Ventricular Arrhythmias Among Patients With Advanced Heart Failure: A Population-Based Study.
Background The epidemiology of ventricular arrhythmias (VAs) in patients with advanced heart failure (HF) is not well defined. Methods and Results Residents of Olmsted County, Minnesota, with advanced HF from 2007 to 2017 were identified using the 2018 European Society of Cardiology criteria. Billing codes were used to capture VAs; severe VAs requiring emergency care were defined as events associated with emergency department visits or hospitalizations. The cumulative incidence of VAs postadvanced HF was estimated with the Kaplan-Meier method. Multivariable Cox analyses were used to determine the following: (1) Predictors of severe VAs postadvanced HF; and (2) Impact of severe VAs on mortality. Of 936 patients with advanced HF, 261 (27.9%) had a history of VA. The 1-year cumulative incidence of severe VAs postadvanced HF was 5.4%. Prior VAs (hazard ratio [HR] 2.22 [95% CI, 1.26-3.89], P=0.006) and left ventricular ejection fraction <40% (HR, 3.79 [95% CI, 1.72-8.39], P<0.001) were independently associated with increased severe VA risk postadvanced HF. New-onset severe VAs were associated with increased mortality (HR, 4.41 [95% CI, 2.80-6.94]; P<0.001), whereas severe VAs in patients with prior VAs had no significant association with mortality risk (HR, 1.08 [95% CI, 0.65-1.78]; P=0.77). Severe VAs were associated with increased mortality in patients without implantable cardioverter defibrillators (HR, 4.89 [95% CI, 2.89-8.26]; P<0.001), but not in patients with implantable cardioverter defibrillators (HR, 1.42 [95% CI, 0.92-2.19]; P=0.11). Conclusions Patients with left ventricular ejection fraction <40% and prior VAs have increased risk of severe VA postadvanced HF. New-onset severe VAs or severe VAs without implantable cardioverter defibrillators postadvanced HF are associated with increased mortality.


Laparoscopic pyeloplasty.
Open pyeloplasty has long been considered the gold standard for the relief of ureteropelvic junction (UPJ) obstruction, but the incisional morbidity led urologists to explore less invasive alternatives such as endopyelotomy and the Acucise cutting balloon. Laparoscopic pyeloplasty was introduced in 1993 and has since been performed in patients as young as 2.5 years. The operation should be considered in patients with UPJ obstruction caused by a crossing vessel, high ureteral insertion, failed prior procedures, high-grade hydronephrosis, or marginal differential renal function. Hynes-Anderson, Foley Y-V, and Fenger procedures can all be performed laparoscopically, generally with excellent results. The procedure requires advanced laparoscopic skills and so is available in only a few medical centers at present.


Acute metabolic decompensation due to influenza in a mouse model of ornithine transcarbamylase deficiency.
The urea cycle functions to incorporate ammonia, generated by normal metabolism, into urea. Urea cycle disorders (UCDs) are caused by loss of function in any of the enzymes responsible for ureagenesis, and are characterized by life-threatening episodes of acute metabolic decompensation with hyperammonemia (HA). A prospective analysis of interim HA events in a cohort of individuals with ornithine transcarbamylase (OTC) deficiency, the most common UCD, revealed that intercurrent infection was the most common precipitant of acute HA and was associated with markers of increased morbidity when compared with other precipitants. To further understand these clinical observations, we developed a model system of metabolic decompensation with HA triggered by viral infection (PR8 influenza) using spf-ash mice, a model of OTC deficiency. Both wild-type (WT) and spf-ash mice displayed similar cytokine profiles and lung viral titers in response to PR8 influenza infection. During infection, spf-ash mice displayed an increase in liver transaminases, suggesting a hepatic sensitivity to the inflammatory response and an altered hepatic immune response. Despite having no visible pathological changes by histology, WT and spf-ash mice had reduced CPS1 and OTC enzyme activities, and, unlike WT, spf-ash mice failed to increase ureagenesis. Depression of urea cycle function was seen in liver amino acid analysis, with reductions seen in aspartate, ornithine and arginine during infection. In conclusion, we developed a model system of acute metabolic decompensation due to infection in a mouse model of a UCD. In addition, we have identified metabolic perturbations during infection in the spf-ash mice, including a reduction of urea cycle intermediates. This model of acute metabolic decompensation with HA due to infection in UCD serves as a platform for exploring biochemical perturbations and the efficacy of treatments, and could be adapted to explore acute decompensation in other types of inborn errors of metabolism.


