The interaction between pilocarpine and hexobarbital in male rats.
The interaction between pilocarpine and hexobarbital was studied in male rats. Hexobarbital was infused continously. The dose needed to obtain an EEG criterion (the "silent second") was determined. The ensuing anesthesia times after these equi-anesthetic doses were also recorded. At different times prior to the hexobarbital threshold determination the rats were pretreated with 25-200 mg/kg of pilocarpine. In most experimental series pretreatment with methylatropine (2 mg/kg s.c.) was also given to reduce the effects of pilocarpine on peripheral cholinergic sites. In the dose-response study pilocarpine was given 1 h prior to the hexobarbital threshold determination. Pilocarpine in doses of 25-50 mg/kg increased the amount of hexobarbital needed to obtain the "silent second". With higher doses of pilocarpine, increases in hexobarbital thresholds were seen if no convulsion had been induced by the pilocarpine treatment. If a convulsion was recorded the dose of hexobarbital was reduced. Similar results were obtained in the time-effect studies where more convulsions tended to appear if the time between the dose of pilocarpine and the dose of hexobarbital was increased. In animals without convulsions the effect of pilocarpine on the dose of hexobarbital was counteracted by atropine (8 mg/kg i.p.). The ensuing anesthesia times were increased in the pilocarpine pretreated animals, which could be due to either the pilocarpine dose, the increased dose of hexobarbital needed to obtain the "silent second", or both. No regression between body temperature and dose of hexobarbital was found, but there was a regression with the ensuing anesthesia times. The effects of pilocarpine with an increase in hexobarbital threshold is similar to the changes seen in the threshold in the abstinence after chronic barbital treatments. More important, however, is that both increases are reduced by convulsions. Could pilocarpine be a model for the changes in the abstinence after barbital?


Outcome of unstable angina in patients with diabetes mellitus.
This prospective hospital-based, case-control study compares the outcome of unstable angina in non-insulin dependent diabetic patients and non-diabetic control subjects. One hundred and sixty-two diabetic patients and 162 non-diabetic control patients with unstable angina were entered into the study. The 3-month mortality was 8.6% (95% confidence interval, CI = 4.4-12.9%) in diabetic patients and 2.5% (CI = 0.1-4.9%) in control patients (p = 0.014). The 1-year mortality was 16.7% (CI = 10.9%-22.4%) in diabetic patients and 8.6% (CI = 4.4%-12.9%) in non-diabetic patients (p = 0.029). Diabetic patients received beta-blockade and underwent coronary angiography and angioplasty less frequently than controls; the frequency of unstable angina, of acute myocardial infarction, and coronary artery bypass grafting was similar in both groups at 1 year of follow-up. It is concluded that diabetic patients with unstable angina have a higher mortality than non-diabetic patients and that this difference is largely accounted for by early (first 3 months) mortality.


Lamellar bodies of cultured human fetal lung: content of surfactant protein A (SP-A), surface film formation and structural transformation in vitro.
Lamellar bodies were isolated from dexamethasone and T3-treated explant cultures of human fetal lung, using sucrose density-gradient centrifugation. We examined their content of surfactant apoprotein A (SP-A), and their ability to form surface films and to undergo structural transformation in vitro. SP-A measured by ELISA composed less than 2% of total protein within lamellar bodies; this represented, as a minimum estimate, a 2-12-fold enrichment over homogenate. One- and two-dimensional gel electrophoresis also suggested that SP-A was a minor protein component of lamellar bodies. Adsorption of lamellar bodies to an air/water interface was moderately rapid, but accelerated dramatically upon addition of exogenous SP-A in ratios of 1:2-16 (SP-A:phospholipid, w/w). Similar adsorption patterns were seen for lamellar bodies from fresh adult rat and rabbit lung. Lamellar bodies incubated under conditions that promote formation of tubular myelin underwent structural rearrangement only in the presence of exogenous SP-A, with extensive formation of multilamellate whorls of lipid bilayers (but no classical tubular myelin lattices). We conclude that lamellar bodies are enriched in SP-A, but have insufficient content of SP-A for structural transformation to tubular myelin and rapid surface film formation in vitro.


Robot assisted laparoscopic pelvic lymphadenectomy at the time of radical cystectomy rivals that of open surgery: single institution report.
The purpose of this study was to analyze the pelvic lymph node dissection (PLND) and margin status using a standard technique in the first 35 patients undergoing robot-assisted radical cystectomy (RARC) at our institution while establishing a robotics program, and then to compare the results to the past 35 open radical cystectomy (ORC) performed at our institution. After obtaining institutional review board approval, we reviewed the clinical and pathologic data from 70 consecutive patients with clinically localized bladder cancer who underwent radical cystectomy with PLND from April 2007 to June 2009. Thirty-five operations were performed open and 35 used the da Vinci robotic system. The PLND was performed in all patients using the same template. There was no significant difference between the ORC and RARC group in regards to patient characteristics, tumor stage (43% ORC and 40% RARC having pT3/pT4 disease), and node status (29% N+ in each group). The median total lymph node yield was similar, with 15 (interquartile range [IQR] 11, 22) in the ORC group and 16 (IQR 11, 24) in the RARC group (P = 0.5). One patient who underwent RARC had a positive margin compared with 3 patients in the ORC group. The initial 35 RARC with PLND performed at our institution compared with the last 35 ORC resulted in equivalent lymph node yield and similar rates of positive margins. RARC with PLND is feasible, safe, and effective when performed at a high-volume center by an experienced team.


Xanthones induce cell-cycle arrest and apoptosis in human colon cancer DLD-1 cells.
We investigated the antiproliferative effects of four structurally similar prenylated xanthones, alpha-mangostin, beta-mangostin, gamma-mangostin, and methoxy-beta-mangostin, in human colon cancer DLD-1 cells. These xanthones differ in the number of hydroxyl and methoxy groups. Except for methoxy-beta-mangostin, the other three xanthones strongly inhibited cell growth at 20 microM and their antitumor efficacy was correlated with the number of hydroxyl groups. Hoechst 33342 nuclear staining and nucleosomal DNA-gel electrophoresis revealed that the antiproliferative effects of alpha- and gamma-mangostin, but not that of beta-mangostin, were associated with apoptosis. It was also shown that their antiproliferative effects were associated with cell-cycle arrest by affecting the expression of cyclins, cdc2, and p27; G1 arrest was by alpha-mangostin and beta-mangostin, and S arrest by gamma-mangostin. These findings provide a relevant basis for the development of xanthones as an agent for cancer prevention and combination therapy with anti-cancer drugs.


Do historical changes in parent-child relationships explain increases in youth conduct problems?
The coincidence of historical trends in youth antisocial behavior and change in family demographics has led to speculation of a causal link, possibly mediated by declining quality of parenting and parent-child relationships. No study to date has directly assessed whether and how parenting and parent-child relationships have changed. Two national samples of English adolescents aged 16-17 years in 1986 (N = 4,524 adolescents, 7,120 parents) and 2006 (N = 716 adolescents, 734 parents) were compared using identical questionnaire assessments. Youth-reported parental monitoring, expectations, and parent-child quality time increased between 1986 and 2006. Ratings of parental interest did not change. Parenting differences between affluent and disadvantaged families narrowed over time. There was thus little evidence of a decline in quality of parenting for the population as a whole or for disadvantaged subgroups. Parent-reported youth conduct problems showed a modest increase between 1986 and 2006. Findings suggested that the increase in youth conduct problems was largely unrelated to observed change in parent-child relationships.


Iron deposition in cranial bone marrow with sickle cell disease: MR assessment using a fat suppression technique.
Thirteen patients with sickle cell disease (SCD) undergoing transfusion therapy and 8 control patients were examined by magnetic resonance imaging to discriminate bone marrow change due to iron deposition from hematologic marrow hyperplasia. Using T1-weighted spin echo images, only two subjects showed extremely low signal intensity marrow compatible with iron deposition. However, using T2-weighted fast spin echo images with fat suppression, cranial bone marrow in SCD patients with transfusion therapy showed considerably lower signal than that of controls. The main cause of marrow signal decrease in SCD patients with transfusion therapy was considered to be iron deposition due to repeated transfusion therapy rather than red marrow hyperplasia.


VRN1-ratio test for polyploid wheat.
The duplications of the dominantVrn-A1alleles as well as theVRN-B1gene, revealed for the first time, are new sources of polymorphism in polyploid wheat at these agronomically valuable genomic locations. Flowering time is an important trait in wheat breeding. In spring wheat, this feature is mainly determined by the variants and number of the homoeologous dominant VRN1 alleles. Previously, multiplication of the recessive vrn-A1 allele was shown for winter hexaploid wheat (Würschum et al., BMC Genet 29:16-96, 2015). In the present study, VRN1 gene copy-number variation as well as the copy number of VRN-A1 with the alternative exon 4 haplotype were investigated in spring and winter accessions of different tetraploid and hexaploid wheat species. Two ratio tests were optimized based on end-point quantification of PCR fragments and results were verified by a qPCR assay. It was defined that since the genomic environment affects the accessibility of amplified VRN1 regions, the DNA template should be fragmented for proper quantification of VRN1 copy number during PCR-based assays. For the first time, it was shown that the dominant Vrn-A1 alleles are most often duplicated in hexaploid wheat. In tetraploid wheat, both the dominant and recessive alleles were represented as a single haploid copy, and in only two accessions of T. dicoccum, vrn-A1b.3 was duplicated. Multiplication of VRN-A1 was often associated with awnless spikes. Five haploid combinations of the recessive vrn-A1 copies with alternative exon 4 were identified in hexaploid wheat. Finally for the first time, duplication of VRN-B1 was found in hexaploid wheat of T. compactum and T. spelta. These results expand our knowledge of the genetic diversity of VRN1 genes in wheat and provide additional strategies for the manipulation of flowering time in this strategic crop.


