Investigation of the degradation mechanism of 5-aminosalicylic acid in aqueous solution.
The solution degradation of the antiinflammatory agent 5-aminosalicylic acid (5-ASA) was investigated in order to elucidate a mechanism for degradation. Two degradation pathways were considered: decarboxylation by analogy to 4-aminosalicylic acid (4-ASA) decomposition and oxidation from consideration of 5-ASA's aromatic ring substitution pattern (i.e., relation to p-aminophenol). The oxidation of 5-ASA was investigated using cyclic voltammetry and flow electrolysis. These studies showed that 5-ASA is more easily oxidized than is 4-ASA and that 5-ASA undergoes a two-electron, two-proton oxidation consistent with formation of 5-ASA-quinoneimine (5-ASA-QI). This oxidation is followed by subsequent complex chemistry. The decomposition of 5-ASA in solution was examined under a variety of conditions. 5-ASA decomposes most rapidly under conditions promoting oxidation and is most stable under conditions tending to inhibit oxidation. Decarboxylation was not found to be a significant degradation pathway.


Cabergoline in Treatment of Methamphetamine-Dependent Patients and Its Effect on Serum Level of Glial Cell-Derived Neurotrophic Factor: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.
Methamphetamine use disorder is an important public health problem, especially in the younger generation, and associated with various psychiatric, cognitive, social, economic, and legal issues. Cabergoline, a drug with dopaminergic properties and long half-life, has been considered for the treatment of stimulant dependence. The systemic use of cabergoline has been shown to increase glial cell-derived neurotrophic factor (GDNF) expression. In this study, we investigated the effects of cabergoline on the serum level of GDNF and its effect on abstaining from methamphetamine in individuals treated for methamphetamine use disorder. Sixty male subjects with methamphetamine use disorder were randomly assigned to 2 groups receiving cabergoline and placebo, respectively. During a 12-week follow-up, we compared the serum level of GDNF, urine test results for methamphetamine use, and depression scale between the 2 groups. We found that serum GDNF was lower in subjects who used methamphetamine than healthy subjects (p < 0.0001). However, the serum level of GDNF was not associated with cabergoline use. The rising number of cases testing positive in the placebo group showed a trend resulting in no significant difference between cases testing positive and negative (p = 0.585) at the end of week 12. In the verum group, however, the significantly high number of cases who tested negative - sober - for substances observed in early stages (weeks 7-8) continued to remain significantly higher till the end of the study (p = 0.043), resembling an association between treatment with cabergoline and remaining sober. Although reduced during treatment, recovery from depression was not associated with cabergoline treatment. The findings of this study confirmed the effect of cabergoline in reducing methamphetamine use. However, a serum level of the GDNF increase, as seen in animal studies, was not associated with cabergoline treatment of human subjects. This study was registered at the Iranian Registry of Clinical Trials (TRN:IRCT2015050422077N1, October 06, 2015, https://en.irct.ir/trial/19134).


Exploring trust development in families of children towards surgical and emergency care providers: A scoping review of the literature.
Trust is central to the therapeutic relationship between patients and their providers, yet little is known about how it is developed in the unique context of children facing surgical emergencies. We sought to identify factors fostering trust development, gaps, and areas for improvement. We searched eight databases from inception to June 2021 to identify studies focusing on trust in pediatric surgical and urgent care settings. PRISMA-ScR protocols were followed, and screening carried out by two independent reviewers. Data collection included study characteristics, outcomes, and results. Out of 5578 articles screened, 12 fulfilled the inclusion criteria. Four major trust constructs were identified: competence, communication, dependability, and caring. Despite various instruments used, all studies reported a high level of parental trust. Nearly all studies (11/12) noted trust depending on parents' sociodemographic background, with ethnicity (3/12) and level of education and language barriers (2/12) limiting parents' confidence in physicians. High trust levels significantly correlated with effective communication and perceived quality of care. Most effective interventions enhancing trust included communication and caring trust constructs (10/12) rather than competence and dependability (5/12). Parents' individual experiences, development of compassionate interactions, and practice of family-centered care appeared important in developing trust. Improving communication and providing compassionate care, as well as encouraging a patient-centered approach, appear to be most effective in promoting trust in pediatric surgical and urgent settings. Our findings can guide future educational interventions towards strengthening parental trust and promoting child- and family-centered care in pediatric surgical settings.


Molecular-Based Immunohistochemical Algorithm for Uterine Leiomyosarcoma Diagnosis.
The morphologic assessment of uterine leiomyosarcoma (LMS) may be challenging, and diagnostic immunohistochemical (IHC) analysis is currently lacking. We evaluated the genomic landscape of 167 uterine LMS by targeted next-generation sequencing (NGS) to identify common genomic alterations. IHC analyses corresponding to these genomic landmarks were applied to a test cohort of 16 uterine LMS, 6 smooth muscle tumors of uncertain malignant potential (STUMP), and 6 leiomyomas with NGS data and a validation cohort of 8 uterine LMS, 12 STUMP, 21 leiomyomas and leiomyoma variants, 7 low-grade endometrial stromal sarcomas, and 2 diagnostically challenging uterine smooth muscle tumors. IHC results were individually interpreted by 3 pathologists blinded to NGS data. Overall, 94% of LMS showed ≥1 genomic alteration involving TP53, RB1, ATRX, PTEN, CDKN2A, or MDM2, with 80% showing alterations in ≥2 of these genes. In the test cohort, an initial panel of p53, Rb, PTEN, and ATRX was applied, followed by a panel of DAXX, MTAP, and MDM2 in cases without abnormalities. Abnormal p53, Rb, PTEN, and ATRX IHC expression was seen in 75%, 88%, 44%, and 38% of LMS, respectively, in the test cohort. Two or more abnormal IHC results among these markers were seen in 81% of LMS. STUMPs demonstrated only 1 IHC abnormality involving these markers. No IHC abnormalities were seen in leiomyomas. In the validation cohort, abnormal p53, Rb, and PTEN IHC results were seen in LMS, whereas rare STUMP or leiomyomas with bizarre nuclei showed IHC abnormalities involving only 1 of the markers. Abnormalities in ≥2 markers were present in both diagnostically challenging smooth muscle tumors, confirming LMS. Concordance was excellent among pathologists in the interpretation of IHC (κ = 0.97) and between IHC and NGS results (κ = 0.941). Uterine LMS exhibit genomic landmark alterations for which IHC surrogates exist, and a diagnostic algorithm involving molecular-based IHC may aid in the evaluation of unusual uterine smooth muscle tumors.


Improved liquid chromatography-mass spectrometry performance in quantitative analysis using a nanosplitter interface.
Several pairs of analytes in plasma were investigated to demonstrate the successful utility of a novel interface in quantitative bioanalytical LC-MS and LC-MS/MS. Recently in our laboratory, an interface (the nanosplitter) was developed that allows the coupling of normal-bore liquid chromatography with microelectrospray mass spectrometry. The post-column concentric split minimizes turbulence and is shown to produce significant gains in the mass spectrometric signal. This configuration of the splitter allows sampling of the center portion of the parabolic HPLC plug, which maintains chromatographic integrity while producing high split ratios and effectively conserving nearly 99.9% of the sample. When utilizing a Finnigan mass spectrometer (with a heated capillary interface design), the signal gain with the nanosplitter ranged from 5 to 16 times the peak area obtained using the conventional interface without splitting. The linearity of the nanosplitter and conventional interface are shown to be comparable for all analytes tested. The nanosplitter was also fitted to a Sciex mass spectrometer and the results were compared to those from turbo ionspray. While in this case no significant signal improvement was observed, when normalized to the actual analyte mass introduced into the MS, the mass sensitivity was still increased 270-fold. The variations in signal gain utilizing the nanosplitter on instruments from different manufacturers reflect the inherent differences in the source designs while confirming the benefits of coupling high flow LC separations with low flow mass spectrometric detection.


Brachytherapy and local excision for sphincter preservation in T1 and T2 rectal cancer.
To report long-term results of brachytherapy after local excision (LE) in the treatment of T1 and T2 rectal cancer at risk of recurrence due to residual subclinical disease. Between 1989 and 2007, 32 patients undergoing LE and brachytherapy were followed prospectively for a mean of 6.2 years. Estimates of local recurrence (LR), disease-specific survival (DSS), and overall survival (OS) were generated. Treatment-related toxicity and the effect of known prognostic factors were determined. There were 8 LR (3 T1, 5 T2), of which 5 were salvaged surgically. Median time to the 8 LR was 14 months, and the 5-year rate of local control was 76%. Although there have been 9 deaths to date, only 5 were from disease. Five-year DSS and OS rates were 85% and 78%, respectively. There were 4 cases of Grade 2-3 radionecrosis and 1 case of mild stool incontinence. The sphincter was preserved in 27 of 32 patients. Local excision and adjuvant brachytherapy for T1 and T2 rectal cancer is an appealing treatment alternative to immediate radical resection, particularly in the frail and elderly who are unable to undergo major surgery, as well as for patients wanting to avoid a permanent colostomy.


Mammalian neural crest cells participate in normal embryonic development on microinjection into post-implantation mouse embryos.
The production of chimaeric mice by aggregating pre-implantation mouse embryos or by injection of cells into the blastocyst has been of great value in analysing the regulation of early mammalian development and in dissecting the relationships of early cell lineages. While the totipotent cells of the pre-implantation embryo can be grown in vitro and thus are readily accessible to experimental manipulation, this is not possible after the embryo has implanted into the uterus. This problem has severely hampered the analysis of cell migration and of cell lineage relationships in later stages of mammalian development. In contrast, the chicken embryo can be manipulated experimentally throughout embryo-genesis and this has made the bird a favourable system for studying patterns of cell migration in the development of higher vertebrates. In mammals, the introduction of retroviruses and haematopoietic cells has provided two means of probing post-implantation development by direct intervention. I report here that cultured neural crest cells, when microinjected into 9-day-old mouse embryos, can migrate over considerable distances and participate in normal development, and the resulting chimaeric animals show pigmentation derived from the donor cells in hair and iris. The introduction of cells into post-implantation embryos may provide the means of studying patterns of cell migration in mammalian development at a level of sophistication which so far has been restricted to the chicken system.


