PNH from mutations of another PIG gene.
In this issue of Blood, Krawitz et al report on a patient with paroxysmal nocturnal hemoglobinuria (PNH) who does not have a mutation of PIG-A, but in whom instead both alleles of PIG-T (another gene involved in glucosylphosphatidylinositol [GPI] biosynthesis) have inactivating mutations, one in the germ line and one somatic.


Pseudoxanthoma elasticum and pregnancy.
A 29-year-old woman affected by pseudoxanthoma elasticum gave birth to her second child in our department, thirteen months after the delivery of her first boy. Her care illustrates many of the potential risks of this rare autosomal systemic disorder. In order to detect any changes due to pregnancy, ophthalmologic and cardiologic screening examinations should be performed in the beginning of the pregnancy and repeated several weeks after the delivery. During labor, epidural anesthesia seems to be more advantageous.


Pessimism concerning palliative bypass procedures for established malignant esophagorespiratory fistulas: a report of 18 patients.
Eighteen patients with established malignant esophagorespiratory fistulas due to primary esophageal cancer were managed by substernal gastric bypass and isolation of the cancerous esophageal segment. Seven fistulas were esophagotracheal and 11 were esophagobronchial. Ten patients died in the hospital between two days and six weeks after operation. Eight patients left the hospital, surviving an average of 3 1/2 months, but 2 patients lived 5 and 7 months, respectively. Unrelenting respiratory infection and clinical inanition caused 7 hospital deaths in patients reestablished on oral alimentation with their fistulas disconnected. Anastomotic leaks occurred in 5 patients; three of these leaks closed. In the other 2 patients, cervicomediastinal sepsis and bilateral pneumonia with respiratory failure caused death. One patient died of anoxic cardiac arrest 48 hours postoperatively. Fifteen of the 18 patients resumed oral alimentation, but the overall results of palliative surgical therapy achieved in this series were not observably worthwhile for the majority.


Assessment of genetic diversity among wild rose in Morocco using ISSR and DAMD markers.
Morocco is considered one of the main biodiversity hotspots in the Mediterranean region and contains various plant species including wild and domestic Rosa. This genus is the most important among cultivated ornamental plants in the world, with a high economic value in cosmetics, pharmaceutical industries, and floriculture. In the present study, genetic diversity among the collected accessions of wild Rosa species in Morocco was assessed using Inter-Simple Sequence Repeat (ISSR) and Directed Amplification of Minisatellites DNA (DAMD) markers. Results confirmed that both markers used have a good efficiency to assess genetic diversity in wild roses. Ten ISSR and eight DAMD primers amplified 276 and 203 loci, with an average of 27.4 and 25 polymorphic alleles per primer, respectively. The polymorphic information content (PIC) values were 0.34 with ISSR and 0.31 with DAMD. Analysis of molecular variance (AMOVA) showed that genetic variation in wild rose occurs mainly within populations (86%) rather than between populations (14%). The region of Azrou (Middle Atlas of Morocco) is the area that registered the highest genetic diversity in the present study with He = 0.21. The 39 rose accessions were divided into three main groups with among-group similarity of 30%. Principal component analysis and the hierarchical classification were consistent with genetic relationships derived by structure analysis. The findings revealed that the patterns of grouping are weakly correlated with geographical origin. ISSR and DAMD markers showed that the accessions have a good genetic diversity.


Migration and transformation of Cd in four crop rotation systems and their potential for remediation of Cd-contaminated farmland in southern China.
A crop rotation system combining agricultural production with phytoremediation is an economical and sustainable method of remediation of cadmium (Cd)-contaminated farmland. This study focuses on migration and transformation of Cd in rotation systems and the influencing factors. In a two-year field experiment, four rotation systems were evaluated: traditional rice and oilseed rape (TRO), low-Cd rice and oilseed rape (LRO), maize and oilseed rape (MO), and soybean and oilseed rape (SO). Oilseed rape is a remediation plant in rotation systems. Compared to 2020, the grain Cd concentrations of traditional rice, low-Cd rice, and maize in 2021 decreased by 73.8%, 65.7%, and 24.0% (below the safety limits), respectively. However, soybean increased by 71.4%. The LRO system featured the highest oil content of rapeseed (about 50%) and economic output/input ratio (1.34). Removal efficiency of total Cd in soil was 10.03% (TRO) > 8.3% (LRO) > 5.32% (SO) > 3.21% (MO). Crop uptake of Cd was influenced by bioavailability of soil Cd, and soil environmental factors regulated the bioavailable Cd. Redundancy analysis (RDA) indicated that soil nitrate‑nitrogen (NO3--N) had a dominant impact on bioavailable Cd in soil, with variance contributions of 56.7% for paddy-upland (TRO and LRO) and 53.5% for dryland (MO and SO) rotation systems. The difference reflected that ammonium N (NH4+-N) was a secondary factor in paddy-upland rotations, while it was the available phosphorus (P) in dryland rotations, with variance contributions of 10.4% and 24.3%, respectively. The comprehensive evaluation of crop safety, production, economic benefits, and remediation efficiency revealed that the LRO system was efficient and more acceptable to local farmers, providing a new direction for the utilization and remediation of Cd-contaminated farmland.


Inhibition of copper-catalyzed cysteine oxidation by nanomolar concentrations of iron salts.
Problems caused by the presence of adventitious metals in buffers and reagents are well recognized in studies of metal-catalyzed oxidation reactions. In most cases, metal contamination leads to an increase in rate, and chelating agents are inhibitory. In the present study, however, the rate of copper-catalyzed oxidation of cysteine was found to be increased by buffer purification with Chelex resin or by addition of micromolar concentrations of the specific iron chelator desferrioxamine (DFO). These effects are attributable to inhibition of copper-catalyzed oxidation by adventitious iron. In purified buffer at pH 7.25, containing 0.4 microM copper, cysteine was oxidized at a rate of 32 microM/min. Addition of iron salts to this buffer caused a dose-related decrease in this rate, up to a maximum of 85%. A 50% decrease in rate was recorded at an iron concentration of only 11 nM. Other transition metals were without effect. Similar effects of purification or addition of DFO on the rate of cysteine oxidation were seen in Tris, glycylglycine, Mops, and Pipes buffers. Catalase decreased the rate of cysteine oxidation, but the sensitivity to iron was similar in the presence and absence of catalase. Copper-catalyzed oxidation of cysteamine and reduced glutathione was much less sensitive to inhibition by iron. Our results offer an explanation for the conflicting literature reports of the effects of chelating agents and catalase on cysteine oxidation, and emphasize the need for buffer purification or addition of DFO in studies concerned with the oxidation or cytotoxicity of this thiol. The exceptional sensitivity of copper-catalyzed cysteine oxidation to iron makes this an attractive system for monitoring the iron content of buffers, and may also have application for determining the free iron content of physiological fluids.


Biological significance of MYC and CEBPD coamplification in urothelial carcinoma: Multilayered genomic, transcriptional and posttranscriptional positive feedback loops enhance oncogenic glycolysis.
The aim of this study is to decipher the underlying mechanisms of CCAAT/enhancer-binding protein delta (CEBPD)-enhanced glycolysis as well as the biological significance of CEBPD and MYC coamplification in urothelial carcinoma (UC). In vitro analyses were conducted to examine the effects of altered CEBPD or MYC expression on UC cells. The in vivo effects of CEBPD overexpression in a high-glucose environment on tumour growth were investigated in xenografted induced diabetic severe combined immunodeficiency/beige mice. Data mining was used to cross-validate the associations between CEBPD and MYC copy number and transcriptional expression, quantitative reverse transcription-polymerase chain reaction, immunohistochemistry, chromogenic in situ hybridization, and in situ hybridization targeting microRNA were performed on 635 UC patient samples and xenograft samples. UC patient survival in relation to diabetes was validated by using the National Health Insurance Research Database. CEBPD and MYC coamplification (29.6%) occurred at a high frequency, MYC expression promoted chromosomal instability, facilitating CEBPD copy number gain and expression. CEBPD promoted glucose uptake and lactate production by upregulating SLC2A1 and HK2, leading to mitochondrial fission, increased extracellular acidification rate and decreased oxygen consumption rate to fuel cell growth. CEBPD upregulated HK2 expression through multiple regulation pathways including MYC stabilization, suppression of FBXW7 transactivation and MYC-independent transcriptional suppression of hsa-miR-429. Clinical and xenografted experiments confirmed the growth advantage of CEBPD in relation to glucose metabolic dysregulation and the significant correlations between the expression of these genes. We confirmed that CEBPD has an oncogenic role in UC by activating AKT signalling and initiating metabolic reprogramming from mitochondrial oxidative phosphorylation to glycolysis to satisfy glucose addiction. These novel CEBPD- and MYC-centric multilayered positive feedback loops enhance cancer growth that could complement theranostic approaches.


Laser-assisted subepithelial keratectomy enhancement of residual myopia after primary myopic LASEK: six-month results in 10 eyes.
To determine whether residual myopia after primary laser-assisted subepithelial keratectomy (LASEK) can be corrected by repeated LASEK and whether this procedure is safe and effective. University Eye Clinic, University of Regensburg, Regensburg, Germany. Laser-assisted subepithelial keratectomy was performed in 10 eyes that had had primary LASEK for myopia. The initial mean spherical equivalent (SE) was -6.2 diopters (D) (range -2.5 to -8.0 D), and the residual mean SE was -1.6 D (range -1.0 to -3.0 D). The retreatment ratio was 7.6%. The exposure time of the corneal epithelium to alcohol (20% ethanol) was 30 seconds plus an additional 10 to 15 seconds in cases of strong epithelial adherence. Laser ablation was performed with a Keracor 117 excimer laser (Chiron Technolas). The follow-up after the second LASEK treatment was 6 months. The epithelial flap for repeated LASEK was successfully created in all 10 eyes. The postoperative course in the eyes was uneventful. Six months after LASEK enhancement, the SE refraction was within +/-0.5 D in all eyes. No eye lost more than 1 line of best corrected visual acuity, and the uncorrected visual acuity was 20/20 or better in 8 eyes. Significant haze was not observed after repeated LASEK (mean 0.35 before and 6 months after LASEK enhancement). Laser-assisted subepithelial keratectomy enhancement appears to be safe and effective for the correction of residual myopia after primary LASEK. Repeated epithelial flap preparation is possible without technical modifications.


