Redefining major hepatic resection for colorectal liver metastases: Analysis of 1111 liver resections.
A major hepatic resection is currently defined as resection of 3 or more segments. The aim of this study was to analyse the post-operative morbidity and mortality of hepatic resections in relation to the number of segments excised. From January 2000 to December 2010, 1111 liver resections were performed for colorectal liver metastases (CRLM). Data were collected from a prospectively maintained database and analysed according to the extent of resection performed. 457 patients had 1-2, 362 had 3-4 and 292 had 5-6 segments resected respectively. In comparing 1-4 vs. 5-6 segments, overall morbidity (16.7% vs 40.7%; p < 0.001), hepatic failure (0.6% vs 10.6%; p < 0.001); mean hospital stay (8 vs 13.5 days; p = 0.000), mean ICU stay (4.4 vs 6.5 days; p = 0.01), 60-day mortality (0.7% vs 3.4%; p = 0.002), and 90-day mortality (0.7% vs 3.4%; p = 0.002) were significantly different. When analysing the 3-4 vs 5-6 segment resections, morbidity (21.8% vs 40.7%; p < 0.001), hepatic failure (1.4% vs 10.6%; p = 0.000), 60-day mortality (0.7% vs 3.4%; p = 0.002), and 90-days mortality (0.8% vs 3.4%; p = 0.023) remained statistically significant. Differences in outcome would suggest a revision of the current classification. Only when 5 or more segments are excised for CRLM should a liver resection be considered "major".


Effect of E1 type prostaglandin on hypoxemia in a cyanotic congenital cardiac malformation.
Prostaglandin type E1 has been administered on 4 different occasions in a newborn with a ductus-dependent complex congenital cyanotic heart disease. Dramatic improvement of the arterial oxygen concentration followed each prostaglandin infusion. Increased pulmonary circulation and widening of the ductus arteriosus were seen on angiographic examination. Transient flushing of the skin and mild pyrexia were the only complications noted. It is advised that prostaglandin type E1 be used in ductus-dependent heart diseases as an emergency therapy when indicated.


A homogeneous assay for relative affinity of binding proteins using a green fluorescent protein tag and membrane disk.
When the association between a ligand immobilized on a membrane disk and a fluorescence-labeled analyte was monitored with a fluorescent microplate reader, the time-dependent increase in fluorescence intensity of the reaction mixture was observed. A novel assay system for the specific interaction based on this phenomenon was designated the homogeneous assay for fluorescence concentrated on membrane (HAFCOM). In this study, streptococcal protein G (SpG) and glycogen-binding subunit R5 of protein phosphatase 1 (PPP1R5) tagged by green fluorescent protein (GFP) were used as the fluorescence-labeled analytes, and the affinity change caused by various amino acid substitutions was measured with HAFCOM. From the site-directed mutagenesis of SpG and PPP1R5, it was clarified that (i) the association rate constant of the Lys454Pro/Glu456Gln mutant of SpG to goat immunoglobulin G was almost equivalent to that of the wild-type but its dissociation rate constant was about 2.7 times that of the wild-type and (ii) the amino acid substitutions of Phe180 in PPP1R5 reduced glycogen-binding by 30-50%. Since HAFCOM using the GFP-tagged analyte requires no special chemicals and instruments, this system can easily and economically assay the specific interaction between target protein and ligand.


Associations of sickness absence and disability pension due to mental and somatic diagnoses when aged 60-64 with paid work after the standard retirement age; a prospective population-based cohort study in Sweden.
The proportion of people working beyond age 65 is increasing. We aimed to explore whether sickness absence (SA) and disability pension (DP) due to mental, somatic, or both diagnoses when aged 60-64 were associated with being in paid work when aged 66-71. This prospective population-based cohort study included all 98,551 individuals who in 2010 turned 65 years, lived in Sweden, and were in paid work at some point when aged 60-64. Data from three nationwide registers were used with 2010 as baseline, with SA or/and DP as the exposure variables (2005-2009) and paid work as the outcome variable (2011-2016). Logistic regression was conducted to calculate odds ratios (OR) with 95% confidence intervals (CI) for the association between exposures and outcome, controlling for sociodemographic factors. The analyses were also stratified by sex. Nearly half were in paid work during follow-up. Those with SA due to mental diagnoses had lower likelihood of being in paid work among both sexes (women OR: 0.76; 95% CI: 0.69-0.84; men 0.74; 0.65-0.84), while this association was smaller for SA due to somatic diagnoses (women 0.87; 0.84-0.91; men 0.92; 0.89-0.96). SA due to both mental and somatic diagnoses was associated with a lower likelihood of paid work for men (0.77; 0.65-0.91), but not women (0.98; 0.88-1.09). Regardless of diagnosis group and sex, DP had the strongest association with not being in paid work (women mental DP 0.39; 0.34-0.45; women somatic DP 0.38; 0.35-0.41; women mental and somatic DP 0.28; 0.15-0.56; men mental DP 0.36; 0.29-0.43; men somatic DP 0.35; 0.32-0.38; men mental and somatic DP 0.22; 0.10-0.51). Combined SA and/or DP demonstrated ORs in-between the diagnosis groups of SA and DP alone (e.g., mental SA and/or DP women and men combined 0.61; 0.57-0.65). SA and DP were negatively associated with being in paid work after the standard retirement age of 65. The association was especially strong for DP, irrespective of diagnosis group. Moreover, compared to somatic diagnoses, SA due to mental diagnoses had a stronger association with not being in paid work. More knowledge is needed on how mental SA impedes extending working life.


Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection.
Recent reports highlight a new clinical syndrome in children related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1-multisystem inflammatory syndrome in children (MIS-C)-which comprises multiorgan dysfunction and systemic inflammation2-13. We performed peripheral leukocyte phenotyping in 25 children with MIS-C, in the acute (n = 23; worst illness within 72 h of admission), resolution (n = 14; clinical improvement) and convalescent (n = 10; first outpatient visit) phases of the illness and used samples from seven age-matched healthy controls for comparisons. Among the MIS-C cohort, 17 (68%) children were SARS-CoV-2 seropositive, suggesting previous SARS-CoV-2 infections14,15, and these children had more severe disease. In the acute phase of MIS-C, we observed high levels of interleukin-1β (IL-1β), IL-6, IL-8, IL-10, IL-17, interferon-γ and differential T and B cell subset lymphopenia. High CD64 expression on neutrophils and monocytes, and high HLA-DR expression on γδ and CD4+CCR7+ T cells in the acute phase, suggested that these immune cell populations were activated. Antigen-presenting cells had low HLA-DR and CD86 expression, potentially indicative of impaired antigen presentation. These features normalized over the resolution and convalescence phases. Overall, MIS-C presents as an immunopathogenic illness1 and appears distinct from Kawasaki disease.


Fully Automatic Assessment of Background Parenchymal Enhancement on Breast MRI Using Machine-Learning Models.
Automated measurement and classification models with objectivity and reproducibility are required for accurate evaluation of the breast cancer risk of fibroglandular tissue (FGT) and background parenchymal enhancement (BPE). To develop and evaluate a machine-learning algorithm for breast FGT segmentation and BPE classification. Retrospective. A total of 794 patients with breast cancer, 594 patients assigned to the development set, and 200 patients to the test set. 3T and 1.5T; T2 -weighted, fat-saturated T1 -weighted (T1 W) with dynamic contrast enhancement (DCE). Manual segmentation was performed for the whole breast and FGT regions in the contralateral breast. The BPE region was determined by thresholding using the subtraction of the pre- and postcontrast T1 W images and the segmented FGT mask. Two radiologists independently assessed the categories of FGT and BPE. A deep-learning-based algorithm was designed to segment and measure the volume of whole breast and FGT and classify the grade of BPE. Dice similarity coefficients (DSC) and Spearman correlation analysis were used to compare the volumes from the manual and deep-learning-based segmentations. Kappa statistics were used for agreement analysis. Comparison of area under the receiver operating characteristic (ROC) curves (AUC) and F1 scores were calculated to evaluate the performance of BPE classification. The mean (±SD) DSC for manual and deep-learning segmentations was 0.85 ± 0.11. The correlation coefficient for FGT volume from manual- and deep-learning-based segmentations was 0.93. Overall accuracy of manual segmentation and deep-learning segmentation in BPE classification task was 66% and 67%, respectively. For binary categorization of BPE grade (minimal/mild vs. moderate/marked), overall accuracy increased to 91.5% in manual segmentation and 90.5% in deep-learning segmentation; the AUC was 0.93 in both methods. This deep-learning-based algorithm can provide reliable segmentation and classification results for BPE. 3 TECHNICAL EFFICACY STAGE: 2.


Induction of a 70 kD protein associated with the selective cytotoxicity of beta-carotene in human epidermal carcinoma.
Beta-carotene and canthaxanthin at concentrations of 70 or 300 microM were shown to inhibit the proliferation of cultured human squamous cells (SK-MES lung carcinoma and SCC-25 oral carcinoma) in a 5 hr cell density assay. Responses were similar for both tumor cell lines, ranging from 71-84% inhibition. In contrast, equimolar concentrations of alpha-tocopherol gave only 19-36% inhibition of SCC-25, but 50-75% inhibition of SK-MES cell density. Equimolar reduced glutathione resulted in 4-15% stimulation of SCC-25 and 22-25% inhibition of SK-MES cell proliferation. With cultured normal keratinocytes, treated final cell densities did not differ significantly from those of controls. Two additional assays measuring the metabolic generation of formazan (MTT assay) and [5-3H]thymidine incorporation were in substantial agreement with the growth inhibition pattern. Thus both continuous and cyclic cellular processes are involved in the tumor-specific response. Onset of the response to beta-carotene alone or in combination with alpha-tocopherol is signalled within 1-2 hours of treatment by the appearance of a unique 70 kD heat-shock protein.


Molecular regulation of phospholamban function and expression.
Intracellular levels of cAMP regulated by the beta-adrenergic actions of catecholamines play a key in the metabolic, electrical, and mechanical performance of the cardiac muscles. Among a number of biological actions of cAMP, the excitation-contraction coupling process in cardiac myocytes is markedly affected by cAMP through its stimulatory effect on cAMP-dependent protein kinase. Phospholamban, which is expressed in the sarcoplasmic reticulum of cardiac, slow-twitch skeletal, and smooth muscles, is one of the substrates for cAMP-dependent protein kinase. Phospholamban regulates the activity of Ca ATPase in the sarcoplasmic reticulum membranes in a manner dependent on the phosphorylation state of cAMP-dependent protein kinase, thereby changing the mechanical performance of the cardiac muscles. This Ca regulatory mechanism of phospholamban-Ca ATPase system is mediated by a direct protein-protein interaction between two proteins. This review focuses on recent advances in understanding the role of phospholamban molecule in the regulation of Ca transport by cardiac muscle sarcoplasmic reticulum.


