CT and MRI diagnosis of cerebrovascular disease: going beyond the pixels.
Cerebrovascular disease is one of the leading causes of morbidity and mortality in the United States, with an incidence of approximately 500,000 cases of stroke per year. Tremendous strides in the diagnosis of stroke have been made in recent years, although the main diagnostic tools available remain CT, MRI, and MR angiography. Because new treatment options are being developed, it has become imperative to analyze these anatomic studies more intensively and critically, with an eye toward eliciting vital pathophysiological information. This article reviews various imaging findings in that light and offers a perspective on the radiologist's role in the management of patients with these conditions.


Identification of novel B cell epitopes in Fiber-2 protein of duck adenovirus 3 and their application.
Duck adenovirus 3 (DAdV-3), a newly emerged duck adenovirus, has resulted in significant economic losses to the duck industry across China since 2014. However, little is known about the B cell epitopes in major antigen of DAdV-3 and the serological approach for detection of DAdV-3 is not available. In this study, four monoclonal antibodies (mAbs) specific to Fiber-2 protein of DAdV-3 were first generated and designated as 2G10, 3D9, 5E6, and 6B12. Indirect immunofluorescence assay (IFA) showed that all of the mAbs reacted with the Fiber-2. Moreover, mAbs 2G10, 5E6, and 6B12 demonstrated good activity with Fiber-2 in Western blot. Notably, the Fiber-2 could be immunoprecipitated efficiently by mAb 3D9. Epitope mapping revealed that mAbs 2G10, 3D9, 5E6, and 6B12 recognized 397-429aa, 463-481aa, 67-99aa, and 1-66aa of Fiber-2, respectively. Besides, a novel sandwich ELISA for efficient detection of DAdV-3 was developed based on mAb 3D9 and horseradish peroxidase (HRP) conjugated mAb 3D9. The sandwich ELISA only reacted with DAdV-3 but not with other duck-associated viruses. The limit of detection of the ELISA was 6.25 × 103 TCID50/mL. Overall, the mAbs generated laid the foundation for elucidating the critical role of Fiber-2 in mediating infection and pathogenesis, and the sandwich ELISA approach established here provided efficient and rapid serological diagnostic tool for DAdV-3.


Engaging patients as teachers in a baccaulaureate nursing reproductive health care course: A qualitative study.
Teaching nursing students about the principles and practical application of person-centered care is an essential yet challenging component of nursing education. Integrating patients as teachers to share their personal stories of maternity care can elicit positive outcomes toward students achieving course objectives. To determine how the educational experience of having patients as teachers in the classroom could influence students' awareness of patients' perceptions of their maternity care, delivering person-centered care and the roles of nursing in their future practice. Retrospective qualitative study of student reflections. Reproductive health course within a BSN program. Ninety-nine second semester BSN student reflections. Two course faculty and a qualitative nurse researcher conducted a thematic content analysis of written student reflections. Three primary themes emerged from the students' reflections of hearing patient and family advisors describe their maternity experiences: 1) awareness of the impact of nursing practice on patient and family well-being, 2) awareness of personal biases and emotions about difficulties in maternity care, and 3) appreciation to hear from patients directly as part of didactic coursework. Including patients as teachers is an enhanced method to aid nursing students in understanding the humanistic and impactful roles of nursing in the clinical setting.


Braun's Lipoprotein Facilitates OmpA Interaction with the Escherichia coli Cell Wall.
Gram-negative bacteria such as Escherichia coli are protected by a complex cell envelope. The development of novel therapeutics against these bacteria necessitates a molecular level understanding of the structure-dynamics-function relationships of the various components of the cell envelope. We use atomistic MD simulations to reveal the details of covalent and noncovalent protein interactions that link the outer membrane to the aqueous periplasmic region. We show that the Braun's lipoprotein tilts and bends, and thereby lifts the cell wall closer to the outer membrane. Both monomers and dimers of the outer membrane porin OmpA can interact with peptidoglycan in the presence of Braun's lipoprotein, but in the absence of the latter, only dimers of OmpA show a propensity to form contacts with peptidoglycan. Our study provides a glimpse of how the molecular components of the bacterial cell envelope interact with each other to mediate cell wall attachment in E. coli.


Insight on the structural, electronic and optical properties of Zn, Ga-doped/dual-doped graphitic carbon nitride for visible-light applications.
The density functional theory (DFT) was applied for the first time to study the doping and co-doping of Ga and Zn metals on graphitic carbon nitride (g-C3N4). The doping of these metal impurities into g-C3N4 leads to a significant decrease in the bandgap energy. Moreover, the co-doping leads to even lower bandgap energy than either individual Zn or Ga-doped g-C3N4. The theoretical electronic and optical properties including the density of state (DOS), energy levels of the frontier orbital, excited state lifetime, and molecular electrostatic potential of the doped and co-doped g-C3N4 support their application in UV-visible light-based technologies. The quantum mechanical parameters (energy band gap, binding energy, exciton energy, softness, hardness) and dipole moment exhibit higher values (ranging from 1.36 to 4.94 D) compared to the bare g-C3N4 (0.29 D), indicating better solubility in the water solvent. The time-dependent DFT (TD-DFT) calculations showed absorption maxima in between the UV-Vis region (309-878 nm). Additionally, charge transfer characteristics, transition density matrix (TDM), excited state lifetime and light harvesting efficiency (LHE) were investigated. Overall, these theoretical studies suggest that doped and co-doped g-C3N4 are excellent candidates for electronic semiconductor devices, light-emitting diodes (LEDs), solar cells, and photodetectors.


Cytokine profile of viral and autoimmune chronic active hepatitis.
Patients with hepatitis have multiple immunologic abnormalities, which may be related to cytokine production. We examined the in vitro production of interleukins (IL-2, IL-4, IL-6), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) in purified peripheral blood mononuclear cells (PBMCs) of patients with hepatitis B virus positive (HBV), acute viral hepatitis (A-HBV), HBV + chronic active hepatitis (HBV-CAH), and autoimmune-type chronic active hepatitis (AI-ACH). IFN-gamma and TNF-alpha production were characteristically higher in patients with A-HBV than in healthy control subjects (p < 0.001). However, patients with AI-CAH produced highly elevated levels of IL-4 and IL-6 compared with patients with A-HBV and HBV-CAH and healthy control subjects. The cytokine profile (PBMC-induced IL-2, IL-4, IL-6, IFN-gamma, and TNF-alpha production) is different in A-HBV, HBV-CAH, and AI-CAH disease. The increased cytokine secretion (IFN-gamma and TNF-alpha in A-HBV and IL-4 and IL-6 in AI-CAH) could reflect altered relative frequencies of different cell phenotypes in these diseases. Specific cytokine production may be important in the pathophysiology associated with diverse inflammatory states in patients with hepatitis.


Comparative study on the status of microplastics in different functional areas of Tuticorin, Southeast coast of India.
Microplastics (MPs) and the pollutants associated with them pose a significant risk to the aquatic ecosystems. This study analysed the spatial and seasonal differences in MPs in terms of diversity, inventory and associated heavy metals, and assessed the risk carried by MPs in different functional areas of Tuticorin, southeast coast of India. The mean MPs abundance varies from 5.67 ± 3.1 to 94.66 ± 6.5 items/L in water and 6 ± 1.73 to 147 ± 18.6 items/kg in sediment. More MPs are found in monsoon water and post-monsoon sediment. Fibre-shaped polyethylene (PE) and polypropylene (PP) MPs have a dominant presence in all seasons. They might derive from synthetic clothing, derelict fishing gear and improper dumping of plastic waste in this region. The carbonyl index (CI) of PE varies from 0.01 to 1.2 and that of PP from 0.03 to 0.98. The high surface oxidation rate (with CI ≥ 0.31) indicates the weathering level of MPs. The high microplastics diversity index (MPDII) of the Fishing Harbour points to the diverse pollution sources. The inventory of MPs is expressed in terms of their weight-based accumulation. Higher inventory of MPs is detected in the water (0.018 ton/km2) and sediment (2.03 ton/km2) of Fishing Harbour. The scanning electron microscope (SEM) images of MPs reveal various surface morphologic features like cracks, protrusion, void space, and adsorbed microorganisms. Energy dispersive X-ray spectroscopy (EDAX) shows the presence of metals (Mn, Cu, Zn, Ni, K, Ca, Cr, Mg, Ti, Cd, As, Se, Fe, Al, and Si) on the MPs surfaces. The polymer hazard index (PHI) indicates a III to IV chemical risk level. All the information obtained from the analysis presents a clear image of the nature and distribution of MPs in this region.


Inhibition of tamoxifen's therapeutic effects by emodin in estrogen receptor-positive breast cancer cell lines.
This study was aimed to investigate the combination effect of endoxifen and emodin on estrogen receptor (ER) positive breast cancer cell lines and to explain the mechanism of the combination effect. We conducted this study on MCF-7 (ER+/human epidermal growth factor receptor-2 [HER2]-), T47D (ER+/HER2-), ZR-75-1 (ER+/HER2+), and BT474 (ER+/HER2+) cell lines, which confirmed combination effect of endoxifen and emodin. Optimal concentrations for combination were determined to study the effects on proliferation of MCF-7 and ZR-75-1 cells. Analysis of the combination effect was carried out in the CompuSyn software. The combination of downstream mechanisms, and combined effects of other similar compounds were tested on the MCF-7 and ZR 75-1 cell lines. Protein expression was confirmed by western blot. The combination of endoxifen and emodin had antagonistic effects on MCF-7 and ZR-75-1cell lines (combination index > 1). We validated the antagonistic effect in T47D and BT474 cell lines. During the combined treatment, the results showed elevated amounts of cyclin D1 and phosphorylated extracellular signal-regulated kinase (pERK). Analysis of drug interactions showed antagonistic effect between endoxifen and chemical compounds similar to emodin, such as chrysophanol or rhein, in MCF-7 and ZR-75-1 cells. Addition of emodin attenuated tamoxifen's treatment effect via cyclin D1 and pERK up-regulation in ER-positive breast cancer cell lines.