Association of preterm outcome with maternal systemic lupus erythematosus: a retrospective cohort study.
Maternal systemic lupus erythematosus (SLE) is at greater risk of pregnancy complications and is associated with increased risk of preterm delivery. However hardly any study has looked at the influence of SLE on the outcomes of preterm infants. This study aimed to explore the influence of SLE on the outcomes of preterm infants. In this retrospective cohort study, preterm infants born to mothers with SLE from Shanghai Children's Medical Center during 2012 to 2021 were enrolled. Infants were excluded if they were died during hospitalization or has major congenital anomalies and neonatal lupus. Exposure was defined as mother diagnosed SLE before or during pregnancy. Maternal SLE group was matched with Non-SLE group by gestational age, birth weight and gender. Clinical data has been extracted from patients' records and registered. Major morbidities of premature and biochemical parameters in the two groups were compared using multiple logistic regression. One hundred preterm infants born to 95 mothers with SLE were finally enrolled. The mean (standard deviation) of gestational age and birth weight were 33.09 (7.28) weeks and 1768.50 (423.56) g respectively. There was no significant difference in major morbidities between SLE group and non-SLE group. Compared with non-SLE group, SLE off-spring had significantly lower leukocytes, neutrophiles after birth, neutrophils and platlet in one week (mean difference: -2.825, -2.001, -0.842, -45.469, respectively). Among SLE group, lower birth weight and smaller gestational age were observed in SLE mothers with disease active during pregnancy, kidney involved, blood system involved and not taking Aspirin during pregnancy. In the multivariable logistic regression analysis, exposure to aspirin during pregnancy reduced the risk of very preterm birth and increased the incidence of survive without major morbidities among preterm infants born to SLE mothers. Born to mothers with SLE may not increase the risk of major premature morbidities, but the hematologic profile of SLE preterm infants may be different from preterm infants born to women without SLE. The outcome of SLE preterm infants is associated with maternal SLE status and may benefit from maternal aspirin administration.


Single-cell deconstruction of stem-cell-driven schistosome development.
Schistosomes cause one of the most devastating neglected tropical diseases, schistosomiasis. Their transmission is accomplished through a complex life cycle with two obligate hosts and requires multiple radically different body plans specialized for infecting and reproducing in each host. Recent single-cell transcriptomic studies on several schistosome body plans provide a comprehensive map of their cell types, which include stem cells and their differentiated progeny along an intricate developmental hierarchy. This progress not only extends our understanding of the basic biology of the schistosome life cycle but can also inform new therapeutic and preventive strategies against the disease, as blocking the development of specific cell types through genetic manipulations has shown promise in inhibiting parasite survival, growth, and reproduction.


Precision genetic cellular models identify therapies protective against ER stress.
Rare monogenic disorders often share molecular etiologies involved in the pathogenesis of common diseases. Congenital disorders of glycosylation (CDG) and deglycosylation (CDDG) are rare pediatric disorders with symptoms that range from mild to life threatening. A biological mechanism shared among CDG and CDDG as well as more common neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis, is endoplasmic reticulum (ER) stress. We developed isogenic human cellular models of two types of CDG and the only known CDDG to discover drugs that can alleviate ER stress. Systematic phenotyping confirmed ER stress and identified elevated autophagy among other phenotypes in each model. We screened 1049 compounds and scored their ability to correct aberrant morphology in each model using an agnostic cell-painting assay based on >300 cellular features. This primary screen identified multiple compounds able to correct morphological phenotypes. Independent validation shows they also correct cellular phenotypes and alleviate each of the ER stress markers identified in each model. Many of the active compounds are associated with microtubule dynamics, which points to new therapeutic opportunities for both rare and more common disorders presenting with ER stress, such as Alzheimer's disease and amyotrophic lateral sclerosis.


High-Throughput Screening of Compound Neurotoxicity Using 3D-Cultured Neural Stem Cells on a 384-Pillar Plate.
Assessing the neurotoxicity of test chemicals has typically been performed using two-dimensionally (2D)-cultured neuronal cell monolayers and animal models. The in vitro 2D cell models are simple and straightforward compared to animal models, which have the disadvantage of being relatively low throughput, expensive, and time consuming. Despite their extensive use in this area of neurotoxicology research, both models often do not accurately recapitulate human outcomes. To bridge this gap and attempt to better replicate what happens in vivo, three-dimensionally (3D) cultured neural stem cells (NSCs) encapsulated in hydrogels on a 384-pillar plate have been developed via miniature 3D bioprinting. This technology allows users to print NSCs on a pillar plate for rapid 3D cell culture as well as high-throughput compound screening. For this, the 384-pillar plate with bioprinted NSCs is sandwiched with a standard 384-well plate with growth medium for 3D culture, allowing researchers to expose the cells to test compounds and stain them with various fluorescent dyes for a suite of high-content imaging assays, including assays for DNA damage, mitochondrial impairment, cell membrane integrity, intracellular glutathione levels, and apoptosis. After acquiring cell images from an automated fluorescence microscope and extracting fluorescence intensities, researchers can obtain the IC50 value of each compound to evaluate critical parameters in neurotoxicity. Here, we provide a detailed description of protocols for cell printing on a 384-pillar plate, 3D NSC culture, compound testing, 3D cell staining, and image acquisition and analysis, which altogether will allow researchers to investigate mechanisms of compound neurotoxicity with 3D-cultured NSCs in a high-throughput manner. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Three-dimensional neural stem cell culture on a 384-pillar plate Basic Protocol 2: Compound treatment and cell staining Basic Protocol 3: Image acquisition, processing, and data analysis.


Prevalence of abdominal obesity among Chinese adults in 2011.
The prevalence of abdominal obesity is increasing dramatically worldwide. This study aimed to estimate the current prevalence of abdominal obesity from the 2011 China Health and Nutrition Survey (CHNS) and compare the data with other countries. Waist circumference (WC) of 12,326 Chinese adults (aged 20 years or older) from the 2011 CHNS were analyzed by age group and region. Abdominal obesity was defined as a WC ≥90 cm for men and WC ≥80 cm for women based on World Health Organization (WHO) recommendations for Asians. In 2011, the age-adjusted mean WC was 85.9 cm (95% confidence interval [CI], 85.6-86.2 cm) for men and 80.7 cm (95% CI, 80.4-80.9 cm) for women. Based on the WHO recommendations, the age-adjusted prevalence of abdominal obesity was 44.0% (95% CI, 43.1%-44.8%) overall, 35.3% (95% CI, 34.1%-36.6%) in men, and 51.7% (95% CI, 50.5%-52.9%) in women. Moreover, the age-adjusted prevalence was 44.0% (95% CI, 42.7%-45.2%) in rural populations, 42.5% (95% CI, 40.7%-44.2%) in urban populations, and 45.2% (95% CI, 43.5%-46.9%) in megacity populations. The prevalence in China (35.3% for men and 51.7% for women) was lower than in Japan (50.8% for men) and the United States (43.5% for men and 64.7% for women). Similar results were observed when applying the criteria suggested by the Working Group on Obesity in China. In 2011, the age-adjusted prevalence of abdominal obesity in China was 35.3% in men and 51.7% in women.


The Role of Cervical Symptoms in Post-concussion Management: A Systematic Review.
Patients with cervicogenic symptoms following a concussion have shown a disproportionate rate of delayed symptom resolution. However, the prevalence of cervicogenic symptoms in the acute stages following a concussion and the percentage of those patients who continue on to suffer delayed symptom resolution is poorly described in the literature. To provide a comprehensive report on the clinical prevalence, diagnostic methods, and potential treatment options for cervicogenic symptoms that are elicited during acute and chronic phases following a concussion. Electronic searches were conducted in PubMed, SPORTDiscus, ICL, CINAHL and PEDro, from inception to May 2020, to identify original research articles on concussion involving cervicogenic symptoms. We assessed each included article for risk of bias, methodological quality, level of evidence and evidence quality. The articles were categorized into three topics: (1) prevalence of post-concussion cervicogenic symptoms; (2) diagnostic testing for cervicogenic symptoms, and (3) treatment techniques for cervicogenic symptoms. The initial review resulted in 1443 abstracts, of which 103 abstracts met the inclusion criteria of our research. After the review of full text, 80 articles were excluded, which resulted in a total of 23 articles for this systematic review. Prevalence of cervicogenic symptoms in the acute stages ranged from 7 to 69% and increased to 90% in patients experiencing persistent post-concussive symptoms. Neck pain at initial evaluation increased risk of developing persistent post-concussive symptoms (PPCS) by 2.58-6.38 times. Patient-reported outcome measures (e.g., Neck Disability Index, Dizziness Handicap Inventory, and Rivermead Post-Concussion Questionnaire) can identify patients with cervicogenic symptoms that should be further differentiated by clinical testing. Lastly, treatment using graded cervical manual therapy has shown to reduce time to symptom resolution and medical clearance. Cervicogenic symptoms are prevalent in the acute and chronic stages following concussion, which if not diagnosed appropriately increase the likelihood of PPCS. Several clinical tests are available to help differentiate cervicogenic symptoms; however, lack of awareness and hesitation by practitioners limits their use. More randomized controlled trials are necessary to evaluate the effectiveness of cervical specific treatment programs for PPCS.


Epigenetic alterations in hematopoietic malignancies.
Gene discovery efforts in patients with hematopoietic malignancies have brought to the forefront a series of mutations in genes thought to be involved in the epigenetic regulation of gene transcription. These mutations occur in genes known, or suspected, to play a role in modifying cytosine nucleotides on DNA and/or altering the state of histone modifications. Genes such as ASXL1, DNMT3A, EZH2, IDH1/2, MLL1, and TET2 all have been shown to be mutated and/or translocated in patients with myeloid malignancies. Intriguingly, many of the alterations affecting DNA cytosine modifications in myeloid malignancies (mutations in DNMT3A, IDH1/2, and TET2) have also been found in patients with T-cell lymphomas, and EZH2 mutations appear to be critical in T-cell acute lymphoblastic leukemia development as well. In addition, the discovery of frequent mutations in CREBBP, EP300, EZH2, and MLL2 in B-cell lymphomas suggests that epigenetic alterations play a critical role in lymphomagenesis. The purpose of this review is to present functional evidence of how alterations in these epigenetic modifiers promote hematopoietic transformation. The conclusions drawn from these data are valuable in understanding biological mechanisms and potential therapeutic targets.


Accidental epidural catheter infusion of potassium chloride for postoperative analgesia: A case report.
An infusion of 100cc of 0,2% potassium chloride was accidental performed through a thoracic epidural catheter, inserted to perioperative analgesia, to a 66years old man who was scheduled for right hemicolectomy, 48hours after surgery. Paresis of upper limbs, flaccid paralysis of lower limbs and a sensitive level at T8 was observed. An epidural lavage with an initial dose of 20cc of saline was slowly injected, followed for a saline infusion of 20cc per hour. Neurologic signs were totally reverted some hours later and 24hours after the incident the physical exam was normal. We reviewed the clinical presentation of the complication and its mechanisms, the more frequent clinical evolution, as well as treatment measures and strategies to prevent the incident.


