Biocompatibility enhancement of hemodialysis membranes using a novel zwitterionic copolymer: Experimental, in situ synchrotron imaging, molecular docking, and clinical inflammatory biomarkers investigations.
The aim of the current research study is to conduct a comparative assessment of biocompatibility of zwitterionic-coated polyether sulfone (PES) clinical hemodialysis (HD) membranes using both theoretical and experimental methods. Fibrinogen plays a key role in assessing membrane hemocompatibility since its membrane-surface adsorption triggers several biological reactions, complete thrombosis and embolism. As a result, adsorption of fibrinogen on the untreated PES surface and novel synthesized PES coated with poly 3-((3-(3-carboxy-2,5-dimethyltridecanamido) propyl) dimethylammonio) propane-1-sulfonate as a zwitterion (ZW) was compared. Specifically, the comparison was conducted using in situ synchrotron based micro computed tomography imaging (SR-μCT), Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) spectroscopy, and Scanning Electron Microscopy (SEM). The in situ SR-μCT showed that fibrinogen adsorption and membrane fouling were intense on PES membrane surface. However, there was insignificant fouling in the middle layer of zwitterion coated PES membrane (PES-ZW). Moderate shifting of peaks was observed in ATR-FTIR spectra of the adsorbed fibrinogen when compared to the bulk protein spectra, which may be due to the conformational transformations occurring during the adsorption process. The spectral features indicate that PES-ZW surface has a lower adsorption affinity for fibrinogen than that for the PES surface. In this innovative study, the use of molecular modeling docking to evaluate the interaction of fibrinogen active pose with PES-ZW and PES models with the aim of gaining an in depth understanding of the functional group responsible for the interactions was explored. The PES and PES/zwitterion hemodialysis membrane models indicated minimum binding energies with fibrinogen by -6.00 and -6.70 kcal/mol, respectively. Docking studies thus suggest that the membrane's sulfone functional groups play an essential key role during the fibrinogen interaction and adsorption. The HD patients' uremic samples were incubated in vitro with PES and PES-ZW membranes for the inflammatory biomarkers released of Serpin/Antithrombin-III, Properdin, C5a, IL-1α, IL-1β, TNF-α, and IL6. This study's results emphasize that even though a neutral charge of synthesized novel zwitterion PES, which enhances biocompatibility, the sulfone group still significantly affected the interactions with fibrinogen.


Meta-analysis of the changes of peripheral blood regulatory T cell to CD4+ T cell ratio in patients with systemic sclerosis.
Current reports on the changes in peripheral blood regulatory T cell (Tregs) to CD4+ T cell ratio in systemic sclerosis (SSc) patients are varied in their conclusions. We therefore performed a meta-analysis to identify the actual change in the proportion of peripheral Tregs in SSc. Three databases, namely EMBASE, ISI web of knowledge, and Pubmed were systematically searched for relevant literature. Approximately 250 SSc patients and controls from several studies were included in this analysis. Comprehensive Meta Analysis Version 2.0 software was used to conduct the meta-analysis. Six studies were included in the meta-analysis. Results of the meta-analysis showed high degree of heterogeneity (I2 = 96.98), and a random-effect model was used in the subsequent analysis. The ratio of circulating Tregs to CD4+ T cell in SSc was lower than in controls, but not statistically significantly so (-0.61 ± 0.94, P = 0.52). Subgroup analysis did not identify any potential source of heterogeneity. This meta-analysis indicated that Tregs might play a less prominent immunosuppressive role in the immune system in SSc patients, but needs further confirmation.


Surgical Treatment of Temporomandibular Joint Derangement: 30-Year Follow-Up of Temporomandibular Joint Discectomy, a Case Report and Literature Review.
The improvement in diagnostic accuracy, improvement of the endoscopic equipment, better selection of patients for open TMJ surgery, and increased focus on research and education are promising for the treatment of the group of patients with TMJ derangements. In the future, prospective randomized clinical trials need to be performed to give the clinician guidelines as to which type of intervention should be chosen in a particular patient base on accepted criteria for diagnosis and treatment of TMJ derangement.


[Assay of erythrocyte, platelet and serum superoxide dismutase, glutathione peroxidase and catalase in rheumatoid polyarthritis].
The authors present a study of superoxide dismutase, catalase and glutathione peroxidase in hemolysis product, platelets and serum of 23 patients with rheumatoid polyarthritis and 11 healthy subjects. The nature of the treatment enables to divide the 23 patients into 3 groups: group I (8 cases): no treatment; Group II (7 cases): steroid therapy alone; group III (8 cases): basic treatment associated (3 cases) or not (5 cases) to steroid therapy. Statistical analysis shows no significant difference, whatever the environment and the treatment contemplated. The significance of these results is discussed and compared with literature data concerning only enzymatic activities and not the blood levels as in the present study.


A 3D-printed vanperio educative dental model - A review report of its chairside evaluation.
Patient education and demonstration of osseous defects by teachers and clinicians are difficult even though there are different models made up of metal, plastic, plaster, stone, and acrylic. To overcome such difficulty, 3D printed Vanperio model was printed for multifunctional activity. The aim of this article was to provide information on the 3D printed VANPERIO model and its implications in the field of periodontics and general dentistry. Vanperio model proves to be a promising model for teachers, students, and clinicians in the field of periodontics and general dentistry as it helps in patient education, student learning and also for various demonstrations which is not possible to achieve in other available expensive models.


Valuing Air Quality Using Happiness Data: The Case of China.
This paper estimates the monetary value of cutting PM2.5, a dominant source of air pollution in China. By matching hedonic happiness in a nationally representative survey with daily air quality data according to the dates and counties of interviews in China, we are able to estimate the relationship between local concentration of particulate matter and individual happiness. By holding happiness constant, we calculate the tradeoff between the reduction in particulate matter and income, essentially a happiness-based measure of willingness-to-pay for mitigating air pollution. We find that people on average are willing to pay ¥258 ($42, or 1.8% of annual household per capita income) per year per person for a 1% reduction in PM2.5.


Outdoor and indoor monitoring of livestock-associated Culicoides spp. to assess vector-free periods and disease risks.
Within the last few decades Culicoides spp. (Diptera: Ceratopogonidae) emerged Europe-wide as a major vector for epizootic viral diseases e.g. caused by Bluetongue (BT) or Schmallenberg virus. In accordance with the EU regulation 1266/2007, veterinary authorities are requested to determine vector-free periods for loosing trade and movement restrictions of susceptible livestock. Additionally, the widely used basic reproduction number [Formula: see text] is optionally applied for risk assessment of vector-borne diseases. Values of R0 < 1 indicate periods with no disease transmission risk. For the determination of vector-free period and R0 a continuously operating daily Culicoides spp. monitoring in Vienna (Austria) was established. It covered the period 2009-2013 and depicts the seasonal vector abundance indoor and outdoor. Future BT and African horse sickness (AHS) outbreak risks were estimated by projecting R0 to climate change scenarios. Therefore, temperature-dependent vector parameters were applied. The vector-free period lasted about 100 days inside stables, while less than five Culicoides were trapped outdoors on 150 days per season, i.e. winter half year. Additionally, the potential outbreak risk was assessed for BT and AHS. For BT, a basic reproduction number of R0 > 1 was found each year between June and August. The periods without transmission risk, i.e. R0 < 1, were notably higher (200 days). Contrary, values of R0 < 1 were estimated for AHS during the whole period. Finally, the basic reproduction numbers were projected to the future by using temperature forecasts for the period 2014-2100. While the mean summer peak values for BT increase from of R0 = 2.3 to R0 = 3.4 until 2100 (1.1/100 years), no risk for AHS was estimated even under climate warming assumptions. Restrictions to trade and movement are always associated with an economic impact during epidemic diseases. To minimize these impacts, risk assessments based on the vector-free period or the basic reproduction number R0 can essentially support veterinary authorities to improve protection and control measurements.


Differential proteomic analysis of acute contusive spinal cord injury in rats using iTRAQ reagent labeling and LC-MS/MS.
In this experimental study, differential labeling with isobaric tags for relative and absolute quantitation (iTRAQ) reagents followed by liquid chromatography (LC) and tandem mass spectrometry (MS/MS) proteomic approach was used to investigate differences in the proteome of rat spinal cord at 24 h following a moderate contusion injury. Spinal cord protein samples from the injury epicenter (or from sham controls) were trypsinized and differentially labeled with iTRAQ isotopic reagents. The differentially labeled samples were then combined into one sample mixture, separated by LC, and analyzed using MS/MS. Proteins were quantified by comparing the peak areas of iTRAQ reporter fragment ions in MS/MS spectra. The outcome of this analysis revealed that proteins involved in ubiquitination, endocytosis and exocytosis, energy metabolism, inflammatory response, oxidative stress, cytoskeletal disruption, and vascular damage were significantly altered at 24 h following spinal cord injury (SCI). This study demonstrates the utility of the iTRAQ method in proteomic studies and provides further insights into secondary events that occur during acute times following SCI.


Mitochondrial function is differentially affected upon oxidative stress.
The mechanisms that lead to mitochondrial damage under oxidative stress conditions were examined in synaptosomes treated with ascorbate/iron. A loss of membrane integrity, evaluated by electron microscopy and by LDH leakage, was observed in peroxidized synaptosomes and it was prevented by pre-incubation with vitamin E (150 microM) and idebenone (50 microM). ATP levels decreased, in synaptosomes exposed to ascorbate/iron, as compared to controls. NADH-ubiquinone oxidoreductase (Cx I) and cytochrome c oxidase (Cx IV) activities were unchanged after ascorbate/iron treatment, whereas succinate-ubiquinone oxidoreductase (Cx II), ubiquinol cytochrome c reductase (Cx III) and ATP-synthase (Cx V) activities were reduced by 55%, 40%, and 55%, respectively. The decrease of complex II and ATP-synthase activities was prevented by reduced glutathione (GSH), whereas the other antioxidants tested (vitamin E and idebenone) were ineffective. However, vitamin E, idebenone and GSH prevented the reduction of complex III activity observed in synaptosomes treated with ascorbate/iron. GSH protective effect suggests that the oxidation of protein SH-groups is involved in the inhibition of complexes II, III and V activity, whereas vitamin E and idebenone protection suggests that membrane lipid peroxidation is also involved in the reduction of complex III activity. These results may indicate that the inhibition of the mitochondrial respiratory chain enzymatic complexes, that are differentially affected by oxidative stress, can be recovered by specific antioxidants.


