Amlodipine activates the endothelial nitric oxide synthase by altering phosphorylation on Ser1177 and Thr495.
The Ca2+ antagonist amlodipine increases the generation of nitric oxide (NO) from native and cultured endothelial cells. The aim of this investigation was to determine whether or not the activation of the endothelial NO synthase (eNOS) by this Ca2+ antagonist is related to alterations in eNOS phosphorylation. In isolated, pre-contracted, endothelium-intact porcine coronary arteries, amlodipine elicited an NO-mediated relaxation and a leftward shift in the concentration-relaxation curve to bradykinin. Moreover, the Ca2+ antagonist increased the generation of NO from native endothelial cells, as detected by electron spin resonance spectroscopy and stimulated an 8-fold increase in cyclic GMP levels in cultured endothelial cells. In unstimulated endothelial cells, eNOS was not phosphorylated on Ser1177 but was phosphorylated on Thr495. Amlodipine elicited the phosphorylation of Ser1177 and attenuated Thr495 phosphorylation, with a time course similar to that of eNOS activation. The amlodipine-induced relaxation of porcine coronary arteries was attenuated by the B2 kinin receptor antagonist, icatibant, but this antagonist did not affect amlodipine-induced changes in eNOS phosphorylation in cultured endothelial cells. Moreover, amlodipine elicited the NO-mediated relaxation of rat aortic rings which do not express the B2 receptor. Amlodipine time-dependently attenuated the phosphorylation of protein kinase C (PKC) in endothelial cells, with a time course similar to the changes in eNOS phosphorylation, and prevented the phorbol-12-myristate-13-acetate-induced activation of PKC. The PKC inhibitor, Ro 31-8220, also elicited the phosphorylation of Ser1177 and the dephosphorylation of Thr495 in cultured cells and induced a leftward shift in the concentration-relaxation curve to bradykinin in rings of porcine coronary artery. The Ca2+ antagonist, amlodipine, enhances endothelial NO generation by inducing changes in the phosphorylation of eNOS. Although the activation of eNOS was related to the activation of the B2 kinin receptor in the porcine coronary artery, a B2 receptor-independent mechanism involving the inhibition of PKC appears to account for the effects observed in the rat aorta as well as in cultured endothelial cells.


Impact of renal transplantation on erectile dysfunction due to chronic renal failure in male patients.
Erectile dysfunction can be defined as the persistent inability of man to achieve penile erection and maintain it sufficient for satisfactory coitus. The objectives of this study were to find out the impact of successful renal transplantation on the degree and frequency of erectile dysfunction. Thirty patients of end stage renal disease that were on regular haemodialysis and candidates of renal transplantation of age range 20-55 years were included in the study after getting informed consent. Erectile functions were assessed by history, examination, investigations and international index of erectile function (IIEF) before and 3 and 6 months after renal transplantation, other information regarding disease and patient were collected in the performa. Out of thirty patients 14 (46.6%) patients had sever erectile dysfunction while 16 (53.3%) patients had moderate erectile dysfunction in the pre renal transplantation period. After three months of renal transplantation 15 (50%) had severe erectile dysfunction, 6 (20%) patients moderate erectile dysfunction and 9 (30%) patients mild erectile dysfunction. After six months 11 (36.6%), 10 (33.3%) and 8 (26.6%) patients had severe, moderate and mild erectile dysfunction respectively. There was improvement in 40%, no change in 53.3% and deterioration in 6.6% patients in the erectile functions after getting renal transplantation for end stage renal disease.


Ruthenium-Based Photoactivated Chemotherapy.
Ruthenium(II) polypyridyl complexes form a vast family of molecules characterized by their finely tuned photochemical and photophysical properties. Their ability to undergo excited-state deactivation via photosubstitution reactions makes them quite unique in inorganic photochemistry. As a consequence, they have been used, in general, for building dynamic molecular systems responsive to light but, more particularly, in the field of oncology, as prodrugs for a new cancer treatment modality called photoactivated chemotherapy (PACT). Indeed, the ability of a coordination bond to be selectively broken under visible light irradiation offers fascinating perspectives in oncology: it is possible to make poorly toxic agents in the dark that become activated toward cancer cell killing by simple visible light irradiation of the compound inside a tumor. In this Perspective, we review the most important concepts behind the PACT idea, the relationship between ruthenium compounds used for PACT and those used for a related phototherapeutic approach called photodynamic therapy (PDT), and we discuss important questions about real-life applications of PACT in the clinic. We conclude this Perspective with important challenges in the field and an outlook.


Role of GLIS3 in thyroid development and in the regulation of gene expression in thyroid specific Glis3KO mice.
Loss of GLI-Similar 3 (GLIS3) function in mice and humans causes congenital hypothyroidism (CH). In this study, we demonstrate that GLIS3 protein is first detectable at E15.5 of murine thyroid development, a time when GLIS3 target genes, such as Slc5a5 (Nis), become also expressed. We further show that Glis3KO mice do not display any major changes in prenatal thyroid gland morphology indicating that CH in Glis3KO mice is due to dyshormonogenesis rather than thyroid dysgenesis. Analysis of thyroid-specific Glis3 knockout (Glis3-Pax8Cre) mice fed either a normal or low-iodine diet (ND or LID) revealed that, in contrast to ubiquitous Glis3KO mice, thyroid follicular cell proliferation and the expression of cell cycle genes were not repressed suggesting that the inhibition of thyroid follicular cell proliferation in ubiquitous Glis3KO mice is related to loss of GLIS3 function in other cell types. However, the expression of several thyroid hormone biosynthesis-, extracellular matrix (ECM)-, and inflammation-related genes was still suppressed in Glis3-Pax8Cre mice particularly under conditions of high blood levels of thyroid stimulating hormone (TSH). We further demonstrate that treatment with TSH, protein kinase A (PKA) or adenylyl cyclase activators or expression of constitutively active PKA enhances GLIS3 protein and activity, suggesting that GLIS3 transcriptional activity is regulated in part by TSH/TSHR-mediated activation of the PKA pathway. This mechanism of regulation provides an explanation for the dramatic increase in GLIS3 protein expression and the subsequent induction of GLIS3 target genes, including several thyroid hormone biosynthetic genes, in thyroid follicular cells of mice fed a LID.


Quantitative analysis of glutathione in human brain tumors.
Reduced glutathione (gamma-glutamylcysteinylglycine, GSH) plays an important role in the protection of cells against damage from free radicals and other electrophils and also influences cellular radiosensitivity, cellular response to hyperthermia, and cytotoxicity to some kinds of chemotherapeutic agents. The concentrations of GSH in 40 primary and metastatic brain tumors were quantitatively analyzed, and GSH was localized in these tumors by a novel o-phthalaldehyde histofluorescence method. The level of GSH was 195.2 +/- 57.1 micrograms/gm (mean +/- standard deviation) in glioblastomas multiforme, 444.1 +/- 105.1 micrograms/gm in normal brain tissues, and 614.4 +/- 237.4 micrograms/gm in meningiomas. The differences in GSH levels between glioblastomas and normal brain tissues and between glioblastomas and meningiomas were statistically significant (p less than 0.01). The mean GSH level in astrocytoma grades II and III was 321.9 +/- 11.8 micrograms/gm. The difference in the GSH level between glioblastomas and astrocytomas was statistically significant (p less than 0.05). Radiosensitive tumors, such as multiple myeloma, germinoma, and small-cell carcinoma, showed low GSH levels. These data suggest the possibility that the GSH may be a predictor for the efficacy of radiation therapy. The cytochemical study showed GSH localized in the cytoplasm; although it stained well in meningioma tissue, GSH was not well stained in sections of multiple myeloma. The endothelial proliferation did not stain well in glioblastoma, which seems to imply that this area is vulnerable to attack by free radicals from irradiation and/or chemotherapy.


Chemical Leslie effect in a chiral smectic-C^{★} film: Nonsingular target patterns.
We analyze experimentally and theoretically the winding and unwinding of the c[over ⃗] director in a chiral smectic-C^{★} film crossed by an ethanol flow. This leads to a target pattern under crossed polarizers when the +1 defect imposed by the boundary conditions is pinned on the edge of the film. We show that the target is deformed at the center of the film when it is subjected to a flow of ethanol because of the presence of two recirculation vortices of chemohydrodynamical origin. This deformation and the two vortices disappear during the unwinding of the target when the ethanol flow is stopped. This unambiguously shows that the target deformation is due to the vortices and not to the elastic anisotropy. These two points are confirmed theoretically. An estimate of the two so-called chemomechanical and chemohydrodynamical Leslie coefficients is also derived from this study.


Clinical Results of the Advanced Neurovascular Access Catheter System Combined With a Stent Retriever in Acute Ischemic Stroke (SOLONDA).
The Advanced Neurovascular Access (ANA) thrombectomy system is a novel stroke thrombectomy device comprising a self-expanding funnel designed to reduce clot fragmentation by locally restricting flow while becoming as wide as the lodging artery. Once deployed, the ANA device allows distal aspiration combined with a stent retriever to mobilize the clot into the funnel where it remains copped during extraction. We investigated the safety and efficacy of ANA catheter system. SOLONDA (Solitaire in Combination With the ANA Catheter System as Manufactured by Anaconda) was a prospective, open, single-arm, multicenter trial with blinded assessment of the primary outcome by an independent core lab. Patients with anterior circulation vessel occlusion admitted within 8 hours from symptom onset were eligible. The primary end point was successful reperfusion (modified Thrombolysis in Cerebral Infarction score 2b-3) with ≤3 passes of the ANA device in combination with stent retriever, before the use of rescue therapy in the intention to treat population. Primary predefined analysis was noninferiority as compared to the performance end point observed in HERMES (High Effective Reperfusion Using Multiple Endovascular Devices). After enrollment of 74 patients, an interim analysis was conducted, and the trial Steering Committee decided to terminate recruitment due to safety and performance objectives were reached. Mean age was 71.6 (SD 8.9) years, 46.6% women and median National Institutes of Health Stroke Scale on admission 14 (interquartile range, 10-19). Successful reperfusion within 3 passes before rescue therapy was achieved in 60/72 (83.3% [95% CI, 74.7%-91.9%]) with a rate of complete reperfusion (modified Thrombolysis in Cerebral Infarction score 2c-3) of 60% (95% CI, 48.4%-71.1%; 43/72 patients). After noninferiority was confirmed (P<0.01), the ANA device also showed superiority in the rate of successful reperfusion with ≤3 passes (P=0.02). First-pass successful recanalization rate was 55.6% (95% CI, 44.1%-67.0%), with a first-pass complete recanalization rate of 38.9% (95% CI, 27.6%-50.1%). Rescue therapy to obtain a modified Thrombolysis in Cerebral Infarction score 2b-3 was needed in 12/72 (17%) patients. At 90 days, the rate of favorable functional outcome (modified Rankin Scale score 0-2) was 57.5% (95% CI, 46.2%-68.9%), and the rate of excellent functional outcome (modified Rankin Scale score 0-1) was 45.2% (95% CI, 33.8%-56.6%). The rate of severe adverse device related was 1.4%. In this clinical experience, the ANA device achieved a high rate of complete recanalization with a preliminary good safety profile and favorable 90 days clinical outcomes. URL: https://www. gov; Unique identifier: NCT04095767.