Pathophysiology of nAChRs: Limbic circuits and related disorders.
Human epidemiological studies have identified links between nicotine intake and stress disorders, including anxiety, depression and PTSD. Here we review the clinical evidence for activation and desensitization of nicotinic acetylcholine receptors (nAChRs) relevant to affective disorders. We go on to describe clinical and preclinical pharmacological studies suggesting that nAChR function may be involved in the etiology of anxiety and depressive disorders, may be relevant targets for medication development, and may contribute to the antidepressant efficacy of non-nicotinic therapeutics. We then review what is known about nAChR function in a subset of limbic system areas (amygdala, hippocampus and prefrontal cortex), and how this contributes to stress-relevant behaviors in preclinical models that may be relevant to human affective disorders. Taken together, the preclinical and clinical literature point to a clear role for ACh signaling through nAChRs in regulation of behavioral responses to stress. Disruption of nAChR homeostasis is likely to contribute to the psychopathology observed in anxiety and depressive disorders. Targeting specific nAChRs may therefore be a strategy for medication development to treat these disorders or to augment the efficacy of current therapeutics.


In-silico optimisation of tileable philips digital SiPM based thin monolithic scintillator detectors for SPECT applications.
Over the last decade one of the most significant technological advances made in the field of radiation detectors for nuclear medicine was the development of Silicon Photomultipler (SiPM) sensors. At present only a small number of SiPM based radiation detectors for Single Photon Emission Computed Tomography (SPECT) applications have been explored, and even fewer experimental prototypes developed. An in-silico investigation into the optimal design of a Philips DPC3200 SiPM photosensor-based thin monolithic scintillator detector for SPECT applications was undertaken using the Monte Carlo radiation transport modelling toolkit Geant4 version 10.5. The performance of the 20 different SPECT radiation detector configurations, 4 scintillator materials (NaI(Tl), GAGG(Ce), CsI(Tl) and LaBr3(Ce)) and 5 thicknesses (1-5 mm), were determined through the use of seven figures of merit. It was found that a crystal thickness range of 4-5 mm was required for all four materials to ensure acceptable energy resolution, sensitivity and spatial resolution performance with the Philips DPC3200 SiPM. Any thinner than this and the performance of all four materials was found to degrade rapidly due to a high probability of material specific fluorescence x-ray escape after incident gamma/x-ray photoelectric absorption. When factoring in each material's magnetic resonance imaging compatibility, hygroscopy, and cost, it was found that CsI(Tl) represents the most promising material to construct tileable Philips digital SiPM based thin monolithic scintillator detectors for SPECT applications.


Inhibitory effects of cadralazine and its metabolite, ISF-2405, on contractions and the level of cytosolic Ca2+ in vascular smooth muscle.
The inhibitory effects of a hypotensive agent, cadralazine and its metabolite, ISF-2405, on the level of cytosolic Ca2+ ([Ca2+]cyt) and on contractions were examined in isolated vascular smooth muscle. Cadralazine slightly inhibited the transient norepinephrine-induced contraction in rabbit aorta and canine femoral, renal and mesenteric arteries and saphenous vein, and prostaglandin F2 alpha-induced contractions in canine basilar and coronary arteries. In contrast, ISF-2405 inhibited the contractions induced by prostaglandin F2 alpha in canine basilar and coronary arteries and those induced by norepinephrine in canine renal and femoral arteries and rabbit aorta. In aorta, ISF-2405 inhibited the increase in [Ca2+]cyt and muscle tension caused by norepinephrine. A Ca2+ channel blocker, verapamil, inhibited the norepinephrine-stimulated increase in [Ca2+]cyt more potently than it inhibited the increase in muscle tension, and ISF-2405 inhibited the verapamil-resistant part of the contraction. In Ca2(+)-free solution, norepinephrine induced transient increases in [Ca2+]cyt and muscle tension. ISF-2405 inhibited these changes. However, ISF-2405 did not inhibit the transient contraction induced by caffeine in the aorta. These results suggest that cadralazine is metabolized to ISF-2405 and inhibits vascular smooth muscle contraction by inhibiting receptor-mediated Ca2+ influx, Ca2+ release and Ca2+ sensitization of contractile elements.


The transient appearance of IgM antibodies in the bile of rats injected with Salmonella enteritidis.
Following the intravenous injection of 2 X 10(8) killed Salmonella enteritidis into rats, high levels of specific antibodies were detected in the serum and bile after 4 days. The level in serum persisted while that in bile had virtually disappeared by day 7. On the basis of gel filtration on Ultrogel AcA22 the activity in bile was found to be associated with the IgM fraction. The transient nature of the biliary response was further evidenced by the association of the agglutinating activity with a four-fold increase in the concentration of IgM and the presence of complement-fixing bactericidal antibody. Initial evidence suggests that the source of the biliary IgM is from cells within the liver rather than transport of IgM from blood to bile. It is proposed that immune stimulation by blood-borne microorganisms can lead to a pulse of IgM in the bile, providing rapid augmentation of other local immune processes in the gastrointestinal tract.


The safety and efficacy of hydroxycarbamide in infants with sickle cell anemia.
The BABYHUG study is the first randomized controlled prospective trial of hydroxycarbamide in infants with sickle cell anemia to look at its effect on organ function. Almost 200 patients were recruited, irrespective of disease severity, over a 3-year period and followed for 2 years. The primary end points of splenic function and glomerular filtration rate were not reached. The trial did show a benefit in frequency of pain, dactylitis, acute chest syndrome, hospital admissions and transfusion requirements. Adverse effects were low.


Preparation and characterization of single-enzyme nanogels.
Enzymes have been incorporated in nanostructures in order to provide robust catalysts for valuable reactions, particularly those performed under harsh and denaturing conditions. This chapter describes the encapsulation of enzymes in polyacrylamide nanogels by a two-step in situ polymerization process for preparing robust biocatalysts. The first step in this process is the generation of vinyl groups on the enzyme surface, while the second step involves in situ polymerization using acrylamide as the monomer. Encapsulation of the enzyme in the hydrophilic, porous, and flexible polyacrylamide gel of several nanometers thick would help to both give a significantly enhanced thermostability and prevent the removal of essential water by polar solvents. The hydrophilic flexible polymer shell also allows the protein structure to undergo necessary conformational transitions during the catalytic reaction and, at the same time, impose marginal mass transfer restrictions for the substrates entering across the polymer shell. The effectiveness of this method is demonstrated with horseradish peroxidase (HRP), carbonic anhydrase, and lipase. The impacts of such an encapsulation on the activity and stability of enzymes are also discussed.


Neural and behavioral reactions to partners and strangers in monogamous female titi monkeys (Plecturocebus cupreus).
Pair bonding in humans and other socially monogamous species can have positive effects on health and well-being. These attachments also come with the potential for challenges such as separation, jealousy, or grief. Much of the work on the neurobiology of pair bonding in non-human primates has been carried out in coppery titi monkeys (Plecturocebus cupreus), a monogamous South American monkey, although these studies have been primarily in males. In the current study, we utilized female titi monkeys to experimentally examine responses to their monogamous male partner vs. a male stranger or being alone. Positron emission tomography (PET) scans were performed on eight adult female titi monkeys from well-established pairs. We used a within-subjects design in which each female underwent three different conditions after the fluorodeoxyglucose F18 (FDG) injection: a) the subject was reunited with her partner, b) encountered a stranger, or c) was alone in the experimental cage. Behavioural observations were recorded, and plasma assayed for cortisol. Females housed alone showed higher cortisol compared with either the partner or stranger conditions. FDG uptake was higher in the amygdala and hippocampus when interacting with the stranger than the partner. Proximity modulated the relationship between social condition and FDG uptake in several areas. Females entered into mutual proximity more frequently with the partner than with the stranger. Female titi monkeys have different physiological, neural, and behavioural reactions to being with their partner, a stranger male, or being alone.


Monitoring the Mitochondrial Presequence Import Pathway In Living Mammalian Cells with a New Molecular Biosensor.
Most mitochondrial proteins are encoded by the nuclear genome, synthesized in the cytosol, and imported into the organelle. Mitochondrial protein import is therefore vital for the maintenance of mitochondrial function and cell survival. Alterations in this process are suspected to contribute to various diseases, including neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. Our understanding of the cytosolic signaling mechanisms and posttranslational modifications regulating the mitochondrial import process is still in its infancy and hampered by the lack of tools for its dynamic assessment in cells. We recently engineered an inducible molecular biosensor for monitoring one of the main mitochondrial import routes, the so-called presequence pathway, using a quantitative luminescence-based readout. Here, we provide basic guidelines for using this probe in common cell types of general use in the scientific community: HEK293T cells, human fibroblasts, and mouse primary neurons. These guidelines can serve as a starting point for the development of more elaborated protocols for the dynamic investigation of the presequence import pathway and its regulation in relevant physiological and pathological conditions.


A neuroimaging biomarker for Individual Brain-Related Abnormalities In Neurodegeneration (IBRAIN): a cross-sectional study.
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that poses a worldwide public health challenge. A neuroimaging biomarker would significantly improve early diagnosis and intervention, ultimately enhancing the quality of life for affected individuals and reducing the burden on healthcare systems. Cross-sectional and longitudinal data (10,099 participants with 13,380 scans) from 12 independent datasets were used in the present study (this study was performed between September 1, 2021 and February 15, 2023). The Individual Brain-Related Abnormalities In Neurodegeneration (IBRAIN) score was developed via integrated regional- and network-based measures under an ensemble machine learning model based on structural MRI data. We systematically assessed whether IBRAIN could be a neuroimaging biomarker for AD. IBRAIN accurately differentiated individuals with AD from NCs (AUC = 0.92) and other neurodegenerative diseases, including Frontotemporal dementia (FTD), Parkinson's disease (PD), Vascular dementia (VaD) and Amyotrophic Lateral Sclerosis (ALS) (AUC = 0.92). IBRAIN was significantly correlated to clinical measures and gene expression, enriched in immune process and protein metabolism. The IBRAIN score exhibited a significant ability to reveal the distinct progression of prodromal AD (i.e., Mild cognitive impairment, MCI) (Hazard Ratio (HR) = 6.52 [95% CI: 4.42∼9.62], p < 1 × 10-16), which offers similar powerful performance with Cerebrospinal Fluid (CSF) Aβ (HR = 3.78 [95% CI: 2.63∼5.43], p = 2.13 × 10-14) and CSF Tau (HR = 3.77 [95% CI: 2.64∼5.39], p = 9.53 × 10-15) based on the COX and Log-rank test. Notably, the IBRAIN shows comparable sensitivity (beta = -0.70, p < 1 × 10-16) in capturing longitudinal changes in individuals with conversion to AD than CSF Aβ (beta = -0.26, p = 4.40 × 10-9) and CSF Tau (beta = 0.12, p = 1.02 × 10-5). Our findings suggested that IBRAIN is a biologically relevant, specific, and sensitive neuroimaging biomarker that can serve as a clinical measure to uncover prodromal AD progression. It has strong potential for application in future clinical practice and treatment trials. Science and Technology Innovation 2030 Major Projects, the National Natural Science Foundation of China, Beijing Natural Science Funds, the Fundamental Research Funds for the CentralUniversity, and the Startup Funds for Talents at Beijing Normal University.