Perinatal alterations of thyroid hormones and behaviour in adult rats.
Several studies have shown the relevance of the neuroendocrinological system in the development and function of the nervous system. In order to observe the influence of thyroid hormones during development on the behaviour of adult rats we induced dysthyroid states during the perinatal period. Results indicate that some behaviours are more susceptible to the action of thyroid hormones than others. We observed that the thyroid hormone deficiency causes an increase of activity in animals in spite of a large period of rehabilitation. Thyroxine-treated rats showed an anxiogenic behavioural pattern in the elevated plus-maze, while animals rehabilitated from perinatal deficit of thyroid hormones showed an anxiolitic pattern. These findings suggest that an excess of thyroid hormones has less effect on behaviour than a deficiency of these hormones.


Impact of bilateral versus unilateral mastectomy on short term outcomes and adjuvant therapy, 2003-2010: a report from the National Cancer Data Base.
Rates of bilateral mastectomy (BM) have increased, but the impact on length of stay (LOS), readmission rate, 30-day mortality, and time to adjuvant therapy is unknown. Using the National Cancer Data Base, we selected 390,712 non-neoadjuvant AJCC stage 0-III breast cancer patients who underwent either unilateral mastectomy (UM) or BM from 2003 to 2010 with and without reconstruction. We used chi-square and logistic regression models for the analysis. A total of 315,278 patients (81 %) had UM, and 75,437 (19 %) had BM; 97,031 (25 %) underwent reconstruction. The number of median days from diagnosis to UM increased from 19 days in 2003 to 28 days in 2010, and for BM, increased from 21 to 31 days (p < 0.001). BM was independently associated with a longer time to surgery when adjusting for patient, facility, and tumor factors and reconstruction (OR 1.11; 95 % CI 1.07-1.15; p < 0.001). Reconstructed patients were twice as likely to have a longer time to surgery (OR 2.07; 95 % CI 2.01-2.14; p < 0.001). The median LOS was 1 day (range 0-184 days) for UM versus 2 (range 0-182) for BM (p < 0.001); 30-day mortality and readmission rates were not different between BM and UM. The median number of days from diagnosis to definitive chemotherapy, hormonal therapy, and radiation therapy was significantly greater in the BM group. Delays to surgical and adjuvant treatment are significantly longer for BM irrespective of reconstruction, and these delays have increased over the study period. These findings can be used by clinicians to counsel patients on BM.


A role for RUNX1 in hematopoiesis and myeloid leukemia.
Since its discovery from a translocation in leukemias, the runt-related transcription factor 1/acute myelogenous leukemia-1 (RUNX1/AML1), which is widely expressed in hematopoietic cells, has been extensively studied. Many lines of evidence have shown that RUNX1 plays a critical role in regulating the development and precise maintenance of mammalian hematopoiesis. Studies using knockout mice have shown the importance of RUNX1 in a wide variety of hematopoietic cells, including hematopoietic stem cells and megakaryocytes. Recently, target molecular processes of RUNX1 in normal and malignant hematopoiesis have been revealed. Although RUNX1 is not required for the maintenance of hematopoietic stem cells, it is required for the homeostasis of hematopoietic stem and progenitor cells, and expansion of hematopoietic stem and progenitor cells due to RUNX1 deletion may be an important cause of human leukemias. Molecular abnormalities cooperating with loss of RUNX1 have also been identified. These findings may lead to a further understanding of human leukemias, and suggest novel molecular targeted therapies in the near future.


Memory Impairments and Psychosis Prediction: A Scoping Review and Theoretical Overview.
Impairments in memory functions are among the most robust correlates of schizophrenia and of poor functional outcomes in individuals with psychotic disorders. Prospective, longitudinal studies are crucial to determining the meaning of these deficits in relation to mechanisms associated with the onset and course of these disorders.The objective of this review is to examine the literature concerning premorbid memory impairments during the prodromal phase of psychosis to address three primary questions 1) are memory impairments present among individuals with a clinical high risk syndrome? 2) are memory deficits in clinical high risk cases predictive of future conversion to psychosis? and 3) what are the underlying neural correlates of memory impairment in clinical high risk individuals and are they also predictive of future conversion?PubMed and Google Scholar databases were systematically searched. The primary inclusion criteria were to select studies that 1) were original research articles published in a peer-reviewed journal in the past 25 years, 2) studied subjects at clinical high risk for psychosis or in the prodromal phase of illness, and 3) included examinations into verbal memory performance in those at clinical high risk for psychosis.64 articles were identified and screened for eligibility. The review included 34 studies investigating verbal memory impairment in clinical high risk individuals compared to controls. The average effect size of verbal learning total recall was .58, indicating a moderate level of impairment in verbal learning among individuals at clinical high risk for psychosis as compared to healthy controls. Of studies that predicted time to conversion, indices of memory, particularly declarative and verbal working memory, were especially predictive of future conversion. Finally, when examining investigations of the neural correlates of memory dysfunction in the clinical high risk state, findings suggest altered activation and functional connectivity among medial temporal lobe regions may underlie differences in memory performance between clinical high risk individuals and healthy controls.Findings to date strongly indicate that memory impairments are present during the premorbid phase of psychosis and that verbal memory impairment in particular is predictive of future conversion to psychosis. Evidence from fMRI studies is fairly consistent in showing greater activation of memory-related regions during retrieval among clinical high risk cases who convert, with less consistent evidence of altered functional connectivity in the encoding phase. These findings support the use of verbal learning and memory measures in the psychosis prediction and prevention field.


Investigating cis-acting regulatory variation using assays of relative allelic expression.
Assays of relative allelic expression offer a powerful means of exploring the influence of cis-acting regulatory variation. In this article, we provide a general assay protocol and discuss practical and theoretical considerations for the design and interpretation of relative allelic expression analysis.


alpha-L-Fucosyltransferases related to biosynthesis of blood group substances in human Saliva.
alpha-L-Fucosyltransferases were demonstrated in human saliva which catalyze the transfer of L-fucose from GDP-L-[14C]-fucose to oligosaccharides from human milk. An alpha-(1 yields 4)-L-fucosyltransferase that synthesizes lacto-N-fucopentaose II and lacto-N-difucohexaose I from lacto-N-tetraose and lacto-N-fucopentaose I, respectively, was detected in saliva samples of Le(a--b+) secretors and Le(a+b--) non-secretors in which Lea substance was secreted. This enzyme activity was demonstrable neither in saliva samples of Le(a--b--) secretors nor non-secretors. An alpha-(1 yields 2)-L-fucosyltransferase, that synthesizes lacto-N-fucopentaose I from lacto-N-tetraose, was detected in saliva samples from Le(a--b+) secretors which secreted H and Leb substances and from Le(a--b--) secretors which secreted only H substance. An alpha-(1 yields 3)-L-fucosyltransferase was present in all saliva samples of different ABO and Lewis blood groups, irrespective of their ABH secretor status of the donors. The fucosyltransferases in saliva were activated by Mn++ or Mg++ ions, and were inhibited by ATP, GTP and EDTA. They had a broad pH optimum between pH 5.0 and 6.5.


Marinobufagenin and cyclic strain may activate endothelial NADPH oxidase, contributing to the adverse impact of salty diets on vascular and cerebral health.
Limited but provocative ecologic epidemiology suggests that dietary salt may play a central role in the genesis of not only of stroke, but also dementia, including Alzheimer's disease. Impairment of nitric oxide bioactivity in the cerebral microvasculature is a likely mediator of this effect. Salted diets evoke increased adrenal secretion of the natriuretic steroid marinobufagenin (MBG), which promotes natriuresis via inhibition of renal tubular Na+/K+-ATPase; this effect is notably robust in salt-sensitive rodent strains in which other compensatory natriuretic mechanisms are subnormally efficient. MBG-mediated inhibition of sodium pumps in vascular smooth muscle likely plays a role in the hypertension induced by salty diets in these rodents. However, salt sensitivity in humans is associated with increased vascular mortality and ventricular hypertrophy independent of blood pressure; this suggests that MBG may be pathogenic via mechanisms unrelated to blood pressure control. Indeed, recent evidence indicates that MBG, via interaction with alpha1 isoforms of the sodium pump, can activate various intracellular signaling pathways at physiological concentrations too low to notably inhibit pump activity. An overview of current evidence suggests the hypothesis that MBG - as well as the cyclic strain induced by hypertension per se - may induce endothelial oxidative stress by activating NADPH oxidase. If so, this could rationalize the increase in vascular and systemic oxidative stress observed in salt-sensitive rodents fed salty diets, or in rodents infused with MBG; moreover, if this effect is a particularly prominent determinant of oxidative stress in cerebrovascular endothelium, it might help to explain the virtual absence of stroke and dementia in low-salt societies. As a corollary of this hypothesis, it can be predicted that spirulina-derived phycobilins, which appear to mimic the physiological role of bilirubin as an inhibitor of NAPDH oxidase complexes, may have potential for ameliorating the adverse health impacts of MBG and of salty diets. Potassium-rich diets are also likely to be protective in this regard, as they should suppress MBG production via their natriuretic impact, while their stimulatory effect on sodium pump activity may exert a hyperpolarizing effect on plasma membranes that suppresses NADPH oxidase activity.


AMPK is not required for the effect of metformin on the inhibition of BMP6-induced hepcidin gene expression in hepatocytes.
The biguanide metformin is used for its antidiabetic effect for many years but how metformin acts remains poorly understood and controversial. AMP-activated protein kinase (AMPK), a protein kinase that plays a key role in maintaining energy homeostasis, is assumed to be one of the prime targets of metformin. However, since our demonstration that AMPK is not required for the beneficial effects of metformin on the control of glycemia, the list of AMPK-independent actions of metformin is rapidly increasing. Given the conflicting results on the effects of metformin we sought, using our genetic mouse models deficient in the catalytic subunits of AMPK, to determine whether this kinase is involved in the effects of metformin on the expression of the iron-regulatory hormone hepcidin, as recently proposed. Here we demonstrate, using different approaches, either isolated hepatocytes that lack AMPK, or direct AMPK activators, that, AMPK activation is not necessary for metformin to inhibit BMP6-induced hepcidin gene expression. These results may shed new lights on the increasingly recognized AMPK-independent metformin's molecular action, an important area of current research.


Location of flow axis line in the left ventricle and its interaction with local myocardial motion.
The interaction between local myocardial motion and blood flow dynamics should be assessed to evaluate left ventricular pump function. The contour map of the absolute value of blood flow velocity in the left ventricle (LV) was drawn. The ridgeline of the contour was defined as the "flow axis line". LV wall motion was assessed by the tracing endocardial border in consecutive B-mode images and by myocardial tissue velocity distribution obtained by the optical flow method. The location of the main flow axis line was affected by the local myocardial movement in the short axis direction. The flow axis line method is superior to the previous investigations on two-dimensional blood flow analysis because it considered three-dimensional blood flow. The flow axis line represents not only intracardiac blood flow structure but also its interaction with the cardiac wall motion.


Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis.
The global burden of non-alcoholic fatty liver disease (NAFLD) parallels the increase in obesity rates across the world. Although overweight and obesity status are thought to be an effective indicator for NAFLD screening, the exact prevalence of NAFLD in this population remains unknown. We aimed to report the prevalence of NAFLD, non-alcoholic fatty liver (NAFL), and non-alcoholic steatohepatitis (NASH) in the overweight and obese population. In this systematic review and meta-analysis, we searched Medline and Embase from database inception until March 6, 2022, using search terms including but not limited to "non-alcoholic fatty liver disease", "overweight", "obesity", and "prevalence". Cross-sectional and longitudinal observational studies published after Jan 1, 2000, written in or translated into English were eligible for inclusion; paediatric studies were excluded. Articles were included if the number of NAFLD, NAFL, or NASH events in an overweight and obese population could be extracted. Summary data were extracted from published reports. The primary outcomes were the prevalence of NAFLD, NAFL, and NASH in an overweight and obese population and the prevalence of fibrosis in individuals who were overweight or obese and who had NAFLD. A meta-analysis of proportions was done with the generalised linear mixed model. This study is registered with PROSPERO (CRD42022344526). The search identified 7389 articles. 151 studies met the inclusion criteria and were included in the meta-analysis. In the pooled analysis comprising 101 028 individuals, the prevalence of NAFLD in the overweight population was 69·99% (95% CI 65·40-74·21 I2=99·10%), the prevalence of NAFL was 42·49% (32·55-53·08, I2=96·40%), and the prevalence of NASH was 33·50% (28·38-39·04, I2=95·60%). Similar prevalence estimates were reported in the obese population for NAFLD (75·27% [95% CI 70·90-79·18]; I2=98·50%), NAFL (43·05% [32·78-53·97]; I2=96·30%) and NASH (33·67% [28·45-39·31]; I2=95·60%). The prevalence of NAFLD in the overweight population was the highest in the region of the Americas (75·34% [95% CI: 67·31-81·93]; I2=99·00%). Clinically significant fibrosis (stages F2-4) was present in 20·27% (95% CI 11·32-33·62; I2= 93·00%) of overweight individuals with NAFLD and in 21·60% (11·47-36·92; I2=95·00%) of obese patients with NAFLD while 6·65% (4·35-10·01; I2=58·00%) of overweight individuals with NAFLD and 6·85% (3·85-11·90; I2=90·00%) of obese individuals with NAFLD had advanced fibrosis (stages F3-4). This study summarises the estimated global prevalence of NAFLD, NAFL, and NASH in overweight and obese individuals; these findings are important for improving the understanding of the global NAFLD burden and supporting disease management in the at-risk overweight and obese population. None.


Cavity cooling of a single atom.
All conventional methods to laser-cool atoms rely on repeated cycles of optical pumping and spontaneous emission of a photon by the atom. Spontaneous emission in a random direction provides the dissipative mechanism required to remove entropy from the atom. However, alternative cooling methods have been proposed for a single atom strongly coupled to a high-finesse cavity; the role of spontaneous emission is replaced by the escape of a photon from the cavity. Application of such cooling schemes would improve the performance of atom-cavity systems for quantum information processing. Furthermore, as cavity cooling does not rely on spontaneous emission, it can be applied to systems that cannot be laser-cooled by conventional methods; these include molecules (which do not have a closed transition) and collective excitations of Bose condensates, which are destroyed by randomly directed recoil kicks. Here we demonstrate cavity cooling of single rubidium atoms stored in an intracavity dipole trap. The cooling mechanism results in extended storage times and improved localization of atoms. We estimate that the observed cooling rate is at least five times larger than that produced by free-space cooling methods, for comparable excitation of the atom.


Outcome After 68Ga-PSMA-11 versus Choline PET-Based Salvage Radiotherapy in Patients with Biochemical Recurrence of Prostate Cancer: A Matched-Pair Analysis.
The purpose of this analysis was primarily to analyze biochemical-recurrence free survival (BRFS) after positron emission tomography (PET)-guided salvage radiotherapy (sRT) in a large cohort, and to further compare BRFS after PSMA vs. choline PET/ computer tomography (CT)-based sRT. This retrospective analysis is based on 421 patients referred for PSMA or choline PET/CT after radical prostatectomy due to biochemically recurrent or persistent disease. BRFS (PSA: 0.2 ng/mL) was defined as the study endpoint. Cox regression analyses were performed to assess the impact of different clinical parameters on BRFS. Additionally, propensity score matching was performed to adjust patient cohorts (PSMA vs. choline PET/CT-based sRT). The median follow-up time was 30 months. BRFS at three years after sRT was 58%. In the multivariate analysis, only PSA before PET imaging and PSA before sRT were significantly associated with BRFS (p < 0.05). After propensity score matching, 272 patients were further analyzed; there was no significant difference in three-year BRFS between patients with PSMA PET-based vs. choline PET-based sRT (55% vs. 63%, p = 0.197). The present analysis confirmed the overall high BRFS rates after PET-based sRT and the strong prognostic effect of PSA level prior to sRT. PSMA PET-based sRT did not have superior BRFS rates when compared with choline PET-based sRT.


Prosthodontic Principles in Dental Implantology: Adjustments in a Coronavirus Disease-19 Pandemic-Battered Economy.
More patients are requesting fixed prosthesis to replace missing teeth. More than 5 million dental implants are placed annually in the United States. This number will decrease in 2020 owing to the coronavirus disease-19 pandemic. The edentulous patient has a decreased quality of life. Prosthodontic rehabilitation/reconstruction of edentulism improves overall quality of life. Patient-reported outcome measures are subjective reports of patients' perceptions of their oral health status and the impact that it has on their quality of life. This chapter contains a variety of prosthodontic principles for the reader to help satisfy the needs and expectations of the patient.


Biogeochemical classification of South Florida's estuarine and coastal waters.
South Florida's watersheds have endured a century of urban and agricultural development and disruption of their hydrology. Spatial characterization of South Florida's estuarine and coastal waters is important to Everglades' restoration programs. We applied Factor Analysis and Hierarchical Clustering of water quality data in tandem to characterize and spatially subdivide South Florida's coastal and estuarine waters. Segmentation rendered forty-four biogeochemically distinct water bodies whose spatial distribution is closely linked to geomorphology, circulation, benthic community pattern, and to water management. This segmentation has been adopted with minor changes by federal and state environmental agencies to derive numeric nutrient criteria.


Alteration of LncRNA expression in mice placentae after frozen embryo transfer is associated with increased fetal weight.
The birthweight after frozen embryo transfer (FET) was significantly higher compared with fresh embryo transfer (fresh ET), while the mechanism remains unclear. In this study, we transferred vitrified-warmed or fresh mice blastocysts into pseudopregnant recipients (n = 11 each group) produced by natural mating to avoid the influence of superovulation. The fetal weight, placental weight, placental efficiency and placental architecture were studied at E18.5. Placental RNA-Seq analysis was used to identify candidate different lncRNAs and mRNAs between the FET group and the fresh ET group. We found that the fetal weight was increased in the FET group, with increased placental efficiency and the proportion of placental function related labyrinth zone area. 554 lncRNAs and 1012 mRNAs were differentially expressed. KEGG and GO enrichment analyses showed these differentially expressed lncRNAs and their targeted mRNAs might be related to placental morphogenesis. Furthermore, the most differentially expressed 15 lncRNAs and 15 mRNAs were validated by qRT-PCR, we found the LncRNA embryonic stem cells expressed 1 (Lncenc1) was significantly decreased, and Gjb5, which played an important role in labyrinth zone development, was increased. Gjb5 protein increase was further confirmed by Western blot. Lncenc1 and Gjb5 had 48 predicted co-targeted miRNAs, while the correlation analysis of Lncenc1 and Gjb5 mRNA showed a significant inverse correlation. The results showed that FET treatment might enhance the placental function to increase mouse fetal weight via the network diagram of Lncenc1-miRNA-Gjb5.


Novel Compounds with Promising IDO1 Inhibitory Activity As New Cancer Drug Candidates: Derivatives Of N, N'-diphenylurea Linked With 1,2,3-triazole.
To explore potential indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors, we designed a series of compounds incorporating urea and 1,2,3-triazole structures. IDO1 enzymatic activity experiments with the synthesized compounds were used to verify their molecular-level activity; for instance, the half maximal inhibitory concentration value of compound 3c was 0.07 μM. Our research has yielded a series of novel IDO1 inhibitors which may be beneficial in the development of drugs targeting IDO1 for cancer treatment.


Patterns of primary and secondary therapy for prostate cancer in elderly men: analysis of data from CaPSURE.
We examined patterns of primary treatment for prostate cancer in men 75 years or older. Data were obtained from the multi-institutional CaPSURE database on the type of primary therapy performed in men younger than 75, or 75 years old or older. Primary therapy was defined as watchful waiting, radical prostatectomy, brachytherapy, brachytherapy plus external beam radiotherapy, external beam radiotherapy or primary androgen deprivation therapy. The chi-square test and multinomial logistic regression analysis were performed to identify predictors of the type of primary therapy and outcomes. A greater proportion of patients 75 years or older were white, single, had multiple comorbidities, low income and low education, and were classified as being at high risk compared to those younger than 75 years (43% vs 25%). On multivariate analysis adjusted for sociodemographic factors, diagnostic risk category and the number of comorbidities at diagnosis patients 75 years or older were less likely to be treated with primary therapy than with watchful waiting regardless of the risk category or comorbidity level. Older patients with high risk cancer are far more likely to be observed regardless of the burden of comorbidity. A more tailored approach to prostate cancer therapy that considers comorbidity and functional level to determine primary therapy may be more appropriate. Well selected older patients with high risk disease, particularly those with low comorbidity levels, may derive survival benefit from a primary therapy other than watchful waiting. Alternatively elderly patients with low risk disease may be better treated with watchful waiting.