Primary Amine-Functionalized Mesoporous Phenolic Resin-Supported Palladium Nanoparticles as an Effective and Stable Catalyst for Water-Medium Suzuki-Miyaura Coupling Reactions.
Metal nanoparticles have been recognized and widely explored as unique catalysts for carbon-carbon coupling reactions. However, due to their extreme tendency to agglomeration, the generation and stabilization of metal nanoparticles in a porous matrix is an important research field. Herein, novel mesoporous phenolic resin-supported palladium nanoparticles (Pd@NH2-MPRNs) were prepared via direct anionic exchange followed by gentle reduction by using primary amine-functionalized ordered mesoporous phenolic resin as the support. The obtained Pd@NH2-MPRN material still possessed large surface area and ordered two-dimensional hexagonal mesoporous structure. Meanwhile, uniform and well-dispersed palladium nanoparticles were formed in the mesoporous channels, which could be attributed to an efficient complexation and stabilization effect derived from the primary amine groups. As a result, it can promote Suzuki coupling of less activated aromatic bromides to various biaryls in water with high conversion and selectivity. This excellent performance was attributed to small particle sizes, ordered mesopores, and a hydrophobic pore surface, which resulted in the decreased diffusion limitation and the increased active site accessibility. It is noted that it is competitive with the best palladium catalysts known for water-medium Suzuki coupling reaction, and it can be reused at least seven times without significant reduction in the catalytic efficiency, showing a good recyclability. Therefore, this work provides a new potential platform for designing and fabricating robust ordered mesoporous-polymer-supported metal nanoparticles for various catalytic applications.


Microwave absorption enhancement of 2-dimensional CoZn/C@MoS2@PPy composites derived from metal-organic framework.
Metal-organic framework (MOF) materials have caused widespread concerns in the field of microwave absorption, due to the unique microstructure and electronic state. Herein, the CoZn/C@MoS2@polypyrrole (PPy) composites were prepared through MOF self-template method. The MoS2 sheets and PPy shell incorporated for optimizing impedance matching of two-dimensional (2D) CoZn/C composites. The introduction of MoS2 sheets and PPy shell endowed the composites with enhanced microwave absorption. The as-prepared CoZn/C@MoS2@PPy composites showed a minimum reflection loss (RL) of -49.18 dB with the thickness of 1.5 mm. In addition, the effective absorption bandwidth (EAB, RL values exceeding -10 dB) covered 4.56 GHz, which showed greater performances than CoZn/C composites under a lower thickness (<2 mm). This work not only provides a facile route for fabricating MOF-derived carbon-based composites as microwave absorbers, but also broadens the application of MOF materials.


Sex-specific responses to winter flooding, spring waterlogging and post-flooding recovery in Populus deltoides.
Winter flooding events are common in some rivers and streams due to dam constructions, and flooding and waterlogging inhibit the growth of trees in riparian zones. This study investigated sex-specific morphological, physiological and ultrastructural responses to various durations of winter flooding and spring waterlogging stresses, and post-flooding recovery characteristics in Populus deltoides. There were no significant differences in the morphological, ultrastructural and the majority of physiological traits in trees subjected to medium and severe winter flooding stresses, suggesting that males and females of P. deltoides were winter flooding tolerant, and insensitive to winter flooding duration. Males were more tolerant to winter flooding stress in terms of photosynthesis and chlorophyll fluorescence than females. Females displayed greater oxidative damage due to flooding stress than males. Males developed more efficient antioxidant enzymatic systems to control reactive oxygen species. Both sexes had similarly strong post-flooding recovery capabilities in terms of plant growth, and physiological and ultrastructural parameters. However, Males had better recovery capabilities in terms of pigment content. These results increase the understanding of poplars's adaptation to winter flooding stress. They also elucidate sex-specific differences in response to flooding stress during the dormant season, and during post-flooding recovery periods.


Inhibition of acetylcholinesterase accelerates axon terminal withdrawal at the developing rat neuromuscular junction.
In developing skeletal muscles, the rate at which superfluous innervation is lost from the endplates depends on the general level of neuromuscular activity. Whether it is activity of the presynaptic or postsynaptic structures (or both) that is critical is not well established. In this work, we transitorily inhibited the AChE of soleus muscle in postnatal rats, in order to increase postsynaptic activity, without directly altering activity of the nerve terminals. We then followed the time course of disappearance of axon terminals from the endplates of treated and normal muscles, using electron-microscope techniques. Three hours after inhibition of AChE, the muscle fibres exhibited local supercontracture and ultrastructural damage in the region of the endplate, consistent with local elevation of Ca2+ levels. At the same time, small electron-opaque vesicles, apparently of muscular origin, appeared in the synaptic cleft. The nerve terminals, however, were entirely normal in number and appearance. One day after treatment, endplates of esterase-inhibited muscles showed accelerated loss of nerve terminals, compared to endplates of normally developing muscles. No further loss of nerve terminals occurred, once AChE activity returned at the endplate. These results suggest that the rate at which superfluous nerve terminals retract from the developing neuromuscular junction is regulated by the level of activation of the muscle. It seems likely that activity of postsynaptic sites may similarly regulate changes in innervation patterns, in other developing or adapting neuro-neuronal or neuro-effector systems.


Use of an oral assessment tool to improve practice.
An oral assessment tool was developed alongside care plans in a neurosciences unit, including the rationale for interventions, to provide nurses with an evidence-based means of providing mouth care. Awareness and standards of mouth care improved as a result of introducing the tool and care plans.


Genome-wide association studies reveal the coordinated regulatory networks underlying photosynthesis and wood formation in Populus.
Photosynthesis and wood formation underlie the ability of trees to provide renewable resources and perform ecological functions; however, the genetic basis and regulatory pathways coordinating these two linked processes remain unclear. Here, we used a systems genetics strategy, integrating genome-wide association studies, transcriptomic analyses, and transgenic experiments, to investigate the genetic architecture of photosynthesis and wood properties among 435 unrelated individuals of Populus tomentosa, and unravel the coordinated regulatory networks resulting in two trait categories. We detected 222 significant single-nucleotide polymorphisms, annotated to 177 candidate genes, for 10 traits of photosynthesis and wood properties. Epistasis uncovered 74 epistatic interactions for phenotypes. Strikingly, we deciphered the coordinated regulation patterns of pleiotropic genes underlying phenotypic variations for two trait categories. Furthermore, expression quantitative trait nucleotide mapping and coexpression analysis were integrated to unravel the potential transcriptional regulatory networks of candidate genes coordinating photosynthesis and wood properties. Finally, heterologous expression of two pleiotropic genes, PtoMYB62 and PtoMYB80, in Arabidopsis thaliana demonstrated that they control regulatory networks balancing photosynthesis and stem secondary cell wall components, respectively. Our study provides insights into the regulatory mechanisms coordinating photosynthesis and wood formation in poplar, and should facilitate genetic breeding in trees via molecular design.


The pro-inflammatory action of tumour necrosis factor-α in non-alcoholic steatohepatitis is independent of the NSMAF gene product.
The role of tumour necrosis factor-α (TNF-α) in the development of non-alcoholic steatohepatitis remains unclear. We evaluated the role of TNF-α and NSMAF gene product factor associated with neutral sphingomyelinase activation, a protein adaptor of the TNF-α receptor-1, in a mouse model of non-alcoholic steatohepatitis. Mice deficient either for TNF-α or factor associated with neutral sphingomyelinase activation, as well as control animals, were fed a methionine and choline-deficient diet for 5 weeks. Liver histology, serum glucose, triglycerides, cholesterol and alanine aminotransferase levels were compared between groups. Weight loss, decrease of serum triglyceride and glucose levels and increase of alanine aminotransferase levels were attenuated in TNF(-/-) mice. Similarly, we found a significantly lower lobular inflammation in TNF(-/-) mice. Liver expression of transforming growth factor-β, peroxisome proliferator-activated receptor-γ(1, 2) and monocyte chemoattractant protein-1 was attenuated in TNF(-/-) mice. In addition, the phosphatidylcholine/phosphatidylethanolamine liver ratio decrease was less important in TNF(-/-) mice. The increase in hepatic sphingomyelin and ceramide levels was less pronounced in TNF(-/-) animals. Whereas TNF-α modulates the inflammatory process that underlies methionine and choline-deficient diet-induced non-alcoholic steatohepatitis, its effects are not mediated by factor associated with neutral sphingomyelinase activation. Whether changes in liver lipids, like phosphatidylcholine and ceramide, are causally involved in tumour necrosis factor-mediated liver inflammation remains an open issue.


Mucocele of the appendix: pseudomyxoma peritonei and intracytoplasmic canaliculus-like structures.
A case of pseudomyxoma peritonei associated with mucocele of the appendix is reported. To date there is no general agreement as to whether this entity (pseudomyxoma) should be categorized as a malignant lesion. The presence of intracellular canaliculus-like structures adds support to those investigators who believe that pseudomyxoma peritonei reflects a form of malignant disease.


[Functions of the adrenal cortex in patients with supratentorial brain tumors and their prognostic value for surgical intervention].
The functional activity of the adrenal cortex was studied pre- and postoperatively in patients with pituitary adenomas, craiopharyngiomas and supratentorial meningiomas. With the hypothalamus function preserved, the patients developed varying degrees of stress-responses in the postoperative period. Severe morphological injuries to the hypothalamus make the normal response to surgical trauma impossible. With some functional centers preserved, the diencephalo-catabolic syndrome develops. Severe injuries of the diencephalon, with its adaptative function completely lost, result in the development of the diencephalic areactive syndrome.


Archaea: The Final Frontier of Chromatin.
The three domains of life employ various strategies to organize their genomes. Archaea utilize features similar to those found in both eukaryotic and bacterial chromatin to organize their DNA. In this review, we discuss the current state of research regarding the structure-function relationships of several archaeal chromatin proteins (histones, Alba, Cren7, and Sul7d). We address individual structures as well as inferred models for higher-order chromatin formation. Each protein introduces a unique phenotype to chromatin organization, and these structures are put into the context of in vivo and in vitro data. We close by discussing the present gaps in knowledge that are preventing further studies of the organization of archaeal chromatin, on both the organismal and domain level.


Early functional rehabilitation compared with traditional immobilization for acute Achilles tendon ruptures : a meta-analysis.
The aim of this meta-analysis was to assess the prognosis after early functional rehabilitation or traditional immobilization in patients who underwent operative or nonoperative treatment for rupture of the Achilles tendon. PubMed, Embase, Web of Science, and Cochrane Library were searched for randomized controlled trials (RCTs) from their inception to 3 June 2020, using keywords related to rupture of the Achilles tendon and rehabilitation. Data extraction was undertaken by independent reviewers and subgroup analyses were performed based on the form of treatment. Risk ratios (RRs) and weighted mean differences (WMDs) (with 95% confidence intervals (CIs)) were used as summary association measures. We included 19 trials with a total of 1,758 patients. There was no difference between the re-rupture rate (RR 0.84 (95% CI 0.56 to 1.28); p = 0.423), time to return to work (WMD -1.29 (95% CI -2.63 to 0.05); p = 0.060), and sporting activity (WMD -1.50 (95% CI -4.36 to 1.37); p = 0.306) between the early functional rehabilitation and the traditional immobilization treatment strategies. Early rehabilitation up to 12 weeks yielded significantly better Achilles tendon Total Rupture Scores ((ATRS) WMD 5.11 (95% CI 2.10 to 8.12); p < 0.001). Patients who underwent functional rehabilitation had significantly lower limb symmetry index of heel-rise work ((HRW) WMD -4.19 (95% CI -8.20 to 0.17); p = 0.041) at one year. Early functional rehabilitation is safe and provides better early function and the same functional outcome in the longer term. Cite this article: Bone Joint J 2021;103-B(6):1021-1030.


