Electromagnetic drag forces between HTS magnet and tube infrastructure for hyperloop.
Maglevs are typically accelerated using electromagnetic propulsion and levitation. High-temperature superconducting (HTS) magnets along with electrodynamic suspension (EDS) and linear synchronous motors are one of the best options for Hyperloop. However, the strong magnetic fields generated by HTS magnets on the pods inevitably interact with the magnetic and conductive structures in the vacuum tubes, along with the tube itself, while the pods move through the tubes. This interaction is observed as a drag force on the pods, significantly reducing the propulsion efficiency. This study comprehensively analyzes the electromagnetic drag force (EDF) generated by HTS magnets on pods, which accounts for most of the drag forces faced by Hyperloop. Theoretical analysis and 3D FEA simulations are performed to analyze the propulsion forces with HTS magnets and all the drag forces on the pods. The EDF generated by AISI 1010 steel rebars in concrete guideways is even greater than the designed propulsion forces of 40 kN. Consequently, high-manganese (Hi-Mn) steel and insulated steel rebars are adopted and analyzed using 3D FEA simulations. The EDFs generated by the AISI 1010 steel and Hi-Mn steel vacuum tubes are determined by varying the distance between the HTS magnets and tubes at 50 and 1200 km/h, respectively; a minimum distance of 0.75 m is determined by a drag force below 8 kN within their operating velocities. Lastly, the total EDFs of the AISI 1010 steel and Hi-Mn steel tubes with EDS rails are obtained through the optimal design of rebars and tubes. The simulation results show that the total EDFs can be significantly reduced to below 10 kN (approximately 25% of the designed propulsion force after the levitation of pods).


WITHDRAWN: In vitro ubiquitination of small heterodimer partner and effects of K122/123R double point mutation on transcriptional modulation.
Ahead of Print article withdrawn by publisher.


Time course decomposition of cell heterogeneity in TFEB signaling states reveals homeostatic mechanisms restricting the magnitude and duration of TFEB responses to mTOR activity modulation.
TFEB (transcription factor EB) regulates metabolic homeostasis through its activation of lysosomal biogenesis following its nuclear translocation. TFEB activity is inhibited by mTOR phosphorylation, which signals its cytoplasmic retention. To date, the temporal relationship between alterations to mTOR activity states and changes in TFEB subcellular localization and concentration has not been sufficiently addressed. mTOR was activated by renewed addition of fully-supplemented medium, or inhibited by Torin1 or nutrient deprivation. Single-cell TFEB protein levels and subcellular localization in HeLa and MCF7 cells were measured over a time course of 15 hours by multispectral imaging cytometry. To extract single-cell level information on heterogeneous TFEB activity phenotypes, we developed a framework for identification of TFEB activity subpopulations. Through unsupervised clustering, cells were classified according to their TFEB nuclear concentration, which corresponded with downstream lysosomal responses. Bulk population results revealed that mTOR negatively regulates TFEB protein levels, concomitantly to the regulation of TFEB localization. Subpopulation analysis revealed maximal sensitivity of HeLa cells to mTOR activity stimulation, leading to inactivation of 100 % of the cell population within 0.5 hours, which contrasted with a lower sensitivity in MCF7 cells. Conversely, mTOR inhibition increased the fully active subpopulation only fractionally, and full activation of 100 % of the population required co-inhibition of mTOR and the proteasome. Importantly, mTOR inhibition activated TFEB for a limited duration of 1.5 hours, and thereafter the cell population was progressively re-inactivated, with distinct kinetics for Torin1 and nutrient deprivation treatments. TFEB protein levels and subcellular localization are under control of a short-term rheostat, which is highly responsive to negative regulation by mTOR, but under conditions of mTOR inhibition, restricts TFEB activation in a manner dependent on the proteasome. We further identify a long-term, mTOR-independent homeostatic control negatively regulating TFEB upon prolonged mTOR inhibition. These findings are of relevance for developing strategies to target TFEB activity in disease treatment. Moreover, our quantitative approach to decipher phenotype heterogeneity in imaging datasets is of general interest, as shifts between subpopulations provide a quantitative description of single cell behaviour, indicating novel regulatory behaviors and revealing differences between cell types.


Transducers in medical ultrasound: Part One. Ferro-electric ceramics versus polymer piezoelectric materials.
A wide variety of transducer shapes and applications exists in the field of diagnostic ultrasound. As a basic material ferro-electric ceramics are used almost exclusively, but polymer piezoelectric material seems a new alternative. By comparing in a qualitative way the most relevant parameters of these materials, a state of the art judgement may be made about their applicability in diagnostic ultrasound.


CaMKIIβ-mediated LIM-kinase activation plays a crucial role in BDNF-induced neuritogenesis.
LIM-kinase 1 (LIMK1) regulates actin cytoskeletal reorganization by phosphorylating and inactivating actin-depolymerizing factor and cofilin. We examined the role of LIMK1 in brain-derived neurotrophic factor (BDNF)-induced neuritogenesis in primary-cultured rat cortical neurons. Knockdown of LIMK1 or expression of a kinase-dead LIMK1 mutant suppressed BDNF-induced enhancement of primary neurite formation. By contrast, expression of an active form of LIMK1 promoted primary neuritogenesis in the absence of BDNF. BDNF-induced neuritogenesis was inhibited by KN-93, an inhibitor of Ca(2+) /calmodulin-dependent protein kinases (CaMKs), but not by STO-609, an inhibitor of CaMK-kinase (CaMKK). CaMKK activity is required for the activation of CaMKI and CaMKIV, but not CaMKII, which suggests that CaMKII is principally involved in BDNF-induced enhancement of neuritogenesis. Knockdown of CaMKIIβ, but not CaMKIIα, suppressed BDNF-induced neuritogenesis. Active CaMKIIβ promoted neuritogenesis, and this promotion was inhibited by knockdown of LIMK1, indicating that CaMKIIβ is involved in BDNF-induced neuritogenesis via activation of LIMK1. Furthermore, in vitro kinase assays revealed that CaMKIIβ phosphorylates LIMK1 at Thr-508 in the kinase domain and activates the cofilin-phosphorylating activity of LIMK1. In summary, these results suggest that CaMKIIβ-mediated activation of LIMK1 plays a crucial role in BDNF-induced enhancement of primary neurite formation.


Community-based physical activity and nutrition programme for adults with metabolic syndrome in Vietnam: study protocol for a cluster-randomised controlled trial.
Metabolic syndrome (MetS) is a cluster of risk factors for cardiovascular diseases and type II diabetes. In Vietnam, more than one-quarter of its population aged 50-65 have MetS. This cluster-randomised controlled trial aims to evaluate the effectiveness of interventions to increase levels of physical activity and improve dietary behaviours among Vietnamese adults aged 50-65 years with MetS. This 6-month community-based intervention includes a range of strategies to improve physical activity and nutrition for adults with MetS in Hanam, a province located in northern Vietnam. 600 participants will be recruited from 6 communes with 100 participants per commune. The 6 selected communes will be randomly allocated to either an intervention group (m=3; n=300) or a control group (m=3; n=300). The intervention comprises booklets, education sessions, resistance bands and attending local walking groups that provide information and encourage participants to improve their physical activity and healthy eating behaviours during the 6-month period. The control group participants will receive standard and 1-time advice. Social cognitive theory is the theoretical concept underpinning this study. Measurements will be taken at baseline and postintervention to evaluate programme effectiveness. The research protocol was approved by the Curtin University Human Research Ethics Committee (approval number: HR139/2014). The results of the study will be disseminated through publications, reports and conference presentations. ACTRN12614000811606.


Early Postoperative Aqueous Suppression Therapy and Surgical Outcomes of Ahmed Tube Shunts in Refractory Glaucoma.
To compare early vs. delayed use of aqueous suppressants on Ahmed glaucoma valve (AGV) outcomes. Single-center retrospective comparative case series. Patients who underwent AGV surgery at Wills Eye Hospital in the period between 2016 and 2021. Retrospective review of AGV surgery at Wills Eye Hospital 2016 to 2021 for refractory glaucoma. Two groups were created: group 1 or those who received early aqueous suppressant therapy in the first 2 weeks postoperatively whenever the intraocular pressure (IOP) was > 10 mmHg, and group 2 or those who received delayed treatment after 2 weeks whenever the IOP exceeded the target pressure. Aqueous suppressant therapy included topical beta blockers, carbonic anhydrase inhibitors, and/or alpha agonists. The primary outcome measures were the frequency of hypertensive phase (HP) defined as IOP > 21 mmHg in first 3 months after an initial reduction to 21 mmHg or less in the first postoperative week not caused by tube obstruction or retraction, and month-12 surgical failure defined as 5 ≥ IOP > 21 mmHg on 2 consecutive visits, vision decline to no light perception (NLP), or glaucoma reoperation. Secondary outcome measures included changes in visual acuity (VA), IOP, and glaucoma medications at 12 months. Predictive factors for surgical failure were also identified. A total of 407 eyes of 391 patients (260 in group 1, 147 in group 2) with similar baseline characteristics were included. Hypertensive phase was more common in group 2 than 1 (41.5% vs. 18.5%; P < 0.001). At month 12 (N = 303 eyes), group 1 was less likely to fail than group 2 (21.2% vs. 36.8%, P = 0.003). Multivariate regression analysis showed that HP (odds ratio [OR] = 10.47, P < 0.001), delayed aqueous suppression use (OR = 2.17, P = 0.003), and lower baseline VA (OR = 1.56, P = 0.015) were the strongest predictors of month-12 failure. Early use of aqueous suppressants may lower the risk of HP and improve AGV outcomes. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.


Susac's syndrome--pathogenesis, clinical variants and treatment approaches.
Susac's syndrome is a rare disease that is characterised by the clinical triad of encephalopathy, branch retinal artery occlusion, and sensorineural hearing loss. It was first described as a distinctive syndrome by Susac in 1979. There have been 304 reported individual patients with Susac's syndrome. Etiopathogenesis is not clear, although it is now thought that it is an immune-mediated endotheliopathy that affects the microvasculature of the brain, retina, and inner ear. Antiendothelial cell antibodies (AECAs) play an important role in mediating the endothelial cell injury with consequent deposition of thrombotic material in the lumen of the small vessel. In biopsies of the brain, microinfarcts with atrophy of the white and grey matter could be detected. These microinfarcts are caused by a microangiopathic process with arteriolar wall proliferation, lymphocytic infiltration and basal lamina thickening. At clinical onset, the most common manifestation was central nervous system symptoms, followed by visual symptoms and hearing disturbances. Diagnosis is based on Magnetic Resonance Imaging (MRI), retinal fluorescein angiography, and audiometry; these are considered crucial tests to enable diagnosis. Antiendothelial cell antibodies (AECAs) are also of diagnostic relevance. Based on the hypothesis of being an autoimmune disease, treatment has to be immunosuppressive. In addition, anticoagulation measures, antiplatelet agents and antivasospastic agents should be considered. The majority of patients did not initially present with the complete triad of symptoms. An appropriate approach would be to perform a search for absent components of the triad if the clinical presentation is suggestive of Susac's syndrome. Improved understanding of the presentation of Susac's syndrome will prevent misdiagnosis and ensure that patients receive the best possible care.


