor vasculature clones are derived from a common precursor. Quantitative lineage analysis reveals founder clones diminish in frequency and are replaced by subclones as tumors evolve. These tumor-specific blood vessels are characterized by a developmental switch to a more invasive and immunologically silent phenotype. Gene expression profiling and pathway analysis reveals selection for traits promoting upregulation of alternative angiogenic programs such as unregulated HGF-MET signaling and enhanced autocrine signaling through VEGF and PDGF. Furthermore, we show a developmental switch in the expression of functionally significant primary lymphocyte adhesion molecules on tumor endothelium, such as the loss in expression of the mucosal addressin MAdCAM-1, whose counter receptor a4β7 on lymphocytes controls lymphocyte homing. Changes in adhesive properties on tumor endothelial subclones are accompanied by decreases in expression of lymphocyte chemokines CXCL16, CXCL13, CXCL12, CXCL9, CXCL10, and CCL19. These evolutionary patterns in the expressed genetic program within tumor endothelium will have both a quantitative and functional impact on lymphocyte distribution that may well influence tumor immune function and underlie escape mechanisms from current antiangiogenic pharmacotherapies.


Fabrication of biomimetic bone grafts with multi-material 3D printing.
Extrusion deposition is a versatile method for the 3D printing of biomaterials such as hydrogels, ceramics, and suspensions. Recently, a new class of emulsion inks were developed that can be used to create tunable, hierarchically porous materials with a cure-on-dispense method. Propylene fumarate dimethacrylate (PFDMA) was selected to fabricate bone grafts using this technology due to its established biocompatibility, osteoconductivity, and good compressive properties. Scaffolds fabricated from PFDMA emulsion inks displayed compressive modulus and yield strength of approximately 15 and 1 MPa, respectively. A decrease in infill (from 100% to 70%) resulted in a six-fold increase in permeability; however, there was also a corollary decrease in mechanical properties. In order to generate scaffolds with increased permeability without sacrificing mechanical strength, a biomimetic approach to scaffold design was used to reinforce the highly porous emulsion inks with a dense cortical shell of thermoplastic polyester. Herein, we present an open source method for printing multi-material bone grafts based on PFDMA polyHIPEs with hierarchical porosity and reinforced with a dense shell of poly(ε-caprolactone) (PCL) or poly(lactic acid) (PLA). A multi-modal printing setup was first developed that combined paste extrusion and high temperature thermoplastic extrusion with high positional accuracy in dual deposition. Scaffolds printed with a PCL shell displayed compressive modulus and yield strength of approximately 30 and 3 MPa, respectively. Scaffolds printed with a PLA shell showed compressive modulus and yield strength of approximately 100 and 10 MPa, respectively. By combining this new paste extrusion of emulsion inks with traditional thermoplastic extrusion printing, we have created scaffolds with superior strength that promote cell viability and proliferation of human mesenchymal stem cells. The development of this technique shows great promise for the fabrication of a myriad of other complex tissue engineered scaffolds.


Potential Mechanisms Underlying Hypoxia-Induced Diabetes in a Rodent Model: Implications for COVID-19.
Previous studies reported that repetitive hypoxia in rat pups reduces insulin secretion and elevates fasting blood glucose levels; these sequelae persisted for several months. This report describes how episodic hypoxic events elevate a chloride ion exporter, K+-Cl- cotransporter-2 (KCC2), in the plasma membrane of insulin-secreting pancreatic β-cells. We assume that acute diabetic symptoms observed in rat pups with periodic oxygen desaturation could result from a lack of blood insulin levels due to disturbed β-cell function. This acute hypo-insulinemia may result from a disruption in chloride balance in β-cells arising from an imbalanced KCC2-NKCC1 (chloride exporter-importer) density as a consequence of periodic oxygen desaturation. Mechanistically, we postulate that a reduced insulin secretion due to the KCC2-NKCC1 imbalance subsequent to acute oxygen desaturation could result in hyperglycemia in rat pups, paralleling symptoms shown in patients with COVID-19 who experienced acute respiratory distress.