Saccadic and smooth pursuit eye movements attenuate postural sway similarly.
Saccadic eye movements reduce body sway, yet visually pursuing a moving dot seems to increase body sway. However, how these two types of eye movements affect postural control remains ambiguous, particularly for smooth pursuit eye movements. The aim of this study was to examine the effects of saccade and smooth pursuit eye movements on body sway magnitude during low and high frequencies. Ten young adults (19.5 ± 1.9 years) participants were required to stand upright, barefoot for 70s using a bipedal stance, with feet hip width apart, fixating or pursuing a target that was displayed on a monitor positioned 100 cm away from their eyes. Each participant performed three trials using both types of eye movements, in particular, slow and fast saccades, and slow and fast smooth pursuit movements. Body sway was obtained using reflective markers attached to a participant's head and trunk, which were recorded by two video cameras. The results indicated that body sway was reduced during both saccadic eye movements and smooth pursuit movements when compared to fixation, independent of visual frequencies. These results suggested similarities in the control of saccades and smooth pursuit on postural control.


Association of Intracranial Aneurysms With Aortic Aneurysms in 125 Patients With Fusiform and 4253 Patients With Saccular Intracranial Aneurysms and Their Family Members and Population Controls.
Background Varying degrees of co-occurrence of intracranial aneurysms (IA) and aortic aneurysms (AA) have been reported. We sought to compare the risk for AA in fusiform intracranial aneurysms (fIA) and saccular intracranial aneurysms (sIA) disease and evaluate possible genetic connection between the fIA disease and AAs. Additionally, the characteristics and aneurysms of the fIA and sIA patients were compared. Methods and Results The Kuopio Intracranial Aneurysm Database includes all 4253 sIA and 125 fIA patients from its Eastern Finnish catchment population, and 13 009 matched population controls and 18 455 first-degree relatives to the IA patients were identified, and the Finnish national registers were used to identify the individuals with AA. A total of 33 fIA patients were studied using an exomic gene panel of 37 genes associated with AAs. Seventeen (14.4%) fIA patients and 48 (1.2%) sIA patients had a diagnosis of AA. Both fIA and sIA patients had AAs significantly more often than their controls (1.2% and 0.5%) or relatives (0.9% and 0.3%). In a competing risks Cox regression model, the presence of fIA was the strongest risk factor for AA (subdistribution hazard ratio 7.6, 95% CI 3.9-14.9, P<0.0005). One likely pathogenic variant in COL5A2 and 3 variants of unknown significance were identified in MYH11, COL11A1, and FBN1 in 4 fIA patients. Conclusions The prevalence of AAs is increased slightly in sIA patients and significantly in fIA patients. fIA patients are older and have more comorbid diseases than sIA patients but this alone does not explain their clinically significant AA risk.


Adherence to guidelines-recommended diagnostic testing was associated with overall survival in patients with diffuse large B-cell lymphoma after rituximab-based treatment: an observational cohort study.
This study assessed the impact of adherence to guidelines-recommended diagnostic testing on treatment selection and overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL) initiated on rituximab-based first line of treatment (1-LOT). This retrospective cohort study used a nationwide electronic health record-derived de-identified database, including diagnostic testing information on immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and karyotype analysis that were abstracted from pathology reports or clinical visit notes, where available. The study included patients above 18 years old who were diagnosed with DLBCL between January 2011 and December 2019 and initiated on rituximab-based 1-LOT. Patients were classified into 'non-adherence,' 'partial-adherence' and 'complete-adherence' groups according to the evidence/documentation of a confirmed known result for IHC and molecular profiling tests (FISH and karyotyping) on a selection of the markers prior to the initiation of 1-LOT. Logistic regression was used to evaluate associations of adherence to diagnostic testing with 1-LOT between R-CHOP and other rituximab-based regimens. Median OS after the start of rituximab-based 1-LOT was calculated using the Kaplan-Meier method. Multivariable-adjusted Cox proportional hazards regression was used to assess the risk of all-cause death after initiation of 1-LOT by the degrees of adherence to guidelines-recommended diagnostic testing. In total, 3730 patients with DLBCL who initiated on rituximab-based 1-LOT were included. No association was found between adherence to guidelines-recommended diagnostic testing and treatment selection of 1-LOT for R-CHOP versus other rituximab-based regimens. Patients with a higher degree of adherence to guidelines-recommended diagnostic testing survived longer (median OS at 5.1, 6.9 and 7.1 years for 'non-adherence,' 'partial-adherence' and 'complete-adherence' groups, respectively [log-rank p < 0.001]) and had a decreased mortality risk (multivariable-adjusted hazard ratio with 95% confidence intervals at 0.83 [0.70-0.99] for 'partial-adherence' and 0.77 [0.64-0.91] for 'complete-adherence' groups, respectively). Patients' adherence to guidelines-recommended diagnostic testing were associated with better survival benefit, reinforcing the need for adoption of diagnostic testing guidelines in routine clinical care.


Significant reduction in dental cone beam computed tomography (CBCT) eye dose through the use of leaded glasses.
In light of the increased recognition of the potential for lens opacification after low-dose radiation exposures, we investigated the effect of leaded eyeglasses worn during dental cone-beam computerized tomography (CBCT) procedures on the radiation absorbed dose to the eye and suggest simple methods to reduce risk of radiation cataract development. Dose measurements were conducted with the use of 3 anthropomorphic phantoms: male (Alderson radiation therapy phantom), female (CIRS), and juvenile male (CIRS). All exposures were performed on the same dental CBCT machine (Imtec, Ardmore, OK) using 2 different scanning techniques but with identical machine parameters (120 kVp, 3.8 mA, 7.8 s). Scans were performed with and without leaded glasses and repeated 3 times. All measurements were recorded using calibrated thermoluminescent dosimeters and optical luminescent dosimetry. Leaded glasses worn by adult and pediatric patients during CBCT scans may reduce radiation dose to the lens of the eye by as much as 67% (from 0.135 ± 0.004 mGy to 0.044 ± 0.002 mGy in pediatric patients). Leaded glasses do not appear to have a deleterious effect on the image quality in the area of clinical significance for dental imaging.


Fast Gelation of Ti3 C2 Tx MXene Initiated by Metal Ions.
Gelation is an effective way to realize the self-assembly of nanomaterials into different macrostructures, and in a typical use, the gelation of graphene oxide (GO) produces various graphene-based carbon materials with different applications. However, the gelation of MXenes, another important type of 2D materials that have different surface chemistry from GO, is difficult to achieve. Here, the first gelation of MXenes in an aqueous dispersion that is initiated by divalent metal ions is reported, where the strong interaction between these ions and OH groups on the MXene surface plays a key role. Typically, Fe2+ ions are introduced in the MXene dispersion which destroys the electrostatic repulsion force between the MXene nanosheets in the dispersion and acts as linkers to bond the nanosheets together, forming a 3D MXene network. The obtained hydrogel effectively avoids the restacking of the MXene nanosheets and greatly improves their surface utilization, resulting in a high rate performance when used as a supercapacitor electrode (≈226 F g-1 at 1 V s-1 ). It is believed that the gelation of MXenes indicates a new way to build various tunable MXene-based structures and develop different applications.


Adenosine as a neuromodulator in neurological diseases.
Adenosine is a modulator of brain function uniquely positioned to integrate excitatory and inhibitory neurotransmission. The past few years brought a wealth of new data fostering our understanding of how the adenosine system is involved in the pathogenesis of neurological diseases. Thus, dysregulation of the adenosine system is implicated in epileptogenesis and cell therapies have been developed to locally augment adenosine in an approach to prevent seizures. While activation of inhibitory adenosine A(1) receptors is beneficial in epilepsy, chronic pain and cerebral ischemia, inhibition of facilitatory A(2A) receptors has profound neuroprotective effects, which are currently exploited in clinical trials in Parkinson's disease. A new era of adenosine-based therapies has begun, with the prospect to cover a wide range of neurological diseases.


Regulation of the growth of Epstein-Barr virus-infected B cells: temporal profile of the in vitro development of three distinct cytotoxic cells.
The time course of the appearance of cytotoxic cells was examined in cocultures of E-rosetting (E+) cells and EBV-infected non-T cells (4:1 ratio) from the blood of VCA-positive healthy adults. Classical HNK-1+ NK cells were present at the initiation of the cultures and they produced 76 +/- 2% specific 51Cr-release from K-562 cells, but they did not effectively lyse the NK-resistant Daudi cells, nor did they kill autologous EBV-induced lymphoblasts (LCLEBV). The NK activity decreased during the first week in culture to 40 +/- 7% cytotoxicity. At the same time, nonspecific cytotoxic cells capable of killing Daudi as well as K562 developed and persisted into the third week in culture when it declined. This later nonspecific cytotoxicity was mediated by 4F2+, T8-, HNK-1- activated E+ cells. After 10 days in culture, killing of autologous LCLEBV increased continuously, from 4 +/- 3% at Day 10 to 38 +/- 4% by Day 22. The cytotoxicity to LCLEBV was mediated by classical T8+ CTL, and it was antigen specific and at least partially HLA Class I restricted. The regression of BEBV growth that occurs in E+/BEBV cocultures coincides with the development of this CTL-mediated cytotoxicity.


Electrochemiluminescence from a biocatalysis accelerated N-(aminobutyl)-N-(ethylisoluminol)/dissolved O2 system for microRNA detection.
A kind of biocatalyst, laccase, has been employed as a biocompatible coreactant accelerator to efficiently catalyze coreactant (dissolved O2) for generating high local concentration of superoxide radical (O2•-), acquiring high-intense electrochemiluminescence (ECL) emission of ABEI (N-(aminobutyl)-N-(ethylisoluminol))/dissolved O2 system. Furthermore, a modified strand displacement reaction with excellent amplification efficiency was constructed by replacing traditional single strand DNA to the hairpin DNA as template for triggering the immobilization of more signal probes. As a result, the biosensor for microRNA-21 determination has preeminent selectivity and favorable sensitivity with detection limit down to 80.8 aM. Significantly, the devised strategy has blazed a new path for seeking more coreaction accelerators with splendid biocompatibility thus promoting the application of ternary ECL systems in biological analysis and clinical diagnosis.