Rapid and complete occlusion of a heat and moisture exchange filter by pulmonary edema (clinical report).
A case of near fatal obstruction of a breathing system is described, due to occlusion of a heat and moisture exchange filter in a patient with pulmonary edema. Previous reports have described cases of mechanical obstruction to fresh gas flow due to an accumulation of a bolus of fluid within the filter housing. However, in this case, the cause of occlusion was due to the protein and cell debris contained in a small amount of pulmonary edema fluid interacting with the filter membrane. Obstruction occurred rapidly and without warning, and was difficult to differentiate from the more common diagnoses of bronchospasm or tension pneumothorax. Outwardly the filter appeared normal, and routine protocol for emergency management of suspected breathing system obstruction initially failed to identify the site of occlusion. Minimal contamination by proteinaceous fluid may cause rapid and complete occlusion of a breathing system filter. Blockage of the breathing system filter and catheter mount should be considered in cases of unexplained breathing system occlusion. The use of a fresh breathing system without a filter for each patient, as recommended by The American Center for Disease Control and the American Society of Anesthesiologists, would have prevented this scenario from occurring.


Lovastatin (mevinolin) in the treatment of heterozygous familial hypercholesterolemia. A multicenter study.
To evaluate the efficacy and tolerability of lovastatin under controlled conditions in heterozygous familial hypercholesterolemia. Randomized, double-blind, placebo-controlled, multicenter trial. Five lipid clinics with a central laboratory and coordinating center. 101 adult patients with heterozygous familial hypercholesterolemia. Patients were on a lipid-lowering diet throughout the study. After a 4-week placebo baseline period, patients were randomized to five equal treatment groups. Each group received a different sequence of placebo or lovastatin 5 to 40 mg twice daily or 20 to 40 mg once daily in the evening, during three consecutive 6-week periods. The mean reductions in total plasma cholesterol and low-density lipoprotein cholesterol across the dosage ranges were 14% to 34% and 17% to 39%, respectively (p compared with zero and placebo less than 0.01). High-density lipoprotein cholesterol and apolipoproteins AI and AII rose slightly. Apolipoprotein B fell substantially at the higher dosage levels (-23% at 40 mg twice daily, p less than 0.01), indicating a reduction in the concentration of circulating low-density lipoprotein particles. Maximum response was achieved in 4 to 6 weeks. Twice-daily dosing was slightly more efficient than once-daily dosing. Of those patients receiving 40 mg twice a day, 89% had a fall in low-density lipoprotein cholesterol of at least 20%, and 61% had a fall of at least 40%. Adverse effects attributable to lovastatin were minimal, and no patient was withdrawn from the study. Lovastatin was well tolerated and effective in the treatment of familial hypercholesterolemia.


Induction of Chondrogenic Differentiation in Human Mesenchymal Stem Cells Cultured on Human Demineralized Bone Matrix Scaffold under Hydrostatic Pressure.
Articular cartilage damage is still a troublesome problem. Hence, several researches have been performed for cartilage repair. The aim of this study was to evaluate the chondrogenicity of demineralized bone matrix (DBM) scaffolds under cyclic hydrostatic pressure (CHP) in vitro. In this study, CHP was applied to human bone marrow mesenchymal stem cells (hBMSCs) seeded on DBM scaffolds at a pressure of 5 MPa with a frequency of 0.5 Hz and 4 h per day for 1 week. Changes in chondrogenic and osteogenic gene expressions were analyzed by quantifying mRNA signal level of Sox9, collagen type I, collagen type II, aggrecan (ACAN), Osteocalcin, and Runx2. Histological analysis was carried out by hematoxylin and eosin, and Alcian blue staining. Moreover, DMMB and immunofluorescence staining were used for glycosaminoglycan (GAG) and collagen type II detection, respectively. Real-time PCR demonstrated that applying CHP to hBMSCs in DBM scaffolds increased mRNA levels by 1.3-fold, 1.2-fold, and 1.7-fold (p < 0.005) for Sox9, Col2, and ACAN, respectively by day 21, whereas it decreased mRNA levels by 0.7-fold and 0.8-fold (p < 0.05) for Runx2 and osteocalcin, respectively. Additionally, in the presence of TGF-β1 growth factor (10 ng/ml), CHP further increased mRNA levels for the mentioned genes (Sox9, Col2, and ACAN) by 1.4-fold, 1.3-fold and 2.5-fold (p < 0.005), respectively. Furthermore, in histological assessment, it was observed that the extracellular matrix contained GAG and type II collagen in scaffolds under CHP and CHP with TGF-β1, respectively. The osteo-inductive DBM scaffolds showed chondrogenic characteristics under hydrostatic pressure. Our study can be a fundamental study for the use of DBM in articular cartilage defects in vivo and lead to production of novel scaffolds with two different characteristics to regenerate both bone and cartilage simultaneously.


First bite syndrome as a presenting symptom of a parapharyngeal space malignancy.
First bite syndrome is a known complication after parapharyngeal space surgery. This syndrome is usually encountered when the surgery is extensive but the parotid gland is preserved. A disruption in the balance between sympathetic and parasympathetic innervation to the parotid gland has been posited to play a role. We report a 74-year-old woman with a parapharyngeal space malignancy who presented with first bite syndrome prior to any surgical intervention. The tumor and left parotid gland were resected via a transcervical approach. During the operation, the sympathetic chain was found to be directly involved with the tumor. The patient reported complete resolution of first bite syndrome immediately after the operation, and remained free of this symptom at 6 months' follow-up. To our knowledge, this is the first report of first bite syndrome presenting prior to any surgical intervention. Parotidectomy, if included in the surgical plan, may lead to the resolution of first bite syndrome.


Lack of CD28 expression on HIV-specific cytotoxic T lymphocytes is associated with disease progression.
During HIV infection, CD8+ T cells lacking the costimulatory molecule CD28 increase in number and proportion. This accumulation is associated with disease activity and possibly with CD8+ T-cell dysfunction. In this study, CD8+CD28+ and CD8+CD28- T cells from 41 HIV-infected individuals at various stages of disease were compared in terms of HIV-specific cytotoxicity, TCR beta V repertoire diversity, and cytokine production. We found that the CD28 phenotype of anti-HIV CTL evolves in parallel with disease progression and disease activity. Absolute numbers of CD4+ T cells and CD4+/CD8+ T-cell ratios progressively decreased in 3 groups with an increasing prevalence of CD28- HIV-specific CTL. Conversely, HIV replication levels progressively increased in parallel with the prevalence of CD28- HIV-specific CTL. Repertoire diversity at the level of TCR beta V gene family expression was maintained at normal levels for both CD28+ and CD28- T cells at all stages of infection. Diversity at the level of junctional length polymorphism was more restricted in the CD8+CD28- T-cell population, but this difference remained relatively constant through different stages of infection. Both CD28+ and CD28- T cells produced IL-2 and IFN-gamma, regardless of disease stage and/or the predominant CD28 phenotype of anti-HIV CTL.


Materials for Electrochemiluminescence: TADF, Hydrogen-Bonding, and Aggregation- and Crystallization-Induced Emission Luminophores.
Electrochemiluminescence (ECL) is a rapidly growing discipline with many analytical applications from immunoassays to single-molecule detection. At the forefront of ECL research is materials chemistry, which looks at engineering new materials and compounds exhibiting enhanced ECL efficiencies compared to conventional fluorescent materials. In this review, we summarize recent molecular design strategies that lead to high efficiency ECL. In particular, we feature recent advances in the use of thermally activated delayed fluorescence (TADF) emitters to produce enhanced electrochemiluminescence. We also document how hydrogen bonding, aggregation, and crystallization can each be recruited in the design of materials showing enhanced electrochemiluminescence.


King Devick computerized neurocognitive test scores in professional football players with learning and attentional disabilities.
This study examined outcomes from the King Devick (K-D) in athletes with Learning Disabilities (LD) and attention disorders (ADHD). A total of 574 professional football players from the Canadian Football League (CFL) completed baseline evaluations with computerized neurocognitive testing (CNT) prior to the 2016 competitive season. Player age, education, history of concussion, LD, and ADHD were analyzed for K-D and Immediate Post Concussion Assessment and Cognitive Testing (ImPACT) performance. A series of analyses of co-variance (ANCOVA's) were used to compare participants with a history of LD and ADHD with history of concussion as a co-variate. Approximately 5% of participants reported a diagnosed history of LD and 13% with ADHD. Performance on the K-D test was not significantly correlated with age, education, or history of concussion but was significantly correlated with history of LD and ADHD. Participants with LD performed approximately 6.9 s slower on the K-D test (t[563] = 4.70, p. = 0.0003) and participants with ADHD were approximately 2 s slower (t[572] = 2.04, p. = 0.04). Results indicated that players with a history of diagnosed LD and ADHD performed slower on the K-D test in comparison to athletes with no history of diagnoses. The results of this study underscore the importance of recognizing individualized outcomes when using the K-D.


Bioprinted living tissue constructs with layer-specific, growth factor-loaded microspheres for improved enthesis healing of a rotator cuff.
Substantial challenges remain in constructing the native tendon-to-bone interface for rotator cuff healing owing to the enthesis tissues' highly organized structural and compositional gradients. Herein, we propose to bioprint living tissue constructs with layer-specific growth factors (GFs) to promote enthesis regeneration by guiding the zonal differentiation of the loaded stem cells in situ. The sustained release of tenogenic, chondrogenic, and osteogenic GFs was achieved via microsphere-based delivery carriers embedded in the bioprinted constructs. Compared to the basal construct without GFs, the layer-specific tissue analogs realized region-specific differentiation of stem cells in vitro. More importantly, bioprinted living tissue constructs with layer-specific GFs rapidly enhanced the enthesis regeneration in a rabbit rotator cuff tear model in terms of biomechanical restoration, collagen deposition, and alignment, showing gradient interface of fibrocartilage structures with aligned collagen fibrils and an ultimate load failure of 154.3 ± 9.5 N resembling those of native enthesis tissues in 12 weeks. This exploration provides a feasible strategy to engineer living tissue constructions with region-specific differentiation potentials for the functional repair of gradient enthesis tissues. STATEMENT OF SIGNIFICANCE: Previous studies that employed acellular layer-specific scaffolds or stem cells for the reconstruction of the rotator cuff faced challenges due to their insufficient capability to rebuild the anisotropic compositional and structural gradients of native enthesis tissues. This manuscript proposed a living tissue construct with layer-specific, GFs-loaded µS, which can direct in situ and region-specific differentiation of the embedded stem cells to tenogenic, chondrogenic, and osteogenic lineages for functional regeneration of the enthesis tissues. This bioprinted living tissue construct with the unique capability to reduce fibrovascular scar tissue formation and simultaneously facilitate enthesis tissue remodeling might provide a promising strategy to repair complex and gradient tissues in the future.