Case report: Increased viral receptor expression associated with high viral load and severe pneumonia in a young patient infected with 2009 H1N1 influenza a with no pre-existing conditions.
A case of unusually high severity of influenza pneumonia leading to acute respiratory distress syndrome and death was investigated. This was a previously a healthy 28-year-old man with no underlying conditions, admitted to a hospital during the first wave of influenza pandemic in Thailand in July 2009. He had experienced high fever and influenza-like illness for 5 days before coming to the hospital. He developed acute respiratory distress syndrome and expired on day 7 after admission. In comparison to three other cases of influenza pneumonia in the same outbreak with known risk factors for severe influenza, such as pregnancy and diabetes mellitus, a much higher viral load was detected in the lungs of this patient despite antiviral treatment. In agreement with the high viral load, the lung specimens from this patient, but not the other three patients, showed a high expression of α-2,6-linked sialic acid by lectin staining. The gene responsible for the synthesis of this sialic acid was also found to be upregulated. The data indicated overexpression of the viral receptor as a potential mechanism for severe disease in some patients.


125I-anti-insulin receptor Fab is internalized by cultured human lymphocytes.
When 125I-anti-insulin receptor Fab components are prepared from serum IgG, this univalent material binds to the surface of cultured human lymphocytes and is subsequently internalized by the cell in an identical fashion to the divalent IgG and to 125I-insulin itself.


Diarrhea caused by enterotoxigenic Escherichia coli infection of humans is inhibited by dietary calcium.
In several rat infection experiments, we have shown that dietary calcium inhibits intestinal colonization and translocation of invasive salmonella. The aim of the present study was to find out whether calcium is also protective against enterotoxigenic Escherichia coli (ETEC) infection. This was first tested in our rat model and subsequently verified in a human infection study. Rats were fed a purified diet with either a low or a high amount of calcium phosphate and orally infected with ETEC. In addition, a parallel, double-blind, placebo-controlled intervention study of 3 weeks was performed with 32 healthy men. Subjects largely maintained their habitual diet and consumed either regular milk products (calcium supply, 1100 mg/day) or placebo milk products (calcium supply, 60 mg/day). On day 10, subjects ingested a live but attenuated ETEC strain (strain E1392/75-2A), able to induce mild although short-lived symptoms. Primary outcomes studied were infection-induced diarrhea (total fecal output and relative fecal dry weight) and fecal mucin excretion. In humans, ETEC induced diarrhea in both groups, in that total fecal output doubled and mean relative fecal dry weight dropped from 25% to 20%. Additionally, fecal mucin excretion was increased in both groups. All these fecal parameters were completely normalized in the calcium group on the second infection day, in contrast to the placebo group, which recovered on the third infection day. Likewise, supplemental calcium inhibited ETEC colonization and diarrhea in rats. Calcium in milk products improves human resistance to ETEC infection as it inhibits infectious diarrhea.


In vitro culture systems for hepatitis B and delta viruses.
The development of tissue culture technology has led to invaluable information in many fields of modern virology. Until recently, the lack of an in vitro culture system for the hepatitis B virus (HBV) was a considerable impediment to the study of its life cycle at the cellular and molecular levels. However, it did not prevent its isolation and molecular cloning. Such has been the case also for the hepatitis delta virus (HDV), the genome of which was cloned and sequenced before its replication could be observed in cultured cells. In recent years, tissue culture systems for HBV and HDV have been developed progressively by the identification of permissive, established cell lines for production of virions and susceptible primary hepatocyte cultures for infection assays. I will briefly review here the recent experiments that have contributed to replicate HBV and HDV in cell culture systems.


Strategies to mitigate N2O emissions from biological nitrogen removal systems.
N2O emissions from the biological treatment of sewage, manure, landfill leachates and industrial effluents have gained considerable interest among policy makers and environmental scientists. Estimated global emission rates from these sources can contribute up to 10% of the anthropogenic N2O emissions. Particularly at the level of a treatment plant, the N2O impact can be very significant and reach up to 80% of the operational CO2 footprint. Imperfect nitritation by an imbalance in the two-step nitritation metabolism of ammonia-oxidizing bacteria is considered as the main contributor to N2O production with hydroxylamine and particularly nitrite as key precursors. Monitoring of these compounds is warranted to understand and abate N2O emissions. Mitigation strategies should also comprise optimizations of the process parameters as well as bio-augmentative approaches empowered to restore the functional capacity and to deal with unwanted accumulation of intermediates. These strategies require validation for their effectiveness and costs at full-scale.


Nutritional needs during the first year of life. Some concepts and perspectives.
This article reviews some of the recent changes in thinking that are reflected in two reports (Recommended Nutrient Intakes for Canadians and the FAO/WHO/UNU Report on Energy and Protein Requirements) concerning nutrient requirements for infants below one year of age. The author illustrates the concepts underlying the published requirement estimates and hence some of the principles that should underlie the interpretation and application of the estimates.


Multiplex PCR amplification of ancient DNA.
Multiplex PCR allows the simultaneous amplification of up to dozens of target fragments in a single PCR. It is therefore a powerful tool to obtain many kilobases of continuous sequence from minute amounts of ancient DNA (aDNA), which usually must be amplified in multiple short and overlapping fragments. Because significantly less template is required compared to amplifying each fragment separately, multiplex PCR is particularly beneficial when the fossil material itself, or access to the fossil material, is limited. The recently refined two-step multiplex PCR protocol consists of a first-step reaction (the actual multiplex PCR) that then acts as the template for the second-step PCR. During the second step, nested primers are used in individual amplification reactions. Although the same set of primers can be used in both steps, using a nested set in the second step adds an additional level of selectivity and specificity, minimizing PCR artifacts. This is particularly important when complex mixtures of template DNA, such as aDNA extracts, are amplified.


EUS-guided biliary drainage: a review article.
To demonstrate a comprehensive review of published articles regarding EUS-guided biliary drainage. Review of studies regarding EUS-guided biliary drainage including case reports, case series and previous reviews. EUS-guided hepaticogastrostomy, choledochoduodenostomy and choledochoantrostomy are advanced procedures on biliary and pancreatic endoscopy and together make up the echo-guided biliary drainage. Hepaticogastrostomy is indicated in cases of hilar obstruction, while the procedure of choice is choledochoduodenostomy in distal lesions. Both procedures must be done only after unsuccessful ERCP. The indication of these procedures must be made under a multidisciplinary view while sharing information with the patient or legal guardian. Hepaticogastrostomy and choledochoduodenostomy are feasible when performed by endoscopists with expertise in biliopancreatic endoscopy and advanced echo-endoscopy and should be performed currently under rigorous protocol in educational institutions.


Zirconium Carbide Produced by Spark Plasma Sintering and Hot Pressing: Densification Kinetics, Grain Growth, and Thermal Properties.
Spark plasma sintering (SPS) has been employed to consolidate a micron-sized zirconium carbide (ZrC) powder. ZrC pellets with a variety of relative densities are obtained under different processing parameters. The densification kinetics of ZrC powders subjected to conventional hot pressing and SPS are comparatively studied by applying similar heating and loading profiles. Due to the lack of electric current assistance, the conventional hot pressing appears to impose lower strain rate sensitivity and higher activation energy values than those which correspond to the SPS processing. A finite element simulation is used to analyze the temperature evolution within the volume of ZrC specimens subjected to SPS. The control mechanism for grain growth during the final SPS stage is studied via a recently modified model, in which the grain growth rate dependence on porosity is incorporated. The constant pressure specific heat and thermal conductivity of the SPS-processed ZrC are determined to be higher than those reported for the hot-pressed ZrC and the benefits of applying SPS are indicated accordingly.


Myeloperoxidase deficiency attenuates systemic and dietary iron-induced adverse effects.
Iron deficiency is routinely treated with oral or systemic iron supplements, which are highly reactive and could induce oxidative stress via augmenting the activity of proinflammatory enzyme myeloperoxidase (MPO). To investigate the extent to which MPO is involved in iron-induced toxicity, acute (24 h) iron toxicity was induced by intraperitoneal administration of FeSO4 (25 mg/kg body weight) to MPO-deficient (MpoKO) mice and their wild-type (WT) littermates. Acute iron toxicity was also assessed in WT mice pretreated with an MPO inhibitor, 4-aminobenzoic acid hydrazide. Systemic iron administration up-regulated circulating MPO and neutrophil elastase and elevated systemic inflammatory and organ damage markers in WT mice. However, genetic deletion of MPO or its inhibition significantly reduced iron-induced organ damage and systemic inflammatory responses. In contrast to the acute model, 8 weeks of 2% carbonyl iron diet feeding to WT mice did not change the levels of circulating MPO and neutrophil elastase but promoted their accumulation in the liver. Even though both MpoKO and WT mice displayed similar levels of diet-induced hyperferremia, MpoKO mice showed significantly reduced inflammatory response and oxidative stress than the WT mice. In addition, WT bone-marrow-derived neutrophils (BMDN) generated more reactive oxygen species than MPO-deficient BMDN upon iron stimulation. Altogether, genetic deficiency or pharmacologic inhibition of MPO substantially attenuated acute and chronic iron-induced toxicity. Our results suggest that targeting MPO during iron supplementation is a promising approach to reduce iron-induced toxicity/side effects in vulnerable population.


Ultrafast inactivation of SARS-CoV-2 by 254-nm UV-C irradiation on porous and non-porous media of medical interest using an omnidirectional chamber.
Covid-19 has spurred a renewed interest in decontamination techniques for air, objects and surfaces. Beginning in 2020, urgent effort was done to permit the reuse of UV-C for inactivating SARS-CoV-2. However, those studies diverged widely on the dose necessary to reach this goal; until today, the real value of the sensitivity of the virus to a 254-nm illumination is not known precisely. In this study, decontamination was performed in an original UV-C large decontamination chamber (UVCab, ON-LIGHT, France) delivering an omnidirectional irradiation with an average dose of 50 mJ/cm2 in 60 s. Viral inactivation was checked by both cell culture and PCR test. SARS-CoV-2 was inactivated by UV-C light within 3 s on both porous (disposable gown) and non-porous (stainless steel and apron) surfaces. For the porous surface, an irradiation of 5 min was needed to achieve a completely negative PCR signal. The Z value estimating the sensitivity of SARS-CoV-2 to UV-C in the experimental conditions of our cabinet was shown to be > 0.5820 m2/J. These results illustrate the ability of this apparatus to inactivate rapidly and definitively high loads of SARS-CoV-2 deposited on porous or non-porous supports and opens new perspectives on material decontamination using UV-C.


A novel approach for breast cancer prediction using optimized ANN classifier based on big data environment.
Cancer is caused by the un-controlled division of abnormal cells in a body part. Various cancers exist in this world and one amongst them is breast cancer. Breast cancer (BC) threatens the lives of people and today, it is the secondary prime cause of death in women. Numerous research directions concentrated on the prediction of BC. The prevailing prediction model is time-consuming and have less accuracy. To trounce those drawbacks, this paper proposed a BC prediction system (BCPS) utilizing Optimized Artificial Neural Network (OANN). Primarily, the unprocessed BC data are regarded as the input. The big data (BD) storage comprises some repeated information. Secondarily, such repeated data are eliminated by utilizing Hadoop MapReduce. In the subsequent stage, the data are preprocessed utilizing replacing of missing attributes (RMA) and normalization techniques. Subsequently, the features are generally chosen by utilizing Modified Dragonfly algorithm (MDF). Then, the selected features are inputted for classification. Here, it classifies the features utilizing OANN. Optimization is done by employing the Gray Wolf Optimization (GWO) algorithm. Experiential outcomes are contrasted with prevailing IWDT (Improved Weighted-Decision Tree) in respect of precision, recall, accuracy, and ROC.