The secretion of intestinal alkaline phosphatase (IAP) from the enterocyte.
Rat intestinal alkaline phosphatase exists in two separate forms, differing markedly in the carboxyterminal coding region, as well as in the 3' untranslated regions. It is secreted bound to a phospholipid-rich particle (surfactant-like particle) which appears to have unique properties, but whose role is still uncertain. Evidence is presented to suggest that intestinal alkaline phosphatase secretion is mediated by this particle. The challenge for the future is to study the biology of the surfactant-like particle, to ascertain its role in gut physiology, and to determine how the dual alkaline phosphatases are involved in this specialized secretory apparatus.


What Will It Take to End the HIV/AIDS Epidemic? Linking the Most Disenfranchised Into Care Through Outreach.
The 2015 National HIV/AIDS Strategy renewed its goal of increasing access to care for people living with HIV/AIDS (PLWHA) and called for an increased focus on linkage to care efforts. As many PLWHA face multiple barriers to care and live on the margins of society, adoption of intensive outreach activities is necessary to engage the most disenfranchised PLWHA into care and to ultimately end the HIV epidemic. The Bay Area Network for Positive Health (BANPH), comprising 12+ agencies, established a network outreach model for our linkage-to-care project to engage the hardest-to-reach populations in the San Francisco Bay Area. During the years 2010-2013, BANPH agencies conducted street outreach, analyzed internal tracking systems to identify out-of-care individuals and individuals experiencing tenuous care, and surveyed participants using Apple iPod Touch devices. During the 3-year project, BANPH agencies engaged 602 out-of-care PLWHA and linked 440 to care. On average, outreach workers made 10 contact attempts with a client to link them to care. Sixty-three percent of participants were linked to care on an average of 56 days after initial contact. Factors, including lack of case management, lack of transportation, competing concerns, substance abuse, and HIV stigma, were significantly associated with linkage-to-care outcomes. Intensive outreach efforts could help to reduce barriers to care for hard-to-reach PLWHA, but these efforts require a tremendous amount of time and resources. A network outreach model could help facilitate sharing of limited resources and increase regional outreach capacity for linkage-to-care programs.


Methods for detecting host genetic modifiers of tumor vascular function using dynamic near-infrared fluorescence imaging.
Vascular supply is a critical component of the tumor microenvironment (TME) and is essential for tumor growth and metastasis, yet the endogenous genetic modifiers that impact vascular function in the TME are largely unknown. To identify the host TME modifiers of tumor vascular function, we combined a novel genetic mapping strategy [Consomic Xenograft Model] with near-infrared (NIR) fluorescence imaging and multiparametric analysis of pharmacokinetic modeling. To detect vascular flow, an intensified cooled camera based dynamic NIR imaging system with 785 nm laser diode based excitation was used to image the whole-body fluorescence emission of intravenously injected indocyanine green dye. Principal component analysis was used to extract the spatial segmentation information for the lungs, liver, and tumor regions-of-interest. Vascular function was then quantified by pK modeling of the imaging data, which revealed significantly altered tissue perfusion and vascular permeability that were caused by host genetic modifiers in the TME. Collectively, these data demonstrate that NIR fluorescent imaging can be used as a non-invasive means for characterizing host TME modifiers of vascular function that have been linked with tumor risk, progression, and response to therapy.


Evaluation of Medical Countermeasures Against Ebolaviruses in Nonhuman Primate Models.
Several ebolavirus species, with varying lethality rates, have caused sporadic outbreaks in Africa resulting in human disease. Ebolaviruses also have the potential for use as biological weapons. Currently, there are no licensed vaccines or therapeutics to respond to outbreaks or deliberate misuse of ebolaviruses. Vaccine or therapeutic efficacy testing of medical countermeasures against ebolaviruses requires an animal model of disease; in vitro testing in cell culture cannot reproduce the complicated balance between host-pathogen interactions required for the ultimate licensure of a countermeasure. Depending on the target of the countermeasure, demonstration of efficacy in the nonhuman primate ebolavirus disease models will most likely be required before licensure. Here, we describe the selection and use of nonhuman primates for vaccine and therapeutic studies against ebolaviruses.


CpG in Combination with an Inhibitor of Notch Signaling Suppresses Formalin-Inactivated Respiratory Syncytial Virus-Enhanced Airway Hyperresponsiveness and Inflammation by Inhibiting Th17 Memory Responses and Promoting Tissue-Resident Memory Cells in Lungs.
Respiratory syncytial virus (RSV) is the leading cause of childhood hospitalizations. The formalin-inactivated RSV (FI-RSV) vaccine-enhanced respiratory disease (ERD) has been an obstacle to the development of a safe and effective killed RSV vaccine. Agonists of Toll-like receptor (TLR) have been shown to regulate immune responses induced by FI-RSV. Notch signaling plays critical roles during the differentiation and effector function phases of innate and adaptive immune responses. Cross talk between TLR and Notch signaling pathways results in fine-tuning of TLR-triggered innate inflammatory responses. We evaluated the impact of TLR and Notch signaling on ERD in a murine model by administering CpG, an agonist of TLR9, in combination with L685,458, an inhibitor of Notch signaling during FI-RSV immunization. Activation with CpG or deficiency of MyD88-dependent TLR signaling did not alleviate airway inflammation in FI-RSV-immunized mice. Activation or inhibition of Notch signaling with Dll4, one of the Notch ligands, or L685,458 did not suppress FI-RSV-enhanced airway inflammation either. However, the CpG together with L685,458 markedly inhibited FI-RSV-enhanced airway hyperresponsiveness, weight loss, and lung inflammation. Interestingly, CpG plus L685,458 completely inhibited FI-RSV-associated Th17 and Th17-associated proinflammatory chemokine responses in lungs following RSV challenge but not Th1 or Th2, memory responses. In addition, FI-RSV plus CpG plus L685,458 promoted protective CD8+ lung tissue-resident memory (TRM) cells. These results indicate that activation of TLR signaling combined with inhibition of Notch signaling prevent FI-RSV ERD, and the mechanism appears to involve suppressing proinflammatory Th17 memory responses and promoting protective TRM in lungs.IMPORTANCE RSV is the most important cause of lower respiratory tract infections in infants. The FI-RSV-enhanced respiratory disease (ERD) is a major impediment to the development of a safe and effective killed RSV vaccine. Using adjuvants to regulate innate and adaptive immune responses could be an effective method to prevent ERD. We evaluated the impact of TLR and Notch signaling on ERD by administering CpG, an agonist of TLR9, in combination with L685,458, an inhibitor of Notch signaling, during FI-RSV immunization. The data showed that treatment of TLR or Notch signaling alone did not suppress FI-RSV-enhanced airway inflammation, while CpG plus L685,458 markedly inhibited ERD. The mechanism appears to involve suppressing Th17 memory responses and promoting tissue-resident memory cells. Moreover, these results suggest that regulation of lung immune memory with adjuvant compounds containing more than one immune-stimulatory molecule may be a good strategy to prevent FI-RSV ERD.


Estimation for the bivariate quantile varying coefficient model with application to diffusion tensor imaging data analysis.
Despite interest in the joint modeling of multiple functional responses such as diffusion properties in neuroimaging, robust statistical methods appropriate for this task are lacking. To address this need, we propose a varying coefficient quantile regression model able to handle bivariate functional responses. Our work supports innovative insights into biomedical data by modeling the joint distribution of functional variables over their domains and across clinical covariates. We propose an estimation procedure based on the alternating direction method of multipliers and propagation separation algorithms to estimate varying coefficients using a B-spline basis and an $L_2$ smoothness penalty that encourages interpretability. A simulation study and an application to a real-world neurodevelopmental data set demonstrates the performance of our model and the insights provided by modeling functional fractional anisotropy and mean diffusivity jointly and their association with gestational age and sex.


Engineering of the DNA replication and repair machinery to develop binary mutators for rapid genome evolution of Corynebacterium glutamicum.
Corynebacterium glutamicum is an important industrial workhorse for production of amino acids and chemicals. Although recently developed genome editing technologies have advanced the rational genetic engineering of C. glutamicum, continuous genome evolution based on genetic mutators is still unavailable. To address this issue, the DNA replication and repair machinery of C. glutamicum was targeted in this study. DnaQ, the homolog of ϵ subunit of DNA polymerase III responsible for proofreading in Escherichia coli, was proven irrelevant to DNA replication fidelity in C. glutamicum. However, the histidinol phosphatase (PHP) domain of DnaE1, the α subunit of DNA polymerase III, was characterized as the key proofreading element and certain variants with PHP mutations allowed elevated spontaneous mutagenesis. Repression of the NucS-mediated post-replicative mismatch repair pathway or overexpression of newly screened NucS variants also impaired the DNA replication fidelity. Simultaneous interference with the DNA replication and repair machinery generated a binary genetic mutator capable of increasing the mutation rate by up to 2352-fold. The mutators facilitated rapid evolutionary engineering of C. glutamicum to acquire stress tolerance and protein overproduction phenotypes. This study provides efficient tools for evolutionary engineering of C. glutamicum and could inspire the development of mutagenesis strategy for other microbial hosts.


Mental retardation, mental illness, and seizure diagnosis.
The coexistence of epilepsy in individuals with mental retardation and mental illness is common. Little is known about whether individuals with all three conditions do significantly worse on inpatient units compared to persons with mental retardation and psychiatric disorder but without a seizure diagnosis. During 62 consecutive months, 247 individuals with mental retardation and psychiatric disorders were discharged from a university hospital. A review of discharge summaries yielded 39 individuals with a seizure diagnosis. The only difference between the groups with and without seizures was level of mental retardation. No differences existed with regard to length of stay, transfer to state hospital, psychiatric co-morbidity, or medical illness. Although it is sometimes difficult for many individuals with mental retardation to be admitted to a psychiatric hospital during exacerbations of mental illness, they should not be further stigmatized by presence of a seizure diagnosis.