Red-seaweed biostimulants differentially alleviate the impact of fungicidal stress in rice (Oryza sativa L.).
Red seaweed-derived biostimulants facilitate plant health and impart protection against abiotic stress conditions by their bioactive compounds and plant nutrients. The potency of red seaweed biostimulants (LBS6 and LBD1) on rice cv. IR-64 in response to fungicides induced stress was investigated in this study. Foliar application of LBS6 maintained the stomatal opening and leaf temperature under the fungicidal stress condition. Reactive Oxygen Species (ROS) such as hydrogen peroxide and superoxide radicals were significantly reduced in LBS6-treated stressed plants. After applying seaweed biostimulants, ROS production was stabilized by antioxidants viz., CAT, APX, SOD, POD, and GR. LBS-6 application increased the Ca+ and K+ levels in the stressed plants, which perhaps interacted with ROS and stomatal opening signalling systems, respectively. In the rice plants, fungicidal stress elevated the expression of stress-responsive transcriptional factors (E2F, HSFA2A, HSFB2B, HSFB4C, HSFC1A, and ZIP12). A decline in the transcript levels of stress-responsive genes was recorded in seaweed treated plants. For the first time, we present an integrative investigation of physicochemical and molecular components to describe the mechanism by which seaweed biostimulants in rice improve plant health under fungicidal stress conditions.


Quantitative determination of p-chlorophenoxyisobutyric acid in blood plasma by gas-liquid chromatography.
A gas-liquid chromatographic method for the determination of p-chlorophenoxyisobutyric (CPIB) acid in blood plasma is described. The substance is extracted from acidified plasma into benzene, the extract is evaporated to dryness and the residue is methylated with an alcohol-free solution of diazomethane and submitted to chromatography on a glass column packed with 3% OV-17. Data on the recovery, reproducibility and sensitivity of the method are given. CPIB acid plasma levels in rats after acute and prolonged treatments with the aluminium salt of CPIB acid (Atherolip) are also presented.


Inhibition of HIV-1 infection by lentiviral vectors expressing Pol III-promoted anti-HIV RNAs.
A primary advantage of lentiviral vectors is their ability to pass through the nuclear envelope into the cell nucleus thereby allowing transduction of nondividing cells. Using HIV-based lentiviral vectors, we delivered an anti-CCR5 ribozyme (CCR5RZ), a nucleolar localizing TAR RNA decoy, or Pol III-expressed siRNA genes into cultured and primary cells. The CCR5RZ is driven by the adenoviral VA1 Pol III promoter, while the human U6 snRNA Pol III-transcribed TAR decoy is embedded in a U16 snoRNA (designated U16TAR), and the siRNAs were expressed from the human U6 Pol III promoter. The transduction efficiencies of these vectors ranged from 96-98% in 293 cells to 15-20% in primary PBMCs. A combination of the CCR5RZ and U16TAR decoy in a single vector backbone gave enhanced protection against HIV-1 challenge in a selective survival assay in both primary T cells and CD34(+)-derived monocytes. The lentiviral vector backbone-expressed siRNAs also showed potent inhibition of p24 expression in PBMCs challenged with HIV-1. Overall our results demonstrate that the lentiviral-based vectors can efficiently deliver single constructs as well as combinations of Pol III therapeutic expression units into primary hematopoietic cells for anti-HIV gene therapy and hold promise for stem or T-cell-based gene therapy for HIV-1 infection.


Hepaticopancreaticogastroduodenectomy with transplantation for metastatic islet cell carcinoma in childhood.
Symptomatic islet cell carcinoma of the pancreas with liver metastasis, a rare tumor cured only by complete resection, was unresponsive to chemotherapy and was treated with hepaticopancreaticogastroduodenectomy en bloc resection with transplantation in an 11-year-old girl. This radical surgery in conjunction with adjuvant chemotherapy and interstitial and external beam irradiation has resulted in symptomatic relief and no evidence of disease at 15 months posttransplant.


Spag6 Negatively Regulates Neuronal Migration During Mouse Brain Development.
Sperm-associated antigen 6 (Spag6) is a Chlamydomonas reinhardtii PF16 homologous gene detected in the human testis and is crucial for sperm motility. Neuronal migration is a dynamic process requiring coordinated cytoskeletal remodeling, and Spag6 is co-localized with microtubules in Chinese hamster ovary cells and COS-1 cells. However, the role of Spag6 in neuronal migration remains unclear. Here, we demonstrated that Spag6 was continuously expressed in the developing cerebral cortex. Using in utero electroporation (IUE), we found that overexpression of Spag6 delayed the rate of neuronal migration, rather than affecting the ultimate fate of cortical neurons. Furthermore, overexpression of Spag6 caused a significant decrease in neurite number and length of cortical neurons. Our results indicated that Spag6 controlled neuronal migration as well as neurite branching and elongation.


Stable isotope dilution analysis of succinylacetone using electron capture negative ion mass fragmentography: an accurate approach to the pre- and neonatal diagnosis of hereditary tyrosinemia type I.
A sensitive and accurate isotope dilution assay using electron capture negative ion mass fragmentography was developed for succinylacetone in amniotic fluid, plasma and urine. The method utilizes (D4)-5(3)-methyl-3(5)-isoxasole propionic acid as internal standard. Sample pretreatment consisted of oximation at pH less than 2 to 5(3)-methyl-3(5)-isoxasole propionic acid, clean up using liquid partition chromatography and further derivatization to the pentafluorobenzyl ester. Control values in plasma revealed a mean means = 0.044 mumol/l, range = 0.005-0.163 mumol/l, in urine means = 0.15 mumol/l, range 0.01-0.40 mumol/l corresponding to means = 0.03 mumol/mmol creat., range 0.01-0.14 mumol/mmol creat., and in amniotic fluid means = 0.016 mumol/l, range = 0.001-0.030 mumol/l. The utility of the method was demonstrated by quantification of succinylacetone in urine from patients with hereditary tyrosinemia type I (n = 8, excretion range 2.60-493.3 mumol/l corresponding to 0.67-197.3 mumol/mmol creat.) and in two amniotic fluid samples from fetuses affected with this disorder (concentration of succinylacetone 0.085 and 1.50 mumol/l, respectively). Maternal urine from a woman carrying an affected fetus did not show elevated urinary succinylacetone excretion.


Effect of Vaginal Stretching and Photobiomodulation Therapy on Sexual Function in Women With Pelvic Floor Myofascial Pain - A Randomized Clinical Trial.
Spasm or increased tonus of the pelvic floor muscles (PFM) can cause myofascial pain (MP), which may result in painful intercourse and sexual dysfunction. The effect of vaginal stretching (VS) with photobiomodulation therapy (PBMT) is compared to VS with sham PBMT in overall sexual function, rate and severity of painful intercourse at baseline and after treatment in women with pelvic floor MP. A double-blind randomized clinical trial of 103 women with MP: 1 group received 10 sessions of VS with PBMT (4 Joules of near-infrared light-808 nm at 3 points), and the other group received VS with sham PBMT. Impact of treatment was measured by the number of women experiencing painful intercourse, Pain severity was measured by Visual Analog Scale and sexual function was assessed by the FSFI questionnaire. Variables were assessed at baseline and after ten sessions in the intervention groups. After treatment, the number of women experiencing painful intercourse was significantly lower in both the VS with PBMT group (90.2-55%, P = .001), and VS with sham PBMT group (86.6-46.2%, P < .001). There was a significant reduction in pain measure by Visual Analog Scale (P < .001, [VS with PBMT group: P = .002; VS with sham PBMT group: P < .001]). There was a significant decrease in the number of participants with sexual dysfunction (FSFI score ≤26.55) after the treatment in the VS with PBMT group (92.2-74.5%, P = .003) and in the VS with sham PBMT group (90.4-76.9%, P = .035). Both groups showed improvement in the FSFI pain domain after treatment (P < .001, [VS with PBMT group: P = .038; VS with sham PBMT group: P = .005]). Only the VS with sham PBMT group had a significant increase in FSFI desire and total score (P < .001) after treatment. We found that VS associated or not with PBMT may be effective in reducing complaints of painful intercourse, alleviating pain severity, and reducing the number of women with pelvic floor MP suffering from sexual dysfunction. Strengths of this study are the randomized design and use of validated questionnaires. Limitation of the study is the lack of a long follow-up period and the lack of a usual care comparison group hampers generalizability of the results. VS only and VS with PBMT have short-term efficacy in reducing painful intercourse and reducing a number of women with sexual dysfunction. Frederice CP, de Mira TAA, Machado HC, et al. Effect of Vaginal Stretching and Photobiomodulation Therapy on Sexual Function in Women With Pelvic Floor Myofascial Pain - A Randomized Clinical Trial. J Sex Med 2022;19:98-105.


The impact of intensivists' base specialty of training on care process and outcomes of critically ill trauma patients.
The care of the critically ill trauma patients is provided by intensivists with various base specialties of training. The purpose of this study was to investigate the impact of intensivists' base specialty of training on the disparity of care process and patient outcome. We performed a retrospective review of an institutional trauma registry at an academic level 1 trauma center. Two intensive care unit teams staffed by either board-certified surgery or anesthesiology intensivists were assigned to manage critically ill trauma patients. Both teams provided care, collaborating with a trauma surgeon in house. We compared patient characteristics, care processes, and outcomes between surgery and anesthesiology groups using Wilcoxon tests or chi-square tests, as appropriate. We identified a total of 620 patients. Patient baseline characteristics including age, sex, transfer status, injury type, injury severity score, and Glasgow coma scale were similar between groups. We found no significant difference in care processes and outcomes between groups. In a logistic regression model, intensivists' base specialty of training was not a significant factor for mortality (odds ratio, 1.46; 95% confidence interval; 0.79-2.80; P = 0.22) and major complication (odds ratio, 1.11; 95% confidence interval, 0.73-1.67; P = 0.63). Intensive care unit teams collaborating with trauma surgeons had minimal disparity of care processes and similar patient outcomes regardless of intensivists' base specialty of training.