Remotely Light-Powered Soft Fluidic Actuators Based on Plasmonic-Driven Phase Transitions in Elastic Constraint.
Materials capable of actuation through remote stimuli are crucial for untethering soft robotic systems from hardware for powering and control. Fluidic actuation is one of the most applied and versatile actuation strategies in soft robotics. Here, the first macroscale soft fluidic actuator is derived that operates remotely powered and controlled by light through a plasmonically induced phase transition in an elastomeric constraint. A multiphase assembly of a liquid layer of concentrated gold nanoparticles in a silicone or styrene-ethylene-butylene-styrene elastic pocket forms the actuator. Upon laser excitation, the nanoparticles convert light of specific wavelength into heat and initiate a liquid-to-gas phase transition. The related pressure increase inflates the elastomers in response to laser wavelength, intensity, direction, and on-off pulses. During laser-off periods, heating halts and condensation of the gas phase renders the actuation reversible. The versatile multiphase materials actuate-like soft "steam engines"-a variety of soft robotic structures (soft valve, pnue-net structure, crawling robot, pump) and are capable of operating in different environments (air, water, biological tissue) in a single configuration. Tailored toward the near-infrared window of biological tissue, the structures actuate also through animal tissue for potential medical soft robotic applications.


Tailored modulation of stemness and drug resistance marker characteristics in K-Ras mutant lung cancer cells via PD-L1 gene suppression.
We aimed to analyze the association of tumor cell-specific Programmed Cell Death Ligand 1 (PD-L1) expression with stemness markers and multi-drug resistance genes in non-small cell lung cancer. ATP Binding Cassette Subfamily G Member 2 (ABCG2), Aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), CD44, Epithelial cell adhesion molecule (EPCAM), Kruppel-like factor 4 (KLF4), MYC Proto-Oncogene (MYC), Nanog Homeobox (NANOG), SRY-Box Transcription Factor 2 (SOX2) as well as ATP Binding Cassette Subfamily C Member (ABCC) 1-6, ABCC10-12 with ATP Binding Cassette Subfamily B Member (ABCB) 1 and ABCB4-9 belongs to ABC transporters family were analyzed and their correlation with PD-L1 was evaluated using Cancer Cell Line Encyclopedia and The Cancer Genome Atlas data sets. We validated potential lung cancer stemness markers harboring ABCG2, CD44, ALDH1A1 and SOX-2, which are affected as a result of siRNA-mediated suppression of PD-L1 via flow cytometry. K-Ras downstream signaling proteins as well as multidrug resistance proteins were also investigated. PD-L1 was found to be positively correlated with CD44, whereas negatively correlated with ALDH1A1 (Pearson r = 0.44, r = -0.48; respectively) in 45 K-Ras mutated NSCLC cells based on CCLE database. While ABCC5 was dominantly decreased in K-Ras mutant lung cancer cells affected by PD-L1 gene suppression, expression changes were observed in the activation of distinct signaling pathways in a cell line-dependent manner. The evaluation of markers in lung adenocarcinoma with different types of K-Ras mutations in terms of both stemness and drug resistance markers will contribute to the development of personalized immunotherapy regimens.


Sensitivity of subgroup F adenoviruses to interferon.
The subgroup F adenoviruses were tested for their ability to induce interferon in semi-permissive human cells (Chang conjunctiva) and non-permissive cells (HEF, human embryo lung fibroblasts). These cells did not produce interferon spontaneously or in response to infection by either of these adenoviruses. It was concluded that interferon induction in response to subgroup F adenovirus infection is not a likely explanation of limited virus growth in culture. Adenovirus 40 and Ad41, unlike Ad2, were found to be sensitive to human lymphoblastoid interferon in Chang conjunctival cells. The addition of Ad2 to cells before pretreatment with interferon resulted in the partial and complete abrogation of Ad40 and Ad41 interferon sensitivity, respectively. The suppressive effect of Ad2 on the inhibitory action of interferon and the modulatory function of Ad2 in mixed infection with either Ad40 or Ad41 suggests the inadequate functioning of a subgroup F adenovirus gene product or products involved in suppression of the interferon-induced antiviral state.


Polystyrene microplastics disrupt female reproductive health and fertility via sirt1 modulation in zebrafish (Danio rerio).
Microplastics (MPs) pollution poses an emerging threat to aquatic biota, which could hinder their physiological processes. Recently various evidence has demonstrated the toxic impacts of MPs on cellular and organismal levels, but still, the underlying molecular mechanism behind their toxicity remains ambiguous. The hypothalamic-pituitary-gonadal (HPG) axis regulates the synthesis and release of sex steroid hormones, and SIRT1 plays a vital role in this process. The current study aimed to elucidate the harmful effects of MPs on female reproduction via SIRT1 modulation. Healthy female zebrafish were exposed to different concentrations (50 and 500 µg/L) of polystyrene microplastics (PS-MPs). The results revealed a significant change in the gonadosomatic index (GSI) after exposure to PS-MPs. In addition, the decreased fecundity rate displayed an evident dosage effect, indicating that exposure to PS-MPs causes deleterious effects on fertilization. Furthermore, significantly enhanced levels of reactive oxygen species (ROS) and apoptotic signals through the TUNEL assay were evaluated in different treated groups. Moreover, morphological alterations in the gonads of zebrafish exposed to MPs were also observed through H&E staining. The subsequent change in plasma steroid hormone levels (E2/T ratio) showed an imbalance in hormonal homeostasis. Meanwhile, to follow PS-MPs' effects on the HPG axis via SIRT1 modulation and gene expression related to steroidogenesis, SIRT1/p53 pathway was evaluated through qPCR. The altered transcription levels of genes indicated the plausible interference of PS-MPs on the HPG axis function. Our in-silico molecular docking study proves that PS-MPs efficiently bind and inhibit endocrine receptors and SIRT1. Thus, these findings add to our understanding of the probable molecular mechanisms of reproductive impairment caused by PS-MPs in zebrafish.


Risk estimation of neuroblastoma patients using molecular markers.
The pediatric tumor neuroblastoma is a heterogeneous disease: Patients' clinical courses can range from spontaneous regression to fatal progression of the disease. Accordingly, treatment protocols vary from "wait and see" approaches to intensive multimodal therapies. Accurate risk estimation of the patients is therefore mandatory to choose the most adequate therapy. Current trials stratify by a limited number of clinical variables, such as stage of the disease and age of the patient at diagnosis, as well as molecular markers, such as amplification of the oncogene MYCN and loss of the short arm of chromosome 1. However, misclassifications of patients still occur, and thus, a precise prediction of the clinical courses remains a challenge of neuroblastoma research. In recent years, genomic alterations and gene expression profiles of this neoplasm have been characterized thoroughly. It has been shown that the diverse clinical phenotypes are reflected by both specific cytogenetic aberrations and distinct gene expression patterns. Moreover, a variety of DNA copy number changes and gene expression-based classifiers have been described that could predict the outcome of neuroblastoma patients more precisely than established prognostic variables. In this review, the recent advances in the detection and evaluation of molecular prognostic markers for neuroblastoma patients are summarized, and their current and potential contribution to risk stratification systems is discussed.


Evaluation of acridinedione analogs as potential SARS-CoV-2 main protease inhibitors and their comparison with repurposed anti-viral drugs.
The main protease (Mpro) of SARS-CoV-2 is involved in the processing of vital polypeptides required for viral genome replication and transcription and is one of the best-characterized targets to inhibit the progression of SARS-CoV-2 in infected individuals. We screened a set of novel classes of acridinediones molecules to efficiently bind and inhibit the activity of the SARS-CoV-2 by targeting the Mpro. The repurposed FDA-approved antivirals were taken as standard molecules for this study. Long term (1.1 μs) MD simulations were performed to analyze the conformational space of the binding pocket of Mpro bound to the selected molecules. The molecules DSPD-2 and DSPD-6 showed more favorable MM-PBSA interaction energies and were seated more deeply inside the binding pocket of Mpro than the topmost antiviral drug (Saquinavir). Moreover, DSPD-5 also exhibited comparable binding energy to Saquinavir. The analysis of per residue contribution energy and SASA studies indicated that the molecules showed efficient binding by targeting the S1 subsite of the Mpro binding pocket. The DSPD-2, DSPD-6, and DSPD-5 could be developed as potential inhibitors of SARS-CoV-2. Moreover, we suggest that targeting molecules to bind effectively to the S1 subsite could potentially increase the binding of molecules to the SARS-CoV-2 Mpro.


The effect of dorsal cochlear nucleus ablation on tinnitus in rats.
A growing body of evidence implies that the dorsal cochlear nucleus (DCN) plays an important role in tinnitus. To test the hypothesis that the rostral output of the DCN is necessary for the experience of chronic tinnitus, the dorsal DCN and the dorsal acoustic stria of rats with psychophysical evidence of tinnitus was ablated. If the DCN plays a necessary role in the generation of chronic tinnitus, ablating the DCN should decrease the evidence of tinnitus in subjects previously shown to have tinnitus. Contrary to prediction, bilateral dorsal DCN ablation did not significantly (n=11, p=0.707) affect the psychophysical evidence of tinnitus, and ipsilateral dorsal DCN ablation appeared to increase the evidence of tinnitus (n=9, p=0.018) compared to pre-ablation performance. It was concluded that the DCN does not act as a simple feed-forward source of chronic tinnitus. Alternative hypotheses were considered, among them that elevated DCN activity following acoustic trauma triggers persistent pathological changes distributed across more than one level of the auditory system. In addition to serving as a trigger, the DCN may also modify the experience of tinnitus, since the evidence of tinnitus was enhanced by ipsilateral DCN ablation.


The molecular basis for the difference in charge between pre-beta- and alpha-migrating high density lipoproteins.
Several subspecies of human high density lipoprotein (HDL) exist, and particle surface charge is one parameter that can be used to distinguish them. For instance, pre-beta HDL has a lower negative surface charge than the bulk of plasma HDL resulting in slower migration when subjected to electrophoresis in an agarose gel at pH 8.6. The molecular basis for the variations in HDL particle surface charge have been established in this work. Quantitative analysis of electrophoretic mobilities in agarose gels indicates that the surface potentials of reconstituted pre-beta HDL and alpha-HDL3 are -7.6 and -11.4 mV, respectively. The difference of 3.8 mV corresponds to an apparent 1e more net negative charge on alpha-migrating HDL3. The contributions of the lipid and protein components to the charge of HDL3 were defined using reconstituted particles (rHDL) containing various combinations of HDL3 protein and lipid. The surface potentials of spherical and discoidal rHDL are not affected by the particle apoprotein composition. Thin layer chromatography of the HDL3 phospholipid fraction from five normolipidemic subjects revealed that it consists of approximately 84% phosphatidylcholine, 12% sphingomyelin, and 4% phosphatidylinositol (PI) by weight. PI significantly affects the charge of discoidal rHDL and is responsible for approximately 0.7 mV of the surface potential difference between pre-beta- and alpha-HDL. Reconstitution of spherical complexes containing apolipoprotein AI, palmitoyl-oleoyl phosphatidylcholine, and HDL3 neutral lipid esters showed that particles containing a neutral lipid core migrate to an alpha position in an agarose gel. The change in particle shape accounts for approximately 3 mV of the difference in surface potential between pre-beta and alpha-HDL. Overall, the charge of HDL particles is determined by 1) a direct contribution of negative charge from PI molecules in the surface of the lipoprotein and 2) the conformation of the resident apolipoprotein(s) which is influenced by the presence of neutral lipids and the particle shape. This quantitative understanding of surface charge provides a basis for understanding variations in function of HDL subspecies.