Melatonin prevents preeclamptic sera and antiphospholipid antibodies inducing the production of reactive nitrogen species and extrusion of toxic trophoblastic debris from first trimester placentae.
The exact cause of preeclampsia is unknown. However a "toxin" from the placenta triggers the condition via activation of the maternal endothelium. Extracellular vesicles (EVs) from the syncytiotrophoblast, may be an endothelial-activating toxin. Antiphospholipid antibodies (aPL) and preeclamptic sera both induce the production of endothelial cell-activating EVs by mechanisms which may produce excess free-radicals in the placenta. Melatonin is produced by the human placenta and has both direct and indirect anti-free-radical properties and may therefore counter the effects of aPL and preeclamptic sera. First trimester placental explants were exposed to preeclamptic sera or aPL in the presence or absence of melatonin. Nitrosylative damage was assessed in the explants by immunohistochemistry and the effect of EVs from these explants on endothelial cell activation determined by ICAM-1. Release of nitrosylated proteins from the explants was also measured. Placental explants showed reduced secretion of melatonin after treatment with preeclamptic sera. Nitrosylated proteins were more abundant in placentae that had been treated with aPL or preeclamptic sera and EVs from such placentae induced endothelial cell activation. Adding melatonin to the aPL or preeclamptic sera reversed the protein nitrosylation and production of endothelial-activating EVs. Our data are consistent with reports that the levels of circulating melatonin are reduced in preeclampsia and suggest that aPL and factors in preeclamptic sera induce free-radical-mediated damage in the placenta leading to the production of endothelial-activating EVs. Melatonin reversing production of endothelial-activating EVs indicates that melatonin may have therapeutic benefits in women with preeclampsia and/or aPL.


The correlation between anterior cruciate ligament injury in elite alpine skiers and their parents.
The aim of this study was to investigate whether a familiar correlation with anterior cruciate ligament (ACL) injury exists between competitive alpine skiers and their parents. All 593 (293 males, 300 females) elite alpine skiers who have studied at a Swedish alpine Ski High School during 2006 and 2012 answered a questionnaire whether they or their parents had suffered an ACL injury. A total of 418 skiers (70%) answered the questionnaire. Twenty-nine per cent (n = 19) out of the 65 ACL-injured skiers reported that they had a parent (mother or father) who have had an ACL injury. In skiers without an ACL injury (n = 353), the result was 18% (n = 64). An odds ratio of 1.95 (95% confidence interval 1.04-3.65) was found to suffer an ACL injury if you have a parent who has had an ACL injury compared with if you have a parent without any ACL injury. The findings of the current study demonstrated a family history to tear the ACL between alpine skiers who had studied at a Swedish Ski High School and ACL injuries of their parents. III.


Left ventricular hypertrophy is a common echocardiographic abnormality in severe obstructive sleep apnea and reverses with nasal continuous positive airway pressure.
To determine cardiac structural abnormalities by echocardiography in subjects with severe obstructive sleep apnea (OSA), and to determine the long-term effects of nasal continuous positive airway pressure (CPAP) on such abnormalities. Polysomnography was conducted on oximetry-screened patients who showed a desaturation index > 40/h and > or = 20% cumulative time spent below 90%. From these, 25 patients with severe OSA but without daytime hypoxemia underwent echocardiography prior to, then 1 month and 6 months following initiation of CPAP treatment. Outpatient sleep disorders center. Of the 25 patients, 13 patients (52%) had hypertension by history or on physical examination. Baseline echocardiograms showed that severe OSA was associated with numerous cardiovascular abnormalities, including left ventricular hypertrophy (LVH) [88%], left atrial enlargement (LAE) [64%], right atrial enlargement (RAE) [48%], and right ventricular hypertrophy (16%). In all patients (intent to treat) as well as those patients compliant with CPAP therapy (84% > 3 h nightly), there was a significant reduction in LVH after 6 months of CPAP therapy as measured by interventricular septal distance (baseline diastolic mean, 13.0 mm; 6-month mean after CPAP, 12.3 mm; p < 0.02). RAE and LAE were unchanged after CPAP therapy. LVH was present in high frequency in subjects with severe OSA and regressed after 6 months of nasal CPAP therapy.


Physical function (PF) is a strong predictor for length of stay, complications, readmission, and mortality among patients across different diagnoses. Still, systematic assessment of PF in hospitalised patients is not common, and if, only among the oldest. In this review, we suggest implementation of an easily applicable and validated test battery using the Cumulated Ambulation Score for basic mobility, Handgrip strength for general muscle strength, and the 30s Chair Stand Test for combined function and muscle strength for early identification and treatment of reduced PF in adult patients across diagnoses.


Molecular characterization and comparative expression analysis of two teleostean pro-inflammatory cytokines, IL-1β and IL-8, from Sebastes schlegeli.
Interleukin 1β (IL-1β) and interleukin 8 (IL-8) are two major pro-inflammatory cytokines which play a central role in initiation of inflammatory responses against bacterial- and viral-infections. IL-1β is a member of the interleukin 1 family proteins and IL-8 is classified as a CXC-chemokine. In the current study, putative IL-1β and IL-8 counterparts were identified from a black rockfish transcriptomic database and designated as RfIL-1β and RfIL-8. The RfIL-1β cDNA sequence consists of 1140 nucleotides with a 759bp open reading frame (ORF) which encodes a 252 amino acid (aa) protein, whereas the RfIL-8 cDNA sequence (898bp) harbors a 300bp ORF encoding a 99 aa protein. Furthermore, the RfIL-1β aa sequence contains an IL-1 super family-like domain and an N-terminal IL-1 super family propeptide, while the amino acid sequence of RfIL-8 consists of a typical chemokine-CXC domain. Analysis of sequenced BAC clones containing RfIL-1β and RfIL-8 showed each gene to contain 4 exons interrupted by 3 introns. Pairwise comparison and phylogeny analysis of these cytokine sequences clearly revealed their closer relationship with other corresponding members of teleosts compared to birds and mammals. Constitutive differences in RfIL-1β and RfIL-8 mRNA expression were detected in a tissue-specific manner with the highest expression of each mRNA in spleen tissue. Two immune challenge experiments were conducted with Streptococcus iniae and polyinosinic:polycytidylic acid (poly I:C; a viral double stranded RNA mimic), and transcripts were quantified in spleen and peripheral blood cells. Significantly increased RfIL-1β and RfIL8 transcript levels were detected with almost similar profile patterns, further suggesting a putative involvement of these pro-inflammatory cytokines in the rockfish immunity.


Anaemia among adults in Kassala, Eastern Sudan.
The increased heterogeneity in the distribution of social and biological risk factors makes the epidemiology of anaemia a real challenge. A cross-sectional study was conducted at Kassala, Eastern Sudan during the period of January-March 2011 to investigate the prevalence and predictors of anaemia among adults (> 15 years old). Out of 646, 234 (36.2%) adults had anaemia; 68 (10.5%); 129 (20.0%) and 37 (5.7%) had mild, moderate and severe anaemia, respectively. In logistic regression analyses, age (OR = 1.0, CI = 0.9-1, P = 0.7), rural vs. urban residency (OR = 0.9, CI = 0.7-1.3, P = 0.9), female vs. male gender (OR = 0.8, CI = 0.6-1.1, P = 0.3), educational level ≥ secondary level vs. < secondary level (OR = 1.0, CI = 0.6-1.6, P = 0.8) and Hudandawa vs. non-Hudandawa ethnicity (OR = 0.8, CI = 0.6-1, P = 0.1) were not associated with anaemia. There was a high prevalence of anaemia in this setting, anaemia affected adults regardless to their age, sex and educational level. Therefore, anaemia is needed to be screened for routinely and supplements have to be employed in this setting.


Isoelectric-focusing behavior of acid hydrolases in rat kidney lysosomes. Effects of the pH gradient, autolysis and neuraminidase.
Isoelectric focusing was used to study the multiple forms of acid phosphatase, arylsulfatase, beta-glucuronidase and beta-N-acetylhexosaminidase in lysosomes isolated from rat kidney. The isoelectric points of the main protein and hydrolase peaks were 1-1.5 units lower when electrofocusing was done in a pH 3-10 gradient than in a pH 10-3 gradient, apparently because the lysosomal constituents aggregated strongly at their isoelectric points and tended to settle somewhat in the gradient due to gravity. In the extended pH gradient the acidic form of each hydrolase occurred as asingle, relatively discrete peak. However, when pooled acidic fractions were refocused in a restricted pH gradient (pH 6-3 or 3-5) multiple acidic enzyme and protein components were resolved with isoelectric points between 2.7 and 5.1. When autolysis was minimized by extracting lysosomal fractions at alkaline pH (0.2% Triton X-100, 0.1%p-nitrophenyloxamic acid, 0.1 M glycine buffer, pH9) and including 0.1%p-NITROPHENYLOXAMIC ACID, AN INHIBITOR OF LYSOSOMAL NEURAMINIDASE AND CATHEPSIN D, in the pH gradient, arylsulfatase, beta-glucuronidase and beta-N-acetylhexosaminidase occurred in two forms, an acidic form with an isoelectric point of about 4.4, and a basic form with an isoelectric point close to 6.2, 6.7 and 8.0, respectively. Acid phosphatase occurred in three forms with isoelectric points of 4.1, 5.6 and 7.4. When some autolytic digestion was permitted by extracting lysosomal fractions in an acidic medium (0.2% Triton X-100, 0.1 M sodium acetate buffer, pH 5.2) AT 0-4DEGREES C and omitting p-nitrophenyloxamic acid from the gradient, the acidic form of beta-glucuronidase and the intermediate form of acid phosphatase were lost, the isoelectric points of the acidic forms of acid phosphatase, arylsulfatase and beta-N-acetylhexosaminidase were increased 0.6-1.2 units, and the isoelectric point of the basic forms of acid phosphatase, arylsulfatase and beta-glucuronidase was increased 0.5 unit. When lysosomal extracts were incubated with bacterial neuraminidase before electrofocusing, the acidic forms of acid phosphatase, arylsulfatase and beta-glucuronidase were largely lost, the isoelectric point of the acidic form of beta-N-acetylhexosaminidase was increased from 4.5 to 6.4, and the isoelectric points of the basic forms of all four hydrolases were increased 0.5-1.5 units. Autoincubation of lysosomal extracts in vitro at pH 5.2 PRODUCED SIMILAR, THOUGH LESS MARKED, effects. cont'd


Robotic-assisted thoracoscopic resection of anterior mediastinal cystic teratoma: a case report and literature review.
Mediastinal teratomas are rare tumors that frequently occur in the anterior mediastinum. The majority of these tumors are benign and slow growing. Due to their low malignant potential, the treatment for these tumors is surgical resection. More recently, the surgical management has shifted from invasive approaches such as a sternotomy to minimally invasive ones such as robotic-assisted thoracoscopic resections utilizing lung isolation ventilation. We present a rare case of a locally advanced mediastinal teratoma requiring resection, which was initially attempted thoracoscopically using double lung ventilation. A 43 year-old female was found to have an anterior mediastinal mass during work-up for an intermittent cough in 2009. Chest imaging and biopsy at the time showed evidence of a cystic teratoma without concerning features. She underwent imaging surveillance until 2018, when repeat chest imaging showed increasing growth and worrisome radiologic features concerning for malignant degeneration. She underwent an elective robotic-assisted thoracoscopic resection utilizing double lung ventilation, but due to extensive involvement of the right lung, pericardium, superior vena cava, and right phrenic nerve the patient had to be repositioned and started on single lung ventilation mid-procedure to facilitate a safe and complete resection. Anterior mediastinal teratomas can be successfully removed by robotic-assisted thoracoscopic resections utilizing single lung ventilation. Though robotic-assisted thoracoscopic resection utilizing double lung ventilation can be effective in performing certain procedures such as lung wedge resections, thymectomy, pleural biopsies and minimally invasive cardiac procedures, it is limited in removing locally advanced mediastinal tumors.