Success of mental health referral among pregnant and postpartum women with psychiatric distress.
This study measured rates of and determined factors associated with mental health service use among a cohort of 465 pregnant and postpartum women receiving care from publicly funded obstetric clinics. Women underwent a diagnostic evaluation, were provided with at least one mental health referral and were encouraged to seek treatment; follow-up with provision of additional referrals occurred at 1, 3 and 6 months after the initial assessment. Logistic regression was used to estimate the relationship between clinical and psychosocial factors and self-reported mental health service use. Of the referred women, 38.1% attended at least one mental health visit, while only 6% remained in treatment during the entire 6-month follow-up interval. Postpartum women were more likely than pregnant women to attend a mental health treatment visit [odds ratio (OR)=4.17]. Being born in the United States (OR=2.06), being exposed to interpersonal violence (OR=2.52) and being unemployed (OR=2.69) were associated with attending at least one mental health-care visit. Women who received a behavioral health referral to the same site as their prenatal or postpartum care were more likely than those referred offsite to attend a mental health treatment visit (OR=3.23). Despite active follow-up, rates of accessing and particularly continuing in mental health treatment were low. More work is needed to support the integration of specialty behavioral health services in primary care settings accessed by perinatal women.


Two-Stage sampling designs for gene association studies.
We consider two-stage case-control designs for testing associations between single nucleotide polymorphisms (SNPs) and disease, in which a subsample of subjects is used to select a panel of "tagging" SNPs that will be considered in the main study. We propose a pseudolikelihood [Pepe and Flemming, 1991: JASA 86:108-113] that combines the information from both the main study and the substudy to test the association with any polymorphism in the original set. SNP-tagging [Chapman et al., 2003: Hum Hered 56:18-31] and haplotype-tagging [Stram et al., 2003a; Hum Hered 55:27-36] approaches are compared. We show that the cost-efficiency of such a design for estimating the relative risk associated with the causal polymorphism can be considerably better than for a single-stage design, even if the causal polymorphism is not included in the tag-SNP set. We also consider the optimal selection of cases and controls in such designs and the relative efficiency for estimating the location of a causal variant in linkage disequilibrium mapping. Nevertheless, as the cost of high-volume genotyping plummets and haplotype tagging information from the International HapMap project [Gibbs et al., 2003; Nature 426:789-796] rapidly accumulates in public databases, such two-stage designs may soon become unnecessary.


Insights into structure-activity relationship of GABAA receptor modulating coumarins and furanocoumarins.
The coumarins imperatorin and osthole are known to exert anticonvulsant activity. We have therefore analyzed the modulation of GABA-induced chloride currents (I(GABA)) by a selection of 18 coumarin derivatives on recombinant α(1)β(2)γ(2S) GABA(A) receptors expressed in Xenopus laevis oocytes by means of the two-microelectrode voltage clamp technique. Osthole (EC(50)=14 ± 1 μM) and oxypeucedanin (EC(50)=25 ± 8 μM) displayed the highest efficiency with I(GABA) potentiation of 116 ± 4 % and 547 ± 56 %, respectively. I(GABA) enhancement by osthole and oxypeucedanin was not inhibited by flumazenil (1 μM) indicating an interaction with a binding site distinct from the benzodiazepine binding site. In general, prenyl residues are essential for the positive modulatory activity, while longer side chains or bulkier residues (e.g. geranyl residues) diminish I(GABA) modulation. Generation of a binary classification tree revealed the importance of polarisability, which is sufficient to distinguish actives from inactives. A 4-point pharmacophore model based on oxypeucedanin - comprising three hydrophobic and one aromatic feature - identified 6 out of 7 actives as hits. In summary, (oxy-)prenylated coumarin derivatives from natural origin represent new GABA(A) receptor modulators.


The influence of orthognathic surgery on the perception of personality traits: A scoping review.
The purpose of this scoping review was to determine the current state of evidence regarding the influence of orthognathic surgery on the perception of personality traits in dysmorphic patients by laypersons. The MEDLINE database was searched for relevant studies using the search strategy: ("Personality"[Mesh]) AND ("Orthognathic Surgery"[Mesh] OR "Orthognathic Surgical Procedures"[Mesh]). A qualitative and quantitative synthesis of the results was performed. Descriptive statistics were used. The PRISMA-ScR guidelines were followed. Five studies, published between 2012 and 2018, remained after screening. Seventy-two dysmorphic patients and 12 class I control individuals were rated based on a total of 296 pre- and postoperative photographs or videos. The available data showed concordant results. Dysgnathic patients were more negatively perceived than class I patients for both aesthetic and personality dimensions. Compared to control class I patients, class II patients were perceived as more flexible, less confident, and less intelligent, whereas class III patients were characterized by dominance, aggressivity, and brutality. Dysgnathic patients showed an improvement in the postoperative ratings but did not reach the ratings attributed to the control class I group in most traits evaluated. This added understanding should help surgeons to counsel their patients in a realistic and reasonable manner.


Effects of water characteristics on nitrate reduction by the Fe0/CO2 process.
In this study, CO2 was bubbled into Fe0-contained solution to create an acidic environment favorable to reduction of aqueous nitrate under various water qualities. Results showed that nitrate of 30 mg l(-1) could be removed from solutions almost completely within 30 min under the conditions of 2 g Fe0 l(-1) and CO2 bubbling flow rate of 200 ml min(-1). It was observed from the Fe0/CO2 system that one mole of nitrate reduced by Fe0 led to the formation of 6.6 mol of ferrous ions. The removal of nitrate increases with increasing Fe0 dosage, however, the removal makes no difference as the Fe0 is applied at a relatively higher dosage. In the system with various water qualities, nitrate removal was inhibited significantly in the presence of humic acid. Calcium ions strongly retard nitrate removal, whereas chloride ions promote the reduction of nitrate in a significant way. Sodium ions impose only slight inhibitive effect on nitrate removal. Water molecule in the studied system can be of significance due to its competitive capability of electrons released from Fe0.


A Printer Indexing System for Color Calibration with Applications in Dietary Assessment.
In image based dietary assessment, color is a very important feature in food identification. One issue with using color in image analysis in the calibration of the color imaging capture system. In this paper we propose an indexing system for color camera calibration using printed color checkerboards also known as fiducial markers (FMs). To use the FM for color calibration one must know which printer was used to print the FM so that the correct color calibration matrix can be used for calibration. We have designed a printer indexing scheme that allows one to determine which printer was used to print the FM based on a unique arrangement of color squares and binarized marks (used for error control) printed on the FM. Using normalized cross correlation and pattern detection, the index corresponding to the printer for a particular FM can be determined. Our experimental results show this scheme is robust against most types of lighting conditions.


Addressing economic and health challenges of COVID-19 in Bangladesh: Preparation and response.
This article mainly explores the economic and health challenges faced by Bangladesh amid COVID-19 and the policies taken by the government of Bangladesh to tackle the economic and health issues. Bangladesh is ranked as one of the worst-hit countries in terms of total corona infections. Affecting the social, economic, and health sectors of the country, COVID-19 pandemic has dampened the overall economic well-being and thus GDP growth along with skyrocketing poverty, inequality, and unemployment nationwide. To tackle these crises, the government has initiated effective policy measures which, in turn, enhanced the recovery rate of COVID-19 positive patients and strengthened the recovery of economic indicators. Therefore, this article suggests other hard-hit COVID-19 affected countries following the recovery model of Bangladesh to encounter the economic and health challenges due to the coronavirus pandemic.


A new approach to enantiopure C3-symmetric molecules.
Chiral base chemistry has been used to create three chiral centres in one pot on a C3-symmetric substrate. The potential of this new approach to C3-symmetric molecules is exemplified by the creation of an enantiopure C3v-symmetric triol, triphosphane and tripyridine. A ruthenium complex of the last compound has been studied by X-ray crystallography.


Racial/ethnic and sex differences in the association between light at night and actigraphy-measured sleep duration in adults: NHANES 2011-2014.
Historically minoritized individuals experience greater exposure to light at night, yet it is unclear whether the association between light at night and sleep duration vary by race/ethnicity or sex. We examined the association between light at night and sleep duration by race/ethnicity and sex. Participants (N = 6089, mean age=49.5, 52% women, 13% Asian, 27% Black, 14% Mexican, 46% White) in the 2011-2014 National Health and Nutrition Examination Survey underwent 9-day of actigraphy. Light at night was defined as light exposure within the 5-hour activity nadir (L5). Sleep duration within a 24-hour period was analyzed as short (<7 hours) or long (>9 hours) compared to recommended (≥7 and <9 hours). Poisson models were fit to estimate the association between light at night and sleep duration after adjustment for covariates. Light at night was most common among Black participants, who also had the shortest sleep duration. Overall, light at night was associated with 80% higher prevalence of short sleep duration [1.80 (1.49, 2.18)]. Compared to no-light at night, low and high light at night were associated with higher prevalence of short sleep duration, [1.61 (1.31, 1.98) and 2.01 (1.66, 2.44), respectively]. Associations varied by race/ethnicity and sex. Light at night was associated with shorter sleep duration in Black, Mexican and White females and Mexican and White males only. Black males exposed to light at night vs. no-light at night had lower prevalence of long sleep duration. There were no associations between light at night and sleep duration among Asian participants. Light at night was associated with shorter sleep duration, particularly among females. Targeting light exposure may help to improve sleep duration.


