A comparative, randomized trial of concentration-controlled sirolimus combined with reduced-dose tacrolimus or standard-dose tacrolimus in renal allograft recipients.
The clinical safety and efficacy of sirolimus plus reduced-dose tacrolimus was evaluated in de novo renal allograft recipients enrolled in a comparative, open-label study. One hundred twenty-eight renal allograft recipients were randomly assigned (1:1) to receive reduced-dose tacrolimus plus sirolimus (rTAC) or standard-dose tacrolimus and sirolimus (sTAC) for 6 months. The primary efficacy endpoint was calculated creatinine clearance values at 6 months. Demographic variables were similar between groups. At 6 months, mean (± standard deviation) calculated creatinine clearance was significantly improved in the rTAC group (63.8 vs 52.7 mL/min, P = .005), although mean serum creatinine values were not significantly different. Patient survival (95.2% and 96.9%) and graft survival (93.7% and 98.5%) were similar between the rTAC and sTAC groups, respectively. Acute rejection rates were 17.5% with rTAC and 7.7% with sTAC (P = .095). The rTAC regimen provided effective immunosuppression and was associated with improved creatinine clearance. Adequate immunosuppressant exposure must be achieved in the early postoperative period to minimize the risk of acute rejection.


XAV939 Improves the Prognosis of Myocardial Infarction by Blocking the Wnt/β-Catenin Signalling Pathway.
Myocardial infarction (MI) is closely related to the Wnt signalling pathway, but the role of XAV939 (a Wnt/β-catenin signalling pathway blocker) in MI has not been elucidated. The purpose of this study was to explore the role of XAV939 in mouse hearts and to provide a new and feasible treatment for improving the prognosis of MI. C57BL/6 (male, 8 weeks old, 20-25 g) mice were selected for our study. The MI model was made by ligating the left anterior descending coronary artery. On day 28 after the operation, cardiac function was examined by echocardiography. Infarct size, fibrosis, and angiogenesis were individually measured by TTC assays, Masson's trichrome staining, and CD31 analysis, respectively. Apoptosis was examined by TdT-mediated dUTP nick-end labelling (TUNEL) staining. The expression of Wnt, β-catenin, caspase 3, Bax, and Bcl-2 was determined by western blotting. XAV939 successfully blocked Wnt/β-catenin signalling pathway activation in cardiomyocytes after MI by promoting the degradation of β-catenin. XAV939 suppressed fibrosis and apoptosis, promoted angiogenesis, reduced myocardial infarct size and improved cardiac function after MI. XAV939 can reduce myocardial infarct size and improve cardiac function by blocking the Wnt/β-catenin signalling pathway, which may provide a new strategy for improving the prognosis of MI.


Iodine Supplemented Diet Positively Affect Immune Response and Dairy Product Quality in Fresian Cow.
The effects of iodine supplementation on the whole-transcriptome of dairy cow using RNA sequencing has been investigated in this study. Iodine did not influence the milk composition, while an improvement was observed in the immune response as well as in the quality of dairy product. Indeed, the iodine intake specifically influenced the expression of 525 genes and the pathway analysis demonstrated that the most affected among them were related to immune response and oxidative stress. As a consequence, we indirectly showed a better response to bacterial infection because of the reduction of somatic cell counts; furthermore, an improvement of dairy product quality was observed since lipid oxidation reduced in fresh cheese. Such findings, together with the higher milk iodine content, clearly demonstrated that iodine supplementation in dairy cow could represent a beneficial practice to preserve animal health and to improve the nutraceutical properties of milk and its derived products.


Safety and Efficacy of Enoxaparin in Pregnancy: A Systematic Review and Meta-Analysis.
International guidelines support the use of low molecular weight heparins for the treatment of thromboembolism and thromboprophylaxis during pregnancy. However, evidence of the benefit and harm associated with specific low molecular weight heparins such as enoxaparin is dated. No current systematic review and meta-analysis describing the safety and efficacy of enoxaparin for thromboembolism and thromboprophylaxis during pregnancy exists. PubMed, Embase, and Cochrane databases were searched on August 17, 2018 for clinical trials or observational studies in pregnant women receiving enoxaparin; patients with a prosthetic heart valve were excluded. Risk ratios (RR) with 95% confidence intervals (CI) were calculated using a random effects model, and heterogeneity was measured using the I2 statistic. Of the 485 records identified in the search, 24 studies published clinical trials, and observational studies were found dating back to 2000. Only one observational cohort and one randomized control trial focused on the use of enoxaparin for thromboprophylaxis and therefore efficacy was not assessed; the other studies included women with recurrent pregnancy loss (15 studies), history of placental vascular complications (five studies), and recurrent in vitro fertilization failure (two studies) and were therefore analyzed in terms of safety only. Bleeding events were non-significantly more often reported for enoxaparin compared to untreated controls (RR 1.35 [0.88-2.07]) but less often reported for enoxaparin versus aspirin (RR 0.93 [0.62-1.39]); thromboembolic events, thrombocytopenia, and teratogenicity were rarely reported events; in patients with a history of recurrent pregnancy loss, encouragingly the rates of pregnancy loss were significantly lower for enoxaparin compared to untreated controls (RR 0.58 [0.34-0.96]) and enoxaparin + aspirin versus aspirin alone (RR 0.42 [0.32-0.56]) as well as observably lower for enoxaparin versus aspirin alone (RR 0.39 [0.15-1.01]), though significant heterogeneity was observed (I2 > 60). Literature on the efficacy and safety of enoxaparin for thromboembolism and thromboprophylaxis remains scanty, and therefore efficacy was not assessed; in terms of safety, when including other indications for enoxaparin in pregnancy, we found that enoxaparin was associated with significantly lower complications than aspirin. Given differences in study design and study heterogeneity, pregnancy loss results should be interpreted with caution. Moreover, reports of thromboembolic events, thrombocytopenia, and congenital malformations were rare. Sanofi.


Differing responses of the estuarine bivalve Limecola balthica to lowered water pH caused by potential CO2 leaks from a sub-seabed storage site in the Baltic Sea: An experimental study.
Sub-Seabed CCS is regarded as a key technology for the reduction of CO2 emissions, but little is known about the mechanisms through which leakages from storage sites impact benthic species. In this study, the biological responses of the infaunal bivalve Limecola balthica to CO2-induced seawater acidification (pH7.7, 7.0, and 6.3) were quantified in 56-day mesocosm experiments. Increased water acidity caused changes in behavioral and physiological traits, but even the most acidic conditions did not prove to be fatal. In response to hypercapnia, the bivalves approached the sediment surface and increased respiration rates. Lower seawater pH reduced shell weight and growth, while it simultaneously increased soft tissue weight; this places L. balthica in a somewhat unique position among marine invertebrates.


Tunable molecular packing modes via H- or J-aggregates in the supramolecular helical nanostructures from an achiral C3 symmetric molecule.
The self-assembly of a C3-symmetric molecule benzene-1,3,5-tricarboxylate substituted with methyl cinnamate (BTECM) has been investigated by a reprecipitation method in H2O and cetyltrimethylammonium bromide (CTAB) aqueous solution, respectively. The nanostructures and characteristics of the assemblies were monitored by UV-Vis spectroscopy, fluorescence (FL) spectroscopy, circular dichroism (CD) spectroscopy, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). It was found that helical nanostructures were successfully assembled from the achiral C3 molecule BTECM. More importantly, the helices aggregated via different packing modes in H2O and CTAB aqueous solution. In H2O, the nanostructures underwent a process of particles, fibers and helices via H-type aggregate upon aging. In the case of CTAB aqueous solution (1.2 mM), the helices were translated from particles and the molecules were inclined to aggregate via the J-type mode. In addition, the aggregation process could be accelerated by raising the temperature proved by UV-Vis spectra. A molecular aggregation mechanism was proposed based on the experimental results.


Hypertriglyceridemic waist phenotype in primary health care: comparison of two cutoff points.
We aimed to evaluate the prevalence of hypertriglyceridemic waist (HTGW) phenotype among users of primary health care using two different cutoff points used in the literature. We evaluated adults and elderly individuals of both sexes who attended the same level of primary health care. HTGW phenotype was determined with measurements of waist circumference (WC) and triglyceride levels and compared using cutoff points proposed by the National Cholesterol Education Program - NCEP/ATP III (WC ≥102 cm for men and ≥88 cm for women; triglyceride levels ≥150 mg/dL for both sexes) and by Lemieux et al (WC ≥90 cm for men and ≥85 cm for women; triglyceride levels ≥177 mg/dL for both). Within the sample of 437 individuals, 73.7% was female. The prevalence of HTGW phenotype was high and statistically different with the use of different cutoff points from the literature. The prevalence was higher using the NCEP/ATP III criteria compared to those proposed by Lemieux et al (36.2% and 32.5%, respectively, p<0.05). Individuals with the presence of the phenotype also presented alterations in other traditional cardiovascular risk markers. The HTGW phenotype identified high prevalence of cardiovascular risk in the population, with higher cutoff points from the NCEP/ATP III criteria. The difference in frequency of risk alerts us to the need to establish cutoff points for the Brazilian population.


Inactivation of Stat3 in tumor cells: releasing a brake on immune responses against cancer?
A model of immune evasion mediated by tumors expressing constitutively activated Stat3 was recently proposed in Nature Medicine by Wang et al., suggesting opportunities for a new therapeutic approach for cancer.


Synthesis and biological evaluation of novel isoxazolo[4,3-e]indoles as antibacterial agents.
The synthesis of a new series of 8-bromo-6-alkyl-1-aryl-6H-isoxazolo[4,3-e]indole derivatives is described. All the newly synthesized compounds were screened for their antibacterial activity against Escherichia coli HB101, Staphylococcuse aureus pathogens (methicillin resistant S. aureus and methicillin susceptible S. aureus), Pseudomonas aeruginosa, and Bacillus subtilis; also MIC values of these compounds were determined.


A critical look at capsule contracture in subglandular versus subpectoral mammary augmentation.
A critical comparison of the contracture rate in subglandular versus subpectoral augmentations was done in a personal series (senior author's) of 100 consecutive augmentation patients, 50 with subglandular augmentation and 50 with subpectoral augmentation. The average followup for the series was 27 months. Baker's classification of capsule contracture was utilized. Overall contracture rate in the subglandular group was 58% (29 of 50 patients) while in the subpectoral group it was 22% (11 of 50 patients), p less than 0.0002. Considering only the more severe contractures (Baker III & IV), the subglandular patients had 48% (24/50) while the subpectoral patients had 14% (7/50), p less than 0.0002. Comparing the more severe contractures in individual breasts, the subglandular group had 41% and the subpectoral group had 8%, p less than 0.0001. We conclude that in this personal series of patients, subpectoral placement of the prosthesis has significantly reduced but not eliminated the occurrence of capsule contracture without sacrificing a normal breast appearance.