Oxytocinergic neurons, but not oxytocin, are crucial for male penile erection.
The cumulative evidence suggests that oxytocin is involved in the male sexual behaviors. However, no significant sexual impairments were observed in oxytocin gene knock-out (KO) mice, suggesting that oxytocin is not necessary for sexual behavior in male mice. To better understand the role of oxytocin in male erection, two types of oxytocin gene KO mice were created. In the first type, the oxytocin gene was deleted in the zygote, while in the second type, the oxytocin gene was mutated in adulthood by injecting the CRISPR/Cas9 AAVs. The results showed that disrupting the oxytocin gene at either the embryonic or adult stage did not affect erection, indicating that oxytocin is not necessary for penile erection. Pharmacologically, injecting oxytocin receptor agonist Carbetocin into the VTA of the oxytocin gene KO mice still evoked penile erection. By employing the Oxt-Ires-Cre mice, we found that specifically activating oxytocinergic neurons through chemogenetics strongly induced penile erection, while inhibiting these neurons blocked the erection responses. Furthermore, ablating PVN oxytocinergic neurons abolished the male erection response. In conclusion, although the neuropeptide oxytocin is not essential for male erection, the activity of oxytocinergic neurons is required. Our results might reflect the redundancy in the central nerve system in the sense that many signals contribute to the activation of oxytocinergic neurons to evoke penile erection during sexual behaviors.


Massive true thymic hyperplasia with osseous metaplasia.
True thymic hyperplasia is defined as an increase in both the size and weight of the gland, while maintaining a normal microscopic architecture. Massive true thymic hyperplasia is a rare type of hyperplasia that compresses adjacent structures and causes various symptoms. Limited reports address the imaging findings of massive true thymic hyperplasia. Herein, we report a case of massive true thymic hyperplasia in a 3-year-old girl with no remarkable medical history. Contrast-enhanced CT revealed an anterior mediastinal mass with a bilobed configuration containing punctate and linear calcifications in curvilinear septa, which corresponded to lamellar bone deposits in the interlobular septa. To our knowledge, this is the first report of massive true thymic hyperplasia with osseous metaplasia. We also discuss the imaging features and etiology of massive true thymic hyperplasia with osseous metaplasia.


Single-cell sequencing reveals the heterogeneity and intratumoral crosstalk in human endometrial cancer.
Endometrial cancer (EC) is one of the most common gynecologic malignancies with increasing morbidity. Cell-cell and cell-matrix interactions within the tumour microenvironment (TME) exert a powerful influence over the progression of EC. Therefore, a comprehensive exploration of heterogeneity and intratumoral crosstalk is essential to elucidate the mechanisms driving EC progression and develop novel therapeutic approaches. 4 EC and 2 normal endometrium samples were applied for single-cell RNA sequencing (scRNA-seq) analysis. In addition, we also included the public database to explore the clinical benefits of the single cell analysis. 9 types of cells were identified with specific expression of maker genes. Both the malignant epithelial cells and cells comprising the immune microenvironment displayed a high degree of intertumoral heterogeneity. Notably, the proliferation T cells also showed an exhausted feature. Moreover, the malignant cells may induce an immunosuppressive microenvironment through TNF-ICOS pair. Cancer-associated fibroblasts (CAFs) were divided into four subsets with distinct characteristics and they maintained frequent communications with malignant cells which facilitating the progression of EC. We also found that the existence of vascular CAF (vCAF) may indicate a worse prognosis for EC patients through integrating TCGA database. The TME of human EC remains highly heterogeneous. Out finding that malignant cells interact closely with immune cells and vCAFs identifies potential therapeutic targets.


Knockout of Toll-Like Receptors 2 and 4 Prevents Renal Ischemia-Reperfusion-Induced Cardiac Hypertrophy in Mice.
We investigated whether the pathways linked to Toll-like receptors 2 and 4 (TLRs) are involved in renal ischemia-reperfusion (I/R)-induced cardiac hypertrophy. Wild type (WT) C57BL/6J, TLR2-/- and TLR4-/- mice were subjected to left kidney ischemia for 60 min followed by reperfusion for 5, 8, 12 and 15 days. Proton density magnetic resonance showed alterations in the injured kidney from WT mice, together with signs of parenchymal edema and higher levels of vimentin mRNA, accompanied by: (i) small, but significant, increase in serum urea after 24 h, (ii) 100% increase in serum creatinine at 24 h. A serum peak of inflammatory cytokines occurred after 5 days of reperfusion. Heart weight/body weight and heart weight/tibia length ratios increased after 12 and 15 days of reperfusion, respectively. Cardiac hypertrophy markers, B-type natriuretic peptide (BNP) and α-actin, left ventricle mass, cardiac wall thickness and myocyte width increased after 15 days of reperfusion, together with longer QTc and action potential duration. Cardiac TLRs, MyD88, HSP60 and HSP70 mRNA levels also increased. After 15 days of reperfusion, absence of TLRs prevented cardiac hypertrophy, as reflected by similar values of left ventricular cardiac mass and heart weight/body weight ratio compared to the transgenic Sham. Renal tissular injury also ameliorated in both knockout mice, as revealed by the comparison of their vimentin mRNA levels with those found in the WT on the same day after I/R. The I/R TLR2-/- group had TNF-α, IFN-γ and IL-1β levels similar to the non-I/R group, whereas the TLR4-/- group conserved the p-NF-κB/NF- κB ratio contrasting with that found in TLR2-/-. We conclude: (i) TLRs are involved in renal I/R-induced cardiac hypertrophy; (ii) absence of TLRs prevents I/R-induced cardiac hypertrophy, despite renal lesions seeming to evolve towards those of chronic disease; (iii) TLR2 and TLR4 selectively regulate the systemic inflammatory profile and NF- κB activation.


Workforce survey of PAs' genetic-genomic knowledge, attitudes, and application in practice.
This study surveyed practicing physician associates/assistants (PAs) about their genetics-genomics knowledge, attitudes, and application in practice. A 25-question electronic survey was emailed to each constituent organization of the American Academy of Physician Associates (AAPA) with a description of the study and a request to forward to their members. Additionally, a posting was displayed in the bulletin board section of the online AAPA Huddle. Of the 420 PAs who completed the survey, few are knowledgeable (25%) about or confident (13%) in applying a genomic approach to patient care, although most (61%) think genetics-genomics is important to delivering high-quality care. Remarkably, 97% of PAs surveyed are interested in genetics-genomics continuing medical education. PAs lack knowledge and confidence in integrating genetics-genomics into patient care; however, they have a positive attitude toward genetics-genomics and want to improve their knowledge and confidence through education.


Large variation existed in standardized mean difference estimates using different calculation methods in clinical trials.
The standardized mean difference (SMD) can be calculated from different mean differences (MDs) and standard deviations (SDs). This study aims to investigate how clinical trials calculated, reported and interpreted the SMD, and to examine the variation between different SMDs. We searched the PubMed for randomized controlled trials of general medicine and psychiatry that estimated SMDs. We explored how the SMD was computed and interpreted. We calculated SMDs based on different MDs and SDs, and the variation in these SMD estimates for each study. We included 161 articles. Various MDs and SDs were used to calculate SMDs, yet 69.0% studies failed to provide sufficient details. Variations in SMD estimates using different MDs and SDs in one study could be substantial (median of the absolute differences was 0.3, interquartile range IQR 0.17 to 0.53). However, 68.3% studies interpreted the SMD based on the same reference, Cohen's rule of thumb. The largest variations were observed in studies with small sample sizes and large reported effects. SMDs using different MDs and SDs could vary considerably, but the report was often insufficient and the interpretation was oversimplified. To avoid selective reporting bias and misinterpretation, prespecifying and reporting the method and interpreting the result from multiple perspectives are desirable.


[Effect of adrenalectomy and chemical sympathectomy on the catecholamines content in the central nervous system in hemorrhagic stress].
Content of adrenaline, noradrenaline, dopamine and normetanephrine was estimated by means of trihydroxyindole method in samples of brain and its hypothalamic part from intact, adrenal- and sympathectomized rats within 15 min, 24 and 72 hrs after hemorrhagic stress (3% blood of body weight within 20 min). Stable increase in dopamine content was observed in brain at all the periods studied. Alterations in the noradrenaline turnover in central nervous system were related to the state of peripheral sympathoadrenal system at early posthemorrhagic steps; the phenomenon was not found at the later periods after stress.


Cerebral microdialysis as a monitoring method in subarachnoid hemorrhage patients, and correlation with clinical events--a systematic review.
One of the goals in treating subarachnoid hemorrhage patients is to prevent or minimize vasospasm-induced ischemia. Intracerebral microdialysis is a rapidly developing tool to monitor physiological and pathophysiological changes in chemical processes associated with ischemia. To determine the diagnostic accuracy of microdialysis in detecting ischemia or ischemic events in patients with subarachnoid hemorrhage. A systematic review of clinical studies regarding microdialysis as a monitoring method in patients in the acute stage of subarachnoid hemorrhage was conducted by performing a MEDLINE search using the terms "subarachnoid hemorrhage", "brain ischemia", "intracranial aneurysm", "cerebrovascular accident" and "stroke". These were combined with a search on "microdialysis". The methodological quality of the studies was assessed independently by two reviewers. For each study the grades of recommendation were determined. The search yielded 73 publications of which 13 studies were analysed. The methodological quality of the studies was low,with only 3 studies fulfilling more than 50% of the criteria. Consequently the level of evidence was low. Of the internal validity criteria the characteristics of study populations were similar in most of the studies. The technical assessment varied considerably. A quantitative analysis (meta-analysis) could not be performed because of lack of sufficient data. A qualitative analysis yielded a positive impression with regard to the diagnostic accuracy of microdialysis in detecting ischemic events. There is a positive tendency to use microdialysis as a diagnostic tool for monitoring of ischemic events in subarachnoid hemorrhage patients. However, there is insufficient evidence for the routine use of microdialysis.


FvmnSOD is involved in oxidative stress defence, mitochondrial stability and apoptosis prevention in Fusarium verticillioides.
Superoxide dismutases are key enzymes in elimination of the superoxide anion radical (O2 •- ) generated intracellularly or by exogenous oxidative stress eliciting agents, like menadione. In this study, we investigated the physiological role of the manganese superoxide dismutase-encoding gene in Fusarium verticillioides via the construction of a gene deletion mutant, ΔFvmnSOD and comparing its phenotype with that of the wild-type parental strain and a ΔFvmnSOD' C strain, complemented with the functional manganese superoxide dismutase gene. Deletion of FvmnSOD had no effect on the relative intracellular superoxide ratio but increased the sensitivity of the fungus to menadione sodium bisulphite on Czapek-Dox stress agar plates. The lack of FvmnSOD caused changes in mitochondrial morphology and physiology: The volumetric ratio of these cell organelles in the second hyphal segment, as well as the total, the KCN-sensitive cytochrome c-dependent and the KCN+SHAM (salicylhidroxamic acid)-resistant residual respiration rates, were higher in the mutant as compared to the wild-type and the complemented strains. Nevertheless, changes in the respiration rates were attributable to the higher volumetric ratio of mitochondria found in the gene deletion mutant. Changes in the mitochondrial functions also brought about higher sensitivity to apoptotic cell death elicited by the Penicillium chrysogenum antifungal protein. The gene deletion mutant developed significantly thinner hyphae in comparison to the wild-type strain. Deletion of FvmnSOD had no effect on fumonisin B1 and B2 production of the fungus grown in Myro medium as a static culture.