Feeding frequency and appetite in lean and obese prepubertal children.
To determine the effect of feeding frequency on appetite in normal weight (NW) and obese (OB) prepubertal children, we carried out a prospective, randomized interventional study of 18 NW and 17 OB children ages 6-10. Children received three or five feedings in random order on separate days. Total calories, carbohydrate, protein, and fat composition on each day were equal. Two hours following the last feeding, children were offered ice cream ad lib. The major outcome variable was kilocalories ice cream consumed. A visual analog scale to assess fullness was also administered before consumption of ice cream. We observed that OB children consumed 73.0 ± 37.4 kcal more after five feedings than after three feedings whereas the NW children consumed 47.1 ± 27.8 kcal less. There was significant interaction between meal pattern and weight group indicating that this change in ice cream consumption differed significantly between groups (P = 0.014 by two-factor analysis). Ice cream intake/kg was less in OB compared to NW subjects (P = 0.012). Fullness ratings before ice cream did not differ by meal pattern or weight group. However, pre-ice cream fullness predicted ice cream intake in NW but not OB children. In summary, OB and NW children differed in appetite response to meal frequency. Our data suggest that: (i) satiety in OB children is related more to proximity of calories (larger supper) than to antecedent distribution of calories and; (ii) NW children may be more prone to restrict intake based on subjective fullness.


Historical events and allelic polymorphism at the gametophytic self-incompatibility locus in Solanaceae.
The historical migration rate of a species is often difficult to estimate with neutral markers, because the relationship between the turnover time of the markers and the age of the species commonly remains unknown. Compared with neutral markers, the plant self-incompatibility locus (S) provides a much better source of data for migration-rate estimation due to its high allelic polymorphism and antiquity. Here, the results from extensive surveys of S alleles in two wild solanaceous species, Solanum carolinense and Physalis longifolia, indicate that historical migration rates have differed significantly between the species; the higher migration rate found in S. carolinense appears to have interacted with the balancing selection at the S locus to result in fewer S alleles being maintained in the species. Historical population growth rates estimated via a modified coalescent approach also suggest a faster growing population for S. carolinense than for P. longifolia, which would have further widened their interspecific difference in S-allelle polymorphism. These historical factors may have reduced the probability of new S alleles to prevailing in S. carolinense, leaving old ones segregating at the S locus with little signature of positive selection being currently detectable.


Changes in the referral pattern of child patients from the GDS to the CDS following the introduction of capitation in October 1990. General Dental Services. Community Dental Services.
To observe the changes in the criteria for, rate of, and pattern of, referral of child patients from the General Dental Services (GDS) to the Community Dental Services (CDS) which may have occurred following the introduction of capitation as the method of remuneration for general dental practitioners (GDPs) for the treatment of child patients in The new contract 1990. GDP referral criteria and attitude to capitation were assessed in two districts (North Downs and Weybourne Trusts) using a questionnaire distributed to 179 GDPs. Reasons for referral, and treatment received within the CDS, were collated from the dental records of referred children, before and after the introduction of capitation. The response rate from the GDPs was 87%, of whom 82% had referred child patients to the CDS. The results showed that 65% of GDPs indicated a preference for treatment of children under a fee per item system, whereas only 17% favoured capitation. Although 60% believed that their referral of patients to the CDS had not changed following capitation, an analysis of the referred children's dental records revealed that there had actually been a 57% increase in the number of referrals from GDPs to CDS following the introduction of capitation. The GDPs considered the most important referral criteria were for non cooperation or general anaesthesia. More cooperative children had been referred and more routine restorative procedures, less inhalation sedation and deciduous extractions were carried out following the introduction of capitation. This study has shown that following the introduction of capitation there had been an increase in the number of referrals from the GDS to the CDS.


Temporal soliton switching in a rectangular nonlinear directional coupler.
We address the theory of temporal soliton switching in a planar geometry directional coupler constructed from silica and doped silica glass and operating at the central wavelength of 1.55 microm, significant for erbium-doped amplification. We formulate the field in the coupler in terms of the supermodes of the total structure and take account of the two transverse dimensions of the rectangular channels. In the case of the weak coupling between channels consistent with elimination of pulse breakup, the effect of the fields in the outer corner regions of the channels results in a switching intensity that differs significantly from that derived from coupled-mode theory on the basis of a slab model of the coupler.


Sex-related differences in endothelium-dependent vasodilation of human gingiva.
Sex hormones influence circulation, periodontitis, and wound healing. The aim of the study was to compare the endothelium-dependent and independent vasodilation in human gingiva in men and women. Gingival blood flow was evaluated in twelve male and twelve female subjects with healthy gingiva and no systemic conditions after acetylcholine or nitric oxide donor (NitroPOHL). Agonists were administered into the gingival sulcus at the right secondary incisor (test site). Regional gingival blood flow (GBF) was imaged by Laser Speckle Contrast Imager from the marginal gingiva to the mucogingival junction in four consecutive regions (coronal, midway1, midway2 and apical). Blood flow was expressed in Laser Speckle Perfusion Unit (LSPU). The absolute maximal blood flow change (Dmax), the area under the blood flow curve (AUC), and the time to peak (TTP) were calculated. Males had higher baseline GBF than females (257 ± 18.2 vs. 225 ± 18.8 LSPU, p < 0.001). Acetylcholine and NitroPOHL significantly increased the GBF in all test regions. The Dmax after the acetylcholine was reduced apically compared to the coronal (90 ± 13 LSPU vs. 117 ± 7 LSPU, p < 0.01), but it was similar after NitroPOHL (78 ± 9 LSPU vs. 86 ± 6 LSPU, p = 0.398) in both sexes. The Dmax and AUC were higher, and the TTP was smaller in men in most regions after acetylcholine but not after NitroPOHL. In the human gingiva, the endothelium-independent vasodilation propagates without attenuation in the line of the vascular supply in both sexes. At the same time, the endothelium-dependent ascending vasodilation attenuates similarly in men and women. However, men had more pronounced endothelium-dependent vasodilation than women. Therefore, it might contribute to the increased severity of periodontal disease in men. The study was registered with ClinicalTrials.gov on 09.06.2021 (NCT04918563).


Collective modes in three-dimensional magnonic vortex crystals.
Collective modes in three-dimensional crystals of stacked permalloy disks with magnetic vortices are investigated by ferromagnetic resonance spectroscopy and scanning transmission X-ray microscopy. The size of the arrangements is increased step by step to identify the different contributions to the interaction between the vortices. These contributions are the key requirement to understand complex dynamics of three dimensional vortex crystals. Both vertical and horizontal coupling determine the collective modes. In-plane dipoles strongly influence the interaction between the disks in the stacks and lead to polarity-dependent resonance frequencies. Weaker contributions discern arrangements with different polarities and circularities that result from the lateral coupling of the stacks and the interaction of the core regions inside a stack. All three contributions are identified in the experiments and are explained in a rigid particle model.


The Additive Benefits of Aerobic Exercise and Cognitive Training Postconcussion: Current Clinical Concepts.
Concussion induces the rapid onset of a short-lived neurophysiological disturbance that often results in autonomic nervous system dysfunction. This dysfunction affects both cardiovascular functioning and higher cognitive processing, inducing postconcussion clinical symptoms (somatic, cognitive, or emotional or a combination) and functional disturbances (impaired balance, cognition, and visual-vestibular performance). Current concussion rehabilitation paradigms using aerobic exercise may improve concussion symptoms. Additionally, cognitive training-focused rehabilitation interventions may enhance cognitive function postinjury. Though aerobic exercise and cognitive training-based concussion rehabilitation are successful independently, the multifaceted nature of concussion suggests the potential benefit of integrating both to improve concussion outcomes and clinician implementation. To support this clinical recommendation, we critiqued the existing research in which authors investigated aerobic exercise and cognitive training as postconcussion rehabilitation modalities, identified keys gaps in the literature, and proposed a practical clinical recommendation to integrate both modalities during concussion rehabilitation.


Controversies about effects of low-kilovoltage MDCT acquisition on Agatston calcium scoring.
Recent articles have advocated the possibility of obtaining Agatston coronary calcium scoring at 100 kVp by using a single adapted elevated calcium threshold. To evaluate the influence of kilovoltage potential protocols on the Agatston score, we acquired successive scans of a calcium scoring phantom at 4 levels of kilovoltage potential (80, 100, 120, and 140 kVp, 55 mAs) and measured semiautomatically the individual and the total Agatston score of 6 inserts (of 5-mm and 3-mm diameter) containing hydroxyapatite at different concentrations (800, 400, 200 mg/cm(3)). Our results showed that Agatston scores obtained at various low-kilovoltage potential protocols can be highly overestimated in some particular cases. At 80 kVp, for example, mean measured Agatston score was multiplied by a factor from 1.06 (5-mm highest density insert) to 2.67 (3-mm lowest density insert) compared with the Agatston scores performed at 120 kVp. Indeed in the one hand, reducing kilovoltage potential in multidetector CT acquisitions increase the CT density of coronary calcifications that can be measured on the reconstructed images. On the other hand, Agatston score is a multi-threshold measurement (with a step weighting function). Consequently low kilovoltage potential can lead to overweight some calcifications scores. For these reasons, Agatston score with low kilovoltage potential acquisition cannot be reliably adapted by a unique recalibration of the standard calcium attenuation threshold of 130 HU and requires a standardized CT acquisition protocol at 120 kVp. Alternatives to performing low-dose coronary artery calcium scans are either using coronary calcium scans with reduced tube current (low mAs) at 120 kVp with the iterative reconstructions or using mass/volume scoring (not influenced by kilovoltage potential variations). Finally, we emphasized that incorrect Agatston score evaluation may have important clinical, financial, and health care implications.


Assessment of cleaning and disinfection in the food industry with the rapid ATP-bioluminescence technique combined with the tissue fluid contamination test and a conventional microbiological method.
A quantitative ATP bioluminescence procedure has been used to determine the cleanliness of food processing factories and the results have been compared with those from conventional microbiological culture methods. ATP measurements were combined with the tissue or tissue fluid contamination (TTFC) assessment method to obtain an impression of the amount of inanimate contamination on the sampled surfaces. It was found that, in the sampled food factories, there was poor relation between the two assessment techniques: ATP bio-luminescence combined with TTFC and contact plating. However, either method in its own right is useful to check cleanliness of food industries. ATP measurements do have in addition the great advantage that it is a fast method and is easy to perform.


Maternal ethanol use and selective fetal malnutrition.
Maternal ethanol ingestion may cause fetal injury, particularly impaired somatic and brain growth, by at least two mechanisms: (1) directly, by fetotoxicity from ethanol and/or acetaldehyde; (2) indirectly, by ethanol-induced placental injury and selective fatal malnutrition. There is ample evidence that ethanol and/or acetaldehyde is fetotoxic. In addition, alcoholics are frequently in a state of poor nutrition. However, regardless of maternal nutritional status, ethanol can be placentotoxic, impairing the normal transfer of essential fetal nutrients. Ethanol and/or acetaldehyde has been shown to inhibit placental uptake and/or transfer of amino acids, zinc, and glucose. These effects have been evaluated in animal models and in human tissue. Recent use of the isolated perfused human placental cotyledon has begun to delineate the pathophysiology of ethanol-induced placental injury.


