Efficient knockout of phytoene desaturase gene using CRISPR/Cas9 in melon.
CRISPR/Cas9 system has been widely applied in many plant species to induce mutations in the genome for studying gene function and improving crops. However, to our knowledge, there is no report of CRISPR/Cas9-mediated genome editing in melon (Cucumis melo). In our study, phytoene desaturase gene of melon (CmPDS) was selected as target for the CRISPR/Cas9 system with two designed gRNAs, targeting exons 1 and 2. A construct (pHSE-CmPDS) carrying both gRNAs and the Cas9 protein was delivered by PEG-mediated transformation in protoplasts. Mutations were detected in protoplasts for both gRNAs. Subsequently, Agrobacterium-mediated transformation of cotyledonary explants was carried out, and fully albino and chimeric albino plants were successfully regenerated. A regeneration efficiency of 71% of transformed plants was achieved from cotyledonary explants, a 39% of genetic transformed plants were successful gene edited, and finally, a 42-45% of mutation rate was detected by Sanger analysis. In melon protoplasts and plants most mutations were substitutions (91%), followed by insertions (7%) and deletions (2%). We set up a CRISPR/Cas9-mediated genome editing protocol which is efficient and feasible in melon, generating multi-allelic mutations in both genomic target sites of the CmPDS gene showing an albino phenotype easily detectable after only few weeks after Agrobacterium-mediated transformation.


Clinical features of spinal muscular atrophy (SMA) type 2.
Infantile spinal muscular atrophy (SMA) type 2 is sometimes called intermediate SMA to indicate the disease severity. Generally, psychomotor development is normal until the age of 6 to 8 months, with the acquisition of a stable sitting position. The early signs are muscle weakness, mostly affecting the lower limbs, generalized hypotonia and areflexia. The consequences of motor neuron degeneration are functional and orthopaedic, respiratory, nutritional, socio-professional, and psychological. The implementation of standardized care (i.e., standard of care recommendations) has improved the quality of life and survival outcome of patients. The emergence of innovative therapies, some of which are now available, should further improve the clinical evolution of this disease. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.


Intracellular Ca2+ contributes to K+-induced increase in renal kallikrein secretion.
We have reported that natriuretic effects of K(+) are involved in enhancement of renal kallikrein-kinin system. The study was aimed to examine 1) comparison of augmentative effects of K(+) on urinary KK excretion with non-specific washout effects by trichlormethiazide (thiazide), polyethyleneglycol 200 (PEG) and rapid physiological saline infusion, 2) contribution of Ca(2+) on the K(+)-induced increase in renal kallikrein secretion. Renal kallikrein activities were measured as fluorescence activities of methylcoumarinylamide-labeled synthetic substrate of tissue kallikrein (TK). Increases in urinary TK excretion were simultaneously observed with diuresis caused by thiazide, PEG, and rapid saline infusion. K(+) infusion increased urinary TK excretion with a diuretic response same as the control. K(+), but not thiazide, showed an early increase in renal TK secretion dose dependently in the kidney slices. Increases in renal TK secretion persisted during treatment with K(+). Neither voltage-dependent Ca(2+)-channel blockers such as verapamil and nifedipine nor simultaneous treatment of EDTA affected on the K(+)-induced increase in renal TK secretion. While, EDTA decreased the K(+)-induced increases in renal TK secretion with time. Caffeine also had an early effect on the increase in renal TK secretion. K(+)-induced increases in renal TK secretion was demonstrated even after treatment with ryanodine or depletion of caffeine-sensitive intracellular Ca(2+) by thapsigargin. It was indicated that the increase in renal TK secretion by K(+) depends on the intracellular Ca(2+) and the caffeine-sensitive release of intracellular Ca(2+) may not be involved in this response. Mechanisms for the K(+)-induced increase in renal TK secretion needs to be further elucidated.


Cadmium sulfide quantum dots/dodecahedral polyoxometalates/oxygen-doped mesoporous graphite carbon nitride with Z-scheme and Type-II as tandem heterojunctions for boosting visible-light-driven photocatalytic performance.
It is known that fabrication of tandem heterojunctions between different types of heterojunctions can promote the charge separation. Herein, novel cadmium sulfide quantum dots (CdS QDs)/dodecahedral phosphotungstic acid potassium K3PW12O40 (KPW)/oxygen-doped mesoporous graphite carbon nitride (meso-g-C3N4) nanosheets tandem heterojunctions are prepared by the hydrothermal method combined with direct template calcination and in-situ chemical sedimentation strategy. The results show that tandem heterojunctions formed by the Z-Scheme heterojunction between CdS QDs and KPW and the type-II heterojunction between CdS QDs and meso-g-C3N4 can extend the optical response into visible light region. Importantly, under visible light irradiation, photocatalytic hydrogen production rate and photocatalytic Cr6+ removal rate over CdS/KPW/meso-g-C3N4 is higher than that of KPW and CdS/KPW. This remarkable photocatalytic performance is due to the effective charge separation and transfer of the special tandem heterojunction structure. This novel tandem heterojunction will offer new insights for fabricating other high-performance photocatalytic systems.


Management challenges arising from a traumatic 360 degree cyclodialysis cleft.
We describe the case of a 28-year-old naval officer who attended the ophthalmology service following blunt ocular trauma to the left eye. Clinical examination revealed a shallow anterior chamber, hypotony, and a 360° cyclodialysis cleft. We discuss the management options in this case, with an overview of the current literature.


Hospitality Towards People with Mental Illness in the Church: a Cross-cultural Qualitative Study.
Mental illness is a prevalent concern that affects Christian churches in North America in significant ways. Previous studies on the relationship between mental illness and the church have found that beliefs and practices within the church can contribute to stigma towards people with mental illness. Yet, the typical experience of people with mental illness who attend church has been found to be positive, suggesting that there are considerable resources within the church for supporting those who experience mental health problems. One such resource is the concept of hospitality, which promotes a sense of belonging for those with mental illness in the church. This qualitative study advances the construct of hospitality as a helpful paradigm for addressing mental health needs within the church, capturing perspectives and practices that are currently in place or seen as necessary by church attendees. The study methodology also emphasized the need to incorporate cultural considerations that are appropriate for the racial and ethnic make-up of particular churches. Semistructured focus group interviews were conducted with participants from eight churches that were either predominantly African American, Asian American, Latinx, or multi-ethnic. Findings resulting from content analysis of transcripts indicated that hospitality was a broadly helpful construct for addressing mental health concerns in the church, though some cultural differences existed in the understanding and application of hospitality. Both the interface of the findings with the existing scholarly literature and the relevance of findings for church leaders are discussed.


Clinical impact of matrix-assisted laser desorption ionization-time of flight mass spectrometry combined with antimicrobial stewardship interventions in patients with bloodstream infections in a Japanese tertiary hospital.
Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has the potential to permit early organism identification and optimization of antibiotic therapy. However, MALDI-TOF MS combined with antimicrobial stewardship is available at only a limited number of institutions. Here, we evaluated the clinical impact of implementing MALDI-TOF MS combined with antimicrobial stewardship intervention in patients with bloodstream infections. We conducted a single-centre, prospective cohort study to evaluate the clinical impact of implementing MALDI-TOF MS combined with antimicrobial stewardship intervention in patients with bloodstream infections. Processes and clinical outcomes in patients with bloodstream infections were compared before and after implementation of MALDI-TOF MS. Compared with the conventional identification method, MALDI-TOF MS combined with antimicrobial stewardship intervention significantly decreased the time to organism identification (48.6 ± 46.0 hours vs 78.1 ± 38.9 hours, P < 0.001), effective antimicrobial therapy (12.9 ± 19.0 hours vs 26.2 ± 44.8 hours, P < 0.001) and optimal antimicrobial therapy (53.3 ± 55.0 hours vs 91.7 ± 88.7 hours, P < 0.001. Moreover, the rate of clinical failure (14.0% vs 33.3%, P < 0.001) and incidence of adverse events (7.5% vs 23.9%, P < 0.001) was lower in the MALDI-TOF MS group than in the conventional identification group. A multivariate Cox proportional hazard analysis indicated that implementation of MALDI-TOF MS was a protective factor against clinical failure in patients with bloodstream infections (hazard ratio, 0.61; 95% confidence interval, 0.38-0.99; P = 0.047). Implementation of the MALDI-TOF MS combined with antimicrobial stewardship intervention facilitated early optimization of antimicrobial therapy with a remarkable concomitant reduction in clinical failure and adverse events in patients with bloodstream infections.


Influenza virus hemagglutinin stalk-based antibodies and vaccines.
Antibodies against the conserved stalk domain of the hemagglutinin are currently being discussed as promising therapeutic tools against influenza virus infections. Because of the conservation of the stalk domain these antibodies are able to broadly neutralize a wide spectrum of influenza virus strains and subtypes. Broadly protective vaccine candidates based on the epitopes of these antibodies, for example, chimeric and headless hemagglutinin structures, are currently under development and show promising results in animals models. These candidates could be developed into universal influenza virus vaccines that protect from infection with drifted seasonal as well as novel pandemic influenza virus strains therefore obviating the need for annual vaccination, and enhancing our pandemic preparedness.


KISS1 over-expression suppresses metastasis of pancreatic adenocarcinoma in a xenograft mouse model.
Identifying molecular targets for treatment of pancreatic cancer metastasis is critical due to the high frequency of dissemination prior to diagnosis of this lethal disease. Because the KISS1 metastasis suppressor is expressed at reduced levels in advanced pancreatic cancer, we hypothesized that re-expression of KISS1 would reduce metastases. Highly metastatic S2VP10 cells expressing luciferase (S2VP10L) were transfected with a FLAG-tagged version of KISS1 (KFM), KFMΔSS (with deleted secretion signal sequence), or pcDNA3 control plasmid (CP) and expression was confirmed by RTQ-PCR. SCID mice were implanted orthotopically with S2VP10L cells or transfectants and tumor growth and metastases were monitored using bioluminescence imaging. Mice with S2VP10L-KISS1 tumors developed fewer liver (98%) and lung (99%) metastases than S2VP10L. Unexpectedly, mice with S2VP10L-KFMΔSS tumors also had reduced liver and lung metastases, but had more metastases than mice with S2VP10L-KISS. KISS1 protein was found in the cytoplasm of both KFMΔSS and KISS1-expressing orthotopic tumors by immunohistochemistry. Metastases were not found in lungs of mice with S2VP10L-KISS1 tumors; whereas, KFMΔSS lung sections had regions of concentrated KISS1 staining, suggesting that secretion of KISS1 is needed to reduce metastasis significantly. These data suggest induction of KISS1 expression has potential as an adjuvant treatment for pancreatic cancer.