Lack of acute effect on lidocaine pharmacokinetics from parenteral nutrition.
We tested the hypothesis that amino acids in a parenteral nutrition (PN) solution would result in the decreased metabolism of a model compound, lidocaine. One bolus infusion of lidocaine HCl (1 mg/kg) was administered to seven healthy subjects in association with each of three nutrient regimens: (a) a standard PN solution, (b) 10% dextrose water (D10W), and (c) a meal (control) containing similar fluid volume and caloric, protein, and sodium content as the PN solution. Intravenous nutrients were infused consecutively in a random order at 1 L/12 h. Intravenous and control studies were performed 28 days apart. There was no significant difference in the means (+/- SEM) of total body clearance [7.70 +/- 0.70 (PN) versus 6.78 +/- 0.79 (D10W) versus 7.86 +/- 0.93 (control) ml/min kg], half-life [74.0 +/- 12.2 (PN) versus 89.6 +/- 4.35 (D10W) versus 79.2 +/- 7.22 (control) min], volume of distribution [0.82 +/- 0.15 (PN) versus 0.88 +/- 0.13 (D10W) versus 0.78 +/- 0.13 (control) L/kg], and the fraction of unbound lidocaine in the serum [0.34 +/- 0.025 (PN) versus 0.36 +/- 0.019 (D10W) versus 0.33 +/- 0.020 (control)] among the three nutrient regimens. The concentration-time course of the active metabolite, N-ethylglycyl-2,6-xylidide, did not differ significantly regardless of the nutritional regimen used. Our study indicates that amino acids used for PN do not have any acute effect on lidocaine pharmacokinetics in healthy subjects.


Resistive straight leg raise test, resistive forward bend test and heel compression test: novel techniques in identifying secondary gain motives in low back pain cases.
'Low back pain' (LBP) is a prevalent condition with a majority showing no specific organic pathology. Distinguishing 'secondary gain motives (SGM)' from organic causes is imperative in clinical practice. We describe here, three new tests-resistive straight leg raise test (rSLRT), resistive forward bend test (rFBT) and heel compression test (HCT) to help differentiate patients with 'SGM' from those without. We conducted a prospective study to validate the above tests in predicting non-organic causes as a reason for LBP. 200 patients presenting with low back pain at the senior author's outpatient orthopaedic clinic from Jan 2009 to Nov 2010 were studied. Patients were separated into two groups-'SGM group' (n = 100) and 'non-SGM group' (n = 100). 'SGM group' patients had a history of work-related accidents, road traffic accidents or assault, with a background of ongoing litigation issues or compensation benefits. rSLRT, rFBT, HCT, Schober's test and Waddell's five signs were performed on them. Statistical analysis was done to identify correlations between test results, MRI findings and 'SGM' status. Statistically significant differences were observed between the SGM and non-SGM group (p < 0.0005) for all tests studied. In predicting SGM status, rSLRT showed highest specificity (0.94) and highest positive predictive value (0.925) while HCT showed the highest negative predictive value (0.859). Positive rSLRT was found to be strongly correlated with ≥3 positive Waddell's signs. SGM patients with positive rSLRT tended to show resistance ≤45°. rSLRT, rFBT and HCT (NK triad) are highly practical tests which strongly predict SGM status in patients.


Catalytic independent functions of a protein kinase as revealed by a kinase-dead mutant: study of the Lys72His mutant of cAMP-dependent kinase.
A highly conserved lysine in subdomain II is required for high catalytic activity among the protein kinases. This lysine interacts directly with ATP and mutation of this residue leads to a classical "kinase-dead" mutant. This study describes the biophysical and functional properties of a kinase-dead mutant of cAMP-dependent kinase where Lys72 was replaced with His. Although the mutant protein is less stable than the wild-type catalytic subunit, it is fully capable of binding ATP. The results highlight the effect of the mutation on stability and overall organization of the protein, especially the small lobe. Phosphorylation of the activation loop by a heterologous kinase, 3-phosphoinositide-dependent protein kinase-1 (PDK-1) also contributes dramatically to the global organization of the entire active site region. Deuterium-exchange mass spectrometry (DXMS) indicates a concerted stabilization of the entire active site following the addition of this single phosphate to the activation loop. Furthermore the mutant C-subunit is capable of binding both the type I and II regulatory subunits, but only after phosphorylation of the activation loop. This highlights the role of the large lobe as a scaffold for the regulatory subunits independent of catalytic competency and suggests that kinase dead members of the protein kinase superfamily may still have other important biological roles although they lack catalytic activity.


Effect of polyol detergents on cholesterol and triglyceride absorption. Hypolipidemic action of chronic administration of hydrophobic detergent.
Nonionic detergents were found to affect absorption of neutral lipid and cholesterol. The effects of these detergents were related to their physicochemical properties. The most effective detergents for producing an inhibition of lipid absorption were detergents containing 90% hydrophobic components. Hydrophilic detergents did not interfere with lipid absorption and in some cases, it was facilitated. Studies done over a period of one month demonstrate that addition of a hydrophobic detergent to a high fat-high cholesterol diet results in lower serum levels of cholesterol and triglyceride and prevents cholesterol accumulation in the liver of the rat. This effect was also associated with significant loss of body weight.


Halo-thoracic brace management of odontoid fractures.
Thirteen patients with fracture of the odontoid were treated with halo-thoracic brace. Major trauma was responsible for the fracture in only 5. Neither the degree nor the direction of displacement prevented union, which occurred in all 13. All patients were treated for least 60 days; 11 were treated longer. No complications occurred. The method is recommended based on the results.


Schizophrenia genetics: the search for a hard lead.
To describe the rationale for searching for genes for schizophrenia, prior efforts via candidate gene association and genomewide linkage studies, and to set the stage for the numerous genomewide association studies that will emerge by the end of 2008. Genomewide association studies have identified dozens of new and previously unsuspected candidate genes for many biomedical disorders. At least seven new studies of approximately 20,000 cases plus controls are expected to be completed by the end of 2008. Current results have few implications for clinical practice or research, and it is possible that this recommendation could be dramatically different in a year.


Gestational age and fetal biophysical assessment.
With improved neonatal care, biophysical assessment to detect fetal asphyxia is used increasingly at an earlier gestational age. We have tested five fetal biophysical variables: nonstress test, fetal breathing movements, fetal movements, fetal tone, and amniotic fluid volume 11,012 times in 5582 singleton fetuses in whom there was a normal perinatal outcome. The nonstress test and fetal breathing movements were more likely to be abnormal at 26 to 33 weeks' gestation compared with 34 to 41 weeks. The nonstress test, fetal breathing movements, fetal tone, and amniotic fluid volume were more likely to be abnormal at 42 to 44 weeks' gestation compared with 37 to 41 weeks. Fetal biophysical tests should be interpreted in relation to gestational age.


Simulated environmental transport distances of Lepeophtheirus salmonis in Loch Linnhe, Scotland, for informing aquaculture area management structures.
In the majority of salmon farming countries, production occurs in zones where practices are coordinated to manage disease agents such as Lepeophtheirus salmonis. To inform the structure of zones in specific systems, models have been developed accounting for parasite biology and system hydrodynamics. These models provide individual system farm relationships, and as such, it may be beneficial to produce more generalized principles for informing structures. Here, we use six different forcing scenarios to provide simulations from a previously described model of the Loch Linnhe system, Scotland, to assess the maximum dispersal distance of lice particles released from 12 sites transported over 19 day. Results indicate that the median distance travelled is 6.1 km from release site with <2.5% transported beyond 15 km, which occurs from particles originating from half of the release sites, with an absolute simulated distance of 36 km observed. This provides information suggesting that the disease management areas developed for infectious salmon anaemia control may also have properties appropriate for salmon lice management in Scottish coastal waters. Additionally, general numerical descriptors of the simulated relative lice abundance reduction with increased distance from release location are proposed.


Diurnal changes in bacterial settlement on the Peyer's patch and surrounding mucosa in the rat ileum and its effect against the intestinal immune system.
Our previous study revealed the diurnal change in the indigenous bacteria settling on the terminal region of the rat ileum. In the present study, we investigated the diurnal change in indigenous bacteria on the most distal ileal Peyer's patch (PP) and surrounding ileal mucosa and explored how stimulation from indigenous bacteria for a day affects the intestinal immune system at the beginning of the light phase. Histological measurement revealed that bacteria adjacent to the follicle-associated epithelium of PP and to the villous epithelium of the surrounding ileal mucosa are more abundant at zeitgeber time (ZT)0 and ZT18 than at ZT12. On the other hand, tissue-section 16S rRNA amplicon sequencing revealed no significant difference between ZT0 and ZT12 in the bacterial composition on the ileal tissue including the PP. One-day treatment with an antibiotic (Abx) successfully impaired the settlement of bacteria around the ileal PP. In transcriptome analysis, 1-day Abx treatment led to the downregulation of several chemokines in both PP and ordinary ileal mucosa at ZT0. Histological analysis of the 1-day Abx group revealed decreases in both CD68+ macrophages in PP and naphthol AS-D chloroacetate esterase stain-positive mast cells in the ileal villi. Together, these findings suggest that the colonies of indigenous bacteria on the distal ileal PP and surrounding mucosa expand during the dark phase, which might lead to the expression of genes to regulate the intestinal immune system and contribute to the homeostasis of at least macrophages in PP and mast cells in the ileal mucosa.


VE-cadherin is a critical endothelial regulator of TGF-beta signalling.
VE-cadherin is an endothelial-specific transmembrane protein concentrated at cell-to-cell adherens junctions. Besides promoting cell adhesion and controlling vascular permeability, VE-cadherin transfers intracellular signals that contribute to vascular stabilization. However, the molecular mechanism by which VE-cadherin regulates vascular homoeostasis is still poorly understood. Here, we report that VE-cadherin expression and junctional clustering are required for optimal transforming growth factor-beta (TGF-beta) signalling in endothelial cells (ECs). TGF-beta antiproliferative and antimigratory responses are increased in the presence of VE-cadherin. ECs lacking VE-cadherin are less responsive to TGF-beta/ALK1- and TGF-beta/ALK5-induced Smad phosphorylation and target gene transcription. VE-cadherin coimmunoprecipitates with all the components of the TGF-beta receptor complex, TbetaRII, ALK1, ALK5 and endoglin. Clustered VE-cadherin recruits TbetaRII and may promote TGF-beta signalling by enhancing TbetaRII/TbetaRI assembly into an active receptor complex. Taken together, our data indicate that VE-cadherin is a positive and EC-specific regulator of TGF-beta signalling. This suggests that reduction or inactivation of VE-cadherin may contribute to progression of diseases where TGF-beta signalling is impaired.