A modified thumb spica splint for thumb injuries in the ED.
There are a significant number of hand and upper extremity injuries treated in US emergency departments (EDs) each year. Many of these involve the thumb and wrist. These injuries encompass the range from fractures, strains, and sprains to more specific injuries such as gamekeeper thumb and de Quervain tenosynovitis. These injuries often require diagnosis, splinting, and referral to a hand or orthopedic surgeon. The splint described in this article is presently being used for patients with de Quervain tenosynovitis, but it may have more widespread application in emergency medicine. It is a safe and simple splint that is underused in EDs for splinting thumb injuries.


Investigating unexplained infertility.
In an attempt to reduce the number of couples whose basic infertility evaluation fails to reveal any abnormality, 57 couples with the diagnosis of unexplained infertility were further investigated by ultrasound monitoring for folliculogenesis, sperm antibody testing, hamster egg penetration assay, and major histocompatibility (human leukocyte antigen) typing. The use of these techniques allowed the diagnosis of luteinized unruptured follicle in 5% (three patients), sperm antibodies in 5% (three patients), low sperm penetration in 11% (six patients), and human leukocyte antigen-B locus homozygosity in 37% (21 couples). When the incidence of B locus homozygosity among the 57 couples with unexplained infertility was compared with that in 51 fertile couples, the difference was significant at p = 0.025. Thus by adding the diagnostic tools of ultrasound monitoring of folliculogenesis, sperm antibody testing, hamster egg penetration assay, and major histocompatibility antigen typing, the diagnosis of unexplained infertility can be reduced by 60%.


Efficacy of botulinum toxin A in upper limb function of hemiplegic patients.
Botulinum toxin A has been reported to reduce spasticity and increase the comfort of hemiplegic patients. The aim of this study was to assess the efficacy of the treatment on disability, especially in manual activities, and to attempt to identify predictive factors of improvement. Twenty patients (mean age: 54.4 years; M: 14; right hemiplegia: 12) were included, with a delay of at least three months after unilateral hemispheric stroke. Botulinum toxin A (BOTOX) was injected into the arm adductors (8 cases), forearm flexors (17 cases), pronators, wrist and finger flexors (20 cases),with a total dose of 200 to 300 U. Examination (day 1 and 15, month 2 and 5) consisted of spasticity assessment (modified Ashworth scale), muscle strength, passive range of motion (goniometry), and pain, followed by functional tests, especially the Rivermead Motor Assessment (RMA) and Nine-hole Peg Test (NHPT). Performance in daily living was assessed with the Functional Independence Measure (FIM), and an original analysis of hand grasp, grip and pinches used in domestic activities (9 items), and of comfort of patients and caregivers. Significant reduction in spasticity was observed on the elbow flexors, pronators, wrist and fingers flexors, especially at day 15 (mean 0.90 to 1 point), with wide variations in effect. Muscle strength was increased in wrist and fingers extensors, with concomitant increase in the opening of the thumb to index finger space. There was no effect on the NHPT requiring distal manipulation, but the RMA, which especially concerned picking up and releasing a tennis ball, showed significant improvement. Furthermore, use of the upper limb in daily living increased, particularly for internal grasping of objects, and for grasping by the top, transporting and releasing of objects. Patients and caregivers re ported facilitation in dressing, and in proximal and distal care of the upper limb. The global flexor position of the limb improved. Ad verse reactions were rare and mostly consisted of transitory pain during injection. The improvement in the RMA was better explained by the quality of the initial motor command on distal prehension (positive correlation with motor strength), and that in hand using in domestic activities by a lower level of spasticity on pronators and wrist flexors (negative correlations with spasticity). Conversely, the severity of the motor deficit (negative correlations with motor strength) and a high level of spasticity before injection (positive correlations with spasticity) mostly explained the improvement in comfort. In conclusion, botulinum toxin A is efficient in improving hand use in patients with relatively preserved distal motricity, and in increasing comfort in patients with severe global disorders.


Kinetics and thermodynamics of diacetyl reduction with NADPH by alpha-dicarbonyl reductase from pigeon liver.
alpha-dicarbonyl reductase from pigeon liver catalyzes diacetyl reduction with NADPH via an ordered Bi-Bi mechanism in which the coenzyme is the leading substrate, as deduced from the inhibition pattern by products and by acetone. The activation energy of the reaction has been calculated as 16.6 kcal/mol, delta H and delta F as 15.6 and 15.3 kcal/mol, respectively, and delta S as 1 cal/mol per k. Kinetic constants obtained for substrates (KmNADPH = 15 microM, KsNADPH = 10 microM; Kmdiacetyl = 0.5 mM, Ksdiacetyl = 0.35 mM) and products (KiNADP 50 microM; Kiacetoin = 100 mM) are about 10 times lower than those reported for this enzyme in the reduction of diacetyl with NADH. This confirms that NADPH is its physiological coenzyme.


International migration and biodemographical behaviour: a study of Italians in Belgium.
This paper describes the matrimonial and reproductive behaviour of Italians who migrated to Belgium after the Second World War. Migrants were either already married, or later became married, to other Italians. Among the children of migrants, men equally chose Italian or Belgian wives but women tended to prefer Italian partners. Italian-Belgian marriages were more frequent among the better educated groups. Family size is smaller among migrants marrying after migration and in heterogamous marriages. Significant differences in birth intervals are found when marriage occurred before or after migration, between generations, and between homogamous and heterogamous marriages.


Maxillary stability following Le Fort I osteotomy using prebent plates and wire fixation in patients undergoing surgery for OSAS.
The purpose of this study was to analyze the stability of Le Fort I maxillary advancement in the vertical and horizontal directions using a combination of wire and rigid fixation in patients undergoing surgery to treat obstructive sleep apnea (OSA). Wire osteosynthesis can be performed quicker and at a reduced cost. The lateral cephalograms of 21 patients were evaluated preoperatively (T0), immediately postoperatively (T1), and at least 6 months postoperatively (T2). Four cephalometric points were used to measure movement in the horizontal and vertical directions. Mean values were determined, and data were statistically analyzed by ANOVA to determine differences between time points. Of the four points analyzed, the average maxillary advancement in the horizontal direction was 7.48 mm and the relapse was 0.56 mm with absence of statistically significant differences between the measurements taken (T1) and (T2). There was a 5% probability of error in the vertical movements at the points I and posterior nasal spine. The combination of two pre-bent plates in piriform aperture with osteosynthesis using surgical steel wires in the zygomatic buttress in patients undergoing maxillary surgery for OSA stabilized the large horizontal maxillary advancements and enhanced vertical stability in the first molar and A point regions.


Isolation and characterization of an adenovirus and isolation of its adenovirus-associated virus in cell culture from foals with respiratory tract disease.
An adenovirus was isolated from a foal with respiratory tract disease. The virus produced cytopathic effects (CPE) in equine embryo kidney (EEK) cell culture, contained deoxyribonucleic acid (DNA), was resistant to chloroform and pH 3, and was moderately resistant to heat. The virus caused hemagglutination of human (type O) erythrocytes. Viral density was 1.34 g/cm,3 and diameter was 75 nm. An adenovirus-associated virus (AAV) isolated from the infected cell culture was 22 nm in diameter. These viruses are classified as equine adenovirus and equine AAV.


Intranodal meningothelial proliferation in a patient with Cowden syndrome: a case report.
Ectopic meningothelial proliferations are rare and can occur in a multitude of extracranial/spinal anatomic locations. Perineurioma is another uncommon entity that shares similar histological characteristics to those found in meningothelial proliferations. These include bland spindle cells with thin, bipolar nuclei; eosinophilic cytoplasm; and indistinct cell borders, arranged in short fascicles with whorl formation. Given their uncommon occurrence and shared histological and immunohistochemical features, their distinction can present a diagnostic challenge. Immunohistochemical studies can provide guidance when attempting to distinguish between these 2 lesions. Here, we present an unusual case of a patient with Cowden syndrome who was discovered to have a meningothelial proliferation within an axillary lymph node. To the best of our knowledge, this is the first case in which a meningothelial proliferation has been identified in a lymph node. Furthermore, the occurrence in a patient with Cowden syndrome is intriguing and raises the possibility of a pathogenetic link.


Clinical assessment of fractured implant abutment screws: The Bernese silicone replica technique.
Fractured implant abutment screws can be retrieved with repair or rescue devices. However, whether the screw was completely retrieved or the inner implant body was damaged may be uncertain. A silicone replica technique was recently implemented in Bern and may be the most predictable method available at the moment for clinically assessing the internal implant body. This technique is straightforward and precise and may help dentists determine the internal implant condition when managing a fractured screw.


Global identification of natural antisense transcripts in Gossypium hirsutum and Gossypium barbadense under chilling stress.
Natural antisense transcripts (NATs) in model plants have been recognized as important regulators of gene expression under abiotic stresses. However, the functional roles of NATs in crops under low temperature are still unclear. Here, we identified 815 and 689 NATs from leaves of Gossypium hirsutum and G. barbadense under chilling stress. Among those, 224 NATs were identified as interspecific homologs between the two species. The correlation coefficients for expression of NATs and their cognate sense genes (CSG) were 0.43 and 0.37 in G. hirsutum and G. barbadense, respectively. Furthermore, expression of interspecific NATs and CSGs alike was highly consistent under chilling stress with correlation coefficients of 0.90-0.91. Four cold-associated NATs were selected for functional validation using virus-induced gene silencing (VIGS). Our results suggest that CAN1 engage in the molecular regulation of chilling stress by regulating SnRK2.8 expression. This highly conserved NAT have valuable potential for applications in breeding cold-tolerant cotton.


Reciprocal regulation of actin filaments and cellular metabolism.
For cells to adhere, migrate and proliferate, remodeling of the actin cytoskeleton is required. This process consumes a large amount of ATP while having an intimate connection with cellular metabolism. Signaling pathways that regulate energy homeostasis can also affect actin dynamics, whereas a variety of actin binding proteins directly or indirectly interact with the anabolic and catabolic regulators in cells. Here, we discuss the inter-regulation between actin filaments and cellular metabolism, reviewing recent discoveries on key metabolic enzymes that respond to actin remodeling as well as historical findings on metabolic stress-induced cytoskeletal reorganization. We also address emerging techniques that would benefit the study of cytoskeletal dynamics and cellular metabolism in high spatial-temporal resolution.