Orthognathic surgery and orthodontics associated with orofacial harmonization: Case report.
Orthognathic surgery aims to restore the functional and esthetic standards of the face and non-surgical or minimally invasive procedures have been optimizing the results of facial orthosurgical treatments. This case report aimed to show the use of minimally invasive techniques that, associated with orthognathic surgery, represent a trend in current oral and maxillofacial rehabilitation. A female patient, 28 years old, white, sought care from the Dentistry team of the São Vicente de Paulo Hospital, in Passo Fundo, Brazil, complaining of mandibular prognathism, anteroposterior maxillary deficiency, dental crowding, malocclusion, functional and esthetic changes that negatively affected her psychosocial interactions and stomatognathic function. The treatment involved orthodontics, orthognathic surgery, and orofacial harmonization with dermal fillers. The multidisciplinarity among the specialties of Oral and Maxillofacial Surgery and Traumatology, Orthodontics, and Orofacial Harmonization add and contribute to the process of planning and implementing the treatment proposed, as well as the prognosis toward patient satisfaction. The surgical procedure associated with minimally invasive facial harmonization not only corrected the functional complaint of the patient but also played an important role in improving facial harmony, contributing significantly to self-esteem.


The human alpha-type proteasomal subunit HsC8 forms a double ringlike structure, but does not assemble into proteasome-like particles with the beta-type subunits HsDelta or HsBPROS26.
The eukaryotic proteasome is a barrel-shaped protease complex made up of four seven-membered rings of which the outer and inner rings may contain up to seven different alpha- and beta-type subunits, respectively. The assembly of the eukaryotic proteasome is not well understood. We cloned the cDNA for HsC8, which is one of the seven known human alpha-type subunits, and produced the protein in Escherichia coli. Recombinant HsC8 protein forms a complex of about 540 kDa consisting of double ringlike structures, each ring containing seven subunits. Such a structure has not earlier been reported for any eukaryotic proteasome subunit, but is similar to the complex formed by the recombinant alpha-subunit of the archaebacterium Thermoplasma acidophilum (Zwickl, P., Kleinz, J., and Baumeister, W. (1994) Nat. Struct. Biol. 1, 765-770). The ability of HsC8 to form alpha-rings suggests that these complexes may play an important role in the initiation of proteasome assembly in eukaryotes. To test this, we used two human beta-type subunits, HsBPROS26 and HsDelta. Both these beta-type subunits, either in the proprotein or in the mature form, exist in monomers up to tetramers. In contrast to the alpha- and beta-subunit of T. acidophilum, coexpression of the human beta-type subunits with HsC8 does not result in the formation of proteasome-like particles, which would be in agreement with the notion that proteasome assembly in eukaryotes is much more complex than in archaebacteria.


Clinical patterns and outcome of early-onset inflammatory bowel disease.
We sought to determine whether extremely-early-onset childhood inflammatory bowel disease (age <6 years; 20 ulcerative colitis [UC], 8 Crohn disease [CD], 2 indeterminate, sequentially diagnosed) was clinically more severe than in older children (6-17 years; 19 UC, 39 CD, 2 indeterminate). Early-onset UC was marked by less abdominal pain at presentation, but an aggressive course with a significant reduction in weight-for-age, increased use of immunosuppressants, and more surgery. Children with early-onset CD were more likely to have bloody stools at presentation and an isolated colitis. This study supports the suggestion that inflammatory bowel disease phenotype differs in early-onset disease.


Leucocyte classification for leukaemia detection using image processing techniques.
The counting and classification of blood cells allow for the evaluation and diagnosis of a vast number of diseases. The analysis of white blood cells (WBCs) allows for the detection of acute lymphoblastic leukaemia (ALL), a blood cancer that can be fatal if left untreated. Currently, the morphological analysis of blood cells is performed manually by skilled operators. However, this method has numerous drawbacks, such as slow analysis, non-standard accuracy, and dependences on the operator's skill. Few examples of automated systems that can analyse and classify blood cells have been reported in the literature, and most of these systems are only partially developed. This paper presents a complete and fully automated method for WBC identification and classification using microscopic images. In contrast to other approaches that identify the nuclei first, which are more prominent than other components, the proposed approach isolates the whole leucocyte and then separates the nucleus and cytoplasm. This approach is necessary to analyse each cell component in detail. From each cell component, different features, such as shape, colour and texture, are extracted using a new approach for background pixel removal. This feature set was used to train different classification models in order to determine which one is most suitable for the detection of leukaemia. Using our method, 245 of 267 total leucocytes were properly identified (92% accuracy) from 33 images taken with the same camera and under the same lighting conditions. Performing this evaluation using different classification models allowed us to establish that the support vector machine with a Gaussian radial basis kernel is the most suitable model for the identification of ALL, with an accuracy of 93% and a sensitivity of 98%. Furthermore, we evaluated the goodness of our new feature set, which displayed better performance with each evaluated classification model. The proposed method permits the analysis of blood cells automatically via image processing techniques, and it represents a medical tool to avoid the numerous drawbacks associated with manual observation. This process could also be used for counting, as it provides excellent performance and allows for early diagnostic suspicion, which can then be confirmed by a haematologist through specialised techniques.


Immunohistochemical localization of interleukin-6 in peripheral human endocrine glands.
Interleukin-6 (IL-6) is a pleiotropic cytokine with differentiation and growth-promoting effects. Extensive studies in experimental animals denote that IL-6 is produced in various endocrine organs and participates in the local control of endocrine cell function. The expression of this cytokine in human endocrine glands, however, has only been examined in a limited number of studies. We investigated the immunohistochemical expression and localization of IL-6 in a variety of peripheral human endocrine glands. In the adrenals, IL-6 immunoreactivity was detected in all three zones of the cortex. The reticularis and glomerulosa zones were more heavily stained as compared with the slight immunoreactivity of the fasciculata zone. In the adrenal medulla, chromaffin and sustentacular cells were variably positive. A substantial number of follicular thyroid cells were strongly immunoreactive for IL-6 in all normal and hyperplastic thyroids examined. Parafollicular cells were negative. Parathyroid chief cells were mildly positive; selective and more intense staining was observed in acidophilic cells. Pancreatic islet cells were variably positive. In the testis positive staining was selectively observed in both Leydig and Sertoli cells. In conclusion, IL-6 immunoreactivity is present in almost all the human endocrine glands and it expressed in a cell-specific manner. These observations provide further support for the existence of local immune-endocrine interactions.


The circadian demethylation of a unique intronic deoxymethylCpG-rich island boosts the transcription of its cognate circadian clock output gene.
We demonstrate that there is a tight functional relationship between two highly evolutionary conserved cell processes, i.e., the circadian clock (CC) and the circadian DNA demethylation-methylation of cognate deoxyCpG-rich islands. We have discovered that every circadian clock-controlled output gene (CCG), but not the core clock nor its immediate-output genes, contains a single cognate intronic deoxyCpG-rich island, the demethylation-methylation of which is controlled by the CC. During the transcriptional activation period, these intronic islands are demethylated and, upon dimerization of two YY1 protein binding sites located upstream to the transcriptional enhancer and downstream from the deoxyCpG-rich island, store activating components initially assembled on a cognate active enhancer (a RORE, a D-box or an E-box), in keeping with the generation of a transcriptionally active condensate that boosts the initiation of transcription of their cognate pre-mRNAs. We report how these single intronic deoxyCpG-rich islands are instrumental in such a circadian activation/repression transcriptional process.


Evidence-Based Assessment of Child Obsessive Compulsive Disorder: Recommendations for Clinical Practice and Treatment Research.
Obsessive-compulsive disorder (OCD) presents heterogeneously and can be difficult to assess in youth. This review focuses on research-supported assessment approaches for OCD in childhood. Content areas include pre-visit screening, diagnostic establishment, differential diagnosis, assessment of comorbid psychiatric conditions, tracking symptom severity, determining psychosocial functioning, and evaluating clinical improvement. Throughout this review, similarities and differences between assessment approaches geared towards clinical and research settings are discussed.


The association between oxidative balance score and lung function: A nationwide cross-sectional survey.
Given the impact of oxidative imbalance on the development of airway pathologies, this study was undertaken to investigate the association between oxidative balance (OB) scores and lung function in the adult Korean population. Data of 17,368 adults with available OB scores and pulmonary function test results were extracted from the 2013-2019 Korean National Health and Nutrition Examination Surveys. Multivariable logistic regression models were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for reduced forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) per 1-point decrease in OB score. Dose dependent association of reduced lung function with OB scores was also investigated. Males, low-income subjects, individuals with comorbidities, and those with reduced pulmonary function had lower OB scores (representing oxidative balance). Overall, the association between oxidative imbalance and reduced lung function was remarkable in FVC than FEV1 (OR [95% CI], 1.06 [1.04-1.07] vs. 1.03 [1.02-1.04]; both p < 0.001). Linear relationships between the level of reduced lung function and OB scores were significantly noted (p for trend<0.001 in both FEV1 and FVC). Our findings suggest that oxidative imbalance is associated with reduced pulmonary function.


Prevailing oxic environments in the Pacific Ocean during the mid-Cretaceous Oceanic anoxic event 2.
The occurrence of Oceanic Anoxic Event 2 (OAE2) 94 million years ago is considered to be one of the largest carbon cycle perturbations in the Earth's history. The marked increase in the spatial extent of the anoxic conditions in the world's oceans associated with OAE2 resulted in the mass accumulation of organic-rich sediments. Although extensive oceanographic studies of OAE2 have been undertaken in the Atlantic Ocean, the Tethys Sea, and the epicontinental seas of Europe and America, little is known about OAE2 in the Pacific Ocean. Here, we present high-resolution carbon-isotope and degree of pyritization (DOP) data from marine sequences that formed along the continental margins of North America and Asia below the northeastern and northwestern Pacific Ocean. The predominance of low DOP values in these areas revealed that the continental margins of the Pacific Ocean were oxic for most of the OAE2 interval.


Effects of food and ethnicity on the pharmacokinetics of venadaparib, a next-generation PARP inhibitor, in healthy Korean, Caucasian, and Chinese male subjects.
Venadaparib is a next-generation poly(ADP-ribose) polymerase inhibitor under development for treating gastric cancer. This study aimed to evaluate the effects of food and ethnicity on the pharmacokinetics (PKs) and safety of venadaparib after a single oral administration in healthy Korean, Caucasian, and Chinese male subjects. In this randomized, open-label, single-dose, two-sequence, two-period, and crossover study, Korean and Caucasian subjects received venadaparib 80 mg in each period (fasted or fed state) with a seven-day washout. In an open-label, single-dose study, Chinese subjects received venadaparib 80 mg only in the fasted state. Serial blood samples were collected up to 72 h post-dosing. Twelve subjects from each ethnic group completed the study. The geometric mean ratios (90% confidence intervals) of the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the last measurable time point (AUClast) of venadaparib for the fed to fasted state were 0.82 (0.7457-0.9094) and 1.02 (0.9088-1.1339) in Koreans, and 0.77 (0.6871-0.8609) and 0.96 (0.9017-1.0186) in Caucasians, respectively. No statistically significant differences were observed in Cmax (P-value = 0.45) or AUClast (P-value = 0.30) among the three ethnic groups. A single venadaparib dose was well-tolerated. The overall systemic exposure of venadaparib was not affected by the high-fat meal, despite delayed absorption with a decreased Cmax in the fed state. The PK profiles were comparable among the Korean, Caucasian, and Chinese subjects. A single venadaparib 80 mg dose was safe and well-tolerated in both fasted and fed states.