Toxicological relationships between proteins obtained from protein target predictions of large toxicity databases.
The combination of models for protein target prediction with large databases containing toxicological information for individual molecules allows the derivation of "toxiclogical" profiles, i.e., to what extent are molecules of known toxicity predicted to interact with a set of protein targets. To predict protein targets of drug-like and toxic molecules, we built a computational multiclass model using the Winnow algorithm based on a dataset of protein targets derived from the MDL Drug Data Report. A 15-fold Monte Carlo cross-validation using 50% of each class for training, and the remaining 50% for testing, provided an assessment of the accuracy of that model. We retained the 3 top-ranking predictions and found that in 82% of all cases the correct target was predicted within these three predictions. The first prediction was the correct one in almost 70% of cases. A model built on the whole protein target dataset was then used to predict the protein targets for 150000 molecules from the MDL Toxicity Database. We analysed the frequency of the predictions across the panel of protein targets for experimentally determined toxicity classes of all molecules. This allowed us to identify clusters of proteins related by their toxicological profiles, as well as toxicities that are related. Literature-based evidence is provided for some specific clusters to show the relevance of the relationships identified.


[Hygienic assessment of biological reservoir pollution in Eastern Siberia and the North].
The paper presents the characteristics of microbial communities in the water reservoirs of Eastern Siberia and North and their changes depending on the anthropogenic pollution and analyzes antibiotic resistance in microorganisms. The water contamination with pathogenic viruses was revealed in relation to the man-made load, which may be a criterion for assessing the epidemiological situation on the territories.


Sexual differentiation of the mechanism controlling the preovulatory discharge of luteinizing hormone in sheep.
Silastic capsules containing estradiol-17beta were implanted subcutaneously into male and female sheep which had been gonadectomized as adults, In both sexes, this treatment resulted in a prompt decrease in serum LH concentrations reflecting a negative feedback suppression of tonic LH secretion. In females but not males, this decrease was followed, within 24 h, by an LH surge after which circulating LH declined to low levels resembling those in intact ewes during the luteal phase of the estrous cycle. In males, only a sustained reduction in circulating LH was observed. Three weeks after placement of the initial estradiol implants, while serum LH levels were low and stable, additional estradiol implants were inserted. This additional treatment effected step-like increments in circulating estradiol to approximately 20 or 55 pg/ml (depending on the number of implants) and elicited single or multiple LH discharges in females but failed to induce LH surges in males. These findings lead to the conclusion that the mechanism which governs the cyclic mode of LH secretion in sheep, as in rats, undergoes sexual differentiation. Further, the presence of multiple LH surges in some females suggests that an increment and sustained elevation in circulating estradiol can induce the occurrence, or permit the expression, of consecutive signals for the LH surge in the ovariectomized ewe.


Hysterical abdominal distention simulating acute intestinal obstruction. With report of a case.
In hysterical abdominal distention the symptoms may so closely simulate those of obstruction of the bowel that needless laparotomy is carried out.CLUES THAT INDICATE HYSTERICAL DISTENTION RATHER THAN ORGANIC CAUSE ARE: (1) History of vomiting but without dehydration; (2) complaint of severe pain although temperature, pulse and the number of leukocytes in the blood all are normal; (3) normal tympanic quality of the abdomen; (4) distention out of proportion to the amount of gas observed in x-ray examination; (5) pronounced lordosis caused by thrusting the abdomen forward; and (6) remission of distention when the patient is under general anesthesia. It must be remembered, however, that even when there is strong suspicion of hysterical cause, distention may actually be due to obstruction. In the case herein reported, obstructive adhesion finally did occur after the patient had had numerous exploratory operations in which the viscera were observed to be normal.


Particle acceleration in colliding flows: Binary star winds and other double-shock structures.
A shock wave propagating perpendicularly to an ambient magnetic field accelerates particles considerably faster than in the parallel propagation regime. However, the perpendicular acceleration stops after the shock overruns a circular particle orbit. At the same time, it may continue in flows resulting from supersonically colliding plasmas bound by a pair of perpendicular shocks. Although the double-shock acceleration mechanism, which we consider in detail, is not advantageous for thermal particles, preenergized particles may avoid the premature end of acceleration. We argue that if their gyroradius exceeds the dominant turbulence scale between the shocks, these particles might traverse the intershock space repeatedly before being carried away by the shocked plasma. Moreover, entering the space between the shocks of similar velocities u_{1}≈u_{2}≈c, such particles start bouncing between the shocks at a fixed angle ≈35.3^{∘} to the shock surface. Their drift along the shock fronts is slow, V_{d}∼|u_{2}-u_{1}|≪c, so that it will take N∼Lc/|u_{2}-u_{1}|d≫1 bounces before they escape the accelerator (here, L is the size of the shocks and d is the gap between them). Since these particles more than tenfold their energy per cycle (two consecutive bounces), we invoke other possible losses that can limit the acceleration. They include drifts due to rippled shocks, the nonparallel mutual orientation of the upstream magnetic fields, and radiative losses.


Shape Memory Alloys Applied to Automotive Adaptive Aerodynamics.
Shape memory alloys (SMAs) are gaining popularity in the fields of automotive and aerospace engineering due to their unique thermomechanical properties. This paper proposes a numerical implementation of a comprehensive constitutive model for simulating the thermomechanical behavior of shape memory alloys, with temperature and strain as control variables to adjust the shape memory effect and super elasticity effect of the material. By implementing this model as a user subroutine in the FE code Abaqus/Standard, it becomes possible to account for variations in material properties in complex components made of shape memory alloys. To demonstrate the potential of the proposed model, a skid plate system design is presented. The system uses bistable actuators with shape memory alloy springs to trigger plate movement. The kinematics and dynamics of the system are simulated, and effective loads are generated by the shape memory alloy state change due to the real temperature distribution in the material, which depends on the springs' geometrical parameters. Finally, the performance of the actuator in switching between different configurations and maintaining stability in a specific configuration is assessed. The study highlights the promising potential of shape memory alloys in engineering applications and demonstrates the ability to use them in complex systems with accurate simulations.


Juvenile dermatomyositis: recognition and treatment.
Juvenile dermatomyositis (JDM) is a multisystem disease characterized by acute and chronic lymphocytic inflammation of the skeletal muscle and skin. The disease is marked early in its course by the presence of a vasculopathy or vasculitis, and later by the development of calcinosis. Research has focused on the epidemiology, etiology, and pathogenesis of the disease with, until more recently, limited therapeutic interventions. This article highlights treatment regimens, both traditional and more recent interventions. Traditional treatment for JDM includes high dose corticosteroid treatment with additional agents used in resistant disease or children with unwarranted adverse effects. Traditional therapy begins with daily oral corticosteroids, with intravenous corticosteroids utilized in severe disease; however, recent data suggests that short-term use of intravenous corticosteroids will allow a short-term improvement in strength, with no long-term change in outcome. More recent investigations suggest that early intervention with additional immunomodulatory agents will allow for a faster recovery, with less medication and disease sequelae. Use of methotrexate as an agent early in the disease course is becoming common place. Methotrexate, in conjunction with oral corticosteroids, allows a rapid improvement in symptoms, and allows for a more rapid reduction in corticosteroid dose. Methotrexate is considered as a steroid sparing agent, whether oral or intravenous corticosteroids are used. Additional immunomodulatory agents include the use of cyclosporine with or without methotrexate. Intravenous immunoglobulin has been reported to have benefit in resistant disease. There are exciting new agents which have great potential in treating JDM. Many of these agents are termed biologics and are being tested in adult myositis and juvenile arthritis. These include tumor necrosis factor (TNF)-alpha inhibitors, such as a chimeric monoclonal antibody to TNF-alpha, and a recombinant soluble human TNF receptor (p75)-Fc fusion protein. Many other new biological agents are also being tested in myositis.


Outbreak of Bilateral Endophthalmitis After Immediate Sequential Bilateral Cataract Surgery.
Since bilateral simultaneous postoperative endophthalmitis (BSPOE) after immediate sequential bilateral cataract surgery (ISBCS) can be devastating for the patient, evaluating such cases in depth is important to maintaining patient safety. To evaluate whether a systemic breach of sterility was associated with an outbreak of BSPOE after ISBCSs performed on the same day at a single community-based eye clinic. This retrospective case series included all patients diagnosed with BSPOE at ophthalmology departments in Denmark following an infectious outbreak after ISBCSs performed at a single community-based eye clinic in December 2022. Bilateral simultaneous postoperative endophthalmitis acquired after ISBCS. Patient recovery from BSPOE after ISBCS was evaluated based on clinical and microbiological reports. A woman aged 71 years, a man aged 84 years, and a woman aged 79 years consecutively presented with symptoms of endophthalmitis at regional eye departments 4 to 8 days after ISBCS performed on the same date at the same eye clinic. Five of 6 infected eyes underwent vitrectomy, and all eyes received an intravitreous injection of antibiotics. The same strain of Staphylococcus epidermidis was isolated in 4 of 5 eyes that underwent vitrectomy. Contamination of viscoelastics was ruled out with repeated cultures. One eye was eviscerated due to phthisis. In another patient, the final visual acuity of the eye most severely affected was 20/63 Snellen equivalents. Visual acuity of the remaining eyes recovered to 20/25 (3 eyes in 2 patients) and 20/20 (1 eye) Snellen equivalents. The finding of the same strain of S epidermidis in all patient cultures suggests a systemic breach of sterility at the clinic on the day of ISBCS. The outcome of these cases emphasizes the need to adhere to a strict surgical methodology and sterile principles during ISBCS.


Thromboxane A2 receptor gene polymorphism is associated with the serum concentration of cat-specific immunoglobulin E as well as the development and severity of asthma in Chinese children.
Thromboxane A2 and its receptor (TBXA2R) are involved in the constriction of vascular and respiratory smooth muscles. The T924C polymorphism in the TBXA2R gene was recently found to be associated with asthma in Japanese adults but not in children. Its relationship with atopy or asthma severity in children has not been defined. To investigate this further, we first assessed the severity of asthma in Chinese children using a standardized questionnaire modified from the Disease Severity Score and spirometric evaluation. Then, peripheral blood was analyzed for serum total and aeroallergen-specific immunoglobulin E (IgE) levels, and TBXA2R T924C genotypes were determined by restriction fragment length polymorphism (RFLP) analysis. One-hundred and fifty three asthmatic patients and 57 control children were recruited, of respective mean ages 9.9 and 11.0 years (p = 0.07). The mean logarithmic serum total IgE concentration was 2.57 and 2.09, respectively, for the asthmatic group and control group (p < 0.0001). Atopy was detected in 132 (86%) asthmatics and 33 (58%) controls. A significant association was observed between T924C and the diagnosis of atopic asthma (p = 0.044; odds ratio: 1.84). In addition, those asthmatics homozygous for the mutant allele in T924C had a lower forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) (p = 0.032 and 0.002, respectively). Among our asthmatic patients, the TBXA2R T924C polymorphism correlated with the concentration of cat-specific IgE in serum (p = 0.046). Nonetheless, this gene marker did not show an association with the serum total IgE concentration or any clinical indicator of asthma severity. In conclusion, our results suggest that the T924C marker in the TBXA2R gene is associated, in Chinese children, with an increased susceptibility of developing atopic asthma. This marker is also associated with the extent of allergic sensitization to cat, as well as with reduced FEV1 and FVC values.