Barriers and facilitators for implementing a new screening tool in an emergency department: A qualitative study applying the Theoretical Domains Framework.
The aim was to identify the factors that were perceived as most important as facilitators or barriers to the introduction and intended use of a new tool in the emergency department among nurses and a geriatric team. A high incidence of functional decline after hospitalisation for acute medical illness has been shown in the oldest patients and those who are physically frail. In Denmark, more than 35% of older medical patients acutely admitted to the emergency department are readmitted within 90 days after discharge. A new screening tool for use in the emergency department aiming to identify patients at particularly high risk of functional decline and readmission was developed. Qualitative study based on semistructured interviews with nurses and a geriatric team in the emergency department and semistructured single interviews with their managers. The Theoretical Domains Framework guided data collection and analysis. Content analysis was performed whereby new themes and themes already existing within each domain were described. Six predominant domains were identified: (1) professional role and identity; (2) beliefs about consequences; (3) goals; (4) knowledge; (5) optimism and (6) environmental context and resources. The content analysis identified three themes, each containing two subthemes. The themes were professional role and identity, beliefs about consequences and preconditions for a successful implementation. Two different cultures were identified in the emergency department. These cultures applied to different professional roles and identity, different actions and sense making and identified how barriers and facilitators linked to the new screening tool were perceived. The results show that different cultures exist in the same local context and influence the perception of barriers and facilitators differently. These cultures must be identified and addressed when implementation is planned.


The Experimental Study of Bacterial Evolution and Its Implications for the Modern Synthesis of Evolutionary Biology.
Since the 1940s, microbiologists, biochemists and population geneticists have experimented with the genetic mechanisms of microorganisms in order to investigate evolutionary processes. These evolutionary studies of bacteria and other microorganisms gained some recognition from the standard-bearers of the modern synthesis of evolutionary biology, especially Theodosius Dobzhansky and Ledyard Stebbins. A further period of post-synthesis bacterial evolutionary research occurred between the 1950s and 1980s. These experimental analyses focused on the evolution of population and genetic structure, the adaptive gain of new functions, and the evolutionary consequences of competition dynamics. This large body of research aimed to make evolutionary theory testable and predictive, by giving it mechanistic underpinnings. Although evolutionary microbiologists promoted bacterial experiments as methodologically advantageous and a source of general insight into evolution, they also acknowledged the biological differences of bacteria. My historical overview concludes with reflections on what bacterial evolutionary research achieved in this period, and its implications for the still-developing modern synthesis.


Facial profile based evaluation of gingival zenith position in maxillary central incisors among Saudi, Indian & Bangladeshi population.
Recently quantitative evaluation of gingival zenith position was evaluated in different facial forms suggesting clinicians may need to evaluate patients facial form and then decide to distalise the Gingival Zenith position in relation to Vertical Bisected Midline (VBM). The aim of the study was to quantitatively evaluate the gingival zenith width in convex, concave and straight facial profiles for Saudi, Indian and Bangladeshi nationals. 114 subjects of each Saudi, Indian & Bangladeshi nationality were grouped into convex, concave and straight profile based on angle of convexity. Gingival zenith position (GZP) on #11 and #21 was evaluated on the scanned dental plaster model using CBCT. Inter and Intra group comparison was done using one-way ANOVA test. Mean GZP values ranged from 0.84 mm to 1.10 mm, 0.75 mm to 1.02 mm and 0.87 mm to 1.14 mm for Saudi, Indian and Bangladeshi subjects respectively. Statistically significant (p < 0.05) difference was observed in convex, concave and straight profile subjects of these nationalities. GZP variation does exist in different facial profiles of Saudi, Indian & Bangladeshi nationalities with respect to central incisors. These findings help clinician to consider facial profile as important entity in designing the smile following restorative and prosthetic procedures such as crown lengthening, teeth selection, implant esthetics and laminates.


Learning time-varying categories.
Many kinds of objects and events in our world have a strongly time-dependent quality. However, most theories about concepts and categories either are insensitive to variation over time or treat it as a nuisance factor that produces irrational order effects during learning. In this article, we present two category learning experiments in which we explored peoples' ability to learn categories whose structure is strongly time-dependent. We suggest that order effects in categorization may in part reflect a sensitivity to changing environments, and that understanding dynamically changing concepts is an important part of developing a full account of human categorization.


Correction to: Corneal Epithelial Findings in Patients with Multiple Myeloma Treated with Antibody-Drug Conjugate Belantamab Mafodotin in the Pivotal, Randomized, DREAMM-2 Study.
The authors of the above mentioned article would like to highlight the following corrections, based upon recent changes to the FDA label and guidance on the use of belamaf.


Acquired hepatocerebral degeneration and hepatic encephalopathy: one or two entities?
Acquired hepatocerebral degeneration (AHD) and hepatic encephalopathy (HE) are neurological complications of chronic liver disease (CLD) with portosystemic shunt. While HE is common, AHD is a rare entity, and the clinical imaging relationships observed in small series lack validation in large patient cohorts. The aim of this study was to characterize a cohort of AHD patients and to explore possible associations with HE coexistence. We performed a retrospective analysis of patients with a working AHD diagnosis, between 2008 and 2019. Clinical, laboratory, imaging and neuropsychological results at first neurological observation were reviewed and compared between the 'AHD' group and the 'AHD with HE' group. A total of 76 patients were recruited. The most frequent neurological manifestations were neuropsychiatric (93.4%) and extrapyramidal (84.2%). Only 38% of patients had hypermanganesemia. Compared with the AHD group, the AHD with HE group had more hyperkinetic movement disorders (71.4% vs. 38.5%; P = 0.05), a higher number of patients on the dementia spectrum (57.7% vs. 20%; P = 0.04), higher median ammonia levels (P = 0.014) and more widespread cortico-subcortical and pyramidal involvement on brain magnetic resonance imaging. Nineteen patients underwent liver transplantation, with significantly improved survival (P = 0.006). Hepatic encephalopathy and AHD often coexist in the same patient. Seventy-six patients with CLD and AHD were evaluated, making this one of the largest reported AHD cohorts. Blood manganese level was a weak diagnostic marker in AHD. Early liver function restoration through liver transplantation improved survival. Our report provides a detailed description of the phenotype and long-term outcome of AHD, with relevance for diagnosis and treatment.


Maize Defective Kernel605 Encodes a Canonical DYW-Type PPR Protein that Edits a Conserved Site of nad1 and Is Essential for Seed Nutritional Quality.
Pentatricopeptide repeat (PPR) proteins involved in mitochondrial RNA cytidine (C)-to-uridine (U) editing mostly result in stagnant embryo and endosperm development upon loss of function. However, less is known about PPRs that are involved in farinaceous endosperm formation and maize quality. Here, we cloned a maize DYW-type PPR Defective Kernel605 (Dek605). Mutation of Dek605 delayed seed and seedling development. Mitochondrial transcript analysis of dek605 revealed that loss of DEK605 impaired C-to-U editing at the nad1-608 site and fails to alter Ser203 to Phe203 in NAD1 (dehydrogenase complex I), disrupting complex I assembly and reducing NADH dehydrogenase activity. Meanwhile, complexes III and IV in the cytochrome pathway, as well as AOX2 in the alternative respiratory pathway, are dramatically increased. Interestingly, the dek605 mutation resulted in opaque endosperm and increased levels of the free amino acids alanine, aspartic acid and phenylalanine. The down- and upregulated genes mainly involved in stress response-related and seed dormancy-related pathways, respectively, were observed after transcriptome analysis of dek605 at 12 d after pollination. Collectively, these results indicate that Dek605 specifically affects the single nad1-608 site and is required for normal seed development and resulted in nutritional quality relevant amino acid accumulation.


Facial plastic surgery and face recognition algorithms: Interaction and challenges. A scoping review and future directions.
Face recognition (FR) technology can be used in wide range of applications such as identity authentication, access control, and surveillance. Interests and research activities in face recognition have increased significantly over the past twenty years. Plastic surgery procedures can significantly alter facial appearance, thereby posing a serious challenge even to the state-of-the-art face matching algorithms. The purpose of this work was to detail the interaction between facial plastic surgery and facial recognition software and discuss the new challenges of this interaction. The authors critically reviewed the literature from January 2000 to September 2019, to identify articles reporting interactions between facial plastic surgery and facial recognition algorithms and discuss the new challenges of these interactions. Controlled vocabulary terms and keywords were used in the search strategy and two authors independently analyzed data. Factors included in the analysis were: Author, Journal, Year, Scope, Study design, Plastic surgery, Data (volume, origin and processing), Identification accuracy and Conclusion (interaction/challenge). Forty-three research articles underwent data extraction and 28 articles were included in quantitative synthesis. Of the 28 articles, the most common study designs were experimental evaluation (n=15, 53,5%), Evaluation Study studies (n=7, 25%) and Review studies (n=4, 14,3%). Fifty percent of the articles have been published in the last 4 years (14 articles, 50%). Most of the study scope was informatics (64,3%). Only 10 articles were published in medical journals. Rhytidectomy (face lift) is the most challenging procedure for the FR algorithms. Data volume varied from 4 to 2878 subjects. The proposed algorithms provide at least 15 to 99% better identification performance. Among these, only two papers discuss the new challenges of the interaction between facial plastic surgery and Face Recognition Algorithms. In the context of advances in artificial intelligence, Internet connectivity and data integration, the purpose of this review is, to look forward to analyze the new interactions of facial plastic surgery and facial recognition algorithms, and to suggest avenues for future research and clinical application of this technology. Furthermore, to evaluate if plastic surgeons are prepared to discuss this technology with their patients. Plastic surgeons should be prepared to answer questions from patients about the fundamentals of facial recognition technology, and the potential effects of plastic surgery on facial recognition technology performance. Continued efforts are needed to provide scientifically rigorous data of facial biometric identification after facial plastic surgery and to include these notions in the routine consultation or consent process for patients seeking aesthetic facial surgery.


Venom phenotype conservation suggests integrated specialization in a lizard-eating snake.
Biological specialization reduces the size of niche space while increasing efficiency in the use of available resources. Specialization often leads to phenotypic changes via natural selection aligning with niche space constraints. Commonly observed changes are in size, shape, behavior, and traits associated with feeding. One often selected trait for dietary specialization is venom, which, in snakes, often shows variation dependent on diet across and within species. The Neotropical Blunt-headed Treesnake (Imantodes cenchoa) is a highly specialized, rear-fanged, arboreal, lizard hunter that displays a long thin body, enlarged eyes, and a large Duvernoy's gland. However, toxin characterization of I. cenchoa has never been completed. Here, we use RNA-seq and mass spectrometry to assemble, annotate, and analyze the venom gland transcriptomes of four I. cenchoa from across their range. We find a lack of significant venom variation at the sequence and expression levels, suggesting venom conservation across the species. We propose this conservation provides evidence of a specialized venom repertoire, adapted to maximize efficiency of capturing and processing lizards. Importantly, this study provides the most complete venom gland transcriptomes of I. cenchoa and evidence of venom specialization in a rear-fanged snake, giving insight into selective pressures of venom across all snake species.