Delay in diagnosis of pulmonary tuberculosis increases the risk of pulmonary cavitation in pastoralist setting of Ethiopia.
Delay in diagnosis and treatment of pulmonary tuberculosis (PTB) leads to severe disease, adverse outcomes and increased transmission. Assessing the extent of delay and its effect on disease progression in TB affected settings has clinical and programmatic importance. Hence, the aim of this study was to investigate the possible effect of delay on infectiousness (cavitation and smear positivity) of patients at diagnosis in Somali pastoralist area, Ethiopia. A cross-sectional study was conducted between December 2017 and October 2018, and 434 newly coming and confirmed PTB patients aged ≥15 years were recruited in five facilities. Data were collected using interview, record-review, anthropometry, Acid-fast bacilli and chest radiography techniques. Log-binomial regression models were used to reveal the association of delay and other factors associated with cavitation and smear positivity, and ROC Curve was used to determine discriminative ability and threshold delays. Median age of patients was 30 years. Of all, 62.9% were males, and 46.5% were pastoralists. Median diagnosis delay was 49 days (IQR = 33-70). Cavitation was significantly associated with diagnosis delay [P < 0.001]; 22.2% among patients diagnosed within 30 days of illness and 51.7% if delay was over 30 days. The threshold delay that optimizes cavitation was 43 days [AUC (95% CI) = 0.67(0.62-0.72)]. Smear positivity was significantly increased in patients delayed over 49 days [p = 0.02]. Other factors associated with cavitation were age ≤ 35 years [APR (95% CI) =1.3(1.01-1.6)], chronic diseases [APR (95% CI) = 1.8(1.2-2.6)] and low MUAC*female [APR (95% CI) = 1.8(1.2-2.8)]. Smear positivity was also associated with age ≤ 35 years [APR (95% CI) =1.4(1.1-1.8)], low BMI [APR (95% CI) =1.3(1.01-1.7)] and low MUAC [APR (95% CI) =1.5(1.2-1.9)]. This study highlights delay in diagnosis of pulmonary TB remained high and increased infectiousness of patients in pastoral settings of Ethiopia. Hence, delay should be targeted to improve patient outcomes and reduce transmission in such settings.


Coronavirus disease 2019 (COVID-19) among nonphysician healthcare personnel by work location at a tertiary-care center, Iowa, 2020-2021.
We describe COVID-19 cases among nonphysician healthcare personnel (HCP) by work location. The proportion of HCP with coronavirus disease 2019 (COVID-19) was highest in the emergency department and lowest among those working remotely. COVID-19 and non-COVID-19 units had similar proportions of HCP with COVID-19 (13%). Cases decreased across all work locations following COVID-19 vaccination.


Content Validation of an Instrument for the Assessment of School Teachers' Levels of Knowledge of Diabetes through Expert Judgment.
The objective of this study was to describe the content validation, through expert judgment, of a questionnaire for determining the level of knowledge that school teachers have of diabetes in order to design relevant educational interventions to improve the health of school-aged children. This psychometric study involved 15 experts who assessed each of the items in the instrument. The results revealed that the strength of agreement shown by the questionnaire ranged from substantial to almost perfect in its four dimensions, with the characteristics of "sufficiency" and "relevance" having the highest scores (0.982 and 0.903, respectively) based on the judgments made by the participating experts. Regarding statistical significance, the characteristics "sufficiency", with p < 0.001, and "relevance", with p = 0.001, were particularly relevant. The overall degree of understandability for the new version of the instrument was high (91.54%). The psychometric results obtained from validation of the "grado de conocimientos sobre diabetes en docentes del ámbito escolar" (Spanish for "level of knowledge of diabetes in school teachers")-GCDDaE questionnaire through expert judgment and the pre-test indicate that it is recommended for use as it is both relevant and quick and easy to administer.


[Profuse subcutaneous nodules in a Tunisian patient: Kaposi sarcoma revealing AIDS].
The purpose of this report is to describe a case involving Kaposi sarcoma as the inaugural manifestation of HIV infection at the full-blown AIDS stage. The patient was a 59-year-old Tunisian man who presented with profuse subcutaneous nodules and multiple lymph nodes. Treatment was based on antiretroviral therapy in association with radiotherapy.


Oropharyngeal dysphagia may occur in late-onset Pompe disease, implicating bulbar muscle involvement.
Late-onset Pompe disease (presenting after 12 months of age) often presents with limb-girdle and respiratory weakness, but oropharyngeal dysphagia has not been reported previously. A retrospective review of all late-onset Pompe disease patients evaluated in the neuromuscular clinic at Duke University Medical Center from 1999-2010 was performed. Twelve patients were identified and 3 had symptoms of oropharyngeal dysphagia. The medical record was reviewed, including the results of electromyography, videofluroscopic swallow examinations, and motor speech examination including instrumental assessment of lingual force with the Iowa Oral Performance Instrument. Oropharyngeal dysphagia was mild in two cases and severe in one. One of the two patients with mild severity demonstrated oral stage swallow signs; in the other, residual material was observed in the area of the cervical esophagus. In the patient with severe oropharyngeal dysphagia, both the oral and pharyngeal stages of swallowing were affected with penetration and aspiration documented. The degree of swallowing impairment appeared to correlate with overall physical strength and function. Oropharyngeal dysphagia may occur in patients with late-onset Pompe disease, implicating bulbar muscle involvement. Screening for symptoms of dysphagia may help reduce morbidity and mortality, while improving understanding of the late-onset Pompe disease phenotype. Further studies, including examination of the relationship between lingual weakness and oropharyngeal dysphagia, are warranted.


Dual latent tuberculosis screening with tuberculin skin tests and QuantiFERON-TB assays before TNF-α inhibitor initiation in children in Spain.
Tumor-necrosis-factor-α inhibitors (anti-TNF-α) are associated with an increased risk of tuberculosis (TB) disease, primarily due to reactivation of latent TB infection (LTBI). We assessed the performance of parallel LTBI screening with tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube assays (QFT-GIT) before anti-TNF-α treatment in children with immune-mediated inflammatory disorders in a low TB-burden setting. We conducted a multicenter cohort study involving 17 pediatric tertiary centers in Spain. LTBI was defined as the presence of a positive TST and/or QFT-GIT result without clinical or radiological signs of TB disease. A total of 270 patients (median age:11.0 years) were included, mainly with rheumatological (55.9%) or inflammatory bowel disease (34.8%). Twelve patients (4.4%) were diagnosed with TB infection at screening (LTBI, n = 11; TB disease, n = 1). Concordance between TST and QFT-GIT results was moderate (TST+/QFT-GIT+, n = 4; TST-/QFT-GIT+, n = 3; TST+/QFT-GIT-, n = 5; kappa coefficient: 0.48, 95% CI: 0.36-0.60). Indeterminate QFT-GIT results occurred in 10 patients (3.7%) and were associated with young age and elevated C-reactive protein concentrations. Eleven of 12 patients with TB infection uneventfully completed standard LTBI or TB treatment. During a median follow-up period of 6.4 years, only 2 patients developed TB disease (incidence density: 130 (95% CI: 20-440) per 100,000 person-years), both probable de novo infections. A substantial number of patients were diagnosed with LTBI during screening. The dual strategy identified more cases than either of the tests alone, and test agreement was only moderate. Our data show that in children in a low TB prevalence setting, a dual screening strategy with TST and IGRA before anti-TNF-α treatment is effective. • The optimal screening strategy for latent tuberculosis in children with immune-mediated inflammatory disorders remains uncertain. • Children receiving anti-TNF-α drugs are at increased risk of developing severe tuberculosis disease. • A dual screening strategy, using TST and an IGRA assay, identified more children with latent tuberculosis than either of the tests alone. • Identification and treatment of latent tuberculosis before initiation of anti-TNF-α therapy averted incident tuberculosis cases.


Mg2+-induced proton release from Escherichia coli ribosome and ribosomal RNA.
Escherichia coli ribosome released protons upon addition of Mg2+. The Mg2+-induced proton release was studied by means of the pH-stat technique. The number of protons released from a 70 S ribosome in the Mg2+ concentration range 1-20 mM was about 30 at pH 7 and 7.6, and increased to about 40 at pH 6.5. The rRNA mixture extracted from 70 S ribosome showed proton release of amount and of pH dependence similar to those of the 70 S ribosome but the ribosomal protein mixture released few. This indicates that rRNA is the main source of the protons released from ribosome. The pH titration of rRNA showed that the pKa values of nucleotide bases were downward shifted upon Mg2+ binding. This pKa shift can account for the proton release. The Scatchard plots of proton release from rRNA and ribosome were concave upward, showing that the Mg2+-binding sites leading to proton release were either heterogeneous or had a negative cooperativity. A model assuming heterogeneous Mg2+-binding sites is shown to be unable to explain the proton release. Electrostatic field effect models are proposed in which Mg2+ modulates the electrostatic field of phosphate groups and the potential change induces a shift of the pKa values of bases that leads to the proton release. These models can explain the main features of the proton release.


Successful ventricular assist device placement in transposition of the great arteries with pulmonary hypertension.
The use of ventricular assist devices in patients with complex congenital heart disease has not been well described. We present a case of successful ventricular assist device support in a 38-year-old man with congenitally corrected transposition of the great arteries and severe secondary pulmonary hypertension.


Intensity-effects of strengthening exercise on thigh muscle volume, pro- or anti-inflammatory cytokines, and immunocytes in the older adults: A randomized controlled trial.
This study investigated the intensity-effects of strength training on thigh muscle mass, cytokines, and immunocytes in the older adults. A total of 81 participated in this study. Participants were assigned randomly to four groups: control group (CON), low- (LSE), moderate- (MSE), and high-intensity strength exercise (HSE) groups. Three exercise groups worked out for 50 min/day, 3 days/week for 12 weeks. In the thigh volume analyzed by computed tomography, the exercise groups showed a significant increase in the muscle mass, with a clear pattern of change observed in the groups who exercised with moderate to high intensity. The lowest levels of interleukin (IL)-6 in the MSE group (-20.94%) and tumor necrosis factor-α in the HSE group (-28.75%) were observed. Notably, IL-10 showed a significant increase (35.72%) only in the MSE group. In the CON group, natural killer (NK) cells showed a decrease, while in the exercise groups, their levels increased. The highest levels of NK cells were observed in the HSE group. Similar patterns of change were observed in CD4 T cells and CD19 B cells. CD3 and CD8 T cells exhibited significant increases in the MSE and HSE groups. This study presents evidence that engaging in moderate to high-intensity exercise may have a positive impact on cytokines and immunocytes by increasing muscle mass in older adults who may have sarcopenia. Engaging in strength training exercises is considered crucial for maintaining the health of older individuals who are susceptible to sarcopenia. When resistance exercises are performed at a moderate to strenuous intensity, it is anticipated that positive changes can occur in cytokines and immunocytes. These changes can be observed through improvements in thigh muscle volumes as measured by computed tomography.