The complete mitochondrial genome sequence of Cynoglossus abbreviatus (Pleuronectiformes: Cynoglossidae) with control region translocation and tRNA-Gln gene inversion.
Cynoglossus abbreviatus (Cynoglossidae, Soleoidei) is characterized by a bilaterally asymmetrical with both eyes on the left side. In this study, the complete mitogenome of this tongue sole has been reported for the first time. The gene order in C. abbreviatus mitogenome possesses a novel rearrangement like other tonguefish. The tRNA-Gln gene moves from the light strand to the heavy strand, accompanied by tRNA-Ile gene shuffling, leaving a large non-coding region (88 bp) between these two tRNAs. Additionally, the control region translocates to the place between ND1 and tRNA-Gln genes. The total length is 16,417 bp, with 30.9%, 29.5%, 24.9% and 14.7% for A, T, C and G, respectively (60.4% for AT content). These molecular data will provide useful information about the mechanism of gene reorganization in Cynoglossidae mitogenome and further phylogenetic study on Pleuronectiformes.


Brow Ptosis: Is Transblepharoplasty Internal Browpexy Suitable for Everyone?
Transcutaneous internal browpexy can provide patients with mild-to-moderate lateral brow ptosis, stabilization and modest lift of the lateral brow. Questions regarding effectiveness of this procedure and appropriate indications remain. The authors measured consecutive patients who underwent upper eyelid blepharoplasty with transblepharoplasty internal browpexy (TIB) September 2014 to December 2017. Pre- and postoperative brow elevation was assessed based on before and after photographs of each patient. Patient photographs were assessed for medial and lateral brow elevation, brow contouring and asymmetry. Optimal lateral brow elevation was classified as bilateral symmetrical and above the supraorbital rim for women, and symmetrical and at the supraorbital rim for men. A total of 239 patients underwent bilateral TIB and 39 underwent unilateral TIB (517 eyelids in total). Pre- and post-operative measurements were taken in 98 patients (41%), with an average elevation of the lateral brow position of 2.54 mm.Six patients had an underlying infection in the first postoperative week that resolved completely. Three patients underwent a second stage direct brow lift repair and 3 needed unrecognized ptosis repair as a second stage. Transblepharoplasty internal browpexy is an important tool that can be used in most patients with lateral and central brow ptosis, asymmetric brow ptosis and irregular contour of the brow. Additionally, browpexy adds to the success and longevity of upper blepharoplasty, while preventing early recurrence of lateral upper eyelid hooding. Patients with significant ptosis, heavy brows, medial greater than lateral ptosis, and post-facial palsy may not be good candidates for this procedure.


Genetic diversity of mitochondrial cytochrome b gene in Chinese native buffalo.
The origins of the domestic water buffalo remain contentious. To better understand the origins of Chinese water buffalo, we sequenced the complete mitochondrial cytochrome b (MT-CYB) gene from 270 individuals representing 13 Chinese domestic swamp buffalo populations. We found genetic evidence of introgression of river buffalo into Chinese swamp buffalo herds. Swamp buffalo haplotypes can be divided into two highly divergent lineages (A and B), suggesting that Chinese native swamp buffalo have two maternal origins. We found that the A→G transition in the buffalo MT-CYB gene stop codon resulted in buffalo haplotypes being terminated by one of two stop codons: AGA or AGG. AGA is common to river buffalo and lineage A of swamp buffalo, while AGG is specific to lineage B of swamp buffalo. Lineage A appears to have been domesticated in China. Further genetic evidence is required to clarify the origins of lineage B.


Global assessment of nutrition risk factors in the elderly.
Global assessment of nutrition risk factors in the elderly consists of subject's history, physical examination, and laboratory tests, which are the indispensable mode to establish definite nutritional disorders. This is illustrated in a study of 150 free-living elderly Thais participating in the Global Assessment of Nutritional Risk Factors in the Thai Elderly. They consisted of 50 men and 100 women, aged 60-86 years and were an affluent urban population. Diet-related chronic diseases including overall obesity, abdominal obesity, dyslipidemia, impaired glucose tolerance, diabetes mellitus, and hypertension were the major nutritional problems affecting their life and well-being. Thus appropriate nutritional intervention must be provided to improve their impaired health status.


Incidence of high altitude illnesses among unacclimatized persons who acutely ascended to Tibet.
High altitude illnesses pose health threats to unwary travelers after their acute ascent to high altitude locations. The incidence of high altitude illnesses among unacclimatized persons who acutely ascend to Tibet has not been previously reported. In the present study, we surveyed the incidence of high altitude illness among 3628 unacclimatized persons who had no previous high altitude experience and who traveled to Tibet by air to an altitude of 3600 m. These subjects were asked to answer questions in a written questionnaire about symptoms associated with high altitude illnesses that occurred within 2 weeks of their first arrival, their severity, and possible contributing factors. Physical examination and appropriate laboratory tests were also performed for hospitalized subjects. We found that 2063 respondents had mild acute mountain sickness with an incidence of 57.2%, and 249 (12.07%) of them were hospitalized for treatment. The incidence of high altitude pulmonary edema was 1.9%, while no case of high altitude cerebral edema was found. Additionally, there was no report of death. Psychological stresses and excessive physical exertions possibly contributed to the onset of HAPE. Acute mountain sickness is common among unacclimatized persons after their acute ascent to Tibet. The incidence of HAPE and HACE, however, is very low among them.


Self-criticism in therapist training: A grounded theory analysis.
The primary objective of this study is to engender an understanding of how therapists-in-training experience and cope with self-criticism in the context of their clinical training and therapy experiences. In this study, trainees were interviewed about their experience of self-criticism related to psychotherapy practice and these interviews were subjected to a grounded theory analysis generating a core self-critical process. The analysis highlighted the vulnerability of self-criticism in therapists' training experiences, especially when they related to balancing the "expert" role while maintaining authentic interactions with their clients. The results also described ways in which self-criticism is mitigated by a sense of interpersonal safety and the provision of clinical freedom and flexibility in therapists' training. The implications for future psychotherapy research and clinical training within clinical training environments are discussed.


Melatonin protects against COPD by attenuating apoptosis and endoplasmic reticulum stress via upregulating SIRT1 expression in rats.
The apoptosis of bronchial and alveolar epithelial cells plays a key role in chronic obstructive pulmonary disease (COPD). The endoplasmic reticulum (ER) stress induced by cigarette smoke contributes to apoptosis. Previous studies demonstrated that melatonin prevented the development of COPD. In addition, silent information regulator 1 (SIRT1) had a protective effect against COPD. However, it remains unclear whether SIRT1 is involved in the protection of melatonin against COPD. In this study, 32 male Wistar rats were randomly assigned to 4 groups: Control, COPD, COPD + Mel, and COPD + Mel + EX527. Rats were challenged with cigarette smoke and lipopolysaccharide with or without melatonin or EX527 (a selective inhibitor of SIRT1). The lung histopathology, apoptotic index, as well as the protein expressions of cleaved caspase-3, SIRT1, C/EBP homologous protein, and caspase-12 in the lung tissues were measured. These results demonstrated that melatonin attenuated apoptosis and ER stress in the lung tissues of rats with COPD. In addition, melatonin increased SIRT1 expression in lung tissues of rats with COPD, while inhibition of SIRT1 by EX527 upregulated ER stress and abolished the protective effect of melatonin against apoptosis. In conclusion, these findings suggested that melatonin protected against COPD by attenuating apoptosis and ER stress via upregulating SIRT1 expression in rats.


Gene-gene interaction of ATG5, ATG7, BLK and BANK1 in systemic lupus erythematosus.
Autophagy-related gene 5 (ATG5), ATG7, B-lymphoid tyrosine kinase (BLK) and B-cell scaffold protein with ankyrin repeats 1 (BANK1) are involved in B-cell signaling; several genome-wide association studies detected these genes as candidates involved in systemic lupus erythematosus (SLE). We aimed to replicate the association of these genes with SLE in Chinese Han and to search for possible gene-gene interactions. TaqMan single-nucleotide polymorphism (SNP) genotyping was used to detect rs548234, rs665791 in ATG5, rs11706903 in ATG7, rs2736340 in BLK and rs10516487 in BANK1 in 382 SLE patients and 660 healthy controls. The epistasis effect was analyzed by logistic regression, multifactor dimensionality reduction (MDR) and linear regression analysis. SLE was associated with frequency of rs548234 (P = 0.010; odds ratio [OR] = 1.298), rs2736340 (P = 2.47 × 10-5 ; OR = 1.574) and rs10516487 (P = 0.002; OR = 0.642). Although no epistasis effects were found among three autophagy-related gene loci or with rs2736340 and rs10516487, BLK and BANK1 had the closest interaction effect on logistic regression analysis (P = 0.013; OR = 1.205), MDR (P < 0.0001), and linear regression analysis (P = 0.0017; R2 = 0.1806). The risk genotype TT of rs2736340 was associated with decreased messenger RNA level of BLK; BLK transcript level was lower in SLE patients than healthy controls. We confirmed the association of rs548234, rs2736340 and rs10516487 with SLE in Chinese Han and reinforced our hypothesis of their epistasis effect in regulating B-cell signaling in SLE.


Development of a High-Throughput Laboratory Bioassay for Testing Potential Attractants for Terrestrial Snails and Slugs.
Invasive snails and slugs are among the most damaging pests of vegetables, fruits, ornamentals, grains, and forage throughout the world. Current control strategies are focused almost exclusively on molluscicides, which are ineffective under some conditions, and which can have serious nontarget effects. A major aim of this study was to develop a generic high-throughput bioassay method for use in identifying attractants for terrestrial gastropods, with the overall goal of developing attractant-based control methods for pest gastropods. Here, we demonstrate the use of the bioassay method in screening a wide variety of foodstuffs and other possible sources of attractants, using the pest snail Cornu aspersum Müller (Pulmonata, Helicidae) and the pest slug Deroceras reticulatum Müller (Pulmonata, Agriolimacidae) as test animals. Among a large number of food items and previously reported attractants tested, chopped fresh cucumber (Cucumis sativus) was the most attractive substrate for both species. Our results also showed that previous feeding experience influences subsequent food choice to some extent, but regardless of previous feeding experience, chopped cucumber was as attractive or more attractive than any other substrate tested.