One-year myopia control efficacy of cylindrical annular refractive element spectacle lenses.
To evaluate the 1-year myopia control efficacy of a spectacle lens with annular cylindrical microstructures. A total of 118 consecutive eligible children aged 8-12 years with -1.00 D to -4.00 D of spherical component myopia and <1.50 D astigmatism were enrolled between August 2020 and November 2020 at the Eye Hospital of Wenzhou Medical University. Participants were randomly assigned to wear cylindrical annular refractive element (CARE) (n = 61) or single-vision (n = 57) spectacle lenses. Cycloplegic autorefraction (spherical equivalent refraction [SER]) and axial length (AL) were measured at baseline and 6-month intervals. Adaptation and compliance questionnaires were administered during all visits. Among 118 randomized participants, 96 (81.4%) were included in the analyses (mean [SE] age, 10.4 [0.6] years; 49 [51.0%] were female; mean [SE] spherical equivalent refractive error, -2.67 [0.66] D; mean [SE] axial length, 24.75 [0.77] mm). Adjusted 1-year myopia progression was -0.56 D for CARE and -0.71 D for single-vision spectacle lenses. The difference in progression was 0.14 D (95% CI, -0.04 to 0.32) for CARE vs single vision. Adjusted 1-year eye growth was 0.27 mm for CARE and 0.35 mm for single vision. The difference in eye growth was 0.09 mm (95% CI, -0.15 to -0.02) for CARE vs single vision. All groups adapted to their lenses with no reported adverse events, complaints, or discomfort. Among children with myopia, treatment with cylindrical annular refractive element spectacle lenses significantly reduced the rate of axial elongation over 1 year compared with single-vision spectacle lenses.


Characterization of TATA-containing genes and TATA-less genes in S. cerevisiae by network topologies and biological properties.
The TATA box is the core sequence of the promoter and the binding site of many transcription factors. Based on the presence or absence of TATA box, genes can be defined as TATA-containing or TATA-less genes. Many important stress-response functions and highly variable expression patterns are found to be correlated with the TATA box. However, until now, the relationships and differences between TATA-containing and TATA-less genes remain unclear. In this study, based on the transcriptional profiling of the Saccharomyces cerevisiae genome, the perturbation sensitivity (PS) network is constructed. The topological and biological properties are used to investigate differences between TATA-containing and TATA-less genes. Significant differences are found in all topological properties and most of the biological properties. Notably, the TF number, determined mathematically by the number of transcription factors regulating a gene, demonstrates the highest discrimination between TATA-containing and TATA-less genes when all properties are estimated by the F-score.


Asymmetry of lumbar muscles fatigability with non-specific chronic low back pain patients.
Non-specific chronic low back pain (NSCLBP) patients present with reduced back extensor muscle endurance which could be explained by the higher fatigability of their lumbar muscles. However, studies investigating lumbar muscle fatigability have shown contradictory findings. Furthermore, none investigated potential asymmetry in lumbar muscle fatigability, despite neuromuscular asymmetry being reported as a risk factor for NSCLBP. The present study's primary purpose was to determine whether NSCLBP patients presented with higher lumbar muscle fatigability and fatigability asymmetry than asymptomatic participants. Thirty NSCLBP patients and 23 asymptomatic participants performed the Sorensen test. The median frequencies from the electromyographs of the right and left erector spinae longissimus (ESL) and lumbar multifidus (LMF) were measured during the test. A linear regression was performed on the median frequencies on each muscle. Slope and initial median frequency were extracted to characterize fatigability. Asymmetry was quantified by the absolute differences between right-side and left-side muscle pairs. NSCLBP patients presented significantly poorer back extensor muscle endurance than asymptomatic participants. No differences were found between NSCLBP patients and asymptomatic participants in terms of fatigability or fatigability asymmetry for either the ESL or LMF. The initial median frequency in both muscles was significantly lower among NSCLBP patients. The present study showed that NSCLBP patients did not present higher fatigability or higher fatigability asymmetry in lumbar muscles than asymptomatic participants. The heterogeneity of the NSCLBP population, due to the absence of any specific etiology, may explain these findings. These slides can be retrieved under Electronic Supplementary Material.


Hsa_circ_0000301 facilitates the progression of cervical cancer by targeting miR-1228-3p/IRF4 Axis.
With the broadened application of gene expression profiles analysis, the role of miRNA and circRNA are of increasing concern in recent years, especially during the pathogenesis of cancer. However, to date, the reported on this area in cervical cancer are limited. In this study, Weighted Gene Co-Expression Network Analysis (WGCNA) and differential gene expression analysis were utilized to screen out differentially expressed (DE) circular RNAs in cervical cancer, and then we predicted and screened the combined microRNAs (miRNA) and downstream mRNAs to construct circular (circ)RNA-miRNA-mRNA network. As a result, a regulatory circular (circ)RNA-miRNA-mRNA with 1 circRNA node, 4 miRNA nodes, 135 mRNA nodes were constructed in an attempt to provide novel biomarkers for the pathogenesis of cervical cancer. In addition, enrichment analysis including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed on mRNAs in the network. After further screening of mRNAs by two online databases of GEPIA2 and RNAyhrid, precise target genes were obtained. Next, we screened out four target genes (CXCL16, IRF4, OAS3 and PTGER3) by constructing the protein-protein interaction (PPI) network, and mapped them to the initial network to reconstruct the circRNA-miRNA-mRNA network. Notably, the low expression of IRF4 was demonstrated to be associated with a significantly poorer overall survival in the GEPIA2 database, which was also verified by the immunofluorescence of the sections in Human Protein Atlas (HPA). The upstream miRNA corresponding to IRF4 is hsa-miR-1228-3p. From above concern, it can conclude that hsa_circ_0000301/hsa-miR-1228-3p/IRF4 may be involved in the occurrence and development of cervical cancer. However, the specific mechanism should be further studied and confirmed.


On Sphallambyx mexicanum and key to species of Sphallambyx (Coleoptera, Cerambycidae, Cerambycinae).
The male of Sphallambyx mexicanum Galileo Martins, 2007 is described for the first time; the geographical distribution of the species is expanded to Guatemala, Costa Rica, and Panama. Sphallambyx chabrillacii (Thomson, 1857) is formally excluded from the fauna of Costa Rica. A key to species of Sphallambyx Fragoso, 1982 is provided.


Evaluating Left Ventricular Systolic Synchronicity with Real-Time 3D Echocardiography in Newborns.
Knowing the normal values of left ventricular (LV) systolic synchronicity in the early neonatal period is very important for understanding myocardial function. This retrospective study analyzed data of 105 newborns who were examined using real-time 3-dimensional echocardiography (RT3DE). The time to the point of minimal regional systolic volume (Tmsv) was measured from volume-time curves in each segment. Standard deviation (SD) and maximal difference (Dif) of Tmsv were calculated from 16 (6 basal/6 mid/4 apical), 12 (6 basal/6 mid), and 6 (basal) LV segments with the corresponding parameters adjusted for the R-R interval. Influences of age, sex, gestational age, birth weight, and heart rate on parameters were explored. Data showed no significant difference among Tmsv-16-SD, Tmsv-12-SD, and Tmsv-6-SD. A strong correlation was found between Tmsv-6-SD and Tmsv-6-Dif (r = 0.83, P < 0.001), Tmsv-12-SD and Tmsv-6-SD (r = 0.77, P < 0.001), and Tmsv-12-Dif and Tmsv-6-Dif (r = 0.76, P < 0.001) and a moderate correlation was found between Tmsv-16-SD and Tmsv-16-Dif (r = 0.66, P < 0.001), Tmsv-6-SD and Tmsv-12-Dif (r = 0.62, P < 0.001), and Tmsv-12-SD and Tmsv-6-Dif (r = 0.61, P < 0.001). Heart rate correlated negatively with Tmsv (r = - 0.03 to - 0.11, P < 0.004-0.000), but had no effect on parameters adjusted for %R-R. Age, sex, gestational age, and birth weight did not affect any of these parameters. Tmsv-Dif and Tmsv-SD measured from 16 segments using RT3DE are useful as possible parameters for evaluating LV systolic synchronicity in normal newborns.


Targeting ERK/COX-2 signaling pathway in permethrin-induced testicular toxicity: a possible modulating effect of matrine.
Permethrin (PER), the prevalent synthetic pyrethroid, was reported to have genotoxic effects along with male reproductive organs impairment. Matrine, the Chinese herb chief alkaloid constituent, is used extensively owing to its recognized pharmacological properties. The study included 30 rats allocated equally into three groups; Group I: Control group, Group II: PER group and Group III: Matrine treated PER group. All groups were subjected to the measurement of Steroidogenic acute regulatory (StAR) gene expression by PCR technique while testosterone, phosphorylated Extracellular signal-regulated Kinase 1/2 (p-ERK1/2) and Cyclooxygenase 2 (COX-2) levels were assessed by ELISA technique. Malondialdehyde (MDA), total antioxidant capacity (TAC) and glutathione peroxidase (GPx) were also detected spectrophotometrically in addition to assessment of DNA fragmentation. Testicular histological structure as well as sperm count and morphology were studied. Matrine improved testicular toxicity evidenced by significant upregulation of StAR gene expression, elevation of testosterone level and significant decrease of p-ERK1/2 and COX-2 levels. Moreover, enhancements of the antioxidant status together with improvement of the histological findings were observed. These findings could pave the way for matrine to be used as a promising therapeutic agent in treatment of PER toxicity.


The relation between food intake and abomasal emptying and small intestinal transit time in sheep.
The relation between the level of food intake and gastrointestinal motility and digesta flow in the abomasum and small intestine was studied in sheep fitted with nichrome-wire electrodes in the gut wall, an abomasal and a duodenal catheter and a terminal ileal cannula. Abomasal volume and outflow were calculated from CrEDTA dilution in six sheep and small intestinal transit time by the passage of Phenol Red in ten sheep. The frequency of the migrating myoelectric complex of the small intestine was not altered by the level of food intake but the duration of the periods of irregular spiking activity, the amplitude of abomasal activity and the frequency of duodenal rushes were decreased as the level of food intake was decreased. There was a linear relation between the level of food intake (FI) and abomasal outflow (mean with SEM: 327 (69) ml/h for each kg FI/d; P less than 0.01), and abomasal volume (mean with SEM: 344 (50) ml/kg FI per d; P less than 0.001), without any significant change in the half-time of marker dilution in the abomasum. Small intestinal transit time decreased with an increase in food intake (mean with SEM: -54.9 (5.6) min/kg FI per d; P less than 0.001). It is concluded that abomasal volume and the rate of digesta flow from the abomasum and along the small intestine are linearly related to the level of food intake.