JDP2 inhibits the epithelial-to-mesenchymal transition in pancreatic cancer BxPC3 cells.
Pancreatic carcinoma is one of the most malignant and aggressive cancers. Increased motility and invasiveness of pancreatic cancer cells are believed to be associated with epithelial-to-mesenchymal transition (EMT). However, the molecular basis of EMT in pancreatic cancer cells is poorly understood. In this study, we examined the relationship between Jun dimerization protein 2 (JDP2), which is an AP-1 inhibitor, and EMT in human pancreatic carcinoma cells. We demonstrated that transforming growth factor-β1 (TGF-β1) promoted epidermal growth factor (EGF)-induced EMT in co-treated human pancreatic BxPC3 cells and that JDP2 overexpression reversed the EMT that was induced by co-treatment with TGF-β1 and EGF. These results suggest that EGF plays a principal role in EMT through its association with TGF-β1 in human pancreatic BxPC3 cells and that JDP2 may be a molecular target for pancreatic carcinoma intervention.


Development of Inapparent Dengue Associated With Increased Antibody Levels to Aedes aegypti Salivary Proteins: A Longitudinal Dengue Cohort in Cambodia.
We established the first prospective cohort to understand how infection with dengue virus is influenced by vector-specific determinants such as humoral immunity to Aedes aegypti salivary proteins. Children aged 2-9 years were enrolled in the PAGODAS (Pediatric Assessment Group of Dengue and Aedes Saliva) cohort with informed consent by their guardians. Children were followed semi-annually for antibodies to dengue and to proteins in Ae. aegypti salivary gland homogenate using enzyme-linked immunosorbent assays and dengue-specific neutralization titers. Children presented with fever at any time for dengue testing. From 13 July to 30 August 2018, we enrolled 771 children. At baseline, 22% (173/770) had evidence of neutralizing antibodies to 1 or more dengue serotypes. By April 2020, 51 children had symptomatic dengue while 148 dengue-naive children had inapparent dengue defined by neutralization assays. In a multivariate model, individuals with higher antibodies to Ae. aegypti salivary proteins were 1.5 times more likely to have dengue infection (hazard ratio [HR], 1.47 [95% confidence interval {CI}, 1.05-2.06]; P = .02), particularly individuals with inapparent dengue (HR, 1.64 [95% CI, 1.12-2.41]; P = .01). High levels of seropositivity to Ae. aegypti salivary proteins are associated with future development of dengue infection, primarily inapparent, in dengue-naive Cambodian children. NCT03534245.


Effect of morphinone on opiate receptor binding and morphine-elicited analgesia.
Specific binding of 3H-naloxone to opiate receptors was found to be irreversibly inactivated by morphine. This inactivation exhibited pseudo-first-order kinetics. The presence of sulfhydryl compounds or morphine during incubation with morphinone proved good protection. Morphinone-pretreated mice blocked the analgesic effect of morphine. The possible mechanism for these observations is proposed as follows: morphinone binds covalently to sulfhydryl group of opiate receptors, and inactivates irreversibly opiate binding sites, thus blocking the analgesic effect of morphine.


Utility of a webinar to educate trainees on UK core surgical training (CST) selection - A cross sectional study and future implications amidst the COVID-19 pandemic.
The application process for Core Surgical Training (CST) in the United Kingdom (UK) is competitive and hence, careful preparation is required for trainees to obtain their posts of choice. There are multiple resources for preparation for selection including face-to-face courses and online question banks, however there is a paucity of webinars to educate trainees. With the cancellation of such courses due to social distancing restrictions caused by the Covid-19 pandemic, this cross-sectional study aims to evaluate the usefulness of a webinar to educate trainees on CST selection in the UK. A free online webinar was held on a single day by a second year core surgical trainee and was attended by 111 junior doctors. Beforehand, all attendees were invited to complete a survey on Google Forms (Google, USA) to ascertain their level of experience with webinars, obtain demographic information and elicit their level of knowledge about CST selection using a 1-5 Likert scale. Most attendees were in Foundation Year 2 (38.7%) and many had not previously attended a webinar as part of CST application preparation (93.7%). Over half of respondents (55.0%) preferred a webinar over a face-to-face tutorial, appreciating the flexibility, convenience and zero financial cost associated. Many candidates received minimal advice on CST application by their Foundation School (47.7%) and 50.5% of respondents rated their confidence on the application process at '3 out of 5.' Our study suggests webinars have been underused in preparation for CST applications. Traditional courses and advice from colleagues are more popular ways in which applicants prepare for selection. However, given the degree of uncertainty surrounding the return of face-to-face courses due to the Covid-19 pandemic, preparation for CST application may become increasingly reliant on online materials, which may result in an increased demand for high quality, engaging and informative webinars.


Effects of soil properties on heavy metal bioavailability and accumulation in crop grains under different farmland use patterns.
Mining activities have increased the accumulation of heavy metals in farmland soil and in food crops. To identify the key soil properties influencing heavy metal bioavailability and accumulation in food crops, 81 crop samples and 81 corresponding agricultural soil samples were collected from rape, wheat, and paddy fields. Heavy metal (copper (Cu), zinc (Zn), lead (Pb), cadmium (Cd), iron (Fe), and manganese (Mn)) concentrations in soils and rape, wheat, rice grains were determined using inductively coupled plasma atomic emission spectroscopy, and soil physicochemical properties (pH, organic matter, total nitrogen, total phosphorus, available phosphorus, and available potassium (AK)) were analyzed. Soil extractable metals were extracted using various single extractants (DTPA, EDTA, NH4OAc, NH4NO3, and HCl). The average concentrations of Cu, Zn, Pb, Cd, and Mn in the soil samples all exceeded the local geochemical background value (background values of Cu, Zn, Pb, Cd, and Mn are 43.0, 81.0, 28.5, 0.196, and 616 mg/kg, respectively), and Cd over-standard rate was the highest, at 98%. Furthermore, soil total Cd concentrations (0.1-24.8 mg/kg) of more than 86% of the samples exceeded the soil pollution risk screening value (GB 15618-2018). The sources of Cu, Zn, Pb, Cd, and Mn in soils were mainly associated with mining activities. The key factors influencing heavy metal bioavailability were associated with the types of extractants (complexing agents or neutral salt extractants) and the metals. Cd and Pb concentrations in most wheat and rice grain samples exceeded the maximum allowable Cd and Pb levels in food, respectively, and Cd concentrations in approximately 10% of the rice grain samples exceeded 1.0 mg/kg. Furthermore, rice and wheat grains exhibited higher Cd accumulation capacity than rape grains, and despite the high soil Cd concentrations in the rape fields, the rape grains were safe for consumption. High soil pH and AK restricted Cd and Cu accumulation in wheat grains, respectively. Soil properties seemed to influence heavy metal accumulation in rice grains the most.


METTL3 potentiates progression of cervical cancer by suppressing ER stress via regulating m6A modification of TXNDC5 mRNA.
N6-methyladenosine (m6A) is the most abundant chemical modification on mRNA and plays significant roles in many bioprocesses. However, the functions of m6A on cervical cancer (CC) tumorigenesis remain unclear. Here we found methyltransferase-like 3 (METTL3), a core member of the m6A methyltransferase family, was greatly upregulated as an independent prognostic factor in CC. Mechanistically, the transcription factor ETS1 recruited P300 and WDR5 which separately mediated H3K27ac and H3K4me3 histone modification in the promoter of METTL3 and induced METTL3 transcription activation. Furthermore, we identified TXNDC5 as a target of METTL3-mediated m6A modification through MeRIP-seq, and revealed that METTL3-mediated TXNDC5 expression relied on the m6A reader-dependent manner. Functionally, we verified that METTL3 promoted proliferation and metastasis of CC cells by regulating of TXNDC5 expression through in vitro and in vivo experiments. In addition, our study verified the effect of METTL3/TXNDC5 axis on ER stress. Taken together, METTL3 facilitates the malignant progression of CC, suggesting that METTL3 might be a potential prognostic biomarker and therapeutic target for CC.


Two families with TET3-related disorder showing neurodevelopmental delay with craniofacial dysmorphisms.
TET3 at 2p13.1 encodes tet methylcytosine dioxygenase 3, a demethylation enzyme that converts 5-methylcytosine to 5-hydroxymethylcytosine. Beck et al. reported that patients with TET3 abnormalities in either an autosomal dominant or recessive inheritance fashion clinically showed global developmental delay, intellectual disability, and dysmorphisms. In this study, exome sequencing identified both mono- and biallelic TET3 variants in two families: a de novo variant NM_001287491.1:c.3028 A > G:p.(Asn1010Asp), and compound heterozygous variants NM_001287491.1:c.[2077 C > T];[2896 T > G],p.[Gln693*];[Cys966Gly]. Despite the different inheritance modes, the affected individuals showed similar phenotypic features. Including these three patients, only 14 affected individuals have been reported to date. The accumulation of data regarding individuals with TET3-related disorder is necessary to describe their clinical spectrum.