[Medical care of persons aged 25-84 years with acute myocardial infarction in Kaunas in 1996 (ischemic heart disease register data)].
To evaluate peculiarities of medical care provided for patients with acute myocardial infarction (AMI) depending on sex and age in Kaunas in 1996. Kaunas community-based ischemic heart disease register conducted according to the WHO MONICA Project methodology was the source of the data. Number of diagnosed acute myocardial infarctions among Kaunas population aged 25-84 years in 1996 was 1269. Only 28 day AMI survivors were considered in the present study (n=626). During first 4 hours from onset of chest pain male patients sought for medical assistance as frequently as female AMI patients: 38.1% and 34.0%, respectively. A mobile team provided first medical aid in 62.3% of cases. Thrombolytics were used in each 11th men and in 3% of women. Percutaneous coronary angioplasty was carried out in 4.9 and 1.2% of men and women, respectively. Coronary angiography and angioplasty were more often performed in men (13.1 and 4.9%, respectively) than in women (2.7 and 1.2, respectively).


Development of artificial intelligence tools for invasive Doppler-based coronary microvascular assessment.
Coronary flow reserve (CFR) assessment has proven clinical utility, but Doppler-based methods are sensitive to noise and operator bias, limiting their clinical applicability. The objective of the study is to expand the adoption of invasive Doppler CFR, through the development of artificial intelligence (AI) algorithms to automatically quantify coronary Doppler quality and track flow velocity. A neural network was trained on images extracted from coronary Doppler flow recordings to score signal quality and derive values for coronary flow velocity and CFR. The outputs were independently validated against expert consensus. Artificial intelligence successfully quantified Doppler signal quality, with high agreement with expert consensus (Spearman's rho: 0.94), and within individual experts. Artificial intelligence automatically tracked flow velocity with superior numerical agreement against experts, when compared with the current console algorithm [AI flow vs. expert flow bias -1.68 cm/s, 95% confidence interval (CI) -2.13 to -1.23 cm/s, P < 0.001 with limits of agreement (LOA) -4.03 to 0.68 cm/s; console flow vs. expert flow bias -2.63 cm/s, 95% CI -3.74 to -1.52, P < 0.001, 95% LOA -8.45 to -3.19 cm/s]. Artificial intelligence yielded more precise CFR values [median absolute difference (MAD) against expert CFR: 4.0% for AI and 7.4% for console]. Artificial intelligence tracked lower-quality Doppler signals with lower variability (MAD against expert CFR 8.3% for AI and 16.7% for console). An AI-based system, trained by experts and independently validated, could assign a quality score to Doppler traces and derive coronary flow velocity and CFR. By making Doppler CFR more automated, precise, and operator-independent, AI could expand the clinical applicability of coronary microvascular assessment.


Viral IRES RNA structures and ribosome interactions.
In eukaryotes, protein synthesis initiates primarily by a mechanism that requires a modified nucleotide 'cap' on the mRNA and also proteins that recruit and position the ribosome. Many pathogenic viruses use an alternative, cap-independent mechanism that substitutes RNA structure for the cap and many proteins. The RNAs driving this process are called internal ribosome-entry sites (IRESs) and some are able to bind the ribosome directly using a specific 3D RNA structure. Recent structures of IRES RNAs and IRES-ribosome complexes are revealing the structural basis of viral IRES' 'hijacking' of the protein-making machinery. It now seems that there are fundamental differences in the 3D structures used by different IRESs, although there are some common features in how they interact with ribosomes.


Dual-task walking on real-world surfaces: Adaptive changes in walking speed, step width and step height in young and older adults.
Age-related changes in dual-task walking are well established, but research in this topic is based on evidence from laboratory rather than real-world studies. We investigated how dual-task walking on real-world surfaces affects young and older adults' gait characteristics and cognitive resource allocation. Sixteen young (aged 19-35, 12 female) and fifteen older adults (aged 70-85, 7 female) with no major neurological or musculoskeletal disorders walked at a self-selected speed on forty-metre outdoor paths that had asphalt or grass surface. They walked with or without a cognitive task (counting backwards). Cognitive task difficulty was individually adjusted at 80 % accuracy. Participants performed the three tasks in Single Task (ST Asphalt, ST Grass, ST Cognitive) and Dual Task context (DT Asphalt-Cognitive, DT Grass-Cognitive). The two groups showed similar dual task effects in cognition and walking speed, both of which were slower when dual-task walking. Older adults' steps were wider overall but only young adults widened their step width when dual-task walking on grass compared to asphalt. Similarly, young adults' step height increased from single to dual-task walking when on grass, where older adults' did not. The lack of adaptation of step width and height when dual-task walking may leave older adults vulnerable to tripping or falling in common real-world conditions, such as while walking on grass, gravel, or uneven city sidewalks. Considering this, the built environment should be made more accessible to facilitate older adults' safe walking.


Optimal first trimester preeclampsia prediction: a comparison of multimarker algorithm, risk profiles and their sequential application.
To compare performance of multimarker algorithm, risk profiles and their sequential application in prediction of preeclampsia and determining potential intervention targets. Maternal characteristics, ultrasound variables and serum biomarkers were collected prospectively at first trimester. Univariate analysis identified preeclampsia associated variables followed by logistic regression analysis to determine the prediction rule. Combined characteristics of the cardiovascular, metabolic and the personal risk factors were compared to the multimarker algorithm and the sequential application of both methods. Out of 2433 women, 108 developed preeclampsia (4.4%). Probability scores considering nulliparity, prior preeclampsia, body mass index, diastolic blood pressure and placental growth factor had an area under the receiver operating characteristic curve 0.784 (95% CI = 0.721-0.847). While the multimarker algorithm had the lowest false negative rate, sequential application of cardiovascular and metabolic risk profiles in screen positives reduced false positives by 26% and identified blood pressure and metabolic risk in 49/54 (91%) women with subsequent preeclampsia as treatable risk factors. Sequential application of a multimarker algorithm followed by determination of treatable risk factors in screen positive women is the optimal approach for first trimester preeclampsia prediction and identification of women that may benefit from targeted metabolic or cardiovascular treatment. © 2015 John Wiley & Sons, Ltd.


Right ventricular diastolic function and exercise capacity in COPD.
Decreased exercise capacity in chronic obstructive pulmonary disease (COPD) is incompletely explained by pulmonary pathologic and physiologic abnormalities. We evaluated the extent to which right ventricular diastolic function (RVDF) is associated with exercise capacity in COPD. Fifty-one patients with COPD were evaluated by echocardiography, spirometry, and the 6 min walk test (6MWT). RVDF was assessed using 4 echocardiographic parameters: 1) the ratio of tricuspid valve (TV) early (E) and late (A) inflow velocities (TV E/A) 2) TV early tissue Doppler velocity (TV e') 3) TV deceleration time (DT) and 4) the ratio of TV E and e' velocities (TV E/e'). Multiple linear regression was used to examine the extent to which these parameters were associated with 6MWT distance. All models adjusted for age, sex, post-bronchodilator FEV1/FVC, resting heart rate, and use of supplemental O2 during 6MWT. A regression model was calculated for each of the 4 markers of RVDF. Forty-seven percent of the sample had GOLD stage III or IV COPD. All 51 subjects had preserved left ventricular ejection fraction (LVEF, mean = 71.7%, SD = 7.8%). A higher TV E/A ratio was associated with increased 6MWT distance (p = 0.001). TV e', TV DT and TV E/e' did not have a statistically significant association with 6MWT distance in regression models. In a cohort with moderate to severe COPD and normal LVEF, TV E/A was associated with 6MWT distance after adjusting for relevant demographic and medical covariates. RV diastolic dysfunction may independently contribute to exercise intolerance in COPD.


Transesophageal echocardiographic diagnosis of intracardiac entrapment of a Swan-Ganz catheter in open heart operation.
A Swan-Ganz catheter entrapment by a suture in the right atrial wall during open heart operation is presented. The diagnosis of the suture entrapment of the Swan-Ganz catheter to the right atrial wall was established by direct observation of the specific movement pattern of the cardiac structures when manual traction was applied from outside by a transesophageal echocardiographic examination.


Subcutaneous emphysema: an unusual presentation of foreign body in the airway.
Six children with a foreign body in the airway presented with progressive subcutaneous emphysema as a clinical feature. The aim of this report is to highlight this unusual clinical presentation of foreign body in the tracheobronchial tree. A peculiar arrangement of fascial planes in the neck, chest, and abdomen and an excessive pressure gradient at the alveolar level, facilitates extraalveolar migration of air in the subcutaneous tissue.


Role of fascin in the proliferation and invasiveness of esophageal carcinoma cells.
Fascin, an actin-bundling protein, induces membrane protrusions and increases cell motility in various transformed cells. The overexpression of fascin in esophageal squamous cell carcinoma (ESCC) has been described only recently, but the roles and mechanism still remained unclear. Here, by using RNA interference (RNAi), we have stably silenced the expression of the fascin in EC109 cells, an ESCC cell line. Down-regulation of fascin resulted in a suppression of cell proliferation and as well as a decrease in cell invasiveness. Furthermore, we revealed that fascin might have functions in regulating tumor growth in vivo. The effect of fascin on cell invasiveness correlated with the activation of matrix metalloproteases such as MMP-2 and MMP-9. We examined that fascin down-expression also led to a decrease of c-erbB-2 and beta-catenin at the protein level. These results suggested that fascin might play crucial roles in regulating neoplasm progression of ESCC.


The sella in childhood hypothyroidism.
Two sellar configurations have been noted in primary childhood hypothyroidism. In the older child the sella appears unusually round and slightly enlarged, and the term "cherry" sella has been used to describe its appearance. Enlargement is due to rebound hypertrophy of the pituitary gland and is reversible with adequate, early treatment. If reversal of these changes is not accomplished one should consider the possibility of an adenoma having developed. In the young child an infant the sella appears more immature and "bowl-like". Enlargement is not a prominent feature in this age group, and indeed was difficult to detect with certainty. Both configurations, but especially the "cherry" sella of the older child, are characteristic enough to enable one to suggest the diagnosis of primary hypothyroidism from lateral skull films.


DFT-B3LYP study of interactions between host biphenyl-1-aza-18-crown-6 ether derivatives and guest Cd(2+): NBO, NEDA, and QTAIM analyses.
This report present the results of natural energy decomposition analysis (NEDA), natural bond orbital (NBO), and quantum theory of atoms in molecules (QTAIM) calculations of three derivatives of biphenyl-1-aza-18-crown-6 ether and their 1:1 complexes with Cd(2+). All calculations used the B3LYP density functional theory in combination with the 6-311G and WTBS basis sets for ligands and Cd(2+) ion, respectively. Ligands 1 and 3 have a single 1-aza-18-crown-6, substituent; ligand 2 has two such substituents. The results show that, in the optimized geometries of the complexes, the distance between N and Cd(2+) is greater than the distance between O and Cd(2+). NBO and QTAIM data confirm these results. There was no stabilization energy or bond critical point for N · · · Cd(2+) in NBO or QTAIM, respectively. Data show that the O · · · Cd(2+) interaction is a kind of closed shell interaction. The trend of the calculated stabilization energy was similar to the experimental data. Different contributions of interaction energies for complex formation were analyzed by NEDA, and the results show that the main component of the interactions is accounted for by polarization.