Priorities for mixtures health effects research.
In order to better inform scientific decision making in the occupational environment, we need a better understanding of the toxicology of mixed exposures. In particular, we need an understanding of the dose-response relationship from the level of individual or population exposure down to the molecular level (and then back up again from the molecular level to the specific health-related response of the organism as a whole). Mixtures toxicology is proving to be different from single-chemical toxicology in several fundamental but barely recognized ways: Knowledge gained in mixtures research should be able to improve current risk assessment and mitigation or intervention methods. In NIOSH's National Occupational Research Agenda (NORA) three priority areas have been identified:


Relationship between the structure and microcirculation of the optic disc region and myopic traction maculopathy in highly myopic eyes.
To explore the characteristics and influencing factors structural and microcirculatory of optic disc and peripapillary tissue in eyes with myopia traction maculopathy (MTM). There were 100 eyes from 77 patients in this study. We used 1:1 matching axial length in myopic eyes. Patients were divided into two groups according to the presence or absence of MTM. Fundus structure parameters were obtained by swept source optical coherence tomography (SS-OCT), and the optic disc microcirculation parameters were obtained by OCT angiography (OCTA). MTM group were older (P = 0.001) and had poorer Best-corrected Visual Acuity (BCVA) (P = 0.011), the optic disc-fovea distance (DFD) was longer (P < 0.019), optic disc tilt was greater (P < 0.001), area of peripapillary atrophy (PPA) was larger (P < 0.001), and PPA/optical disc area (ONH) was higher (P < 0.001). The peripapillary scleral thickness (PST) was lower in the MTM group (P < 0.001). The mean peripapillary choroidal thickness (PCT) (P < 0.001) and PCT in the 10 orientations were significantly lower in the MTM group than in the NMTM group (all P < 0.01). Vascular density in the nasosuperior (NS) region of the optic disc was significantly lower in the MTM group (P = 0.037). The generalized estimating equation suggested that PPA area (P = 0.028), mean PCT (P = 0.008), superior PCT (P = 0.027), inferonasal PCT (P = 0.040), temporoinferior PCT (P = 0.013), and PST (P = 0.046) correlated with MTM. Age, axial length, optic disc tilt, PPA area, mean PCT, and optic disc central zone (0-2 mm) vascular density (all P < 0.05) were significantly correlated with PST. The enlarged PPA area and thinner PCT and PST in eyes with MTM are more significant. Lower PST in high myopia was related to abnormalities of PCT and microcirculation. Clinical Trial Registration number: ChiCTR2100046590.


Developmental GABAergic deficit enhances methamphetamine-induced apoptosis.
Neuroanatomical evidence suggests that GABAergic deficits and progressive cortical atrophy occur with schizophrenia. To evaluate the hypothesis that neurodevelopmental deficits affect neurodegeneration occurring with schizophrenia, this study examined a novel animal model for schizophrenia-related neurodevelopmental GABAergic deficit in neurodegenerative progression. The prenatal N-methyl-D-aspartate (NMDA) receptor hypofunction model that induces neurodevelopmental GABAergic deficit in the medial prefrontal cortex (mPFC) was used to examine whether adult offspring of Sprague-Dawley rats exhibited disruption of prepulse inhibition (PPI), enhancement of methamphetamine (METH) (2.5 mg/kg)-induced glutamate release in the mPFC and the emergence of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive neurons in this brain region. Offspring of dams exposed to NMDA receptor antagonist MK-801 on days 15-18 of pregnancy (MK-801 offspring) showed reduced density of parvalbumin-immunoreactive GABAergic interneurons in the mPFC, PPI disruption on postnatal days 63 (P63) and 35 (P35) and an enhanced METH (2.5 mg/kg)-induced glutamate release. Repeated administration of this psychostimulant increased the emergence of TUNEL-positive cells. These findings suggest that prenatal blockade of NMDA receptors induces a neurodevelopmental GABAergic deficit. The decrease in the density of GABAergic neurons might be related to disruption of sensorimotor gating (PPI), enhanced METH-induced release of glutamate in the mPFC and a repeated METH injection-induced increase in apoptosis in this region of the brain in adult animals.


Cigarette and cannabis use trajectories among adolescents in treatment for attention-deficit/hyperactivity disorder and substance use disorders.
Cigarette smoking is common in adolescents with attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUD). However, little is known about the relationship between cigarette and cannabis use trajectories in the context of treatment for both ADHD and SUD. To address this research gap, we report collateral analyses from a 16-week randomized, controlled trial (n=303) of osmotic-release methylphenidate (OROS-MPH) in adolescents with ADHD concurrently receiving cognitive behavioral therapy (CBT) targeting non-nicotine SUD. Participants completed cigarette and cannabis use self-report at baseline and throughout treatment. Analyses were performed to explore the relationships between cigarette smoking, cannabis use, and other factors, such as medication treatment assignment (OROS-MPH versus placebo). Baseline (pre-treatment) cigarette smoking was positively correlated with cannabis use. Negligible decline in cigarette smoking during treatment for non-nicotine SUD was observed in both medication groups. Regular cigarette and cannabis users at baseline who reduced their cannabis use by >50% also reduced cigarette smoking (from 10.8±1.1 to 6.2±1.1 cigarettes per day). Findings highlight the challenging nature of concurrent cannabis and cigarette use in adolescents with ADHD, but demonstrate that changes in use of these substances during treatment may occur in parallel.


The risks of major osteoporotic fractures in patients with schizophrenia: a population-based 10-year follow-up study.
The aim of the study is to explore the incidence and the risks associated with major osteoporotic fractures, all-cause mortality with osteoporotic fractures and the effect of the psychiatric drug exposure in patients with schizophrenia during a 10-year follow-up period. Two nationwide cohorts were selected from the Taiwan National Health Insurance Research Database (NHIRD) consisting of 30,335 patients with schizophrenia (age ≥ 40 years) and 121,340 age- and sex-matched control participants without schizophrenia. The psychiatric proportion of days covered (PDC) is an indicator of the intensity of drug exposure in patients with schizophrenia. The incidence and risk factors of major osteoporotic fractures were calculated for both cohorts. Additionally, the patient survival rate after major osteoporotic fractures was also calculated. During a 10-year follow-up period, 1677 (5.53%) schizophrenia and 4257 (3.51%) control subjects had major osteoporotic fractures (P < 0.001). The schizophrenia patients with a PDC > 0.1 showed a significantly higher incidence of major osteoporotic fractures than did the non-schizophrenia controls; however, those with a psychiatric PDC ≤ 0.1 did not. After adjustment, the psychiatric PDC was significantly and independently associated with the risk of major osteoporotic fractures except some medical morbidities but the schizophrenia diagnosis was not. In addition, among all 5934 patients with major osteoporotic fracture, the adjusted mortality hazard ratio for psychiatric PDC was 1.92 (95% CI = 1.63-2.26). Patients with schizophrenia are at a higher risk for major osteoporotic fractures than the general population and also have a higher mortality rate due to major osteoporotic fractures. These findings may be caused by psychiatric drug use rather than schizophrenia, which suggests that directions can be taken in future studies.


Evaluation and treatment of urinary incontinence. Report of a physician survey.
To determine practice patterns related to the evaluation and treatment of urinary incontinence (UI). Stratified random sample of physicians surveyed initially by mail with telephone follow-up. Four counties in Central Oklahoma. One hundred fifty-five physicians in 4 specialties: family practice, internal medicine, obstetrics/gynecology, and urology. Self-reported evaluation and treatment of UI and training in treatment of UI. The overall rate of response was 80%. Physicians miss opportunities to identify patients with UI. Despite substantial specialty variation, behavioral treatments and medications for UI, relative to the Agency for Health Care and Policy Research clinical guidelines, are underused. More than 40% of internists and family practitioners routinely recommended absorbent pads. Only 17% of physicians were aware of the clinical guidelines. Physicians identified deficiencies in their level of preparation to evaluate and treat UI. Reports of practice patterns also suggest deficiencies.


Cardiac transplantation.
Cardiac transplantation is a proven, accepted mode of therapy for selected patients with end-stage heart failure, but the inadequate number of suitable donor hearts available ultimately limits its application. This chapter reviews adult cardiac transplantation, with an emphasis on the anesthetic considerations of the heart transplant operation itself.


Zonally contrasting shifts of the tropical rainbelt in response to climate change.
Future changes in the position of the intertropical convergence zone (ITCZ; a narrow band of heavy precipitation in the tropics) with climate change could affect the livelihood and food security of billions of people. Although models predict a future narrowing of the ITCZ, uncertainties remain large regarding its future position, with most past work focusing on zonal-mean shifts. Here we use projections from 27 state-of-the-art (CMIP6) climate models and document a robust zonally-varying ITCZ response to the SSP3-7.0 scenario by 2100, with a northward shift over eastern Africa and the Indian Ocean, and a southward shift in the eastern Pacific and Atlantic Oceans. The zonally-varying response is consistent with changes in the divergent atmospheric energy transport, and sector-mean shifts of the energy flux equator. Our analysis provides insight about mechanisms influencing the future position of the tropical rainbelt, and may allow for more robust projections of climate change impacts.


NEAR-EARTH ASTEROID LIGHTCURVE ANALYSIS AT THE CENTER FOR SOLAR SYSTEM STUDIES: 2019 MARCH-JULY.
Lightcurves for 38 near-Earth asteroids (NEAs) obtained at the Center for Solar System Studies (CS3) from 2019 March-July were analyzed for rotation period, peak-to-peak amplitude, and signs of satellites or tumbling.