Allogeneic bone marrow transplantation for high-risk acute lymphoblastic leukemia in first remission: long-term results for 42 patients conditioned with an intensified regimen (TBI, high-dose Ara-C and melphalan).
Attempts to improve the efficacy of pretransplant conditioning regimens have been published, the potential of a better antileukemic effect being impaired by more frequent and severe toxicities. The efficacy of an intensified regimen, TAM (TBI, high-dose cytosine arabinoside and melphalan), is evaluated by analyzing long-term follow-up of a homogenous group of 42 high-risk ALL patients allografted in first CR. Age at time of BMT was 25.9 +/- 10.4 years (3-41). Twenty-two patients had more than three adverse prognostic factors. Ten patients had a Ph chromosome. Probability of overall survival was 45 +/- 9%, and for all surviving patients median follow-up time was 66 months. Event-free survival was 40 +/- 8% at 7 years after transplantation and the expected relapse rate reached 31%. Twenty-two deaths occurred, six after a relapse but 16 appeared to be directly due to the BMT procedure. None of the pretransplant characteristics significantly affected outcome after BMT. TAM appeared to be an efficient antileukemic therapy for conditioning high-risk ALL patients before allogeneic transplantation, but was still very toxic. The use of TAM in adult ALL patients in first CR is not recommended and the real role of intensified conditioning regimens remains to be demonstrated.


The cardiovascular effects of partial liquid ventilation in newborn lambs after experimental meconium aspiration.
To study the effects of partial liquid ventilation with perfluorocarbon on cardiovascular function, pulmonary gas exchange, and lung mechanics in term newborn lambs with pulmonary hypertension induced by tracheal instillation of human meconium. Prospective, randomized study. Research Unit at a university-affiliated hospital. Twelve term newborn lambs (<6 days old). Lambs were studied in two groups (n = 6): meconium aspiration (3-5 ml/kg 20% meconium solution) managed on pressure-limited conventional mechanical ventilation with or without partial liquid ventilation with perfluorocarbon. Heart rate, systemic and pulmonary arterial pressures, arterial pH and blood gases, cardiac output, and pulmonary mechanics were measured. Partial liquid ventilation in term newborn lambs with experimental meconium aspiration did not alter cardiovascular profile: heart rate, systemic arterial pressure, and cardiac output maintained initial values throughout the experiment. There was a significant improvement in gas exchange (oxygenation increased from values of <100 torr to 338 torr, and ventilation reached normal values in 15 mins). Dynamic compliance increased in 30 mins, reaching basal values (1.1 +/- 0.3 ml/cm H(2)O per kg). Despite the good response (blood gases and cardiovascular profile) to partial liquid ventilation in meconium aspiration syndrome, pulmonary hypertension did not decrease. Partial liquid ventilation with perfluorocarbon could be a good noninvasive alternative technique that improves gas exchange and pulmonary mechanics in meconium aspiration syndrome without impairing cardiovascular function.


Las17p-Vrp1p but not Las17p-Arp2/3 interaction is important for actin patch polarization in yeast.
The actin cytoskeleton plays a central role in many important cellular processes such as cell polarization, cell division and endocytosis. The dynamic changes to the actin cytoskeleton that accompany these processes are regulated by actin-associated proteins Wiskott-Aldrich Syndrome Protein (WASP) (known as Las17p in yeast) and WASP-Interacting Protein (WIP) (known as Vrp1p in yeast). Both yeast and human WASP bind to and stimulate the Arp2/3 complex which in turn nucleates assembly of actin monomers into filaments at polarized sites at the cortex. WASP-WIP interaction in yeast and humans are important for Arp2/3 complex stimulation in vitro. It has been proposed that these interactions are also important for polarized actin assembly in vivo. However, the redundancy of actin-associated proteins has made it difficult to test this hypothesis. We have identified two point mutations (L80T and H94L) in yeast WASP that in combination abolish WASP-WIP interaction in yeast. We also identify an N-terminal fragment of Las17p (N-Las17p1-368) able to interact with Vrp1p but not Arp2/3. Using these mutant and truncated forms of yeast WASP we provide novel evidence that WASP interaction with WIP is more important than interaction with Arp2/3 for polarized actin assembly and endocytosis in yeast.


The adaptive aging brain.
The aging brain is shaped by many structural and functional alterations. Recent cross-disciplinary efforts have uncovered powerful and integrated adaptive mechanisms that promote brain health and prevent functional decline during aging. Here, we review some of the most robust adaptive mechanisms and how they can be engaged to protect, and restore the aging brain.


Tracking metabolite dynamics in plants via indirect 13C chemical shift imaging with an interleaved variable density acquisition weighted sampling pattern.
Developing and evaluating an improved sampling pattern to track the dynamics of labeled substances in plants using indirect (13)C chemical shift imaging. An algorithm to split an acquisition weighted sampling pattern into several undersampled sub-images is presented. The sampling patterns are used in CSI moving phantom experiments as well as in in vivo POCE-CSI experiments on barley stem and grain. Reconstruction is performed traditionally or by compressed sensing. The moving phantom experiments show that the sampling pattern can reduce motion artifacts at the cost of an increased overall noise. The in vivo experiments demonstrate the feasibility of extracting a time series from a single imaging experiment. The sampling pattern is suitable for tracking the uptake of label substances into plant material. The use of compressed sensing allows an increased spatial and temporal resolution.


Characterization of high amylose corn starch-cinnamaldehyde inclusion films for food packaging.
The antibacterial films prepared from high amylose corn starch-cinnamaldehyde (HACS-CIN) inclusion complex were reported in this work and the different structural, mechanical, physicochemical and antibacterial properties of the films were investigated. The FT-IR results supported that the CIN was encapsulated in the helical structure of HACS by self-assembly. The encapsulation efficiency was as high as 39.19%, and the releasing rate results showed HACS-CIN inclusion films could slow down the volatilization of CIN. The films showed excellent mechanical properties with tensile strength of 14.77 MPa and elongation at break of 44.95%; and good transparency with visible light transmittance of 70%. UV transmittance test showed good UV-blocking property with UV light transmittance of 30%. Antibacterial test indicated an inhibitory effect on S. aureus and E. coli. Strawberry preservation experiment showed the films delayed the shelf life of strawberries. This work provides the HACS-CIN inclusion films are potential candidates for biodegradable food packaging.


Identifying the essential nodes in network pharmacology based on multilayer network combined with random walk algorithm.
Compared with the general complex network, the multilayer network is more suitable for the description of reality. It can be used as a tool of network pharmacology to analyze the mechanism of drug action from an overall perspective. Combined with random walk algorithm, it measures the importance of nodes from the entire network rather than a single layer. Here a four-layer network was constructed based on the data about the action process of prescriptions, consisting of ingredients, target proteins, metabolic pathways and diseases. The random walk algorithm was used to calculate the betweenness centrality of the protein layer nodes to get the rank of their importance. According to above method, we screened out the top 10% proteins that play a key role in treatment. Prescriptions Xiaochaihu Decoction was taken as example to prove our method. The selected proteins were measured with the ones that have been validated to be associated with the treated diseases. The results showed that its accuracy was no less than the topology-based method of single-layer network. The applicability of our method was proved by another prescription Yupingfeng Decoction. Our study demonstrated that multilayer network combined with random walk algorithm was an effective method for pre-screening vital target proteins related to prescriptions.


When to Abandon the Arthroscopic Bankart Repair: A Systematic Review.
Bone loss is a major factor in determining surgical choice in patients with anterior glenohumeral instability. Although bone loss has been described, there is no consensus on glenoid, humeral head, and bipolar bone loss limits for which arthroscopic-only management with Bankart repair can be performed. To provide guidelines for selecting a more complex repair or reconstruction (in lieu of arthroscopic-only Bankart repair) in the setting of glenohumeral instability based on available literature. An electronic search of the literature for the period from 2000 to 2019 was performed using PubMed (MEDLINE). Studies were included if they quantified bone loss (humeral head or glenoid) in the setting of anterior instability treated with arthroscopic Bankart repair. Systematic review. Level 4. Study design, level of evidence, patient demographics, follow-up, recurrence rates, and measures of bone loss (glenoid, humeral head, bipolar). A total of 14 studies met the inclusion criteria. Of these, 10 measured glenoid bone loss, 5 measured humeral head bone loss, and 2 measured "tracking" without explicit measurement of humeral head bone loss. Measurement techniques for glenoid and humeral head bone loss varied widely. Recommendations for maximum glenoid bone loss for arthroscopic repair were largely <15% of glenoid width in recent studies. Recommendations regarding humeral head loss were more variable (many authors providing only qualitative descriptions) with increasing attention on glenohumeral tracking. It is essential that a standardized method of glenoid and humeral head bone loss measurements be performed preoperatively to assess which patients will have successful stabilization after arthroscopic Bankart repair. Glenoid bone loss should be <15%, and humeral head lesions should be "on track" if an arthroscopic-only Bankart is planned. If there is greater bone loss, adjunct or open procedures should be performed.


Complications and concurrent disease associated with canine hyperadrenocorticism.
In untreated hyperadrenocorticism, clinical problems may result from metastasis of an adrenocortical carcinoma, growth of a pituitary tumor, or complications associated with sustained hypercortisolemia itself, such as hypertension, cardiovascular disease, thromboembolism, glucose intolerance, and increased susceptibility to infection. This article discusses the origin, diagnosis, and treatment of the many complications associated with hyperadrenocorticism.


Bioactive DNA from extracellular vesicles and particles.
Extracellular vesicles (EVs) and particles (EPs) have recently emerged as active carriers of molecular biomarkers and mediators of intercellular communication. While most investigations have focused exclusively on the protein, lipid and RNA constituents of these extracellular entities, EV/EP DNA remains poorly understood, despite DNA being found in association with virtually all EV/EP populations. The functional potential of EV/EP DNA has been proposed in a number of pathological states, including malignancies and autoimmune diseases. Moreover, the effectiveness of cell-free DNA as the biomarker of choice in emerging liquid biopsy applications highlights the role that EV/EP DNA may play as a novel disease biomarker. In this review, we provide a comprehensive overview of EV/EP DNA studies conducted to date, with a particular focus on the roles of EV/EP DNA as a functional mediator and molecular biomarker in various pathologic states. We also review what is currently known about the origins, structure, localisation and distribution of EV/EP DNA, highlighting current controversies as well as opportunities for future investigation.


Filarial paramyosin: cDNA sequences from Dirofilaria immitis and Onchocerca volvulus.
The nucleotide sequence of a cDNA copy of the Dirofilaria immitis paramyosin gene was determined. The sequence was 2545 nucleotides in length, consisting of a single open reading frame of 848 amino acids capable of encoding a protein with a calculated molecular weight of 98,000. The cDNA clone was not complete, but probably includes over 97% of the coding region of the gene. We have previously observed that the cloned D. immitis paramyosin is recognized by sera from humans infected with Onchocerca volvulus. To determine the extent of homology at the protein level, we screened a cDNA library of O. volvulus with an antiserum made against D. immitis paramyosin. Ten recombinant clones were partially sequenced, comprising a total of 1186 nucleotides or 389 amino acids. The amino acid sequence of D. immitis paramyosin was 99% identical to the O. volvulus paramyosin. We also compared the amino acid sequence to other cloned paramyosins, and noted that 92% of the amino acids were identical to those of Caenorhabditis elegans, and 34% identical to those of Schistosoma mansoni. Comparison of the paramyosin sequence between different species revealed a hierarchy of similarities: (1) a 7-amino-acid repeat with apolar residues in the a and d position as the most conserved, followed by (2) the amino acid sequence and (3) the DNA sequence.