Quantitative microlaryngoscopic measurements of vocal fold polyps, glottal gap and their relation to vocal function.
The purpose of this study was to quantify the size of vocal fold polyps and to investigate the relationship between the glottal gap and parameters of acoustic voice analysis and phonetography. Eighty-one microlaryngoscopic images and digital recordings of voices (acoustic analysis and phonetogram) acquired from the patients with vocal fold polyps (VFPs) were employed in this study. Vocal fold (VF) images were collected during routine direct microlaryngoscopy using Moller-Wedel Universa 300 surgical microscope, 3-CCD Elmo 768 x 576-pixel color video camera and a 300 W Xenon light source. Acoustic voice analysis and phonetography were established using Dr. Speech (Tiger Electronics Inc.) software. Microlaryngoscopic images were processed by original software created by ELINTA and displayed on a monitor. The relative lengths and widths of vocal fold polyps as well as percentage area of VFP were calculated. The Pearson's correlation was applied to reveal the correlation between VFP dimensions and acoustic voice parameters. There were no statistically significant differences between the dimensions of left and right vocal folds and VFPs. Statistically significant slight to mild correlations between measured dimensions of VFP acoustic and phonetogram parameters were revealed, with HNR and phonetogram area showing the strongest correlation to the size of VFPs. The results of our study confirm that quantitative microlaryngoscopic measurements of vocal fold polyp and glottal gap dimensions may be a useful tool for objective assessment of glottic incompetence and voice impairment.


Molecular cloning, tissue expression and protein structure prediction of the porcine 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGR) gene.
3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGR) is the rate-limiting enzyme for cholesterol synthesis. Its activity is regulated via a negative feedback mechanism through sterols and non-sterol metabolites derived from mevalonate, the product of the reaction catalyzed by reductase. Here, we cloned a full-length transcript of porcine HMGR by RT-PCR and RACE. The porcine HMGR cDNA (2864 bp,GenBank accession no. DQ432054) contains a 2658 bp open reading frame and shares 91% identify with those of human and cattle, and 85%, 85% and 84% identify with the HMGR coding sequences of Norway rat, golden hamster, and house mouse, respectively. The deduced porcine HMGR protein consists of 885 amino acids with a calculated molecular mass of 97.15 kDa(GenBank accession no. ABD96089). The amino acid sequence similarities correspond to 95%, 95%, 92%, 92% and 92% when compared with human, cattle, Norway rat, golden hamster and house mouse sequences, respectively. The structure and function of HMGR deduced protein product were predicted by bioinformatic approaches. HMGR-specific transcripts were found in 15 different tissues from pig by RT-PCR and Real-time PCR. The relative expression level of HMGR was high in liver, heart, kidney, bladder and subcutaneous fat, medium in lung, uterus and large intestine, and low in cerebrum, spleen, spinal cord, stomach, ovary, longissimus muscle, and small intestine. The SNPs analysis of HMGR showed that there were five SNPS and three of them are synonymous mutations and the other two are missense mutations. Taken together, our data may lay a ground for further investigation of HMGR's functions and regulatory mechanisms in swine.


When the client is armed or dangerous: management of violent and difficult clients in primary care.
Health care settings and providers are not immune to violent or disruptive behavior by clients or by strangers off the street. Verbal abuse and threats of violence can escalate to physical attacks directed against health care practitioners. This article discusses the management of violent or dangerous patients in the primary care setting. Characteristics of potentially violent patients are reviewed, along with assessment clues useful in predicting violent behavior. Specific interventions to counteract or diffuse a potentially violent situation are proposed.


Proposal of criteria for dyserythropoiesis in the diagnosis of myelodysplastic syndromes.
The percentage manifesting dysplasia in bone marrow needed to qualify as significant is ≥10 % in each lineage. However, detailed analyses of this threshold have not been reported. Here, we analyzed dyserythropoiesis (dysE) in 109 myelodysplastic syndromes (MDS) patients with 21 immune thrombocytopenia (ITP)/12 hemolytic anemia (HA) patients as a control. In present study, mild megaloblastic erythroblasts were specifically named 'red cell with abnormal chromatin clumping (RCACC)'. RCACC ≥10 % in erythroblasts was observed in 29 % of ITP patients and 58 % of HA patients. The numbers of MDS patients with RCACC in erythroblasts <10, 10-19 and ≥20 % were 1, 3, and 105, respectively. We analyzed dysE criteria according to the WHO classification (original WHO dysE). Most of our MDS patients (98 %) had original WHO dysE ≥20 %. The ITP patients with original WHO dysE ≥10 % was 48 %, and there were no ITP patients had original WHO dysE ≥20 %. Sixty-seven percent of HA patients had original WHO dysE ≥10 %, and three patients (25 %) had original WHO dysE ≥20 %. Raising the threshold of the original WHO dysE from 10 to 20 or 30 % may provide more suitable criteria. If RCACC is not included in dysE criteria, we think that '10 %' is a suitable threshold for the determination of dyserythropoiesis.


Acanthamoeba species isolated from Philippine freshwater systems: epidemiological and molecular aspects.
Free-living amoeba (FLA) research in the Philippines is still in its infancy but has, by far, demonstrated the presence of potentially pathogenic species. Acanthamoeba may cause sight-threatening and central nervous system infections to humans, yet its epidemiologic distribution from local environmental sources is yet to be defined. The present study aimed to provide a baseline epidemiologic distribution of Acanthamoeba spp. in freshwater systems in the Philippines and establish potential pathogenicity of isolates through thermo-tolerance assay. A total of 63 water samples were collected from 13 freshwater systems all over the Philippine archipelago. The low-volume (50 ml) water samples were processed and cultured on non-nutrient agar lawned with Escherichia coli and observed for amoebic growth using light microscopy. Amoebic culture demonstrated 14.28% (9/63) positivity while further molecular testing of culture-positive plates using Acanthamoeba-specific primers demonstrated 100% (9/9) confirmation of Acanthamoeba species. Genotyping of Acanthamoeba isolates revealed T1, T3, T4, T5, T7, T11, and T15 genotypes. Thermo-tolerance assay demonstrated that T5 and T7 genotypes were potentially pathogenic strains. The evidence of environmental distribution of Acanthamoeba spp. in the freshwater systems in the Philippines and thermo-tolerance profile of isolates are significant aspects of amoeba study in public health and calls for initiatives in the dissemination of relevant information and the expansion of knowledge, awareness, and policies on pathogenic waterborne amoeba to mitigate, prevent, detect, and report cases of human infections.


Mesenchymal-epithelial interactions in the skin: aiming for site-specific tissue regeneration.
Since trunk skin (or non-palmoplantar skin) is less durable under mechanical stress than sole skin (palm, plantar or palmoplantar skin), conventional trunk-derived skin grafts (including the trunk dermis) commonly result in erosion and ulceration when transplanted on to plantar wounds caused by various injuries including, diabetes mellitus or collagen diseases (including systemic sclerosis, polyarthritis nodosa and rheumatoid arthritis). However, trunk-derived epidermis can adopt a plantar phenotype, characterized by keratin 9 expression, hypopigmentation and thick suprabasal layers, through factors derived from plantar dermal fibroblasts in the wounds. Thus, intractable plantar wounds with exposed bones can be treated with the combination of bone marrow exposure, occlusive dressing and epidermal grafting. The higher expression of dickkopf 1 (DKK1), an inhibitor of canonical Wnt/beta-catenin signals, in the plantar dermis partly explains these phenomena. Thus, mesenchymal-epithelial interactions play important roles not only in embryogenesis (the embryonic development) but also in maintaining the homeostasis of adult tissue. The topographical (site-specific) interactions of growth factors and substances, including DKKs, fibroblast growth factors (FGFs) and transforming growth factor-beta (TGF-beta) family proteins including bone morphogenetic proteins (BMPs), may explain the site-specific differences in the skin in addition to the expression patterns of HOX genes and sonic hedgehogs (Shhs). We review the importance of dermal-epidermal interactions in tissue homeostasis and regeneration, especially in palms and soles.


Impact of Phage Therapy on Multidrug-Resistant Escherichia coli Intestinal Carriage in a Murine Model.
The growing resistance of bacteria to antibiotics is a major global public health concern. An important reservoir of this resistance is the gut microbiota. However, limited data are available on the ability of phage therapy to reduce the digestive carriage of multidrug-resistant bacteria. Four novel lytic phages were isolated in vitro for efficacy against an extended-spectrum beta-lactamase-producing (ESBL) Escherichia coli strain also resistant to carbapenems through a carbapenemase OXA-48. The first step was to develop models of ESBL E. coli digestive carriage in mice. The second step was to test the efficacy of an oral and rectal phage therapy (a cocktail of four phages or microencapsulated phage) to reduce this carriage. The two most intense models of digestive carriage were obtained by administering amoxicillin (0.5 g·L-1) continuously in the drinking water (Model 1) or pantoprazole (0.1 g·L-1) continuously in the drinking water, combined with amoxicillin (0.5 g·L-1), for the first 8 days (Model 2). Oral administration of the phage cocktail to Model 1 resulted in a transient reduction in the concentration of ESBL E. coli in the faeces 9 days after the bacterial challenge (median = 5.33 × 108 versus 2.76 × 109 CFU·g-1, p = 0.02). In contrast, in Model 2, oral or oral + rectal administration of this cocktail did not alter the bacterial titre compared to the control (area under the curve, AUC, 3.49 × 109; 3.41 × 109 and 3.82 × 109 for the control, oral and oral + rectal groups, respectively; p-value > 0.8 for each two-by-two group comparison), as well as the administration of an oral microencapsulated phage in Model 1 (AUC = 8.93 × 109 versus 9.04 × 109, p = 0.81). Oral treatment with amoxicillin promoted digestive carriage in mice, which was also the case for the addition of pantoprazole. However, our study confirms the difficulty of achieving efficacy with phage therapy to reduce multidrug-resistant bacterial digestive carriage in vivo.


Zinc biosorption, biochemical and molecular characterization of plant growth-promoting zinc-tolerant bacteria.
Zinc plays a key role in plant nutrition at low levels; however, at higher concentrations Zn ions can be highly phytotoxic and plant growth-promoting rhizobacteria can be used to reduce such metal toxicity. In the present investigation we had reported the zinc biosorption and molecular characterization of plant growth-promoting zinc-tolerant bacteria. Initially, thirty bacteria having zinc solubilizing ability were screened for MIC against zinc ion and displayed high value of MIC ranging from 2.5 to 62.5 mM. Biochemically, all the 30 isolates showed significant difference in the 6 biochemical tests performed. The molecular diversity studies based on the repetitive DNA PCR viz, REP, ERIC and BOX elements showed significant genetic diversity among these 30 zinc-tolerant bacteria. These ZTB strains also showed multiple PGP activities and all ZTB strains were found positive for production of IAA, GA3 and ammonia, whereas 24 were found positive for ACC deaminase activity, 8 showed siderophore production and 9 ZTB isolates were positive for HCN production. Out of 30 isolates, 24 showed phosphorus solubilization activity, 30 showed potash solubilization, 15 showed silica solubilization and 27 showed phytase production activities. All the 30 ZTB stains showed zinc solubilization up to 0.25% insoluble ZnO in the medium, whereas at 2% ZnO in MSM only 12 isolates showed solubilization which were further selected for zinc biosorption and pot studies. The heavy metal removal studies revealed that ZTB stains were able to remove zinc ions effectively from the medium efficiently and the highest zinc biosorption (< 90%) was recorded with the bacterial strain Z-15. Further, the inoculation of ZTB strains under zinc stress conditions (pot containing 1000 mg/kg Zn) resulted in significant increase of shoot length, root length and total chlorophyll content in maize seedlings compared with the uninoculated control. The partial 16S rDNA sequence of the potential ZTB isolates viz. Z-15, Z-24, Z-28 and Z-29 revealed their identity as Serratia sp. The ability of these zinc-tolerant bacteria to tolerate the toxic level of zinc may serve as suitable candidates for developing microbial formulations for the growth of crop plants in Zn-contaminated areas.