Safety and Predictors of 30-Day Adverse Events of Laryngeal Framework Surgery: An Analysis of ACS-NSQIP data.
To characterize and identify predictors of 30-day adverse events in patients undergoing laryngeal framework surgery (LFS). This study is a retrospective analysis of the National Surgical Quality Improvement dataset. LFS cases were identified from the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) database from 2008 to 2018. Demographic variables, patient comorbidities, and perioperative outcomes (any adverse event, 30-day readmission, 30-day reoperation, and unplanned intubation) were extracted. Patient-specific and surgery-specific factors associated with perioperative adverse events were examined using descriptive statistics and univariate logistic regression (LR). Of 283 patients who underwent LFS, 225 underwent laryngoplasty medialization, 56 underwent laryngoplasty medialization with arytenoidectomy or arytenoidopexy via an external approach, and 2 underwent local myocutaneous or fasciocutaneous advancement flap along with laryngoplasty. Medical comorbidities were present in 33.6% of patients and 57.9% were American Society of Anesthesiologists (ASA) Class III/IV (57.9%). LFS was performed as same-day surgery in 30.7% of cases. Fourteen patients (4.9%) suffered an adverse condition within 30 days following surgery. In univariate LR, ASA Class III or IV (odds ratio [OR] 4.6, 95% confidence interval [CI] 1.2-30.1) was the only predictor associated with any adverse event. Arytenoid adduction (AA) was associated with increased risk of reoperation within 30 days of the initial surgery (OR 6.4, 95% CI 1.0-49). LFS is a generally safe procedure with infrequent perioperative adverse events. In the ACS-NSQIP database, ASA classification of III or IV was associated with a higher risk for any 30-day adverse event and AA was associated with a higher risk for 30-day reoperation. 4 Laryngoscope, 132:1414-1420, 2022.


Prion disease with a 144 base pair insertion: unusual cerebellar prion protein immunoreactivity.
Sporadic, acquired, and genetic human prion diseases are characterized neuropathologically by distinct deposition patterns of the abnormal, disease-associated form of the prion protein (PrP(sc)). In addition to mutations in the prion protein gene (PRNP), PrP(sc) immunostaining patterns correlate with molecular phenotypes of prion diseases defined by the PRNP polymorphism at codon 129 and with protease-resistant PrP classified by Western blotting. Some point or insertional PRNP mutations share similar clinical and neuropathological phenotypes, whereas others show great variability even within the same family. Here we report a patient who presented clinically as sporadic Creutzfeldt-Jakob disease (CJD). Histologically moderate spongiform change was seen in cerebral and cerebellar cortical areas. Neuronal loss was restricted mainly to the occipital cortex and the basal ganglia. Surprisingly, numerous eosinophilic globular structures were noted in the molecular layer and the parahippocampal gyrus. These globules showed intense PrP immunopositivity using anti-PrP antibodies against different epitopes. They were stained with PAS but lacked congophilia and birefringence in polarized light. Ultrastructurally, globules were composed of 21-nm-thick intermingled filaments without dense core. Genetic analysis revealed a PRNP 144 base pair insertion. Our case reinforces the importance of molecular genetic diagnosis, especially in those patients who lack a family history of prion disease and show unusual neuropathological changes. It also widens the phenotypic spectrum of prion diseases. The phenotypic variability within the same mutation suggests further, yet uncharacterized, genetic or epigenetic influence on phenotype in these diseases.


Informed consent for clinical trials: in search of the "best" method.
To review the literature on comparisons between different methods of obtaining informed consent for clinical trials. Eight hundred and twelve articles were traced, in the process of conducting a systematic review of the ethics of clinical trials, by searching a number of sources: bibliographic databases (Medline, Psychlit and BIDS science and social science indices), hand searches, personal contacts, an original collection and a systematic follow-up of reference lists. Fourteen research reports were found which provided comparative data on different methods of obtaining informed consent. Eleven of these used a randomised design. Studies were classified according to three outcome measures (anxiety, consent rate and understanding). The results of the various studies suggest that giving people more information and more time to reflect tends to be associated with a lower consent rate. There seems to be an optimal level of information about side-effects such that patients are not overburdened by detail, while grasping the most important risks. More information in general is associated with greater awareness of the research nature of the trial, voluntariness of participation, right to withdraw and (available) alternative treatments. This result does not, however, extend to explanations of the concept of randomisation on which the literature is contradictory--sometimes more information is associated with increased understanding of the concept and sometimes it is not. Although divulging less information seems to be associated with less anxiety, there is evidence of an interaction with knowledge--high levels of knowledge are significantly associated with less anxiety, irrespective of consent method. The more that patients know before they are invited to participate in a trial, the better equipped they are to cope with the informed consent procedure. There is some evidence to suggest that there is an optimal amount of information which enhances patient understanding and which might, in turn, reduce anxiety. However. the studies were not altogether conclusive. More work needs to be carried out, especially on public understanding of science and on how different ways of explaining scientific concepts affect that understanding.


Correction of aortic coarctation in neonates: mortality and late results.
To determine those factors that affect mortality and to analyze long-term results, the records of 44 infants who underwent repair of aortic coarctation at less than 90 days of age were examined. There were 14 operative and 8 late deathes (mean, 4.3 months postoperatively). Subsequent operation, generally to repair or palliate associated anomalies, was required 22 times in 20 patients and was a source of considerable mortality. There is evidence that earlier total repair of associated anomalies might improve survival. Sufficient data were available on 17 of the 22 survivors to assess long-term results. The outcome was considered excellent in 8 patients, fair in 4, and poor in 5. Revision of the coarctation repair due to growth failure of the anastomosis was required in 1 patient. Aggressive surgical management is recommended in these infants because, despite a high early mortality, a considerable proportion of excellent results can be anticipated in what is otherwise a hopeless situation.


Update on the pathological roles of prostaglandin E2 in neurodegeneration in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons. The pathogenesis of ALS remains largely unknown; however, inflammation of the spinal cord is a focus of ALS research and an important pathogenic process in ALS. Prostaglandin E2 (PGE2) is a major lipid mediator generated by the arachidonic-acid cascade and is abundant at inflammatory sites. PGE2 levels are increased in the postmortem spinal cords of ALS patients and in ALS model mice. Beneficial therapeutic effects have been obtained in ALS model mice using cyclooxygenase-2 inhibitors to inhibit the biosynthesis of PGE2, but the usefulness of this inhibitor has not yet been proven in clinical trials. In this review, we present current evidence on the involvement of PGE2 in the progression of ALS and discuss the potential of microsomal prostaglandin E synthase (mPGES) and the prostaglandin receptor E-prostanoid (EP) 2 as therapeutic targets for ALS. Signaling pathways involving prostaglandin receptors mediate toxic effects in the central nervous system. In some situations, however, the receptors mediate neuroprotective effects. Our recent studies demonstrated that levels of mPGES-1, which catalyzes the final step of PGE2 biosynthesis, are increased at the early-symptomatic stage in the spinal cords of transgenic ALS model mice carrying the G93A variant of superoxide dismutase-1. In addition, in an experimental motor-neuron model used in studies of ALS, PGE2 induces the production of reactive oxygen species and subsequent caspase-3-dependent cytotoxicity through activation of the EP2 receptor. Moreover, this PGE2-induced EP2 up-regulation in motor neurons plays a role in the death of motor neurons in ALS model mice. Further understanding of the pathophysiological role of PGE2 in neurodegeneration may provide new insights to guide the development of novel therapies for ALS.


Real-time three-dimensional echocardiography: segmental analysis of the right ventricle in patients with repaired tetralogy of fallot.
The accurate assessment of right ventricular (RV) function and dimensions has important prognostic implications in patients with repaired tetralogy of Fallot (ToF). Three-dimensional imaging is the preferred methodology to evaluate RV function. Novel postprocessing software applications to evaluate three-dimensional data have provided insight into RV function and dimensions by analyzing the various RV components (inlet, apical trabecular, outlet). The aim of this study was to characterize regional RV function and dimensions with real-time three-dimensional echocardiography (RT3DE) in patients with repaired ToF. Forty-one patients with repaired ToF (age range, 8-18 years) and 20 control subjects were enrolled. Global and segmental RV volumes and ejection fraction (EF) were assessed with RT3DE and compared between patients with repaired ToF and controls. Segmental analysis on RT3DE demonstrated that the apical trabecular region was the most remodeled RV component in patients with repaired ToF, with significantly increased end-diastolic volume and end-systolic volume compared with controls (59 ± 19 vs 41 ± 16 mL and 36 ± 13 vs 24 ± 8 mL, respectively; P = .001 for both). However, EF was preserved at that region. In contrast, EF was reduced at the RV inlet (53 ± 6% vs 58 ± 7%, P = .003) and outlet (44 ± 16% vs 52 ± 10% (P = .032). Patients with repaired ToF show characteristic RV remodeling as assessed with RT3DE. At the apical trabecular region, the largest volumes were observed compared with control patients, whereas EF at the inlet and outlet components was significantly impaired. RT3DE may facilitate future studies of segmental RV volumes and function in patients with repaired ToF.