Synthesis and antiprogestational properties of novel 17-fluorinated steroids.
Progesterone receptor (PR) plays a key role in reproductive functions, and compounds that inhibit progesterone action (antiprogestins) have potential use in the treatment of estrogen- and progesterone-dependent diseases, including uterine leiomyomas and breast cancer. In the present study, we chemically synthesized novel 17-fluorinated steroids and evaluated the cytotoxicity profiles of these compounds in T47D breast cancer cells compared to the activity of known antiprogestins, including ZK230 211, RU-486, CDB2914, CDB4124 and ORG33628. We analyzed in vitro receptor-binding assays and PR-transactivation assays to establish the antiprogestational activity of these molecules. The representative antiprogestin EC304 was found to inhibit in vitro tumorigenicity in a dose-dependent fashion in T47D cells by a colony formation assay at 1 and 10nM concentrations. The potent in vivo antiprogestational activity of EC304 was also demonstrated in an antinidation assay for the interruption of early pregnancy in rats. The strong antiprogestational activity and absence of antiglucocorticoid activity in EC compounds may demonstrate their utility in the treatment of leiomyoma, endometriosis and breast cancer.


MicroRNA-590 is an EMT-suppressive microRNA involved in the TGFβ signaling pathway.
Over the last few decades, the epithelial-to-mesenchymal transition (EMT) has been identified as being involved in a number of aspects of physiological processes and various pathological events, including embryonic development and renal fibrosis. Transforming growth factor‑β receptor 2 (TGFβR2) is a widely studied gene, which fulfils a vital role in the TGFβ signaling pathway and exerts a crucial function in the progression of EMT. Previous studies demonstrated that the dysregulation of microRNAs (miRNAs) is considered to be associated with the EMT process. However, the precise functional involvement of miRNAs in EMT remains to be fully elucidated. In the present study, the level of miR‑590 was decreased in an EMT model in vitro and in vivo. Furthermore, the overexpression of miR‑590 inhibited EMT by upregulating the epithelial marker, E‑cadherin, and downregulating the mesenchymal markers, laminin, α‑smooth muscle actin (α‑SMA) and collagen, in the human kidney 2 (HK2) cell line. Furthermore, TGFβR2 was negatively regulated by miR‑590. In addition, performing a knockdown of TGFβR2 with small‑interfering RNA had an effect similar to miR‑590 on EMT in the HK2 cell line, whereas the transfection of pCMV‑tag2B‑TGFβR2 reversed the effect of miR‑590 on EMT in HK2 cells. Taken together, the present study demonstrated that miR-590 is a novel EMT-suppressive microRNA, which targets TGFβR2.


The yin and the yang of follicular lymphoma cell niches: role of microenvironment heterogeneity and plasticity.
Follicular lymphoma (FL) results from the malignant transformation of germinal center B cells and is characterized by recurrent genetic alterations providing a direct growth advantage or facilitating interaction with tumor microenvironment. In agreement, accumulating evidences suggest a dynamic bidirectional crosstalk between FL B cells and surrounding non-malignant cells within specialized tumor niches in both invaded lymph nodes and bone marrow. Infiltrating stromal cells, macrophages, and T/NK cell subsets either contribute to anti-tumor immune response, or conversely form a tumor supportive network promoting FL B cell survival, growth, and drug resistance. This review depicts the phenotypic heterogeneity and functional plasticity of the most important FL cell partners and describes their complex interplay. We also unravel how malignant B cells recruit and subvert accessory immune and stromal cells to trigger their polarization toward a supportive phenotype. Based on these observations, innovative therapeutic approaches have been recently proposed, in order to benefit from local anti-tumor immunity and/or to selectively target the protective cell niche.


A model for the involvement of the small nucleolar RNA (U3) in processing eukaryotic ribosomal RNA.
The nucleotide sequence of chick pre-rRNA between 5.8S and 28S rRNAs is 85% G + C and has the potential to form many different secondary structures. A model is presented in which a small nucleolar RNA, U3, and its associated proteins act as an RNA isomerase to position the pre-rRNA for processing. Cleavage could be performed either by a nuclease present in the U3RNP or by a ribonuclease directed to the proper form of the pre-rRNA.


Acetabular fractures in elderly.
This study aimed to determine characteristics of acetabular fractures in the elderly by evaluating clinical course and computed tomography-based radiological features between low- and high-energy acetabular fractures. We reviewed 178 consecutive patients with acetabular fractures aged ≥60 years from six centers. Low-energy fractures (group 1) were identified in 23 (12.9%) patients and high-energy fractures (group 2) in 155 (87.1%) patients. We compared demographics, radiological findings, and clinical course between the groups. Average age (70.6 vs. 67.8 years, p = 0.046) and ratio of females (47.8% vs. 23.2%, p = 0.021) were significantly higher in group 1 than in group 2. The Charlson comorbidity index was also higher in group 1, but no other demographics showed difference. More patients in group 2 than in group 1 underwent surgery (91.6% vs. 73.9%); however, more in group 1 underwent minimally invasive surgery (17.4% vs 4.5%). Anterior column-associated fracture patterns occurred in 91.4% and 38.7% of cases in groups 1 and 2, respectively. Most fractures were displaced (>2 mm); 68% of which were comminuted. Furthermore, 24.2% of the fractures had superior dome impaction, whereas 23.0% were associated with posterior wall impaction. Patients who sustained low-energy acetabular fractures were mostly women, were older, and had more comorbidities. Radiological findings of low-energy acetabular fractures showed anterior column involvement associated with injury to the quadrilateral surface. Additionally, it was observed to be commonly combined with comminution and impacted fragments.


Trying to unravel the mysteries of chemobrain.
As more patients live for longer after cancer treatment, oncologists and neurologists are working together to learn more about chemotherapy-induced cognitive impairment. David Holmes reports.


Growth hormone preserves cardiac sarcoplasmic reticulum Ca2+ release channels (ryanodine receptors) and enhances cardiac function in cardiomyopathic hamsters.
Growth hormone (GH) improves cardiac function in experimental models of heart failure and human dilated cardiomyopathy. However, the mechanism by which GH increases myocardial contractility is not entirely clear. Our aim was to examine the effects of GH on cardiac function and cardiac sarcoplasmic reticulum Ca2+ release channels (ryanodine receptors, RyR) in the hearts of UM-X7.1 cardiomyopathic hamsters during the development of heart failure. Experimental and healthy control hamsters were examined at the age of 20 weeks. Recombinant human GH (2 mg/kg/day, s.c.) or vehicle was then administered for 3 weeks. We examined (i) the in vivo left ventricular (LV) size and LV systolic function using transthoracic echocardiography, (ii) the density (Bmax) and affinity (Kd) of high-affinity [3H] ryanodine binding sites in crude homogenates from normal and cardiomyopathic hamster hearts. Vehicle-treated UM-X7.1 hamsters exhibited significant increases in left ventricular end-diastolic diameter and end-systolic diameter (LVESd), and a significant decrease in LV fractional shortening (FS). GH-treatment attenuated the increase in LVESd and reduced the LV chamber size, and also significantly increased LVFS. Vehicle-treated UM-X7.1 hamsters exhibited a significantly lower Bmax than control hamsters (0.34 +/- 0.04 vs 0.44 +/- 0.06 pmol/mg, p < 0.05), and the treatment with GH in UM-X7.1 hamsters significantly attenuated the reduction of Bmax (0.42 +/- 0.03 pmol/mg vs vehicle-treated group (0.34 +/- 0.04 pmol/mg), p < 0.05). Kd did not differ significantly between the experimental groups. In normal control hamsters, GH treatment with this dose did not significantly enhance LV systolic function or the density of RyRs. There was no significant difference in terms of the connective-tissue volume-fraction, myocyte size and capillary density between the GH- and vehicle-treated groups of UM-X7.1 hamsters. GH treatment may improve cardiac function by preserving the density of RyRs and enhancing cellular function in cardiomyopathic hamster hearts.


Enhanced killing of androgen-independent prostate cancer cells using inositol hexakisphosphate in combination with proteasome inhibitors.
Effective treatments for androgen-independent prostate cancer (AIPCa) are lacking. To address this, emerging therapeutics such as proteasome inhibitors are currently undergoing clinical trials. Inositol hexakisphosphate (IP6) is an orally non-toxic phytochemical that exhibits antitumour activity against several types of cancer including PCa. We have previously shown that treatment of PC3 cells with IP6 induces the transcription of a subset of nuclear factor-kappaB (NF-kappaB)-responsive and pro-apoptotic BCL-2 family genes. In this study, we report that although NF-kappaB subunits p50/p65 translocate to the nucleus of PC3 cells in response to IP6, inhibition of NF-kappaB-mediated transcription using non-degradable inhibitor of kappaB (IkappaB)-alpha does not modulate IP6 sensitivity. Treatment with IP6 also leads to increased protein levels of PUMA, BIK/NBK and NOXA between 4 and 8 h of treatment and decreased levels of MCL-1 and BCL-2 after 24 h. Although blocking transcription using actinomycin D does not modulate PC3 cell sensitivity to IP6, inhibition of protein translation using cycloheximide has a significant protective effect. In contrast, blocking proteasome-mediated protein degradation using MG-132 significantly enhances the ability of IP6 to reduce cellular metabolic activity in both PC3 and DU145 AIPCa cell lines. This effect of combined treatment on mitochondrial depolarisation is particularly striking and is also reproduced by another proteasome inhibitor (ALLN). The enhanced effect of combined MG132/IP6 treatment is almost completely inhibited by cycloheximide and correlates with changes in BCL-2 family protein levels. Altogether these results suggest a role for BCL-2 family proteins in mediating the combined effect of IP6 and proteasome inhibitors and warrant further pre-clinical studies for the treatment of AIPCa.


Lipoic acid confers protection against oxidative injury in non-neuronal and neuronal tissue.
In the past decade or so, a convincing link between oxidative stress and degenerative conditions has been made and with the knowledge that oxidatiye changes may actually trigger deterioration in cell function, a great deal of energy has focussed on identifying agents which may have possible therapeutic value in combating oxidative changes. One agent which has received attention, because of its powerful antioxidative effects, particularly in neuronal tissue, is lipoic acid.


Evidence for the existence of receptor--receptor interactions in the central nervous system. Studies on the regulation of monoamine receptors by neuropeptides.
Substance P (SP) (10(-8) M) can rapidly reduce the affinity and increase the density of 3H-5-HT binding sites in spinal cord membranes. CCK-8 and CCK-4 (10(-8) M) can rapidly and differentially change the characteristics of 3H-spiperone striatal binding sites linked to DA receptors of the D2 type. CCK-4 increase and CCK-8 reduce the number of striatal binding sites for 3H-spiperone, indicating for the first time separate CCK-4 binding sites. CCK-4 (10(-8) M) but not CCK-8 (10(-8) M) can rapidly reduce the affinity and increase the number of the 3H-spiperone binding sites linked to 5-HT receptors of the dorsal cerebral cortex of rats. CCK-8 (10(-8) M) only produces a trend for a small increase in the Bmax values of these receptors. These results again imply the existence of separate CCK-4 binding sites in this case in the cerebral cortex. Glutamate (10(-6) M), but not N-methyl-D-aspartate (10(-6) M) can rapidly change the characteristics of the 3H-N-propylnorapomorphine (3H-NPA) binding sites in striatal membranes of rats. Glutamate (10(-6) M) increases the density and especially reduces the affinity of the 3H-NPA binding sites, which label D2 and D3 types of DA receptors. Taken together the present findings give evidence that neuropeptide receptors and glutamate receptors can in vitro rapidly modulate the characteristics of different types of DA and 5-HT receptors by way of receptor--receptor interactions at the comodulate level or at the local circuit level. It is hypothesized that these receptor--receptor interactions are of importance for the encoding of short-term memory.