Oncology healthcare providers' implementation of the 5A's model of brief intervention for smoking cessation: patients' perceptions.
Health care providers (HCPs) can play an important role in promoting smoking cessation and preventing relapse. Public Health Service guidelines recommend the "5A's" model of brief intervention. The goal of the current study was to examine cancer patients' perceptions of 5A's model implementation by their oncology HCPs. This study included 81 thoracic and 87 head and neck cancer patients at a large NCI-designated comprehensive cancer center. Patients completed questionnaires assessing perceptions of their oncology HCPs' implementation of the 5A's model of brief intervention. Results indicate partial implementation of the 5A's model. The majority of patients reported that their providers had asked about smoking and advised them to quit, however; only half reported that their interest in quitting had been assessed, and few reported assistance in quitting or follow-up. Delivery of the 5A's was greater among patients who requested cessation advice from their HCPs. The current findings suggest a need to increase adherence to the 5A's in the oncology setting. Efforts to increase smoking cessation treatment provision by HCPs may improve the rate of cessation among cancer patients, and ultimately translate into better long-term cancer treatment outcomes.


MutationalPatterns: comprehensive genome-wide analysis of mutational processes.
Base substitution catalogues represent historical records of mutational processes that have been active in a cell. Such processes can be distinguished by various characteristics, like mutation type, sequence context, transcriptional and replicative strand bias, genomic distribution and association with (epi)-genomic features. We have created MutationalPatterns, an R/Bioconductor package that allows researchers to characterize a broad range of patterns in base substitution catalogues to dissect the underlying molecular mechanisms. Furthermore, it offers an efficient method to quantify the contribution of known mutational signatures within single samples. This analysis can be used to determine whether certain DNA repair mechanisms are perturbed and to further characterize the processes underlying known mutational signatures. MutationalPatterns allows for easy characterization and visualization of mutational patterns. These analyses willsupport fundamental research into mutational mechanisms and may ultimately improve cancer diagnosis and treatment strategies. MutationalPatterns is freely available at http://bioconductor.org/packages/MutationalPatterns .


Comparison of Th1 and Th2 cytokines production in ovine lymph nodes during early pregnancy.
As a fetal allograft to the mother, early conceptus regulates the intrauterine immune and systemic immune responses during early pregnancy in sheep. However, expression of T helper 1 (Th1) and Th2 cytokines in maternal lymph nodes is unclear during early pregnancy in sheep. In this study, inguinal lymph nodes were obtained on day 16 of the estrous cycle and on days 13, 16 and 25 of pregnancy (n = 4 for each group) in ewes, and qRT-PCR, western blot and immunohistochemistry were used to compare the expression of Th1 and Th2 cytokines in the lymph nodes. Our results showed that there were the highest levels of Th1 cytokines (IFN-γ, TNF-β and IL-2) and Th2 cytokines (IL-4, IL-5, IL-6 and IL-10) in the lymph nodes on day 13 or 16 of pregnancy. Furthermore, there were a downregulation of TNF-β and IL-2 and an upregulation of IL-5 and IL-10 on day 25 of pregnancy compared with that in nonpregnancy, with no significant difference in the expression of IFN-γ, IL-4, and IL-6 between the ewes on day 25 of pregnancy and nonpregnancy. The immunohistochemistry results showed that the IL-2 and IL-10 proteins were limited to the subcapsular sinus and trabeculae in the cortex, lymph sinus. In conclusion, early pregnancy exerted its effects on the lymph node and induced a Th2-biased response, which was essential for a normal pregnancy in sheep.


Direct evidence for (G)O6···H2-N4(C)+ hydrogen bonding in transient G(syn)-C+ and G(syn)-m5C+ Hoogsteen base pairs in duplex DNA from cytosine amino nitrogen off-resonance R1ρ relaxation dispersion measurements.
NMR relaxation dispersion studies have shown that Watson-Crick G-C and A-T base pairs in duplex DNA exist in dynamic equilibrium with their Hoogsteen counterparts. Hoogsteen base pairs form through concurrent rotation of the purine base about the glycosidic bond from an anti to a syn conformation and constriction of the C1'-C1' distance across the base pair by ∼2 Å to allow Hoogsteen type hydrogen bonding. Owing to their unique structure, Hoogsteen base pairs can play important roles in DNA recognition, the accommodation, recognition, and repair of DNA damage, and in DNA replication. NMR relaxation dispersion experiments targeting imino nitrogen and protonated base and sugar carbons have provided insights into many structural features of transient Hoogsteen base pairs, including one of two predicted hydrogen bonds involving (G)N7···H-N3(C)+ and (A)N7···H-N3(T). Here, through measurement of cytosine amino (N4) R1ρ relaxation dispersion, we provide direct evidence for the second (G)O6···H2-N4(C)+ hydrogen bond in G(syn)-C+ transient Hoogsteen base pairs. The utility of cytosine N4 R1ρ relaxation dispersion as a new sensitive probe of transient Hoogsteen base pairs, and cytosine dynamics in general, is further demonstrated by measuring G(syn)-C+ Hoogsteen exchange near neutral pH and in the context of the naturally occurring DNA modification 5-methyl cytosine (m5C), in DNA samples prepared using chemical synthesis and a 15N labeled m5C phosphoramidite.


Cutaneous microenvironment responsive microneedle patch for rapid gene release to treat subdermal tumor.
Transdermal gene therapy is a useful treatment for many skin lesions. By penetrating stratum corneum directly, microneedle patch (MNP) has been widely investigated to improve transdermal gene delivery. However, considering the operability and patience compliance, quick gene release was required after insertion. In this research, by utilizing acidic cutaneous environment, pH-responsive polyelectrolyte multilayers (PEM) were coated on the surface of polycaprolactone (PCL) microneedles by layer-by-layer assembly to realize rapid gene release. Dimethylmaleic anhydride-modified polylysine (PLL-DMA), a charge reversible polymer, was introduced to PEM. The PEM composed of two parts: the transition layers of (PLL-DMA/polyethyleneimine)12 and the gene-loaded layers of (p53 expression plasmid/polyethyleneimine)16. Microneedle patch modified with such PEM was marked as tr-MNP. In following experiment, Hoechst 33258 dyed model DNA was used to track modification process, fluorescent intensity of tr-MNP was obviously strengthened while the number of bilayers increased and the morphology could be maintained. Each tr-MNP could load 31μg model DNA and improve gene release. To prove this character, MNP without transition layers (ntr-MNP) was fabricated as control. Tr-MNP could release 33% of model DNA in simulative cutaneous environment (phosphate buffer saline; pH=5.5) while ntr-MNP could only release 4%. That was because PLL-DMA could achieve charge reversal in acidic cutaneous environment, leading to the collapse of transition layers and promoted the gene release. In vivo experiment showed tumor inhibit efficacy of tr-MNP treated mice could reach 90.1% while that of ntr-MNP treated mice and intravenous administration mice was only 46.4% and 30.5%. Overall, the pH-responsive gene loaded MNP could treat subcutaneous tumor efficiently and showed potential to be a platform to load many biomacromolecule.


Effects of Probiotics on Intermediate Cardiovascular Outcomes in Patients with Overweight or Obesity: A Systematic Review and Meta-Analysis.
Clinical trials evaluating the effect of probiotics on cardiovascular intermediate outcomes have been scarce in recent years. We systematically evaluated the efficacy of probiotics on intermediate cardiovascular outcomes in patients with overweight or obesity. We searched for randomized controlled trials (RCTs) in four databases (until August 2021) that evaluated the effects of probiotics versus controls on intermediate cardiovascular outcomes. The outcomes were body mass index (BMI), weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), glucose, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels. Inverse variance random effects meta-analyses were used. The effects were reported as mean difference (MD), with their 95% confidence intervals (95% CI). The quality of evidence (QoE) was assessed with GRADE (grading of recommendations, assessment, development and evaluations) methodology. A total of 25 RCTs were included (n = 2170), with a range of follow-up from two to six months. Probiotics likely reduced BMI (MD -0.27 kg/m2, 95%CI: -0.35 to -0.19; 17 RCTs; I2 = 26%, QoE: moderate), as well as likely reduced weight (MD -0.61 kg, 95%CI: -0.89 to -0.34; 15 RCTs; I2 = 0%, QoE: moderate), and may have slightly reduce LDL (MD -4.08 mg/dL; 95%CI: -6.99 to -1.17; 9 RCTs; I2 = 87%, QoE: low) in comparison to the controls. However, probiotics had no effect on SBP (MD -0.40 mmHg; 95%CI: -5.04 to 4.25; 7 RCTs; I2 = 100%, QoE: very low), DBP (MD -1.73 mmHg; 95%CI: -5.29 to 1.82; 5 RCTs; I2 = 98%, QoE: very low), glucose (MD -0.07 mg/dL; 95%CI -0.89 to 0.75; I2 = 96%, QoE: very low), HDL (MD -1.83 mg/dL; 95%CI: -4.14 to 2.47; 14 RCTs; I2 = 98%, QoE: very low), or triglycerides (MD -3.29 mg/dL, 95%CI -17.03 to 10.45; 14 RCTs, I2 = 95%, QoE: very low) compared to control arms, and the evidence was very uncertain. In obese or overweight patients, BMI, weight, and LDL were lower in patients who received probiotics compared to those who received controls. Other lipids, glucose, and blood pressure were not affected by the probiotics.


Short-chain fatty acid formation in the hindgut of rats fed oligosaccharides varying in monomeric composition, degree of polymerisation and solubility.
The contents of short-chain fatty acids were investigated in rats fed lactitol, lactulose and four fructo-oligosaccharides of different degree of polymerisation and solubility. Fructo-oligosaccharides with a low degree of polymerisation (2-8) generated the highest levels of butyric acid all along the hindgut, whereas fructo-oligosaccharides with a high degree of polymerisation (10-60) generated the highest levels of propionic acid. These specific differences were also generally reflected in the caecal pools and molar proportions of short-chain fatty acids. The lower solubility of the fructo-oligosaccharides was related to a lower degree of caecal fermentation. Lactulose and lactitol yielded high proportions of acetic acid and low proportions of butyric acid. It is concluded that both the degree of polymerisation and the solubility may affect short-chain fatty acid formation, whereas the fructose content per se seem to be of less importance. This may be of interest when designing foods with specific health effects.