Urban and rural differences in dietary intake, weight status and nutrition knowledge of black female students.
The objective of this study was to examine dietary intake, weight status and nutrition knowledge of young black South African women in order to identify urban-rural differences. A group of 115 black female students attending a first-year pre-registration program at the University of the North participated in the study. A quantified food frequency questionnaire was used to gather data on each student's diet prior to entering the university. Height, weight, waist and hip measurements were taken, and body mass index (BMI) and waist-tohip ratio (WHR) were calculated for each participant. Each student also completed a nutrition knowledge test (NKT). Mean dietary intakes were generally comparable to the recommended dietary allowances (RDA), with the exception of calcium, zinc and iron, which were lower. Urban women consumed significantly more sugar (65.8 vs 52.2 g) and confectionery (290.4 vs 183.7 g), and significantly less legumes (6.3 vs 18.9 g), than did rural women. The prevalence of overweight (BM1 >= 25) was high in urban (22.7%) and rural (22.9%) women and WHR was significantly greater (P = 0.0003) in rural women (0.76) compared with urban ones (0.73). Nutrition knowledge test scores were poor (mean = 40.7%) and no urban-rural differences were found. There was a positive correlation between NKT and energy, protein, carbohydrate, fibre, calcium, zinc, thiamin, niacin, and folate intakes.


The Effects of 10-week Integrated Neuromuscular Training on Fundamental Movement Skills and Physical Self-efficacy in 6-7-Year-Old Children.
Duncan, MJ, Eyre, ELJ, and Oxford, SW. The effects of 10-week integrated neuromuscular training on fundamental movement skills and physical self-efficacy in 6-7-year-old children. J Strength Cond Res 32(12): 3348-3356, 2018-Integrated neuromuscular training (INT) has been suggested as an effective means to enhance athletic potential in children. However, few studies have reported the effects of school-based INT programs. This study examined the effect of INT on process and product fundamental movement skill measures and physical self-efficacy in 6-7-year-old children. Ninety-four children from 2 primary schools were randomized into either a 10-week INT program or a control group (CON) (n = 41). Results indicated significantly greater increases in process fundamental movement skill (FMS) scores in INT vs. CON (p = 0.001). For product measures of FMS, 10-m sprint time, counter movement jump, seated medicine ball throw and standing long jump (all p = 0.001), all significantly increased to a greater extent in the INT group vs. CON. A significant group (INT vs. CON) × time (pre vs. post) × gender interaction for physical self-efficacy revealed increased physical self-efficacy pre to post INT, compared with CON but only for boys (p = 0.001). For girls, physical self-efficacy was not significantly different before to after the 10-week period for INT and CON groups. The results of this study suggest that replacing 1 of the 2 weekly statutory physical education (PE) lessons with an INT program over a 10-week period results in positive improvements in fundamental movement skill quality and outcomes in 6-7-year-old children. Integrated neuromuscular training also appears to increase physical self-esteem to a greater extent than statutory PE but only in boys.


Enhanced Production of Gypenoside LXXV Using a Novel Ginsenoside-Transforming β-Glucosidase from Ginseng-Cultivating Soil Bacteria and Its Anti-Cancer Property.
Minor ginsenosides, such as compound K, Rg₃(S), which can be produced by deglycosylation of ginsenosides Rb₁, showed strong anti-cancer effects. However, the anticancer effects of gypenoside LXXV, which is one of the deglycosylated shapes of ginsenoside Rb₁, is still unknown due to the rarity of its content in plants. Here, we cloned and characterized a novel ginsenoside-transforming β-glucosidase (BglG167b) derived from Microbacterium sp. Gsoil 167 which can efficiently hydrolyze gypenoside XVII into gypenoside LXXV, and applied it to the production of gypenoside LXXV at the gram-scale with high specificity. In addition, the anti-cancer activity of gypenoside LXXV was investigated against three cancer cell lines (HeLa, B16, and MDA-MB231) in vitro. Gypenoside LXXV significantly reduced cell viability, displaying an enhanced anti-cancer effect compared to gypenoside XVII and Rb₁. Taken together, this enzymatic method would be useful in the preparation of gypenoside LXXV for the functional food and pharmaceutical industries.


Coinfection of Avibacterium paragallinarum and Gallibacterium anatis in Specific-Pathogen-Free Chickens Complicates Clinical Signs of Infectious Coryza, Which Can Be Prevented by Vaccination.
Avibacterium paragallinarum and Gallibacterium anatis are recognized bacterial pathogens both infecting the respiratory tract of chickens. The present study investigated outcomes of their coinfection by elucidating clinical signs, pathologic lesions, and bacteriologic findings. Additionally, the efficacy of a commercially available vaccine to prevent diseases caused by A. paragallinarum and G. anatis was evaluated. Birds inoculated with G. anatis alone did not present any clinical signs and gross pathologic lesions in the respiratory tract. However, clinical signs of infectious coryza were reproduced in nonvaccinated birds that were challenged with A. paragallinarum alone or together with G. anatis . Such clinical signs were more severe in the coinfected group, including the death of four birds. Some of the birds that were vaccinated and challenged showed mild clinical signs at 7 days postinfection (dpi). Inflammation of sinus infraorbitalis was the most prominent gross pathologic lesion found in the respiratory tract of nonvaccinated birds inoculated either with A. paragallinarum and G. anatis or A. paragallinarum alone. In the reproductive tract, hemorrhagic follicles were observed in nonvaccinated birds that were infected either with G. anatis alone or together with A. paragallinarum . In vaccinated birds, no gross pathologic lesions were found except in one bird that was coinfected with both the pathogens characterized by mucoid tracheitis. Bacteriologic investigations revealed that multiplication of G. anatis at 7 dpi was supported by the coinfection with A. paragallinarum . Altogether, it can be concluded that simultaneous infection of A. paragallinarum and G. anatis can increase the severities of disease conditions in chickens. In such a scenario, vaccination appears to be an effective tool for prevention of the disease, as protection was conferred based on clinical, pathologic, bacteriologic, and serologic data.


Cyclic AMP and immune responses: identification of prostaglandin E-producing cells in mouse spleens.
Previous work has shown that normal mice respond to the intravenous injection of sheep erythrocytes (SRBC) with a transient increase in splenic cyclic AMP peaking after 2 minutes, and this cyclic AMP response has been shown to be due to prostaglandins (PGs) released from antigen-specific cells. In the present study, the cell type responsible for PG production in response to antigen was determined using a fluorescence-activated cell sorter (FACS) and an electron microscope. C57Bl/6 mice injected with SRBC showed a 2% increase of PGE-producing spleen cells relative to controls. In control mice injected with phosphate-buffered saline (PBS), 19% of the spleen cells produced PGE. An electron microscopic study of PGE-producing cells sorted on FACS showed that they were small lymphocytes and plasma cells. In addition, nude mice also increased the number of PGE-producing spleen cells in response to antigen. These findings suggest that lymphocytes involving at least B-cells respond to antigen with an increase in PGE production.


Nutrition management, nitrogen efficiency, and income over feed cost on dairy farms in Costa Rica.
Twenty-two dairy farms in two ecologically different zones were visited repeatedly during the dry and wet seasons of 1995 to evaluate nutrition and pasture management, N efficiency on the farm, and income over feed costs with the use of a management support program. Excessive amounts of concentrates were fed, and no differences in amounts were detected between seasons. Utilization of forage was consequently low and even negligible on some farms. The amount of crude protein in the diet was generally too high. The removal of N from the farms via milk and culling represented 27 and 31% of the total N input for the two regions, respectively. The income over feed costs per cow ($3.04 and $1.84/d, respectively) was considered reasonable despite the high amount of concentrates.


Central and peripheral effects of physical exercise without weight reduction in obese and lean mice.
To investigate the central (hypothalamic) and peripheral effects of exercise without body weight change in diet-induced obesity (DIO). Twelve-week-old male C57Bl/6 mice received a control (C) or a high-fat diet (H). Half of them had free access to running wheels for 5 days/week for 10 weeks (CE) and HE, respectively). Hypothalamic expression of genes related to energy homeostasis, and leptin (Stat3 and p-Stat3) and insulin (Akt and p-Akt) signaling were evaluated. Glucose and leptin tolerance, peripheral insulin sensitivity, and plasma insulin, leptin and adiponectin were determined. Perigonadal and retroperitoneal fat depots were increased by diet but reduced by exercise despite lack of effect of exercise on body weight. Blood glucose during intraperitoneal glucose tolerance test (ipGTT) was higher and glucose decay during intraperitoneal insulin tolerance test (ipITT) was lower in H and HE compared with C and CE. Exercise increased liver p-Akt expression and reduced fast glycemia. High-fat diet increased plasma insulin and leptin. Exercise had no effect on insulin but decreased leptin and increased adiponectin. Leptin inhibited food intake in all groups. Hypothalamic total and p-Stat3 and Akt were similar amongst the groups despite higher plasma levels of leptin and insulin in H and HE mice. High-fat diet modulated gene expression favoring a positive energy balance. Exercise only marginally changed the gene expression. Exercise induced positive changes (decreased fast glycemia and fat depots; increased liver insulin signaling and adiponectin concentration) without weight loss. Thus, despite reducing body weight could bring additional benefits, the effects of exercise must not be overlooked when weight reduction is not achieved.


Human trabecular meshwork cell behavior is influenced by collagen scaffold pore architecture and glycosaminoglycan composition.
Glaucoma is a degenerative eye disease in which damage to the optic nerve leads to a characteristic loss of vision. The primary risk factor for glaucoma is an increased intraocular pressure that is caused by an imbalance of aqueous humor generation and subsequent drainage through the trabecular meshwork (TM) drainage system. The small size, donor tissue limitations, and high complexity of the TM make it difficult to research the relationship between the TM cells and their immediate environment. Thus, a biomaterial-based approach may be more appropriate for research manipulations and in vitro drug development platforms. In this work, human TM (hTM) cells were cultured on various collagen scaffolds containing different glycosaminoglycans (GAGs) and different pore architectures to better understand how hTM cells respond to changes in their extracellular environment. Cellular response was measured by quantifying cellular proliferation and expression of an important extracellular matrix protein, fibronectin. The pore architecture of the scaffolds was altered using freeze-casting technique to make both large and small pores that were aligned or with a non-aligned random structure. The composition of the scaffolds was altered with the addition of chondroitin sulfate and/or hyaluronic acid. It was found that the hTM cells grown on large pore scaffolds proliferate more than those grown on small pores. There was an increase in the fibronectin expression with the incorporation of GAGs, and its morphology was changed by the underlying pore architecture. This work will help provide an insight into the behavior of hTM cells when introducing changes in their microenvironment.