Comparison of routine and selective use of intraoperative angiography during aneurysm surgery: a prospective assessment.
Whether routine intraoperative angiography is necessary for cerebral aneurysm surgery is currently under debate. In this study the authors prospectively assessed the cerebrovascular surgeon's accuracy in predicting the need for intraoperative angiography. Between January 2002 and January 2003, 200 consecutive patients (141 female and 59 male patients, mean age 52.8 years) with 235 aneurysms underwent routine intraoperative angiography. Before the operation, the surgeons indicated whether they believed that intraoperative angiography was necessary. Their responses were recorded as "intraoperative angiography necessary" or "intraoperative angiography unnecessary." Regardless of the response, all patients underwent intraoperative angiography after the aneurysm had been clipped. Changes in treatment resulting from intraoperative angiography were compared with surgeons' preoperative predictions of the need for intraoperative angiography. Intraoperative angiography was predicted to be necessary in 41 cases (20%) and unnecessary in 159 cases (80%). Its use altered treatment in 14 patients. Seven of these patients were among the group in which intraoperative angiography was deemed necessary and seven were in the group in which it was considered unnecessary. In the latter group, two patients had residual aneurysms, three had parent vessel occlusion, and two had previously undiagnosed aneurysms. Only one patient (0.5%) sustained a major intraoperative complication attributed to angiography. Given the frequency of significant disease that remains undetected if intraoperative angiography is used on a selective basis and the low complication rate associated with the procedure, the use of intraoperative angiography should be considered in the majority of aneurysm cases.


The COMT Val158Met polymorphism regulates the effect of a dopamine antagonist on the feedback-related negativity.
Consistent with dopamine accounts of internal and external feedback processing, prior work showed that the dopamine D2 receptor antagonist sulpiride modulates the relationship between the dopaminergic COMT Val158Met polymorphism and the error-related negativity (ERN). Here, we tested in an independent sample whether this Gene × Substance interaction generalizes to the feedback-related negativity (FRN), which presumably shares underlying dopaminergic mechanisms with the ERN. N = 83 female participants genotyped for COMT Val158Met received 200 mg sulpiride versus placebo and performed a virtual ball-catching task. The FRN to positive versus negative feedback was modulated by a significant COMT × Substance interaction. Mirroring prior work on the ERN, the tendency of the FRN to be more pronounced for VAL+ versus MET/MET carriers after placebo was reversed by sulpiride. The findings thus provide new evidence for dopaminergic models of feedback processing.


Using opioid analgesics to manage chronic noncancer pain in primary care.
Opioid analgesics have been considered the drugs of choice for the treatment of moderate to severe cancer and postoperative pain. Cultural attitudes and concerns about abuse have inhibited their use for a larger population of patients who have chronic noncancer pain. Medical literature was searched from 1990 to 1998 using the key words "opioid analgesics," "opioid abuse," and "chronic pain." I have also drawn from more than 20 years of experience prescribing opioid analgesics for chronic pain. A case series analysis of 30 patients using opioid analgesics for periods ranging from 6 months to 17 years was performed. The World Health Organization has published a "three-step ladder" guide to treatment of cancer pain graded from mild to severe; this guide can be readily applied to the treatment of pain from all sources. Opioid analgesics are the mainstay of treatment for moderate to severe pain. Chronic pain patients offer some difficult challenges for busy primary care physicians. The unique pharmacologic characteristics of opioid medications are important in outpatient management. A four-sheet office management protocol helps to focus efficiently on important clinical issues related to pain control, to monitor for opiate abuse, and to incorporate pain management more effectively in the overall primary care plan of the patient.


Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis, and imatinib responsiveness.
Since serum tryptase levels are elevated in some patients with myeloproliferative disorders, we examined their utility in identifying a subset of patients with hypereosinophilic syndrome (HES) and an underlying myeloproliferative disorder. Elevated serum tryptase levels (> 11.5 ng/mL) were present in 9 of 15 patients with HES and were associated with other markers of myeloproliferation, including elevated B12 levels and splenomegaly. Although bone marrow biopsies in these patients showed increased numbers of CD25+ mast cells and atypical spindle-shaped mast cells, patients with HES and elevated serum tryptase could be distinguished from patients with systemic mastocytosis and eosinophilia by their clinical manifestations, the absence of mast cell aggregates, the lack of a somatic KIT mutation, and the presence of the recently described fusion of the Fip1-like 1 (FIP1L1) gene to the platelet-derived growth factor receptor alpha gene (PDGFRA). Patients with HES and elevated serum tryptase were more likely to develop fibroproliferative end organ damage, and 3 of 9 died within 5 years of diagnosis in contrast to 0 of 6 patients with normal serum tryptase levels. All 6 patients with HES and elevated tryptase treated with imatinib demonstrated a clinical and hematologic response. In summary, elevated serum tryptase appears to be a sensitive marker of a myeloproliferative variant of HES that is characterized by tissue fibrosis, poor prognosis, and imatinib responsiveness.


An international consensus for assessing internet gaming disorder using the new DSM-5 approach.
For the first time, the Diagnostic and Statistical Manual for Mental Disorders (DSM-5) introduces non-substance addictions as psychiatric diagnoses. The aims of this paper are to (i) present the main controversies surrounding the decision to include internet gaming disorder, but not internet addiction more globally, as a non-substance addiction in the research appendix of the DSM-5, and (ii) discuss the meaning behind the DSM-5 criteria for internet gaming disorder. The paper also proposes a common method for assessing internet gaming disorder. Although the need for common diagnostic criteria is not debated, the existence of multiple instruments reflect the divergence of opinions in the field regarding how best to diagnose this condition. We convened international experts from European, North and South American, Asian and Australasian countries to discuss and achieve consensus about assessing internet gaming disorder as defined within DSM-5. We describe the intended meaning behind each of the nine DSM-5 criteria for internet gaming disorder and present a single item that best reflects each criterion, translated into the 10 main languages of countries in which research on this condition has been conducted. Using results from this cross-cultural collaboration, we outline important research directions for understanding and assessing internet gaming disorder. As this field moves forward, it is critical that researchers and clinicians around the world begin to apply a common methodology; this report is the first to achieve an international consensus related to the assessment of internet gaming disorder.


Translational control of nuclear lamin B1 mRNA during oogenesis and early development of Xenopus.
Cytoplasmic polyadenylation of specific mRNAs is commonly correlated with their translational activation during development. A canonical nuclear polyadenylation element AAUAAA (NPE) and cytoplasmic polyadenylation element(s) (CPE) are necessary and sufficient for polyadenylation during egg maturation. We have characterized cis-acting sequences of Xenopus nuclear lamin B1 mRNA that mediate translational regulation. By injection of synthetic RNAs into oocytes we show that the two CPE-like elements found in the 3'-untranslated region of B1 mRNA act as translational repressors in oocytes. The same CPEs in conjunction with the NPE confer transient polyadenylation and translational activation during egg maturation. Poly(A) length determination of the endogenous lamin B1 mRNA reveals a gradual increase of poly(A) tail length in early development up to mid-blastula, and a shortening of poly(A) tails during gastrulation and neurulation. The same kinetic and extent of polyadenylation and poly(A) tail shortening is observed with synthetic RNAs injected into fertilized eggs. Polyadenylation and translational activation of these RNAs is independent of the two CPEs and a NPE during early development. While translational regulation of lamin B1 mRNA functions in parts via established mechanisms, the pattern of polyadenylation and deadenylation during early development points to a novel mode of translational regulation.