Dependence of the acoustic propulsion of nano- and microcones on their orientation and aspect ratio.
Recent research revealed the orientation-dependent propulsion of a cone-shaped colloidal particle that is exposed to a planar traveling ultrasound wave. Here, we extend the previous research by considering nano- and microcones with different aspect ratios and studying how the propulsion of a particle depends on its orientation and aspect ratio. We also study how the orientation-averaged propulsion of a cone-shaped particle, which corresponds to an isotropic ultrasound field, depends on its aspect ratio and identify an aspect ratio of 1/2 where the orientation-averaged propulsion is particularly strong. To make our simulation results easier reusable for follow-up research, we provide a corresponding simple analytic representation.


Brackiella oedipodis gen. nov., sp. nov., gram-negative, oxidase-positive rods that cause endocarditis of cotton-topped tamarin (Saguinus oedipus).
A gram-negative, oxidase-positive, rod-shaped bacterium isolated from the heart of a cotton-topped tamarin was characterized by 16S rDNA sequence analysis, SDS-PAGE of whole-cell proteins, fatty acid analysis and biochemical tests. Outer-membrane proteins, iron-regulated outer-membrane proteins, lipopolysaccharides and siderophore production were studied. On the basis of the results, the organism belongs to the beta-Proteobacteria where it forms a separate line of descent, for which a novel genus and species are proposed, Brackiella oedipodis (LMG 19451T = DSM 13743T = NCIMB 13739T). Nearest phylogenetic neighbours of the new genus are Taylorella, Pelistega, Bordetella, Alcaligenes and Achromobacter.


One-step synthesis of water-soluble AgInS2 and ZnS-AgInS2 composite nanocrystals and their photocatalytic activities.
Water-soluble AgInS(2) (AIS) nanocrystals (NCs) have been synthesized for the first time in the presence of GSH as capping ligand in aqueous media at low temperature of 95 °C. The investigations on the effects of various experimental variables including pH value, GSH/In, In/Ag, and In/S ratios on the optical properties showed that the long time, pH of 8.5 and large GSH/In ratio could increase the intensity of the shorter wavelength (position not changed) emission, while the ratios of In/Ag and In/S could affect the emission wavelength and intensity as well as the intensity ratio of longer to shorter wavelength emission with the shorter wavelength emission tunable from 560 to 660 nm. After modifying with ZnS, the obtained ZnS-AgInS(2) (ZAIS) NCs show both slightly blue-shifted stronger PL emission and higher quantum yield increasing to 5 fold. The obtained AIS and ZAIS NCs showed promising photocatalytic activities in the degradation of rhodamine B.


Predicting childhood chronic kidney disease severity in infants with posterior urethral valve: a critical analysis of creatinine values in the first year of life.
Posterior urethral valve (PUV) is a leading cause of chronic kidney failure in children. Studies have shown that a creatinine nadir above historical cutoff values of 0.8 or 1.0 mg/dL correlates with worse kidney outcomes. The ability to use nadir creatinine more discriminately as a test of kidney outcomes is otherwise limited. We performed a retrospective review of 102 infants treated with primary valve ablation prior to 1 year of age. Patient factors including creatinine at presentation (Cr-P), nadir within 6 weeks after ablation (Cr-6 W), and nadir within 1 year after ablation (Cr-1Y) were assessed as predictors of final chronic kidney disease (CKD) severity. An optimal threshold for four CKD levels was defined in incremental fashion using binary outcome with receiver operating characteristic (ROC). Multivariable logistic regression models compared Cr-P, Cr-6 W, and Cr-1Y while adjusting for patient factors. Boys were ablated at mean age of 36.3 days and followed for 6.6 years (± 3.7). When compared to other demographics, only creatinine remained independently predictive of CKD outcomes on multivariable analysis. ROC analysis demonstrated excellent diagnostic accuracy for Cr-6 W and Cr-1Y (p < 0.001) and acceptable accuracy for Cr-P (p < 0.005). Using the Cr-6 W and Cr-1Y models, high sensitivity and specificity creatinine nadir cutoffs were determined to predict each CKD outcome. The severity of childhood CKD can be predicted with high accuracy using the creatinine nadir within 6 weeks of ablation. The cutoff values described can be incorporated into a clinical setting for patient counseling and individual risk stratification.


An orally active, small-molecule TNF inhibitor that disrupts the homotrimerization interface improves inflammatory arthritis in mice.
Excessive signaling by the proinflammatory cytokine TNF is involved in several autoimmune diseases, including rheumatoid arthritis (RA). However, unlike the approved biologics currently used to treat this and other conditions, commercially available small-molecule inhibitors of TNF trimerization are cytotoxic or exhibit low potency. Here, we report a TNF-inhibitory molecule (TIM) that reduced TNF signaling in vitro and was an effective treatment in a mouse model of RA. The initial lead compound, TIM1, attenuated TNF-induced apoptosis of human and mouse cells by delaying the induction of proinflammatory NF-κB and MAPK signaling and caspase 3- and caspase 8-dependent apoptosis. TIM1 inhibited the secretion of the proinflammatory cytokines IL-6 and IL-8 by disrupting TNF homotrimerization, thereby preventing its association with the TNF receptor. In a mouse model of collagen-induced polyarthritis, the more potent TIM1 analog TIM1c was orally bioavailable and reduced paw swelling, histological indicators of knee joint pathology, inflammatory infiltration of the joint, and the overall arthritis index. Orally delivered TIM1c showed immunological effects similar to those elicited by intraperitoneal injection of the FDA-approved TNF receptor decoy etanercept. Thus, TIM1c is a promising lead compound for the development of small-molecule therapies for the treatment of RA and other TNF-dependent systemic inflammation disorders.


Initiators in processes leading to hearing loss identification in Finnish children.
The objective was to examine processes leading to the diagnosis of hearing loss in children. The subjects were 328 children (hearing loss >30 dB HL) fitted with hearing aids in Helsinki University Central Hospital. The risk factor initiated hearing loss detection in 31%, whereas parental suspicion accounted for 26% and hearing screening at the well-baby clinics for 20% of the subjects. Parents were foremost to suspect hearing loss at the age spoken language normally emerges (1.5-3.4 years). Screening was equally effective irrespective of the severity of hearing loss. Parents with misgivings of hearing impairment in their child should have compliant access to audiological units.


Expression of thrombospondin-1 gene mRNA and protein in the placenta in gestosis.
The expression of TSP-1 gene mRNA and TSP-1 protein in the placental tissue was studied during normal pregnancy and in gestosis. The formation of placental tissue in normal gestation was associated with expression of TSP-1 gene mRNA and of TSP-1 protein. Gestosis was associated with inflammatory reaction in the placenta characterized by increased counts of lymphocytes and macrophages in the villous stroma and involution degenerative changes in tissue. Disorders in placental villi maturation and branching in gestosis were paralleled by hyperexpression of TSP-1 gene mRNA by placental cells and hyperexpression of TSP-1 protein predominating in the stromal elements of terminal villi and near villous vessels.


Dynamics of carbon dioxide emission during cracking in peanut shell biochar-amended soil.
As a primary source of greenhouse gas emissions and a carbon sink, soil plays a key role in climate regulation. The development of cracks in soil strongly influences CO2 emissions, and soil amendment with biochar has been shown to reduce cracking. However, the impact of biochar on CO2 emissions during soil cracking is not well understood. This study investigates the release of CO2 flux during the cracking of peanut shell biochar-amended soil. The biochar-amended soil was incubated at a constant temperature of 35 °C for 160 h with periodic photography and analysis of CO2 concentration and soil moisture. To achieve continuous monitoring of incubation soil, a new coupled sensor was specially designed to measure CO2 concentration and soil moisture, based on the Arduino microcontroller. Measured results reveal that peanut shell biochar reduced the evaporation rate by 29 % compared to unamended soil, resulting in slower soil cracking caused by water loss. The biochar also decreased the shrinkage crack length by 20 % compared to unamended soil. In addition, the crack volume fraction was reduced by 16 % after the peanut shell biochar amendment. Due to the reduction of the soil crack channel openings during drying shrinkage when biochar was applied to the soil, cumulative CO2 fluxes were also reduced by 5 % compared to unamended soil. The presence of biochar induced more stable and larger compounds with the soil particles, which blocked the crack propagation path and inhibited further development of the crack.


miR-188-5p inhibits proliferation, migration, and invasion in gallbladder carcinoma by targeting Wnt2b and Smad2.
Gallbladder carcinoma (GBC) commonly occurs in gastrointestinal malignancy and has the fifth highest mortality rate among gastrointestinal malignancy. Recently, miR-188-5p, a small noncoding RNA, has been implicated in various types of cancer such as nasopharyngeal carcinoma, oral squamous cell carcinoma, liver cancer, and prostate cancer. However, the effect of miR-188-5p on GBC remains unclear. Here, we demonstrated that miR-188-5p was downregulated in GBC tissues, and downregulation of miR-188-5p correlated with larger tumor size, lymph node metastasis, and extensive metastasis. In addition, the overall survival time of patients with higher miR-188-5p expression was significantly longer than that of patients with low-miR-188-5p expression. Moreover, downregulation of miR-188-5p promoted the proliferation, migration, and invasion of GBC cells, while its overexpression inhibited cell invasion and induced cell apoptosis, and arrested GBC growth in vivo. Importantly, miR-188-5p-dependent tumorigenesis was correlated with Wnt/β-catenin signaling and p-38/JNK signaling. In conclusion, miR-188-5p plays a direct role in GBC tumorigenesis. Our study suggests that miR-188-5p could serve as a novel diagnosis marker and therapeutic target in GBC.