Understanding and responding to severe and enduring patient distress resulting from episodes of healthcare.
This article focuses on the severe, long-term and debilitating distress that may be experienced by patients as a result of their interactions with healthcare professionals and services. It is essential for healthcare professionals to be able to respond effectively to severe patient distress resulting from episodes of healthcare. Severe and enduring patient distress can occur in response to neglect - even when unintentional, misdiagnosis, surgical errors and/or deficits in the quality of care. Severe and enduring distress experienced by patients may go unacknowledged; the long-term consequences may not be recognised, or resolution may be presumed following formal apologies or receipt of compensation. An emphasis on the duty of candour has increased awareness of the importance of honesty and acknowledgement of adverse events or 'near misses' in the healthcare setting, in improving the relationship between patients and healthcare professionals.


Assessment of the quality of life of spinal cord injury patients in Peshawar.
To assess the quality of life of spinal cord injury patients. This cross-sectional study was conducted at Paraplegic Centre Hayatabad, Peshawar, Pakistan, from November 2015 to January 2016, and comprised spinal cord injury patients. A 26-item World Health Organisation quality of life questionnaire was used. Some of the patients were recruited from the paraplegic centre while others participated by filling an online questionnaire. SPSS 20 was used for data analysis. Of the 54 participants, 35(64.8%) were male and 19(35.2%) were female. Besides, 50(92.6%) participants were paraplegic while 4(7.4%) were tetraplegic. The overall mean score for the physical health domain was 54.79±18.39, psychological health domain 52.33±19.37, social relationship 58.79±20.69 and environmental domain 54.11±17.25. Patients with spinal cord injuries had moderate level of quality of life.


Changes in dietary glycemic index and glycemic load in Australian adults from 1995 to 2012.
Background: Australians have used the glycemic index (GI) since 1995; however, there are no data on changes in carbohydrate quality over time.Objectives: The aim was to compare average dietary GI and glycemic load (GL), and contributing carbohydrate foods, in the 2 most recent national dietary surveys.Design: Dietary data from adult participants of national nutrition surveys conducted in 1995 (the 1995 Australian National Nutrition Survey; n = 8703) and 2012 (the 2011-2012 National Nutrition and Physical Activity Survey; n = 6278), collected by a single 24-h recall, were analyzed. The differences in mean dietary GI and GL between surveys were compared by using 1-factor ANOVA. The main sources of dietary GL in the 2 surveys were also assessed. Multiple linear regression was performed to examine the contributions of the food groups to interindividual variations in dietary GI and GL.Results: Overall, dietary GI and GL decreased by 5% and 12%, respectively, from 1995 to 2012 (GI on glucose standard: 56.5 ± 6.2 compared with 53.9 ± 6.8, respectively; GL: 153.3 ± 62.1 compared with 135.4 ± 58.5, respectively; both P < 0.001). Breads were the main contributor to GL at both time points. Potatoes and sweetened beverages contributed less, whereas cereal-based dishes contributed more in 2012 than in 1995. The top 20 GL-contributing food groups explained less interindividual variation in dietary GI (R2: 0.376 compared with 0.290) and GL (R2: 0.825 compared with 0.770) in 2012 than in 1995.Conclusion: Although the average dietary GI and GL declined between 1995 and 2012, trends in specific carbohydrate foods suggest that Australians are avoiding potatoes and sugary beverages in favor of a greater variety of carbohydrate foods, particularly cereal products.


Salivary concentrations of urea released from a chewing gum containing urea and how these affect the urea content of gel-stabilized plaques and their pH after exposure to sucrose.
The objectives were to: (1) determine the salivary concentrations of urea during 20 min chewing of a sugar-free gum containing 30 mg of urea; (2) measure the degree to which this urea would diffuse into a gel-stabilized plaque; (3) study the effect of the urea on the fall and subsequent rise in pH (Stephan curve) on exposure to 10% sucrose for 1 min; (4) model the measurements 2 and 3 mathematically. In point 1, the salivary urea concentration of the 12 subjects peaked at 47 mmol/l in the first 2 min of gum chewing, falling within 15 min to the unstimulated salivary concentration of 3.4 mmol/l. Recovery of urea from the saliva averaged 81.5%. 'Plaques' of 1% agarose or 67% dead bacteria in agarose accumulated urea from the saliva roughly as expected, whereas those plaques containing 8% live and 59% dead Streptococcus vestibularis showed negligible accumulation. Computer modelling showed this difference to be due to urease of live bacteria breaking down the urea as rapidly as it entered the plaque. Simulation of the effect of gum chewing subsequent to initiation of a Stephan curve in the latter type of plaque showed a rapid rise in pH but then a fall again on return to unstimulated conditions. This fall had not been seen in previous studies, with Streptococcus oralis, nor was it predicted by the computer modelling. Neither experimental simulation nor computer modelling suggested that chewing urea-containing gum before exposure to sucrose would have any effect on a subsequent Stephan curve. Thus chewing gum is only likely to inhibit caries when it is chewed after consumption of fermentable carbohydrate, rather than before.


Separation and determination of seleno amino acids using gas chromatography hyphenated with inductively coupled plasma mass spectrometry after hollow fiber liquid phase microextraction.
A new derivatization-extraction method for preconcentration of seleno amino acids using hollow fiber liquid phase microextraction (HF-LPME) was developed for the separation and determination of seleno amino acids in biological samples by gas chromatography-inductively coupled plasma mass spectrometry (GC-ICP-MS). Derivatization was performed with ethyl chloroformate (ECF) to improve the volatility of seleno amino acids. Parameters influencing microextraction, including extraction solvent, pH of sample solution, extraction time, stirring speed, and inorganic salt concentration have been investigated. Under the optimal conditions, the limits of detection (LODs) obtained for Se-methyl-selenocysteine (SeMeCys), selenomethionine (SeMet), and selenoethionine (SeEth) were 23, 15, and 11 ng Se l(-1), respectively. The relative standard deviations (RSDs) were 14.6%, 16.4%, and 19.4% for SeMeCys, SeMet, and SeEth (c = 1.0 ng ml(-1), n = 7), respectively, and the RSDs for SeMeCys, SeMet could be improved obviously if SeEth was utilized as the internal standard. The proposed method was applied for the determination of seleno amino acids in extracts of garlic, cabbage, and mushroom samples, and the recoveries for the spiked samples were in the range of 96.8-108% and 93.4-115% with and without the use of SeEth as internal standard. The developed method was also applied to the analysis of SeMet in a certified reference material of SELM-1 yeast and the determined value is in good agreement with the certified value.


Pernicious anaemia, intragastric bacterial overgrowth, and possible consequences.
Intragastric bacterial colonization is well known in pernicious anaemia (PA), but its consequences have rarely been investigated. We have studied the clinical history, blood samples, and endoscopic biopsies from the stomach and duodenum of 80 patients with PA. In a random subgroup of 22 patients gastric juice was collected for aerobic culture and for estimation of nitrate, nitrate-reducing bacteria, nitrite, and N-nitrosamines; duodenal juice was studied in parallel in eight of these subjects. Gastric and duodenal juice had high bacterial counts; faecal organisms were found in 14 patients. The mean count of nitrate-reducing bacteria was significantly higher than in a control group of patients with peptic ulcer disease (p less than 0.001), as was the nitrite concentration (p less than 0.001). Thirty-three of the 80 patients had gastric dysplasias; 1 early gastric carcinoma was also found. Duodenitis was present in 39 out of 80 cases, in 6 associated with partial villous atrophy. A history of malabsorption and/or chronic intermittent diarrhoea was obtained significantly more often from patients with duodenitis. Four patients developed acute gastroenteritis shortly before or during the time of the study, two having a salmonella infection. Bacterial overgrowth in PA may be facilitated by altered immunological conditions, since low serum levels of IgA and IgG were found in this patient group.


Complement, Kinins, and Hereditary Angioedema: Mechanisms of Plasma Instability when C1 Inhibitor is Absent.
Plasma of patients with types I and II hereditary angioedema is unstable if incubated in a plastic (i.e., inert) vessel at 37 °C manifested by progressively increasing formation of bradykinin. There is also a persistent low level of C4 in 95 % of patients even when they are symptomatic. These phenomena are due to the properties of the C1r subcomponent of C1, factor XII, and the bimolecular complex of prekallikrein with high molecular weight kininogen (HK). Purified C1r auto-activates in physiologic buffers, activates C1s, which in turn depletes C4. This occurs when C1 inhibitor is deficient. The complex of prekallikrein-HK acquires an inducible active site not present in prekallikrein which in Tris-type buffers cleaves HK stoichiometrically to release bradykinin, or in phosphate buffer auto-activates to generate kallikrein and bradykinin. Thus immunologic depletion of C1 inhibitor from factor XII-deficient plasma (phosphate is the natural buffer) auto-activates on incubation to release bradykinin. Normal C1 inhibitor prevents this from occurring. During attacks of angioedema, if factor XII auto-activates on surfaces, the initial factor XIIa formed converts prekallikrein to kallikrein, and kallikrein cleaves HK to release bradykinin. Kallikrein also rapidly activates most remaining factor XII to factor XIIa. Additional cleavages convert factor XIIa to factor XIIf and factor XIIf activates C1r enzymatically so that C4 levels approach zero, and C2 is depleted. There is also a possibility that kallikrein is generated first as a result of activation of the prekallikrein-HK complex by heat shock protein 90 released from endothelial cells, followed by kallikrein activation of factor XII.


A Conserved Secondary Structural Element in the Coding Region of the Influenza A Virus Nucleoprotein (NP) mRNA Is Important for the Regulation of Viral Proliferation.
Influenza A virus is a threat to humans due to seasonal epidemics and infrequent, but dangerous, pandemics that lead to widespread infection and death. Eight segments of RNA constitute the genome of this virus and they encode greater than eight proteins via alternative splicing of coding (+)RNAs generated from the genomic (-)RNA template strand. RNA is essential in its life cycle. A bioinformatics analysis of segment 5, which encodes nucleoprotein, revealed a conserved structural motif in the (+)RNA. The secondary structure proposed by energy minimization and comparative analysis agrees with structure predicted based on experimental data using a 121 nucleotide in vitro RNA construct comprising an influenza A virus consensus sequence and also an entire segment 5 (+)RNA (strain A/VietNam/1203/2004 (H5N1)). The conserved motif consists of three hairpins with one being especially thermodynamically stable. The biological importance of this conserved secondary structure is supported in experiments using antisense oligonucleotides in cell line, which found that disruption of this motif led to inhibition of viral fitness. These results suggest that this conserved motif in the segment 5 (+)RNA might be a candidate for oligonucleotide-based antiviral therapy.