A noncoding regulatory RNA Gm31932 induces cell cycle arrest and differentiation in melanoma via the miR-344d-3-5p/Prc1 (and Nuf2) axis.
Emerging evidence has shown that long non-coding RNAs (lncRNAs) play an important role in inhibiting tumor cell proliferation and inducing differentiation. In this study, integrative analysis of whole transcriptome sequencing data demonstrated that lncRNA-Gm31932 is significantly decreased in all-trans retinoic acid (ATRA)-induced and sodium 4-phenylbutanoate (PB-4)-induced mouse melanoma B16 cells. Silencing lncRNA-Gm31932 could inhibit B16 cell proliferation, with cell cycle arrest at the G0/G1 phase and obvious differentiation characteristics, e.g., increased cell volume, melanin content and tyrosinase (Tyr) activity. Furthermore, a series of experiments (luciferase reporter assay, RNA pull-down assay, and western blotting) showed that lncRNA-Gm3932 down-regulated Prc1 and Nuf2 by competitively sponging miR-344d-3-5p, which subsequently reduced the expression of cell cycle-related proteins CDK2, CDC2, and Cyclin B1, and increased the expression of P21 and P27. Moreover, silencing lncRNA-Gm31932 could significantly inhibit tumor growth in B16 melanoma-bearing mice. Taken together, these results indicate that as a possible signaling pathway for ATRA and PB-4, lncRNA-Gm31932 can induce cell cycle arrest and differentiation via miR-344d-3-5p/Prc1 (and Nuf2) axis.


Synthesis and structure activity relationships of novel non-peptidic metallo-aminopeptidase inhibitors.
Racemic derivatives of 3-amino-2-tetralone were synthesised and evaluated for their ability to inhibit metallo-aminopeptidase activities. New compounds substituted in position 2 by methyl ketone, substituted oximes or hydroxamic acids as well as heterocyclic derivatives were evaluated against representative members of zinc-dependent aminopeptidases: leucine aminopeptidase (E.C. 22.214.171.124), aminopeptidase-N (E.C. 188.8.131.52), Aeromonas proteolytica aminopeptidase (E.C. 220.127.116.11), and the aminopeptidase activity of leukotriene A(4) hydrolase (E.C. 184.108.40.206). Several compounds showed K(i) values in the low micromolar range against the 'one-zinc' aminopeptidases, while most of them were rather poor inhibitors of the 'two-zinc' enzymes. This interesting selectivity profile may guide the design of new, specific inhibitors of target mammalian aminopeptidases with one active site zinc.


MiR-23b-3p promotes postmenopausal osteoporosis by targeting MRC2 and regulating the Wnt/β-catenin signaling pathway.
Postmenopausal osteoporosis (PMOP) is one of the most common metabolic bone diseases in postmenopausal women. Increasing evidence has indicated that microRNAs (miRNAs) play vital regulatory roles during osteoporosis progression. This study aimed to investigate the potential function of miR-23b-3p in the osteogenic differentiation of human bone marrow mesenchymal stem cells (hMSCs). PMOP was induced in mice by bilateral ovariectomy. X-ray absorptiometry was applied to detect BMD and BMC in PMOP mice. Luciferase reporter assay and RIP assay were utilized to investigate the relationship between miR-23b-3p and MRC2. We found the upregulation of miR-23b-3p in bone tissues of PMOP mice. Silencing of miR-23b-3p relieved PMOP in mice. Moreover, miR-23b-3p knockdown facilitated the osteogenic differentiation of hMSCs by increasing the expression of Runx2, OCN, Osterix and promoting ALP activity. Mechanistically, MRC2 is a downstream target gene of miR-23b-3p. MRC2 knockdown significantly rescued the promoting effect of lenti-miR-23b-3p inhibitor on osteogenic differentiation of hMSCs. Furthermore, miR-23b-3p targeted MRC2 to inhibit the Wnt/β-catenin pathway during the osteogenic differentiation of hMSCs. In summary, inhibition of miR-23b-3p alleviates PMOP by targeting MRC2 to inhibit the Wnt/β-catenin signaling, which may provide a novel molecular insight for osteoporosis therapy.


Determination of pilocarpic acid in human plasma by capillary gas chromatography with mass-selective detection.
A novel, highly sensitive method for the determination of pilocarpic acid (PA) in human plasma is described. In addition, the method provides for the conversion of the lactone, pilocarpine (P), to PA so that a total drug presence can be determined. Using novel high-performance liquid chromatographic conditions capable of separating P, isopilocarpine (I-P), PA and isopilocarpic acid (I-PA) from each other and from endogenous plasma impurities, it was confirmed that P exclusively and quantitatively converts to PA in heparinized human plasma during storage. For the determination of PA, the selective extraction of PA from protein-free plasma was accomplished using two different solid-phase extraction (SPE) cartridges in two consecutive SPE steps. After extraction, PA was lactonized with trifluoroacetic acid back to P, and both P and an internal standard were acylated using heptafluorobutyric anhydride (HFBA). The trifluoroacetylated derivatives were monitored using gas chromatography (GC) with mass spectrometric (MS) detection. This procedure allowed the sensitive and reliable determination of PA with a limit of quantification (LOQ) of 1 ng/ml, which could not be achieved using previously described methods. The assay was validated in the concentration range of 1 to 10 ng/ml with an intra-day precision (expressed as the coefficient of variation, C.V.) ranging from 9.9 to 0.5%. Inter-day precision for the quality control standard at 2.5 ng/ml showed a C.V. of 10.2%. Accuracy ranged from 94 to 102%. The assay was used to monitor the maximum systemic exposure to P, administered by the ocular route, in terms of total plasma PA (P and PA).


Palliative and end-of-life care for children with diffuse intrinsic pontine glioma: results from a London cohort study and international survey.
More than 90% of patients with diffuse intrinsic pontine glioma (DIPG) will die within 2 years of diagnosis. Patients deteriorate rapidly during the disease course, which severely impairs their quality of life. To date, no specific research on this clinically important subject has been conducted. This study aimed to compile an inventory of symptoms experienced, interventions applied, and current service provision in end-of-life care for DIPG. We performed a retrospective cohort study of children with DIPG, aged 0-18 years, who received treatment under the care of 2 London hospitals. Symptoms, interventions, and services applied during the 12 weeks before death were analyzed. In addition, we conducted a global questionnaire-study among health care professionals. In more than 78% of DIPG patients, problems concerning mobility, swallowing, communication, consciousness, and breathing arose during end-stage disease. Supportive drugs were widely prescribed. The use of medical aids was only documented in <15% of patients. Palliative and end-of-life care was mostly based on the health care professional's experience; only 21% of the questionnaire respondents reported to have a disease-specific palliative care guideline available. This research assessed the current state of palliative and end-of-life care for children with DIPG. Our results show the variability and complexity of symptoms at end-stage disease and the current lack of disease-specific guidelines for this vulnerable group of patients. This first descriptive paper is intended to act as a solid basis for developing an international clinical trial and subsequent guideline to support high-quality palliative and end-of-life care.


The degree of blood pressure evaluation and end organ damage with severe hypertension: a case-control study.
To investigate the association of blood pressure and end-organ damage in patients with severe hypertension in a case-controlled manner, 26 patients with syndromes of acute end-organ damage and severe hypertension were compared with 25 patients with severe but asymptomatic hypertension for a variety of demographic, clinical, and basic laboratory values. Differences were assessed with the Chi-square test and multiple logistic regression analysis. End-organ damage was significantly associated with a degree of systolic and diastolic blood pressure elevation, a history of hypertensive crisis, serum creatinine, and a history of alcohol use, in multivariate analysis. The relationship to creatinine and a history of hypertensive crisis were not present in univariate analysis. The possible relationships of these factors to the pathophysiology of hypertensive crisis are discussed.


Rooting dynamics of Medicago sativa seedlings growing in association with Bothriochloa caucasica.
Medicago sativa was seeded into an established sward of Bothriochloa caucasica. Two frequencies of sward defoliation were compared to a nondefoliated control. Although 84 to 92% of the root mass at 0-20 cm belonged to B. caucasica during the spring and summer samplings, defoliation generally reduced the root mass of B. caucasica. During the summer, aboverground mass of B. caucasica ranged from 735 to 1220 g m-2 and 295 to 410 g m-2 for control and defoliation treatments, respectively. Defoliation apparently reduced the competitive effects of B. caucasica on M. sativa, as taproot and lateral root mass of M. sativa was much higher in defoliated than in control plots by the end of the growing season. Predawn xylem potential of M. sativa was 0.4 to 0.8 MPa more negative in control than in defoliated plots from mid-summer to fall. Thus, we suggest that the transpirational demand of undefoliated B. caucasica reduced soil moisture available to M. sativa, thereby reducing its growth and survival during late summer and fall, compared to defoliated treatments.


Synergistic effect of SCF and G-CSF on stem-like properties in prostate cancer cell lines.
Bone marrow metastases are formed in the late phases of prostate cancer disease. Stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) are present in the microenvironment of the bone marrow and play a vital role in cell biology therein. The present study was to investigate the influence of SCF and G-CSF on stem-like properties in prostate cancer cell lines. Upon stimulation with SCF or G-CSF, higher levels of CD117, ABCG2, and CD44 were observed in PC-3 and DU145 cells examined by flow cytometry. Simultaneously, the expressions of Oct3/4 and Nanog were upregulated. Moreover, quantitative real-time PCR verified that the increased Nanog under the stimulations was mostly derived from NANOGP8. In parallel with the increasing expressions of these proteins, higher colony and sphere formation efficiencies were seen in these cells in response to the cytokine stimulations. Furthermore, a synergistic effect of SCF and G-CSF on colony and sphere formations and ABCG2 expression was disclosed. Our results indicate a favorable bone marrow niche for prostate cancer cells where higher levels of cell stemness are maintained at least partly by the cytokines SCF and G-CSF.