Noninvasive Assessment of Carotid Pulse Pressure Values: An Accelerometric-Based Approach.
Central pulse pressure (cPP) is increasingly investigated as possible independent predictor of cardiovascular risk and carotid pulse pressure (carPP) can be used as a surrogate of cPP. Despite its importance, carPP measurement remains challenging in clinical practice. The aim of this study was to introduce a new easier-to-use method for noninvasive carPP evaluation based on the use of a MEMS accelerometer. carPP values (carPP(acc)) were obtained in 22 subjects (10 males, 47 ±17 years, hypertension: 50%) postprocessing and double integrating the accelerometric signals. carPP(acc) measurements were compared with tonometric assessments (carPP(ton)), and ultrasound-derived measurements (carPP(us)). Moreover, accelerometric carotid pressure waveforms (P(acc)) were contrasted in terms of shape to those obtained by tonometry (P(ton)) and ultrasound images elaboration (P(US)), calculating the root mean square error (RMSE(ton), RMSE(US)) and the regression coefficients (r(ton) and r(US)). Moreover, both the repeatability and reproducibility analyses were performed. carPP(acc) values (45.9 ±10.6 mmHg) were significantly correlated with carPP(ton) (47.5 ±11.3 mmHg) and carPP(US) (43.3 ±8.4 mmHg) assessments (R = 0.94, p < 0.0001 and R = 0.80, p < 0.0001, respectively). The validity of the accelerometric approach was confirmed by morphological parameters ( RMSE(ton) = 5 ±1.95 mmHg, RMSE(US) = 5.5 ±2.3 mmHg, r(ton) = 0.94 ±0.04, r(US) = 0.93 ±0.04). Coefficient of variation (CV) was equal to 6.2% for the repeatability analysis, while CV values for interoperator and intersession reproducibilities were 8.9% and 9.4%, respectively. The proposed approach, providing an easier and more available measurement, could represent a valid alternative to existing and used technique for carPP assessment.


The utility of gallium-68 DOTATOC PET/CT in lymphangioleiomyomatosis.
Somatostatin receptor functional imaging is of limited utility as an imaging biomarker in LAM, but other PET/CT modalities may be of use https://bit.ly/3l6BVZp.


Psychologic Impacts on Diabetic Neuropathic Pain.
Many Americans cope with painful diabetic neuropathy (DN) as a sequela of high rates of diabetes mellitus in the US population. Appropriate management of this complex, debilitating chronic pain condition requires thorough evaluation through a biopsychosocial framework. This review aims to synthesize findings from original research studies and analyze the psychological factors that influence the experience of, and treatments for, DN pain. Existing clinical literature suggests a wide breadth of psychological factors impacting DN pain. One research study detailed the demographic characteristics of DN patients most likely to have significant anxiety or depressive symptoms, and have emotional distress adversely impacting their response to therapies. A retrospective study demonstrated a correlation between patients' mindfulness-based stress reduction and improvement in DN pain severity. In addtion, a small-scale, randomized controlled pilot study supported cognitive-behavioral therapy as a superior intervention to conventional medical treatments in reducing DN patients' pain severity and pain interference, even when not accompanied by significant improvement in depressive symptoms. This review of investigations into psychological factors implicated in DN pain suggests that diagnosable mental health conditions as well as discrete, adverse thinking processes both exert significant influences on DN pain. This review further brings attention to the beneficial impact that psychotherapeutic modalities can have on DN pain.


The Vascular Endothelial Growth Factor Inhibitors Ranibizumab and Aflibercept Markedly Increase Expression of Atherosclerosis-Associated Inflammatory Mediators on Vascular Endothelial Cells.
Recent studies have suggested that the VEGF inhibitors, Ranibizumab and Aflibercept may be associated with an excess of cardiovascular events, potentially driven by increasing atheroma instability, leading to plaque rupture and clinical events. Inflammation plays a key role in the progression of atherosclerotic plaque and particularly conversion to an unstable phenotype. Here, we sought to assess the in vitro effects of these drugs on the expression of key inflammatory mediators on endothelial cells. Human coronary artery endothelial cells were co-incubated for 16h with Ranibizumab (0.11nM) or Aflibercept (0.45nM), as determined by each drug's peak serum concentration (Cmax). Expression at protein (ELISA) and gene (RT-PCR) level of inflammatory chemokines CCL2, CCL5 and CXC3L1 as well as gene expression for the cell adhesion molecules VCAM-1, ICAM-1 and the key NF-κb protein p65 was assessed. VEGF-A protein levels were also determined. Both drugs significantly increased chemokine, cell adhesion molecule (CAM) and p65 expression, while decreasing VEGF-A protein secretion. At equivalent Cmax concentrations, Aflibercept was significantly more pro-inflammatory than Ranibizumab. Reduction of secreted VEGF-A levels significantly attenuated inflammatory effects of both drugs, whereas blockade of the VEGF-A receptor or silencing of VEGF-A gene synthesis alone had no effect, suggesting that binding of drug to secreted VEGF-A is crucial in promoting inflammation. Finally, blockade of Toll-like receptor 4 significantly reduced inflammatory effects of both drugs. We demonstrated here, for the first time, that both drugs have potent pro-inflammatory effects, mediated via activation of Toll-like receptor 4 on the endothelial cell surface by drug bound to VEGF-A. Further studies are required to investigate whether these effects are also seen in vivo.


Meta-Analysis of Interrater Reliability of Supervisory Performance Ratings: Effects of Appraisal Purpose, Scale Type, and Range Restriction.
Objectives: This reliability generalization study aimed to estimate the mean and variance of the interrater reliability coefficients (r yy ) of supervisory ratings of overall, task, contextual, and positive job performance. The moderating effect of the appraisal purpose and the scale type was examined. It was hypothesized that the ratings collected for research purposes and multi-item scales have higher r yy . It was also examined whether r yy was similar for the four performance dimensions. Method: A database consisting of 224 independent samples was created and hierarchical sub-grouping meta-analyses were conducted. Results: The appraisal purpose was a moderator of r yy for the four performance dimensions. Scale type was a moderator of r yy for overall and task performance collected for research purposes. The findings also suggest that supervisors seem to have less difficulty evaluating overall job performance than task, contextual, and positive performance. The best estimates of the observed r yy for overall job performance are 0.61 for research-collected ratings and 0.45 for administrative-collected ratings. Conclusions: (1) Appraisal purpose moderates r yy and researchers and practitioners should be aware of its effects before collecting ratings or using empirically-derived interrater reliability distributions, (2) Scale type seems to moderate r yy in the case of the ratings collected for research purposes, only, (3) overall job performance is more reliably rated than task, contextual, and positive performance. Implications for research and practice are discussed.


Antidepressant treatment for chronic depressed patients should not be discontinued prior to anesthesia.
To investigate whether antidepressants administered to patients for chronic depression patients should be continued or discontinued before anesthesia. We studied 80 depressed patients who were scheduled to undergo orthopedic surgery under general anesthesia. The patients were divided randomly into two groups; patients in Group A (n=40) continued antidepressants before surgery and patients in Group B (n=40) discontinued antidepressants 72 hr before surgery. Two (5%) out of 40 patients in Group A and eight (20%) out of 40 patients in Group B had deterioration of depressive symptoms (P=0.04). Delirium or confusion during the perioperative course occurred in five patients (13%) in Group A and in 12 (30%) in Group B (P=0.05). There were no significant differences in incidence (5 vs 6%) of hypotension and arrhythmias during anesthesia between the two groups. Antidepressants administered to depressed patients should be continued before anesthesia. Discontinuation of antidepressants did not increase the incidence of hypotension and arrhythmias during anesthesia, but increased symptoms of depression and delirium or confusion.


Multicenter ophthalmic and nutritional age-related macular degeneration study--part 2: antioxidant intervention and conclusions.
The experimental design, subjects, procedures and baseline data for the prospective double blind dry ARMD-antioxidant intervention study have been described in Part 1. At eight DVA medical centers, 32 patients (group one) were assigned a placebo and 39 patients (group two) a "broad spectrum" antioxidant capsule. Data was collected in five areas: demographic; ophthalmic; dietary analysis of daily food intake; serum analysis; and adverse gastrointestinal symptoms. Data was serially acquired at baseline, 6 months, 12 months and 18 months, and was analyzed by univariate repeated factors ANOVA, p = 0.05. Group two (antioxidant po BID) maintained their distance LogMAR visual acuity (p = 0.03), while there was a trend toward both stabilized near M print (p = 0.07) and 6 cycle/degree contrast sensitivity (p approximately 0.10), in left eyes. However, group two (antioxidant) also had increased cortical opacification of the right lens (p = 0.04), compared to group one (placebo). Self perceived stabilization of vision was reported by subjects in group two and supported the objective data (Pearson chi square; p = 0.05). A specific 14 component antioxidant capsule taken twice daily stabilized but did not improve dry ARMD over the study period of 1.5 years. The ARMD stabilized eyes had less advanced disease functionally but not by fundus appearance. Decreased intake of cardioprotective nutrients (vitamin E, zinc, magnesium, B6 and folate) in ARMD patients remained constant over the course of the trial.


Tuberculosis drug discovery: Progression and future interventions in the wake of emerging resistance.
The emergence of drug resistance continues to afflict TB control where drug resistant strains have become a global health concern. Contrary to drug-sensitive TB, the treatment of MDR/XDR-TB is more complicated requiring the administration of second-line drugs that are inefficient than the first line drugs and are associated with greater side effects. The emergence of drug resistant Mtb strains had coincided with an innovation void in the field of drug discovery of anti-mycobacterials. However, the approval of bedaquiline and delamanid recently for use in MDR/XDR-TB has given an impetus to the TB drug discovery. The review discusses the drug discovery efforts in the field of tuberculosis with a focus on the strategies adopted and challenges confronted by TB research community. Here, we discuss the diverse clinical candidates in the current TB drug discovery pipeline. There is an urgent need to combat the current TB menace through multidisciplinary approaches and strategies making use of the recent advances in understanding the molecular biology and pathogenesis of Mtb. The review highlights the recent advances in drug discovery, with the host directed therapeutics and nanoparticles-drug delivery coming up as important tools to fight tuberculosis in the future.


Endophthalmitis as a first manifestation of right-sided endocarditis in a patient with patent foramen ovale.
Endogenous endophthalmitis is a rare complication of endocarditis, rendering poor visual prognosis. We report a case of a 66-year-old female with renal failure who presented with fever, ocular pain, and purulent eye discharge. After a diagnosis of endogenous endophthalmitis, she was treated with antibiotics and enucleation of the eye. Due to persistent fever and positive blood cultures, a transesophageal echocardiography was undertaken, disclosing a large mural vegetation in the right atrium, catheter-associated vegetations, and a patent foramen ovale. Endocarditis is an uncommon source of endogenous endophthalmitis, and has rarely been associated to right-sided endocarditis and paradoxical septic embolization.