Analysis of mutations in the E6 oncogene of human papillomavirus 16 in cervical cancer isolates from Moroccan women.
Worldwide, cervical cancer is the second most common cancer in women. High-risk human papillomavirus (HPV) play a crucial role in the etiology of cervical cancer and the most prevalent genotype is HPV16. HPV 16 intratypic variants have been reported to differ in their prevalence, biological and biochemical properties. The present study was designed to analyze and identify HPV type 16 E6 variants among patients with cervical cancer in Morocco. A total of 103 HPV16 positive samples were isolated from 129 cervical cancer cases, and variant status was subsequently determined by DNA sequencing of the E6 gene. Isolates from patients were grouped into the European (E), African (Af) and North-American (NA1) phylogenetic clusters with a high prevalence of E lineage (58.3%). The Af and NA1 variants were detected in 31.1% and 11.6% of the HPV16 positive specimens, respectively, whereas, only 3% of cases were prototype E350T. No European-Asian (EA), Asian (As) or Asian-American (AA) variants were observed in our HPV16-positive specimens. At the amino acid level, the most prevalent non-synonymous variants were L83V (T350G), H78Y (C335T), E113D (A442C), Q14D (C143G/G145T) and R10I (G132T), and were observed respectively in 65%, 41.8%, 38.8%, 30.1% and 23.3% of total samples.Moreover, HPV16 European variants were mostly identified in younger women at early clinical diagnosis stages. Whereas, HPV16 Af variants were most likely associated with cervical cancer development in older women with pronounced aggressiveness. This study suggests a predominance of E lineage strains among Moroccan HPV 16 isolates and raises the possibility that HPV16 variants have a preferential role in progression to malignancy and could be associated with the more aggressive nature of cervical cancer.


Low calcium reperfusion of ischemic myocardium.
The mechanisms underlying protection of ischemic myocardium by reperfusion with solutions containing reduced concentrations of calcium (CA) were studied in isolated vascularly perfused rabbit interventricular septa at 37 degrees C. After 45 min of total ischemia adenosine triphosphate (ATP), and phosphocreatine (PC) contents fell to 6.8 +/- 0.82, and 12.4 +/- 2.0 micrometer/g dry tissue (dt) (+/- S.E.M.). After 5 min of reperfusion with 0.75 mM Ca these values had recovered significantly to 10.3 +/- 1.0, and 33.3 +/- 3.6, (micrometer/g dt), while reperfusion with 2.5 mM Ca produced 5.9 +/- 1.0 and 22.0 +/- 2.6 (micrometer/g dt). The significantly greater recovery of ATP and PC after 0.75 mM Ca reperfusion persisted after an additional 25 min of reperfusion with 2.5 mM Ca when compared to septa reperfused for the entire 30 min with 2.5 mM Ca. When mechanical work was reduced by cessation of stimulation during the first 5 min of reperfusion, ATP, PC and total creatine (TC) recovery were significantly improved in muscles exposed to 2.5 mM Ca but showed no additional improvement in muscles reperfused with 0.75 mM Ca. A further reduction to 100 micrometers Ca reperfusion in quiescent muscles did significantly improve ATP, PC and TC recovery. Quiescence achieved with 16.0 mM K impaired ATP, PC and TC recovery. This effect was reversed by 100 micrometers CA reperfusion. Measurements of mitochondrial oxygen consumption, respiratory control and ADP/O showed results parallel to the ATP, PC and TC determinations. Both mechanical work and CA itself influence mitochondrial respiration, ATP, PC and TC content after ischemia. As previously demonstrated for mechanical function, metabolic recovery can be improved by interventions limited to the first 5 min of reperfusion.


Opium consumption and pancreatic cancer: A meta-analysis.
Pancreatic cancer represents a serious public health problem worldwide. Due to its high mortality, efforts on identifying risk factors are very important since only a few risk-related factors have been well established. The present study aimed to address this knowledge gap by estimating the risk of pancreatic cancer associated with opium use. We performed a thorough literature search of PubMed, Web of Science and Scopus, which yielded 3 case-control and 1 cohort study which were included in the analysis. A meta-analysis was conducted using the DerSimonian and Laird inverse-variance approach as the random effects method. The pooled risk ratio for pancreatic cancer in opium users was significantly increased (RR=1.98, 95 % CI 1.33-2.96, p = 0.0008) compared to never users. Subgroup analyses identified a significantly increased risk for pancreatic cancer in men (RR=1.74, 95 % CI 1.22-2.47, p = 0.002), in persons who consumed both raw teriak and refined shireh opium (RR=4.21, 95 % 1.27-13.93, p = 0.02) and in persons who smoked opium (RR=4.21, 95 % 1.27-13.93, p = 0.02). The findings of this study will help in efforts aimed at prevention of pancreatic cancer. Still, further epidemiological research is necessary.


Pharmacotherapy for Treatment-Resistant Depression: Antidepressants and Atypical Antipsychotics.
Treatment-resistant depression (TRD) affects one in three patients with major depressive disorder and is associated with increased risk of all-cause mortality. Studies of real-world practices suggest that antidepressant monotherapy continues to be the most widely used treatment after inadequate response to a first-line treatment. However, rates of remission with antidepressants in TRD are suboptimal. Atypical antipsychotics are the most widely studied augmentation agent and aripiprazole, brexpiprazole, cariprazine, quetiapine extended-release, and olanzapine-fluoxetine combination are approved for depression. Benefits of using atypical antipsychotics for TRD has to be weighted against their potential adverse events, such as weight gain, akathisia, and tardive dyskinesia.


An investigation of withdrawal symptoms shown by opiate addicts during and subsequent to a 21-day in-patient methadone detoxification procedure.
Methadone detoxification procedures are widely accepted as a satisfactory way of withdrawing opiate addicts from drugs. There have, however, been comparatively few empirical studies which have examined the development and course of withdrawal symptoms in opiate addicts in response to such detoxification procedures. This study investigates the opiate withdrawal syndrome in a group of 116 opiate addicts during and subsequent to a gradual oral methadone detoxification programme. Withdrawal symptoms peak at the end of the methadone schedule and decline steadily thereafter. Not until 40 days after the beginning of the withdrawal regime have symptom levels returned to normal. It is suggested that this protracted withdrawal response is not entirely satisfactory and alternative clinical and research options are proposed. The results fail to support the accepted view that dose is a major determinant of withdrawal severity. Low dose users did not experience less severe withdrawal symptoms than high dose users. This finding together with those of a previous study suggest that this issue also warrants further research attention.


A shared genetic architecture between adhesive capsulitis and Dupuytren disease.
The etiology of adhesive capsulitis involves inflammation, thickening, and fibrosis of the shoulder capsule. The underlying genetic factors are poorly understood. The purpose of this study was to identify genetic variants associated with adhesive capsulitis using the UK Biobank (UKB) cohort and compare them with variants associated with Dupuytren disease investigating a common etiology between the 2 fibrotic disorders. A genome-wide association study (GWAS) was performed using data from UKB with 10,773 cases of adhesive capsulitis, and a second GWAS was performed with 8891 cases of Dupuytren disease. Next, a comparison of association statistics was performed between adhesive capsulitis and Dupuytren disease using the data from both GWAS. Finally, single-nucleotide polymorphisms (SNPs) previously reported from candidate gene studies for adhesive capsulitis and Dupuytren disease were tested for association with adhesive capsulitis and Dupuytren disease using the summary statistics from their respective GWAS. The UKB GWAS for adhesive capsulitis identified 6 loci that reached genome-wide statistical significance: a cluster of 11 closely linked SNPs on chromosome 1; a single SNP on chromosome 2; a single SNP on chromosome 14; 2 closely linked SNPs on chromosome 21; 33 closely linked SNPs on chromosome 22; and 3 closely linked SNPs on the X chromosome. These SNPs were associated with 8 different genes including TSPAN2/NGF, SATB2, MRPL52/MMP14, ERG, WNT7B, and FGF13. A GWAS for Dupuytren disease was performed and a comparison to the adhesive capsulitis GWAS showed 13 loci significantly associated with both phenotypes. A validation attempt of 6 previously reported SNPs associated with adhesive capsulitis using UKB summary statistics was unable to confirm any of the previously reported SNPs (all P > .19). All 23 previously reported SNPs associated with Dupuytren disease were confirmed using the UKB summary statistics (P < 2.1 × 10-3) CONCLUSION: This GWAS investigating adhesive capsulitis has identified 6 novel loci involving 8 different genes to be associated with adhesive capsulitis. A GWAS investigating Dupuytren disease was performed and compared to the adhesive capsulitis GWAS, and 13 common loci were identified between the 2 disorders with genes involved in pathologic fibrosis. We were unable to validate the SNPs in candidate genes previously reported to be associated with adhesive capsulitis although we were able to confirm all previously reported SNPs associated with Dupuytren disease. The strong genetic overlap between the adhesive capsulitis and Dupuytren disease loci suggests a similar etiology between the 2 diseases.


Kinking of the internal carotid artery. Clinical significance and surgical management.
Observations of a series of fifteen surgically treated coiled and kinked internal carotid arteries are reported. The kinked internal carotid artery may be clinically significant and can cause cerebral infarction, even in the absence of atherosclerosis. Each patient must be thoroughly investigated and evaluated individually. One must distinguish simple tortuosity without blood flow obstruction from critical kinking of the internal carotid artery. If a patient with angiographic confirmation is symptomatic and other causes are eliminated, surgical correction should be carefully considered, especially if rotational cerebral ischemia is present. The surgical treatment of choice is resection of the redundant internal carotid artery with reimplantation and thromboendarterectomy of any associated plaque. Kinking of the internal carotid artery may lead to aneurysm formation requiring a difficult surgical resection. Although the evidence for a precise causal relationship between kinking of the internal carotid artery and cerebrovascular symptoms is sometimes difficult to establish, it is our belief that a more aggressive surgical approach may be warranted in this potentially disabling and even fatal condition.


Results of combined phacoemulsification and viscocanalostomy in patients with cataract and pseudoexfoliative glaucoma.
Coexisting pseudoexfoliation glaucoma (PEXG) and cataract represents a special challenge. Although phacotrabeculectomy is an effective procedure, it combines the risks of phacoemulsification and trabeculectomy. This study evaluates phacoviscocanalostomy to manage eyes with PEXG and cataract. We conducted a prospective noncomparative study that included 30 consecutive eyes of 22 patients with uncontrolled PEXG and cataract. Phacoviscocanalostomy was performed in all. Success rate based on postoperative intraocular pressure (IOP) reduction and requirement for topical antiglaucoma medication was evaluated as the main outcome measure. Visual acuity and complication rates were secondary outcomes. The mean follow-up was 18.6 months +/-6.2 (SD) (range 12 to 36 months). There was statistically significant decrease in mean IOP from 25.3+/-5.2 mmHg preoperatively to 13.5+/-6.0 mmHg 1 day after surgery (p< .05), 12.3+/-3.1 mmHg at the final follow-up (p< .05), and at all evaluations to the last postoperative visit. Only three eyes (10%) required a single antiglaucoma medication to achieve the target IOP. A complete surgical success (IOP <21 mmHg without medication) was achieved in 90%, while a qualified success (IOP <21 mmHg with or without glaucoma medication) was achieved in 100% of cases. Complications included Descemet membrane microperforations (13.3%), macroperforation (3.3%), zonular dehiscence (6.6%), and transient postoperative IOP spike (3.3%). Phacoviscocanalostomy achieved excellent IOP control and visual acuity improvement in pseudoexfoliation patients with coexisting cataract and glaucoma. Complication rate was low and did not affect the surgical outcome.