Changes of Age-related Auricular Cartilage Plasticity and Biomechanical Property in a Rabbit Model.
Ear molding is an emerging technique that can correct auricular deformities. Treatment initiation time is the most important prognostic determinant of ear molding. Here, we aimed to examine why auricular cartilage plasticity appeared to diminish with age. Thus, we characterized age-related changes in the biomechanical, biochemical, and morphological properties of auricular cartilage. New Zealand rabbits were used as the experimental animal. We examined immature [postnatal 0 day (P0), 5 days (P5), 15 days (P15)], young [2 months (2M)], and mature [6 months (6M)] rabbits. Rabbits' ears were splinted and folded using adhesive fixation strips. Folding duration ranged from 1 day to 5 days to 10 days. Photographs were taken to calculate the retained fold angle. Cartilage morphology and extracellular matrix (ECM) content were examined histologically (using hematoxylin-eosin, Safranin O, elastic Van Gieson, and Masson's trichrome). Water content, DNA content, and cell density were also analyzed. Biomechanical properties were measured using a Nano indenter. Immature ears had smaller angles after strip removal, and the angled deformation lasted a longer time. Cartilage matrix compositions, including glycosaminoglycan (GAG), elastin fiber, and collagen, increased over development. The water content, DNA content, and cell density decreased with age. Young's modulus was significantly higher in mature cartilage. Here, we successfully established an animal model of ear molding and demonstrated that immature cartilage was associated with better plasticity. We also found that the cartilage's biomechanical property increased with the accumulation of ECM. The biomechanical change could underlie age-related shape plasticity. NA Laryngoscope, 133:88-94, 2023.


Alumina cream-induced focal motor epilepsy in cats. IV. Peduncular and midline tegmental lesions.
The effect of peduncular and midline tegmental lesions on EEG-EMG patterns of type B and C alumina cream-induced focal motor seizures was studied on cats with chronically implanted electrodes and cannula lesion systems. EEG patterns included number, amplitude and contralateral propagation of type B spikes and occurrence and duration of type C tonic-clonic discharges. EMG patterns included phasic multiple unit activity (EMG MUA) time locked to the onset of type B EEG spikes and time locked to the onset (contradversive OTCD) and end (clonic ETCD) of type C tonic-clonic EEG paroxysmal discharges. (1) Lesions of the middle third of the cerebral peduncle, ipsilateral to the cortical epileptogenic focus, blocked type B muscular convulsions and significantly decreased phasic EMG MUA at contralateral face, neck and limbs. (2) Bilateral peduncular lesions blocked clonic type C muscular convulsions and significantly decreased phasic clonic ETCD EMG MUA at the same body regions. (3) Midline tegmental lesions blocked phasic type C muscular convulsions and significantly decreased phasic contradversive OTCD EMG MUA at neck muscles. (4) Bilateral peduncular lesions significantly increased and midline tegmental lesions significantly decreased (below the previous interictal) contradversive OTCD EMG MUA. (5) Neither peduncular nor midline tegmental lesions significantly changed EEG patterns of type B and C seizures.


Synthesis of a new series of 4-chloro-2-mercapto-5-methylbenzenesulfonamide derivatives with potential antitumor activity.
The syntheses of S-(5-chloro-4-methyl-2-sulfamoylphenyl)alkanethio (or benzothio)hydrazonates (3a-3o) and potassium S-(5-chloro-2-cyanoamidatesulfonyl-4-methylphenyl)alkanethio (or benzothio)hydrazonates (4-10) are described. The compounds 3e, 3i-3o, 7 and 8 were screened at the National Cancer Institute (NCI) for their activities against a panel of 59 tumor cell lines and relationships between structure and antitumor activity in vitro are discussed. The compounds 3e, 3j, 3l-3o and 7 exhibited reasonable activity against numerous human tumor cell lines. The prominent compound 3l showed significant activity against some cell lines of leukemia (SR), melanoma (SK-MEL-5), CNS cancer (SF-539), ovarian cancer (OVCAR-3, OVCAR-4) and breast cancer (MDA-MB-231/ACTT) (GI50 values in the range 0.3-0.9 microM). Furthermore, compound 8 exhibited the high selectivity against renal cancer (A498) cells (GI50 < 0.01 microM, TGI = 2.3 microM and LC50 = 35.7 microM).


Improved approximate rips filtrations with shifted integer lattices and cubical complexes.
Rips complexes are important structures for analyzing topological features of metric spaces. Unfortunately, generating these complexes is expensive because of a combinatorial explosion in the complex size. For n points in R d , we present a scheme to construct a 2-approximation of the filtration of the Rips complex in the L ∞ -norm, which extends to a 2 d 0.25 -approximation in the Euclidean case. The k-skeleton of the resulting approximation has a total size of n 2 O ( d log k + d ) . The scheme is based on the integer lattice and simplicial complexes based on the barycentric subdivision of the d-cube. We extend our result to use cubical complexes in place of simplicial complexes by introducing cubical maps between complexes. We get the same approximation guarantee as the simplicial case, while reducing the total size of the approximation to only n 2 O ( d ) (cubical) cells. There are two novel techniques that we use in this paper. The first is the use of acyclic carriers for proving our approximation result. In our application, these are maps which relate the Rips complex and the approximation in a relatively simple manner and greatly reduce the complexity of showing the approximation guarantee. The second technique is what we refer to as scale balancing, which is a simple trick to improve the approximation ratio under certain conditions.


Negative regulation of ERK activity by VRK3-mediated activation of VHR phosphatase.
Extracellular signal regulated kinases (ERKs) represent a signalling hub in many physiological responses and have pivotal functions in cell proliferation, differentiation, development and death, as well as in synaptic plasticity. Mitogen-activated protein kinase phosphatases (MKPs) selectively inactivate ERKs by dephosphorylating critical phosphothreonine and phosphotyrosine residues. Transcriptional induction of MKP expression and posttranscriptional stabilization of MKP mRNA are well-documented as negative-feedback mechanisms for ERK signalling. Vaccinia-related kinase 3 (VRK3) is a member of the novel VRK family, but its function has not been defined. Here, we show that VRK3 suppresses ERK activity through direct binding to one of the MKPs, vaccinia H1-related (VHR), which specifically dephosphorylates and inactivates ERK in the nucleus. Notably, VRK3 enhances the phosphatase activity of VHR by a mechanism independent of its kinase activity. VRK3 is therefore a member of a new class of phosphatase-activating kinases that regulate the activity of ERK. Our findings show that direct interaction of VHR with VRK3 posttranslationally regulates ERK signalling.


Diagnosis and treatment of injury to the second and third carpometacarpal joints.
We describe the diagnosis, treatment, and follow-up of a group of 13 patients with hand pain traced to pathologic conditions of the second or third carpometacarpal joints. Missed diagnosis was universal. With suspicion raised by history of injury or repeated stress and point tenderness on examination, diagnosis was confirmed by complete pain relief after injection of 1% lidocaine locally. In management of patients with occult pain in the hand, attention should be directed to the second or third carpometacarpal joints. Arthrodesis with use of an inverted triangular graft from the base of the metacarpal provides predictable and lasting relief.


The arachidonic acid and its metabolism pathway play important roles for Apostichopus japonicus infected by Vibrio splendens.
Improving the immune ability and guiding healthy culture for sea cucumber by purposefully screening the significant differential metabolites when Apostichopus japonicus (A. japonicus) is infected by pathogens is important. In this study, 35 types of significant differential metabolites appeared when A. japonicus were infected by Vibrio splendens (VSI group) compared with the control A. japonicus group (CK group) by using liquid chromatography-mass spectrometry (LC-MS/MS)-based untargeted metabolomics. Based on that finding, the 10 types of key metabolic pathways were analyzed by MetPA. The "arachidonic acid (ARA) metabolism" pathway, which was screened by three elevated biomarkers: ARA, prostaglandin F2α and 2-arachidonoyl glycerol, had an important impact on immune stress in A. japonicus. Due to the similar changes in several metabolites in its metabolic pathway, the ARA metabolic pathway was selected for further study. The activities of ACP, AKP and lysozyme, which are important innate immune-related enzymes, the survival rates of A. japonicus infected with V. splendidus and the relative content of ARA in the body wall detected by GC-MS were all upregulated significantly by exogenous daily 0.60% and 1.09% ARA consumption over a short period of approximately 7 days. These results demonstrated that ARA and its metabolic pathway indeed played important roles in the immunity of A. japonicus infected by the pathogen. The findings also provide novel insights for the effects of metabolites in A. japonicum healthy culture.


Central and peripheral catecholamine depletion by 1-methyl-4-phenyl-tetrahydropyridine (MPTP) in rodents.
1-Methyl-4-phenyl-tetrahydropyridine (MPTP) given in single doses to rats depleted norepinephrine concentration in heart and mesenteric artery but had little effect on catecholamine concentration in brain. MPTP did not share with amphetamine the ability to cause persistent depletion of striatal dopamine in iprindole-treated rats. Administration of MPTP via osmotic minipumps implanted s.c. for 24 hrs after a loading dose of MPTP in rats resulted in depletion of striatal dopamine and its metabolites one week later. MPTP in vitro was a reasonably potent, competitive and reversible inhibitor of MAO-A (monoamine oxidase type A). MPTP appeared to inhibit MAO-A in rat brain in vivo as determined by its antagonism of the inactivation of MAO-A by pargyline and by its antagonism of the increase in dopamine metabolites resulting from the administration of Ro 4-1284, a dopamine releaser. The inhibition of MAO-B by MPTP in vitro was noncompetitive, time-dependent, and not fully reversed by dialysis, consistent with the findings of others that MPTP is acted upon by MAO-B. In mice, four successive daily doses of MPTP is acted upon by MAO-B. In mice, four successive daily doses of MPTP given s.c. resulted in marked depletion of dopamine and its metabolites one week later, and the depletion of dopamine was completely prevented by pretreatment with deprenyl, which inhibited MAO-B but not MAO-A. These and other studies in rodents may help in elucidating the mechanisms involved in the destructive effects of MPTP on striatal dopamine neurons that lead to symptoms of Parkinson's disease in humans and in monkeys.