Complexation of 5-fluorosalicylic acid with copper(II): a pH-potentiometric, UV-vis spectroscopic, and electron spin resonance study by the two-dimensional simulation of spectra.
The copper(II)-5-fluorosalicylic acid system was investigated in water and 50 v/v% water-methanol mixture by pH potentiometry combined with UV-vis spectrophotometry, and by the two-dimensional ESR simulation method, respectively. The data revealed that the stable paramagnetic mono- and bis(salicylato) copper(II) complexes [CuLH(-1)] and [CuL2H(-2)](2-) are formed, and at low excess of ligand, the ESR-silent mixed hydroxo complex [Cu2L2H(-3)](-) is also a major species. By the two-dimensional ESR simulation method, the species [CuL]+ in the acidic region, and the minor dimer [Cu2L2H(-2)] were also identified, and the cis and trans isomers of [CuL2H(-2)](2-) were characterized. In frozen solutions, the ESR analysis revealed a slight rhombic distortion of coordination polyhedra for the latter three species.


Analysis of Early Kidney Injury-Related Factors in Patients with Hypertension and Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS).
The aim of this study was to analyze the related factors of obstructive sleep apnea hypopnea syndrome (OSAHS) that would affect early kidney injury in patients with hypertension (Hyp). A total of 457 Hyp patients with nocturnal snoring were selected for polysomnography (PSG). The patients were divided into four groups according to the apnea hypopnea index (AHI), and the related factors that would impact blood urea, creatinine, 24 hr urinary protein (24 hr UTP), 24 h urinary microalbuminuria and serum cystatin C (Cyst C) were analyzed in the groups. Severe OSAHS (OR = 4.880, 95% CI = 1.577~15.099) was the influencing factor for 24 hr UTP; blood pressure control (OR = 2.335, 95% CI = 1.326~4.112) and Obesity (OR = 2.072, 95% CI = 1.236~3.474) were the influencing factors for 24 hr urinary microalbuminuria; age (OR = 1.996, 95% CI = 1.366~2.917), blood pressure control (OR = 2.895, 95% CI = 1.267~6.615) and severe OSAHS (OR = 6.093, 95% CI = 1.267~29.303) were the influencing factors for Cyst C. As for the Hyp patients associated with OSAHS, severe OSAHS were the influencing factors for 24 hr UTP; blood pressure control and Obesity were the influencing factors for 24 hr urinary microalbuminuria; age, blood pressure control and severe OSAHS were the influencing factors for Cyst C. OSAHS is a risk factor of early kidney injury.


Widening the Spectrum of Risk Factors, Comorbidities, and Prodromal Features of Parkinson Disease.
The prodromal phase of Parkinson disease (PD) may last for more than 10 years. Recognition of the spectrum and occurrence of risk factors, comorbidities, and prodromal features of PD can increase understanding of the causes and development of the disease and help identify individuals at risk. To identify the association of a subsequent diagnosis of PD with a range of risk factors and prodromal features, including lifestyle factors, comorbidities, and potential extracerebral manifestations of PD. This was a case-control study using insurance claims of outpatient consultations of patients with German statutory health insurance between January 1, 2011, and December 31, 2020. Included were patients with incident diagnosis of PD without a previous diagnosis of parkinsonism or dementia and controls matched 1:2 for age, sex, region, and earliest year of outpatient encounter. Exposures were selected based on previous systematic reviews, case-control and cohort studies reporting on risk factors, comorbidities, and prodromal features of PD. Previously postulated risk factors and prodromal features of PD, using the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) coding. A total of 138 345 patients with incident PD (mean [SD] age, 75.1 [9.8] years; 73 720 male [53.3%]) and 276 690 matched controls (mean [SD] age, 75.1 (9.8) years; 147 440 male [53.3%]) were identified. Study participants were followed up for a mean (SD) of 6.0 (2.0) years. Consistent with previous reports, risk factors and prodromal features associated with PD included traumatic brain injury, odds ratio (OR), 1.62; 95% CI, 1.36-1.92; alcohol misuse, OR, 1.32; 95% CI, 1.21-1.44; hypertension, OR, 1.29; 95% CI, 1.26-1.31; anosmia, OR, 2.16; 95% CI, 1.59-2.93; and parasomnias (including RBD), OR, 1.62; 95% CI, 1.42-1.84. In addition, there were associations with restless legs syndrome (OR, 4.19; 95% CI, 3.91-4.50), sleep apnea (OR, 1.45; 95% CI, 1.37-1.54), epilepsy (OR, 2.26; 95% CI, 2.07-2.46), migraine (OR, 1.21; 95% CI, 1.12-1.29), bipolar disorder (OR, 3.81; 95% CI, 3.11-4.67), and schizophrenia (OR, 4.48; 95% CI, 3.82-5.25). The following diagnoses were also found to be associated with PD: sensory impairments beyond anosmia, such as hearing loss (OR, 1.14; 95% CI, 1.09-1.20) and changes of skin sensation (OR, 1.31; 95% CI, 1.21-1.43). There were also positive associations with skin disorders (eg, seborrheic dermatitis, OR, 1.30; 95% CI, 1.15-1.46; psoriasis, OR, 1.13; 95% CI, 1.05-1.21), gastrointestinal disorders (eg, gastroesophageal reflux, OR, 1.29; 95% CI, 1.25-1.33; gastritis, OR, 1.28; 95% CI, 1.24-1.33), conditions with a potential inflammatory component (eg, seronegative osteoarthritis, OR, 1.21; 95% CI, 1.03-1.43), and diabetes types 1 (OR, 1.32; 95% CI, 1.21-1.43) and 2 (OR, 1.24; 95% CI, 1.20-1.27). Associations even 5 to 10 years before diagnosis included tremor (odds ratio [OR], 4.49; 95% CI, 3.98-5.06), restless legs syndrome (OR, 3.73; 95% CI, 3.39-4.09), bipolar disorder (OR, 3.80; 95% CI, 2.82-5.14), and schizophrenia (OR, 4.00; 95% CI, 3.31-4.85). Results of this case-control study suggest that the associations found between PD and certain risk factors, comorbidities, and prodromal symptoms in a representative population may reflect possible early extrastriatal and extracerebral pathology of PD. This may be due to shared genetic risk with PD, medication exposure, or direct causation, or represent pathophysiologically relevant factors contributing to the pathogenesis of PD.


The T393C polymorphism of GNAS1 as a predictor for chemotherapy sensitivity and survival in advanced non-small-cell lung cancer patients treated with gemcitabine plus platinum.
The GNAS1 gene is linked to proapoptotic signaling and correlates closely with clinical outcomes in many human cancers. The aim of this study was to evaluate whether the T393C polymorphism of the GNAS1 gene could be used as a chemotherapy sensitivity and prognosis predictive marker of advanced non-small-cell lung cancer (NSCLC) treated with gemcitabine plus platinum (GP). In this study, we performed the PCR-restriction fragment length polymorphism assay to examine the genotypes of the GNAS1 T393C polymorphism in 131 peripheral blood DNA specimens from advanced NSCLC patients with GP treatment. The frequencies of the CC, CT, and TT genotypes in 131 advanced NSCLC cases were 25.2, 47.4, and 26.7%, respectively. The favorable TT genotype was significantly correlated with better overall survival (OS; P < 0.05) and longer progress-free survival (PFS; P < 0.05) compared with the CT or CC genotype. In the multivariate Cox proportional hazards model, the GNAS1 T393C polymorphism was independently associated with overall survival after adjusting the clinicopathological factors (P < 0.05). This study suggests that the TT genotype of the GNAS1 T393C polymorphism could be an independent prognostic marker to predict chemotherapy sensitivity, favorable OS and PFS in advanced NSCLC patients with GP treatment.


Antigen-specific suppression of collagen arthritis by adoptive transfer of spleen cells.
Wistar-Furth (W-F) rats were given 10(9) syngeneic spleen cells, suspended in Hanks' balanced salt solution (HBSS), intravenously on Day 0 to investigate the mechanisms involved in antigen-specific suppression of collagen arthritis. These cells were pooled from W-F donors which had been injected iv on Days -21, -14, and -7 with rat red blood cells (RBC) coupled with glutaraldehyde to either native chick type II collagen, denatured type II collagen, or native type I collagen. All recipients were immunized with an emulsion of native type II collagen in incomplete Freund's adjuvant on Day 1 to induce collagen arthritis. There was a decreased incidence of arthritis, by clinical and radiographic assessments, in rats receiving spleen cells from donors previously administered native type II collagen-coupled RBC compared to those given spleen cells obtained from donors treated with denatured type II or native type I collagen-coupled RBC [18 of 30 (60%) arthritic vs 20 of 20 (100%) and 19 of 20 (95%) arthritic, for the three groups, respectively, P less than 0.01 for both comparisons]. The incidence of arthritis in 35 rats administered HBSS iv 1 day prior to immunization (83%) and 10 immunized rats given no iv injections (100%) was also significantly higher (P less than 0.05) than the incidence in the antigen-relevant experimental group. Hemagglutinating antibody titers and delayed-type hypersensitivity (DTH) to collagen were lower in the recipients of cells from donors administered native type II collagen-coupled RBC, whereas IgG antibody titers to collagen were unaltered. These results demonstrate that passively transferred spleen cells can attenuate collagen arthritis and sensitization in an antigen-specific manner.


Challenges in corticosteroid dose regulation in a patient with autoimmune thyroid disease and neuropsychiatric syndrome: A running commentary.
In the following, we report a therapeutic challenge faced by reduction in corticosteroid therapeutic dosage in a patient diagnosed with Hashimoto's encephalopathy (HE), which is equivalent to corticosteroid-responsive encephalopathy related to autoimmune thyroiditis and often misdiagnosed as neuropsychiatric status. The patient developed psychiatric symptoms.