Identification of autoantibody-negative autoimmune type 2 diabetic patients.
Islet autoimmunity has long been recognized in the pathogenesis of type 1 diabetes and is becoming increasingly acknowledged as a component in the pathogenesis of type 2 diabetes. Islet reactive T cells and autoantibodies have been demonstrated in type 1 diabetes, whereas islet autoimmunity in type 2 diabetes has been limited to islet autoantibodies. In this study, we investigated whether islet reactive T cells might also be present in type 2 diabetic patients and how islet reactive T cells correlate with β-cell function. Adult phenotypic type 2 diabetic patients (n = 36) were screened for islet reactive T-cell responses using cellular immunoblotting and five islet autoantibodies (islet cell antibody, GADA, insulin autoantibody, insulinoma-associated protein-2 autoantibody, and zinc transporter autoantibody). We identified four subgroups of adult phenotypic type 2 diabetic patients based on their immunological status (Ab(-)T(-), Ab(+)T(-), Ab(-)T(+), and Ab(+)T(+)). The Ab(-)T(+) type 2 diabetic patients demonstrated T-cell responses similar to those of the Ab(+)T(+) type 2 diabetic patients. Data were adjusted for BMI, insulin resistance, and duration of diabetes. Significant differences (P < 0.02) were observed among groups for fasting and glucagon-stimulated C-peptide responses. T-cell responses to islet proteins were also demonstrated to fluctuate less than autoantibody responses. We have identified a group of adult autoimmune phenotypic type 2 diabetic patients who are Ab(-)T(+) and thus would not be detected using autoantibody testing alone. We conclude that islet autoimmunity may be more prevalent in adult phenotypic type 2 diabetic patients than previously estimated.


Discussion of Identification, Estimation and Approximation of Risk under Interventions that Depend on the Natural Value of Treatment Using Observational Data, by Jessica Young, Miguel Hernán, and James Robins.
Young, Hernán, and Robins consider the mean outcome under a dynamic intervention that may rely on the natural value of treatment. They first identify this value with a statistical target parameter, and then show that this statistical target parameter can also be identified with a causal parameter which gives the mean outcome under a stochastic intervention. The authors then describe estimation strategies for these quantities. Here we augment the authors' insightful discussion by sharing our experiences in situations where two causal questions lead to the same statistical estimand, or the newer problem that arises in the study of data adaptive parameters, where two statistical estimands can lead to the same estimation problem. Given a statistical estimation problem, we encourage others to always use a robust estimation framework where the data generating distribution truly belongs to the statistical model. We close with a discussion of a framework which has these properties.


Anti-lipid phosphate phosphohydrolase-3 (LPP3) antibody inhibits bFGF- and VEGF-induced capillary morphogenesis of endothelial cells.
Angiogenesis, or the remodeling of existing vasculature serves as a lifeline to nourish developing embryos and starved tissues, and to accelerate wound healing, diabetic retinopathy, and tumor progression. Recent studies indicate that angiogenesis requires growth factor activity as well as cell adhesion events mediated by alpha5beta1 and alphavbeta3 integrins. We previously demonstrated that human lipid phosphate phosphohydrolase-3 (LPP3) acts as a cell-associated ligand for alpha5beta1 and alphavbeta3 integrins. Here, we test the hypothesis that an anti-LPP3 antibody can inhibit basic fibroblast growth factor (bFGF)-and vascular endothelial growth factor (VEGF)-induced capillary morphogenesis of endothelial cells (ECs). We report that bFGF and VEGF up-regulate LPP3 protein expression in ECs. Immunoprecipitation analyses show that LPP3 is a cell surface protein and undergoes N-glycosylation. Fluorescent activated cell sorting (FACS) data suggest that anti-LPP3-RGD detects native neoepitope on the surface of activated ECs. Moreover, we demonstrate LPP3 protein expression in tumor endothelium alongside VEGF. The embedding of ECs into three-dimensional type I collagen in the presence of bFGF and VEGF induce capillary formation. Importantly, we show that the addition of an anti-LPP3 antibody specifically and significantly blocks bFGF- and VEGF-induced capillary morphogenesis of ECs. These data suggest that activated ECs as well as tumor endothelium express LPP3 protein. In an in vitro assay, the anti-LPP3-RGD specifically blocks bFGF and VEGF induced capillary morphogenesis of ECs. Our results, therefore, suggest a role for LPP3 in angiogenesis.


Tetanus: an uncommon cause of dysphagia.
A 53-year-old woman was examined at our medical center because of progressive dysphagia of 14 days' duration and a severe inability to open her mouth and swallow saliva. A barium esophagogram showed no obstruction, but pooling of barium in the hypopharynx suggested a neuromuscular disorder. The clinical diagnosis of tetanus was confirmed by electromyography. With appropriate therapy, the patient recovered during a period of 6 weeks. This case illustrates both an uncommon cause of dysphagia and an uncommon initial manifestation of tetanus.


An emotional functioning item bank of 24 items for computerized adaptive testing (CAT) was established.
To improve measurement precision, the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group is developing an item bank for computerized adaptive testing (CAT) of emotional functioning (EF). The item bank will be within the conceptual framework of the widely used EORTC Quality of Life questionnaire (QLQ-C30). On the basis of literature search and evaluations by international samples of experts and cancer patients, 38 candidate items were developed. The psychometric properties of the items were evaluated in a large international sample of cancer patients. This included evaluations of dimensionality, item response theory (IRT) model fit, differential item functioning (DIF), and of measurement precision/statistical power. Responses were obtained from 1,023 cancer patients from four countries. The evaluations showed that 24 items could be included in a unidimensional IRT model. DIF did not seem to have any significant impact on the estimation of EF. Evaluations indicated that the CAT measure may reduce sample size requirements by up to 50% compared to the QLQ-C30 EF scale without reducing power. On the basis of thorough psychometric evaluations, we have established an EF item bank of 24 items. This will allow for more precise and flexible measurement of EF, while maintaining backward compatibility with the QLQ-C30 EF scale.


Binding of high-mobility-group proteins HMG 14 and HMG 17 to DNA and histone H1 as influenced by phosphorylation.
We have used affinity chromatography to study the effects of phosphorylation of calf thymus high-mobility-group proteins HMG 14 and HMG 17 on their binding properties towards calf thymus single- and double-stranded DNA and histone H1. Without in vitro phosphorylation, HMG 14 and HMG 17 eluted from double-stranded DNA-columns at 200 mM NaCl. HMG 14 was released from single-stranded DNA-column at 300 mM NaCl and from H1-column at 130 mM NaCl, whereas the corresponding values for HMG 17 were 230 mM and 20 mM, respectively. Phosphorylation of HMG 14 and HMG 17 by cAMP-dependent protein kinase (A-kinase) decreased markedly their affinity (270 mM and 200 mM NaCl, respectively) for single-stranded DNA, whereas HMG 14 phosphorylated by nuclear protein kinase II (NII-kinase) eluted only slightly (290 mM NaCl) ahead of the unphosphorylated protein. HMG 14 phosphorylated by both A-kinase and NII-kinase eluted from double-stranded DNA-columns almost identically (190 mM NaCl) with the unphosphorylated protein. Interestingly, phosphorylation of HMG 14 by NII-kinase increased considerably its affinity for histone H1 and the phosphorylated protein eluted at 200 mM NaCl. Phosphorylation of HMG 14 by A-kinase did not alter its interaction towards histone H1. These results indicate that modification of HMG 14 by phosphorylation at specific sites may have profound effects on its binding properties towards DNA and histone H1, and that HMG 17 has much weaker affinity for single-stranded DNA and histone H1 than HMG 14.


Advanced Approach to Asian Lower Blepharoplasty.
The lower eyelid is one of the commonest areas Asian patients present for rejuvenation. The spectrum of patients presenting for treatment ranges from the young to the more mature. Young patients present with "premature" aging due to an anatomical predisposition. These are patients we figuratively call those who "do not age well." Even patients with strong skeletal support manifest aging, in a predictable and progressive manner. Such patients eventually benefit from quality esthetic surgery of the lower eyelid and mid cheek.


Insulin induces production of new elastin in cultures of human aortic smooth muscle cells.
Diabetes mellitus accelerates atherosclerotic progression, peripheral angiopathy development, and arterial hypertension, all of which are associated with elastic fiber disease. However, the potential mechanistic links between insulin deficiency and impaired elastogenesis in diabetes have not been explored. Results of the present study reveal that insulin administered in therapeutically relevant concentrations (0.5 to 10 nmol/L) selectively stimulates formation of new elastic fibers in cultures of human aortic smooth muscle cells. These concentrations of insulin neither up-regulate collagen type I and fibronectin deposition nor stimulate cellular proliferation. Further, the elastogenic effect of insulin occurs after insulin receptor activation, which triggers the PI3K downstream signaling pathway and activates elastin gene transcription. In addition, the promoter region of the human elastin gene contains the CAAATAA sequence, consistent with the FoxO-recognized element, and the genomic effects of insulin occur after removal of the FoxO1 transcriptional inhibitor from the FoxO-recognized element in the elastin gene promoter. In addition, insulin signaling facilitates the association of tropoelastin with its specific 67-kDa elastin-binding protein/spliced form of β-galactosidase chaperone, enhancing secretion. These results are crucial to understanding of the molecular and cellular mechanisms of diabetes-associated vascular disease, and, in particular, endorse use of insulin therapy for treatment of atherosclerotic lesions in patients with type 1 diabetes, in which induction of new elastic fibers would mechanically stabilize the developing plaques and prevent arterial occlusions.


Ultrastructure of syncytiotrophoblast-like cells in seminomas of the testis.
An ultrastructural examination of five syncytiotrophoblast-like cells (STLC) from three otherwise pure seminomas was performed. All five STLC demonstrated ultrastructural features identical to those of normal syncytiotrophoblastic cells. The STLC were surrounded by sinusoidal spaces and cells whose ultrastructure was compatible with that of seminoma cells, though the presence of cytotrophoblastic cells cannot be excluded with certainty. We conclude that STLC in seminomas are indeed syncytiotrophoblastic and their genesis remains an enigma.