Neurochemical changes and neurotoxic effects of an acute treatment with sydnocarb, a novel psychostimulant: comparison with D-amphetamine.
Sydnocarb [(phenylisopropyl)N-phenylcarbamoylsydnonimine; SYD] was introduced to clinical practice in Russia as a psychostimulant drug used for the treatment of asthenia and apathy, which accompany schizophrenia and manic depression. It has been described as a psychostimulant with addiction liability and toxicity less than amphetamine (AMPH). The precise cellular mechanisms by which sydnocarb elicits its psychostimulant effect are still unclear. At present its neurochemical and neurotoxic effects are compared to those of AMPH in the striatum, the main input structure of the basal ganglia. The expression of c-fos protein in striatal neurons was much more increased after a single injection of D-AMPH (5 mg/kg) than after an equimolar concentration of SYD (23.8 mg/kg) in both the anterior and the posterior part of the striatum. Using in situ hybridization on striatal slices, we observed that AMPH increased the striatal levels of preprodynorphin (PPDYN) mRNAs in both parts of the striatum, while SYD did not affect basal levels of PPDYN mRNAs. Furthermore, AMPH and SYD increased striatal preprotachykinin (PPT-A) and preproenkephalin (PPE) mRNA levels. The effects of AMPH and SYD on PPT-A-mRNA levels were similar. A differential effect of AMPH and SYD was observed only on the PPE-mRNA levels measured in the anterior striatum where SYD increased these levels more than AMPH. The acute neurotoxicity of these two psychostimulants was analyzed by measuring their effects on the parameters of oxidative stress, such as nitric oxide (NO) generation, as well as specific indices of lipid peroxidation (i.e., thiobarbituric acid reactive substances; TBARS), while, on the other hand, the alpha-tocopherol level was taken as an index of antioxidant defense processes. Measuring generation of NO directly by electron paramagnetic resonance, it was observed that AMPH shows a more pronounced increase in comparison to SYD, in the striatum and in cortex. TBARS levels in the striatum and cortex were significantly less enhanced than AMPH after a single injection of SYD. Similarly, the alpha-tocopherol level was decreased only by AMPH in the striatum, and neither AMPH nor SYD had any effect in the cortex. Results show that a single injection of a high dose of AMPH is able to induce several neurotoxic effects. The study also demonstrates that SYD has mild neurochemical effects as well as fewer neurotoxic properties than AMPH.


Coupling between phosphate and calcium homeostasis: a mathematical model.
We developed a mathematical model of calcium (Ca) and phosphate (PO4) homeostasis in the rat to elucidate the hormonal mechanisms that underlie the regulation of Ca and PO4 balance. The model represents the exchanges of Ca and PO4 between the intestine, plasma, kidneys, bone, and the intracellular compartment, and the formation of Ca-PO4-fetuin-A complexes. It accounts for the regulation of these fluxes by parathyroid hormone (PTH), vitamin D3, fibroblast growth factor 23, and Ca2+-sensing receptors. Our results suggest that the Ca and PO4 homeostatic systems are robust enough to handle small perturbations in the production rate of either PTH or vitamin D3 The model predicts that large perturbations in PTH or vitamin D3 synthesis have a greater impact on the plasma concentration of Ca2+ ([Ca2+]p) than on that of PO4 ([PO4]p); due to negative feedback loops, [PO4]p does not consistently increase when the production rate of PTH or vitamin D3 is decreased. Our results also suggest that, following a large PO4 infusion, the rapidly exchangeable pool in bone acts as a fast, transient storage PO4 compartment (on the order of minutes), whereas the intracellular pool is able to store greater amounts of PO4 over several hours. Moreover, a large PO4 infusion rapidly lowers [Ca2+]p owing to the formation of CaPO4 complexes. A large Ca infusion, however, has a small impact on [PO4]p, since a significant fraction of Ca binds to albumin. This mathematical model is the first to include all major regulatory factors of Ca and PO4 homeostasis.