Cortical Granularity Shapes the Organization of Afferent Paths to the Amygdala and Its Striatal Targets in Nonhuman Primate.
The prefrontal cortex (PFC) and insula, amygdala, and striatum form interconnected networks that drive motivated behaviors. We previously found a connectional trend in which granularity of the ventromedial and orbital PFC/insula predicted connections to the amygdala, and also the breadth of amygdalo-striatal efferents, including projections beyond the "classic" ventral striatum. To further interrogate connectional relationships among the cortex, amygdala, and striatum, and to further define the "limbic" (amygdala-recipient) striatum, we conducted tract tracing studies in two cohorts of macaques (male n = 14, female n = 1). We focused on the cortico-amygdalo-striatal (indirect) and cortico-"limbic" striatal (direct) paths originating in the entire PFC and insula. Larger datasets and a quantitative approach revealed "cortical rules" in which cortical granularity predicts the complexity and location of projections to both the basal nucleus of the amygdala and striatum. Remarkably, projections from "cortical-like" basal nucleus to the striatum followed similar patterns. In both "direct" and "indirect" paths to the "limbic" striatum, agranular cortices formed a "foundational," broad projection, and were joined by inputs from progressively more differentiated cortices. In amygdalo-striatal paths, the ventral basal nucleus was the "foundational" input, with progressively more dorsal basal nucleus regions gradually adding inputs as the "limbic" striatum extended caudally. Together, the "indirect" and "direct" paths followed consistent principles in which cortical granularity dictated the strength and complexity of projections at their targets. Cluster analyses independently confirmed these connectional trends, and also highlighted connectional features that predicted termination in specific subregions of the basal nucleus and "limbic" striatum.SIGNIFICANCE STATEMENT The "limbic" system broadly refers to brain circuits that coordinate emotional responses. Here, we investigate circuits of the amygdala, which are involved in coding the emotional value of external cues, and their influence on the striatum. Regions of prefrontal cortex (PFC) and insula form gradients of overlapping inputs to the amygdala's basal nucleus, which feed forward to the striatum. Direct cortical inputs to these "amygdala-recipient" striatal areas are surprisingly organized according to similar principles but subtly shift from the "classic" ventral striatum to the caudal ventral striatum. Together, these distinct subsystems, cortico-amygdalo-striatal circuits and direct cortico-striatal circuits, provide substantial opportunity for different levels of internal, sensory, and external experiences to be integrated within the striatum, a major motor-behavioral interface.


A Next-Generation Air-Stable Palladium(I) Dimer Enables Olefin Migration and Selective C-C Coupling in Air.
We report a new air-stable PdI dimer, [Pd(μ-I)(PCy2 t Bu)]2 , which triggers E-selective olefin migration to enamides and styrene derivatives in the presence of multiple functional groups and with complete tolerance of air. The same dimer also triggers extremely rapid C-C coupling (alkylation and arylation) at room temperature in a modular and triply selective fashion of aromatic C-Br, C-OTf/OFs, and C-Cl bonds in poly(pseudo)halogenated arenes, displaying superior activity over previous PdI dimer generations for substrates that bear substituents ortho to C-OTf.


Ionic liquid-mediated selective conversion of CO₂ to CO at low overpotentials.
Electroreduction of carbon dioxide (CO(2))--a key component of artificial photosynthesis--has largely been stymied by the impractically high overpotentials necessary to drive the process. We report an electrocatalytic system that reduces CO(2) to carbon monoxide (CO) at overpotentials below 0.2 volt. The system relies on an ionic liquid electrolyte to lower the energy of the (CO(2))(-) intermediate, most likely by complexation, and thereby lower the initial reduction barrier. The silver cathode then catalyzes formation of the final products. Formation of gaseous CO is first observed at an applied voltage of 1.5 volts, just slightly above the minimum (i.e., equilibrium) voltage of 1.33 volts. The system continued producing CO for at least 7 hours at Faradaic efficiencies greater than 96%.


Liver metabolomic changes identify biochemical pathways in hemorrhagic shock.
Despite ongoing advances in treatment, thousands of patients still die annually from complications due to hemorrhagic shock, a condition causing dramatic physiologic and metabolic changes as cells switch to anaerobic metabolism in response to oxygen deprivation. As the shift from aerobic to anaerobic metabolism occurs in the peripheral tissues during shock, the liver must increase production of endogenous glucose as well as process excess lactate produced in the periphery. This places the liver at the center of metabolic regulation in the body during hemorrhagic shock. Therefore, we hypothesized that liver tissue from pigs during an in vivo model of hemorrhagic shock (n = 6) would reflect resultant metabolic changes. The in vivo model of shock consisted of 45 min of shock followed by 8 h of hypotensive resuscitation (80 mmHg) and subsequent normotensive resuscitation (90 mmHg) ending 48 h after the shock period. Control groups of pigs (n = 3) (1) shock with no resuscitation, and (2) only anesthesia and instrumentation, also were included. Metabolic changes within the liver after shock and during resuscitation were investigated using both proton ((1)H) and phosphorous ((31)P) nuclear magnetic resonance (NMR) spectroscopy. Concentrations of glycerylphosphorylcholine (GPC) and glycerylphosphorylethanolamine (GPE) were significantly lower at 8 h after shock, with recovery to baseline by 23 and 48 h after shock. Uridine diphosphate-glucose (UDP-glucose), and phosphoenolpyruvate (PEP) were elevated 23 h after shock. These results indicate that (1)H and (31)P NMR spectroscopy can be used to identify differences in liver metabolites in an in vivo model of hemorrhagic shock, indicating that metabolomic analysis can be used to elucidate biochemical events occurring during this complex disease process.


Prevalence of susceptibility to tetanus and diphtheria in health care workers in Catalonia.
A seroprevalence study of tetanus and diphtheria was carried out in a sample of 537 health care workers in Catalonia. The prevalence of protective antibodies against tetanus was 93.9% (95% confidence interval: 91.5-95.7). The prevalence of protective antibodies against diphtheria was 46.4% (95% confidence interval: 42.1-50.7). Tetanus protection should be improved in health care workers born before 1975. The immune status against diphtheria was poor, with less than half of people born before 1975 correctly immunized.


A Potent Germline-like Human Monoclonal Antibody Targets a pH-Sensitive Epitope on H7N9 Influenza Hemagglutinin.
The H7N9 influenza virus causes high-mortality disease in humans but no effective therapeutics are available. Here we report a human monoclonal antibody, m826, that binds to H7 hemagglutinin (HA) and protects against H7N9 infection. m826 binds to H7N9 HA with subnanomolar affinity at acidic pH and 10-fold lower affinity at neutral pH. The high-resolution (1.9 Å) crystal structure of m826 complexed with H7N9 HA indicates that m826 binds an epitope that may be fully exposed upon pH-induced conformational changes in HA. m826 fully protects mice against lethal challenge with H7N9 virus through mechanisms likely involving antibody-dependent cell-mediated cytotoxicity. Interestingly, immunogenetic analysis indicates that m826 is a germline antibody, and m826-like sequences can be identified in H7N9-infected patients, healthy adults, and newborn babies. These m826 properties offer a template for H7N9 vaccine immunogens, a promising candidate therapeutic, and a tool for exploring mechanisms of virus infection inhibition by antibodies.


Effects of ethylene oxide and ethylene inhalation on DNA adducts, apurinic/apyrimidinic sites and expression of base excision DNA repair genes in rat brain, spleen, and liver.
Ethylene oxide (EO) is an important industrial chemical that is classified as a known human carcinogen (IARC, Group 1). It is also a metabolite of ethylene (ET), a compound that is ubiquitous in the environment and is the most used petrochemical. ET has not produced evidence of cancer in laboratory animals and is "not classifiable as to its carcinogenicity to humans" (IARC, Group 3). The mechanism of carcinogenicity of EO is not well characterized, but is thought to involve the formation of DNA adducts. EO is mutagenic in a variety of in vitro and in vivo systems, whereas ET is not. Apurinic/apyrimidinic sites (AP) that result from chemical or glycosylase-mediated depurination of EO-induced DNA adducts could be an additional mechanism leading to mutations and chromosomal aberrations. This study tested the hypothesis that EO exposure results in the accumulation of AP sites and induces changes in expression of genes for base excision DNA repair (BER). Male Fisher 344 rats were exposed to EO (100 ppm) or ET (40 or 3000 ppm) by inhalation for 1, 3 or 20 days (6h/day, 5 days a week). Animals were sacrificed 2h after exposure for 1, 3 or 20 days as well as 6, 24 and 72 h after a single-day exposure. Experiments were performed with tissues from brain and spleen, target sites for EO-induced carcinogenesis, and liver, a non-target organ. Exposure to EO resulted in time-dependent increases in N7-(2-hydroxyethyl)guanine (7-HEG) in brain, spleen, and liver and N7-(2-hydroxyethyl)valine (7-HEVal) in globin. Ethylene exposure also induced 7-HEG and 7-HEVal, but the numbers of adducts were much lower. No increase in the number of aldehydic DNA lesions, an indicator of AP sites, was detected in any of the tissues between controls and EO-, or ET-exposed animals, regardless of the duration or strength of exposure. EO exposure led to a 3-7-fold decrease in expression of 3-methyladenine-DNA glycosylase (Mpg) in brain and spleen in rats exposed to EO for 1 day. Expression of 8-oxoguanine DNA glycosylase, Mpg, AP endonuclease (Ape), polymerase beta (Pol beta) and alkylguanine methyltransferase were increased by 20-100% in livers of rats exposed to EO for 20 days. The only effects of ET on BER gene expression were observed in brain, where Ape and Pol beta expression were increased by less than 20% after 20 days of exposure to 3000 ppm. These data suggest that DNA damage induced by exposure to EO is repaired without accumulation of AP sites and is associated with biologically insignificant changes in BER gene expression in target organs. We conclude that accumulation of AP sites is not a likely primary mechanism for mutagenicity and carcinogenicity of EO.


Hormonal receptor status, Ki-67 and HER2 expression: Prognostic value in the recurrence of ductal carcinoma in situ of the breast?
Local recurrence is considered a major concern in patients diagnosed with ductal carcinoma in situ (DCIS), as its invasive occurrence is associated with high rates of distant disease and mortality. This study aims to assess the possible correlation of hormonal receptor status, Ki-67 and HER2 expression with recurrence rates in women with DCIS, taking also into account the potential prognostic effects of grade and age at diagnosis. 230 consecutive patients with DCIS were included in this study. Invasive and non-invasive recurrence events were recorded, as a total. Clinicopathological information, as well as PR positivity, ER positivity, HER2 positivity and ki-67 expression were analyzed. Multivariable Cox regression analysis was performed, examining the risk factors for recurrence. Recurrence was noted in 17.8% of cases; the median follow-up was 44 months. Higher grade (adjusted HR = 1.72, 95%CI: 1.06-2.78), age at diagnosis (adjusted HR = 0.60, 95%CI: 0.43-0.83), Ki-67 expression (adjusted HR = 1.78, 95%CI: 1.11-2.88), and type of administered treatment were independently associated with increased recurrence rates. Recurrence rates were not significantly associated with ER, PR status or HER2 expression. In addition to high grade, administered treatment and younger age at diagnosis, high Ki-67 expression seems to be independently associated with increased likelihood of recurrence in patients with DCIS. Future studies with additional molecular markers seem necessary to further improve the identification of high-risk patients for DCIS recurrence.