A glucuronated flavone TMMG spatially targets chondrocytes to alleviate cartilage degeneration through negative regulation of IL-1β.
Chondrocytes are the only resident cell types that form the extracellular matrix of cartilage. Inflammation alters the anabolic and catabolic regulation of chondrocytes, resulting in the progression of osteoarthritis (OA). The potential of TMMG, a glucuronated flavone, was explored against the pathophysiology of OA in both in vitro and in vivo models. The effects of TMMG were evaluated on chondrocytes and the ATDC5 cell line treated with IL-1β in an established in vitro inflammatory OA model. An anterior cruciate ligament transection (ACLT) model was used to simulate post-traumatic injury in vivo. Micro-CT and histological examination were employed to examine the micro-architectural status and cartilage alteration. Further, serum biomarkers were measured using ELISA to assess OA progression. In-vitro, TMMG reduced excessive ROS generation and inhibited pro-inflammatory IL-1β secretion by mouse chondrocytes and macrophages, which contributes to OA progression. This expression pattern closely mirrored osteoclastogenesis prevention. In-vivo results show that TMMG prevented chondrocyte apoptosis and degradation of articular cartilage thickness, subchondral parameters, and elevated serum COMP, CTX-II, and IL-1β which were significantly restored in 5 and 10 mg.kg-1day-1 treated animals and comparable to the positive control Indomethacin. In addition, TMMG also improved cartilage integrity and decreased the OARSI score by maintaining chondrocyte numbers and delaying ECM degradation. These findings suggest that TMMG may be a prospective disease-modifying agent that can mitigate OA progression.


High circulating microRNA-122 expression is a poor prognostic marker in patients with hepatitis B virus-related hepatocellular carcinoma who undergo radiofrequency ablation.
Aim of this study was to investigate the prognostic potential of plasma microRNA-122 levels in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma after hepatic resection or radiofrequency ablation (RFA). A total of 120 patients with HBV-related hepatocellular carcinoma who underwent hepatic resection (n=63) or RFA (n=57) were included. The pretreatment plasma microRNA-122 level was assessed using quantitative real time polymerase chain reaction, and the correlation between microRNA-122 expression and various clinical parameters was investigated. Multivariate Cox regression analysis demonstrated that, in all patients, a low platelet count (<100×10(9)/L), low albumin level (≤3.5g/dL.), and advanced tumor stage (modified Union for International Cancer Control stage III/IV) were independent prognostic factors for disease-free survival, while a low albumin level and advanced tumor stage were independent prognostic factors for overall survival (OS). In a subgroup analysis of patients who underwent RFA, the patients with high miR-122 expression (>100) had significantly lower OS on Kaplan-Meier analysis (P=0.042). Furthermore, high microRNA-122 expression (hazard ratio [HR]=2.67; 95% confidence interval [CI]=1.12-6.35; P=0.026) and advanced tumor stage (HR=2.27; 95% CI=1.23-4.18; P=0.009) were independent risk factors for poor OS in patients treated with RFA. The combination of microRNA-122 and tumor stage resulted in an area under the curve of 0.818 for predicting 1-year OS in patients who underwent RFA. High plasma microRNA-122 expression was associated with poor OS in patients with HBV-related hepatocellular carcinoma who underwent RFA.


Two interchangeable forms of ciguatoxin.
Ciguatoxin, the principal toxin responsible for ciguatera, isolated from moray eel viscera, has been separated into two distinct components by alumina chromatography. A series of chromatographies showed that the two components are interchangeable. This proves that ciguatoxin is a single molecular entity. Both forms were crystallized and their 1H NMR spectra were recorded.


Quality of life in families of children with congenital heart disease.
Within a family perspective on quality of life (QL) with congenital heart disease, the study investigates parental QL, and patients' health-related QL as reported by themselves and by their parents. We examined the hypotheses that parental QL moderates the parental proxy reports. Sixty-nine patients (7-20 years, 61% male) and their caregivers participated in a computer-assisted QL-assessment. Children's self-rated and proxy-rated QL correlated moderately, with the highest intra-class correlation on the subscale psychological well-being/functioning (r = 0.61; p < 0.001), less convergence in physical well-being/functioning (r = 0.49; p < 0.001) and absent correlation in the evaluation of intra-family relationships. Parental QL was correlated both with the children's self-rated QL (r = 0.42; p < 0.05) and children's parent-rated QL (r = 0.60; p < 0.001). Support for the moderator hypotheses is indicated by the results of regression analyses demonstrating a significant interaction effect of parental QL and patients' self-reported QL in predicting parental proxy reports on their children's QL. Post-hoc tests reveal that parents with low own QL agree significantly more with their children than parents with high QL. Parent-child agreement on the children's QL is limited and reflects complementary subjective viewpoints. Psychosocial interventions should be family-focused and provide support for patients' and their caregivers' QL.


Cortical representations of pitch in monkeys and humans.
Pitch perception is crucial for vocal communication, music perception, and auditory object processing in a complex acoustic environment. How pitch is represented in the cerebral cortex has for a long time remained an unanswered question in auditory neuroscience. Several lines of evidence now point to a distinct non-primary region of auditory cortex in primates that contains a cortical representation of pitch.


Diagnostic value of circulating genetically abnormal cells to support computed tomography for benign and malignant pulmonary nodules.
The accuracy of CT and tumour markers in screening lung cancer needs to be improved. Computer-aided diagnosis has been reported to effectively improve the diagnostic accuracy of imaging data, and recent studies have shown that circulating genetically abnormal cell (CAC) has the potential to become a novel marker of lung cancer. The purpose of this research is explore new ways of lung cancer screening. From May 2020 to April 2021, patients with pulmonary nodules who had received CAC examination within one week before surgery or biopsy at First Affiliated Hospital of Zhengzhou University were enrolled. CAC counts, CT scan images, serum tumour marker (CEA, CYFRA21-1, NSE) levels and demographic characteristics of the patients were collected for analysis. CT were uploaded to the Pulmonary Nodules Artificial Intelligence Diagnostic System (PNAIDS) to assess the malignancy probability of nodules. We compared diagnosis based on PNAIDS, CAC, Mayo Clinic Model, tumour markers alone and their combination. The combination models were built through logistic regression, and was compared through the area under (AUC) the ROC curve. A total of 93 of 111 patients were included. The AUC of PNAIDS was 0.696, which increased to 0.847 when combined with CAC. The sensitivity (SE), specificity (SP), and positive (PPV) and negative (NPV) predictive values of the combined model were 61.0%, 94.1%, 94.7% and 58.2%, respectively. In addition, we evaluated the diagnostic value of CAC, which showed an AUC of 0.779, an SE of 76.3%, an SP of 64.7%, a PPV of 78.9%, and an NPV of 61.1%, higher than those of any single serum tumour marker and Mayo Clinic Model. The combination of PNAIDS and CAC exhibited significantly higher AUC values than the PNAIDS (P = 0.009) or the CAC (P = 0.047) indicator alone. However, including additional tumour markers did not significantly alter the performance of CAC and PNAIDS. CAC had a higher diagnostic value than traditional tumour markers in early-stage lung cancer and a supportive value for PNAIDS in the diagnosis of cancer based on lung nodules. The results of this study offer a new mode of screening for early-stage lung cancer using lung nodules.


Diagnosis of carcinoma of the breast by fine needle aspiration cytology.
During a six year period, 1,953 fine needle aspiration cytologies (FNAC) were performed for lumps of the breast. Of these, 355 were diagnosed as carcinoma of the breast. The FNAC was performed on an outpatient basis and the pathologic interpretation was available within 30 to 60 minutes. The treatment strategy was always guided by the clinical impression of the physician. If the results of a suspected mass were negative on FNAC, biopsy was performed and histologic study gave the final diagnosis. There were no false-positive results and only 6 per cent were false-negative findings diagnosed later by open biopsy. The over-all accuracy rate was 90 per cent plus 4 per cent diagnosed on cytologic examination as "suspicious" and which proved to be malignant. Based upon our accumulated results, simplicity of performing the test, its low cost, the extremely low morbidity, the immediate response and, above all, an over-all high accuracy rate, we conclude that FNAC is a highly recommended method for the diagnosis of carcinoma of the breast.


White Matter Connectivity between Structures of the Basal Ganglia using 3T and 7T.
Analysis of the basal ganglia has been important in investigating the effects of Parkinson's disease as well as treatments for Parkinson's disease. One method of analysis has been using MRI for non-invasively segmenting the basal ganglia, then investigating significant parameters that involve the basal ganglia, such as fiber orientations and positional markers for deep brain stimulation (DBS). Following enhancements to optimizations and improvements to 3T and 7T MRI acquisitions, we utilized Lead-DBS on human connectome project data to automatically segment the basal ganglia of 49 human connectome project subjects, reducing the reliance on manual segmentation for more consistency. We generated probabilistic tractography streamlines between each segmentation pair using 3T and 7T human connectome diffusion data to observe any major differences in tractography streamline patterns that can arise due to tradeoffs from different field strengths and acquisitions. Tractography streamlines generated between basal ganglia structures using 3T images showed less standard deviation in streamline count than using 7T images. Mean tractography streamline counts generated using 3T diffusion images were all higher in count than streamlines generated using 7T diffusion images. We illustrate a potential method for analyzing the structural connectivity between basal ganglia structures, as well as visualize possible differences in probabilistic tractography that can arise from different acquisition protocols.


Exposure to e-cigarette information and advertising in social media and e-cigarette use in Australia: A mixed methods study.
The aim of this study was to explore how e-cigarette users in Australia accessed e-cigarette information and advertising on social media platforms. The mixed-methods study design included a survey and semi-structured interviews. Data were collected from March 2019 to July 2019 in Australia. Interviews were conducted following survey participation. Analysis of survey results examined associations between social media and advertising factors and use of e-cigarettes. Thematic analysis methods were applied to interview responses to explore e-cigarette information search and advertising exposure in different social media channels. The survey had 185 respondents and 14 participated in the interviews. The average social media use time was 11.4 h/week (SD ± 2.05). A total of 91 (49.2 %) participants sought out relevant information and 104 (56.2 %) were exposed to e-cigarette advertisements on social media platforms. Participants who searched for e-cigarette information on social media were more likely to report past (OR = 5.04; 95 % CI 2.23-11.42; p = 0.001) or current e-cigarette use (OR = 9.27; 95 % CI 4.22-20.34; p = 0.001), compared to participants who had never used e-cigarettes. The same relationship was observed for exposure to e-cigarette advertising. Thematic analysis of interviews revealed the diversity of sources of information for e-cigarettes, the pervasiveness of advertising, and the importance of peer recommendations. Australian e-cigarette users seek or are exposed to e-cigarette information on a variety of social media platforms. Access to e-cigarette information was concentrated among e-cigarette users but peer influence may be a risk for uptake among non-smokers.