Immunomodulation in female B₆C₃F₁ mice following treatment with the HIV protease inhibitor saquinavir for 28 days by gavage.
Saquinavir (SQV) is a protease inhibitor that binds to the protease active site of the human immunodeficiency virus and prevents the cleavage of viral polyproteins resulting in the formation of non-infectious virus particles. The purpose of these studies was to determine the potential effects of SQV on the immune system in female B₆C₃F₁ mice. SQV was administered by gavage twice daily for 28 days at total doses of 300, 600, and 1200 mg/kg/day. No significant differences were observed in body weight, or the weights of spleen, thymus, liver, kidneys, or lungs. Exposure to SQV produced no biologically meaningful changes in hematological parameters. However, a statistically significant increase in the number of T-cells (23%) was observed at the high dose level of SQV. The number of splenic immature T-cells (CD4+CD8+ cells) also showed increases of 46% and 92% at the 600 and 1200 mg/kg dose levels, respectively. The immunoglobulin M antibody-forming cell (AFC) response was significantly increased by 41% when the data were expressed as AFC/10⁶ spleen cells at the 1200 mg/kg dose level. Treatment with SQV had no effects on the mixed leukocyte response. Overall, the activities of natural killer cells and cytotoxic T-cells were not altered in SQV-treated animals when compared to vehicle controls. In addition, exposure to SQV did not affect host resistance in the B16F10 melanoma model. In conclusion, SQV produced an enhancement of the humoral immune response, possibly through modulating T-cell function in female B₆C₃F₁ mice.


Glutaredoxin AtGRXC2 catalyses inhibitory glutathionylation of Arabidopsis BRI1-associated receptor-like kinase 1 (BAK1) in vitro.
Reversible protein phosphorylation, catalysed by protein kinases, is the most widely studied post-translational modification (PTM), whereas the analysis of other modifications such as S-thiolation is in its relative infancy. In a yeast-two-hybrid (Y2H) screen, we identified a number of novel putative brassinosteroid insensitive 1 (BR1)-associated receptor-like kinase 1 (BAK1) interacting proteins including several proteins related to redox regulation. Glutaredoxin (GRX) C2 (AtGRXC2) was among candidate proteins identified in the Y2H screen and its interaction with recombinant Flag-BAK1 cytoplasmic domain was confirmed using an in vitro pull-down approach. We show that BAK1 peptide kinase activity is sensitive to the oxidizing agents H2O2 and diamide in vitro, suggesting that cysteine oxidation might contribute to control of BAK1 activity. Furthermore, BAK1 was glutathionylated and this reaction could occur via a thiolate-dependent reaction with GSSG or a H2O2-dependent reaction with GSH and inhibited kinase activity. Surprisingly, both reactions were catalysed by AtGRXC2 at lower concentrations of GSSG or GSH than reacted non-enzymatically. Using MALDI-TOF MS, we identified Cys353, Cys374 and Cys408 as potential sites of glutathionylation on the BAK1 cytoplasmic domain and directed mutagenesis suggests that Cys353 and Cys408 are major sites of GRXC2-mediated glutathionylation. Collectively, these results highlight the potential for redox control of BAK1 and demonstrate the ability of AtGRXC2 to catalyse protein glutathionylation, a function not previously described for any plant GRX. The present work presents a foundation for future studies of glutathionylation of plant receptor-like protein kinases (RLKs) as well as for the analysis of activities of plant GRXs.


Both sides nanopatterned tubular collagen scaffolds as tissue-engineered vascular grafts.
Two major requirements for a tissue-engineered vessel are the establishment of a continuous endothelium and adequate mechanical properties. In this study, a novel tubular collagen scaffold possessing nanopatterns in the form of channels (with a 650 nm periodicity) on both sides was designed and examined after seeding and co-culturing with vascular cells. Initially, the exterior of the tube was seeded with human vascular smooth muscle cells (VSMCs), cultured for 14 days, and then human internal thoracic artery endothelial cells (HITAECs) were seeded on the inside of the tube and cultured for a further week. Microscopy revealed that nano-scale patterns could be reproduced on collagen with high fidelity and preserved during incubation in vitro. The VSMCs were circumferentially orientated with the help of these nanopatterns and formed multilayers on the exterior, while HITAECs formed a continuous layer on the interior, as is the case in natural vessels. Both cell types were observed to proliferate and retain their phenotypes in the co-culture.