Inhibitory effect of central ghrelin on steroid synthesis affecting reproductive health in female mice.
Ghrelin is a 28-amino acid peptide hormone that regulates ovarian steroid hormone synthesis; however, there is limited evidence regarding the regulation of this pathway by ghrelin in mice ovary. Thus, we aimed to investigate whether central ghrelin action plays a role in murine reproductive health by inhibiting steroid synthesis. Further, we sought to examine the mechanism of central ghrelin action in ovarian steroid hormone synthesis. After the administration of intracerebroventricular ghrelin (1 nmol), we found reduced serum concentrations of oestradiol and progesterone and reduced secretion of follicle-stimulating hormone and luteinising hormone. Although ghrelin reduced 3β-hydroxysteroid dehydrogenase mRNA and protein levels in the hypothalamus, it did not affect the expression of steroidogenic acute regulatory protein and cytochrome P450 17A1. In the ovary, central ghrelin regulation indirectly inhibited the mRNA and protein levels of steroidogenic acute regulatory protein, cytochrome P450 17A1, and 3β-hydroxysteroid dehydrogenase. Moreover, no changes were observed in the expression of proliferating cell nuclear antigen and phosphorylation of extracellular signal-regulated kinase. We hypothesised that central ghrelin regulation suppressed serum oestradiol and progesterone levels by indirectly inhibiting the expression of steroidogenic acute regulatory protein, cytochrome P450 17A1, and 3β-hydroxysteroid dehydrogenase in the ovary. In this regulation, the suppressed secretion of the follicle-stimulating hormone and luteinising hormone in the pituitary by ghrelin could be involved. Furthermore, hypothalamic 3β-hydroxysteroid dehydrogenase expression is reduced by ghrelin injection.


A conservative treatment option for a single missing premolar using a partial veneered restoration with the SR Adoro system.
This report describes a step-by-step sequence for preparation for a posterior partial veneered restoration for a space closure using a Maryland bridge-design veneered with a heat-cured composite resin. The modality provides sound posterior occlusal function, combined with a psychological satisfaction to the patient of regaining a missing tooth. The preparation takes into account the design for resin-bonded prostheses. This article presents the preparation and build-up method for a metal reinforced posterior partial veneered restoration through a conservative palatal approach for a highly aesthetic result.


Correction: Use of Deep Learning to Predict Acute Kidney Injury After Intravenous Contrast Media Administration: Prediction Model Development Study.
[This corrects the article DOI: 10.2196/27177.].


JBC Gallery: 2017 AMI Salon Annual Meeting Salon.
The Gallery for this issue of the JBC features the award-winning illustration and media from the Association of Medical Illustrators' 2017 Salon. The illustrations, interactive content, and motion media featured in our Gallery were exhibited at the AMI annual meeting held in Austin, Texas.


The marginal branch triangle: Anatomic reference for its location and preservation during cosmetic surgery.
Many studies have been dedicated toward bettering the understanding of the anatomy of this branch and the relative danger zone. However, most of these articles have focused on identifying the location of this branch based on its trajectory and associations with deep structures, causing some difficulties for aesthetic surgeons to identify its location during facial aesthetic surgery. Here, we present the concept of the marginal nerve triangle; its contents, relations and clinical applications in cosmetic surgery are discussed. This is an anatomical study performed using 64 hemifaces from 32 Peruvian fresh cadavers (25 men and 7 women). They were dissected manually and observed macroscopically by the authors. The marginal nerve and the related structures were dissected from its origin to the terminal branches and associated with the described triangular area. The marginal branch of the facial nerve was found to lie in the described triangle in all cases. This is a triangular area formed by the intersection of three points located at the lateral commissure of the mouth, the mastoid apophysis and a point located over the anterior border of the extracellular matrix (ECM) muscle with a line which intersects the lateral commissure of the mouth and the mandibular groove. The trajectory of the marginal and cervical branches of the facial nerve can be reliably and easily found at the described triangle following the reference points. This study will help guide surgeons to these branches of the facial nerve as it applies to aesthetic surgery.


Yersinia enterocolitica infection--an unrecognized cause of acute and chronic neurological disease? A 10-year follow-up study on 458 hospitalized patients.
The purpose of the present study was to obtain further information about nervous system involvement associated with Yersinia enterocolitica infection. During the period 1974-1983, the infection was diagnosed by antibody response (agglutination titer or ELISA) and/or isolation of the microorganism in 458 hospitalized patients. 2 patients presented with acute symptoms of the peripheral nervous system, and 6 with symptoms of the central nervous system. The 458 patients were followed for 4-14 years (until 1987). During the follow-up period another 6 patients developed chronic neurological conditions; 4 with peripheral symptoms, and 2 with central symptoms. 11 of the 14 patients experienced persistent complaints. In 1991 (10-17 years after the diagnosis of yersiniosis), 6 patients still had significant antibody response (ELISA). The possibility that the immunologically competent Yersinia enterocolitica might have initiated the chronic neurological disease in these patients should not be disregarded.


Biomagnification of endocrine disrupting chemicals (EDCs) by Pleuronectes yokohamae: Does P. yokohamae accumulate dietary EDCs?
We evaluated the potential for biomagnification of endocrine disrupting chemicals (EDCs) such as nonylphenol (NP), octylphenol (OP), bisphenol A (BP), and natural estrogens such as estrone (E1) and 17β-estradiol (E2) in a benthic fish, Pleuronectes yokohamae. The assimilation efficiencies (AE) of most EDCs ranged from 88 to 96% suggesting that they were efficiently incorporated and assimilated into P. yokohamae, except for NP (50%). However, the biomagnification factor (BMF) values were <1.0 suggesting that the compounds were not biomagnifying. Additionally, three of the target EDCs were not detected (BP, E1 and E2). Glucuronidation activity towards BP (11.44 ± 2.5 nmol/mg protein/min) and E2 (12.41 ± 3.2 nmol/mg protein/min) was high in the intestine suggesting that EDCs were glucuronidated prior to excretion into bile. Thus, we conclude that biomagnification of dietary EDCs is reduced in P. yokohamae because of effective glucuronidation.


15-Deoxy-Δ(12,14)-prostaglandin J2 inhibits IL-13 production in T cells via an NF-κB-dependent mechanism.
Interleukin (IL)-13 is a cytokine produced by activated CD4(+) T cells that plays a critical role in promoting allergic responses and tumor cell growth. The 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)) is a natural ligand for the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ), a known regulator of anti-inflammatory activities. We determined the effects of 15d-PGJ(2) on IL-13 expression in the Jurkat E6.1 T-cell line and in peripheral blood mononuclear cells. Semi-quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay revealed that treatment of activated T cells with 15d-PGJ(2) significantly decreased IL-13 mRNA transcription and secretion, respectively. This inhibition by 15d-PGJ(2) was independent of PPAR-γ since treatment with GW9662, an irreversible antagonist of the nuclear receptor, produced no effect. Our data also revealed the involvement of nuclear factor-κB in mediating 15d-PGJ(2)-dependent down regulation of IL-13 expression. Collectively, these results demonstrate the potential of 15d-PGJ(2) in attenuating expression and production of IL-13 in activated T cells.


A clinical assessment of a patch test kit marketed to U.K. hairdressers for detecting hair dye allergy.
In 2004 a U.K.-based company developed and marketed a patch test kit (Colourstart); Trichocare, Ridgmont, Beds, U.K.) for use by hairdressers. It is intended to assess whether clients have a 'problem with hair dye' and promotes itself as the 'only practical solution to sensitivity testing'. However, a patient presented with a hair dye reaction that had not been detected while using this patch test system. To assess the Colourstart system in the next seven consecutive patients presenting with a history of adverse reactions to hair dyes. The Colourstart system was tested in parallel with commercially available hair dye patch test reagents, where applicable. Only three of seven patients allergic to p-phenylenediamine were detected using this system and one patient allergic to toluene-2,5-diamine sulphate was not detected using this system. The results raise concerns about the sensitivity of this kit for consumer protection, but also wider questions about the regulation, use and interpretation of 'home diagnostic patch test kits' in general.


Two cDNA clones (FsDhn1 and FsClo1) up-regulated by ABA are involved in drought responses in Fagus sylvatica L. seeds.
Two abscisic acid (ABA)-responsive clones (FsDhn1 and FsClo1) were isolated from a cDNA library of ABA-treated seeds of Fagus sylvatica L. FsDhn1 codes for type-II late embryogenesis abundant (LEA) proteins, also known as dehydrins. The corresponding transcripts were ABA-induced and expressed when seeds were artificially dried. FsClo1 codes for a caleosin, a calcium-binding protein. By expressing FsCLO1 as a fusion protein in Escherichia coli, we obtained biochemical evidence of its ability to bind calcium, a second messenger involved in ABA signaling. This cDNA clone is seed specific, shows a LEA expression pattern and is also induced by ABA and dehydration treatments. The relationship of both genes with seed responses to ABA is discussed.


Haemodynamics in the horse: 2. Intracardiac, pulmonary arterial and aortic pressures.
The paper reports the changing pressure values during the cardiac cycle recorded from various chambers of the heart and great vessels using 2 catheter-mounted transducers, 9 cm apart. Pulse pressures are calculated. Transvalval pressure differences are determined taking account of the effect of hydrostatic pressure between the 2 sensors. The effects of some valvular lesions and arrhythmias and of changes in intrathoracic pressure are also described.


Degradation of endomorphin-2 at the supraspinal level in mice is initiated by dipeptidyl peptidase IV: an in vitro and in vivo study.
Endomorphin-2 (Tyr-Pro-Phe-PheNH(2)) was discovered as an endogenous ligand for the mu-opioid receptor. The physiological function of endomorphin-2 as a neurotransmitter or neuromodulator may cease through the rapid enzymatic process in the synapse of brain, as for other neuropeptides. The present study was conducted to examine the metabolism of endomorphin-2 by synaptic membranes prepared from mouse brain. Major metabolites were free tyrosine, free phenylalanine, Tyr-Pro and PheNH(2). Both the degradation of endomorphin-2 and the accumulation of major metabolites were inhibited by specific inhibitors of dipeptidyl peptidase IV, such as diprotin A and B. On the other hand, the accumulation of Phe-PheNH(2) and Pro-Phe-PheNH(2) was increased in the presence of bestatin, an aminopeptidase inhibitor, whereas that of free phenylalanine and PheNH(2) was decreased. Furthermore, purified dipeptidyl peptidase IV hydrolyzed endomorphin-2 at the cleavage site, Pro(2)-Phe(3) bond. Thus, degradation of endomorphin-2 by brain synaptic membranes seems to take place mainly through the cleavage of Pro(2)-Phe(3) bond by dipeptidyl peptidase IV, followed by release of free phenylalanine and PheNH(2) from the liberated fragment, Phe-PheNH(2) by aminopeptidase. We have also examined that the effect of diprotin A on the antinociception induced by intracerebroventricularly administered endomorphin-2 in the mouse paw withdrawal test. Diprotin A simultaneously injected with endomorphin-2 enhanced endomorphin-2-induced antinociception. These results indicate that dipeptidyl peptidase IV may be an important peptidase responsible for terminating endomorphin-2-induced antinociception at the supraspinal level in mice.