Myosin P-light chain isoenzymes in the human heart: evidence for diphosphorylation of the atrial P-LC form.
We studied myosin light chains (LC) of human atrium and ventricle of normal and diseased individuals by a high-resolution 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) technique. Atrial LCs (ALC-1, ALC-2 (= P-LC)) revealed both higher molecular weights and lower isoelectric points (IEP) than their ventricular counterparts (VLC-1, VLC-2 (= P-LC)). Different P-LC forms with their distinct myosin isoenzymes have been designated as P-LC-polymorphism and myosin P-LC isoenzymes, respectively. In the dephosphorylated state two VLC-2 forms (VLC-2 and VLC-2*) with the same MW and different IEP, but only one ALC-2 form, were found. In the partially phosphorylated state ALC-2 appeared to be single- and double-phosphorylated (three spots in the 2D-PAGE), whereas the two VLC-2 forms appeared to be single-phosphorylated each (four spots in the 2D-PAGE). Phosphoryl-transfer from ATP to the P-LC forms was studied using skinned fibers incubated with MLCK (myosin light chain kinase) and (gamma-32P)ATP. Ventricular myosin P-LC isoenzyme pattern was usually the same in normal and diseased patients: the VLC-2 to VLC-2* ratio was approx. 70/30, but in one patient with valvular heart disease (VHD) the relation was 55/45 (shift to the VLC-2* form). In hypertrophied atria of VHD patients a shift of the myosin P-LC isoenzyme pattern to the VLC-2* form occurred, too.


The Role of PET/CT in the Era of Immune Checkpoint Inhibitors: State of Art.
Immune checkpoint inhibitors (ICI) have achieved astonishing results and improved overall survival (OS) in several types of malignancies, including advanced melanoma. However, due to a peculiar type of anti-cancer activity provided by these drugs, the response patterns during ICI treatment are completely different from that with "old" chemotherapeutic agents. To provide an overview of the available literature and potentials of 18F-FDG PET/CT in advanced melanoma during the course of therapy with ICI in the context of treatment response evaluation. Morphologic criteria, expressed by Response Evaluation Criteria in Solid Tumors (RECIST), immune-related response criteria (irRC), irRECIST, and, more recently, immune-RECIST (iRECIST), along with response criteria based on the metabolic parameters with 18F-Fluorodeoxyglucose (18FFDG), have been explored. To overcome the limits of traditional response criteria, new metabolic response criteria have been introduced on time and are being continuously updated, such as the PET/CT Criteria for the early prediction of Response to Immune checkpoint inhibitor Therapy (PECRIT), the PET Response Evaluation Criteria for Immunotherapy (PERCIMT), and "immunotherapy-modified" PET Response Criteria in Solid Tumors (imPERCIST). The introduction of new PET radiotracers, based on monoclonal antibodies combined with radioactive elements ("immune-PET"), are of great interest. Although the role of 18F-FDG PET/CT in malignant melanoma has been widely validated for detecting distant metastases and recurrences, evidences in course of ICI are still scarce and larger multicenter clinical trials are needed.


Prevalence of congenital heart defects in Europe, 2008-2015: A registry-based study.
The total prevalence of congenital heart defects (CHDs) varies by populations and over time. Studies that examine trends in the prevalence of CHD in different regions may shed light on our understanding of the occurrence of CHD and the impact of different risk factors. To examine trends in total and live birth prevalence of nonsyndromic CHD in Europe between the years 2008 and 2015 and to investigate if the decreasing trend reported by previous studies is continuing. Cases of CHD delivered between January 1, 2008 and December 31, 2015 notified to 25 population-based EUROCAT (European Surveillance of Congenital Anomalies) registries in 14 countries, formed the population-based case-series. Prevalence (total/live) rates and 95% confidence intervals were calculated as the number of cases per 10,000 births (live and stillbirths). Time trends in prevalence of all nonsyndromic CHDs and for three CHD severity groups (very severe, severe, and less severe) were plotted using a Poisson regression multilevel approach. The total prevalence of nonsyndromic CHD was 57.1 per 10,000 births (live births and stillbirths) for the 8-year period and remained stable across the three CHD severity groups while the live birth prevalence was 60.2 per 10,000 births. There was considerable variation in the reported total CHD prevalence and the direction of trends by registry. A decreasing prevalence of CHD was observed for the Norway and England/Wales registries, whereas the CHD prevalence increased for registries in Italy and Croatia. The total prevalence of CHD in Europe between the years 2008 and 2015 remained stable for all CHD and across the three CHD severity groups. The decreasing trend reported by previous studies has not continued. However, we found significant differences in the total and live birth prevalence by registry.


Human papillomaviruses (HPV) in gynaecological cytology: from molecular biology to clinical testing.
Molecular epidemiological and pathological studies show that different HPV types are associated with different cervical lesions allowing classification of the viruses into types associated with 'high', 'intermediate' and 'low' risk of cervical neoplasia. However, HPV infection often regresses and, where it is associated with neoplasia, is an early event. This suggests that other factors are involved in the carcinogenic process, and there is some mechanistic basis for the interaction of epidemiologically defined factors with HPV infection in the process of cervical carcinogenesis. With the refinement of techniques for HPV detection in clinical material, HPV testing is now a realistic possibility, but how this should be performed and in what clinical situation(s) is still uncertain. Particular areas of interest are: (i) the assessment of patients with borderline cytological changes or mild dyskaryosis; and (ii) the definition of those patients at greater risk of invasive disease. Clinical trials are needed before the utility of HPV testing can be properly assessed.


Which injured patients with moderate fibrinogen deficit need fibrinogen supplementation?
In severely injured patients, fibrinogen supplementation is recommended when fibrinogenemia is < 1.5 g L-1, but some teams have suggested to use higher thresholds (fibrinogenemia < 2.0 g L-1 or FIBTEM clot amplitude at 5 min (A5) values < 11 mm). The goal of this study was to specify in patients with a moderate fibrinogen deficit (MFD) whether some admission characteristics would be associated with fibrinogen administration at 24 h. Prospective analysis of retrospectively collected data from a trauma registry (01/2011-12/2019). MFD-C was defined by a fibrinogenemia 1.51-1.99 g L-1 or the corresponding FIBTEM-A5 values (MFD-A5) that were determined from linear regression and ROC curve analysis. Administration of fibrinogen were described according to the following admission parameters: shock index (SI) > 1, hemoglobin level < 110 g L-1 (HemoCue®), and base deficit > 5 mEq L-1. Data are expressed as count (%), median [IQR]. 1076 patients were included in the study and 266 (27%) had MFD-C, among them, 122/266 (46%) received fibrinogen. Patients with MFD-C who received fibrinogen were more severely injured (ISS: 27 [19-36] vs. 24 [17-29]) and had more impaired vital signs (base deficit: 5.4 [3.6-7.8] vs. 3.8 [2.0-6.0]). Linear regression analysis found a positive correlation between fibrinogen level and FIBTEM-A5 (r: 0.805). For a fibrinogen level < 1.5 g L-1 and < 2.0 g L-1, FIBTEM-A5 thresholds were 6 mm (sensitivity 85%, specificity 83%, AUC: 0.934) and 9 mm (sensitivity 84%, specificity 69%, AUC: 0.874), respectively. MFD-A5 values (185 (27%) patients) were defined as a FIBTEM-A5 between 7 and 9 mm. More than 50% of MFD-C patients presenting a SI > 1, a hemoglobin level < 110 g L-1, or a base deficit > 5.0 mEq L-1 received fibrinogen. The relative risk [95% CI] for fibrinogen administration (SI > 1) were 1.39 [1.06-1.82] for MFD-C, and 2.17 [1.48-3.19] for MFD-A5. Results were not modified after adjustment on the ISS. We have shown in this study an association between shock parameters and fibrinogen administration. Further studies are needed to determine how these parameters may be used to guide fibrinogen administration in trauma patients with MFD.


The Return of the Geneticist: Theodosius Dobzhansky, Edward Chapin, and Museum Taxonomy.
In Fall 1939, as war engulfed Europe, the author of one of the most influential texts on genetics and evolution, Theodosius Dobzhansky, wrote a letter to curator of insects at the United States National Museum, Edward Albert Chapin. Dobzhansky wished to know what Chapin thought about his pursuing some taxonomic work on an old fascination of his: lady-bird beetles. This paper examines the resulting correspondence as a window into Dobzhansky's attitude toward taxonomy, the different pressures on geneticists and taxonomists when wrestling with how to name species, the relation between biological theory and taxonomic practice, and how claims regarding human races may have motivated Dobzhansky's continued interest in the work of beetle taxonomists. In doing so, this article builds on the work of Paul Farber and others to highlight the importance of including museums, taxonomy, and the naturalist tradition within the history of twentieth-century biology.


Fuzzy clustering algorithm for university students' psychological fitness and performance detection.
Students' psychological fitness is unavoidable, hindering personal development, social interactions, peer influence, and adolescence. Academic stress may be the most dominant factor affecting college students' mental well-being. Therefore, improving the monitoring of mental health issues among college students is a vital topic for study. However, identifying the student's stress level is challenging, leading to uncertainty. Hence, this paper suggests Heuristic Fuzzy C-means Clustering Algorithm (HFCA) for analyzing college students' stress levels, psychological well-being and academic performance detection. The data are collected from the Kaggle stress dataset for predicting student mental health. This study investigates the psychological factors affecting students' academic performance using the suggested HFCA. Students' performance may be predicted using the Fuzzy Cognitive Map (FCM) in this study. This study used fuzzy clustering algorithms to discover the most crucial aspects of student success, such as student involvement and satisfaction. A better understanding of the risk factors for and protective factors against poor mental health can serve as the basis for developing policies and targeted interventions to prevent mental health problems and guarantee that at-risk students can access the help they need. The experimental analysis shows the proposed method HFCA to achieve a high student performance ratio of 96.7%, cognitive development ratio of 97.2%, student engagement ratio of 97.5% and prediction ratio of 95.1% compared to other methods.


Performance of Activities of daily living in people with multiple sclerosis.
Multiple sclerosis (MS) may result in activity and participation limitations, including the performance of activities of daily living (ADL). This study aims at systematically investigate ADL performance by using Assessment of Motor and Process Skills (AMPS) in people with MS (PwMS) of all disease types and within the Kurtzke Expanded Disability Status Scale (EDSS) range from 1.0 - 8.0. Eight multiple sclerosis (MS) centres participated in data collection of a consecutive sample of PwMS. Participants were referred for assessment to occupational therapy (OT) by treating physician or recruited from neurology department in each hospital and assessed by EDSS and AMPS. The AMPS is an observational, criterion referenced ADL assessment, providing values for a person's ADL performance in terms of motor and process skills. Criterion referenced cut-off scores were established at 2.0 for motor skills and at 1.0 for process skills and both values above the cut-off score indicate competent (independent, safe, efficient and effortless) ADL performance. Process skills refer to the act of carrying out a series of actions and is summarized in terms of efficiency, like initiating without pauses, continuing actions through to completion, performing actions in logical order (sequences), choosing, and completing the task as planned (heeds). Two hundred and ten PwMS were recruited (48 +/- 13 years of age, 145 women/65 men, average disease duration was 11.8 +/- 9.6 years, average EDSS was 4.8+/-1.8). Average motor skills score was 1.01+/- 1.12 (indicating need for assistance with evidence of increased clumsiness/physical effort) and average process skills score was 1.02 +/- 0.66 (risk zone, questionable efficiency and more likely to need assistance). Overall, motor skills and process skills decreased with increasing EDSS score. No need for assistance in motor skills was indicated in subjects with lower EDSS scores (1.0 - 2.5). In higher EDSS group (≥4.5), 57% of subjects needed assistance in motor skills and 27% in process skills. The competency in process skills was either questionable or reduced within all EDSS scores. However, 33-38% of subjects with higher EDSS scores (6.0-8.5) showed competent performance in process skills. Overall correlation between motor and process scores was moderate (r = 0.56, p<0.0001), but no significant relationships between motor and process skills were found in the lower EDSS (1-2.5) and high EDSS scores (8-8.5). Further, EDSS and disease type were significant predictors, explaining 52.7% of motor skills and 22.3% of process skills performance. Problems in ADL performance were found in EDSS categories 1.0 to 8.0 and in all disease types, therefore it is advisable to screen all PwMS for ADL deficits and provide relevant rehabilitation interventions.