Defining the attributes expected of graduating veterinary medical students, part 2: external evaluation and outcomes assessment.
We have previously defined a set of 62 attributes-12 in the area of professional characteristics, 28 addressing knowledge and understanding, and 22 delineating skills-that veterinary students should be expected to have demonstrated by the time of their graduation (Walsh DA, Osburn BI, Christopher MM. Defining the attributes expected of graduating veterinary medical students. J Am Vet Med Assoc 219:1358-1365, 2001). We have used this set of attributes as the basis of an outcomes assessment completed by California practitioners to determine whether graduates from the University of California School of Veterinary Medicine are meeting these expectations. Based upon this assessment, these 62 defined attributes appear to reflect very well practicing veterinarians' views and expectations of DVM graduates. The survey results also indicate that, overall, the recent University of California graduates are meeting these set of expectations. Simultaneously, the outcomes assessment focused attention on several areas, including private practice management, work expectations for successful practice, and surgical capabilities. For each, California practitioners recommended that the definition of the expectation be expanded and that the level of achievement by graduates be improved. Defining a set of attributes expected of veterinary graduates is a key step in obtaining an effective outcomes assessment of a professional educational program.


The hydraulic conductance of Fraxinus ornus leaves is constrained by soil water availability and coordinated with gas exchange rates.
Leaf hydraulic conductance (Kleaf) is known to be an important determinant of plant gas exchange and photosynthesis. Little is known about the long-term impact of different environmental factors on the hydraulic construction of leaves and its eventual consequences on leaf gas exchange. In this study, we investigate the impact of soil water availability on Kleaf of Fraxinus ornus L. as well as the influence of Kleaf on gas exchange rates and plant water status. With this aim, Kleaf, leaf conductance to water vapour (gL), leaf water potential (Psileaf) and leaf mass per area (LMA) were measured in F. ornus trees, growing in 21 different sites with contrasting water availability. Plants growing in arid sites had lower Kleaf, gL and Psileaf than those growing in sites with higher water availability. On the contrary, LMA was similar in the two groups. The Kleaf values recorded in sites with two different levels of soil water availability were constantly different from each other regardless of the amount of precipitation recorded over 20 days before measurements. Moreover, Kleaf was correlated with gL values. Our data suggest that down-regulation of Kleaf is a component of adaptation of plants to drought-prone habitats. Low Kleaf implies reduced gas exchange which may, in turn, influence the climatic conditions on a local/regional scale. It is concluded that leaf hydraulics and its changes in response to resource availability should receive greater attention in studies aimed at modelling biosphere-atmosphere interactions.


Dual adaptive filtering by optimal projection applied to filter muscle artifacts on EEG and comparative study.
Muscle artifacts constitute one of the major problems in electroencephalogram (EEG) examinations, particularly for the diagnosis of epilepsy, where pathological rhythms occur within the same frequency bands as those of artifacts. This paper proposes to use the method dual adaptive filtering by optimal projection (DAFOP) to automatically remove artifacts while preserving true cerebral signals. DAFOP is a two-step method. The first step consists in applying the common spatial pattern (CSP) method to two frequency windows to identify the slowest components which will be considered as cerebral sources. The two frequency windows are defined by optimizing convolutional filters. The second step consists in using a regression method to reconstruct the signal independently within various frequency windows. This method was evaluated by two neurologists on a selection of 114 pages with muscle artifacts, from 20 clinical recordings of awake and sleeping adults, subject to pathological signals and epileptic seizures. A blind comparison was then conducted with the canonical correlation analysis (CCA) method and conventional low-pass filtering at 30 Hz. The filtering rate was 84.3% for muscle artifacts with a 6.4% reduction of cerebral signals even for the fastest waves. DAFOP was found to be significantly more efficient than CCA and 30 Hz filters. The DAFOP method is fast and automatic and can be easily used in clinical EEG recordings.