Immunohistochemical study of anaplastic meningioma with special reference to the phenotypic change of intermediate filament protein.
The phenotypic changes in the transformation of classic or atypical meningioma to anaplastic meningioma were investigated. Among nine patients with anaplastic meningioma, four men and five women ranging in age from 32 to 75 years, four cases were identified as anaplastic meningioma at the first operation (de novo type), while five cases were identified as classic or atypical meningioma at the first operation but at recurrence had transformed to anaplastic meningioma (secondary type). Immunohistochemical analysis was performed with the avidin-biotin complex method using monoclonal antibodies for glial fibrillary acidic protein, cytokeratin, alpha-internexin, neurofilament proteins (70 kd, 168 kd, and 200 kd), desmin, vimentin, CD34, Ki-67, epithelial membrane antigen, and S-100 protein. Immunohistochemical analysis showed positive immunoreactivity for cytokeratin, alpha-internexin, neurofilament proteins, vimentin, and glial fibrillary acidic protein during the course of progression. Expression of epithelial membrane antigen decreased with malignant progression. Marked expression of cytokeratin was observed in anaplastic meningioma. Ki-67 labeling index increased at every recurrence of both the de novo and secondary types. The major phenotypic changes in the transformation of meningioma from the classic to the anaplastic type are loss of meningioma architecture, decreased expression of epithelial membrane antigen, increased expression of vimentin, and metaplastic expression of alpha-internexin and neurofilament triplet proteins.


Lundberg and his Waves.
This historical vignette revisits the main contributions by Nils Lundberg, a neurosurgeon, that were published in the late 1950s and early 1960s. The Lundberg studies also definitively established that symptoms of abnormal brainstem function resulted from abnormal intracranial pressure (ICP), and moreover, even variations in ICP could produce clinical symptoms. The most innovative result of continuous monitoring was the discovery of plateau-shaped waves that produced paradoxical symptoms previously designated as "decerebrate" and "tonic fits" or "acute coning."


Enhancement of batch waste activated sludge digestion by microwave pretreatment.
Batch anaerobic digesters were used to stabilize microwave (MW)-irradiated waste activated sludge (WAS). A low temperature range (50-96 degrees C) MW irradiation was applied. Effects of pretreatment temperature (T) and intensity (I), concentration (C) and percentage of sludge pretreated (PT) were investigated in a multilevel factorial statistical design containing 54 mesophilic batch reactors by monitoring cumulative biogas production (CBP). Variance analysis (ANOVA) determined that the most important factors affecting WAS solubilization were temperature, intensity, and sludge concentration. Improvements in CBP from WAS were significantly affected by sludge percentage pretreated, temperature, and concentration. Pretreatment resulted in 3.6 +/- 0.6 and 3.2 +/- 0.1 fold increases in soluble to total chemical oxygen demand (SCOD/TCOD) at high and low sludge concentrations, respectively. WAS, microwaved to 96 degrees C, produced the greatest improvement in CBP with 15 +/- 0.5 and 20 +/- 0.3% increases over controls after 19 d of digestion at low and high WAS concentrations. Dewaterability of microwaved sludge was enhanced after anaerobic digestion.


Conceptus-derived cytokines interleukin-1β and interferon-γ induce the expression of acute phase protein serum amyloid A3 in endometrial epithelia at the time of conceptus implantation in pigs.
Serum amyloid A3 (SAA3), an acute phase response protein, plays important roles in opsonization, antimicrobial activity, chemotactic activity, and immunomodulation, but its expression, regulation, and function at the maternal-conceptus interface in pigs are not fully understood. Therefore, we determined the expression of SAA3 in the endometrium throughout the estrous cycle and at the maternal-conceptus interface during pregnancy. Endometrial tissues from pigs at various stages of the estrous cycle and pregnancy and with conceptuses derived from somatic cell nuclear transfer (SCNT), conceptus tissues during early pregnancy, and chorioallantoic tissues during mid- to late pregnancy were obtained and the expression of SAA3 was analyzed. The effects of the steroid hormones, interleukin-1β (IL1B), and interferon-γ (IFNG) on the expression of SAA3 were determined in endometrial explant cultures. SAA3 was expressed in the endometrium during the estrous cycle and pregnancy, with the highest level on day 12 of pregnancy. The expression of SAA3 in the endometrium was significantly higher on day 12 of pregnancy than during the estrous cycle. Early-stage conceptuses and chorioallantoic tissues during mid to late pregnancy also expressed SAA3. The expression of SAA3 was primarily localized to luminal epithelial cells in the endometrium. In endometrial explant cultures, the expression of SAA3 was induced by increasing doses of IL1B and IFNG. Furthermore, the expression of SAA3 decreased significantly in the endometria of pigs carrying conceptuses derived from SCNT on day 12 of pregnancy. These results suggest that the expression of SAA3 in the endometrium during the implantation period increases in response to conceptus-derived IL1B and IFNG. The failure of those appropriate interactions between the implanting conceptus and the endometrium leads to dysregulation of endometrial SAA3 expression, which could result in pregnancy failure. In addition, SAA3 could be a specific endometrial epithelial marker for conceptus implantation in pigs.


Rehabilitation: what do we do with the chronic patient?
Neurologists are often called on to see patients who have low back pain presenting with significant chronicity and disabling pain. Even in situations of chronic low back pain, it has been estimated that a structural diagnosis is made only 60% of the time. Even when a physical diagnosis is made in these cases, it may be irrelevant to the primary causes of persistent pain and disability. This article is designed to point out that, when nonstructural factors are adequately rehabilitated, even in a worst-case occupational injury cohort, remarkable outcomes can be anticipated irrespective of the structural pathology, patient age, or postoperative impairment.


The use of acetylated factor X to prevent feedback activation of factor VIII during factor X activation: a tool for kinetic studies.
The modification of human factor X by 2-sulfo-N-succinimidyl acetate was investigated and shown to produce a factor X species which, when activated, has no activity toward factor VIII. Acylation of factor X (0.9 microM) was carried out in the presence of 1 mM calcium at different reagent concentrations and pH values at 22 degrees C for time courses up to 1 h. Optimal modification was achieved using 0.3 mM reagent at pH 8.0 for 30 min. The modified zymogen, acetylated factor X, is activated at full rates by factor IXa/VIIIa and by the factor X-activating protein of Russell's viper venom. The activated product, acetylated Xa, has an enhanced amidolytic activity (110%) but has almost no detectable clotting activity (0.1%). More importantly, we have shown that acetylated Xa, in contrast to native Xa, does not activate factor VIII. This allows accurate quantitation of factor VIII activation without complications due to positive feedback reactions. We have demonstrated this in an examination of the activation of factor VIII by factor IXa.


Radiographic Signs of Femoroacetabular Impingement Are Associated With Decreased Pelvic Incidence.
To investigate the relation between cam, acetabular version, and pelvic incidence. This was a retrospective analysis of 65 patients with symptomatic hip pain and radiographic signs of femoroacetabular impingement (FAI). Twenty-seven patients were used as a control. All patients received a CT scan of the pelvis that included the sacral endplate. Alpha angle, acetabular version, and pelvic incidence (PI) were measured on 2D CT. Patients were then assigned to 1 of 4 groups: control, cam (alpha angle > 55°, version > 15°), retroverted (alpha angle < 55°, version < 15°), or mixed (alpha angle > 55°, version < 15°). The PI in mixed-type FAI was 46.7° ± 3.7°, which showed a statistically significant decrease from the PI of the control group, 56.1° ± 4.4° (P = .01). The PI for cam-only deformity was 50.8° ± 4.6°, and the PI for retroverted-only deformity was 51.0° ± 4.6°. Neither was statistically different from the control. This study suggests that mixed-type FAI may develop as a response to decreased PI. This result is consistent with previous reports showing decreased PI associated with cam and retroversion deformities. Although the cause of FAI remains controversial, the potential impact of sagittal balance of the pelvis, and specifically, decreased PI, should not be ignored. Level IV, therapeutic case series.


Semantic satiation of emotional words impedes facial expression processing in two stages.
To explore the mechanism of emotional words semantic satiation effect on facial expression processing, participants were asked to judge the facial expression (happiness or sadness) after an emotional word ((cry) or (smile)) or a neutral word ((Ah), baseline condition) was presented for 20 s. The results revealed that participants were slower in judging valence-congruent facial expressions and reported a more enlarged (Experiment 1) and prolonged (Experiment 2) N170 component than the baseline condition. No significant difference in behavior and N170 appeared between the valence-incongruent and the baseline condition. However, the amplitude of LPC (Late Positive Complex) under both valence-congruent/incongruent conditions was smaller than the baseline condition. It indicates that, in the early stage, the impeding effect of satiated emotional words is specifically constrained to facial expressions with the same emotional valence; in the late stage, such an impeding effect might spread to facial expressions with the opposite valence of the satiated emotional word.


The biosensor based on electrochemical dynamics of fermentation in yeast Saccharomyces cerevisiae.
The zymase activity of the yeast Saccharomyces cerevisiae is sensitive to environmental parameters and is therefore used as a microbiological sensor for water quality assessment, ecotoxicological characterization or environmental monitoring. Comparing to bacterial bioluminescence approach, this method has no toxicity, excludes usage of genetically modified microorganisms, and enables low-cost express analysis. This work focuses on measuring the yeast fermentation dynamics based on multichannel pressure sensing and electrochemical impedance spectroscopy (EIS). Measurement results are compared with each other in terms of accuracy, reproducibility and ease of use in field conditions. It has been shown that EIS provides more information about ionic dynamics of metabolic processes and requires less complex measurements. The conducted experiments demonstrated the sensitivity of this approach for assessing biophotonic phenomena, non-chemical water treatments and impact of environmental stressors.


Role of macrophages in inflammatory lymphangiogenesis: Enhanced production of vascular endothelial growth factor C and D through NF-kappaB activation.
The close association of inflammation, angiogenesis and cancer progression is now highlighted, and in this study we especially focused on a close association of inflammation and lymphangiogenesis. We found that proinflammatory cytokine, interleukin-1beta (IL-1beta), could induce lymphangiogenesis in mouse cornea through enhanced production of potent lymphangiogenic factors, VEGF-A, VEGF-C and VEGF-D. IL-1beta-induced lymphangiogenesis, but not angiogenesis, was inhibited by administration of a selective anti-VEGF receptor-3 (VEGFR-3) neutralizing antibody. And in mouse cornea we observed recruitment of monocyte/macrophages and neutrophils by IL-1beta implanted cornea. Depletion of macrophages by a bisphosphonate encapsulated in liposomes inhibited this IL-1beta-induced lymphangiogenesis and also up-regulation of VEGF-A, VEGF-C, and VEGF-D. Furthermore, IL-1beta-induced lymphangiogenesis and angiogenesis were suppressed by NF-kappaB inhibition with marked suppression of VEGF-A, VEGF-C, and VEGF-D expression.