International survey on the identification and neural monitoring of the EBSLN during thyroidectomy.
Surgical management of the external branch of the superior laryngeal nerve (EBSLN) during thyroidectomy is complex. We hypothesized that there exist variations in surgical behaviors patterns in the management of the EBSLN during thyroidectomy. A prospective Web-based anonymous survey (www.surveymonkey.com). The survey, consisting of 22 questions including surgeon demographics, laryngeal examination before and after surgery, and utilization of intraoperative neuromonitoring (IONM) for the management of the recurrent laryngeal nerve (RLN) and the EBSLN, was sent to 673 surgeons worldwide with known interest in thyroid surgery. A total of 170/673 (25.3%) surgeons from five continents with low-volume (11.2%), moderate-volume (27.2%), and high-volume practices (61.5%) completed the survey. Laryngeal preoperative examination was performed by 94% of respondents. IONM was utilized in the RLN management by 95% of respondents. IONM was used for identification of the EBSLN by 26.3% of low-volume versus 68.4% of high-volume surgeons (P = .004), and 93% of respondents felt EBSLN identification with IONM as necessary in voice professionals. Staged thyroidectomy was performed for benign disease by 89.5% of low-volume versus 63.2% of high-volume surgeons (P = .031). Post-thyroid surgery laryngeal examination was performed by 36.8% of low-volume versus 64.9% of high-volume surgeons (P = .032). Laryngeal examination and IONM is used frequently. However, the exact pattern of utilization varies notably with demographic information. Generally, high-volume surgeons, those with otolaryngology background, and younger surgeons more commonly utilize IONM according to existing international neural monitoring study group guidelines. Prospective multicenter studies are needed to guide an evidence-based management of the EBSLN during thyroidectomy.


Perspectives towards antibiotic resistance: from molecules to population.
For a long time, antibiotics have been 'magical weapons' to combat pathogenic microbes. The success of antibiotics is now greatly threatened by resistance to antibiotics and many scientists have already talked about the coming of the postantibiotic era. This special issue is prepared to understand recent research findings and new concepts about antibiotic resistance. Above all, this special issue explores mechanisms for the generation, selection, and spread of antibiotic resistance, and gives insight into what to target to prevent the development of antibiotic resistance. Just as antibiotics came from the concept of "magic bullet", a breakthrough will come from a new concept based on a profound understanding of antibiotic resistance.


Safely extending the indications of laparoscopic liver resection: When should we start laparoscopic major hepatectomy?
Laparoscopic major hepatectomy (LMH) is an innovative procedure that is still in the exploration phase. Although new surgical techniques have learning curves, safety should be maintained from the onset. This retrospective study was conducted to evaluate the safe introduction of LMH. We retrospectively reviewed data from 245 consecutive patients who underwent pure laparoscopic liver resection. Patients were divided into three groups: Phase I, the first 64 cases, all minor hepatectomies; Phase II, cases from the first LMH case to the midmost of the LMH cases (n = 69, including 22 LMHs); Phase III, the most recent 112 cases, including 22 LMHs. Patient characteristics and surgical results were evaluated, and the learning curve was analysed with the cumulative sum (CUSUM) method. The first LMH was adopted after sufficient preparatory experience was gained from performing 64 minor hepatectomies. In cases of LMH, there were no significant differences in the surgical time between Phases II and III (356 vs. 309 min; P = 0.318), morbidity rate (22.7 vs. 31.8 %; P = 0.736), or major morbidity rate (18.2 vs. 9.1 %; P = 0.664); however, estimated blood loss was significantly reduced from Phase II to Phase III (236 vs. 68 mL; P = 0.018). The CUSUM for morbidity also showed similar outcomes through Phases II and III. There is a learning curve associated with laparoscopic liver resection. To maintain a low morbidity rate, 60 laparoscopic minor hepatectomies could provide adequate experience before the adoption of LMH.


Endoscopic submucosal dissection for early gastric cancer.
Endoscopic mucosal resection (EMR) has been accepted as a treatment of early gastric cancer (EGC). The number of EMR procedures for EGC has been increasing because a patient's quality of life after EMR is superior to that after surgical gastrectomy. In Japan, most EMR have been performed using the strip biopsy method; however, in some cases we experienced local recurrences when multiple fragments had been resected by this method. Single-fragment resection is preferable for correct histological diagnosis and a patient's prognosis. Recently, dramatic changes have occurred in the operational technique and design of the accessory apparatus. In 1996, we developed a special endoscopic knife, called the insulation-tipped electrosurgical knife (IT knife), which consists of a conventional diathermic needle knife with a ceramic ball at the top to minimize the risk of perforation. This knife can cut submucosa safely and remove a lesion completely. We named this method endoscopic submucosal dissection (ESD). Using this procedure, 96% of the tumors (471/488) were completely resected in one piece. During the follow-up period, there were no recurrent cases. One-piece resection by ESD using the IT knife improves the quality of life and prognosis for patients with early gastric cancer.


Testing the "epidemiologic paradox" of birth outcomes among Asian immigrant women in Hsin-Chu County, Taiwan.
Taiwan saw an increase in immigration during the last decade. This retrospective study investigated whether immigrant status confers a protective effect on birth outcomes and whether this effect varies across racial/ethnic subgroups in Hsin-Chu County, Taiwan. A total of 30,770 singleton birth certificates from January 1, 2002 to July 31, 2007 were analyzed using ANOVA and logistic regression. Outcomes included low birth weight (LBW, < 2500 g), high birth weight (HBW, > 4000 g), preterm birth (< 37 weeks) and stillbirth. Covariates included maternal age, year of delivery, mode of delivery, medical care institution, infant sex and congenital birth defects. Five models were designed for various analyses. The reference categories included non-immigrant, non-aboriginal Taiwanese and non-Chinese-speaking immigrants. Preterm rate ranged from 6.3% among mainland Chinese to 13.5% among aboriginal Taiwanese. LBW rate ranged from 4.3% among mainland Chinese to 17.3% among aboriginal Taiwanese. HBW rate ranged from 1.2% among aboriginal Taiwanese to 3.4% among mainland Chinese. Stillbirth rate ranged from 0.2% among Indonesians to 0.7% among aboriginal Taiwanese. Adjusted odds ratio (OR) was lower among mainland Chinese (preterm OR, 0.77; LBW OR, 0.62) but higher among aboriginal Taiwanese (preterm OR, 1.79; LBW OR, 2.68; stillbirth OR, 2.92). HBW rate was significantly higher (OR, 1.84) among mainland Chinese. Chinese-speaking immigrants showed significant differences in LBW (OR, 0.57) and HBW (OR, 1.62) compared with non-Chinese-speaking immigrants. An epidemiologic paradox and heterogeneity of birth outcomes were observed among immigrants in this study. However, aboriginal Taiwanese constituted the subgroup with the highest risk. Further research is needed to identify the determinants of birth outcomes.


Optimal medical treatment versus endovascular aortic repair in uncomplicated isolated abdominal aortic dissection.
To report the results of optimal medical treatment (OMT) and endovascular aortic repair (EVAR) in patients with uncomplicated isolated abdominal aortic dissection (IAAD). A retrospective review of 96 consecutive patients with uncomplicated IAAD (uIAAD) managed at a single tertiary vascular unit between January 2011 and July 2021 was conducted. Standard methods for univariate and survival analyses were used. The primary outcomes were all-cause mortality. Secondary end points included uIAAD progression, interventional complications, and follow-up aortic intervention. Initially, 53.1% of patients (51/96) were managed with OMT. No in-hospital deaths occurred. During follow-up, three patients died, and three and two patients who were initially managed with OMT subsequently required endovascular treatment and surgical management, respectively. Initially, 46.9% of patients (45/96) underwent EVAR. One patient died during hospital admission; nine patients had an endoleak after operation and one needed reintervention. Furthermore, during follow-up, five patients died; four patients needed reoperation, one surgery and three endovascular treatments. The overall long-term mortality was 8.4%, and follow-up aortic intervention rate was 9.5% (median follow-up, 54 months; interquartile range, 33-81 months) with no significant difference between groups. Of note, 12 patients (12.6%) suffered uIAAD progression, which was higher in the OMT group than EVAR group (10 [19.6%] vs 2 [4.5%]; P = .03). uIAAD may be managed safely by OMT with regular surveillance, despite the risk of disease progression. Compared with OMT, EVAR could significantly prevent uIAAD progression. For anatomically suitable patients with uIAAD progression and who are unresponsive to OMT, pre-emptive EVAR is a safe and feasible option.


Axonal transcription factors signal retrogradely in lesioned peripheral nerve.
Retrograde axonal injury signalling stimulates cell body responses in lesioned peripheral neurons. The involvement of importins in retrograde transport suggests that transcription factors (TFs) might be directly involved in axonal injury signalling. Here, we show that multiple TFs are found in axons and associate with dynein in axoplasm from injured nerve. Biochemical and functional validation for one TF family establishes that axonal STAT3 is locally translated and activated upon injury, and is transported retrogradely with dynein and importin α5 to modulate survival of peripheral sensory neurons after injury. Hence, retrograde transport of TFs from axonal lesion sites provides a direct link between axon and nucleus.


The Hard Problem is Mainly Hard Work.
Doerig et al. point out that there is now a great deal of evidence bearing directly on our understanding of consciousness. However, they argue that the multiplicity of theories suggest that we have a 'lack of stringent criteria specifying how empirical data constrains ToCs.'


Efferent tectal cells of crucian carp: physiology and morphology.
Tectal cells of the crucian carp (Carassius ararssius) showing antidromic responses evoked by rhombencephalic electrical stimulation were physiologically studied and subsequently stained with Lucifer Yellow CH. The stained efferent tectal cells were fusiform, horizontal, and multipolar. The main axon of these efferent tectal cells descended along the wall of the deep tegmentum and could be traced to the motor area below the cerebellum. The axons gave off their collaterals in several brain areas: 1) descending collaterals in the torus semicircularis, dorso-lateral tegmental area and mesencephalic reticular formation and 2) an ascending collateral in the area between the hypothalamus and tegmentum. Fifty percent of the efferent cells were unresponsive to visual stimuli, but some of these cells were activated by visual or tactile stimulation in conjunction with rhombencephalic electrical stimulation. On the other hand, most of the visually active cells were On-transient and movement sensitive with habituation and some were bimodal.


Triaging TIA/minor stroke patients using the ABCD2 score does not predict those with significant carotid disease.
'Rapid Access' TIA Clinics use the ABCD(2) score to triage patients as it is not possible to see everyone with a suspected TIA <24 h. Those scoring 0-3 are seen within seven days, while patients scoring 4-7 are seen as soon as possible (preferably <24 h). It was hypothesized that patients scoring 4-7 would have a higher yield of significant carotid disease. Prospective study of correlation between Family Doctor (FD) or Emergency Department (ED) ABCD(2) score and specialist consultant Stroke Physician measured ABCD(2) score and prevalence of ≥50% ipsilateral carotid stenosis or occlusion in patients presenting with 'any territory' TIA/minor stroke or 'carotid territory' TIA/minor stroke. Between 1.10.2008 and 31.04.2011, 2452 patients were referred to the Leicester Rapid Access TIA Service. After Stroke Physician review, 1273 (52%) were thought to have suffered a minor stroke/TIA. Of these, both FD/ED referrer and Specialist Stroke Consultant ABCD(2) scores and carotid Duplex ultrasound studies were available for 843 (66%). The yield for identifying a ≥50% stenosis or carotid occlusion was 109/843 (12.9%) in patients with 'any territory' TIA/minor stroke and 101/740 (13.6%) in those with a clinical diagnosis of 'carotid territory' TIA/minor stroke. There was no association between ABCD(2) score and the likelihood of encountering significant carotid disease and analyses of the area under the receiver operating characteristic curve (AUC) for FD/ED referrer and stroke specialist ABCD(2) scores showed no prediction of carotid stenosis (FD/ED: AUC 0.50 (95%CI 0.44-0.55, p = 0.9), Specialist: AUC 0.51 (95%CI 0.45-0.57, p = 0.78). The ABCD(2) score was unable to identify TIA/minor stroke patients with a higher prevalence of clinically important ipsilateral carotid disease.