TREM2 in the pathogenesis of AD: a lipid metabolism regulator and potential metabolic therapeutic target.
Triggering receptor expressed on myeloid cells 2 (TREM2) is a single-pass transmembrane immune receptor that is mainly expressed on microglia in the brain and macrophages in the periphery. Recent studies have identified TREM2 as a risk factor for Alzheimer's disease (AD). Increasing evidence has shown that TREM2 can affect lipid metabolism both in the central nervous system (CNS) and in the periphery. In the CNS, TREM2 affects the metabolism of cholesterol, myelin, and phospholipids and promotes the transition of microglia into a disease-associated phenotype. In the periphery, TREM2 influences lipid metabolism by regulating the onset and progression of obesity and its complications, such as hypercholesterolemia, atherosclerosis, and nonalcoholic fatty liver disease. All these altered lipid metabolism processes could influence the pathogenesis of AD through several means, including affecting inflammation, insulin resistance, and AD pathologies. Herein, we will discuss a potential pathway that TREM2 mediates lipid metabolism to influence the pathogenesis of AD in both the CNS and periphery. Moreover, we discuss the possibility that TREM2 may be a key factor that links central and peripheral lipid metabolism under disease conditions, including AD. This link may be due to impacts on the integrity of the blood-brain barrier, and we introduce potential pathways by which TREM2 affects the blood-brain barrier. Moreover, we discuss the role of lipids in TREM2-associated treatments for AD. We propose some potential therapies targeting TREM2 and discuss the prospect and limitations of these therapies.


Analysis of ionizing radiation induced DNA damage response in human adult stem cells and differentiated neurons.
Findings of neurodegenerative features associated with human radiosensitive syndromes such as Ataxia telangiectasia suggest that DNA repair efficiency is crucial for maintaining the functional integrity of central nervous system. To gain a better understanding of ionizing radiation (IR) induced DNA damage response in undifferentiated and differentiated neural cell types and to evaluate the role of ATM in DNA double strand break (DSB) repair, an in vitro human neural cell differentiation model system was utilized in this study. As compared to adult stem cells, differentiated neurons displayed an attenuated DSB repair response (as judged by the persistence of 53BP1 foci) after IR exposure and the attenuation was even more pronounced in stem cells and neurons after suppression of ATM (Ataxia Telangiectasia Mutated) gene product suggesting the importance of ATM for an optimal DSB repair efficiency in human neural cell types. In corroboration with an attenuated DNA damage response, a sharp decline in the expression levels of several DSB repair genes was observed in neurons. Our results suggest that cellular differentiation modulates the expression of several genes thereby compromising the DSB repair fidelity in post mitotic neurons. Further studies are required to verify whether or not ATM mediated exacerbation of DNA repair deficiency in differentiated neurons leads to neurodegeneration.


Dextrorphan and dextromethorphan attenuate hypoxic injury in neuronal culture.
The dextrorotatory opioid derivatives, dextrorphan and dextromethorphan, can attenuate hypoxic injury in cortical cell cultures. This effect is concentration-dependent in the micromolar range, and not strongly stereospecific, as it can also be demonstrated with the levorotatory enantiomer of dextrorphan, levorphanol. The possibility that these clinically available compounds may have therapeutic utility in hypoxic or ischemic encephalopathy warrants further investigation.


Serum drug concentrations in patients with ischemic heart disease after administration of a sustained release procainamide preparation.
Despite widespread marketing of a sustained release preparation of procainamide hydrochloride (PROCAN-SR, Parke-Davis), published literature demonstrating its efficacy in maintaining uniform serum drug levels over a 6-hour dosing interval is derived from only normal healthy volunteers. Thirty-three patients with ischemic heart disease, ages 30-88 years, were administered 1-4g/24 hours (mean dose 34 mg/kg/day) of PROCAN-SR in 4 equally divided doses on a Q6H schedule. After achievement of steady-state equilibrium drug concentration, procainamide and N-acetylprocainamide levels were determined by high-performance liquid chromatography on sera obtained from blood samples drawn 2, 3.5 and 5 hours after an oral dose. Mean maximal procainamide and N-acetylprocainamide serum concentrations were 4.6 +/- 1.8 microgram/ml and 4.2 +/- 2.1 micrograms/ml respectively. Mean minimal concentrations were 3.5 +/- 1.7 microgram/ml and 3.6 +/- 2.0 micrograms/ml respectively. The mean change in drug concentration was small (1.1 microgram/ml procainamide and 0.6 microgram/ml N-acetylprocainamide) with procainamide and N-acetylprocainamide concentrations varying only by 27 and 15 percent respectively. These data demonstrate in a population of patients with ischemic heart disease, that Q6H dosing with a sustained release procainamide hydrochloride preparation (PROCAN-SR, Parke-Davis) is associated with only a small acceptable variation between maximal and minimal serum procainamide and N-acetylprocainamide concentrations. This preparation should, therefore, offer greater patient convenience and compliance without sacrificing antiarrhythmic efficacy.


The outcomes of transcatheter adrenal ablation in patients with primary aldosteronism: a systematic review and meta-analysis.
The use of transcatheter adrenal ablation as an alternative treatment for primary aldosteronism (PA) patients remains a subject of debate, with outcomes varying widely across existing studies. This meta-analysis aims to evaluate the results of adrenal ablation and estimate the effectiveness and safety of this therapeutic approach. A comprehensive search was conducted across PubMed, Embase, and Cochrane Library databases for studies published up to October 2022. Outcomes analyzed included the combined clinical success rate, biochemical success rate, and complication rate, which were assessed using a random-effects model. Five studies, comprising 234 PA patients, were included in the analysis. The combined clinical success rate was 74% (95% CI: 69%-79%), and the biochemical success rate was 74% (95% CI: 53%-95%). Subgroup analysis revealed that the combined clinical success rate from Unilateral PA (72%, 95% CI: 46%-98%) was similar to the rate from Unilateral + Bilateral (73%, 95% CI: 52.0%-94.0%), while the clinical success rate of the PASO subgroup (78%, 95% CI: 66.0%-89.0%) was higher than the rate of other criteria (51%, 95% CI: 40.0%-63.0%). The combined complication rates were as follows: mild fever, 23% (95% CI: 12%-33%); back pain, 84% (95% CI: 77%-91%); and pleural effusion, 9% (95% CI: 0%-18%). All complications resolved within one week following the procedure. No late complications or ablation-related deaths were reported. Transcatheter adrenal ablation for PA patients is safe and demonstrates a relatively high clinical success rate. Presently, this approach is suitable for PA patients who are unwilling to undergo surgery or receive long-term mineralocorticoid receptor antagonist (MRA) treatment. INPLASY, identifier 2022110076.


ADAM12 is a costimulatory molecule that determines Th1 cell fate and mediates tissue inflammation.
A disintegrin and metalloproteinase (ADAM)12 was previously found to be expressed in T cells in the inflamed brain. However, the function of ADAM12 in T-cell responses in general and in tissue inflammation has not been examined. Here, we studied the role of ADAM12 in T-cell responses, fate determination on activation, and its functions in T cells to mediate tissue inflammation. We identified ADAM12 as a costimulatory molecule that is expressed on naive T cells and downregulated on stimulation. ADAM12 mimics CD28 costimulatory signaling to activate and induce the proliferation of T-helper 1 (Th1) cells. Monoclonal ADAM12 Fab antibodies trigger T-cell activation by amplifying TCR signaling to stimulate T-bet-mediated IFNγ production. Lack of genomic ADAM12 and its knockdown in T cells diminished T-bet and IFNγ production in Th1 cells, whereas other T cells, including Th17 cells, were unaffected. ADAM12 had similar functions in vivo on myelin antigen (MOG35-55)-induced T-cell activation. We found that genetic loss of ADAM12 profoundly alleviated Th1-mediated neuroinflammation and thus disease severity in experimental autoimmune encephalomyelitis, a model of multiple sclerosis. Transcriptomic profiling of MOG35-55-specific ADAM12-/- T cells revealed differentially expressed genes that are important for T-cell activation, proliferation, and costimulatory signaling and Th1 pathogenicity, consistent with their inability to cause T-cell-mediated skin inflammation in a model of adoptive delayed-type hypersensitivity. We conclude that ADAM12 is a T-cell costimulatory molecule that contributes to the pathogenesis of tissue inflammation and a potential target for the treatment of Th1-mediated diseases.


Paediatric nurses' burnout, quality of life and perceived patient adverse events during the COVID-19 pandemic: Testing an integrated model using structural equation modelling.
A model was hypothesised by integrating two theoretical models: the compassion satisfaction-compassion fatigue and empowerment models. This study aimed to assess the extent to which this integrated model can explain the relationships between paediatric nurses' burnout quality of life, perceived patient safety and work-related variables during the COVID-19 pandemic. Nurses' burnout is negatively associated with quality of life (QOL) and positively with patient safety. Several theoretical models were introduced to explain burnout determinants and outcomes such as Golembiewski, Munzenrider and Stevenson model, Leiter and Maslach's process model, and Lee and Ashforth's model. However, few models described burnout in relation to QOL or patient safety. A sample of 225 paediatric nurses responded to questionnaires about burnout, QOL, adverse events and work-related variables. Compassion satisfaction - compassion fatigue and empowerment models were integrated into a single model and tested using structural equation modelling analysis. This study was prepared and is reported according to the STROBE checklist. The final model explained 65% of the variance of burnout and 37% of the variance of QOL. The work-related variables (co-workers' support, job satisfaction, satisfaction with the monthly salary, participation in continuous education and exposure to violence) are predicting paediatric nurses' burnout and quality of life. The Compassion satisfaction - compassion fatigue -Empowerment integrated model allows for assessing the different paths in the relationship between work-related variables and burnout. These results might be essential for nursing managers to develop strategies that improve nurses' work environment and minimise their burnout during COVID-19 pandemic. These strategies should focus on enhancing co-workers' support, job satisfaction and participation in continuous education. Furthermore, paediatric nurses should be protected from any violence.