Development of immunoglobulin M-antibodies after rubella immunization with RA27/3 attenuated live vaccine in teen-agers: remaining problems.
Four-hundred-fourty-two rubella seronegative teen-agers living in Siena and the surroundings were vaccinated with RA 27/3 live attenuated rubella over a two years period (1985-1987). One-hundred-twenty seven vaccinees' sera were randomly selected for the rubella specific antibodies of the IgM class detection with two Elisa Methods; the sera were collected 10 and 30 days after the challenge; in 58 girls a serum sample was also obtained 1 yr later. None of the sera showed reactivity for RF. The comparison between the two Elisa methods gave satisfactory results, the percentage of discrepancies being low (3.9%). Ten days after the immunization the IgM positive sera were only 7.56% (Elisa Abbott) and 5.88% (Elisa Enzygnost Behringwerke). One month later, 86.61% of the specimens showed reactivity for specific IgM antibodies. None of 58 sera gave positive results after 1 yr. Rubella antibodies of the IgG class could be demonstrated in the "screening" sera of 3 IgM negative subjects, when an Elisa method was applied. Nine subjects (7%) repeatedly resulted IgM negative one month after the challenge although a seroconversion was observed using both HAI and EIA. A serum sample was also obtained in 6/9 IgM "non responders" after a rubella epidemic observed in 1988-1989; no subclinical reinfection due to the wild virus was detected in this group, no changes in HAI antibody title nor evidence of IgM class specific response were observed. Although most of the diagnostic aspects related with rubella and rubella vaccination appear to be resolved, it should be underlined that there are several remaining problems especially associated with IgM detection.


Human Chorionic Stem Cells: Podocyte Differentiation and Potential for the Treatment of Alport Syndrome.
Alport syndrome (AS) is a hereditary glomerulopathy caused by a mutation in type IV collagen genes, which disrupts glomerular basement membrane, leading to progressive glomerulosclerosis and end-stage renal failure. There is at present no cure for AS, and cell-based therapies offer promise to improve renal function. In this study, we found that human first trimester fetal chorionic stem cells (CSC) are able to migrate to glomeruli and differentiate down the podocyte lineage in vitro and in vivo. When transplanted into 7-week-old Alport 129Sv-Col4α3(tm1Dec)/J (-/-) mice, a single intraperitoneal injection of CSC significantly lowered blood urea and urine proteinuria levels over the ensuing 2 weeks. In addition, nearly two-thirds of transplanted -/- mice maintained their weight above the 80% welfare threshold, with both males and females weighing more than age-matched nontransplanted -/- mice. This was associated with less renal cortical fibrosis and interstitial inflammation compared to nontransplanted mice as shown by reduction in murine CD4, CD68, and CD45.2 cells. Transplanted CSC homed to glomeruli, where they expressed CR1, VEGFA, SYNAPTOPODIN, CD2AP, and PODOCIN at the RNA level and produced PODOCIN, CD2AP, and COLIVα3 proteins in nontransplanted -/- mice, indicating that CSC have adopted a podocyte phenotype. Together, these data indicate that CSC may be used to delay progression of renal pathology by a combination of anti-inflammatory effects and replacement of the defective resident podocytes.


Mental health difficulties among professional jockeys: a narrative review.
Emerging academic literature and high-profile disclosures of mental health difficulties and mental illness from current and former professional jockeys suggest that further exploration of the mental health of jockeys is required. To date, a comprehensive review of jockeys' mental health has yet to be conducted. To examine the existing literature related to jockeys' mental health, including the prevalence of symptoms associated with mental health difficulties and help-seeking. A narrative review of the literature was conducted with articles screened from inception until January 2021. Sixteen studies were included in the narrative review. Studies covered a range of mental health difficulties which included mood (depression), anxiety, distress, disordered eating and substance misuse. Rates of help-seeking among jockeys were also explored. Results indicated that jockeys reported higher levels of depressive and anxiety symptoms compared with other elite athletes. Substance misuse, in particular adverse alcohol use, also appears greater among jockeys than other elite athletes. Distress symptoms appear comparable with other elite athletes. Risk factors for mental health difficulties included injury, perceived stress, athlete burnout, career dissatisfaction and the contemplation of retirement. Weight-making negatively impacts jockeys' mood and attitudes towards eating, with lower competitive riding weights associated with more disordered eating attitudes. Moreover, help-seeking from mental health professionals appears low. The review identifies a high prevalence of symptoms of mental health difficulties among professional jockeys. Applied recommendations and future research considerations are proposed throughout the review article.