Thrombin generation post elective caesarean section: effect of low molecular weight heparin.
Caesarean section (CS) is a significant risk factor for venous thromboembolism.. Low molecular weight heparin (LMWH) is commonly used for thromboprophylaxis post emergency caesarean delivery. However, no consensus exists regarding LMWH thromboprophylaxis following elective caesarean section. Measures of thrombin formation may indicate the full anticoagulant activity of LMWH in this setting. Anti-Xa, tissue factor pathway inhibitor (TFPI), thrombin anti-thrombin complex (TAT) and endogenous thrombin potential (ETP) were measured in twenty healthy women who received 4,500 IU tinzaparin 6 hours post CS (CS1), twenty women who received 4,500 IU tinzaparin at 10-12 hours post delivery (CS2) and twenty women post spontaneous vaginal delivery (SVD). Prior to initiation of LMWH, TAT levels at 6 hours post delivery were significantly higher in the CS1 and CS2 groups than the SVD group (P<0.002); TAT levels were significantly reduced up to 24 hours post LMWH treatment despite declining anti-Xa levels (P<0.001). In CS1, peak thrombin and ETP were significantly reduced following LMWH prophylaxis (P<0.0001; P<0.002) and reverted to pre-delivery levels 10 hours post LMWH. TFPI levels mirror anti-Xa levels during the 24 hours following LMWH treatment in CS1 group with peak levels coinciding with peak anti-Xa levels 4 hours post injection. In women post caesarean section, anti-Xa levels do not reflect the full anticoagulant effects of LMWH. In-vivo thrombin production (TAT) is effectively reduced even when anti-Xa levels are negligible. LMWH thromboprophylaxis in this healthy cohort of patients appears to have a sustained effect in reducing excess thrombin production post elective caesarean section.


Who endorses conspiracy theories? A moderated mediation model of Chinese and international social media use, media skepticism, need for cognition, and COVID-19 conspiracy theory endorsement in China.
During the COVID-19 pandemic, various conspiracy theories have been circulating through social media platforms. Scholars have raised concerns about the negative ramifications of conspiracy theories, such as the deterrence of preventive measures. Against this backdrop, the current study analyzed an online survey (N = 731) from China and examined the conditional indirect effects of Chinese and international social media use on conspiracy theory endorsement (CTE) regarding COVID-19. Findings showed that Chinese social media use was not associated with CTE, while international social media use was negatively associated with CTE. Moreover, the significant association was mediated by media skepticism. Further, individuals' level of need for cognition (NFC) was found to moderate the indirect effect. That is, among people with higher levels of NFC, the negative indirect effect of international social media use on CTE became stronger. Theoretical and practical implications were discussed.


Sex difference in the principal cytochrome P-450 for tributyltin metabolism in rats.
Tributyltin is metabolized by cytochrome P-450 (CYP) system enzymes, and its metabolic fate may contribute to the toxicity of the chemical. In the present study, it is examined whether sex differences in the metabolism of tributyltin exist in rats. In addition, the in vivo and in vitro metabolism of tributyltin was investigated using rat hepatic CYP systems to confirm the principal CYP involved. A significant sex difference in metabolism occurred both in vivo and in vitro, suggesting that one of the CYPs responsible for tributyltin metabolism in rats is male specific or predominant at least. Eight cDNA-expressed rat CYPs, including typical phenobarbital (PB)-inducible forms and members of the CYP2C subfamily, were tested to determine their capability for tributyltin metabolism. Among the enzymes studied, a statistically significant dealkylation of tributyltin was mediated by CYP2C6 and 2C11. Furthermore, the sex difference in metabolism disappeared in vitro after anti-rat CYP2C11 antibody pretreatment because CYP2C11 is a major male-specific form in rats. These results indicate that CYP2C6 is the principal CYP for tributyltin metabolism in female rats, whereas CYP2C11 as well as 2C6 is involved in tributyltin metabolism in male rats, and it is suggested that CYP2C11 is responsible for the significant sex difference in the metabolism of tributyltin observed in rats.


Design, application and testing of the Work Observation Method by Activity Timing (WOMBAT) to measure clinicians' patterns of work and communication.
Evidence regarding how health information technologies influence clinicians' patterns of work and support efficient practices is limited. Traditional paper-based data collection methods are unable to capture clinical work complexity and communication patterns. The use of electronic data collection tools for such studies is emerging yet is rarely assessed for reliability or validity. Our aim was to design, apply and test an observational method which incorporated the use of an electronic data collection tool for work measurement studies which would allow efficient, accurate and reliable data collection, and capture greater degrees of work complexity than current approaches. We developed an observational method and software for personal digital assistants (PDAs) which captures multiple dimensions of clinicians' work tasks, namely what task, with whom, and with what; tasks conducted in parallel (multi-tasking); interruptions and task duration. During field-testing over 7 months across four hospital wards, fifty-two nurses were observed for 250 h. Inter-rater reliability was tested and validity was measured by (i) assessing whether observational data reflected known differences in clinical role work tasks and (ii) by comparing observational data with participants' estimates of their task time distribution. Observers took 15-20 h of training to master the method and data collection process. Only 1% of tasks observed did not match the classification developed and were classified as 'other'. Inter-rater reliability scores of observers were maintained at over 85%. The results discriminated between the work patterns of enrolled and registered nurses consistent with differences in their roles. Survey data (n=27) revealed consistent ratings of tasks by nurses, and their rankings of most to least time-consuming tasks were significantly correlated with those derived from the observational data. Over 40% of nurses' time was spent in direct care or professional communication, with 11.8% of time spent multi-tasking. Nurses were interrupted approximately every 49 min. One quarter of interruptions occurred while nurses were preparing or administering medications. This method efficiently produces reliable and valid data. The multi-dimensional nature of the data collected provides greater insights into patterns of clinicians' work and communication than has previously been possible using other methods.


The effect of nutritional state on neuromuscular transmission in the rat.
1. Evoked end-plate potentials (e.p.p.s) were recorded in phrenic nerve-hemidiaphragm preparations from rats which had been subjected to periods of dietary restriction. 2. The mean quantum content of the first e.p.p. of trains of e.p.p.s was significantly increased after 1 week of dietary restriction in 30-day-old but not in 110-day-old rats. 3. The mean quantum content of plateau e.p.p.s elicited at a frequency of 10 Hz was not significantly affected by brief periods of dietary restriction in either 30-day-old or 110-day-old rats. 4. In the younger animals there was found to be a decrease in the safety factor of neuromuscular transmission following dietary restriction when this parameter was calculated using previously reported values for the amplitude of spontaneous miniature end-plate potentials (m.e.p.p.s) after such a restricted diet. 5. Such rapid changes in neuromuscular transmission following brief periods of dietary restriction indicate that great care is required in the choice of adequate control animals when food intake is altered by experimental procedures.


Physical Health and Psychological Outcomes in Adult Patients with Long-bone Fracture Non-unions: Evidence Today.
Research has suggested that bone fractures can hinder the health status of patients' life. However, limited research has examined the impact that the healing process of a fracture has on the physical health and psychological state of individuals, particularly in considering the short- and long-term impact of having a fracture that fails to heal and drops into a non-union. The aim of this systematic review is to better understand the impact of fracture non-union to physical health and to respective psychological outcomes. Electronic databases 'PubMed', 'Cochrane', 'PsycInfo', 'Medline', 'Embase', 'Web of Science', and 'CINAHL' were used. Search terms used were nonunion OR non-union OR "non union" OR "long bone" OR "delayed union" AND "quality of life" OR qol OR depression OR anxiety OR psycholog* OR PTSD OR "post-traumatic stress disorder". Studies published in the years 1995 to 2018 were included. Two independent reviewers carried out screening and data extraction. Studies were included if (1) participants were adult (human) patients with a traumatic non-union secondary to fracture/s; (2) outcomes measured included physical health and psychological wellbeing (e.g., PTSD, psychological trauma, depression, anxiety, etc.). Studies received emphasis if they compared those outcomes between: (1) The "non-union" group to a normative, matched population and (2) the "non-union group" to the same group after union was achieved. However, studies that did not use comparison groups were also included. Out of the 1896 papers identified from our thorough literature search, 13 met the inclusion criteria. Quality assessment was done by the Methodological Index for Non-Randomized Studies (MINORS). Findings suggested that non-unions had a detrimental impact on physical health, and psychological difficulties often after recovery. Patients who experience a long bone non-union are at risk of greater psychological distress and lower physical health status. There is a need for early identification of psychological distress in patients with fracture non-unions and psychological provision should become part of the available treatment.


Differential regulation by AT(1) and AT(2) receptors of angiotensin II-stimulated cyclic GMP production in rat uterine artery and aorta.
1. In the present study we determined whether angiotensin II (Ang II) could increase cyclic GMP levels in two blood vessels that exhibit markedly different angiotensin II receptor subtype expression: rat uterine artery (UA; AT(2) receptor-predominant) and aorta (AT(1) receptor-predominant), and investigated the receptor subtype(s) and intracellular pathways involved. 2. UA and aorta were treated with Ang II in the absence and presence of losartan (AT(1) antagonist; 0.1 microm), PD 123319 (AT(2) antagonist; 1 microm), NOLA (NOS inhibitor; 30 microm), and HOE 140 (B(2) antagonist; 0.1 microm), or in combination. 3. Ang II (10 nm) induced a 60% increase in UA cyclic GMP content; an effect that was augmented with PD 123319 and HOE 140 pretreatment, and abolished by cotreatment with losartan, as well as by NOLA. 4. In aorta, Ang II produced concentration-dependent increases in cyclic GMP levels. Unlike effects in UA, these responses were abolished by PD 123319 and by NOLA, whereas losartan and HOE 140 caused partial inhibition. 5. Thus, in rat UA, Ang II stimulates cyclic GMP production through AT(1) and, to a less extent, AT(2) receptors. In rat aorta, the Ang II-mediated increase in cyclic GMP production is predominantly AT(2) receptor-mediated. In both preparations, NO plays a critical role in mediating the effect of Ang II, whereas bradykinin has differential roles in the two vessels. In UA, B(2) receptor blockade may result in a compensatory increase in cyclic GMP production, whilst in aorta, bradykinin accounts for approximately half of the cyclic GMP produced in response to Ang II.