Effects of endogenous dopamine on measures of [18F]N-methylspiroperidol binding in the basal ganglia: comparison of simulations and experimental results from PET studies in baboons.
The effect of endogenous dopamine on PET measures of radioligand binding is important to the measurement of receptor density (or availability) and neurotransmitter interactions in vivo. We recently reported that pretreatment with amphetamine, a drug which stimulates dopamine release, significantly reduced NMS binding in the baboon brain as determined by the product lambda k3 derived from the graphical analysis method for irreversible systems (lambda is the ratio of the forward to reverse plasma to tissue transport constants and k3 is proportional to receptor density) (Dewey et al.: Synapse 7:324-327, 1991). The purpose of this work is twofold: to evaluate the sensitivity and stability of the analysis method used for the NMS data and from simulation studies which include the competitive effects of dopamine on NMS binding to predict the effect of dopamine on the in vivo PET experiment. Using a measured plasma [18F]-NMS input function from a control study in a baboon, simulation data was numerically generated explicitly allowing competition between NMS and dopamine in the calculation. This data was analyzed using the same techniques as used for the experimental data and the results were compared to in vitro calculations. The following conclusions were reached: 1) The effect of dopamine on specific binding was found to be greater in vivo than in vitro because the in vitro equilibrium experiment is controlled only by the relative Kd's of tracer and dopamine while the in vivo experiment also depends upon the halftime of tracer in tissue which is controlled by the tissue-to-plasma transport constant; 2) Experimental evidence from rodent studies (Seeman et al.: Synapse 3:96-97, 1989) and the agreement between PET studies (Wong et al.: Science 234:1558-1563, 1986a) and postmortem human studies (Seeman et al.: Science 225:728-731, 1984) in schizophrenics suggest that NMS is not likely to be affected by normal levels of endogenous dopamine. From the calculations reported here the effective in vivo Kd of dopamine for the NMS binding site would have to be on the order of or greater than 100 nM, assuming a synaptic dopamine concentration of 20 nM, in order that this concentration of dopamine have little effect on NMS binding.


Central adiposity and the overweight risk paradox in aging: follow-up of 130,473 UK Biobank participants.
Background: For older groups, being overweight [body mass index (BMI; in kg/m2): 25 to <30] is reportedly associated with a lower or similar risk of mortality than being normal weight (BMI: 18.5 to <25). However, this "risk paradox" is partly explained by smoking and disease-associated weight loss. This paradox may also arise from BMI failing to measure fat redistribution to a centralized position in later life.Objective: This study aimed to estimate associations between combined measurements of BMI and waist-to-hip ratio (WHR) with mortality and incident coronary artery disease (CAD).Design: This study followed 130,473 UK Biobank participants aged 60-69 y (baseline 2006-2010) for ≤8.3 y (n = 2974 deaths). Current smokers and individuals with recent or disease-associated (e.g., from dementia, heart failure, or cancer) weight loss were excluded, yielding a "healthier agers" group. Survival models were adjusted for age, sex, alcohol intake, smoking history, and educational attainment. Population and sex-specific lower and higher WHR tertiles were <0.91 and ≥0.96 for men and <0.79 and ≥0.85 for women, respectively.Results: Ignoring WHR, the risk of mortality for overweight subjects was similar to that for normal-weight subjects (HR: 1.09; 95% CI: 0.99, 1.19; P = 0.066). However, among normal-weight subjects, mortality increased for those with a higher WHR (HR: 1.33; 95% CI: 1.08, 1.65) compared with a lower WHR. Being overweight with a higher WHR was associated with substantial excess mortality (HR: 1.41; 95% CI: 1.25, 1.61) and greatly increased CAD incidence (sub-HR: 1.64; 95% CI: 1.39, 1.93) compared with being normal weight with a lower WHR. There was no interaction between physical activity and BMI plus WHR groups with respect to mortality.Conclusions: For healthier agers (i.e., nonsmokers without disease-associated weight loss), having central adiposity and a BMI corresponding to normal weight or overweight is associated with substantial excess mortality. The claimed BMI-defined overweight risk paradox may result in part from failing to account for central adiposity, rather than reflecting a protective physiologic effect of higher body-fat content in later life.


13C NMR spectroscopy characterization of particle-size fractionated soil organic carbon in subalpine forest and grassland ecosystems.
Soil organic carbon (SOC) and carbon (C) functional groups in different particle-size fractions are important indicators of microbial activity and soil decomposition stages under wildfire disturbances. This research investigated a natural Tsuga forest and a nearby fire-induced grassland along a sampling transect in Central Taiwan with the aim to better understand the effect of forest wildfires on the change of SOC in different soil particle scales. Soil samples were separated into six particle sizes and SOC was characterized by solid-state 13C nuclear magnetic resonance spectroscopy in each fraction. The SOC content was higher in forest than grassland soil in the particle-size fraction samples. The O-alkyl-C content (carbohydrate-derived structures) was higher in the grassland than the forest soils, but the alkyl-C content (recalcitrant substances) was higher in forest than grassland soils, for a higher humification degree (alkyl-C/O-alkyl-C ratio) in forest soils for all the soil particle-size fractions. High humification degree was found in forest soils. The similar aromaticity between forest and grassland soils might be attributed to the fire-induced aromatic-C content in the grassland that offsets the original difference between the forest and grassland. High alkyl-C content and humification degree and low C/N ratios in the fine particle-size fractions implied that undecomposed recalcitrant substances tended to accumulate in the fine fractions of soils.


Phasic vagal influence on the rate and timing of reflex swallowing.
We investigated the effects of sudden changes in ventilation induced by voluntary hyperpnea and breath-holding on repetitive reflex swallowing elicited by continuous infusion of distilled water into the pharynx in 13 healthy subjects. Ventilation was monitored using a pneumotachograph, and swallowing was identified by submental electromyography with interruption of airflow. We found that voluntary hyperpnea decreased the swallowing frequency whether end-tidal CO(2) tension was maintained at normocapnia or allowed to be hypocapnic. Also, the frequency of swallowing immediately increased with the start of breath-holding, but there was a sudden decrease in swallowing frequency during the hyperpnea observed immediately after the resumption of ventilation (post-breath-holding hyperpnea). The preponderant coupling of swallows with the expiratory phase was lost during voluntary hyperpnea but was maintained during post-breath-holding hyperpnea. These observations may suggest that vagally mediated reflexes are operative in normal physiologic situations and play an important role in the control of swallowing rate as well as in the timing of swallowing in reference to the respiratory cycle.


Parent's confidence as a caregiver.
The purpose of this study was to describe the parent's self-reported confidence as a caregiver. The specific research questions were as follows: • What is the parent's perceived level of confidence when performing infant caregiving activities in the neonatal intensive care unit (NICU)? • What is the parent's projected level of confidence about performing infant caregiving activities on the first day at home? Participants were parents of infants with an anticipated discharge date within 5 days. Inclusion criteria were as follows: parent at least 18 years of age, infant's discharge destination is home with the parent, parent will have primary responsibility for the infant after discharge, and the infant's length of stay in the NICU was a minimum of 10 days. Descriptive, survey research. Participants perceived themselves to be confident in all but 2 caregiving activities when caring for their infants in the NICU, but parents projected a change in their level of confidence in their ability to independently complete infant care activities at home. When comparing the self-reported level of confidence in the NICU and the projected level of confidence at home, the levels of confidence decreased for 5 items, increased for 8 items, and remained unchanged for 2 items. All of the items with a decrease in score were the items with the lowest score when performed in the NICU. All of these low-scoring items are caregiving activities that are unique to the post-NICU status of the infant. Interestingly, the parent's projected level of confidence increased for the 8 items focused on handling and interacting with the infant. The findings of this research provide evidence that nurses may need to rethink when parents become active participants in their infant's medical-based caregiving activities.


Improving Outcomes in Patients with CRC: The Role of Patient Reported Outcomes-An ESDO Report.
Colorectal cancer is one of the most commonly diagnosed cancers worldwide and nearly half of patients will develop metastatic disease at some point during the course of their disease. The goal of anticancer therapy in this context is to extend survival, while trying to maximise the patient's health-related quality of life. To this end, we need to understand how to incorporate patient-reported outcomes into clinical trials and routine practice to accurately assess if treatment strategies are providing clinical benefit for the patient. This review reflects the proceedings of a 2016 European Society of Digestive Oncology workshop, where the authors discussed the use of patient-reported outcomes to measure health-related quality of life when evaluating treatment during the management of colorectal cancer. A summary of the challenges associated with implementing patient-reported outcomes in clinical trials is provided, as well as a review of the current clinical evidence surrounding patient-reported outcomes in metastatic colorectal cancer.


Rat fibrosarcoma as a source of stable co-polymer of type I and type III collagens.
During conventional procedures for the extraction of collagen from rat fibrosarcoma it was observed that a significant fraction of the acid-soluble collagen remained insoluble when subsequently fractionated at neutral pH. Analysis of this collagenous component, using amino acid analysis, cyanogen bromide peptide mapping, proteinase susceptibility and the action of denaturing and reducing agents, revealed different properties when compared to other collagen species. The results indicate that the tumour collagen fraction is probably a stable complex of type I and III collagens. This native collagen heteropolymer represented approximately 18% of the total collagen from rat fibrosarcoma and as such provides a unique natural source of this collagen complex for further analytical studies.


[RARE CASE OF HUGE OMENTAL DERMOID].
Ovarian dermoid cyst is a benign germ cell tumor usually occurring during fertile age. In contrast, giant omental dermoid is extremely rare and is thought to originate from ovarian torsion, detachment and omental implantation. We present a case of a 73 year old patient with 26 cm giant omental dermoid weighing more than 6 kg. During surgery, aspiration of the cystic part facilitated the delivery of the big mass through a relative small abdominal incision.