Use of Sodium-Glucose Cotransporter-2 Inhibitors in Renal Transplant Patients With Diabetes: A Brief Review of the Current Literature.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of oral hypoglycemic agents commonly prescribed in type 2 diabetes (T2D). They have been shown to slow the progression of diabetic nephropathy and improve cardiovascular outcomes in high-risk individuals, although major cardiovascular and renal outcome clinical trials have excluded renal transplant patients. The aim of this review was to determine the outcomes and safety with use of SGLT2 inhibitors in renal transplant patients with diabetes. We conducted a review of randomized controlled trials, cohort studies, case series and case reports that assessed use of SGLT2 inhibitors in patients post-renal transplant with either pre-existing T2D or new-onset diabetes after transplant. The outcomes assessed included blood pressure, renal allograft function (estimated glomerular filtration rate), proteinuria (urinary albumin-to-creatinine ratio), glycemic control, body weight and adverse effects. A total of 9 studies, which included 144 patients, were reviewed. SGLT2 inhibitor use in renal transplant patients demonstrates either a small or nonsignificant reduction in blood pressure and results in overall stable renal allograft function. It also results in modest improvement in glycemic control as well as weight reduction. The incidence of adverse effects is low and reversible, as reported in previous nontransplant clinical trials. Overall, our findings suggest beneficial outcomes with no significant adverse effects or complications with the use of SGLT2 inhibitors in renal transplant patients with diabetes; however, these findings are based on small trials, and thus well-designed trials in this population are warranted.


Immunogenic dialyzable factor derived from a ribosomal fraction of Salmonella typhimurium. I. Preparation of the protective dialyzable factor from the ribosomal fraction by the freeze-thaw procedure.
The preparation, properties, and immunogenicity of the dialyzable factor from a ribosomal fraction of Salmonella typhimurium are described. The ribosomal fraction was purified to eliminate O-antigenic components, by affinity chromatography (Sepharose-anti-O antibody conjugates used as immunoadsorbent). The dialyzable factor was obtained in the concentrated dialysate of the purified ribosomal fraction which was alternately frozen in dry-ice acetone and thawed in an 80 C water bath, for a total of five or six cycles. When this preparation was tested for its ability to protect mice against challenge with 1,000 LD50 of the homologous bacteria, it afforded 100% protection at a dose equivalent to 5.0 micrograms of RNA. The protection conferred by this factor was mainly cell mediated but immune serum enhanced this immunity despite the fact that no antibodies were detected in it. The protective activity of this factor was sensitive to RNase digestion but resistant to proteolytic enzymes. Ion exchange chromatography of this factor with DEAE-Sephadex A-25 (in 7 M Urea-0.02 M Tris-HCl buffer, pH 7.5) resulted in a single A260 peak which was found to be immunogenic. Chemical analysis of this peak after it was concentrated and desalted revealed that this immunogenic fraction was composed mainly of mixed nucleotides. The data indicate that protective immunity conferred by a ribosomal vaccine is associated with RNA but may not require the intact RNA molecule.


Clinical presentation and results of thrombolytic therapy in older patients with massive pulmonary embolism: a comparison with non-elderly patients.
To assess the clinical presentation and effectiveness of thrombolytic therapy in older patients suffering from massive pulmonary embolism. Analysis of a previously reported study of patients with massive pulmonary embolism using a dichotomous classification of age. A medical intensive care unit in one hospital center. All subjects had massive pulmonary embolism as evidenced by scintigraphic and/or angiographic assessment. The 54 patients included in this study were divided into two groups according to age: 28 patients were less than 75 years old and 26 patients were 75 years old or older. All patients received a bolus regimen of single-chain recombinant tissue-type plasminogen and were subsequently treated by heparin and warfarin. Clinical symptoms at admission, resolution of scintigraphic vascular obstruction, death rate, hemorrhagic complications, recurrent pulmonary embolism, and long-term follow-up were compared between both groups. Clinical symptoms at admission were similar in both groups. The mean absolute improvement in the lung scan perfusion defect, the rate of major bleeding, and the long-term evolution were not statistically different between older and younger patients. Clinical symptoms, including hemodynamic condition, did not differ between elderly and nonelderly patients suffering from massive pulmonary embolism. Old age should not preclude thrombolytic therapy in massive pulmonary embolism, provided there is no other contraindication for thrombolytic treatment.


Efficacy and safety of alirocumab, a fully human PCSK9 monoclonal antibody, in high cardiovascular risk patients with poorly controlled hypercholesterolemia on maximally tolerated doses of statins: rationale and design of the ODYSSEY COMBO I and II trials.
Alirocumab is a fully human monoclonal antibody to proprotein convertase subtilisin kexin type 9 (PCSK9) under investigation for treatment of hypercholesterolemia and reduction of cardiovascular events. The COMBO studies, part of the Phase 3 ODYSSEY clinical trial program, are designed to evaluate the efficacy and safety of alirocumab as add-on therapy to stable, maximally tolerated daily statin, with or without other lipid-lowering therapy (LLT), in a planned 966 patients with hypercholesterolemia at high cardiovascular risk. COMBO I ( http://clinicaltrials.gov/show/NCT01644175) is placebo-controlled, with a double-blind treatment period of 52 weeks, and 306 planned patients who may receive other LLTs in addition to statin therapy. COMBO II ( http://clinicaltrials.gov/show/NCT01644188) has a double-blind treatment period of 104 weeks, comparing alirocumab with ezetimibe in 660 planned patients receiving statin therapy (but no other LLTs). The primary efficacy endpoint is the difference between treatment arms in percent change in low-density lipoprotein cholesterol (LDL-C) from baseline to week 24. Both studies utilized a starting dose of alirocumab 75 mg every 2 weeks (Q2W; administered as 1 mL solution via auto-injector). Patients with LDL-C levels ≥70 mg/dL after 8 weeks of treatment were up-titrated in a blinded manner at week 12 to alirocumab 150 mg Q2W (also 1 mL auto-injector). In conclusion, the COMBO studies will provide information on the long-term efficacy and safety of alirocumab in high-risk patients when administered in addition to maximally tolerated statin therapy, with a flexible dosing strategy which allows for individualized therapy based on the degree of LDL-C lowering needed to achieve the desired treatment response. NCT01644175 ( NCT01644175). NCT01644188 ( NCT01644188).


Biguanides: Species with versatile therapeutic applications.
Biguanides are compounds in which two guanidine moieties are fused to form a highly conjugated system. Biguanides are highly basic and hence they are available as salts mostly hydrochloride salts, these cationic species have been found to exhibit many therapeutic properties. This review covers the research and development carried out on biguanides and accounts the various therapeutic applications of drugs containing biguanide group-such as antimalarial, antidiabetic, antiviral, anticancer, antibacterial, antifungal, anti-tubercular, antifilarial, anti-HIV, as well as other biological activities. The aim of this review is to compile all the medicinal chemistry applications of this class of compounds so as to pave way for the accelerated efforts in finding the drug action mechanisms associated with this class of compounds. Importance has been given to the organic chemistry of these biguanide derivatives also.


Cytokeratin 17 as an immunohistochemical marker for intramural cytotrophoblast in human first trimester uteroplacental arteries.
Trophoblast cells, as blastocyst-wall derivatives, are of epithelial origin and differentiate initially into syncytiotrophoblast and cytotrophoblast subpopulations. Cyto- and syncytiotrophoblasts are the two cell types present in the surface cell layers of placental villi. Cytotrophoblastic cells lie in contact with the basal lamina and are the proliferating stem cells that guarantee cytotrophoblast and syncytiotrophoblast persistence. Implantation and placenta formation are mainly based on these two cell types. Villous cytotrophoblasts are the stem cells for all extravillous trophoblast subpopulations, which exhibit strictly regulated invasiveness. One aspect of extravillous trophoblasts is that they invade maternal endometrial spiral arteries and dilate them in order to achieve sufficient fetal blood supply. During this process, trophoblast cells, which are located in the remodelled uteroplacental artery walls, are thus defined as intramural cytotrophoblasts. Trophoblast differentiation is accompanied and defined by alterations in, for example, the translation pattern for cytokeratin genes. In an immunohistochemical study, we have demonstrated that only intramural cytotrophoblasts, from all the trophoblast populations of the junctional zone, express cytokeratin 17. Furthermore, cell shape and vascular architecture indicate that, in human placenta, intra-arterial trophoblast cells reach their destination by migration through the endometrial interstitium with consecutive intravasation. Cytokeratin 17, in particular, can therefore be used as a specific immunohistochemical marker for the intramural trophoblast subpopulation.


Pathophysiology of ventricular tachyarrhythmias : From automaticity to reentry.
Ventricular arrhythmias are a heterogeneous group of arrhythmias and may arise in patients with cardiomyopathy or structurally normal hearts. The electrophysiologic mechanisms responsible for the initiation and maintenance of ventricular tachycardia include enhanced automaticity, triggered activity, and reentry. Differentiating between these three mechanisms can be challenging and usually requires an invasive electrophysiology study. Establishing the underlying mechanism in a particular patient is helpful to define the optimal therapeutic approach, including the selection of pharmacologic agents or delineation of an ablation strategy.


Real time expression of ACC oxidase and PR-protein genes mediated by Methylobacterium spp. in tomato plants challenged with Xanthomonas campestris pv. vesicatoria.
Biotic stress like pathogenic infection increases ethylene biosynthesis in plants and ethylene inhibitors are known to alleviate the severity of plant disease incidence. This study aimed to reduce the bacterial spot disease incidence in tomato plants caused by Xanthomonas campestris pv. vesicatoria (XCV) by modulating stress ethylene with 1-aminocyclopropane-1-carboxylate (ACC) deaminase activity of Methylobacterium strains. Under greenhouse condition, Methylobacterium strains inoculated and pathogen challenged tomato plants had low ethylene emission compared to pathogen infected ones. ACC accumulation and ACC oxidase (ACO) activity with ACO related gene expression increased in XCV infected tomato plants over Methylobacterium strains inoculated plants. Among the Methylobacterium spp., CBMB12 resulted lowest ACO related gene expression (1.46 Normalized Fold Expression), whereas CBMB20 had high gene expression (3.42 Normalized Fold Expression) in pathogen challenged tomato. But a significant increase in ACO gene expression (7.09 Normalized Fold Expression) was observed in the bacterial pathogen infected plants. In contrast, Methylobacterium strains enhanced β-1,3-glucanase and phenylalanine ammonia-lyase (PAL) enzyme activities in pathogen challenged tomato plants. The respective increase in β-1,3-glucanase related gene expressions due to CBMB12, CBMB15, and CBMB20 strains were 66.3, 25.5 and 10.4% higher over pathogen infected plants. Similarly, PAL gene expression was high with 0.67 and 0.30 Normalized Fold Expression, in pathogen challenged tomato plants inoculated with CBMB12 and CBMB15 strains. The results suggest that ethylene is a crucial factor in bacterial spot disease incidence and that methylobacteria with ACC deaminase activity can reduce the disease severity with ultimate pathogenesis-related protein increase in tomato.