Sialoglycoproteins adsorbed by Pseudomonas aeruginosa facilitate their survival by impeding neutrophil extracellular trap through siglec-9.
PA is an opportunistic pathogen that is commonly associated with severe infection in immunocompromised hosts. Siglec-9 binds with Sias by cis interaction on the neutrophil surface, thereby reducing immunological activity. However, neutrophils bind with pathogens through trans interactions of siglec-9 with Sias. Neutrophils kill invading pathogens by NETs, along with extracellular phagocytosis. Here, we report the mode of the adsorption of Sias by PA from host serum, the interaction of PA(+Sias) with human neutrophils, and the resulting neutrophil immunological activity. The α2-3-linked sialoglycoproteins adsorbed by PA exhibited potent binding with the soluble siglec-9-Fc chimeras, CHO-siglec-9 and siglec-9 on neutrophils. The binding between PA(+Sias) and neutrophils was blocked by the synthetic sialoglycan Neu5Acα2-3Galβ1-4GlcNAc, confirming the linkage-specific, Sias-siglec-9 interaction. The PA(+Sias) and siglec-9 interaction on neutrophils reduced the level of ROS and the release of elastase, resulting in a reduction of NETs formation, demonstrating the role of the sialoglycoproteins adsorbed by PA in the weakening of neutrophil activity. The resistance of PA(+Sias) to NETs was made evident by the increased survival of PA(+Sias). Moreover, the decrease in PA(-Sias) survival demonstrated the involvement of NETs formation in the absence of the Sias-siglec-9 interaction. N-actylcysteine or sivelestat-pretreated neutrophils enhanced the survival of PA(-Sias). DNAse-pretreated neutrophils did not exhibit any NETs formation, resulting in the enhanced escape of PA(-Sias). Taken together, one of the survival mechanisms of PA(+Sias) is the diminution of innate immunity via its adsorption of sialoglycoproteins by its engagement of the inhibitory molecule siglec-9. This is possibly a general mechanism for pathogens that cannot synthesize Sias to subvert immunity.


Dietary patterns are associated with body mass index and bone mineral density in Chinese freshmen.
Our objective was to examine associations between dietary patterns and body mass index (BMI) and bone mineral density (BMD) in Chinese freshmen. A cross-sectional study was done in 1319 college freshmen (aged 18.1 ± 1.2 years old). Diet was assessed by using a validated self-administrated food-frequency questionnaire. Blood pressure, weight, height, waist circumference, and hip circumference were measured and bone measurements were done using Quantitative Ultrasound System. Four dietary patterns were identified by factor analysis: Western food, animal protein, calcium food, and Chinese traditional patterns. The prevalence of overweight/obesity and osteopenia/osteoporosis were 8.2% (108/1319) and 28.1% (371/1319). The highest tertile of Western food pattern scores had greater odds of overweight/obesity (highest vs. lowest tertile, odds ratio [OR] = 2.00, 95% confidence interval [CI], 1.24-3.22), and the highest tertile of Chinese traditional pattern scores had lower risk of overweight/obesity (highest vs. lowest tertile, OR = 0.65, 95% CI, 0.53-0.80) in an adjusted model. The calcium food pattern and Chinese traditional pattern were negatively associated with the risk of osteopenia/osteoporosis (highest vs. lowest tertile, OR = 0.59, 95% CI, 0.41-0.87; OR = 0.78, 95% CI, 0.55-0.89) after adjusting for confounders. These findings suggested that there was a positive correlation between Chinese traditional dietary pattern and healthy BMI and BMD and that this same association existed between calcium food pattern and BMD in Chinese freshmen. In contrast, the Western-style diet was negatively correlated with healthy BMI in Chinese freshmen.


Evolutionary struggles between NK cells and viruses.
Natural killer (NK) cells are well recognized for their ability to provide a first line of defence against viral pathogens and they are increasingly being implicated in immune responses against certain bacterial and parasitic infections. Reciprocally, viruses have devised numerous strategies to evade the activation of NK cells and have influenced the evolution of NK-cell receptors and their ligands. NK cells contribute to host defence by their ability to rapidly secrete cytokines and chemokines, as well as to directly kill infected host cells. In addition to their participation in the immediate innate immune response against infection, interactions between NK cells and dendritic cells shape the nature of the subsequent adaptive immune response to pathogens.


The potential applications of fibrin-coated electrospun polylactide nanofibers in skin tissue engineering.
Fibrin plays an important role during wound healing and skin regeneration. It is often applied in clinical practice for treatment of skin injuries or as a component of skin substitutes. We prepared electrospun nanofibrous membranes made from poly(l-lactide) modified with a thin fibrin nanocoating. Fibrin surrounded the individual fibers in the membrane and also formed a thin fibrous mesh on several places on the membrane surface. The cell-free fibrin nanocoating remained stable in the cell culture medium for 14 days and did not change its morphology. On membranes populated with human dermal fibroblasts, the rate of fibrin degradation correlated with the degree of cell proliferation. The cell spreading, mitochondrial activity, and cell population density were significantly higher on membranes coated with fibrin than on nonmodified membranes, and this cell performance was further improved by the addition of ascorbic acid in the cell culture medium. Similarly, fibrin stimulated the expression and synthesis of collagen I in human dermal fibroblasts, and this effect was further enhanced by ascorbic acid. The expression of beta1-integrins was also improved by fibrin, and on pure polylactide membranes, it was slightly enhanced by ascorbic acid. In addition, ascorbic acid promoted deposition of collagen I in the form of a fibrous extracellular matrix. Thus, the combination of nanofibrous membranes with a fibrin nanocoating and ascorbic acid seems to be particularly advantageous for skin tissue engineering.


How changing needs change technological practices during a crisis: An explanation using practice theory.
The COVID-19 pandemic as a global crisis has created an opportunity to examine the theoretical tenets of the technology as routine capability perspective, and its extensions. We argue that the pandemic acted as a crisis that shifted technology use patterns via changing daily routines, or patterns of what we practice, and how we communicate in the social context. Specifically, we focus on changes in human needs as the primary mechanism that mediate the impact of the pandemic crisis on changes in technology practices. We collected survey responses from 213 participants before COVID-19, and 447 after the rapid spread of COVID-19. Empirical results mostly confirmed our hypotheses, and revealed that the pandemic crisis created a significant shift in four practices: communication, browsing, information sourcing, and material sourcing. We also found that the human needs of autonomy and relatedness mediated this relationship between the pandemic crisis and technology practices. These findings provided support for our proposed mediating role of human needs in explaining how major shifts create technology change and extending the technology as routine capability perspective. We conclude with a discussion, implications, and directions for future researchers.


Procedure for the recovery of airborne human enteric viruses during spray irrigation of treated wastewater.
Because of the relatively low number of indigenous enteric viruses recovered from secondary wastewater effluents, their presence in air (aerosols) as a result of wastewater spray irrigation requires extensive sampling. Methodology to allow the recovery of indigenous enteroviruses from aerosols generated at an operational wastewater irrigation site was tested under both laboratory and field conditions.


Sodium balance and antidiuresis in thiazide-treated rats with diabetes insipidus.
A sodium deficit was induced in Brattleboro rats by lowering the dietary sodium content. Urine volume was only slightly reduced. Addition of hydrochlorothiazide to the food caused a small, transient sodium deficit but led to a marked, sustained antidiuresis. The acute administration of a large dose of hydrochlorothiazide produced a larger, sustained sodium deficit but no lasting antidiuresis. These results indicate that sodium depletion cannot account for the antidiuresis of hydrochlorothiazide treatment in diabetes insipidus.


Surgical repair of Kommerell's diverticulum and an aberrant subclavian artery.
The coexistence of Kommerell's diverticulum and an aberrant subclavian artery (ASCA) is a rare congenital variation of the vascular structure. We report our experience of treating aneurysms associated with these anomalies. Between June 2007 and November 2011, five consecutive patients underwent repair of an aneurysm associated with Kommerell's diverticulum and an ASCA at Shiga University Hospital. Four of the five patients had a right-sided aortic arch associated with the ASCA. One patient underwent emergency surgery for a ruptured thoracic aneurysm. The operations performed were descending aorta replacement through right thoracotomy in one patient and total arch replacement through a median thoracotomy, under deep hypothermic circulatory arrest and selective cerebral perfusion, in four patients. No staged operation was required. One patient died of mediastinitis, subsequent to a ruptured Kommerell's diverticulum, 45 days postoperatively. There were no other deaths in the early or late (6-58 months) postoperative period. One patient required re-exploration for bleeding, but none of the patients suffered neurologic complications. Aortic disease with an ASCA and Kommerell's diverticulum can be repaired safely under elective conditions.


Selection of treatment for muscle infiltrating transitional cell bladder cancer.
1. Cancers of the bladder are heterogeneous. 2. A variety of surgical and radiation treatments has been useful in local tumor control. 3. Rational selection for optimal local therapy requires definition of more specific selection criteria. 4. The favorable effects of chemotherapy in patients with advanced bladder cancer warrant clinical investigation of such treatment in adjuvant and neoadjuvant settings while the search for more effective chemotherapy continues.