Blood ethanol testing.
The justification for blood ethanol testing springs from the ubiquitous abuse of alcoholic beverages. Those dealing with patients who abuse alcohol must understand the correlations between dose, time, blood level, and behavior. Enumerated here are the strengths of various testing methods and the requisites for legally defensible testing. The challenge remains to determine blood ethanol levels in such a manner that the results are scientifically valid and legally defensible.


Analytical comparison of natural and pharmaceutical ventricular myosin activators.
Ventricular myosin (βMys) is the motor protein in cardiac muscle generating force using ATP hydrolysis free energy to translate actin. In the cardiac muscle sarcomere, myosin and actin filaments interact cyclically and undergo rapid relative translation facilitated by the low duty cycle motor. It contrasts with high duty cycle processive myosins for which persistent actin association is the priority. The only pharmaceutical βMys activator, omecamtive mecarbil (OM), upregulates cardiac contractility in vivo and is undergoing testing for heart failure therapy. In vitro βMys step-size, motility velocity, and actin-activated myosin ATPase were measured to determine duty cycle in the absence and presence of OM. A new parameter, the relative step-frequency, was introduced and measured to characterize βMys motility due to the involvement of its three unitary step-sizes. Step-size and relative step-frequency were measured using the Qdot assay. OM decreases motility velocity 10-fold without affecting step-size, indicating a large increase in duty cycle converting βMys to a near processive myosin. The OM conversion dramatically increases force and modestly increases power over the native βMys. Contrasting motility modification due to OM with that from the natural myosin activator, specific βMys phosphorylation, provides insight into their respective activation mechanisms and indicates the boilerplate screening characteristics desired for pharmaceutical βMys activators. New analytics introduced here for the fast and efficient Qdot motility assay create a promising method for high-throughput screening of motor proteins and their modulators.


TTN: Topological Transformer Network for Automated Coronary Artery Branch Labeling in Cardiac CT Angiography.
Existing methods for automated coronary artery branch labeling in cardiac CT angiography face two limitations: 1) inability to model overall correlation of branches, since differences between branches cannot be captured directly. 2) a serious class imbalance between main and side branches. Inspired by the application of Transformer in sequence data, we propose a topological Transformer network (TTN), which solves the vessel branch labeling from a novel perspective of sequence labeling learning. TTN detects differences between branches by establishing their overall correlation. A topological encoding that represents the positions of vessel segments in the artery tree, is proposed to assist the model in classifying branches. Also, a segment-depth loss is introduced to solve the class imbalance between main and side branches. On a dataset with 325 CCTA, our method obtains the best overall result on all branches, the best result on side branches, and a competitive result on main branches. TTN solves two limitations in existing methods perfectly, thus achieving the best result in coronary artery branch labeling task. It is the first Transformer based vessel branch labeling method and is notably different from previous methods. This Pre-Clinical Research can be integrated into a computer-aided diagnosis system to generate cardiovascular disease diagnosis report, assisting clinicians in locating the atherosclerotic plaques.


Using reinforcement sensitivity to understand longitudinal links between PTSD and relationship adjustment.
There is limited research testing longitudinal models of how posttraumatic stress disorder (PTSD) severity leads to impaired relationship adjustment. The present study evaluated 2 potential mechanisms among a longitudinal sample of National Guard soldiers deployed to the Iraq War: (1) sensitivity to cues associated with punishment within intimate relationships and (2) sensitivity to cues associated with incentives in intimate relationships. Participants were surveyed by mail 1 year after an extended 16-month combat deployment and again 2 years later. Using a cross-lagged panel analysis with 2 mediators (relationship-specific threat and incentive sensitivity), findings indicated Time 1 PTSD symptom severity significantly eroded relationship adjustment over time through greater sensitivity to cues of relationship-related punishment, but not through incentive sensitivity. Additionally, findings indicated sensitivity to cues of relationship-related threats maintains symptoms of PTSD while sensitivity to cues of relationship-related incentives maintains relationship adjustment. Finally, PTSD symptoms significantly predicted erosion of relationship adjustment over time; however, associations from relationship adjustment to changes in PTSD severity over time were nonsignificant. Findings are discussed within the context of reinforcement sensitivity theory and emotional processing theory of PTSD. (PsycINFO Database Record