Taming the carboxyl group for directed carbometalation: observations on the use of anions, dianions and ester enolates.
Carboxylate anions, dianions and ester enolates provide simultaneous protection and activation for directed carbometalation reactions. Advantage can be taken of the bis-carbanionic character of the intermediate for further controlled C-C bond forming reactions.


[How to write, how to implement and how to evaluate a practice guideline in order to improve quality of care?].
Initiatives of clinical practices improvement have been gradually developing in France for 20 years. Nevertheless, effective implementation of change is still difficult for numerous reasons. The use of clinical practices guidelines is one of the different ways of improvement. It is however necessary to adapt these national guidelines to the specificities of the hospital and the team, to ensure implementation and appropriation by the professionals. These recommendations are thus translated into applicable and concrete standard operating procedures. These documents have to be built by and for the concerned professionals. They are also communication and training tools, precise, directive, uniform in terms of presentation and attractive visually. Once drafted, they have to be distributed widely to the professionals to facilitate implementation. The simple distribution of the recommendations is insufficient to modify the clinical practices and require association of several methods of promotion for an optimal appropriation. How then to make sure of their effective use? Practices evaluation is one of the steps of continuous professional development, including continuous training and analysis of clinical practices by using methods promoted by the "Haute Autorité de santé". One of them is the clinical audit; use of method assessing non-pertinent treatment is interesting too. Analysis of the non-conformities and gaps between theory and practice allows identifying various possible causes (professional, institutional, organizational or personal) in order to implement corrective action plans, in a logic of continuous improvement.


Pleconaril-resistant chronic parechovirus-associated enteropathy in agammaglobulinaemia.
A 14 year old common variable immunodeficiency patient developed severe protein-losing enteropathy. A chronic enteral infection with human parechovirus type 1 and norovirus was diagnosed. Treatment strategies aimed at virus eradication and providing supportive care were ineffective. The antipicornavirus agent pleconaril did not have any effect on viral replication. Symptoms improved on immunosuppressive therapy, suggesting infection-related immune dysregulation in an immunocompromised host.


Understanding children's emotional processes and behavioral strategies in the context of marital conflict.
Marital conflict is a distressing context in which children must regulate their emotion and behavior; however, the associations between the multidimensionality of conflict and children's regulatory processes need to be examined. The current study examined differences in children's (N = 207, mean age = 8.02 years) emotions (mad, sad, scared, and happy) and behavioral strategies to regulate conflict exposure during resolved, unresolved, escalating, and child-rearing marital conflict vignettes. Children's cortisol levels were assessed in relation to child-rearing and resolved conflict vignettes. Anger and sadness were associated with escalating and child-rearing conflicts, fearfulness was related to escalating and unresolved conflicts, and happiness was associated with resolution. Anger was associated with children's strategies to stop conflict, whereas sadness was associated with monitoring and avoidant strategies. Cortisol recovery moderated the link between fearfulness and behavioral regulation. These results highlight the importance of children's emotions and regulatory processes in understanding the impact of marital conflict.


Transmembrane proteins of the tight junctions at the blood-brain barrier: structural and functional aspects.
The blood-brain barrier (BBB) is formed by microvascular endothelial cells sealed by tetraspanning tight junction (TJ) proteins, such as claudins and TAMPs (TJ-associated marvel proteins, occludin and tricellulin). Claudins are the major components of the TJs. At the BBB, claudin-5 dominates the TJs by preventing the paracellular permeation of small molecules. On the other hand, TAMPs regulate the structure and function of the TJs; tricellulin may tighten the barrier for large molecules. This review aims at integrating and summarizing the most relevant and recent work on how the BBB is influenced by claudin-1, -3, -5, -12 and the TAMPs occludin and tricellulin, all of which are four-transmembrane TJ proteins. The exact functions of claudin-1, -3, -12 and TAMPs at this barrier still need to be elucidated.


Production and characterization of mouse monoclonal antibodies reactive to Chikungunya envelope E2 glycoprotein.
Chikungunya fever is an arbovirosis of major impact in public health in Asia and Africa. Chikungunya (CHIK) virus is member of the genus Alphavirus and belongs to the Semliki Forest (SF) antigenic complex. We describe for the first time a panel of monoclonal antibodies (MAbs) reactive to CHIK envelope E2 glycoprotein. For the screening of E2-specific MAbs, we expressed a recombinant soluble CHIK E2 protein in Drosophila S2 cells. Analyzed by immunological methods, MAbs 3C3, 3E4, and 8A4 were selected on the basis of their reactivity. Their epitopes are located to the outer surface of CHIK virion. These MAbs have no cross reactivity with related members of SF antigenic complex with the notable exception of Igbo-Ora virus. Anti-CHIK E2 MAbs 3C3, 3E4, and 8A4 should be helpful for studying the biology of CHIK virus and pathogenesis of disease. The combination of 8A4 and 3E4 is suitable for developing a specific antigen-capture ELISA.


Early Detection of Severe Acute Respiratory Syndrome Coronavirus 2 Antibodies as a Serologic Marker of Infection in Patients With Coronavirus Disease 2019.
Thousands of medical staff have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with hundreds of deaths reported. Such loss could be prevented if there were a serologic assay for SARS-CoV-2-specific antibodies for serological surveillance of its infection at the early stage of disease. Using Chinese hamster ovarian (CHO) cell-expressed full-length SARS-CoV-2 S1 protein as capturing antigen, a coronavirus disease 2019 (COVID-19)/SARS-CoV-2 S1 serology enzyme-linked immunosorbent assay (ELISA) kit was developed and validated with negative samples collected prior to the outbreak or during the outbreak and positive samples from patients confirmed with COVID-19. The specificity of the ELISA kit was 97.5%, as examined against total 412 normal human samples. The sensitivity was 97.1% by testing against 69 samples from hospitalized and/or recovered COVID-19 patients. The overall accuracy rate reached 97.3%. The assay was able to detect SARS-CoV-2 antibody on day 1 after the onset of COVID-19 disease. The average antibody levels increased during hospitalization and 14 days after discharge. SARS-CoV-2 antibodies were detected in 28 of 276 asymptomatic medical staff and 1 of 5 nucleic acid test-negative "close contacts" of COVID-19 patients. With the assays developed here, we can screen medical staff, incoming patients, passengers, and people who are in close contact with the confirmed patients to identify the "innocent viral spreaders," protect the medical staff, and stop further spread of the virus.


Skin lesions of the extensor surfaces of interphalangeal joints: surgical approach.
A method of immediate grafting of interphalangeal joint skin defects after lesions are excised is presented.


Mechanism of interferon action. Biochemical and genetic evidence for the intermolecular association of the RNA-dependent protein kinase PKR from human cells.
The interferon-inducible protein kinase (PKR) is activated by an RNA-dependent autophosphorylation. Structure-function studies of the 551 amino acid PKR kinase from human cells have revealed that catalytic-deficient PKR mutants such as PKR(1-551)K296R display a dominant negative behavior when expressed in transfected cells. The potential for PKR to form protein multimers has therefore been examined. Three types of studies, including both genetic and biochemical analyses, demonstrated that PKR from human cells undergoes an intermolecular association that is not dependent upon RNA. First, the intermolecular association of PKR in vitro was demonstrated in the context of an enzyme-substrate interaction. Purified recombinant histidine-tagged PKR(1-551)K296R mutant protein was phosphorylated by purified wild-type PKR; this intermolecular phosphorylation of PKR was dependent on double-stranded RNA. At a fixed RNA concentration, high concentrations of the HIS-PKR(1-551)K296R mutant both impaired the autophosphorylation of wild-type PKR and blocked the trans-phosphorylation of itself. Second, the yeast two-hybrid system was used to probe the intermolecular association of PKR in vivo. Coexpression of the full-length catalytic-deficient phosphotransfer mutant PKR(1-551)K296R as a fusion protein with the Gal4 activation domain and the Gal4 DNA binding domain resulted in the expression of two Gal4-responsive reporter genes, HIS3 and lacZ. The full-length RNA-binding deficient PKR(1-551)K64E/K296R double mutant also interacted with PKR(1-551)K296R sufficiently to activate Gal4-responsive reporter genes; however, other PKR mutants including PKR(1-280)wt and PKR(281-551)K296R as well as p53, RAS, and BCL2 did not. Third, both PKR(1-551)K296R and PKR(1-551)K64E/K296R enhanced the expression of the reovirus S1 gene and S1/S4 chimeric gene in cotransfected COS cells. By contrast, the expression of the reovirus S4 gene was not enhanced by cotransfection with either PKR(1-551)K296R or PKR(1-551)K64E/K296R. These results indicate that PKR interacts with itself in an intermolecular manner both in vivo and in vitro, and that RNA binding is neither necessary nor sufficient for PKR multimerization.


Prevalence of Depression and Anxiety Among Medical Students and House Staff During the COVID-19 Health-Care Crisis.
The objective of the study was to evaluate the prevalence of anxiety and depression among medical trainees during the initial wave of the COVID-19 pandemic. This was a cross-sectional study of the prevalence of depression and anxiety among medical students, residents, and fellows at a medical university hospital in New York using self-reported PHQ-9 and GAD-7 screening tools administered via an anonymized survey. The study was conducted in April 2020. The authors received 438 responses (33.4% response rate). Nearly half (44.5%) were medical students and female (56.6%). The prevalence of positive screen for depression (45.3%) and anxiety (48.1%) was high. Many reported moderate to severe depression (17.2%) and anxiety (20.3%). Over half (57.3%) experienced significant mood changes and inability to concentrate, and 14.6% had reconsidered their choice of profession since the start of the pandemic. Those who had reconsidered their profession had higher PHQ-9 [8.1 (6.4) vs 4.4 (4.3), p < 0.0001] and GAD-7 scores [8.3 (6.1) vs 4.7 (4.6), p < 0.0001], indicating adverse mental health partly contributed to their reconsideration of choice of profession. Women were more likely to screen positive for anxiety (OR: 1.68) and medical students more likely to screen positive for anxiety (OR: 2.55) and depression (OR: 2.74). The COVID-19 pandemic has placed great strain on health-care resources, including the mental health of medical trainees.