Application of artificial intelligence deep learning in numerical simulation of seawater intrusion.
Seawater intrusion not only causes fresh water shortages in coastal areas, but also has a negative impact on regional economic and social development. Global climate change will affect precipitation, sea level, and many other factors, which will in turn affect the simulation and prediction results for seawater intrusion. By combining groundwater numerical simulation technology, an atmospheric circulation model, artificial intelligence methods, and simulation optimization methods, this study coupled a numerical simulation model of seawater intrusion with an optimization model to optimize the groundwater exploitation scheme in the study area under the condition of climate change. As a result, a groundwater exploitation scheme was obtained for a typical study area, which provided a scientific basis and a reference for the rational development of effective groundwater resource solutions. The results of this study can be described as follows. (1) By introducing the theory and method of deep learning from artificial intelligence, the problem of complex nonlinear mapping between the inputs and outputs of a three-dimensional variable-density seawater intrusion numerical simulation model under the condition of limited number of training samples is effectively solved, and the approximation accuracy of the surrogate model with respect to the simulation model is improved. (2) By solving the optimization model, a reasonable groundwater exploitation scheme was obtained, which provided a scientific basis for the rational development and efficient use of groundwater resources in the study area.


Repair of intra-membranous bone fractures and defects in rats. Immunolocalization of bone and cartilage proteins and proteoglycans.
Osseous healing of experimental fractures and defects in membranous bone was studied in an animal model and the appearance and localization of selected bone and cartilage proteins and proteoglycans determined by polyclonal antibodies. The bone lesions were made in the parietal bone of young rats and subsequently studied on days 3, 5, 8, 15, 30, and 100 after surgery. The bone matrix proteins investigated (62 kDa, bone sialoprotein I and II, and osteopontin) appeared early, adjacent to the periosteal surfaces (pericranium and dura mater) and the marginal bone. The staining reactions were maximal at days 8 or 15 after trauma. Similar patterns were discerned for some cartilage macromolecules studied (58 kDa, 59 kDa, and chondrocalcin), although others showed no labelling whatsoever (148 kDa, and 400 kDa proteins). The proteoglycans PG-S1, PG-S2, and PG-LA were not identified. No callus or cartilage formation were associated with the bone healing process, and the differences between the regenerative pattern of the fractures and defects were limited. The findings emphasize the importance of rigid fixation in craniomaxillofacial surgery.


P. aeruginosa biofilm activates the NLRP3 inflammasomes in vitro.
The ability of P.aeruginosa to form biofilms renders common treatments inefficient, thereby promoting chronic infection. Inflammasomes activate caspase-1, which is important for the maturation of IL-1β and IL-18 and evoke an inflammatory response. We aimed to investigate the activation of inflammasomes induced by P.aeruginosa biofilm. THP-1 cells were mock-infected or infected with PAO1 biofilms. Protein levels of caspase-1 p20, pro-caspase-1, caspase-4 p20, and pro-caspase-4 in THP-1 macrophages were determined by Western blotting. The expression of NLRC4 and NLRP3 was measured by RT-PCR. The production of IL-1β and IL-18 was monitored using ELISA. P. aeruginosa biofilm significantly elevated caspase-1 levels, and decreased NLRC4 levels. Additionally, caspase-4 and NLRP3 levels were significantly increased. P.aeruginosa biofilm significantly enhanced IL-1β and IL-18 production. We concluded that P. aeruginosa biofilm induced the production of IL-1β and IL-18, possibly via NLRP3 inflammasomes, rather than NLRC4 inflammasomes.


Tobacco-alcohol amblyopia neuro-ophthalmological findings and clinical course.
The clinical picture of 40 patients with tobacco-alcohol amblyopia (TAA) is described. In 15 patients the course of the disease was studied longitudinally over a period of 31 months. In addition in six patients the acute development of the disease was studied during a period of four weeks in-patient treatment. TAA is characterised by distinct bilateral visual disturbances, symmetric scotomas, acquired disturbances of colour vision and mostly normal fundi. Visual acuity is usually grossly diminished. Central scotomas were present in 80% of the cases while the centrocecal from prevailed in the rest. The acquired disturbances of colour vision usually concerned the red-green sense (84%). The amplitudes of the visual evoked potentials were always reduced and deformed. In 33% we could not detect a P-100. In 5% the latency of the P-100 was prolonged. Full field stimulation was the best method of defining the P-100. By foveal stimulation the deformations of the amplitudes were more evident. The prognosis of the visual disturbances was unpredictable. The abnormalities improved in one half of the patients, but complete recovery was never reached despite substitution with vitamins.


Pregnancy History and Kidney Disease Progression Among Women Enrolled in Cure Glomerulonephropathy.
Preeclampsia increases the risk for future chronic kidney disease (CKD). Among those diagnosed with CKD, it is unclear whether a prior history of preeclampsia, or other complications in pregnancy, negatively impact kidney disease progression. In this longitudinal analysis, we assessed kidney disease progression among women with glomerular disease with and without a history of a complicated pregnancy. Adult women enrolled in the Cure Glomerulonephropathy study (CureGN) were classified based on a history of a complicated pregnancy (defined by presence of worsening kidney function, proteinuria, or blood pressure; or a diagnosis of preeclampsia, eclampsia, or hemolysis, elevated liver enzymes, and low platelets [HELLP] syndrome), pregnancy without these complications, or no pregnancy history at CureGN enrollment. Linear mixed models were used to assess estimated glomerular filtration rate (eGFR) trajectories and urine protein-to-creatinine ratios (UPCRs) from enrollment. Over a median follow-up period of 36 months, the adjusted decline in eGFR was greater in women with a history of a complicated pregnancy compared to those with uncomplicated or no pregnancies (-1.96 [-2.67, -1.26] vs. -0.80 [-1.19, -0.42] and -0.64 [-1.17, -0.11] ml/min per 1.73 m2 per year, P = 0.007). Proteinuria did not differ significantly over time. Among those with a complicated pregnancy history, eGFR slope did not differ by timing of first complicated pregnancy relative to glomerular disease diagnosis. A history of complicated pregnancy was associated with greater eGFR decline in the years following glomerulonephropathy (GN) diagnosis. A detailed obstetric history may inform counseling regarding disease progression in women with glomerular disease. Continued research is necessary to better understand pathophysiologic mechanisms by which complicated pregnancies contribute to glomerular disease progression.


Neuroimaging findings in Joubert syndrome with C5orf42 gene mutations: A milder form of molar tooth sign and vermian hypoplasia.
Little is known regarding neuroimaging-genotype correlations in Joubert syndrome (JBTS). To elucidate one of these correlations, we investigated the neuroimaging findings of JBTS patients with C5orf42 mutations. Neuroimaging findings in five JBTS patients with C5orf42 mutations were retrospectively assessed with regard to the infratentorial and supratentorial structures on T1-magnetization prepared rapid gradient echo (MPRAGE), T2-weighted images, and color-coded fractional anisotropy (FA) maps; the findings were compared to those in four JBTS patients with mutations in other genes (including three with AHI1 and one with TMEM67 mutations). In C5orf42-mutant patients, the infratentorial magnetic resonance (MR) images showed normal or minimally thickened and minimally elongated superior cerebellar peduncles (SCP), normal or minimally deepened interpeduncular fossa (IF), and mild vermian hypoplasia (VH). However, in other patients, all had severe abnormalities in the SCP and IF, and moderate to marked VH. Supratentorial abnormalities were found in one individual in other JBTS. In JBTS with all mutations, color-coded FA maps showed the absence of decussation of the SCP (DSCP). The morphological neuroimaging findings in C5orf42-mutant JBTS were distinctly mild and made diagnosis difficult. However, the absence of DSCP on color-coded FA maps may facilitate the diagnosis of JBTS.


Effects of CEES and LPS synergistically stimulate oxidative stress inactivates OGG1 signaling in macrophage cells.
2-chloroethyl ethyl sulphide (CEES), a monofunctional analogue of sulfur mustard, is a strong vesicant and an alkylating chemical warfare agent. We studied the molecular mechanism of oxidative stress triggered signaling cascades in murine macrophages exposed to CEES with lipopolysaccharide (LPS). Exposure of CEES with specific dose of LPS stimulates oxidative stress caused increasing level of intracellular ROS and RNS, decreased antioxidant enzymes, increasing bimolecular damage, reduced cell viability, and cell cycle arrest. Synergistic exposure of CEES and LPS provoked significant increase in phosphorylation of MAPKs, Akt, tuberin, that down regulate OGG1 expression and 8-OHdG accumulations. Treatment with Akt and ERK1/2 inhibitors, the cells with constitutively active inhibiting activity of Akt and ERK1/2MAPK significant reduce CEES and LPS challenge tuberin but not the OGG1. In addition, the N-acetylcysteine inhibited ROS/RNS generation, elevation of antioxidants level, expression of ERK1/2, Akt, tuberin phosphorylation, resulted in deceased 8-OHdG accumulation and upregulation of OGG1 protein expression suggesting no involvement of Akt and ERK1/2MAPK pathways after CEES and LPS challenge. Collectively, our results indicate that exposure of CEES and LPS induces oxidative stress and the activation of tuberin, and 8-OHdG accumulation via upstream signaling pathways including Akt and ERK1/2MAPK pathway in macrophages but not the down regulation of OGG1.


Caveolin-1 expression is significantly associated with drug resistance and poor prognosis in advanced non-small cell lung cancer patients treated with gemcitabine-based chemotherapy.
Caveolin-1 was up-regulated in different drug-resistant cancer cell lines and was suggested to confer drug resistance by different mechanisms. However, the relation of caveolin-1 expression and the clinical response to chemotherapy and prognosis in non-small cell lung cancer (NSCLC) remains unknown. Total 73 NSCLC (stages IIIB and IV) patients who received gemcitabine-based chemotherapy and also had tumour specimens available before treatment were assessed for caveolin-1 expression using immunohistochemistry. Immunoreactivity of caveolin-1 was correlated with the response to chemotherapy, the clinicopathologic features, and the progression-free survival (PFS) and overall survival (OS) of all patients. Positive caveolin-1 immunostaining was found in 12 (16.4%) of the 73 patients. Eight of the twelve had disease progression and the other four patients remained stable after chemotherapy. Patients with caveolin-1 expression had a significantly lower response rate (complete or partial response, 0% versus 37.7%; P=0.01) and a poor PFS and OS (median survival time: PFS, 4.6 months versus 6.1 months, P=0.005; OS, 7.0 months versus 14 months, P<0.001) than those without caveolin-1 expression. Moreover, multivariate analyses indicated that caveolin-1 positivity was an independent prognostic factor for disease-free survival (DFS) (P=0.003) and OS (P=0.008), respectively. Caveolin-1 expression significantly correlated with drug resistance and a poor prognosis in advanced NSCLC patients treated with gemcitabine-based chemotherapy.