Patterns of pulmonary arterial anatomy and blood supply in complex congenital heart disease with pulmonary atresia.
To identify the pattern of pulmonary anatomy and pulmonary blood supply, we analyzed the angiocardiograms of 40 patients with pulmonary atresia and complex congenital heart disease. All patients but two (95%) had confluent pulmonary arteries supplied by a patent ductus arteriosus. These two patients (5%) had nonconfluent pulmonary arteries, one with major systemic-pulmonary collateral arteries and absent patent ductus arteriosus and the other with a patent ductus arteriosus supplying the right lung and small collateral arteries supplying the left. The low incidence of pulmonary arterial abnormalities and the uniform pattern of pulmonary blood supply make the patients with pulmonary atresia and complex congenital heart disease potential candidates for palliative operation without cardiac catheterization in the neonatal period.


Structure and expression of c-myc and c-fos proto-oncogenes in thyroid carcinomas.
Tumour specimens from 23 patients with thyroid carcinoma, 22 patients with thyroid adenoma, 3 with Graves' disease, and tissues from 8 normal thyroid glands were analyzed by Southern blot hybridization for the physical state of c-myc and c-fos proto-oncogenes. In 4 patients, both the primary tumour and lymph node metastases were analyzed. No amplification or rearrangement of the two proto-oncogenes was detected. Total RNAs were also analyzed. Elevated levels of the 2.4 kb c-myc RNA and of the 2.2 kb c-fos RNA were found in 13/23 (57%) and 14/23 (61%) of the cancer patients, respectively. High levels of c-myc transcripts were more frequently found in thyroid carcinomas with unfavourable prognosis. Concomitant elevated levels of both c-myc and c-fos RNAs were found in 8 cancers. High levels of c-myc RNA were also found in 1 out of 22 specimens of adenoma, in 1 specimen of Graves' disease and in 2 normal thyroid glands. High levels of c-fos RNA were found in 20 of the 22 adenoma samples and in 2 out of 8 normal thyroid tissues. These data indicate that the overexpression of c-myc and c-fos genes is independent of an alteration of the loci. The high levels of c-fos found in adenoma may be associated with the differentiation state of these tumours.


Method validation for the determination of total mercury in fish muscle by cold vapour atomic absorption spectrometry.
A method was validated for the determination of total Hg in fish muscle using continuous flow cold vapour atomic absorption (CVAAS) after microwave digestion in closed vessels. The method was validated according to European Union Regulations 333/2007 and 657/2002, considering the maximum level for the metal in fish, established by European Union regulation 1881/2006. The procedure for determining linear range, selectivity, recovery, precision, trueness, decision limit (CCα), detection capability (CCβ), measurement uncertainty and robustness of the method is reported. The results of the validation process demonstrate the method fulfils the provisions of the Commission Regulation. The selectivity study indicated that there was no matrix effect on the calibration curve between the concentration range of 1.0 and 30.0 µg Hg l(-1). The mean recovery calculated at six levels of fortification was in the range of 94-104%. The limit of detection (LOD) and limit of quantification (LOQ) values were 4.90 and 15.7 µg kg(-1), while the CCα and CCβ values were 0.517 and 0.533 mg kg(-1), respectively, for the maximum contaminant level of 0.500 mg kg(-1). The relative expanded measurement uncertainty of the method was 0.055 mg kg(-1). The method was not affected by slight variations of some critical factors (ruggedness minor changes) as sample mass and volume of the HNO(3) and H(2)O(2) used in the digestion step. The method allowed accurate confirmation analyses of the CRM DORM 3. In fact, the Z-scores attained in a proficiency test round were well below the reference value of 2.0, proving the excellent performance of the laboratory.


A mild topical steroid leads to progressive anti-inflammatory effects in the skin of patients with moderate-to-severe atopic dermatitis.
Topical glucocorticosteroids are considered an efficient treatment option for atopic dermatitis (AD), but a global assessment of glucocorticosteroid responses on key disease circuits upon weeks to months of treatment is currently lacking. We sought to assess short (4 weeks) and long-term (16 weeks) application of topical glucocorticosteroids on AD skin and define response biomarkers. The effects of triamcinolone acetonide cream 0.025% were assessed based on gene expression and immunohistochemistry studies at baseline, 4 weeks, and 16 weeks in biopsy specimens from 15 patients with moderate-to-severe AD. At 16 weeks, only 3 patients were clinical responders (by using SCORAD50 criteria), but 6 patients qualified as responders based on histologic criteria. Baseline characteristics indicated more severe disease in nonresponders. While 3 of 15 patients experienced only transient benefit after 4 weeks, others showed progressive improvements toward 16 weeks. Topical glucocorticosteroid use in patients with AD resulted in improvements of the AD genomic signature of 25.6% at 4 weeks and 71.8% at 16 weeks, respectively, and even 123.9% in the histologic responder group. Cytokines (IL-12p40, IL-13, IL-22, CCL17, CCL18, peptidase inhibitor 3 [PI3]/elafin, and S100As) showed consistent decreases from baseline toward 16 weeks with corresponding improvements in epidermal disease hallmarks (keratin 16 and loricrin) in lesional skin from responders (P < .05). Nonresponders largely showed lesser/nonsignificant reductions in key inflammatory and barrier markers (keratin 16, IL-13, IL-22, CCL17, CCL18, PI3/elafin, S100As, and loricrin). The combination of IL-21 and IFN-γ baseline expression closely predicted individual clinical glucocorticosteroid responses at 16 weeks of treatment. Our study indicates that even low-potency glucocorticosteroids can broadly affect immune and barrier responses in patients with moderate-to-severe AD, associating higher baseline severity with increased steroid resistance in patients with AD.


Novel mutations in ALDH1A3 associated with autosomal recessive anophthalmia/microphthalmia, and review of the literature.
Autosomal recessive anophthalmia and microphthalmia are rare developmental eye defects occurring during early fetal development. Syndromic and non-syndromic forms of anophthalmia and microphthalmia demonstrate extensive genetic and allelic heterogeneity. To date, disease mutations have been identified in 29 causative genes associated with anophthalmia and microphthalmia, with autosomal dominant, autosomal recessive and X-linked inheritance patterns described. Biallelic ALDH1A3 gene variants are the leading genetic causes of autosomal recessive anophthalmia and microphthalmia in countries with frequent parental consanguinity. This study describes genetic investigations in two consanguineous Pakistani families with a total of seven affected individuals with bilateral non-syndromic clinical anophthalmia. Using whole exome and Sanger sequencing, we identified two novel homozygous ALDH1A3 sequence variants as likely responsible for the condition in each family; missense mutation [NM_000693.3:c.1240G > C, p.Gly414Arg; Chr15:101447332G > C (GRCh37)] in exon 11 (family 1), and, a frameshift mutation [NM_000693.3:c.172dup, p.Glu58Glyfs*5; Chr15:101425544dup (GRCh37)] in exon 2 predicted to result in protein truncation (family 2). This study expands the molecular spectrum of pathogenic ALDH1A3 variants associated with anophthalmia and microphthalmia, and provides further insight of the key role of the ALDH1A3 in human eye development.


CircRNA AFF4 induced by KDM1A promotes osteogenic differentiation through FNDC5/Irisin pathway.
Circular RNA (circ) AFF4 was documented to regulate osteogenesis but the underlying mechanism remains to be elucidated. The preliminary study showed that circ_AFF4 may promote osteogenesis via FNDC5/Irisin. Furthermore, the online prediction tool indicated the interaction of circ_AFF4, insulin-like growth factor-2 mRNA-binding protein 3 (IGF2BP3), FNDC5 and lysine (K)-specific demethylase 1 A (KDM1A). Therefore, this study aims to elucidate the relationships of KDM1A, circ_AFF4, IGF2BP3 and FNDC5/Irisin during osteogenesis. The alkaline phosphatase (ALP) activities and osteogenic-related factors were determined using ALP and alizarin red S (ARS) staining, real-time quantitative PCR(RT-qPCR) and western blot. Immunoprecipitation (RIP), pull-down assay and fluorescence in situ hybridization (FISH) were used to examine the interactions among circ_AFF4/IGF2BP3/FNDC5. A mouse in vivo model was utilized to further confirm the regulatory effect on bone formation. Circ_AFF4 and KDM1A expression levels were increased during osteoinduction of BM-MSCs. Knockdown of circ_AFF4 and KDM1A significantly suppressed BM-MSC osteogenesis. We also proved that KDM1A directly bound to circ_AFF4 and FNDC5 promoter and induced circ_AFF4 and FNDC5 expression. Furthermore, circ_AFF4 enhanced the stability of FNDC5 by generating a circ_AFF4, IGF2BP3 and FNDC5 RNA-protein complex, and thereby induced Irisin and osteogenesis. The in vitro data was confirmed with in vivo model. These findings elucidate that KDM1A induces circ_AFF4, which promotes promote osteogenesis via IGF2BP3. This study indicates that circ_AFF4 may potentially represent a critical therapeutic target for the diseases.


Service quality and accessibility of healthcare facilities: digital healthcare potential in Ho Chi Minh City.
Effective delivery of health services requires adequate quality in healthcare facilities and easy accessibility to health services physically or virtually. The purpose of this study was to reveal how the quality of healthcare facilities varies across the different parts of Ho Chi Minh City and how well residents (N = 9 million) can reach healthcare facilities. By demarcating the deficiently served areas of low accessibility, the study shows where urban planning and digital healthcare could improve accessibility to health services and the quality of services efficiently. The analysis utilised geocoded information on hospitals, clinics, roads and population and the data of the quality scores of healthcare facilities. Quality scores were analysed by hot spot analysis and inverse distance weighting. Accessibility and formation of travel time-based service areas by travel time distances were calculated using road network, driving speed and population data. The results unveiled a centripetal spatial pattern of healthcare facilities and a similar pattern in their quality. Outside the travel time of 30 min for hospitals and 15 min for clinics, the deficiently served areas have a population of 1.1 to 1.2 million. Based on the results and the evidence of digital healthcare, this paper highlights how to develop and plan spatially effective service provision. Especially, it gives grounds to discuss how cost-effective digital healthcare could be applied to improve the accessibility and quality of health services in an urban structure of extensively varying accessibility to health services. The results bring up the need and the means for improving the quality of health services and their cost-efficient availability by location optimisation, road improvements and implementing digital healthcare provided by hospitals and clinics in the city. At the same, this study provides a multidisciplinary approach for planning more equal and efficient health service provision geographically.