Cholinergic-rich brain transplants reverse alcohol-induced memory deficits.
Alcohol-induced memory impairment in man has been attributed to deficiencies in subcortical noradrenergic and cholinergic systems, as well as to damage in midbrain structures. Korsakoff's psychosis, a disease in which alcohol poisoning causes apparently irreversible memory defects, is characterized by lesions in cholinergic and noradrenergic nuclei and by a decrease in the activity of choline acetyltransferase (ChAT) and the content of noradrenaline (NA) in forebrain areas such as cerebral cortex and hippocampus, innervated by these nuclei. Prolonged intake of ethanol in rodents similarly produces signs of noradrenergic and cholinergic deafferentation in the cortex and hippocampus, as well as persistent memory deficits. To test whether alcohol-induced memory impairments depend on cholinergic deafferentation, we transplanted cholinergic-rich fetal basal forebrain cell suspensions into the cortex and hippocampus of alcohol-treated rats. The substantial and persistent memory losses produced in our rats by ethanol intake were associated with an impairment of cholinergic function, and were reversed by cholinergic-rich transplants into cortex and hippocampus.


Reliability and validity of ten consumer activity trackers.
Activity trackers can potentially stimulate users to increase their physical activity behavior. The aim of this study was to examine the reliability and validity of ten consumer activity trackers for measuring step count in both laboratory and free-living conditions. Healthy adult volunteers (n = 33) walked twice on a treadmill (4.8 km/h) for 30 min while wearing ten different activity trackers (i.e. Lumoback, Fitbit Flex, Jawbone Up, Nike+ Fuelband SE, Misfit Shine, Withings Pulse, Fitbit Zip, Omron HJ-203, Yamax Digiwalker SW-200 and Moves mobile application). In free-living conditions, 56 volunteers wore the same activity trackers for one working day. Test-retest reliability was analyzed with the Intraclass Correlation Coefficient (ICC). Validity was evaluated by comparing each tracker with the gold standard (Optogait system for laboratory and ActivPAL for free-living conditions), using paired samples t-tests, mean absolute percentage errors, correlations and Bland-Altman plots. Test-retest analysis revealed high reliability for most trackers except for the Omron (ICC .14), Moves app (ICC .37) and Nike+ Fuelband (ICC .53). The mean absolute percentage errors of the trackers in laboratory and free-living conditions respectively, were: Lumoback (-0.2, -0.4), Fibit Flex (-5.7, 3.7), Jawbone Up (-1.0, 1.4), Nike+ Fuelband (-18, -24), Misfit Shine (0.2, 1.1), Withings Pulse (-0.5, -7.9), Fitbit Zip (-0.3, 1.2), Omron (2.5, -0.4), Digiwalker (-1.2, -5.9), and Moves app (9.6, -37.6). Bland-Altman plots demonstrated that the limits of agreement varied from 46 steps (Fitbit Zip) to 2422 steps (Nike+ Fuelband) in the laboratory condition, and 866 steps (Fitbit Zip) to 5150 steps (Moves app) in the free-living condition. The reliability and validity of most trackers for measuring step count is good. The Fitbit Zip is the most valid whereas the reliability and validity of the Nike+ Fuelband is low.


Promotion of granule cell survival by high K+ or excitatory amino acid treatment and Ca2+/calmodulin-dependent protein kinase activity.
Cerebellar granule cells in culture develop survival requirements which can be met either by chronic membrane depolarization (25 mM K+) or by stimulation of ionotropic excitatory amino acid receptors. We observed previously that this trophic effect is mediated via Ca2+ influx, either through dihydropyridine-sensitive, voltage-dependent calcium channels (activated directly by high K+ or indirectly by kainate) or through N-methyl-D-aspartate receptor-linked ion channels. Steps after Ca2+ entry in the transduction cascade mediating the survival-supporting effect of high K+ and excitatory amino acids have now been examined. Using protein kinase inhibitors (H-7, polymixin B and gangliosides), and modulating protein kinase C activity by treatment with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate, we obtained evidence against the involvement of protein kinase C and cyclic nucleotide-dependent protein kinases in the transduction cascade. On the other hand, calmidazolium (employed as a calmodulin inhibitor) counteracted the trophic effect of elevated K+ with high potency (IC50 0.3 microM), which exceeded by approximately 10-fold the potency for the blockade by the drug of voltage-sensitive calcium channels. The potency of calmidazolium in interfering with the N-methyl-D-aspartate rescue of cells was also much higher in comparison with the inhibition of 45Ca2+ influx through N-methyl-D-aspartate receptor-linked channels. Our results indicated that after calmodulin the next step in the trophic effects involves Ca2+/calmodulin-dependent protein kinase II activity. KN-62, a fairly specific antagonist of this enzyme, compromised elevated K+ or excitatory amino acid-supported cell survival with high potency (IC50 2.5 microM). In the relevant concentration range, KN-62 had little or no effect on Ca2+ entry through either voltage- or N-methyl-D-aspartate receptor-gated channels. Combining information on the toxic action of glutamate in "mature" granule cells with the trophic effect of either excitatory amino acids or high K+ treatment on "young" cells, we conclude that after the initial steps involving calcium in both cases the respective transduction pathways diverge. The toxic action of glutamate seems to be mediated through protein kinase C [Favaron et al. (1990) Proc. natn. Acad. Sci. U.S.A. 87, 1983-1987 whereas a Ca2+/calmodulin-dependent protein kinase, which can be inhibited by KN-62 (but is resistant to gangliosides and to inhibitors whose potency is higher for protein kinase C than for Ca2+ calmodulin-dependent protein kinases, such as H-7 and polymixin B), is involved critically in the trophic effect.


Genetic estimation of correlations and causalities between multifaceted modifiable factors and gastro-oesophageal reflux disease.
Gastro-oesophageal reflux disease (GORD) is a common gastrointestinal dysfunction that significantly affects the quality of daily life, and health interventions are challenging to prevent the risk of GORD. In this study, we used Mendelian randomization framework to genetically determine the causal associations between multifaceted modifiable factors and the risk of GORD. Sixty-six exposures with available instrumental variables (IVs) across 6 modifiable pathways were included in the univariable MR analysis (UVMR). Summary-level genome-wide association studies (GWAS) datasets for GORD were retrieved from the Neale Lab (GORD Neale , Ncases = 29975, Ncontrols = 390556) and FinnGen (GORD Finn , Ncases = 13141, Ncontrols = 89695). Using the METAL software, meta-analysis for single nucleotide polymorphisms (SNPs) from GORD Neale and GORD Finn was conducted with an inverse variance weighted (IVW) fixed-effect model. Moreover, we leveraged partition around medoids (PAM) clustering algorithm to cluster genetic correlation subtypes, whose hub exposures were conditioned for multivariable MR (MVMR) analyses. P-values were adjusted with Bonferroni multiple comparisons. Significant causal associations were identified between 26 exposures (15 risk exposures and 11 protective exposures) and the risk of GORD. Among them, 13 risk exposures [lifetime smoking, cigarette consumption, insomnia, short sleep, leisure sedentary behavior (TV watching), body mass index (BMI), body fat percentage, whole body fat mass, visceral adipose tissue, waist circumference, hip circumference, major depressive disorder, and anxious feeling], and 10 protective exposures (leisure sedentary behavior (computer use), sitting height, hand grip strength (left and right), birth weight, life satisfaction, positive affect, income, educational attainment, and intelligence) showed novel significant causal associations with the risk of GORD. Moreover, 13 exposures still demonstrated independent associations with the risk of GORD following MVMR analyses conditioned for hub exposures (educational attainment, smoking initiation and BMI). In addition, 12 exposures showed suggestive causal associations with the risk of GORD. This study systematically elucidated the modifiable factors causally associated with the risk of GORD from multifaceted perspectives, which provided implications for prevention and treatment of GORD.


Relapsed hydroxychloroquine induced thrombocytopenia in a systemic lupus erythematosus patient.
Hydroxychloroquine is used in the long-term therapy of systemic lupus erythematosus (SLE). Although considered to be a safe treatment, side effects have been documented. An uncommon side effect is thrombocytopenia. In order to establish the diagnosis of thrombocytopenia secondary to Hydroxychloroquine, non-pharmacological causes must be ruled out and it is necessary to determine a recurrence after re-exposure to the drug. We present one case of severe thrombocytopenia occurring in a patient with SLE undergoing treatment with Hydroxychloroquine.


Astragaloside IV, a saponin from Astragalus membranaceus var. mongholicus, induces expressions of heme recycle proteins via signaling of Nrf2/ARE in cultured macrophages.
In traditional Chinese medicine (TCM) theory, "Qi" is classified as energetic essence supporting the life activities in human. "Blood" is categorized as nourishing essence and circulating in the body. "Blood" and "Qi" have an intimate relationship. Astragali Radix (AR; root of Astragalus membranaceus (Fisch.) Bge. Var. mongholicus (Bge.) Hsiao) has a broad spectrum of application for "Qi-Blood" enrichment. Astragaloside IV, a major saponin in AR, has therapeutic functions in erythropoietic, cardiovascular and immune systems. However, the efficacy of astragaloside IV in erythrophagocytosis has not been elucidated. The possible functions of astragaloside IV in heme iron recycling during erythrophagocytosis in cultured macrophage were elucidated. The translational and transcriptional expressions of heme recycling enzymes were determined after incubating of astragaloside IV for 24 h in cultured macrophage. In astragaloside IV-treated macrophage, the expressions, both RNA and protein levels, of regulators of heme recycling, e.g. heme oxygenase-1 (HO-1), ferroportin (FPN), biliverdin reductase A and B (BVRA, BVRB), were markedly induced in dose-dependent manners. In parallel, the transcriptional activity of antioxidant response element, cloned within an expression vector as pARE-Luc and transfected in cultured macrophages, was markedly induced after a challenge with astragaloside IV in a dose-dependent manner. Moreover, the translocation of Nrf2, a transcriptional factor in regulating expression of heme recycling protein, was induced by astragaloside IV, leading to an enrichment at nucleus fraction. Astragaloside IV shed lights in enhancing the expression of heme recycle proteins via Nrf2/ARE signaling pathway.