Comparison of functional and morphologic characteristics of mice models of noise-induced hearing loss.
This study was conducted to compare morphologic and audiologic changes after noise exposure in two different strains of mice (CBA and C57) and to create morphologically proven models of noise-induced hearing loss. Mice were exposed to white noise at 110-dB sound-pressure level for 60 minutes at the age of 1 month. Hearing thresholds and outer hair cell functions were evaluated by auditory brainstem response recordings and distortion product otoacoustic emission immediately and 22 days after noise exposure. Cochlear pathology was observed and compared by light and electron microscopic studies. Both mice strains showed hearing threshold shifts with decreased outer hair cell function immediately and 22 days after noise exposure. More severe auditory brainstem response threshold shifts were observed in C57 mice compared with CBA mice at click, 8-, 16-, and 32-kHz tone-burst stimuli. A cochlear morphologic study demonstrated predominant outer hair cell degeneration at all turns of the cochlea; degeneration was most severe at the basal turn in both mice strains. A scanning electron microscopic study revealed more severe ultrastructural damage of outer hair cells at each turn of the cochlea in C57 mice. The lateral wall of the cochlea was more severely degenerated in CBA mice. Both mice strains showed consistent, permanent noise-induced hearing loss with different susceptibilities and site vulnerabilities. Further studies to investigate the mechanism of the different degree and cochlear site vulnerability to noise exposure between two mice strains are necessary.


Sources, concentrations and risk factors of organochlorine pesticides in soil, water and sediment in the Yellow River estuary.
The environmental occurrence, sources and risk factors of organochlorine pesticides (HCHs and DDTs) and their isomers or metabolites were studied using comprehensive surveys (including soil, surface water, groundwater and sediment sampling) conducted in the Yellow River Delta (YRD). HCHs and DDTs were all detected in multi environmental media. Compared with reported organochlorine pesticide values in China and abroad and with related environmental quality standards, the concentrations of HCHs and DDTs were generally at low levels in the YRD. Composition of OCPs (DDT metabolites and HCH isomers) showed that DDTs in the multiple environments of the YRD not only came from residues of dicofol but also from atmospheric deposition, while HCH pollution results from the historical usage of a mixture of technical HCH and lindane. Furthermore, the sum of Excess Lifetime Cancer Risk (∑ELCR) exposure to HCHs exceeded the generally acceptable risk level of 1.0E-06 recommended by the USEPA for carcinogenic chemicals.


High-Risk Pulmonary Hypertension Does Not Worsen Outcomes in Heart Transplantation.
Pulmonary hypertension (PH) is a relative contraindication to heart transplantation (HT). Multiple studies showed increased mortality in patients with PH. Advances in care may have led to improved outcomes in the modern era. We analyzed patients who underwent HT at our institution between 2014 and 2018. We divided patients into 2 groups based on the presence of high-risk PH defined as either pulmonary vascular resistance >3 Wood units or transpulmonary gradient >15 mm Hg. The primary outcome was survival. Secondary outcomes were post-HT morbidity and changes in hemodynamics. Subsequently, we analyzed national trends of single organ HT recipients with a high-risk PH between 1994 and 2018 from the United Network for Organ Sharing registry. Of 98 patients who underwent HT at our center, 32% had PH. In patients without and with PH, the survival was 100% at 30 days, 87%, and 81% at 3 years (p = 0.96). In both groups, pulmonary vascular resistance and trans-pulmonary gradient decreased after HT. Nationwide data revealed 30-day survival without and with PH at 97% and 98% (p = 0.47) and 3-year survival at 86% and 87% (p = 0.84), respectively, in 2018. The proportion of recipients with PH decreased from 25% in 1994 to 19% in 2018. Recipients of HT with and without high-risk PH had similar early and late mortality in a single-center and nationwide analysis. PH improved immediately after transplant. The United Network for Organ Sharing registry analysis demonstrates continued improvement in survival in patients with PH in the modern era, whereas the relative percentage of recipients with PH decreased over time.


Comparison of patients with and without mental disorders treated for suicide attempts in the emergency departments of four general hospitals in Shenyang, China.
Compare the sociodemographic and psychological characteristics of suicide attempters admitted to emergency departments of general hospitals in China that do and do not meet diagnostic criteria for mental disorders. The Structured Clinical Interview for DSM-IV, the Suicide Ideation Scale, the Hamilton Depression Rating Scale and a quality of life measure were administered to 239 consecutive suicide attempters who were treated in the emergency departments of four randomly selected general hospitals in Shenyang. Among the enrolled subjects, 166 (69.5%) met diagnostic criteria for a current mental disorder. Among these 166 subjects, 62.7% had mood disorders, 14.5% had anxiety disorders, 10.8% had psychotic disorders and 3.6% had substance use disorders. The 73 suicide attempters without a mental disorder were younger, had higher levels of impulsiveness and were more likely to have ideas about being rescued. Multivariate logistic regression analysis identified the following independent predictors of having a current psychiatric disorder in the suicide attempters: female gender (OR=3.67, 95% CI=1.23-10.91), more than 6 years of formal education (OR=1.19, 95% CI=1.04-1.36), a higher score on the suicide ideation scale (OR=1.01, 95% CI=1.00-1.03), a higher score on Hamilton depression rating scale (OR=1.26, 95% CI=1.16-1.37) and a lower score on the quality of life scale (OR=0.75, 95% CI=0.63-0.90). The prevalence of psychiatric disorders in suicide attempters in emergency departments of urban China is lower than that reported in most western countries. Suicide attempters with and without mental illnesses are distinct on a number of important dimensions. Mental health assessment and appropriate discharge planning for patients treated in emergency departments for suicide attempts are crucial components of comprehensive suicide prevention efforts.


Treatment of scabies with oral ivermectin in 15 infants: a retrospective study on tolerance and efficacy.
The incidence of scabies is increasing in Europe, and it often affects children and infants. Although numerous topical treatments have been approved for treatment of scabies in adults, they are often poorly tolerated in infants. One treatment, ivermectin, remains off label for infants weighing < 15 kg. To report our experience on the safety and efficacy of oral ivermectin in refractory scabies in infants. A retrospective study was performed in the dermatology and paediatrics departments of Rouen University Hospital between January 2009 and October 2012. Infants diagnosed with scabies were identified, and the data for those fulfilling the inclusion criteria were analysed. Of 219 infants identified, 15 had received oral ivermectin and had been followed up for at least 3 months. All 15 patients were given two doses of ivermectin, 200 μg kg(-1), at baseline and 14 days later. Of 14 patients contacted 1 month after treatment, 12 had achieved healing. The other two were treated with ivermectin or benzyl benzoate; both healed. Overall, 3 months after the first ivermectin treatment, 13/14 patients had healed and only one had active disease. Ivermectin is generally well tolerated in infants. The 80% rate of healing observed in infants who had failed to respond to at least two other topical treatments suggests that ivermectin could be considered for treatment of infants with recalcitrant or relapsing scabies.


Monoclonal autoantibodies that react with hormones also react with cells not containing those hormones.
Two immunoglobulin M monoclonal autoantibodies, PI-6 and AP-2, were found by immunofluorescence, hormone absorption, and enzyme-linked immunosorbent assay to react with insulin and GH, respectively. The same antibodies were also found to react with a variety of organs that do not contain those hormones. Absorption of PI-6 with insulin, but not with GH, and absorption of AP-2 with GH, but not with insulin, eliminated the capacity of these antibodies to react with all organs tested. It is concluded that these monoclonal antibodies are broadly reactive and recognize epitopes on more than one protein.


Back pain: Prevention and management in the workplace.
Despite all the efforts in studying work-related risk factors for low back pain (LBP), interventions targeting these risk factors to prevent LBP have no proven cost-effectiveness. Even with adequate implementation strategies for these interventions on group level, these did not result in the reduction of incident LBP. Physical exercise, however, does have a primary preventive effect on LBP. For secondary prevention, it seems that there are more opportunities to cost-effectively intervene in reducing the risk of long-term sickness absence due to LBP. Starting at the earliest moment possible with proper assessment of risk factors for long-term sickness absence related to the individual, the underlying mechanisms of the LBP, and also factors related to the workplace by a well-trained clinician, may increase the potential of effective return to work (RTW) management. More research on how to overcome barriers in the uptake of these effective interventions in relation to policy-specific environments, and with regard to proper financing of RTW management is necessary.


Myocardial cell lesions caused by an anabolic hormone.
Early changes in the composition of heart muscle cells of the rat caused by an anabolic hormone were investigated by electron microscopy. Mitochondria and myofibrils showed changes similar to those observed in early heart failure: The mitochondria were swollen and elongated. Their matrix was sparse and the cristae were few in number. The myofibrils showed either disintegration and widened and twisted Z-bands or a complete dissolution of the sarcomeric units.


Alkaptunuria; a case report.
Alkaptonuria is an autosomal recessive disease due to lack of the enzyme homogentisic acid oxidase. Homogentisic Acid (HA) is in the metabolism pathway of phenylalanine. The musculoskeletal symptomatology begins generally in the fourth decade. We reported the case of a 50 year old man who had ochronotic arthropathy and degenerative changes in knee joint and who was treated with total knee arthroplasty. A 50 year old man presented to our outpatient clinic with bilateral knee pain. Pain was exaggerated with effort and decreases with rest. The patient had no medical history. While performing the total knee arhtroplasty for our patient, we discovered intraoperatively the black coloration of the articular cartilage of the knee. At 6 months follow up, the patient was satisfied with the result with no knee pain in the treated knee. Range of knee motion was 0° in total extension to 100° of flexion. Radiological control showed a stable prosthesis not affected by ochronose. Alkaptonuria is caused by lack of the enzyme homogentisic acid oxidase, is a rare autosomal recessive disease leading accumulation of homogentisic acid in connective tissue. This leads to many manifestations such as urinary, cardiac, dermatologic, ophthalmologic or musculoskeletal symptoms. Deposit of Homogentisic acid in articular cartilage gives the characteristic black or dark brown pigmentation of the cartilage. Its clinical traduction is symptomatology of degenerative modifications in multiples joints such as knee, shoulder or hip beside the lumbar spine arthrosis. Alkapyonuria is a very rare condition. Revealed by its orthopedic features is exceptionally. The patients, generally, need articulations replacement and the illness have no effect on its prognosis.


Cancer and Immune Checkpoint Inhibitor Treatment in the Era of SARS-CoV-2 Infection.
Whether cancer patients receiving immune checkpoint inhibitors (ICI) are at an increased risk of severe infection and mortality during the corona pandemic is a hotly debated topic that will continue to evolve. Here, we summarize and discuss current studies regarding COVID-19 and anti-cancer treatment with an emphasis on ICI. Importantly, several lines of evidence suggest that patients currently treated with ICI do not display an increased vulnerability to infection with SARS-CoV-2. Data regarding morbidity and mortality associated with COVID-19 in cancer patients receiving ICI are less clear and often conflicting. Although mostly based on experimental data, it is possible that ICI can promote the exacerbated immune response associated with adverse outcome in COVID-19 patients. On the other hand, mounting evidence suggests that ICI might even be useful in the treatment of viral infections by preventing or ameliorating T cell exhaustion. In this context, the right timing of treatment might be essential. Nevertheless, some cancer patients treated with ICI experience autoimmune-related side effects that require the use of immunosuppressive therapies, which in turn may promote a severe course of infection with SARS-CoV-2. Although there is clear evidence that withholding ICI will have more serious consequences, further studies are urgently needed in to better evaluate the effects of ICI in patients with COVID-19 and the use of ICI during the corona pandemic in general.