Acute fasciolosis in an alpaca: a case report.
The popularity of new world camelids, particularly alpacas, is growing rapidly in Ireland, presenting a clinical challenge to veterinary practitioners who may not have worked with these species previously. To the authors' knowledge, the clinical course of a case of acute fasciolosis in an alpaca has not previously been reported, and fasciolosis has not been reported at all in alpacas in Ireland, making this case report a valuable addition to the current literature. A three-year-old male castrated huacaya alpaca was admitted to UCD Veterinary Hospital with a two-day history of colic and tenesmus. He had been treated with albendazole, dexamethasone and potentiated amoxycillin by the referring veterinary practitioner with no response. On initial clinical exam, sensitivity to abdominal palpation was the only abnormality. However, the alpaca proceeded to show abnormal lying positions, tenesmus and reduced faecal output over the next 24 h. A general blood panel demonstrated moderate anaemia, marked hyperglobulinaemia and moderately increased hepatocellular and hepatobiliary enzyme activity. Abdominal radiography revealed enlargement of the first forestomach compartment without evidence of gastrointestinal obstruction or peritonitis. An abdominal ultrasound exam revealed an elongated, heterogenous mass in the caudoventral abdomen that appeared to be contiguous with the liver. FNA of this mass revealed that it was in fact a liver lobe with biliary stasis and inflammation. Faecal sedimentation demonstrated Fasciola hepatica eggs. In spite of treatment with triclabendazole and supportive treatment including blood transfusion, the alpaca's condition continued to deteriorate and he was euthanised. On post-mortem exam, acute fasciolosis was diagnosed. The clinical presentation and course of a case of acute fasciolosis in an individual alpaca is described, including the results of a range of diagnostic tests that were carried out. The final diagnosis is supported by a description of post-mortem findings. This information will serve as a resource for veterinary practitioners involved in the diagnosis and treatment of similar cases.


Managing diabetes in diabetic patients with COVID: where do we start from?
COVID-19 has and still is sweeping away the national health systems worldwide. In this review, we sought to determine the evidence base proofs on the antidiabetic treatment capable to reduce the risk of COVID-19-related mortality. We have performed a systematic search of published articles using PubMed, and EMBASE from March 2020 to March 31st, 2021. We excluded editorials, commentary, letters to the editor, reviews, and studies that did not have mortality as an outcome. For metformin and insulin only, we performed a meta-analysis using Cochrane RevMan 5.2. Among antidiabetic drugs, metformin was the only drug associated with a reduced risk of mortality. Conversely, insulin appears associated with an increased risk. The other classes of drugs were neutral. The totality of articles reports retrospective data strongly affected by "channeling bias" so that most of the existing results on each class of drugs are driven by the phenotype of patients likely to receive that specific drug by prescription.


Single tube multiplex real-time PCR for the rapid detection of herpesvirus infections of the central nervous system.
Human herpesvirus infection of immunocompromised hosts may lead to central nervous system (CNS) infection and diseases. In this study, a single tube multiplex real-time PCR was developed for the detection of five herpesviruses (HSV-1, HSV-2, VZV, EBV and CMV) in clinical cerebrospinal fluid (CSF) specimens. Two primer pairs specific for the herpesvirus polymerase gene and five hybridization probe pairs for the specific identification of the herpesvirus types were used in a LightCycler multiplex real-time PCR. A singleplex real-time PCR was first optimized and then applied to the multiplex real-time PCR. The singleplex and multiplex real-time PCRs showed no cross-reactivity. The sensitivity of the singleplex real-time PCR was 1 copy per reaction for each herpesvirus, while that of the multiplex real-time PCR was 1 copy per reaction for HSV-1 and VZV and 10 copies per reaction for HSV-2, EBV and CMV. Intra and inter-assay variations of the single tube multiplex assay were in the range of 0.02%-3.67% and 0.79%-4.35%, respectively. The assay was evaluated by testing 62 clinical CSF samples and was found to have equivalent sensitivity, specificity and agreement as the routine real-time PCR, but reducing time, cost and amount of used sample.


Trends in tonsillectomy surgery in children in Scotland 2000-2018.
Tonsillectomy is one of the most common surgical procedures in children but indications and surgical practice change over time. We aimed to identify trends in tonsillectomy procedures in children, in particular the number of procedures performed, the age of child undergoing tonsillectomy and the type of hospital in which the surgery was performed. Review of Scottish Morbidity Records data (SMR01) which are routinely collected after everyday case procedure or overnight stay in all Scottish NHS hospitals. All NHS hospitals in all 14 Scottish health boards. All children (0-16 years) undergoing tonsillectomy, 2000-2018. Number of tonsillectomy procedures; rate of tonsillectomy per 1000 children in the population; number of children aged 0-2 years and 3-4 years undergoing tonsillectomy; health board in which the surgery occurred; diagnostic coding for these episodes; length of stay and readmission within 30 days of surgery. During 2000-2018, there were 50,208 tonsillectomies performed in children in Scotland (mean 2642/year). The number of tonsillectomies per year remained constant (R = 0.322, P = .178) but tonsillectomies performed in children 0-2 years rose from 0.41 to 1.56 per 1000 (R = 0.912, P < .001), and 3-4 years from 3.06 to 6.93 per 1000 (R = 0.864, P < .001). The proportion of all children's tonsillectomies performed up to age 4 rose from 20.6% to 35.9% and up to age 2 from 2.4% to 8.1%. All specialist children's hospitals showed a significant increase in surgery in very young children. Tonsillectomy rates remained static between 2000 and 2018, despite a falling population. More tonsillectomies are now performed for obstructive sleep apnoea, at a young age and in regional children's hospitals. This has important implications for the workload of these specialist hospitals.


The geographic mobility of elderly Canadians.
The monograph Changing Residence: The Geographic Mobility of Elderly Canadians (Northcott, 1988) reviewed the research that had been done up to the mid-1980s on the geographic mobility of older persons in Canada and elsewhere. The purpose of this article is to provide an update and overview of developments in the study of the geographic mobility of seniors since the mid-1980s with a particular emphasis on Canada. In this review, we first examine progress over the past 25 years in research about seniors' geographic mobility and focus on three topics: the relocation and geographic concentration of seniors, seasonal migration ("snowbirds"), and international migration. Second, we assess the current status of research on elder migration in Canada. Finally, we identify future challenges and unanswered questions, and make suggestions for future research.


Cyclodextrinase from Thermococcus sp expressed in Bacillus subtilis and its application in the preparation of maltoheptaose.
Maltoheptaose as malto-oligosaccharides with specific degree of polymerization, has wide applications in food, medicine and cosmetics industries. Currently, cyclodextrinase have been applied as prepared enzyme to prepare maltoheptaose. However, the yield and proportion of maltoheptaose was lower, which is due to limited substrate and product specificity of cyclodextrinase (CDase). To achieve higher maltoheptaose yield, cyclodextrinase with high substrate and product specificity should be obtained. In this study, cyclodextrinase derived from Thermococcus sp B1001 (TsCDase) was successfully expressed and characterized in Bacillus subtilis for the first time. The specific activity of TsCDase was 637.95 U/mg under optimal conditions of 90 °C and pH 5.5, which exhibited high substrate specificity for cyclodextrins (CDs). When the concentration of β-CD was 8%, the yield of maltoheptaose achieved by TsCDase was 82.33% across all reaction products, which exceeded the yields of maltoheptaose in other recent reports. Among malto-oligosaccharides generated as reaction products, maltoheptaose was present in the highest proportion, about 94.55%. This study provides high substrate and product specificity of TsCDase. TsCDase is able to prepare higher yield of maltoheptaose through conversion of β-CD in the food industry.


Severe burnout among critical care workers in Turkey.
To determine the prevalence and risk factors for burnout in the intensive care units (ICU) staff in Turkey. Burnout is prevelant in physicians and nurses in the ICU worldwide. Most ICU workers with burnout plan to leave their professions. Frequent replacement of ICU staff increases cost and decreases the quality of care. Prevalence and risk factors of burnout in ICU staff in Turkey are largely unknown. This is a cross-sectional study. Data were gathered using the Maslach Burnout Inventory (MBI) which was distributed during August 2018, among all 1161 ICU workers in Turkey. Burnout was detected in at least one subscale in 99% of participants and in all 3 subscales in 15% of the participants. Risk factors for emotional exhaustion included female gender (odds ratio [OR]=1.87 [95% CI: 1.26-2.78]; p less than 0.01), alternate-day shift (OR=3.93 [95% CI: 1.66-9.30]; p less than 0.01), and incidence of end of life care (OR=1.01 [95% CI: 1.00-1.03]; p less than 0.01). For depersonalization it included alternate-day shift (OR=2.22 [95% CI: 1.15-4.26]; p less than 0.05), incidence of end of life care (OR=1.02 [95% CI: 1.01-1.03]; p less than 0.01), and for reduced personal accomplishment it included incidence of end of life care (OR=0.97 [95% CI: 0.96-0.98]; p less than 0.01). Conclusion: The results indicated that ICU staff in Turkey had a high rate of burnout.


Hoechst 33258 selectively inhibits group I intron self-splicing by affecting RNA folding.
Fungal pathogens are increasing in prevalence due to an increase in resistant strains and the number of immunocompromised humans. Candida albicans is one of these pathogens, and approximately 40% of strains contain a group I self-splicing intron, which is a potential RNA drug target, in their large subunit rRNA precursor. Here, we report that Hoechst 33258 and derivatives thereof are selective inhibitors of C. albicans group I intron self-splicing with an IC50 of 17 microM in 2 mM Mg2+. Chemical probing of the intron in the presence of Hoechst 33258 reveals that the folding of several nucleotides in the P4/P6 region of the intron is affected. A nucleotide near the J4/5 region is protected from chemical modification in the presence of Hoechst 33258 and several nearby are more reactive; this suggests that this region is the molecule's binding site. These results expand the available information on small-molecule targeting of RNA and suggest that the RNA-targeting scaffold provided by Hoechst may prove valuable in designing compounds that inhibit the functions of RNA.