Concept and application of limbal stem cells.
Cumulative reported evidence indicates that some fraction of limbal basal epithelial cells are the stem cells for corneal epithelial cell proliferation and differentiation. Limbal epithelium is therefore crucial in maintaining the cell mass of corneal epithelium under normal conditions and plays an important role in corneal epithelial wound healing. Deficiency or absence of limbal stem cells explains well the pathogenesis of several ocular surface disorders characterised by defective conjunctival transdifferentiation or conjunctivalisation of cornea. This paper reviews and updates the basic concept of stem cells, the reported findings of limbal stem cells for corneal epithelium, and their therapeutic applications. Through this review, one hopes to gain a more complete understanding and increase proficiency in treating these diseases.


No preference for direct versus averted gaze in autistic adults: a reinforced preferential looking paradigm.
With the overarching objective to gain better insights into social attention in autistic adults, the present study addresses three outstanding issues about face processing in autism. First, do autistic adults display a preference for mouths over eyes; second, do they avoid direct gaze; third, is atypical visual exploration of faces in autism mediated by gender, social anxiety or alexithymia? We used a novel reinforced preferential looking paradigm with a group of autistic adults (n = 43, 23 women) pairwise matched on age with neurotypical participants (n = 43, 21 women). Participants watched 28 different pairs of 5 s video recordings of a speaking person: the two videos, simultaneously displayed on the screen, were identical except that gaze was directed at the camera in one video and averted in the other. After a 680 ms transition phase, a short reinforcement animation appeared on the side that had displayed the direct gaze. None of the groups showed a preference for mouths over eyes. However, neurotypical participants fixated significantly more the stimuli with direct gaze, while no such preference emerged in autistic participants. As the experiment progressed, neurotypical participants also increasingly anticipated the appearance of the reinforcement, based on the location of the stimulus with the direct gaze, while no such anticipation emerged in autistic participants. Our autistic participants scored higher on the social anxiety and alexithymia questionnaires than neurotypicals. Future studies should match neurotypical and autistic participants on social anxiety and alexithymia and complement questionnaires with physiological measures of anxiety. The absence of preference for direct versus averted gaze in the autistic group is probably due to difficulties in distinguishing eye gaze direction, potentially linked to a reduced spontaneous exploration or avoidance of the eye region. Social attention and preference for direct versus averted gaze correlated with alexithymia and social anxiety scores, but not gender.


BAF57 Is a Potential Determinant of Colorectal Cancer Malignancy.
The role of brahma-related gene 1 (BRG1)-associated factor 57 (BAF57), a transcription factor, has been determined in prostate, breast, and ovarian cancer. However, the relationship between BAF57 and colorectal cancer (CRC) is obscure. Thus, we examined the functional correlation between BAF57 expression and oncological malignancy in CRC in vitro. BAF57 expression in WiDr and HT29 CRC cell lines and clinical specimens from CRC patients was analysed by western blotting and/or RT-PCR. BAF57 expression was down-regulated in WiDr cells through siRNA transfection. An invasion assay was also performed to assess malignancy. BAF57 was expressed in both human CRC cell lines. Overall survival and recurrence-free survival rates were significantly reduced in high BAF57-expressing specimens. BAF57 expression was an independent predictive factor for long-term survival. BAF57 correlates with oncological malignancy and may be a novel therapeutic target in CRC.


Fractalkine/CX3CR1 axis modulated the development of pancreatic ductal adenocarcinoma via JAK/STAT signaling pathway.
Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignancy with an estimated 5 year survival rate of approximately 5% of all stages combined. High potential of PDAC metastasis is a leading cause for high mortality and poor prognosis. The majority of patients present with distant metastasis at diagnosis. Fractalkine (FKN) is recognized as a chemokine and a specific ligand of CX3CR1. It has been reported that FKN/CX3CR1 system was upregulated in many types of solid tumors. However, role of FKN/CX3CR1 in PDAC development remains unclear. In the current investigation, we found that FKN and CX3CR1 expression was significantly increased in PDAC tissues, especially in the metastatic samples, and was highly-correlated with severity of PDAC. Ectopic expression of FKN promoted the proliferation and migration of PDAC, while knockdown of CX3CR1 reversed the function of FKN. In addition, PDAC cells with FKN-deficiency showed impaired proliferation and migration activity. The underlying mechanism is that FKN/CX3CR1 activated JAK/STAT signaling, which in turn regulated cell growth. Consistently, in vivo tumorigenesis assay validated the regulatory role of FKN/CX3CR1 in PDAC growth. Our investigation helped understanding the pathogenesis of PDAC occurrence, and demonstrated critical role of FKN/CX3CR1 in PDAC development.


Genome sequence of the plant pathogen Ralstonia solanacearum.
Ralstonia solanacearum is a devastating, soil-borne plant pathogen with a global distribution and an unusually wide host range. It is a model system for the dissection of molecular determinants governing pathogenicity. We present here the complete genome sequence and its analysis of strain GMI1000. The 5.8-megabase (Mb) genome is organized into two replicons: a 3.7-Mb chromosome and a 2.1-Mb megaplasmid. Both replicons have a mosaic structure providing evidence for the acquisition of genes through horizontal gene transfer. Regions containing genetically mobile elements associated with the percentage of G+C bias may have an important function in genome evolution. The genome encodes many proteins potentially associated with a role in pathogenicity. In particular, many putative attachment factors were identified. The complete repertoire of type III secreted effector proteins can be studied. Over 40 candidates were identified. Comparison with other genomes suggests that bacterial plant pathogens and animal pathogens harbour distinct arrays of specialized type III-dependent effectors.


Sphingosylphosphorylcholine blocks ovariectomy-induced bone loss by suppressing Ca2+ /calmodulin-mediated osteoclast differentiation.
Osteoporosis is a disease in which bone mineral density decreases due to abnormal activity of osteoclasts, and is commonly found in post-menopausal women who have decreased levels of female hormones. Sphingosylphosphorylcholine (SPC) is an important biological lipid that can be converted to sphingosine-1-phosphate (S1P) by autotaxin. S1P is known to be involved in osteoclast activation by stimulating osteoblasts, but bone regulation by SPC is not well understood. In this study, we found that SPC strongly inhibits RANKL-induced osteoclast differentiation. SPC-induced inhibitory effects on osteoclast differentiation were not affected by several antagonists of S1P receptors or pertussis toxin, suggesting cell surface receptor independency. However, SPC inhibited RANKL-induced calcineurin activation and subsequent NFATc1 activity, leading to decrease of the expression of Trap and Ctsk. Moreover, we found that bone loss in an experimental osteoporosis mouse model was recovered by SPC injection. SPC also blocked ovariectomy-induced body weight increase and Nfatc1 gene expression in mice. We also found that SPC inhibits RANKL-induced osteoclast differentiation in human macrophages. Since currently available treatments for osteoporosis, such as administration of female hormones or hormone receptor modulators, show serious side effects, SPC has potential as a new agent for osteoporosis treatment.


Is the lobster cockroach Nauphoeta cinerea a valuable model for evaluating mercury induced oxidative stress?
Organic and inorganic forms of mercury are highly neurotoxic environmental contaminants. The exact mechanisms involved in mercury neurotoxicity are still unclear. Oxidative stress appears to play central role in this process. In this study, we aimed to validate an insect-based model for the investigation of oxidative stress during mercury poisoning of lobster cockroach Nauphoeta cinerea. The advantages of using insects in basic toxicological studies include the easier handling, rapid proliferation/growing and absence of ethical issues, comparing to rodent-based models. Insects received solutions of HgCl2 (10, 20 and 40mgL(-1) in drinking water) for 7d. 24h after mercury exposure, animals were euthanized and head tissue samples were prepared for oxidative stress related biochemical determinations. Mercury exposure caused a concentration dependent decrease in survival rate. Cholinesterase activity was unchanged. Catalase activity was substantially impaired after mercury treatment 40mgL(-1). Likewise, GST had a significant decrease, comparing to control. Peroxidase and thioredoxin reductase activity was inhibited at concentrations of 20mgL(-1) and 40mgL(-1) comparing to control. These results were accompanied by decreased GSH levels and increased hydroperoxide and TBARS formation. In conclusion, our results show that mercuric compounds are able to induce oxidative stress signs in insect by modulating survival rate as well as inducing impairments on important antioxidant systems. In addition, our data demonstrates for the first time that Nauphoeta cinerea represents an interesting animal model to investigate mercury toxicity and indicates that the GSH and thioredoxin antioxidant systems plays central role in Hg induced toxicity in insects.


Deletion 2q: two new cases with karyotypes 46,XY,del(2)(q31q33) and 46,XX,del(2)(q36).
We describe the clinical and cytogenetic findings of two patients with deletions of the long arm of chromosome 2. One has an interstitial deletion identical to that found in a previously reported patient, although they are phenotypically dissimilar. The other patient has a terminal deletion, the first such deletion reported to date.


Transrectal ultrasound urodynamics.
Seventy-seven male patients (34 with cervical spine injury, 32 with thoracic spine injury, 9 with lumbosacral spine injury, and 2 with multiple sclerosis) who were referred to our spinal cord injury unit for urologic evaluation had videourodynamic studies using transrectal ultrasound and fluoroscopy. All were studied twice in the same session: first with transrectal ultrasound urodynamics (TRUSU) and the second time with conventional fluoroscopic videourodynamics (VUD). The findings were compared. Efficacy of TRUSU: (1) clearly documented flow of fluid through bladder neck into posterior urethra before clinical leakage occurred per urethra; (2) allowed accurate placement of EMG needle electrodes in external urinary sphincter under visual guidance; (3) provided high-quality imaging of surrounding structures and allowed assessment of bladder neck, prostate, seminal vesicles, and posterior urethra; (4) eliminated radiation exposure to the patient and the examiner, with no time limit imposed on imaging so that repeat studies could be done to evaluate patients on new drug treatments or postoperatively at no increased risks; and (5) its availability to most urologists at their office at considerably less cost to set up than fluoroscopy. In our study TRUSU identified a hypoechoic lesion in the prostate of 1 patient and a tumor in the bladder neck of another patient. Fluoroscopic VUD identified 6 patients with bladder diverticula and 2 with grades 1 and 2 vesicoureteral reflux which TRUSU did not identify. Our experience indicates TRUSU is a valid and preferable alternative to fluoroscopic VUD for patients with spinal cord injury.