Relationship Between Sleep Characteristics and Sudden Unexplained Death Risk in Epilepsy.
Sleep disorders and disturbances are generally underestimated in patients with epilepsy. The aim of this study is to determine the frequency of sleep disturbances and the comorbidity of sleep disorders in people with epilepsy without any complaints about sleep and their relation of sudden unexplained death in epilepsy (SUDEP) risk. Sleep complaints and the presence of sleep disorders were assessed with 4 questionnaires in 139 patients with epilepsy. Subjective sleep features were evaluated with Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), the Berlin Questionnaire for sleep apnea, and restless legs syndrome with International Restless Legs Syndrome Study Group (IRLSSG) severity scale. The presence of rapid eye movement/nonrapid eye movement parasomnia was asked to the patients and their relatives who share the same house. The patients' SUDEP-7 scores were also determined and associations with sleep problems were investigated statistically. Ninety-two patients with focal and 47 patients with generalized epilepsy were evaluated after their consent. The daily sleep quality was poor in 34 (24.5%) patients with PSQI. Daily sleepiness was present in 7 (5%) patients with ESS. Twenty-five patients (18%) had severe sleep apnea risk with the Berlin Questionnaire. Mild or severe RLS was detected in 24 patients (17.2%). There were no significant differences between focal or generalized epilepsy groups' scores. No statistically significant relationship was identified between SUDEP-7 scores and sleep quality or sleep-related disorders. Our results emphasized a remarkable magnitude of the comorbidity of sleep disorders in patients with epilepsy, even for those who do not have complaints about sleep. As SUDEP cases are frequently seen during sleep, it is important to evaluate sleep in patients with epilepsy.


Future therapies in the management of critically ill AIDS patients.
The advent of antiviral therapy for HIV infection and anti-infective agents for the treatment and prophylaxis of Pneumocystis carinii pneumonia has had a significant impact on the survival and quality of life of persons with AIDS and associated conditions. This article discusses zidovudine and other antiviral therapies for HIV infection, as well as some of the new treatment and prophylactic strategies to manage opportunistic infections which can ameliorate the course of advanced HIV infection in patients who may require critical care.


Risk of cerebral venous thrombosis and novel gene polymorphisms of the coagulation and fibrinolytic systems.
Genetic thrombophilic conditions such as those associated with Factor V Leiden (FVL) and the prothrombin mutant (PT G20210A) have been identified as risk factors for cerebral venous thrombosis (CVT). Recently, a single nucleotide polymorphism (SNP) of the thrombin activatable fibrinolysis inhibitor (TAFI G-438A) has been shown to be associated with lower TAFI levels and to decrease the risk for peripheral venous thrombosis. Furthermore, a protective role in juvenile stroke was shown for a SNP of the vitamin K dependent protein Z (PZ Intron F G79A) which is linked with low PZ levels. In 77 consecutive patients with CVT and in 203 randomly selected population controls from the same region of Southern Germany, we investigated the following functional SNPs using PCR and restriction fragment analysis techniques: TAFI G-438A, PZ Intron F G79A, FVL and PT G20210A. The prevalence of FVL tended to be higher (OR 2.08, 95 % CI 0.91-4.75, p = 0.06) and that of PT G20210A (OR 4.57, 95 % CI 1.45-14.44, p = 0.007) was significantly higher in patients with CVT than in controls. The A-allele frequency of the TAFI G-438A polymorphism did not significantly differ between patients (21.3 %) and controls (26.9%; OR 0.71, 95 % CI 0.45-1.12; p = 0.17). For the PZ G79A SNP, the frequency of the A-allele was 19.5% in CVT and 24.6% in controls (OR 0.77, 95 % CI 0.49-1.21; p = 0.31). In this large series of CVT patients, a positive association with established thrombophilic risk factors FVL and especially the PT G20210A mutation was confirmed. In contrast, our study found no significant association of CVT with SNPs of the TAFI and the PZ genes. Other than testing for FVL and the PT G20210A mutation, exploration of these potential thrombophilic variants seems to be of limited value in the investigation of CVT.


The use of Duloxetine in the treatment of male stress urinary incontinence.
Stress urinary incontinence (SUI) is a known complication after prostate surgery. To date no pharmacologic treatment is available. Currently Duloxetine, a serotonin and norepinephrine reuptake inhibitor, is available for women with SUI. This study investigates the effect of Duloxetine on men with SUI after prostate surgery. 56 patients were included in our study. 49 after radical prostatectomy and 7 after TURP. All patients were initially treated with pelvic floor exercises. Thereafter 40 mg Duloxetine was administered twice daily. When taking Duloxetine, the average use of incontinence pads decreased from 3.3 to 1.5 per day. 14 patients needed no and 18 a single pad per day. Most patients reported mild and temporary side effects, 13 patients assessed them to be moderate and 9 being severe. The results of this off-label use show that Duloxetine is effective in men with SUI after prostate surgery even if standard pelvic floor exercises have failed.


Comparison of information on the pharmacokinetic interactions of Ca antagonists in the package inserts from three countries (Japan, USA and UK).
Ca antagonists are one of the most popular classes of drugs used to treat hypertension and angina. These drugs may interact with either CYP3A4 or MDR-1 substrates, with the degree of interaction differing with each drug. We carried out a literature search to examine and compare the extent to which crucial pharmacokinetic (PK) information is included in package inserts (PIs) in Japan, USA and the UK. A MEDLINE search from 1966 to November 2004 was undertaken with the aim of identifying studies on clinical PK drug interactions between seven Ca antagonists that are available in three countries and three CYP3A4 inhibitors (erythromycin, itraconazole and cimetidine), a CYP3A4 inhibitory food, grapefruit juice (GFJ) and the MDR-1 substrate, digoxin. The current PIs for Ca antagonists were obtained from the website of the regulatory authorities or the electronic Medicines Compendium. Of all possible combinations of seven Ca antagonists with three CYP3A4 inhibitor drugs, drug interaction information was available in the literature on nine combinations: Seven of these were listed in the USA PIs, two in the UK PIs, and none in the Japanese PIs. Interaction studies with GFJ were reported for every Ca antagonist; PIs in the USA provided quantitative data for four of these interactions, whereas UK PIs provided quantitative data for only one of the interactions and Japanese PIs provided no quantitative information. The PK data of co-medication of digoxin with Ca antagonists have been reported for every Ca antagonists. The USA PIs provided quantitative data for five Ca antagonists, whereas the UK PIs provided quantitative data for three Ca antagonists and Japanese PIs provided no quantitative data. The literature search revealed that PIs in the USA provided a great deal of quantitative information on PK interactions between Ca antagonists and other drugs or GFJ. In contrast, PIs in the UK and Japan did not provide sufficient information. We conclude that crucial quantitative information on these drug interactions should be incorporated in PIs, especially in Japan and the UK, as a means of assisting healthcare providers.


Contribution of the renin-angiotensin system to the intrarenal resistive index in chronic unilateral partial ureteral obstruction in dogs.
We investigated the role of the renin-angiotensin system on intrarenal hemodynamics in chronic unilateral partial ureteral obstruction (UPUO) using Doppler ultrasound (US). In 11 dogs with chronic UPUO, we determined the renal resistive index (RI) before and 1 h after the intravenous infusion of an angiotensin-converting enzyme (ACE) inhibitor (captopril), an angiotensin II receptor type 1 (ART1) antagonist (L-158,809), and the combination of these two drugs. Change in resistive index (ΔRI) was calculated as RI after the administration of each tested material minus baseline RI. At the baseline measurement, significant differences in RI were seen between obstructed and nonobstructed kidneys. ACE inhibitor, ART1 antagonist, or the combination of these drugs did not result in any significant changes in RI in either obstructed or nonobstructed kidneys. However, in obstructed kidneys, ΔRI in the combination of ACE inhibitor and ART1 antagonist were significantly greater than those in ACE inhibitor or ART1 antagonist alone, whereas there were no significant differences in those values in nonobstructed kidneys. These observations suggest that the renin-angiotensin system in dogs with chronic UPUO may not contribute significantly to the differences in intrarenal RI between obstructed and nonobstructed kidneys. However, the angiotensin-producing pathways and angiotensin II receptor subtypes other than ACE and ART1 may have some different effects between obstructed and nonobstructed kidneys.


18F-Fluorodeoxyglucose PET in Locally Advanced Non-small Cell Lung Cancer: From Predicting Outcomes to Guiding Therapy.
PET using 18-fluorodeoxyglucose (FDG) has become an important part of the work-up for non-small cell lung cancer (NSCLC). This article summarizes advancements in using FDG-PET for patients with locally advanced NSCLC treated with definitive radiation therapy (RT). This article discusses prognostication of outcome based on pretreatment or midtreatment PET metrics, using textural image features to predict treatment outcomes, and using PET to define RT target volumes and inform RT dose modifications. The role of PET is evolving and is moving toward using quantitative image information, with the overarching goal of individualizing therapy to improve outcomes for patients with NSCLC.


Over-expression of the glucagon-like peptide-1 receptor on INS-1 cells confers autocrine stimulation of insulin gene promoter activity: a strategy for production of pancreatic beta-cell lines for use in transplantation.
To develop transplantable beta-cell lines for the treatment of diabetes mellitus, we have taken advantage of the property of INS-1 cells to synthesize and secrete not only insulin, but also small quantities of the insulinotropic hormone glucagon-like peptide-1 (GLP-1). In INS-1 cells over-expressing the beta-cell GLP-1 receptor (GLP-1-R), we have shown, by radioimmune assay and bioassay of conditioned medium, that an autocrine signaling mechanism of hormone action exists whereby self-secreted GLP-1 acts as a competence factor in support of insulin gene transcription. INS-1 cells also exhibit insulin gene promoter activity, as assayed in cells transfected with a rat insulin gene I promoter-luciferase construct (RIP1-Luc). The GLP-1-R agonist exendin-4 stimulates RIP1-Luc activity in a glucose-dependent manner, an effect mediated by endogenous GLP-1-Rs, and is blocked by the serine/threonine protein kinase inhibitor Ro 31-8220. Over-expression of GLP-1-R in transfected INS-1 cells reduces the threshold for exendin-4 agonist action, whereas basal RIP1-Luc activity increases 2.5-fold in the absence of added agonist. The increase of basal RIP1-Luc activity is a consequence of autocrine stimulation by self-secreted GLP-1 and is blocked by introduction of (1) an inactivating W39A mutation in the N-terminus ligand-binding domain of GLP-1-R or (2) mutations in the third cytoplasmic loop that prevent G protein coupling. No evidence for constitutive ligand-independent signaling properties of the GLP-1-R has been obtained. Over-expression of GLP-1-R increases the potency and efficacy of D-glucose as a stimulator of RIP1-Luc. Thus, INS-1 cells over-expressing the GLP-1-R recapitulate the incretin hormone effect of circulating GLP-1, thereby providing a possible strategy by which beta-cell lines may be engineered for efficient glucose-dependent insulin biosynthesis and secretion.