Lipolytic fermentations of stickwater by Geotrichum candidum and Candida lipolytica.
Stickwater, a by-product of the fish meal and oil industry, is an aqueous suspension of fish proteins, lipids, and other materials, and also contains soluble nonprotein nitrogen but not carbohydrate. It is usually partially evaporated by heat to a marketable form called "fish solubles," which is sold with an acid preservative as an animal feed supplement. However, fish solubles are only used to a limited extent in feeds, because the lipids of solubles (averages 11%) are relatively prone to oxidative rancidity development. An investigation was undertaken to digest and/or stabilize lipids in stickwater by lipolytic fermentations and, at the same time, to attempt to increase the protein content as single cell protein. Strains of the yeast Candida lipolytica and the yeast like mold Geotrichum candidum were employed for these investigations. Stickwater fermentations were performed in a laboratory bench top fermentor. Respirometric studies of lipid metabolic activity and microbial observations were periodically performed during these fermentations. Rapid microbial growth and metabolic activity were observed in well aerated cultures. Fermented products were evaluated for chemical composition. Lipid residues were characterized by thin-layer chromatographic procedures. There was evidence of abundant microbial growth, increased lipolytic activity, and decreased lipid content. However, evidence was lacking to show that the protein content of stickwater was actually increased.


Evaluation of HIV serial and parallel serologic testing algorithms in Abidjan, Côte d'Ivoire.
To evaluate HIV serologic testing algorithms based on a combination of three enzyme linked immunosorbent assays (ELISA) for the confirmation of HIV infection in Abidjan, Côte d'Ivoire, where HIV-2 and HIV-1 non-B subtypes are prevalent. A total of 1069 human sera with known serologic status, in addition to a seroconversion and low titer antibody panel were initially tested by six ELISA to determine the sensitivity, specificity and delta values of the assays. On the basis of the performance of the assays, three ELISA (Enzygnost, ICE 1.0.2, and Vironostika) were selected for use in a parallel and serial testing algorithm in analyzing 8283 consecutively collected sera. In the parallel testing algorithm, sera concordantly reactive or non-reactive by Enzygnost and ICE 1.0.2 were considered as true positive or true negative, respectively. In the serial algorithm, sera reactive by Enzygnost were retested by ICE 1.0.2. Sera with discordant results were tested by Vironostika, and the results was considered definitive. All reactive sera, plus a random sample of negative sera were tested for confirmation by Peptilav. In addition, a random sample of reactive sera was tested by Western blot. All ELISA had 100% sensitivity; specificities ranged from 96.8 to 100%. Positive and negative delta values of the ELISA were high (range, 6.89 to 46.07 and -2.05 to -5.75, respectively). Of the 8283 sera, 2054 were considered true positives and were correctly classified by the parallel testing algorithm (sensitivity, 100%). Of the 6229 true negative sera, 6226 were negative by the parallel testing algorithm (specificity, 99.95%). The sensitivity of the serial algorithm was 99.96%, and specificity was 99.95%. None of the 250 concordant ELISA-negative sera in the algorithm that were randomly tested in Peptilav was positive; similarly, all of the 103 concordant ELISA-positive sera were confirmed by Western blot. The three-ELISA algorithm resulted in reagent cost-savings of at least 50% compared with the Peptilav-based algorithm. These results suggest that a combination of ELISA using different principles or antigens in a serial or parallel algorithm is an efficient and cost-effective alternative to the standard algorithm in areas where HIV-1 and HIV-2 are prevalent.


[Feasibility and safety of paclitaxel-eluting balloon for the treatment of de novo coronary lesions].
Objective: To evaluate the safety and feasibility of treating de novo coronary lesions with paclitaxel-eluting balloon. Methods: This is a retrospective study, which enrolled 76 patients with 80 de novo coronary lesions treated with paclitaxel-eluting balloons(<30% residual stenosis and there was no blood flow limited dissection after pretreatment) from April 2015 to November 2016 in Guangdong general hospital. The data of basic characteristics,procedures,devices and follow-up information were retrieved and analyzed. The primary endpoint was the composite of cardiac death, recurrent myocardial infarction and target lesion revascularization. Results: (1)The age was (63.3±10.3) years. There were 68.4%(52/76) acute coronary syndrome patients, prevalence of type 2 diabetes was 36.8%(28/76), and 64.5%(49/76)patients with at least one high bleeding risk. (2)The lesion length was (17.4±7.6)mm, and the stenosis was (88.1±8.2)%.The reference vessel diameter≥2.75 mm accounted for 51.2% (41/80), and bifurcation stenosis accounted for 67.5%(54/80). (3)53.7%(43/80) lesions were pretreated with scoring balloon to optimize plaque modification. The paclitaxel-eluting balloon length and diameter were (22.3±5.5)mm and (2.74±0.52)mm.The residual stenosis was (12.3±10.3)%. Procedural success was 88.8%(71/80).Bail-out stenting rate was 5.0%(4/80). (4)The median follow-up duration was 12(6, 25) months. Primary endpoint occurred in 3 cases (3.9%), including 2 cardiac deaths(1 patient died of recurrent myocardial infarction, and 1 patient died of acute heart failure induced by severe mitral insufficiency), and one patient receivedtarget lesion revascularization. Conclusion: In case of no more than 30% residual stenosis and no blood flow limited dissection after lesion pretreatment,it is safe and feasible to treat de novo coronary lesionsusing paclitaxel-eluting balloon.


What is good medical ethics? A clinician's perspective.
Speaking from the perspective of a clinician and teacher, good medical ethics needs to make medicine better. Over the past 50 years medical ethics has helped shape the culture in medicine and medical practice for the better. However, recent healthcare scandals in the UK suggest more needs to be done to translate ethical reasoning into ethical practice. Focusing on clinical practice and individual patient care, I will argue that, to be good, medical ethics needs to become integral to the activities of health professionals and healthcare organisations. Ethics is like a language which brings a way of thinking and responding to the world. For ethics to become embedded in clinical practice, health professionals need to progress from classroom learners to fluent social speakers through ethical dialogue, ethical reflection and ethical actions. I will end by discussing three areas that need to be addressed to enable medical ethics to flourish and bring about change in everyday clinical care.


Global dynamic analysis of a H7N9 avian-human influenza model in an outbreak region.
In 2013 in China a new type of avian influenza virus, H7N9, began to infect humans and had aroused severe fatality in the infected humans. We know that the spread is from poultry to humans, and the H7N9 avian influenza is low pathogenic in the poultry world but highly pathogenic in the human world, but the transmission mechanism is unclear. Since it has no signs of human-to-human transmission and outbreaks are isolated in some cities in China, in order to investigate the transmission mechanism of human infection with H7N9 avian influenza, an eco-epidemiological model in an outbreak region is proposed and analyzed dynamically. Researches and reports show that gene mutation makes the new virus be capable of infecting humans, therefore the mutation factor is taken into account in the model. The global dynamic analysis is conducted, different thresholds are identified, persistence and global qualitative behaviors are obtained. The impact of H7N9 avian influenza on the people population is concerned. Finally, the numerical simulations are carried out to support the theoretical analysis and to investigate the disease control measures. It seems that we may take people׳s hygiene and prevention awareness factor as a significant policy to achieve the aim of both the disease control and the economic returns.


Iris melanocytoma.
Iris melanocytoma (IM) is a rare benign tumor, but unavoidable in differential diagnosis of pigmented iris lesions. According to the best knowledge of the authors it is for the first time in Serbia that a well-documented case of IM is presented and that the problem of this tumor is discussed. In the left eye of a 47-year-old white female at the iris in a six o'clock position, a highly pigmented, dome shaped lesion with a crater-like cavity in the center and with feathery margins was noticed. There were no signs of infiltration of surrounding tissue or intrinsic vessels and the lens was clear. Visual acuity and intraocular pressure were normal. An ultrasound biomicroscopy (UBM) revealed a well-defined lesion with high internal reflectivity, with a base diameter of 1.25 mm and a thickness of 0.80 mm in the periphery, and 0.53 mm in the central part.The diagnosis of IM of the left eye was established and regular checkups were performed for ten years. No changes in clinical or UBM presentation were established. Awareness of clinical presentation of IM is most important for correct diagnosis. Ultrasound biomicroscopy is a useful diagnostic procedure in the following up of IM.


[Primary carcinoid tumor of the testis: a case report].
A case of pure, primary testicular carcinoid tumor in a 27-seven-year-old male is reported. The patient presented with a painless enlargement of the right testis but the serum markers for testicular cancer, including alpha-fetoprotein, beta-human chorionic gonadotropin and lactate dehydrogenase, were not elevated. Right orchiectomy was performed. Histologically, the tumor showed a typical appearance of carcinoid tumor. Further examinations such as barium studies, computed tomographic scan and Ga scintigraphy, showed no other lesions, and he received an adjuvant chemotherapy of cyclophosphamide, 5-fluorouracil and adriamycin. He is well and free from symptoms 17 months after surgery.


SARS-CoV-2 Spike Protein Post-Translational Modification Landscape and Its Impact on Protein Structure and Function via Computational Prediction.
To elucidate the role of post-translational modifications (PTMs) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein's structure and virulence, we generated a high-resolution map of 87 PTMs using liquid chromatography with tandem mass spectrometry data on the extracted spike protein from SARS-CoV-2 virions and then reconstituted its structure heterogeneity caused by PTMs. Nonetheless, Alphafold2, a high-accuracy artificial intelligence tool to perform protein structure prediction, relies solely on primary amino acid sequence, whereas the impact of PTM, which often modulates critical protein structure and function, is much ignored. To overcome this challenge, we proposed the mutagenesis approach-an in silico, site-directed amino acid substitution to mimic the influence of PTMs on protein structure due to altered physicochemical properties in the post-translationally modified amino acids-and then reconstituted the spike protein's structure from the substituted sequences by Alphafold2. For the first time, the proposed method revealed predicted protein structures resulting from PTMs, a problem that Alphafold2 has yet to address. As an example, we performed computational analyses of the interaction of the post-translationally modified spike protein with its host factors such as angiotensin-converting enzyme 2 to illuminate binding affinity. Mechanistically, this study suggested the structural analysis of post-translationally modified protein via mutagenesis and deep learning. To summarize, the reconstructed spike protein structures showed that specific PTMs can be used to modulate host factor binding, guide antibody design, and pave the way for new therapeutic targets. The code and Supplementary Materials are freely available at https://github.com/LTZHKUSTGZ/SARS-CoV-2-spike-protein-PTM.


Denatonium benzoate as a deterrent to ingestion of toxic substances: toxicity and efficacy.
When ingested at 10 ppm by human beings, denatonium benzoate has an extremely bitter, unpleasant taste. The addition of denatonium benzoate to liquid dish detergents and orange juice reduces the amount ingested by children. The toxicity of denatonium benzoate is low with acute po LD50's in rats of 485-740 mg/kg. The use of bittering agents, such as denatonium benzoate, could reduce the ingestion of toxic substances by dogs, cats, other animals and children and warrants further investigation.