Disseminated histoplasmosis presenting as dental lesion in the absence of a vital organ, the thymus.
We present a case report of a patient who has rare anatomical anomalies and presented with an oral lesion that led to a diagnosis of disseminated histoplasmosis. The case brings forth important clinical considerations for a diagnosis of histoplasmosis.


Reasoning about 'irrational' actions: when intentional movements cannot be explained, the movements themselves are seen as the goal.
Infants and adults are thought to infer the goals of observed actions by calculating the actions' efficiency as a means to particular external effects, like reaching an object or location. However, many intentional actions lack an external effect or external goal (e.g. dance). We show that for these actions, adults infer that the agents' goal is to produce the movements themselves: Movements are seen as the intended outcome, not just a means to an end. We test what drives observers to infer such movement-based goals, hypothesizing that observers infer movement-based goals to explain actions that are clearly intentional, but are not an efficient means to any plausible external goal. In three experiments, we separately manipulate intentionality and efficiency, equating for movement trajectory, perceptual features, and external effects. We find that participants only infer movement-based goals when the actions are intentional and are not an efficient means to external goals. Thus, participants appear to infer that movements are the goal in order to explain otherwise mysterious intentional actions. These findings expand models of goal inference to account for intentional yet 'irrational' actions, and suggest a novel explanation for overimitation as emulation of movement-based goals.


Response of blood flow to warm and cold in normal and low-tension glaucoma patients.
We measured blood flow in the finger in 38 control subjects with normal ocular findings without migraine, 13 control subjects with normal ocular findings with classic migraine, 17 patients with low-tension glaucoma with classic migraine, and 29 patients with low-tension glaucoma without migraine. Three blood flow measurements were recorded: one at baseline, one after immersion in warm water (40 C), and one after ten seconds' exposure to cold water (4 C). The mean baseline flow and the mean flow after exposure to cold was lower in patients with low-tension glaucoma (P = .013 and P less than .001, respectively).


Soluble interleukin-2 receptor and soluble CD8 in serum and cerebrospinal fluid during human immunodeficiency virus-associated neurologic disease.
We have measured levels of soluble interleukin-2 receptor (sIL-2R) and soluble CD8 (sCD8) in serum and cerebrospinal fluid (CSF) of 127 human immunodeficiency virus (HIV)-seropositive and 51 HIV-seronegative individuals. Serum levels of sIL-2R and sCD8 were higher in HIV+ than in HIV- individuals. HIV+ individuals were grouped by neurological status: asymptomatic, abnormal on neuropsychological screening, HIV-related meningitis, inflammatory demyelinating polyneuropathy, opportunistic central nervous system (CNS) infections and HIV-related dementia, myelopathy or sensory neuropathy. Serum levels of sIL-2R and sCD8 were higher in all HIV+ categories compared to HIV- individuals. Patients with HIV-related meningitis had higher levels of sIL-2R and sCD8 than asymptomatic HIV+ individuals, and inflammatory polyneuropathy patients had higher levels of sCD8. CSF levels of sCD8 were higher in all categories of HIV+ than in HIV- individuals. Patients with HIV-related meningitis, inflammatory neuropathy and opportunistic infections had higher levels than asymptomatic individuals. Examination of the time course showed that serum and CSF levels of sIL-2R and sCD8 increased to very high levels during acute HIV infections. Serum levels then declined over several months to relatively stable elevated levels. By 1-2 years after HIV infection sIL-2R was relatively low in CSF, while sCD8 remained elevated with a gradual decrease over the subsequent years of follow-up.


Influence of fed-fasted state on intestinal PEPT1 expression and in vivo pharmacokinetics of glycylsarcosine in wild-type and Pept1 knockout mice.
To determine if fasting would affect the intestinal expression and in vivo functional activity of PEPT1 as determined after oral dosing of the dipeptide glycylsarcosine (GlySar). Systemic exposure and tissue distribution studies were performed in wild-type and Pept1 knockout mice, under fed and fasted conditions, following both intravenous and oral doses of [(14)C]GlySar at 5 nmol/g body weight. Intestinal PEPT1 expression was evaluated by real-time PCR and immunoblot analyses. We found that expression of PEPT1 protein in the small intestine was increased ~2-fold in wild-type mice during fasted as compared to fed conditions. In agreement, systemic exposure and peak plasma concentrations of orally administered GlySar were 40 and 65% greater, respectively, in wild-type mice during fasted vs. fed state. No significant differences were observed between fed and fasted animals during PEPT1 ablation. Tissue distribution of GlySar was unchanged after oral dosing for all four treatment groups. As little as 16 h of fasting can cause significant upregulation of PEPT1 protein expression in the small intestine, which then translates into a significant increase in in vivo oral absorption of GlySar.


Adenosine induces airway hyperresponsiveness through activation of A3 receptors on mast cells.
The mechanisms responsible for the development of airway hyperresponsiveness in asthma are poorly understood. Adenosine levels are high in the lungs of patients with asthma, but a role for adenosine in the development of this cardinal feature of asthma has not been previously reported. To determine the capacity of adenosine to induce airway hyperresponsiveness, and to investigate the mechanisms behind these effects of adenosine on airway physiology. Wild-type C57BL/6 mice were exposed to aerosolized adenosine analog adenosine-5' N-ethylcarboxamide (NECA), and subsequent hyperresponsiveness to methacholine was investigated by measuring airway mechanics after anesthesia and tracheostomy. Similar experiments were conducted with A(1)-deficient, A(3)-deficient, and mast cell-deficient mice, as well as with mast cell-deficient mice engrafted with wild-type (wt) or A(3)(-/-) mast cells. The effect of NECA on methacholine-induced tension development in ex vivo tracheal rings was also examined. Exposure of wt mice to NECA resulted in the robust induction of airway hyperresponsiveness. NECA failed to induce hyperresponsiveness to methacholine in tracheal ring preps ex vivo, and NECA-induced airway hyperresponsiveness in vivo was not affected by the genetic inactivation of the A(1) adenosine receptor. In contrast, NECA-induced airway hyperresponsiveness was abolished in A(3) adenosine receptor-deficient mice and in mice deficient in mast cells. Reconstitution of mast cell-deficient mice with wt mast cells restored hyperresponsiveness, whereas reconstitution with A(3) receptor-deficient mast cells did not. Adenosine induces airway hyperresponsiveness indirectly by activating A(3) receptors on mast cells.


Accurate prediction of hypoxic-ischaemic encephalopathy at delivery: a cohort study.
Hypoxic-ischaemic encephalopathy (HIE) is a major acute neurologic manifestation of perinatal asphyxia associated with significant mortality and morbidity. The study aimed to develop a simple, accurate method of predicting HIE at delivery. Between January 2003 and December 2009, all HIE cases were identified from the 38,404 deliveries at a single tertiary centre. Receiver operating curve (ROC) analysis and multivariate logistic regression assessed the ability of clinical and biochemical assessments to predict HIE. Sixty neonates met the HIE criteria: 39 were moderate-severe HIE. Univariate analyses identified clinical neonatal markers (Apgar scores and neonatal resuscitation level) to be better HIE predictors than biochemical markers (umbilical artery pH, base excess and lactate values). Multivariable models using two to four predictors had areas under ROC curves up to 0.98, sensitivities up to 93% and specificities up to 99%. For moderate-severe HIE, the most effective predictor was neonatal resuscitation level and arterial lactate (ROC 0.98, sensitivity 85%, specificity 99%). The combination of umbilical arterial lactate and neonatal resuscitation level provides a rapid and accurate method of predicting moderate-severe HIE that can identify neonates at birth that may benefit from tertiary care and neuroprotective therapies.


Hemostasis by means of a cautery knife equipped with an air spray for burns over a large area.
In operations in which debridement is performed over a large area (e.g., surgery for whole-body burns), it is necessary to keep the length of the operation short and the amount of blood loss as small as possible to minimize stress to the patient's body. In this study, we developed a cautery knife to which an air spray is attached for surgical procedures in which debridement is performed as treatment for burns over a large area. We have demonstrated herein that this device is very effective for reducing both blood loss and the duration of surgery as well as for simplifying the achievement of hemostasis.


Opioid and benzodiazepine use in the emergency department and the recognition of delirium within the first 24 hours of hospitalization.
Delirium is a common and serious brain dysfunction. The objective of our study was to test the hypothesis that opioids and benzodiazepines exposure in the emergency department (ED) is associated with delirium. This was a retrospective cohort study, including patients aged 65 years and older who were hospitalized from ED at an academic medical center from 2014 to 2017. Medication administration records were used to identify opioids and benzodiazepines given during the ED stay. Nurses used the Delirium Observation Screening Scale (DOSS) twice daily to assess delirium during hospitalization. The outcome was a positive DOSS within 1 day of ED encounter. We used logistic regression to predict the outcome of positive delirium screening by opioids and benzodiazepines. A total of 7927 ED encounters that resulted in hospitalization were included in the analysis. We identified 2008 visits (25.3%) with a positive delirium screen. A total of 3304 (41.7%) received opioids, and 1801 (22.7%) received benzodiazepines. In this cohort, opioids were not associated with an increased odds of delirium (OR 1.00, 95% CI 0.87-1.15). Benzodiazepines were associated with increased odds of delirium (OR 1.37, 95% CI 1.13-1.65), as were benzodiazepines combined with opioids (OR 1.61, 95% CI 1.33-1.97). In this study, the use of benzodiazepines was associated with a risk of delirium. The use of opioids did not increase the risk of delirium. Our findings imply that judicious pain management with opioids in the ED might not increase the risk of delirium.


The principles and best practice of question writing for postgraduate examinations.
Postgraduate medical education has changed enormously in the last 10 years presenting huge logistical challenges for local, regional and national organisations. Assessment is under change in line with major revisions of postgraduate curricula. Old methods of assessment are changing to newer evidence-based methods supported by ongoing research into good practice. This review examines the purpose and practical considerations of written assessment, the pros and cons of different assessment methods and how good practice can be evaluated and quality assured. Good quality assessment comes at a cost in terms of time and money, and organisations need to invest in their assessment strategies to ensure the highest possible standards.