Prenatal diagnosis of cystic fibrosis. II. Meconium ileus in affected fetuses.
Meconium ileus was the presenting feature of cystic fibrosis in 46 per cent of the couples which have been referred for prenatal diagnosis. In fetuses which have been aborted on the basis of alkaline phosphatase isoenzymes assays, meconium ileus represented the only pathological feature of cystic fibrosis, and was observed in three fourths of the cases. Real-time sonographic examination of fetuses at the time of amniocentesis was able to show an echogenic mass in the abdomen corresponding to the meconium ileus, and thus may afford a complementary means of diagnosis.


Rapid detection of fetal aneuploidy using proteomics approaches on amniotic fluid supernatant.
Conventional chromosomal studies or fluorescent in situ hybridization takes days to diagnose fetal aneuploidies during amniocentesis. Here, we evaluated the value of mass spectrometry-based clinical proteomics analysis on amniotic fluid supernatant (AFS) as a rapid detection of fetal aneuploidies. Proteomics profiles generated by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) after fractionating samples with functionalized magnetic beads were used for differentiating 60 normal karyotypic from 20 aneuploid AFS. After the discriminating models were generated using genetic algorithm, we evaluated the clinical efficacy of the models in detecting aneuploidies in two batches (each n=30) of AFS prior to the release of chromosomal diagnoses. Within hours, the two-step proteomics analysis of AFS with the C18 model, followed by the weak cation exchange model, was able to detect aneuploid AFS at 3.3% disease prevalence rate with 100% sensitivity, 72 to 96% specificity, 11 to 50% positive predictive value, and 100% negative predictive value. Clinical proteomics analysis of AFS using magnetic beads-based sample preparation and MALDI-TOF-MS can be used as a rapid detection for fetal aneuploidies. With perfect sensitivity and negative predictive value of the two-step proteomics method, it may be used for rapid detection of aneuploid AFS immediately after amniocentesis. Further large-scale examinations are apparently needed to verify the clinical value of this rapid detection.


Isotropic 3D cardiac cine MRI allows efficient sparse segmentation strategies based on 3D surface reconstruction.
Segmentation of cardiac cine MRI data is routinely used for the volumetric analysis of cardiac function. Conventionally, 2D contours are drawn on short-axis (SAX) image stacks with relatively thick slices (typically 8 mm). Here, an acquisition/reconstruction strategy is used for obtaining isotropic 3D cine datasets; reformatted slices are then used to optimize the manual segmentation workflow. Isotropic 3D cine datasets were obtained from multiple 2D cine stacks (acquired during free-breathing in SAX and long-axis (LAX) orientations) using nonrigid motion correction (cine-GRICS method) and super-resolution. Several manual segmentation strategies were then compared, including conventional SAX segmentation, LAX segmentation in three views only, and combinations of SAX and LAX slices. An implicit B-spline surface reconstruction algorithm is proposed to reconstruct the left ventricular cavity surface from the sparse set of 2D contours. All tested sparse segmentation strategies were in good agreement, with Dice scores above 0.9 despite using fewer slices (3-6 sparse slices instead of 8-10 contiguous SAX slices). When compared to independent phase-contrast flow measurements, stroke volumes computed from four or six sparse slices had slightly higher precision than conventional SAX segmentation (error standard deviation of 5.4 mL against 6.1 mL) at the cost of slightly lower accuracy (bias of -1.2 mL against 0.2 mL). Functional parameters also showed a trend to improved precision, including end-diastolic volumes, end-systolic volumes, and ejection fractions). The postprocessing workflow of 3D isotropic cardiac imaging strategies can be optimized using sparse segmentation and 3D surface reconstruction. Magn Reson Med 79:2665-2675, 2018. © 2017 International Society for Magnetic Resonance in Medicine.


Lisuride in de novo parkinsonian patients: a four-year follow-up.
Lisuride at a mean daily dose of 3.2 mg was given to 15 untreated idiopathic Parkinson's disease patients. There were 10 dropouts, due mainly to inefficacy in the first months of therapy. The parkinsonian pattern in the patients who remained in the study for the full 4 years showed distinct improvement, which was maintained for less than 2 years. The patients did not develop "on-off" phenomena or abnormal involuntary movements during follow-up.


Periodic Acid Modification of Chemical-Bath Deposited SnO2 Electron Transport Layers for Perovskite Solar Cells and Mini Modules.
Chemical bath deposition (CBD) has been demonstrated as a remarkable technology to fabricate high-quality SnO2 electron transport layer (ETL) for large-area perovskite solar cells (PSCs). However, surface defects always exist on the SnO2 film coated by the CBD process, impairing the devices' performance. Here, a facile periodic acid post-treatment (PAPT) method is developed to modify the SnO2 layer. Periodic acid can react with hydroxyl groups on the surface of SnO2 films and oxidize Tin(II) oxide to Tin(IV) oxide. With the help of periodic acid, a better energy level alignment between the SnO2 and perovskite layers is achieved. In addition, the PAPT method inhibits interfacial nonradiative recombination and facilitates charge transportation. Such a multifunctional strategy enables to fabricate PSC with a champion power conversion efficiency (PCE) of 22.25%, which remains 93.32% of its initial efficiency after 3000 h without any encapsulation. Furthermore, 3 × 3 cm2 perovskite mini-modules are presented, achieving a champion efficiency of 18.10%. All these results suggest that the PAPT method is promising for promoting the commercial application of large-area PSCs.


Myocardial systolic strain abnormalities in patients with acromegaly: a prospective color Doppler imaging study.
Heart abnormalities are frequent findings in patients with acromegaly: systolic abnormalities are considered to be secondary to diastolic changes. The aim of the study was to evaluate whether early systolic abnormalities might be revealed in acromegalic patients using the high sensitive color Doppler myocardial imaging (CDMI) technique. Twenty-two consecutive acromegalic patients with active untreated disease (ACROUNTR) were evaluated at baseline and after a 6-month course with SS analogs (SSa) (ACROSSa); 25 healthy subjects served as controls. All subjects underwent conventional 2D-color Doppler echocardiography, pulse wave tissue Doppler imaging (PW-TDI) and CDMI. Mean left ventricular (LV) ejection fraction did not differ in ACROUNTR and in controls; at variance, ACROUNTR patients had reduced mean LV diastolic function (E/A ratio: 0.96+/-0.3 vs controls: 1.6+/-0.3; p<0.002). Impairment of global LV diastolic function was confirmed by PW-TDI in ACROUNTR patients having a normal systolic function. Regional myocardial systolic strain (epsilon) and strain rate (SR) values, indices of regional systolic heart deformation, were lower in ACROUNTR [epsilonsys (S) -19.8+/-2.9 and epsilonsys (L): -17.7+/-2.2] than in controls [epsilonsys (S): -27.9+/-3.8; p<0.001 and epsilonsys (L): -25.3+/-2.6; p<0.001]. In addition, the early phase of diastolic function, evaluated using SR parameters, was impaired in acromegalic patients (p<0.005 vs controls). Strain and SR values were related to serum GH and IGF-I levels (p<0.02) and greatly improved after a 6-month course with SSa [epsilonsys (S) improved to -23.8+/-3.8 (p<0.05) and epsilonsys (L) improved to -24.7+/-2.4 (p<0.03)]. Our study confirms that ACROUNTR patients have impaired diastolic function. More important, our study clearly shows that ACROUNTR patients have an impairment of regional myocardial systolic function, which is not secondary to diastolic changes. These intramyocardial functional abnormalities improved during medical treatment of acromegaly. It is conceivable that GH-IGF-I excess has detrimental effects either on the diastolic or the systolic phases of heart function.


Selective solid phase extraction of trace Sc(III) from environmental samples using silica gel modified with 4-(2-morinyldiazenyl)-N-(3-(trimethylsilyl)propyl)benzamide.
In this study, a new 4-(2-morinyldiazenyl)-N-(3-(trimethylsilyl)propyl)benzamide modified silica gel (SG-MTPB) sorbent was prepared and characterized by FT-IR spectroscopy and studied for separation and preconcentration of Sc(III) prior to its determination by inductively coupled plasma atomic emission spectrometry (ICP-AES). Experimental conditions for effective adsorption of trace Sc(III) were optimized using both batch and column procedures. At pH 3, Sc(III) could be quantitatively adsorbed on the new sorbent. And the adsorbed Sc(III) could be completely eluted by using 2 mL of 6 mol L(-1) of HCl+2% CS(NH(2))(2). Most common coexisting ions did not interfere with the separation and preconcentration of Sc(III) at optimal conditions. The maximum static adsorption capacity of the sorbent for Sc(III) was 600 micaromol g(-1) while the time of 95% adsorption was less than 2 min. The detection limit of present method was found to be 0.085 micarog g(-1), and the relative standard deviation (R.S.D.) was lower than 1.3%. The method was also successfully applied to the preconcentration of trace Sc(III) in the environmental samples with satisfactory results.


Cu-NPs@C Nanosheets Derived from a PVP-assisted 2D Cu-MOF with Renewable Ligand for High-Efficient Selective Hydrogenation of 5-Hydroxymethylfurfural.
5-Hydroxymethylfurfural (HMF) containing C=O, C-O, and furan ring functional groups is an important platform chemical derived from C6 sugars. The selective hydrogenation of C=O in HMF produces 2,5-dihydroxymethylfuran (DHMF), which is a potential sustainable substitute for petroleum-based building blocks. Here, 2,5-furandicarboxylic acid (H2 FDC), a promising sustainable alternative to terephthalic acid, was employed as a renewable ligand to synthesize a novel Cu metal-organic framework (Cu-FDC). With a polyvinyl pyrrolidone (PVP)-assisted approach, 2D Cu-FDC nano-lamellae of micrometer lateral dimensions and nanometer thickness could be obtained, which could be used as a precursor to fabricate 2D oxygen-rich carbon nanosheets embedded with Cu nanoparticles (denoted CFP-300) after a thermal treatment at 300 °C under N2 atmosphere. The synthesized CFP-300 exhibited excellent catalytic performance and stability for the selective hydrogenation of HMF to DHMF. These results demonstrated a sustainable route to synthesize efficient catalysts by employing metal-organic frameworks based on renewable ligands.


Indications and management of preimplantation genetic testing for monogenic conditions: a committee opinion.
This statement is offered to update and expand on the prior American Society for Reproductive Medicine preimplantation genetic testing (PGT) opinion, elucidate the current clinical and technical complexities specific to PGT for monogenic conditions, assist providers in supporting patient understanding of and access to this technology, and offer considerations for the development of future clinical and laboratory guidelines on PGT for monogenic conditions.