[The use of polyelectrolytes for isolation of trypsin inhibitor from industrial waste of fractionation of alfalfa leaf proteins].
Arypsin inhibitor was concentrated from the albumin fraction of alfalfa leaf juice as insoluble complex precipitate with pectin, carboxymethylcellulose sodium salt, and dextran sulfate. The concentration degree varied from 40 to 100, and the yield of the inhibitor was 45-50%. The homogeneous inhibitor was further isolated from solution of the precipitate by affinity chromatography on Trypsin-Sepharose. The final product had a molecular weight of 6.9 kDa, high inhibitory activity (16.6 U per mg protein) and relatively high (about 30%) content of the alpha-helical form.


Ferrocene Derivatives for Improving the Efficiency and Stability of MA-Free Perovskite Solar Cells from the Perspective of Inhibiting Ion Migration and Releasing Film Stress.
Further improvement of the performance and stability of inverted perovskite solar cells (PSCs) is necessary for commercialization. Here, ferrocene derivative dibenzoylferrocene (DBzFe) is used as an additive to enhance the performance and stability of MA- and Br- free PSCs. The results show that the introduction of DBzFe not only passivates the defects in the film but also inhibits the ion migration in the film. The final device achieves a power conversion efficiency (PCE) of 23.53%, which is one of the highest efficiencies currently based on self-assembled monolayers (SAMs). Moreover, it maintains more than 96.4% of the original efficiency when running continuously for 400 h at the maximum power point.


Ternary complex consisting of DNA, polycation, and a natural polysaccharide of schizophyllan to induce cellular uptake by antigen presenting cells.
A natural polysaccharide called schizophyllan (SPG) can form a complex with polynucleotides, and the complex has been shown to deliver biofunctional short DNAs such as antisense DNAs and CpG-DNAs. Although it is a novel and efficient method, there is a drawback: attachment of homo-polynucleotide tails [for example, poly(dA) or poly(C)] to the end of DNA is necessary to stabilize the complex, because DNA heterosequences cannot bind to SPG. The aim of this paper is to present an alternative method in which SPG/DNA complexes can be made without using the tails. The basic strategy is as follows: since SPG can form hydrophobic domains in aqueous solutions, hydrophobic objects should be encapsulated by this domain. DNA alone is highly hydrophilic; however, once DNA/polycation complexes are made, they should be included by the SPG hydrophobic domain. The aim of this paper is to prove the formation of the polycation/DNA/SPG ternary complex. Gel electrophoresis showed that presence of SPG influenced the migration pattern of polycation+DNA mixtures. With increasing the SPG ratio, the zeta potential (zeta) of the polycation+DNA+SPG mixture decreased drastically to reach almost zeta = 0 and the particle size distributions were altered due to the ternary complex formation. Confocal laser scanning microscopy revealed that the polycation/DNA/SPG ternary complexes showed high uptake efficiency when the complexes were exposed to macrophage-like cells (J774.A1). IL-12 secretion was enhanced when CpG-DNA was added as the ternary complex. These features can be ascribed to the fact that J774.A1 has a SPG recognition site called Dectin-1 on the cellular surface and the ternary complex can be ingested by this pathway.


Granulomatous lesions of the cervix uteri in Black patients.
The incidence of tuberculous, bilharzial and amoebic cervicitis in Black patients at Baragwanath Hospital for the past 5 years is presented. The clinical presentation and the macroscopic and microscopic features of each type of cervicitis are discussed. The treatment of each condition is described, and the importance of differentiating cervical carcinoma from granulomatous cervicitis is stressed.


Temperature-related death burden of various neurodegenerative diseases under climate warming: a nationwide modelling study.
Limited knowledge exists regarding the ramifications of climate warming on death burden from neurodegenerative diseases. Here, we conducted a nationwide, individual-level, case-crossover study between 2013 and 2019 to investigate the effects of non-optimal temperatures on various neurodegenerative diseases and to predict the potential death burden under different climate change scenarios. Our findings reveal that both low and high temperatures are linked to increased risks of neurodegenerative diseases death. We project that heat-related neurodegenerative disease deaths would increase, while cold-related deaths would decrease. This is characterized by a steeper slope in the high-emission scenario, but a less pronounced trend in the scenarios involving mitigation strategies. Furthermore, we predict that the net changes in attributable death would increase after the mid-21st century, especially under the unrestricted-emission scenario. These results highlight the urgent need for effective climate and public health policies to address the growing challenges of neurodegenerative diseases associated with global warming.