Chromosome 18q-syndrome and 1p terminal duplication in a patient with bilateral vesico-ureteral reflux: case report and literature revision.
Vesico-ureteral reflux (VUR) is a dynamic event in which a retrograde flow of urine is present into the upper tracts. VUR may occur isolated or in association with other congenital abnormalities or as part of syndromic entities. We present a patient with a bilateral primary VUR, syndromic disease caused by a large deletion of 18q (18q21.3-qter) and terminal duplication of 1p (1p36.32-p36.33). The patient was 8 years old female with a disease including moderate growth retardation, psychomotor retardation, facial dysmorphism, single umbilical artery, umbilical hernia, urachal remnant, bilateral congenital clubfeet and renal-urinary disease. Chromosomal analysis and Array-CGH revealed two heterozygous chromosomal rearrangements: 1p terminal duplication and de novo 18q terminal deletion. She referred to our clinic to evaluation of bilateral hydronephrosis and right renal cortex thinning. Voiding cystourethrography demonstrated bilateral grade IV VUR and dimercaptosuccinic acid renal scintigraphy confirmed right renal cortex thinning and showed a cortical uptake of 75% of the left kidney and 25% of the right kidney. The patient underwent ureterovesical reimplantation after failure of 3 endoscopic submeatal Deflux injections with VUR resolution. This is the first report involving a patient with 18q-syndrome and contemporary presence of 1p chromosomal terminal duplication. The coexistence of two chromosomal rearrangements complicates the clinical picture and creates a chimeric disorder (marked by characteristics of both chromosomal anomalies). Kidney problems, primarily VUR is reported in 15% of patients affected by 18-q syndrome and no cases is reported in the literature regarding a correlation between VUR and 1p36 chromosomal duplication.


Influence of preoperative supplementation of omega-3 fatty acid in the healing of colonic anastomoses in malnourished rats receiving paclitaxel.
To evaluate the effect of preoperative supplementation of omega-3 fatty acids on the healing of colonic anastomoses in malnourished rats receiving paclitaxel. we studied 160 male Wistar rats, divided in two groups: one subjected to malnutrition by pair feeding (M) for four weeks, and another that received food ad libitum (W). In the fourth week, the groups were further divided into two subgroups that received omega-3 or olive oil by gavage. The animals were submitted to colonic transection and end-to-end anastomosis. After the operation, each of the four groups was divided into two subgroups that received intraperitoneal isovolumetric solutions of saline or paclitaxel. mortality was 26.8% higher in the group of animals that received paclitaxel (p = 0.003). The complete rupture strength was greater in well-nourished-oil Paclitaxel group (WOP) compared with the the malnourished-oil Paclitaxel one (MOP). The collagen maturation index was higher in well-nourished-oil saline group (WOS) in relation to the malnutrition-oil-saline group (MOS), lower in malnourished-oil-saline group (MOS) in relation to malnourished-ômega3-saline one (M3S) and lower in the well-nourished-omega3-saline group (W3S) compared with the malnourished-omega3-saline (M3S). The blood vessel count was higher in the malnourished-oil-saline group (MOS) than in the malnourished-oil-paclitaxel group (MOP) and lower in the malnourished-oil-saline group (MOS) in relation to the malnourished-omega3-paclitaxel group (M3P). supplementation with omega-3 fatty acids was associated with a significant increase in the production of mature collagen in malnourished animals, with a reversal of the harmful effects caused by malnutrition associated with the use of paclitaxel on the rupture strength, and with a stimulus to neoangiogenesis in the group receiving paclitaxel.