Colonization with genital mycoplasmas in pregnant women and their neonates and birth weight.
The colonization by genital mycoplasmas of mothers and their newborn infants was examined in 114 pregnant women and their 84 neonates. Urine and cervical swabs were taken from the pregnant women in the last trimester, and urine from the neonates within six days after birth. Ureaplasma urealyticum was found in 73.7% of the pregnant women and in 17.9% of the neonates. Mycoplasma hominis was isolated in 8.8% of the material from the pregnant women and in 1.2% of that from the neonates. The isolation rate of U. urealyticum from newborn girls was significantly higher than that from newborn boys (p less than 0.01). There was no correlation between the germ density in the urine of the pregnant women and that of the neonates. The urine of the neonates harboured as many U. urealyticum as that of the adults. The frequency of colonization by mycoplasmas in the pregnant women or the neonates was not related to the duration of gestation or the babies' birth weight.


Minor degree of reversible renal insufficiency: a frequent complication of adult minimal-change nephrotic syndrome.
We report on a group of 27 patients with minimal-change nephrotic syndrome who presented complete recovery from the nephrotic syndrome and the other clinical signs during follow-up. At the start of the examination an elevated serum urea was found in 10 (37%) and of serum creatinine in 4 (15%) patients. Creatinine clearance was decreased in 10 (37%), systolic blood pressure was elevated in 8 (29%) and diastolic in 11 (41%). Interstitial oedema was found in 3, tubular parenchymal degeneration in 4, slight interstitial mononuclear infiltration in 6 and slight interstitial fibrosis in 1 patient. Complete recovery of renal function was seen in all patients.


Development of the short version of the spielberger state-trait anxiety inventory.
The Spielberger State-Trait Anxiety Inventory (STAI) has been widely used to measure the state and trait components of anxiety. We sought to develop a short, yet reliable and valid form of these scales for use in circumstances where the full-form is not feasible. We abbreviated the scales using item response theory analyses to retain the items that could discriminate the best among participants. One sample (N = 922) completed the state scale, a second sample (N = 2227) completed the trait scale, while a third sample (N = 250) completed the short forms. Our participants completed the Hungarian version of STAI alongside other measures to observe external validity. We calculated cut-off scores for the state (>9.5,) and trait (>13.5) scales. A total of 19.5% and 20.1% of the respondents reached the cut-off scores. The five-item short forms of STAI had sound psychometric properties that are comparable to those obtained on the full-form. The external validity of the scales is also demonstrated. We report detailed descriptive statistics that could be used in further studies as standards. The short scales are reliable measures that could be used in clinical screening and behavioural research; especially where practical considerations preclude the use of a longer questionnaire.


Modulatory impact of cardiac rehabilitation on hyperhomocysteinemia in patients with coronary artery disease and "normal" lipid levels.
In coronary patients with "relatively normal" lipid values and hyperhomocystinemia (levels > or =15 micromol/L), significant 12% reductions in homocysteine levels occurred after cardiac rehabilitation and exercise training. This benefit from cardiac rehabilitation and exercise training may lead to 20% to 30% reductions in overall coronary artery disease risk.


Epoxyqueuosine Reductase Structure Suggests a Mechanism for Cobalamin-dependent tRNA Modification.
Queuosine (Q) is a hypermodified RNA base that replaces guanine in the wobble positions of 5'-GUN-3' tRNA molecules. Q is exclusively made by bacteria, and the corresponding queuine base is a micronutrient salvaged by eukaryotic species. The final step in Q biosynthesis is the reduction of the epoxide precursor, epoxyqueuosine, to yield the Q cyclopentene ring. The epoxyqueuosine reductase responsible, QueG, shares distant homology with the cobalamin-dependent reductive dehalogenase (RdhA), however the role played by cobalamin in QueG catalysis has remained elusive. We report the solution and structural characterization of Streptococcus thermophilus QueG, revealing the enzyme harbors a redox chain consisting of two [4Fe-4S] clusters and a cob(II)alamin in the base-off form, similar to RdhAs. In contrast to the shared redox chain architecture, the QueG active site shares little homology with RdhA, with the notable exception of a conserved Tyr that is proposed to function as a proton donor during reductive dehalogenation. Docking of an epoxyqueuosine substrate suggests the QueG active site places the substrate cyclopentane moiety in close proximity of the cobalt. Both the Tyr and a conserved Asp are implicated as proton donors to the epoxide leaving group. This suggests that, in contrast to the unusual carbon-halogen bond chemistry catalyzed by RdhAs, QueG acts via Co-C bond formation. Our study establishes the common features of Class III cobalamin-dependent enzymes, and reveals an unexpected diversity in the reductive chemistry catalyzed by these enzymes.


Emerging trends in adolescent suicide prevention research.
A comprehensive public health strategy for adolescent suicide prevention includes upstream prevention strategies, strategies for risk recognition, and services for those at risk. Interpersonal trauma and substance use are important prevention targets as each is associated with risk for suicide attempts. Multiple prevention programs target these factors; however, the Family Check-Up, designed to reduce substance use and behavioral problems, also has been associated with reduced suicide risk. Several youth screening instruments have shown utility, and a large-scale trial is underway to develop a computerized adaptive screen. Similarly, several types of psychotherapy have shown promise, and sufficiently powered studies are underway to provide more definitive results. The climbing youth suicide rate warrants an urgent, concerted effort to develop and implement effective prevention strategies.


Altered resting-state neurovascular coupling in patients with pontine infarction.
The risk for motor and cognitive impairment is increased in patients with chronic pontine infarction (PI). In this study, we attempted to explore the alterations of neurovascular coupling (NVC) in order to understand the neural basis of behavioral impairment after PI. Three-dimensional pseudo-continuous arterial spin labeling (3D-pcASL) and resting-state functional magnetic resonance imaging (rs-fMRI) were applied in 49 patients with unilateral PI (left-sided, n = 26; right-sided, n = 23) and 30 matched normal subjects to assess whole-brain cerebral blood flow (CBF) and functional connectivity strength (FCS). We evaluated NVC in each subject by calculating the correlation coefficient between the whole-brain CBF and FCS (CBF-FCS coupling) and the ratio between voxel-wise CBF and FCS (CBF/FCS ratio). The FCS maps were then divided into long-range and short-range FCS to identify the influence of connection distance. The results indicated that the CBF-FCS coupling in the whole-brain level was significantly interrupted in PI patients, and the CBF/FCS ratio in cognition-related brain regions was abnormal. Distance-dependent results demonstrated that PI had a more serious effect on long-range neurovascular coupling. Correlation analysis revealed that the changes in neurovascular coupling were correlated with working memory scores. These findings imply that disruption of neurovascular coupling in the remote-infarction brain regions may underlie the impaired cognitive functions in chronic PI.


Combined effect of ultrasound and nanoclay on adsorption of phenol.
Sorption of phenol onto organophilic bentonite (nanoclay) by ultrasonic irradiation was investigated. Tetrabutyl ammonium chloride (TBAC), N-acetyl-N,N,N trimethyl ammonium bromide (CTAB) and hexadecyl trimethyl ammonium chloride (HDTMA) were used as intercalating agents. Nanoclay was synthesized using sonication technique. TBAC modified nanoclay shows amorphous exfoliated nature, while CTAB and HDTMA modified nanoclay shows intercalating crystalline nature, which was revealed by XRD gram. Further FTIR reveals the presence of NH(2) and (CH(2))(n) groups onto clay platelet. Due to sonication, adsorption equilibrium was achieved within short period of time (10 min). It was found that intraparticle diffusion resistance has overcome due to sonication. The experimental data obtained obeys both Freundlich isotherm model and Langmuir adsorption isotherm model. HDTMA modified nanoclay shows higher parameter values.


Soluble prion protein and its N-terminal fragment prevent impairment of synaptic plasticity by Aβ oligomers: Implications for novel therapeutic strategy in Alzheimer's disease.
The pathogenic process in Alzheimer's disease (AD) appears to be closely linked to the neurotoxic action of amyloid-β (Aβ) oligomers. Recent studies have shown that these oligomers bind with high affinity to the membrane-anchored cellular prion protein (PrP(C)). It has also been proposed that this binding might mediate some of the toxic effects of the oligomers. Here, we show that the soluble (membrane anchor-free) recombinant human prion protein (rPrP) and its N-terminal fragment N1 block Aβ oligomers-induced inhibition of long-term potentiation (LTP) in hippocampal slices, an important surrogate marker of cognitive deficit associated with AD. rPrP and N1 are also strikingly potent inhibitors of Aβ cytotoxicity in primary hippocampal neurons. Furthermore, experiments using hippocampal slices and neurons from wild-type and PrP(C) null mice (as well as rat neurons in which PrP(C) expression was greatly reduced by gene silencing) indicate that, in contrast to the impairment of synaptic plasticity by Aβ oligomers, the cytotoxic effects of these oligomers, and the inhibition of these effects by rPrP and N1, are independent of the presence of endogenous PrP(C). This suggests fundamentally different mechanisms by which soluble rPrP and its fragments inhibit these two toxic responses to Aβ. Overall, these findings provide strong support to recent suggestions that PrP-based compounds may offer new avenues for pharmacological intervention in AD.


Assessing disease severity in Pompe disease: the roles of a urinary glucose tetrasaccharide biomarker and imaging techniques.
Defining disease severity in patients with Pompe disease is important for prognosis and monitoring the response to therapies. Current approaches include qualitative and quantitative assessments of the disease burden, and clinical measures of the impact of the disease on affected systems. The aims of this manuscript were to review a noninvasive urinary glucose tetrasaccharide biomarker of glycogen storage, and to discuss advances in imaging techniques for determining the disease burden in Pompe disease. The glucose tetrasaccharide, Glcα1-6Glcα1-4Glcα1-4Glc (Glc(4) ), is a glycogen-derived limit dextrin that correlates with the extent of glycogen accumulation in skeletal muscle. As such, it is more useful than traditional biomarkers of tissue damage, such as CK and AST, for monitoring the response to enzyme replacement therapy in patients with Pompe disease. Glc(4) is also useful as an adjunctive diagnostic test for Pompe disease when performed in conjunction with acid alpha-glucosidase activity measurements. Review of clinical records of 208 patients evaluated for Pompe disease by this approach showed Glc(4) had 94% sensitivity and 84% specificity for Pompe disease. We propose Glc(4) is useful as an overall measure of disease burden, but does not provide information on the location and distribution of excess glycogen accumulation. In this manuscript we also review magnetic resonance spectroscopy and imaging techniques as alternative, noninvasive tools for quantifying glycogen and detailing changes, such as fibrofatty muscle degeneration, in specific muscle groups in Pompe disease. These techniques show promise as a means of monitoring disease progression and the response to treatment in Pompe disease. © 2012 Wiley Periodicals, Inc.