Impaired intracellular signal transduction via cyclic AMP contributes to cerebral vasospasm in rats with subarachnoid hemorrhage.
No drug can completely prevent vasospasm after subarachnoid hemorrhage. Impaired intracellular signal transduction by cyclic nucleotides might be involved. We investigated effects of intravenous isoproterenol and NKH477 on cerebral blood flow in rats with or without intracisternal injection of autologous blood one week previously. In controls without hemorrhage, isoproterenol at 0.01, 0.1, 1, and 10 mg kg(-1) min(-1) increased cerebral blood flow by 1.2%+/-9.5%, 19.7%+/-12.8%, 46.8%+/-23.5%, and 63.8%+/-32.9% respectively; 10mg kg(-1) min(-1) of isoproterenol increased systemic blood pressure by 66.6%+/-58.1%, while other doses decreased blood pressure. In the subarachnoid hemorrhage group, isoproterenol increased cerebral blood flow by -20.0%+/-6.5%, -7.6%+/-8.7%, 8.2%+/-8.8%, and 35.9%+/-83.1% respectively; 10 mg kg(-1) min(-1) of isoproterenol increased systemic blood pressure by 68.8%+/-79.5%, while other doses decreased blood pressure. In controls, NKH477 at 3, 10, and 30 mg kg(-1) increased cerebral blood flow by 2.3%+/-3.6%, 14.4%+/-7.0%, and 50.7%+/-14.6%, respectively; in the subarachnoid hemorrhage group, NKH477 changed cerebral blood flow by -1.3%+/-2.4%, 4.6%+/-2.8%, and -12.6%+/-10.8% (not significant difference from controls). NKH477 at 30 mg kg(-1) min(-1) decreased systemic blood pressure in both groups, but the effect in the hemorrhage group was greater. Either isoproterenol or NKH477 at appropriate doses can increase cerebral blood flow in vasospasm following subarachnoid hemorrhage without decreasing blood pressure.


Neurocognitive moderation of repetitive transcranial magnetic stimulation (rTMS) effects on cannabis use in schizophrenia: a preliminary analysis.
Repetitive transcranial magnetic stimulation (rTMS) is a promising treatment for cannabis use disorder in schizophrenia; however, gaps in the literature remain as to the potential role of neurocognitive functioning in treatment response. We evaluated the moderating role of select cognitive functions including baseline executive functioning, verbal memory, and sustained attention, and we explore the mediating role of changes in task performance on changes in cannabis use in both active and sham rTMS groups. Participants underwent high-frequency (20 Hz) rTMS applied to the bilateral dorsolateral prefrontal cortex 5x/week for 4 weeks. Weekly self-report of cannabis use and semi-quantitative urinary carboxy-tetrahydrocannabinol levels were recorded. A neurocognitive battery assessing verbal memory, visuospatial working memory, verbal working memory, sustained attention, delayed discounting, and complex planning was administered pre- and post-treatment. Better baseline performance on tasks assessing sustained attention, delayed discounting, and complex planning moderated the extent to which participants in the active group reduced cannabis use. There were no significant indirect pathways between treatment, changes in neuropsychological performance, and changes in cannabis use; however, active rTMS improved complex planning and sustained attention. These preliminary findings suggest that there is a moderating role of sustained attention, delayed discounting, and complex planning on the effects of rTMS on cannabis use. Further, mediation models suggest rTMS may exert direct effects on cannabis use independent of its effects on cognitive functioning in people with SCZ. Trial Registration: clinicaltrials.gov: NCT03189810.


The Role of the Medial Meniscus in Anterior Knee Stability.
Few studies have compared the force distribution between the anterolateral, posterolateral, and medial structures of the knee. To investigate the important structures in an intact knee contributing to force distribution in response to anterior tibial load. Controlled laboratory study. Nine fresh-frozen cadaveric knee specimens underwent robotic testing. First, 100 N of anterior tibial load was applied to the intact knee at 0°, 15°, 30°, 60°, and 90° of knee flexion. The anterior cruciate ligament (ACL), anterolateral capsule, lateral collateral ligament, popliteal tendon, posterior root of the lateral meniscus, superficial medial collateral ligament, posterior root of the medial meniscus (MM), and posterior cruciate ligament were then completely transected in sequential order. After each transection, the authors reproduced the intact knee motion when a 100-N anterior tibial load was applied. By applying the principle of superposition, the resultant force of each structure was determined based on the 6 degrees of freedom force/torque data of each state. At every measured knee flexion angle, the resultant force of the ACL was the largest of the tested structures. At knee flexion angles of 60° and 90°, the resultant force of the MM was larger than that of all other structures with the exception of the ACL. The MM was identified as playing an important role in response to anterior tibial load at 60° and 90° of flexion. In clinical settings, the ACL of patients with a poorly functioning MM, such as tear of the MM posterior root, should be monitored considering the large resultant force in response to an anterior tibial load.


Relationship between the milk yield response to short-term bovine somatotropin treatment and the lipolytic response to adrenaline in dairy cows.
The aim of this experiment was to determine if the milk yield response of dairy cows to short-term treatment with bovine somatotropin (bST) was correlated with the non-esterified fatty-acid (NEFA) response to an adrenaline challenge. Twenty-six multiparous Holstein cows (58+/-5.4 days postpartum) received daily sub-cutaneous injections of saline for 7 days followed by sub-cutaneous injections of 20mg/day of bST for 14 days. On day 7 of the saline treatment and day 14 of the bST treatment the cows were given an intravenous injection of adrenaline (1.4 microg/kg body weight). Blood samples were taken before and after the adrenaline challenge. The difference in milk yield between the saline and the second week of bST treatment (MYR) varied considerably between animals (from -0.4 to +8.0 kg/day). MYR was positively correlated with the change in the basal concentration of NEFA between the saline and second week of bST treatment, as well as with the change in the area under the profile of NEFA above basal values following the adrenaline challenge. It remains to be established whether the greater lipolytic responses to adrenaline of the cows with the greater MYR reflects the deeper negative energy that these animals also experienced or a fundamental difference in the physiology of their adipose tissue.


Reciprocal relationship between interpersonal communication and depressive symptoms and the mediating role of resilience across two years: Three-wave cross-lagged panel model.
Depression among children has been a growing public health concern. It is generally recognized that individuals with depression are likely to have interpersonal malfunctioning. However, there remains a limited scientific understanding of the reciprocal relationship between interpersonal communication and depressive symptoms among rural Chinese children in a longitudinal approach. Therefore, guided by the interpersonal model of depression and the developmental cascade model, the present study conducted a cross-lagged panel analysis study to explore the bidirectional relationship between interpersonal communication and depressive symptoms across three waves among 2188 elementary school students in rural areas of one county of Gansu Province, China. We also examined the mediating effect of resilience and sex differences of the models. Our results showed that depressive symptoms negatively predicted interpersonal communication from T1 to T2 and T2 to T3. Interpersonal communication negatively predicted depressive symptoms from T1 to T2, but not T2 to T3. Furthermore, resilience showed significant partial mediating effects in the reciprocal relationship between interpersonal communication and depressive symptoms. In terms of sex differences, the significant relationship between depressive symptoms at T1 and interpersonal communication at T2 was found to be significant among male students and marginally significant among female students. The full mediating effect of resilience at T1 was found only among male students, whereas resilience at T2 functioned as a full mediator between depressive symptoms at T2 and interpersonal communication at T3 only among female students. First, the present sample consisted of only third and fourth grade (i.e., in T1) students from one county in rural China. Second, the present study examined depressive symptoms instead of depression as a clinical diagnosis. Third, the third wave of the data was collected during COVID-19. The impact of the COVID-19 pandemic could unexpectedly pose on child mental health. The finding underlined the importance of providing comprehensive depression prevention and intervention from fostering children's inner resilience and promoting their ability to navigate interpersonal resources.


Studies on the supramolecular complex of a guanosine with beta-cyclodextrin and evaluation of its anti-proliferative activity.
The behavior of the inclusion behavior of guanosine (GU) with beta-cyclodextrin (β-CD) in the liquid, solid and virtual state were investigated. The absorption and fluorescence spectral were used to determine the inclusion behavior in liquid state. FT-IR, NMR, TGA, DSC, PXRD and FESEM techniques were used to investigate the inclusion behavior in solid-state, meanwhile the virtual state studies are done by molecular docking. The solid inclusion complex (GU: β-CD) was prepared by using the co-precipitation method. The binding constant (K) of (GU: β-CD) was calculated by using Benesi-Hildebrand. Besides that, the 1:1 stoichiometric ratio of inclusion complex was confirmed by using the Benesi-Hildebrand plot and Job's plot of continuous variation method. The most preferable model of GU: β-CD that suggested via molecular docking studies was in good agreement with experimental results. The inclusion complex of GU: β-CD exerted its toxicity effects towards HepG2 cell lines based on the reduced number of cell viability and lowest IC50 value compared to the GU and β-CD viability.


Dephosphorylation of endothelial nitric oxide synthase contributes to the anti-angiogenic effects of endostatin.
Endostatin is an anti-angiogenic factor that inhibits endothelial cell (EC) migration and induces EC apoptosis. Because nitric oxide (NO) plays a key role in vascular endothelial growth factor (VEGF)-induced angiogenesis, we hypothesized that endostatin interferes with the activation of the endothelial NO synthase (eNOS). Human recombinant endostatin significantly reduced VEGF-induced NO-release, which suggests that endostatin inhibits eNOS activation. Because the activation of eNOS by VEGF is associated with the Akt-dependent phosphorylation of eNOS at Ser1177, we investigated whether endostatin interferes with phosphorylation of eNOS. Endostatin reduced VEGF-induced phosphorylation of eNOS at Ser1177, whereas Akt phosphorylation was not affected. Coinciding with the inhibition of eNOS phosphorylation, endostatin completely blocked VEGF-induced EC migration. The NO-donor SNAP reversed the inhibitory effect of endostatin on EC migration. In addition, endostatin significantly inhibited VEGF-induced tube formation, whereas endostatin did not affect tube formation induced by NO. Finally, a non-dephosphorylatable constitutive active eNOS construct (S1177D), but not constitutive active Akt, abolished the inhibitory effect of endostatin on EC migration. Endostatin activated PP2A, which is known to directly dephosphorylate eNOS at Ser1177. Inhibition of PP2A prevented the inhibitory effect of endostatin. Thus, endostatin inhibits VEGF-induced EC migration and angiogenesis upstream of NO-synthesis via dephosphorylation of eNOS at Ser1177.


Recent developments in tunable lasers for spectroscopy.
Advances in tunable lasers over the past few years are reviewed. Particular emphasis is placed on their application to spectroscopy.