Extended Follow-Up of Chronic Immune-Related Adverse Events Following Adjuvant Anti-PD-1 Therapy for High-Risk Resected Melanoma.
Anti-programmable cell death-1 (anti-PD-1) improves relapse-free survival when used as adjuvant therapy for high-risk resected melanoma. However, it can lead to immune-related adverse events (irAEs), which become chronic in approximately 40% of patients with high-risk melanoma treated with adjuvant anti-PD-1. To determine the incidence, characteristics, and long-term outcomes of chronic irAEs from adjuvant anti-PD-1 therapy. This retrospective multicenter cohort study analyzed patients treated with adjuvant anti-PD-1 therapy for advanced and metastatic melanoma between 2015 and 2022 from 6 institutions in the US and Australia with at least 18 months of evaluable follow-up after treatment cessation (range, 18.2 to 70.4 months). Incidence, spectrum, and ultimate resolution vs persistence of chronic irAEs (defined as those persisting at least 3 months after therapy cessation). Descriptive statistics were used to analyze categorical and continuous variables. Kaplan-Meier curves assessed survival, and Wilson score intervals were used to calculate CIs for proportions. Among 318 patients, 190 (59.7%) were male (median [IQR] age, 61 [52.3-72.0] years), 270 (84.9%) had a cutaneous primary, and 237 (74.5%) were stage IIIB or IIIC at presentation. Additionally, 226 patients (63.7%) developed acute irAEs arising during treatment, including 44 (13.8%) with grade 3 to 5 irAEs. Chronic irAEs, persisting at least 3 months after therapy cessation, developed in 147 patients (46.2%; 95% CI, 0.41-0.52), of which 74 (50.3%) were grade 2 or more, 6 (4.1%) were grade 3 to 5, and 100 (68.0%) were symptomatic. With long-term follow-up (median [IQR], 1057 [915-1321] days), 54 patients (36.7%) experienced resolution of chronic irAEs (median [IQR] time to resolution of 19.7 [14.4-31.5] months from anti-PD-1 start and 11.2 [8.1-20.7] months from anti-PD-1 cessation). Among patients with persistent irAEs present at last follow-up (93 [29.2%] of original cohort; 95% CI, 0.25-0.34); 55 (59.1%) were grade 2 or more; 41 (44.1%) were symptomatic; 24 (25.8%) were using therapeutic systemic steroids (16 [67%] of whom were on replacement steroids for hypophysitis (8 [50.0%]) and adrenal insufficiency (8 [50.0%]), and 42 (45.2%) were using other management. Among the 54 patients, the most common persistent chronic irAEs were hypothyroid (38 [70.4%]), arthritis (18 [33.3%]), dermatitis (9 [16.7%]), and adrenal insufficiency (8 [14.8%]). Furthermore, 54 [17.0%] patients experienced persistent endocrinopathies, 48 (15.1%) experienced nonendocrinopathies, and 9 (2.8%) experienced both. Of 37 patients with chronic irAEs who received additional immunotherapy, 25 (67.6%) experienced no effect on chronic irAEs whereas 12 (32.4%) experienced a flare in their chronic toxicity. Twenty patients (54.1%) experienced a distinct irAE. In this cohort study of 318 patients who received adjuvant anti-PD-1, chronic irAEs were common, affected diverse organ systems, and often persisted with long-term follow-up requiring steroids and additional management. These findings highlight the likelihood of persistent toxic effects when considering adjuvant therapies and need for long-term monitoring and management.


COVID-19 vaccines, mobility, and pandemic bureaucracies: Undocumented migrants' perspectives from Italy's Alpine border.
While scholars have noted the deeply unequal effects of the pandemic containment, there has been limited attempt to map the socio-political lives of vaccination policies, particularly from the perspective of undocumented persons moving at state margins. This paper explores how undocumented migrants, who were predominantly male travellers attempting to cross Italy's Alpine borders, encountered Covid-19 vaccines and contemporary legislation. Based on ethnographic observations and qualitative interviews with migrants, doctors, and activists at safehouses both on the Italian and French sides of the Alpine border, we trace how mobility centred decisions to accept or reject vaccines were significantly shaped by exclusionary border regimes. We move beyond the exceptional focus of the Covid-19 pandemic to show how centring visions of health connected to viral risk diverted attention from migrants' wider struggles to move to obtain safety. Ultimately, we argue for a recognition of how health crises are not merely unequally experienced, but may result in the reconfiguration of violent governance practices at state borders.


Spatial distribution of acoustic and elastic properties of human femoral cortical bone.
The purpose of this study is to quantify the spatial distribution of acoustic velocities and elastic properties (elastic constants) on Human femoral cortical bone. Four cross sections (average thickness of 2.09+/-0.27 mm) have been cut transversally between 40% and 70% of the total length and between them parallelepiped samples in each quadrant have been cut. Ultrasonic technique in transmission with immersion focused transducers at 5 MHz and contact transducers 2.25 MHz were used on the cross sections and parallelepiped samples, respectively. The first technique allows relative spatial distribution of velocities to be obtained, meanwhile the second technique allows the direct assessment of elastic constants. For both techniques, bulk velocities were found to be lower at the posterior side with an increase along the length (from 40% to 70% total length) (p < 0.05). Densities and elastic constants show equivalent pattern of variation. These variations are mainly due the cortical porosity related to vascularisation environment. The spatial distribution of velocities exhibits significant radial variation from the endosteal to the periosteal region. This is in agreement with variation of the porosity at that location. Same range of velocities was obtained with both techniques. The range of longitudinal velocities values varies from 3548 to 3967 m/s and between 18.5 and 33.1 GPa for the bulk velocities and axial elastic constants, respectively. Our results are within the range with those found in the literature. However, it must be noted that the range of acoustic and elastic properties variation is concerning the same bone. So, our new results show the ability of the technique to quantify accurately local variation of acoustic and elastic properties (within the section and along the length) of human cortical bone. Furthermore, our immersion technique could be used to assess the spatial distribution of the elastic constants with the knowledge of spatial distribution of densities.


Determinants of operative mortality and long-term survival in patients with unstable angina. The CASS experience.
To identify the factors that determine operative mortality and long-term survival, we analyzed the data from 3,311 patients who underwent surgical therapy for unstable angina according to clinical presentation. Overall operative mortality was 3.9% and no differences in operative mortality were found between patients with coronary insufficiency, new-onset angina, rest angina, or changing patterns of angina. Logistic regression analysis indicated that age, left ventricular score, and presence of a left main stenosis in a left dominant circulation were related to operative mortality. The 7 year cumulative survival rate was 79%. Features predictive of long-term outcome by Cox analysis included left ventricular score, congestive heart failure score, other illness, extent of coronary disease, and cardiomegaly. Operative mortality of those patients who underwent coronary bypass during their initial hospitalization with unstable angina was similar to that of patients who were discharged and readmitted for operation at a later date. Thus, patients with unstable angina demonstrate a relatively low operative mortality, which is unrelated to the clinical presentation. Long-term survival is primarily determined by clinical and angiographic markers of left ventricular dysfunction, associated illness, and the extent of coronary disease.


The first report of cases of pet dogs with naturally occurring cancer treated with the antitumor peptide CIGB-552.
The absence of an effective therapy against human solid tumors has fostered the development of promising antineoplastic therapeutic candidates, as the CIGB-552 peptide. This synthetic peptide has shown to be effective in reducing tumor size and increasing the lifespan in tumor-bearing mice. Therefore, this work was aimed to explore the safety profile and preliminary assessment of antitumor activity of the CIGB-552 peptide therapeutic candidate in a small population of dogs (n=9) having malignant spontaneously-arising solid tumors. The peptide was administered by subcutaneous (s.c.) route, at three dosage levels (0.075, 0.15 and 0.3mg/kg). The results showed no dose-limiting toxicities in any dogs. The antitumor activity observed in dogs receiving CIGB-552 was associated with the reduction in the tumor volume. Given the antitumor effects of CIGB-552 as mediated by COMMD1 protein, which function is highly conserved among eukaryotic organisms, and the similarities of canine and human types of cancer with respect to tumor biology, it is likely that CIGB-552 could demonstrate comparable anti-cancer activity in human patients. Synthetic peptide, COMMD1, Tumor, Dog, CIGB-552.


5'-Peptidyl substituents allow a tuning of the affinity of oligodeoxyribonucleotides for RNA.
The affinity of amide-linked 5'-aminoacyl and 5'-dipeptidyl DNA octamers for two RNA undecamers with 3'-overhangs was measured via UV melting analysis. A sequence-dependent increase in melting points was observed. At low ionic strength, two appended lysine residues elevate melting points more than two additional A:U base pairs.


Protocol for a prospective observational study of conventional treatment and traditional Korean medicine combination treatment for children with cerebral palsy.
Cerebral palsy leads to many complications as well as delayed motor development, and early intensive rehabilitation in infancy, which is based on the theory of brain plasticity, is emphasized. In addition to conventional treatment, including physical, occupational, or speech-language therapies, children also have a demand for traditional Korean medicine interventions such as acupuncture or herbal medicine; however, a lack of evidence has made traditional Korean medicine difficult to implement in practice. We planned a multicentre, prospective, observational study to assess the effectiveness, safety and cost-effectiveness of conventional treatment and traditional Korean medicine combination treatment for children with cerebral palsy. Three hundred children with cerebral palsy aged 6 to 78 months will be recruited from six institutions. Data from each child are collected every month for a one-year period, during which time treatment might be changed or discontinued. A qualified investigator visits the sites to measure effectiveness variables, including Gross Motor Function Measure and Paediatric Evaluation of Disability Inventory. Adverse events and cost-effectiveness variables are collected using surveys conducted at baseline, mid-study, and end of study, as well as monthly tracking surveys. In the analyses, participants will be classified into two groups: group A children will be the conventional treatment group with physical, occupational, speech-language or other conventional rehabilitation therapies, whereas group B children will be the combination treatment group with traditional Korean medicine interventions, that is, herbal medicine, chuna, moxibustion and acupuncture, in addition to conventional treatment. Only a few clinical case reports have evaluated the effectiveness and safety of traditional Korean medicine; therefore, more data are required to provide optimal information to children with cerebral palsy and their guardians. We hypothesized that traditional Korean medicine combination treatment for children with cerebral palsy would have benefits compared with conventional therapy alone. The findings of this study might provide informative data for conducting economic evaluations and developing clinical research on combination treatment for cerebral palsy in South Korea. NCT02223741.


Erratum to "Automatic assessment of dairy cows' rumen function over time and links to feed changes and milk production" (JDS Commun. 3:126-131).
[This corrects the article DOI: 10.3168/jdsc.2021-0165.].


Mechanisms Underlying the Dual Effect of Polyunsaturated Fatty Acid Analogs on Kv7.1.
Polyunsaturated fatty acid (PUFA) analogs represent a new class of potential anti-arrhythmic KV7.1 and KV7.1+KCNE1 channel activators. In this study, we describe dual independent activating effects of negatively charged PUFA analogs on KV7.1 and KV7.1+KCNE1 that are dependent on discrete channel motifs. PUFA analogs are critically dependent on K326 in S6 of KV7.1 to increase the maximum conductance and critically dependent on specific S4 arginines in KV7.1 to shift the voltage dependence of channel opening toward negative voltages. Our findings provide insights into how KV7.1+KCNE1 activators may interact electrostatically both with the pore domain and the voltage-sensing domain to augment channel activity. We believe that the molecular understanding of how PUFA analogs induce dual independent activating effects is an important step toward the development of effective anti-arrhythmic drugs that target KV7.1 channels.


The time course of the electroretinogram of compound eyes in insects and its dependence on special recording conditions.
Electroretinograms recorded from slowly moving insects like the mealworm beetle Tenebrio molitor and the stick insect Carausius morosus are shown to be distorted by the use of electrodes of stainless steel and silver/silver chloride wires, unless they are used in conjunction with amplifiers having extremely high input resistance. Undistorted electroretinograms can also be recorded using micropipettes filled with a suitable electrolyte. The undistorted ERG of Tenebrio molitor is monophasic, as described by Autrum (1950) for Dixippus, and as expected from his rule.