Dysregulation of intestinal epithelial CFTR-dependent Cl- ion transport and paracellular barrier function drives gastrointestinal symptoms of food-induced anaphylaxis in mice.
Food-triggered anaphylaxis can encompass a variety of systemic and intestinal symptoms. Murine-based and clinical studies have revealed a role for histamine and H1R and H2R-pathway in the systemic response; however, the molecular processes that regulate the gastrointestinal (GI) response are not as well defined. In the present study, by utilizing an IgE-mast cell (MC)-dependent experimental model of oral antigen-induced anaphylaxis, we define the intestinal epithelial response during a food-induced anaphylactic reaction. We show that oral allergen-challenge stimulates a rapid dysregulation of intestinal epithelial transcellular and paracellular transport that was associated with the development of secretory diarrhea. Allergen-challenge induced (1) a rapid intestinal epithelial Cftr-dependent Cl- secretory response and (2) paracellular macromolecular leak that was associated with modification in epithelial intercellular junction proteins claudin-1, 2, 3 and 5, E-cadherin and desmosomal cadherins. OVA-induced Cftr-dependent Cl- secretion and junctional protein degradation was rapid occurring and was sustained for 72 h following allergen-challenge. Blockade of both the proteolytic activity and Cl- secretory response was required to alleviate intestinal symptoms of food-induced anaphylaxis. Collectively, these data suggest that the GI symptom of food-induced anaphylactic reaction, secretory diarrhea, is a consequence of CFTR-dependent Cl- secretion and proteolytic activity.


Immobilized cycling enzyme active transport systems. pH feedback control.
Active transport can be induced by applying a pH gradient across a membrane containing a homogeneous mixture of two cycling enzymes. When the two reactions are inversely 'pH active', one producing protons and the other consuming them, a pH feedback control of the functional structure occurs and the active transport function of the membrane can be either stabilized or inhibited according to whether the endogenic pH modifications tend to enhance or reduce the exergonic pH gradient. When it is stabilized, the system looks like a thin active layer surrounded by two diffusive layers, leading to a fairly good model for biological transport systems. Under particular conditions, signals can be emitted.


Chondroprotective effect of salicylate and chloroquine in pyogenic septic arthritis.
This study aims to investigate the effectiveness of salicylate (Aspisol; Bayer AG, Leverkusen, Germany) and chloroquine on preventing cartilage damage in septic arthritis. A septic arthritis model was created by inoculating the knee joint of young rabbits (n=21) with Staphylococcus aureus. Some rabbits with inflicted septic arthritis did not undergo any treatment and served as the control group (n=7). The second group (n=7) was started on salicylate on day 2 to investigate the effects of salicylate on joint cartilage. The third group (n=7) was started on chloroquine on day 2 to investigate the effects of chloroquine on joint cartilage. All three groups underwent arthrotomy, drainage and synoviectomy on day 7 of the experiment. Animals were sacrificed on day 14 and the joint cartilages were extracted. Histopathology, determination of local prostaglandin (PGE)-like activity, and evaluation of hyaluronic acid loss were performed on all samples. The control group and the salicylate group were similar in the extent of joint damage. Salicylate did not prevent joint cartilage damage despite inhibiting PGE synthesis. Chloroquine, despite not inhibiting PGE synthesis, did prevent cartilage destruction. If supported by larger-scale studies, chloroquine could be added to the antibiotic regimen in the treatment of septic arthritis to prevent cartilage damage.


Pre-vascularization of bone tissue-engineered constructs.
Vascularization remains one of the primary obstacles in the repair of bone defects. In the previous issue of Stem Cell Research &Therapy, Pedersen and colleagues show that co-immobilization of endothelial cells and mesenchymal stem cells in a tissue-engineered construct can achieve functional microvascular networks in vivo. These very interesting findings, together with other state-of-the-art research in this field, are presented in this commentary. They highlight the vital role of mesenchymal stem cells as supporting cells to nascent blood vessels. The development of pre-vascularized implants by using clinically relevant cell sources, which could lead to rapid integration into the host tissue, would be of immense interest.


[Role of surgery in the management of pulmonary parasitosis].
Pulmonary parasitosis is scarcely encountered in France, and its diagnosis is quite difficult. If numerous parasites can be responsible for respiratory symptoms, only few of them can develop in the lung parenchyma and lead to complications necessitating a surgical treatment. The most common example is the hydatic disease of the lung. The authors review the biological cycles, clinical forms, diagnostic and treatment principles of those main lung parasites, which deserve surgical consideration.


Single port thoracoscopic diaphragm plication: A novel treatment approach to bilateral phrenic nerve palsy and diaphragm paralysis.
The diaphragm is the primary muscle of respiration. Bilateral paralysis of the diaphragm due to phrenic nerve palsy causes severe dyspnoea and is life threatening. Diaphragmatic Plication has shown great promise in treating diaphragm paralysis and has evolved as operative treatment from an open thoracotomy to multiport and robotic video assisted thoracoscopic surgery. Here we present a case of idiopathic bilateral diaphragm paralysis resulting significant deterioration in lung function tests, supplemental oxygen, and ventilator dependence. The patient was treated with a 2-stage operative plication of each hemidiaphragm through a 2.5 cm single incision thoracoscopic technique, which resulted in normalization of lung function tests, elimination of oxygen dependence and negligible analgesia requirements. This is the first case reported in the literature of a single port VATS plication of the diaphragm for the treatment of bilateral phrenic nerve palsy. Surgery, specifically diaphragm plication, is indicated for patients with significant symptoms and persistent paralysis. Video-assisted thoracoscopic surgery (VATS) has evolved from open operations to smaller incisions, offering improved lung function, postoperative pain, hospital stay, morbidity, and mortality. Single port diaphragmatic plication is a novel approach to the treatment of bilateral phrenic nerve palsy. We make the case for indication of the technique for treatment of diaphragmatic paralysis.


Risks to the stratospheric ozone shield in the Anthropocene : This article belongs to Ambio's 50th Anniversary Collection. Theme: Ozone Layer.
Crutzen (1974) and Crutzen and Ehhalt (1977) presented two key papers in Ambio that in Ambioexemplify how science first revealed to humankind the potential for damage to our ozone shield in the Anthropocene. Crutzen's (1974) review is a sweeping summary of the risks to the ozone layer from supersonic aircraft, chlorofluorocarbons, as well as nuclear weapons testing and nuclear war. Crutzen and Ehhalt (1977) described how the nitrous oxide produced from fertilizers could pose another threat to the stability of the stratospheric ozone layer. The two papers are part of a body of influential scientific work that led to the pioneering Montreal Protocol to Protect the Earth's Ozone Layer to phase out production of chlorofluorocarbons (in 1987), as well as national decisions that slowed or stopped production of supersonic planes (in the 1970s). They remain guideposts today for ongoing international negotiations regarding reducing emissions from fertilizer and limiting nuclear testing.


Safety of shortened infusion times for combined ipilimumab and nivolumab.
Combined ipilimumab and nivolumab induces encouraging response rates in patients with unresectable or metastatic melanoma. However, the approved protocol for dual checkpoint inhibition (3 mg/kg ipilimumab over 90 min and 1 mg/kg nivolumab over 60 min) is time-intensive and several trials have shown that both single agents can be safely administered at faster infusion rates. To investigate whether combined checkpoint inhibition with 3 mg/kg ipilimumab and 1 mg/kg nivolumab can be safely administered over 30 min per agent. We reviewed the rate of infusion-related reactions (IRRs) in the first 12 months of our single-institution experience using shortened infusion times for combined checkpoint inhibition with ipilimumab and nivolumab. Between May 24, 2016 and June 10, 2017, a total of 46 melanoma patients received 100 shortened cycles of combined 3 mg/kg ipilimumab and 1 mg/kg nivolumab. One patient (2.2%; 1/46) had a questionable reaction after administration of 1 mg/kg nivolumab over 30 min, but none of the other patients had a bona fide IRR. Shortened infusion times for combined ipilimumab and nivolumab treatment are safe, thereby facilitating a more efficient use of outpatient facilities and enhancing patient's convenience.


Effects of elexacaftor / tezacaftor / ivacaftor triple combination therapy on glycaemic control and body composition in patients with cystic fibrosis-related diabetes.
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are a group of new drugs for the treatment of cystic fibrosis (CF) and elexacaftor + tezacaftor + ivacaftor (ETI) triple combination therapy has been approved as first choice therapy in the treatment of patients with at least 1 copy of F508del variation. Data on the effects of CFTR modulators on glucose metabolism are limited to small studies with conflicting results. We conducted a prospective observational study on 24 CF patients with CF-related diabetes requiring insulin therapy, with the aim to evaluate the effectiveness of ETI on glucose metabolism, glucose variability and body composition. After six months of treatment, HbA1c and coefficient of variation, measured through flash or continuous glucose monitoring, significantly decreased (median changes: -0.5, P = 0.029 and -6.3, P = 0.008, respectively), despite unchanged insulin requirements. Over the treatment period, percent of fat mass increased by a median value of 3% (p = 0.029).


Inhibition of cholesterol and fatty acid biosynthesis in liver enzymes and chicken hepatocytes by polar fractions of garlic.
Different concentrations of polar fractions, methanol-soluble (MESF), or water-soluble (WASF), of 1-8% equivalent to fresh garlic paste were added to yellow corn-soybean based diets and fed to 5-week-old male broiler chickens for 3 weeks to measure the inhibition of hepatic beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase, cholesterol 7 alpha-hydroxylase (7 alpha-hydroxy) and fatty acid synthetase (FAS). Dose-related decreases in the activities of these enzymes were obtained. Decreases in serum total cholesterol and in low density lipoprotein (LDL) levels were also observed. There was no effect on the level of cholesterol in high density lipoprotein (HDL). The most effective dose for these decreases was found 0.54% (MESF) and 1.2% (WASF) equivalent to 6% of the fresh garlic. The inhibition of HMG-CoA reductase and FAS by 25-300 micrograms of MESF or WASF for 15 min was tested in vitro, in male and female chicken hepatocytes. Inhibitions of activity were dose-dependent and the degree of inhibition increased with duration of incubation (150 micrograms of MESF or WASF 5 to 60 min). Dietary supplementation of odorless WASF of garlic was found to be very effective in lowering the total and LDL cholesterol levels compared to control chickens.