A cross-section analysis of FT3 age-related changes in a group of old and oldest-old subjects, including centenarians' relatives, shows that a down-regulated thyroid function has a familial component and is related to longevity.
several studies suggest that a decreased thyroid activity might be favourable in oldest-old subjects and that subclinical thyroid hyperfunction may be detrimental. to verify whether declining levels of circulating thyroid hormones may contribute to longevity. cross-sectional observational study. all subjects were born in Calabria (southern Italy) and their ancestry in the region was ascertained up to the grandparents. six hundred and four home-dwelling subjects (301 females, 303 males), divided into three groups: 278 individuals 60-85 years old; 179 children or nieces/nephews of centenarians who are 60-85 years old; 147 individuals older than 85 years. thyroid function parameters were measured in the frame of a comprehensive geriatric assessment. FT3 and FT4 levels were negatively associated with age. Lower levels of FT3, FT4 and TSH were found in centenarians' children and nieces/nephews with respect to age-matched controls. Indeed, being a relative of centenarians qualified as an independent correlate of thyroid parameters. age-related subtle thyroid hypofunction (either due to a familial component or due to a reset of the thyroid function occurring between the sixth and the eighth decade of life) appears to be related to longevity.


Metabolic and Endocrine Differences Between Dairy Cows That Do or Do Not Ovulate First Postpartum Dominant Follicles.
Most dairy cows develop the first dominant follicle postpartum within 2 wk after calving, but only about 40% of these follicles produce sufficient estradiol to stimulate ovulation despite having normal ultrasound appearance and growth. This study aimed to characterize metabolic, endocrine, and follicular fluid profiles of cows in which the first dominant follicle postpartum will become ovulatory and those with nonovulatory follicles. Luteinizing hormone pulse frequency, follicular fluid androstenedione, and follicular fluid estradiol concentrations were lower in nonovulatory cows suggesting that the function of theca cells is impaired. In addition, nonovulatory cows had more severe negative energy balance and greater insulin resistance postpartum. This study describes for the first time the steroid hormone profile of early postpartum follicles and shows that a steroidogenic defect most likely occurs in theca cells limiting the amount of androgen precursor available for estradiol production that impairs their ovulatory outcome.


A novel glyceraldehyde-3-phosphate dehydrogenase (GAPDH) promoter for expressing transgenes in the halotolerant alga Dunaliella salina.
A major challenge for efficient transgene expression in Dunaliella salina is to find strong endogenous promoters to drive the transgene expression. In the present study, a novel glyceraldehyde-3-phosphate dehydrogenase (GAPDH) promoter was cloned and used to drive expressions of the bialaphos resistance (bar) gene and of the N-terminal fragment of human canstatin (Can-N). The results showed that the bar gene was transcribed by the GAPDH promoter and integrated into the genome of the transformants of D. salina. Furthermore, the PCR identification, Southern and western blots indicated that Can-N was expressed in transgenic D. salina, demonstrating that the promoter of the D. salina GAPDH gene is suitable for driving expression of heterologous genes in transgenic D. salina.


Rapid development of two factor IXa inhibitors from hit to lead.
Two high-throughput screening hits were investigated for SAR against human factor IXa. Both hits feature a benzamide linked to a [6-5]-heteroaryl via an alkyl amine. In the case where this system is a benzimidazolyl-ethyl amine the binding potency for the hit was improved >500-fold, from 9 μM to 0.016 μM. For the other hit, which contains a tetrahydropyrido-indazole amine, potency was improved 20-fold, from 2 μM to 0.09 μM. X-ray crystal structures were obtained for an example of each class which improved understanding of the binding, and will enable further drug discovery efforts.


Properties of scrapie prion protein liposomes.
Purified scrapie prions contain one identifiable macromolecule, PrP 27-30, which polymerizes into rod-shaped amyloids. The rods can be dissociated with retention of scrapie infectivity upon incorporation of PrP 27-30 into detergent-lipid-protein complexes (DLPC) as well as liposomes. As measured by end-point titration, scrapie infectivity was increased greater than 100-fold upon dissociating the rods into liposomes. The incorporation of PrP 27-30 into liposomes was demonstrated by immunoelectron microscopy using colloidal gold. Detergent extraction of prion liposomes followed by chloroform/methanol extraction resulted in the reappearance of rods, indicating that this process is reversible. Scrapie prion infectivity in rods and liposomes was equally resistant to inactivation by irradiation at 254 nm and was unaltered by exposure to nucleases. A variety of lipids used for producing DLPC and liposomes did not alter infectivity. Fluorescently labeled PrP 27-30 in liposomes was used to study its entry into cultured cells. Unlike the rods which remained as large fluorescent extracellular masses, the PrP 27-30 in liposomes rapidly entered the cells and was seen widely distributed within the interior of the cell. PrP 27-30 is derived by limited proteolysis from a larger protein designated PrP(Sc) which is membrane bound. PrP(Sc) in membrane fractions was solubilized by incorporation in DLPC, thus preventing its aggregation into amyloid rods. The functional solubilization of scrapie prion proteins in DLPC and liposomes offers new approaches to the study of prion structure and the mechanism by which they cause brain degeneration.


[Degradation of C1q, the first subcomponent of the complement sequence, by synovial collagenase from patients with rheumatoid arthritis (author's transl)].
Human C1q is shown to be degraded by high concentrations of RA synovial collagenase (enzyme : substrate ratio 2 : 1). The collagen-like sequence of C1q is attacked by the enzyme. A possible cleavage site is described and compared with the cleavage site in collagen.


Retraction: Mfn2 overexpression attenuates Cardio-Cerebrovascular Ischemia-Reperfusion injury through mitochondrial fusion and activation of the AMPK/Sirt3 signaling.
[This retracts the article DOI: 10.3389/fcell.2020.598078.].


Combined integrin αvβ3 and lactoferrin receptor targeted docetaxel liposomes enhance the brain targeting effect and anti-glioma effect.
The integrin αvβ3 receptor and Lactoferrin receptor (LfR) are over-expressed in both cerebral microvascular endothelial cells and glioma cells. RGD tripeptide and Lf can specifically bind with integrin αvβ3 receptor and LfR, respectively. In our study, RGD and Lf dual-modified liposomes loaded with docetaxel (DTX) were designed to enhance the brain targeting effect and treatment of glioma. Our in vitro studies have shown that RGD-Lf-LP can significantly enhance the cellular uptake of U87 MG cells and human cerebral microvascular endothelial cells (hCMEC/D3) when compared to RGD modified liposomes (RGD-LP) and Lf modified liposomes (Lf-LP). Free RGD and Lf competitively reduced the cellular uptake of RGD-Lf-LP, in particular, free RGD played a main inhibitory effect on cellular uptake of RGD-Lf-LP in U87 MG cells, yet free Lf played a main inhibitory effect on cellular uptake of RGD-Lf-LP in hCMEC/D3 cells. RGD-Lf-LP can also significantly increase penetration of U87 MG tumor spheroids, and RGD modification plays a dominating role on promoting the penetration of U87 MG tumor spheroids. The results of in vitro BBB model were shown that RGD-Lf-LP-C6 obviously increased the transport of hCMEC/D3 cell monolayers, and Lf modification plays a dominating role on increasing the transport of hCMEC/D3 cell monolayers. In vivo imaging proved that RGD-Lf-LP shows stronger targeting effects for brain orthotopic gliomas than that of RGD-LP and Lf-LP. The result of tissue distribution confirmed that RGD-LF-LP-DTX could significantly increase brain targeting after intravenous injection. Furthermore, RGD-LF-LP-DTX (a dose of 5 mg kg-1 DTX) could significantly prolong the survival time of orthotopic glioma-bearing mice. In summary, RGD and LF dual modification are good combination for brain targeting delivery, RGD-Lf-LP-DTX could enhance brain targeting effects, and is thus a promising chemotherapeutic drug delivery system for treatment of glioma.


Involvement of endogenous adenosine in ischaemic preconditioning in swine.
Adenosine release and the subsequent activation of adenosine receptors are involved in ischaemic preconditioning in dogs and rabbits. In the present study, we investigated whether adenosine also mediates ischaemic preconditioning in swine. Swine were used since, due to the lack of an innate collateral circulation, infarct development in this species most closely resembles that observed in humans. In 36 enflurane-anaesthetized swine the impact of increased adenosine breakdown with exogenous porcine adenosine deaminase (5 IU/ml blood/min) on global and regional myocardial function (sonomicrometry), subendocardial blood flow (ENDO, microspheres) and infarct size (IS, triphenyl tetrazolium chloride staining following 90 min ischaemia and 120 min reperfusion) were analysed. Low-flow ischaemia for 90 min at an ENDO of 0.09 +/- 0.04 (mean +/- SD) ml/min/g caused an IS of 13.2 +/- 9.7% (n = 8) of the area at risk. Ischaemic preconditioning by a cycle of 10 min low-flow ischaemia followed by 15 min reperfusion prior to the 90-min ischaemic period (ENDO = 0.06 +/- 0.03 ml/min/g) reduced IS to 2.6 +/- 3.0% (n = 11, P < 0.05). The interstitial adenosine concentration (microdialysis) increased from 1.60 +/- 0.87 nmol/ml to above 10 microM during ischaemia; with intracoronary adenosine deaminase, the interstitial adenosine concentration fell from 1.65 +/- 0.23 to 0.12 +/- 0.07 nmol/ml and did not increase during ischaemia. Adenosine deaminase per se did not alter IS after 90 min ischaemia (n = 7, ENDO = 0.08 +/- 0.04 ml/min/g, IS = 12.1 +/- 6.9%) but abolished the beneficial effect of ischaemic preconditioning (n = 10, ENDO = 0.06 +/- 0.03 ml/min/g, IS = 8.8 +/- 5.8%). For any given ENDO, IS was significantly reduced in the ischaemic preconditioned group compared with the other three groups. Global and regional myocardial function were comparable among all groups of swine. We conclude that endogenous adenosine mediates ischaemic preconditioning also in swine.


Incretin-induced changes in the transcriptome of skeletal muscles of fa/fa Zucker rat (ZFR) with obesity, without diabetes.
Glucagon-like peptide-1 receptor agonists (GLP-1ra) are increasingly used in treating type 2 diabetes and obesity. Exendin-4 (Ex-4), a long acting GLP-1ra, was previously reported to decrease oxidative stress in hepatocytes, adipocytes and skeletal muscle cells in obese nondiabetic fa/fa Zucker rats (ZFR), thereby improving insulin resistance. We aimed first to identify Ex-4-induced changes in the transcriptome of skeletal muscle cells in ZFR. Ontology analysis of differentially expressed genes (DEGs) in ZFR versus lean animals (LR) showed that the extracellular matrix (ECM) is the first most affected cellular compartment, followed by myofibrils and endoplasmic reticulum (ER). Interestingly, among 15 genes regulated in ZFR versus LR, 14 of them were inversely regulated by Ex-4, as further confirmed by RT-qPCR. Picro-Sirius red histological staining showed that decreased ECM fiber area in ZFR is partially restored by Ex-4. Ontology analysis of the myofibril compartment revealed that decreased muscle contractile function in ZFR is partially restored by Ex-4, as confirmed by Phalloidin histological staining that showed a partial restoration by Ex-4 of altered contractile apparatus in ZFR. Ontology analysis of ER DEGs in ZFR versus LR showed that some of them are related to the AMP-activated protein kinase (AMPK) signaling pathway. Phosphorylated AMPK levels were strongly increased in Ex-4-treated ZFR. Altogether, our results suggest that GLP-1ra strongly restructure ECM and reinforce contractile capabilities in ZFR, while optimizing the cellular metabolism through AMPK.