Temporal trends in evidence supporting therapeutic interventions in heart failure and other European Society of Cardiology guidelines.
This study aimed to determine whether any change occurred over time in level of evidence (LoE) of therapeutic interventions supporting heart failure (HF) and other European Society of Cardiology guideline recommendations. We selected topics with at least three documents released between 2008 and April 2022. Classes of recommendations (CoR) and supporting LoE related to therapeutic interventions within each document were collected and compared over time. A total of 1822 recommendations from 18 documents on 6 topics [median number per document = 112, 867 (48%) CoR I] were included in the analysis. There was a trend towards a reduction over time in the percentage of CoR I in HF (46-36-34%), non-ST elevation myocardial infarction (NSTEMI; 78-58-54%), and pulmonary embolism (PE; 65-50-39%) guidelines, with a decrease in the total number of recommendations for HF only. Percentage of CoR I was stable over time around 40% for valvular heart disease (VHD) and atrial fibrillation (AF), and around 60% for cardiovascular prevention (CVP), with an increase in the total number of recommendations for VHD and CVP and a decrease for AF. Among CoR I, 319 (37%) were supported by LoE A, with a decrease over time for HF (56-46-42%), an increase for NSTEMI (29-38-48%) and AF (28-31-36%), a bimodal distribution for PE and CVP, and a lack for VHD. LoE supporting therapeutic recommendations in contemporary European guidelines is generally low. Physicians should be aware of these limitations, and scientific societies promote a greater understanding of their significance and drive future research directions.


Modulation by histamine of the efflux of radiolabeled catecholamines from rat brain slices.
Histamine induced a dose-dependent stimulation of 3H-catecholamine(CA) efflux (superfusion procedure) from hypothalamic, striatal, hippocampal and cortical slices. The extra-hypothalamic regions were the most sensitive to histamine. Efflux of 14C-GABA and 14C-(acetyl)choline was not affected. The effect of histamine on 3H-CA efflux developed slowly, reaching its maximum after 15-20 min. Histamine was inefffective with tissue from reserpinized animals. The major part of the radioactivity released by histamine consisted of CA metabolites. Histamine apparently does not enter catecholaminergic neurons, since tyramine and the CA had no effect on the efflux of 3H-histamine previously taken up by brain slices. After incubation of slices with 3H-CA in the presence of histamine and subsequent superfusion, tyramine or K+ -depolarization induced much less 3H-CA release than from control slices not incubated with histamine. It is suggested that histamine may act as a modulator of presynaptic catecholaminergic processes in the central nervous system by causing a depletion of the transmitter stores in the nerve terminals.


Measurement of the lumbrical muscle activity of the hand using electromyography supported by the ultrasound imaging technique with string navigation.
Although placing surface electrodes on small muscles by palpation is difficult, ultrasound guidance may enable electrode placement on the small muscles. This study aimed to examine whether ultrasound guidance is helpful for placement of electrodes on a small muscle, such as the hand lumbrical muscle. Twelve dominant hands of 12 healthy right-handed adults were included in this study. The first lumbrical muscle belly of the hands was identified using ultrasound guidance with a string navigation technique for placing surface electrodes. This technique was designed to identify the location of the center of the muscle belly under ultrasound imaging using a string. After the electrodes were placed on the muscle belly using this technique, the surface electromyographic signals of the first lumbrical, first dorsal interosseous, and adductor pollicis muscles were recorded. The activity of the lumbrical muscle could be separately measured of the first dorsal interosseous and adductor pollicis muscles. This technique has the potential to enable surface electromyography of small muscles for which placement of surface electrodes by palpation is challenging.


An extra anatomic, close chest approach to manage an aortic arch aneurysm in an 88-year-old woman.
Repair of thoracic arch aneurysms in the octogenarian is associated with a high morbidity and mortality. In this report we describe a minimally invasive approach to repair and arch aneurysm using an endoluminal graft with an extrathoracic, extra anatomic de-branching of the arch vessels. The advantage of this technique includes avoidance of a median sternotomy, cardiopulmonary bypass, and circulatory arrest with a rapid postoperative recovery.


ALDH2 inhibition by lead and ethanol elicits redox imbalance and mitochondrial dysfunction in SH-SY5Y human neuroblastoma cell line: Reversion by Alda-1.
Lead (Pb), a common environmental contaminant, and ethanol (EtOH), a widely available drug of abuse, are well-known neurotoxicants. In vivo, experimental evidence indicates that Pb exposure affects oxidative EtOH metabolism with a high impact on living organisms. On these bases, we evaluated the consequences of combined Pb and EtOH exposure on aldehyde dehydrogenase 2 (ALDH2) functionality. In vitro exposure to 10 µM Pb, 200 mM EtOH, or their combination for 24 h reduced ALDH2 activity and content in SH-SY5Y human neuroblastoma cells. In this scenario, we observed mitochondrial dysfunction characterized by reduced mass and membrane potential, decreased maximal respiration, and spare capacity. We also evaluated the oxidative balance in these cells finding a significant increase in reactive oxygen species (ROS) production and lipid peroxidation products under all treatments accompanied by an increase in catalase (CAT) activity and content. These data suggest that ALDH2 inhibition induces the activation of converging cytotoxic mechanisms resulting in an interplay between mitochondrial dysfunction and oxidative stress. Notably, NAD+ (1 mM for 24 h) restored ALDH2 activity in all groups, while an ALDH2 enhancer (Alda-1, 20 µM for 24 h) also reversed some of the deleterious effects resulting from impaired ALDH2 function. Overall, these results reveal the crucial role of this enzyme on the Pb and EtOH interaction and the potential of activators such as Alda-1 as therapeutic approaches against several conditions involving aldehydes accumulation.


Syndrome of inappropriate secretion of antidiuretic hormone caused by vincristine therapy: a case report of the neuropathology.
The syndrome of inappropriate secretion of antidiuretic hormone is a rare but well-recognized neurotoxic side effect of vincristine therapy. The first neuropathological report of a case is presented. A 6-month-old boy with skin leukemia developed inappropriate secretion of antidiuretic hormone caused by vincristine. Postmortem examination revealed axonal spheroids in the ansa lenticularis and the area surrounded by the substantia innominata, amygdala and supraoptic nucleus. The lesion was confined to that area and the neurosecretory neurons were intact with well preserved neurophysin. The pathological findings suggest that these fibers play a role in the development of inappropriate secretion of antidiuretic hormone caused by vincristine therapy.


Acute and chronic effects of ethanol on fluid transport in the human small intestine.
The effect of acute and chronic administration of ethanol on jejunal and ileal water and electrolyte transport was studied in healthy volunteers by the triple lumen intestinal perfusion technique. The acute perfusion of a glucose-free electrolyte solution containing 2 to 10 g per 100 ml of ethanol in the jejunum or ileum did not cause any significant alterations of sodium or water transport. In contrast, the administration of a folate-deficient diet and ethanol for 2 weeks produced a marked reduction in sodium and water absorption or a small net secretion (control, mean +/-SE: H2O = 0.91 +/- 0.06 ml per min, Na = 130 +/- 8 micronEq per min per 30 cm of intestine versus H2O = -0.13 +/- 0.14 ml per min, Na = -20 +/- 29 micronEq per min per 30 cm, P less than 0.001). These changes were not accompanied by a reduction in serum folate levels. The administration of ethanol with a folate-supplemented diet also produced significant but less pronounced changes in sodium and water transport control: H2O = 1.33 +/- 0.2 ml per min, Na = 185 +/- 34 micronEq per min per 30 cm of intestine versus H2O = 0.48 +/- 0.17 ml per min, Na =65 +/- 16 micronEq per min per 30 cm of intestine, P less than 0.05). From this study it appears that the diarrhea seen in chronic alcoholics can be explained in part by the effect of ethanol on intestinal sodium transport, without any accompanying changes in serum folate levels.


Pulmonary abscess caused by Cladosporium cladosporioides after receiving outpatient chemotherapy.
Cladosporium cladosporioides is one of the most ubiquitous dematiaceous fungi that seldomly occur human infection. Here, we demonstrate a rare case of pulmonary phaeohyphomycosis with a distinctive pulmonary lesion during the nadir period of outpatient chemotherapy against endometrial cancer. In addition to severe neutropenia, excessive exposure to C. cladosporioides at patient's residence was considered as dominant causative factor. More caution is considered necessary for pulmonary phaeohyphomycosis in patients who receive outpatient chemotherapy and are homebound during neutropenic status.


Boosted CO2 photoreduction performance on Ru-Ti3CN MXene-TiO2 photocatalyst synthesized by non-HF Lewis acidic etching method.
Photocatalytic CO2 reduction to produce value-added products is considered a promising solution to solve the global energy crisis and the greenhouse effect. In this study, Ti3CN MXene was synthesized using a Lewis acidic etching method without the usage of toxic hydrofluoric acid (HF). Ti3CN MXene was then used as a support for the in situ hydrothermal growth of TiO2 and Ru nanoparticles. In the presence of 0.5 wt% Ru, Ru-Ti3CN-TiO2 shows CO and CH4 production rates of 99.58 and 8.97 μmol/g, respectively, in 5 h under Xenon lamp irradiation, more than 20.5 and 9.3 times that of commercial P25. The enhancement in photocatalytic activity was attributed to the synergy between the in-situ growth of TiO2 on Ti3CN MXene and Ru nanoparticles. It was proven experimentally that Ti3CN MXene can provide abundant pathways for electron transfer. The separation and transfer of the photo-induced charge were further increased with the help of Ru and Ti3CN MXene, leaving more electrons to participate in the subsequent CO2 reduction reaction. We believe that this work will encourage more attention to designing environment-friendly MXene-based photocatalysts for CO2 photoreduction using the non-HF method.


Glyceraldehyde-3-phosphate dehydrogenase from the newt Pleurodeles waltl. Protein purification and characterization of a GapC gene.
The NAD(+)-dependent cytosolic glyceraldehyde-3-phosphate dehydrogenase (GAPDH, EC 18.104.22.168) has been purified to homogeneity from skeletal muscle of the newt Pleurodeles waltl (Amphibia, Urodela). The purification procedure including ammonium sulfate fractionation followed by Blue Sepharose CL-6B chromatography resulted in a 24-fold increase in specific activity and a final yield of approximately 46%. The native protein exhibited an apparent molecular weight of approximately 146 kDa with absolute specificity for NAD(+). Only one GAPDH isoform (pI 7.57) was obtained by chromatofocusing. The enzyme is an homotetrameric protein composed of identical subunits with an apparent molecular weight of approximately 37 kDa. Monospecific polyclonal antibodies raised in rabbits against the purified newt GAPDH immunostained a single 37-kDa GAPDH band in extracts from different tissues blotted onto nitrocellulose. A 510-bp cDNA fragment that corresponds to an internal region of a GapC gene was obtained by RT-PCR amplification using degenerate primers. The deduced amino acid sequence has been used to establish the phylogenetic relationships of the Pleurodeles enzyme--the first GAPDH from an amphibian of the Caudata group studied so far--with other GAPDHs of major vertebrate phyla.