Collateral Benefits of Evidence-Based Substance Use Prevention Programming During Middle-School on Young Adult Romantic Relationship Functioning.
The quality of romantic relationships formed during early adulthood has critical implications for physical and psychological wellbeing, future romantic relationships, and subsequent parenting of the next generation. The present study evaluates the cross-over effects of the PROSPER-delivered adolescent substance use prevention programming on young adult romantic relationship functioning through a long-term developmental cascade of adolescent skills and behaviors, along with subsequent family-of-origin functioning. Prospective, longitudinal, bivariate growth models were used to analyze the effects of the PROSPER-delivered interventions in a sample of 1008 youths living in rural and semi-rural communities in Iowa and Pennsylvania, starting in sixth grade (AgeM = 11.8; 62% female) who were in a steady romantic relationship at the young adult assessment (AgeM = 19.5). Findings indicated a cascading effect through which PROSPER promotes adolescent problem-solving skills during early-to-mid-adolescence; problem-solving skills were associated with better family functioning during mid-adolescence; and family functioning was associated with better romantic relationship quality, indicated by lower levels of relationship violence and more effective relationship problem-solving in young adulthood. PROSPER, which primarily targets adolescent substance misuse and conduct problem prevention, has lasting, collateral effects that benefit young adults in their romantic relationship functioning - which may have further downstream benefits for their own relationships and those of their children (i.e., intergenerational transmission effects). These findings add to the growing body of literature evidencing important cross-over effects of widely disseminated substance use prevention programs delivered during adolescence.


Comparison of intervertebral fusion rates of different bone graft materials in extreme lateral interbody fusion.
To compare imaging indicators and clinical effects of extreme lateral interbody fusion (XLIF) using allogenic bone, autologous bone marrow + allogenic bone, and rhBMP-2 + allogenic bone as bone graft materials in the treatment of degenerative lumbar diseases.This was a retrospective study of 93 patients with lumbar interbody fusion who underwent the extreme lateral approach from May 2016 to December 2017. According to the different bone graft materials, patients were divided into allogenic bone groups (group A, 31 cases), rhBMP-2 + allogenic bone (group B, 32 cases), and autologous bone marrow + allogenic bone (group C, 30 cases). There were no significant differences in gender, age, lesion segment, preoperative intervertebral space height, and preoperative Oswestry Dysfunction Index (ODI) and visual analogue scale (VAS) scores among the 3 groups (P > .05). Intervertebral space height, bone graft fusion rate, and ODI and VAS scores were compared immediately after surgery, and at 3, 6, and 12 months after surgery.All groups were followed up for 12 months. The intervertebral space height was significantly higher in the 3 groups immediately after surgery and at 3, 6, and 12 months after surgery, in comparison to before surgery (P < .05). There was no significant difference in the intervertebral space height among the 3 groups immediately after surgery and at 3, 6, and 12 months after surgery (P > .05). The fusion rate of group B and C was higher than that of groups A at 3, 6, and 12 months after surgery (P < .05). In the 3 groups, the VAS and ODI scores at 3, 6, and 12 months after surgery were significantly improved compared with the preoperative scores (P < .05). The VAS and ODI scores in groups B and C were significantly higher than those in group A (P < .05), but there was no significant difference between groups B and C (P > .05).The rhBMP-2 + allograft bone combination had good clinical effects and high fusion rate in XLIF.


Structure-activity relationships of 2alpha-substituted androstenedione analogs as aromatase inhibitors and their aromatization reactions.
Aromatase catalyzes the conversion of androstenedione (1a, AD) to estrone through three sequential oxygenations of the 19-methyl group. To gain insight into the spatial nature of the AD binding (active) site of aromatase in relation to the catalytic function of the enzyme, we tested for the ability of 2alpha-substituted (halogeno, alkyl, hydroxy, and alkoxy) ADs (1b-1i) to inhibit aromatase in human placental microsomes as well as their ability to serve as a substrate for the enzyme. All of the steroids inhibited the enzyme in a competitive manner with the apparent K(i)'s ranging from 45 to 1150 nM. 2alpha-Halogeno (F, Cl, and Br) and 2alpha-alkyl (CH3 and CH2CH3) steroids 1b-1f were powerful to good inhibitors (Ki=45-171 nM) whereas steroids 1g-1i, having an oxygen function (hydroxy or alkoxy) at C-2alpha, were poor inhibitors (Ki=670-1150 nM). Aromatization of some of the steroids with placental microsomes was analyzed by gas chromatography-mass spectrometry, indicating that the aromatization rate of the bromide 1d was about two-fold that of the natural substrate AD and that of 2alpha-methoxide 1h was similar to that of AD. Kinetic analysis of the aromatization of androgens revealed that a good substrate was not essentially a good inhibitor for aromatase.


Plant signaling: brassinosteroids, immunity and effectors are BAK !
Plants use the same set of co-receptors to mediate distinct responses to external signals. Brassinosteroid signaling serves as a test case to unravel the mechanisms of receptor-co-receptor activation and initiation of a specific signaling cascade.


Efficacy of a support intervention designed to improve parents' communication with children dealing with parental cancer: a randomized pilot trial.
Cancer-related communication is critical for parents' and children's adaptation to the disease. This randomized pilot study was conducted to test the feasibility, acceptability, and efficacy of a 4-session intervention designed to improve parents' communication. A 4-session intervention was developed to aid parents to support their children through more open/adapted communication. Sixty-six parents were assigned randomly to informational booklet with and without 4-session support intervention arms. Parents' communication self-efficacy, communication behaviors, communication difficulties, knowledge about age-appropriate communication, theoretical knowledge about concerns of children, parenting concerns, and distress were assessed by questionnaires at baseline and post-interventions. Multivariate analyses of variance were performed to compare data between and within groups over time. The intervention attrition rate was 6%. Data from 60 participants were included in analyses. Parents in the informational booklet with 4-session support group increased their communication self-efficacy (F = 4.5, p = 0.04), reduced communication difficulties (F = 4.0, p = 0.05), and increased their knowledge about how to communicate (F = 4.8, p = 0.03). The results indicate that the 4-session intervention is acceptable, and shows preliminary evidence of efficacy. A short support intervention associated with an informational booklet may be useful for parents wishing to improve their communication with their children.


Isolation and sequencing of the Alcaligenes denitrificans azurin-encoding gene: comparison with the genes encoding blue copper proteins from Pseudomonas aeruginosa and Alcaligenes faecalis.
The gene (azu) encoding azurin from Alcaligenes denitrificans has been cloned and sequenced. The gene codes for a pre-protein with a 19-aa signal peptide. Comparison with the sequences coding for the blue copper proteins from Pseudomonas aeruginosa and Alcaligenes faecalis reveals the presence of ntrA and fnr boxes in front of all three genes, instead of a regular [-10, -35]-promoter. In P. aeruginosa, the azu gene is terminated by a bidirectional terminator and flanked by open reading frames on the opposite strand.


Dental caries and the secretory activity of human labial minor salivary glands.
The correlation between caries (DMFS) and labial minor salivary gland activity was studied. The number of labial minor salivary glands and their secretion was lower in individuals with high caries rates. It was found that the regression between the declining number of functional minor salivary glands, their secretion rate and caries grows progressively worse.


Corrigendum to "Non-thermal atmospheric-pressure plasma potentiates mesodermal differentiation of human induced pluripotent stem cells" [Heliyon 8(12) (December 2022) e12009].
[This corrects the article DOI: 10.1016/j.heliyon.2022.e12009.].


Bacterial extracellular vesicles: an emerging avenue to tackle diseases.
A growing body of research, especially in recent years, has shown that bacterial extracellular vesicles (bEVs) are one of the key underlying mechanisms behind the pathogenesis of various diseases like pulmonary fibrosis, sepsis, systemic bone loss, and Alzheimer's disease. Given these new insights, bEVs are proposed as an emerging vehicle that can be used as a diagnostic tool or to tackle diseases when used as a therapeutic target. To further boost the understanding of bEVs in health and disease we thoroughly discuss the contribution of bEVs in disease pathogenesis and the underlying mechanisms. In addition, we speculate on their potential as novel diagnostic biomarkers and how bEV-related mechanisms can be exploited as therapeutic targets.


Secretion of epidermal growth factor-like molecular species by lung parenchymal macrophages: induction by interferon-gamma.
A population of cells enriched for pulmonary interstitial macrophages was obtained by differential adherence of lung parenchymal cells released by dissociation with trypsin. These cells secreted a molecule or molecules that bound to epidermal growth factor (EGF) receptors expressed on pulmonary fibroblasts. Secretion was reproducibly stimulated by exposure of the macrophages to interferon-gamma. Binding to EGF receptors could be blocked by a polyclonal antibody to EGF. It could also be partially blocked by incubation with heparin, suggesting that at least a component of the activity might be due to a member of the heparin-binding subgroup of the EGF family of growth factors. Because pulmonary fibrosis is consistently associated with inflammatory accumulation of activated T-lymphocytes, induction by interferon-gamma of growth factor secretion by macrophages could have pathogenetic importance. We speculate that similar cellular interactions may play a role in the progression of other chronic inflammatory lesions to fibrosis.


[Clinical course and prognostic significance of immunological and functional parameters after severe trauma].
Generalized severe trauma leads to an increased incidence of SIRS, sepsis, and MOF. The aim of this prospective study was to investigate the immunological parameters in terms of their predictive value for multiple organ failure (MOF).HLA-DR expression on peripheral monocytes was analyzed by flow cytometry, the ex vivo endotoxin-stimulated TNFalpha synthesis of whole blood, and the serum levels of IL-6, IL-10, procalcitonin (PCT), and CRP were analyzed by ELISA in 16 severely injured patients with an ISS >25. Initially after trauma elevated serum levels of IL-6, IL-10, and PCT were found, while TNFalpha-producing capacity and HLA-DR expression on monocytes decreased. In patients with MOF a further decrease of HLA-DR expression on days 3-4 after injury was observed accompanied by elevated levels of IL-10 at this time point. However, the TNFalpha-producing capacity was even enhanced in patients with MOF in the 2nd week after trauma. Later PCT levels were also higher in patients with MOF.Monitoring of immunological parameters after severe injury is useful to identify mediator constellations that are associated with the development and clinical course of MOF even in extremely injured patients.