Effect of renal impairment on the pharmacokinetics and safety of dorzagliatin, a novel dual-acting glucokinase activator.
Dorzagliatin is a novel allosteric glucokinase activator targeting both pancreatic and hepatic glucokinase currently under clinical investigation for treatment of type 2 diabetes (T2D). This study aimed to investigate the effect of renal impairment (RI) on dorzagliatin's pharmacokinetics (PKs) and safety, and to guide appropriate clinical dosing in patients with diabetic kidney disease, including end-stage renal disease (ESRD). Based on the results from physiologically-based pharmacokinetic modeling, the predicted outcome of RI on dorzagliatin PK property would be minimum that the plasma exposure area under concentration (AUC) of dorzagliatin in patients with ESRD would increase at about 30% with minimal change in peak concentration (Cmax ) comparing to those in healthy volunteers (HVs). To definitively confirm the prediction, a two-part RI study was designed and conducted based on regulatory guidance starting with the patients with ESRD matched with HVs. Results of the RI study showed minimum difference between patients with ESRD and HVs with respect to dorzagliatin exposure with geometric mean ratio of ESRD to HV at 0.81 for Cmax and 1.11 for AUC. The elimination half-life, volume of distribution, and systemic clearance for dorzagliatin were similar between the two groups. Dorzagliatin was well-tolerated in patients with ESRD during the study. Therefore, RI showed no significant impact on dorzagliatin PK, suggesting that dorzagliatin can be readily used in patients with T2D at all stages of RI without need for dose adjustment.


High-performance organic field-effect transistors based on pi-extended tetrathiafulvalene derivatives.
Aromatic ring-condensed TTF derivatives exhibited excellent p-type FET performances in thin films. Introduction of fused benzene and pyrazine rings to the TTF skeleton was effective to enhance the intermolecular interactions and stability to oxygen. Ordered molecular alignment was confirmed by XRD studies. A pi-stacking structure was observed in the single crystal of diquinoxalinoTTF.


Mobilization of mesenchymal stem cells by granulocyte colony-stimulating factor in rats with acute myocardial infarction.
Intravenous delivery of mesenchymal stem cells (MSCs), a noninvasive strategy for myocardial repair after acute myocardial infarction (MI), is limited by the low percentage of MSCs migration to the heart. The purpose of this study was to test whether granulocyte colony-stimulating factor (G-CSF) would enhance the colonization of intravenously infused MSCs in damaged heart in a rat model of acute MI. After induction of anterior MI, Sprague-Dawley rats were randomized to receive: (1) saline (n=9); (2) MSCs (n=15); and (3) MSCs plus G-CSF (50 microg/kg/day for 5 consecutive days, n=13). Flow cytometry revealed that G-CSF slightly increased surface CXCR4 expression on MSCs in vitro. After completion of G-CSF administration, MSCs showed a significantly lower colonization in bone marrow and a trend toward higher localization in the infarcted myocardium. At 3 months, vessel density in the infarct region of heart was significantly increased in MSCs group and trended to increase in MSCs+G-CSF group. However, echocardiographic and hemodynamic parameters, including left ventricular (LV) end-diastolic diameters, ejection fraction, and +/-dP/dtmax, were not statistically different. Morphological analysis showed that infarct size and collagen content were similar in the three groups. Immunohistochemistry revealed that the combined therapy accelerated endothelial recovery of the blood vessels in the ischemic myocardium. However, myocardial regeneration resulting from MSCs differentiation was not observed. G-CSF enhanced the migration of systemically delivered MSCs from bone marrow to infarcted heart. However, the beneficial effect of this kind of migration is limited, as cardiac function did not improve.


[Optimization of the circulatory percolation process for extraction of radix ginseng rubra].
To optimize the extraction process of Radix Ginseng Rubra. The orthogonal test design was used to test the three main factors of circulatory percolation process, including particle size of herb (A), velocity of percolation(B) and time for extraction (C), and the synthetic score basing on obtained rate of ginsenosides Rg1, Re and extraction efficiency was used as guide. The optimum process conditions relevant to the three main factors were as follows. The coarse powder was percolated at a velocity of 0.2 L/min for six hours. The circulatory percolation process is better than the reflux process and maceration process for extraction of Radix Ginseng Rubra.


[Use of direct oral anticoagulants in the elderly].
Equal safety and efficacy of direct oral anticoagulants as compared to vitamin K antagonists have been shown in elderly and very old patients. The use of these seem to have certain advantages in this special patient cohort: higher drug safety, no need for lab monitoring, less drug-drug interactions and a lower rate of intracranial hemorrhages. However, more data is needed to quantify the exact bleeding risk for geriatric patients. Elderly patients suffer quite frequently from significant comorbidities, such as renal failure, dementia, vision loss etc., which might put them at higher risk to suffer from medication side effects, especially bleeding complications. Routine clinical examinations combined with monitoring of renal function are therefore of paramount importance. Regarding these precautions the use of the new oral anticoagulants in the elderly is hence quite justified and rising.


Effect of Intermittent Fasting (18/6) on Energy Expenditure, Nutritional Status, and Body Composition in Healthy Adults.
This study was aimed at evaluating the effect of intermittent fasting of Ramadan on resting energy expenditure (REE), body composition, and nutritional status. The study was conducted on a total of 27 adults (16 females, 11 males) who were fasting (18 h) in the Ramadan month (May 6-June 3) of 2019. REE was measured using the indirect calorimeter. Dietary energy and nutrient intakes were evaluated by 3-day food records in baseline and post-Ramadan. Body composition and some metabolic parameters were analyzed simultaneously with REE measurements. All measurements were performed two times at baseline, and post-Ramadan. Body weight (-2.9% vs. -1.4%), body mass index (BMI) (-3.1% vs. -2.1%), fat-free mass (-2.7% vs. -1.4%), and hydration status were decreased in both males and females after the Ramadan fasting (p < 0.05). REEs (kcal/d) of the participants were 1708.1 ± 262.50 kcal/d and 1596.5 ± 302.27 kcal/d at baseline and post-Ramadan, respectively (6.5%) (p < 0.05). This decrease in REE (kcal/d) in females was greater than that in males (-8.1% vs. -4.6%). However, no statistically significant difference was found in sleep duration (h), physical activity levels, dietary energy and nutrient intakes, and blood pressures (mm Hg) of both genders compared to baseline (p > 0.05). Intermittent circadian fasting may lead to a decreased energy expenditure and a change in fat-free mass in healthy individuals, and this effect is interpreted as gender-dependent.


Modification and quantification of in vivo EROD live-imaging with zebrafish (Danio rerio) embryos to detect both induction and inhibition of CYP1A.
The visualization of specific activation of the aryl hydrocarbon receptor (AhR) directly in the zebrafish embryo (Danio rerio) via live-imaging is a reliable tool to investigate the presence of dioxin-like substances in environmental samples. The co-existence of inducers and inhibitors of cytochrome P450-dependent monooxygenases (CYP1A) is typical of complex environmental mixtures and requires modifications of the in vivo EROD assay: For this end, zebrafish embryos were used to evaluate the EROD-modifying potentials of common single-compound exposures as well as binary mixtures with the PAH-type Ah-receptor agonist β-naphthoflavone. For chemical testing, chlorpyrifos and Aroclor 1254 were selected; β-naphthoflavone served as maximum EROD induction control. Chlorpyrifos (≤EC10) could be documented to be a strong CYP1A inhibitor causing characteristic edema-related toxicity. Aroclor 1254 resulted in inhibition of CYP1A catalytic activity in a concentration- and specific time-dependent manner. Next to a fast CYP1A induction, CYP1A inhibition could also be detected after 3h short-term exposure of zebrafish embryos to chlorpyrifos. This communication also describes techniques for the quantification of fluorescence signals via densitometry as a basis for subsequent statistical assessment. The co-exposure approach with zebrafish embryos accounts for the nature of potential interaction between CYP1A inducers and inhibitors and thus pays tribute to the complexity of environmental mixtures. The co-exposure EROD live-imaging assay thus facilitates a better understanding of mixture effects and allows a better assessment and interpretation of (embryo) toxic potentials.


Studies of changes in breathing and blood pressure accompanying a cardiogenic hypertensive chemoreflex compared in conscious and anesthetized dogs.
Serotonin activates a cardiogenic hypertensive chemoreflex characterized by sudden hypertension. This study in 16 awake and 12 anesthetized dogs was conducted to examine the influence of changes in breathing or heart rate as they may influence the reflex hypertension. In all 28 dogs, either anesthetized or awake, there is a variable but brief initial reflex bradycardia and in all dogs there is transient ventilatory stimulation, but the response in every dog was characterized by hypertension within at most 10 seconds after administering serotonin. Treatment with atropine regularly eliminated the reflex bradycardia and caused the hypertension to appear soon (average of 6 seconds to maximal level). Atropine did not alter the reflex stimulation of breathing. Since atropine eliminated any transient bradycardia (and associated hypertension) but did not prevent reflex changes in breathing, we do not believe that breathing alteration plays any significant hemodynamic role in this reflex.


[Evaluation of the teamwork in six intensive care units of two university hospitals].
It has been demonstrated that teamwork has a direct positive effect on the quality and the efficiency of patient's care and consequently on hospital costs. 1.To assess attitudes toward the teamwork of nurses and physicians of 6 ICUs in two teaching hospitals. 2.To analyze if there are any relationships between attitudes toward teamwork and socio-demographic variables. 3.To study if there are differences in the attitudes toward teamwork among professionals of the different units. This prospective study evaluated the attitudes of teamwork of 136 professionals with the scale development by Heinemann et al. in 1999. This scale is made up of three subscales that measure the value of being in a team, the efficiency of the team and the function of collaboration of the physician within the team. The majority of professionals had a positive attitude towards teamwork. They obtained a mean score of 97.01 for a maximum of 120 points. In regards to sociodemographic variables, statistically significant differences were only found in gender and professional category, as women and female nurses had better attitudes toward teamwork. There were no differences in attitudes towards teamwork in the different units studied. Attitude toward teamwork by physicians and nurses of the 6 ICUs studied was good. No differences were found between attitudes toward teamwork among the professionals of the different units.