Neuron number and size in prefrontal cortex of children with autism.
Autism often involves early brain overgrowth, including the prefrontal cortex (PFC). Although prefrontal abnormality has been theorized to underlie some autistic symptoms, the cellular defects that cause abnormal overgrowth remain unknown. To investigate whether early brain overgrowth in children with autism involves excess neuron numbers in the PFC. DESIGN, SETTING, AND CASES: Postmortem prefrontal tissue from 7 autistic and 6 control male children aged 2 to 16 years was examined by expert anatomists who were blinded to diagnostic status. Number and size of neurons were quantified using stereological methods within the dorsolateral (DL-PFC) and mesial (M-PFC) subdivisions of the PFC. Cases were from the eastern and southeastern United States and died between 2000 and 2006. Mean neuron number and size in the DL-PFC and M-PFC were compared between autistic and control postmortem cases. Correlations of neuron number with deviation in brain weight from normative values for age were also performed. Children with autism had 67% more neurons in the PFC (mean, 1.94 billion; 95% CI, 1.57-2.31) compared with control children (1.16 billion; 95% CI, 0.90-1.42; P = .002), including 79% more in DL-PFC (1.57 billion; 95% CI, 1.20-1.94 in autism cases vs 0.88 billion; 95% CI, 0.66-1.10 in controls; P = .003) and 29% more in M-PFC (0.36 billion; 95% CI, 0.33-0.40 in autism cases vs 0.28 billion; 95% CI, 0.23-0.34 in controls; P = .009). Brain weight in the autistic cases differed from normative mean weight for age by a mean of 17.6% (95% CI, 10.2%-25.0%; P = .001), while brains in controls differed by a mean of 0.2% (95% CI, -8.7% to 9.1%; P = .96). Plots of counts by weight showed autistic children had both greater total prefrontal neuron counts and brain weight for age than control children. In this small preliminary study, brain overgrowth in males with autism involved an abnormal excess number of neurons in the PFC.


[Effects of histone H3 K4L and K36L mutations on the cell growth and the transcription of GAL1, SSA3 and PHO5 in Saccharomyces cerevisiae].
Post-translational modifications of histones, such as acetylation and methylation, have a pivotal role in regulating gene expression and cell growth. To elucidate the different roles and importance of H3K4 and H3K36 modifications in expression of inducible genes such as Cal1, SSA3, PHO5 and the growth of yeast cell, we constructed three different yeast mutant strains carrying mutations of lysine 4, 36, or both to leucine in the histone H3 tail. Real-time PCR and sensitive assay under the conditions of high temperature, NaCl, caffeine, 6-AU, or other conditions were carried out to characterize the effects of these mutations on cell growth and transcription levels of GAL1, SSA3 and PHO5. The results showed that three histone methylation mutants exhibited more severe growth defects and slower activation of GAL1, SSA3 and PHO5 than those of wild type; H3K4L/H3K36L double mutant strain D436 has the most severe phenotype. H3K4L mutants S4 exhibited more severe defects than those of H3K36L S36 mutants, especially at high temperature and high NaCl stresses. These results show that H3K4L and H3K36L are important for the growth and survival of yeast in unfavorable conditions, and that different mutations have different effects on the expression of single inducible gene, whereas the same mutation has different effects on the activation of different inducible genes in vivo. The post-translational modification of H3K4 is more important than H3K36 on the adaptation to harsh condition for yeast cell. The growth defects of histone mutant strains might arise from the slow activation of inducible gene essential for survival at harsh conditions.


Glucuronan lyases from family PL7 use a Tyr/Tyr syn β-elimination catalytic mechanism for glucuronan breakdown.
TpPL7A and TpPL7B, members of CAZy family PL7, act as β-glucuronan lyases. TpPL7A diverges by lacking the catalytic histidine, identified as the Brønsted base in PL7 alginate lyases. Our research, including TpPL7A's crystal structure, and mutagenesis studies, reveals a shared syn-β-elimination mechanism with a single tyrosine serving as both base and acid catalyst. This mechanism may extend to subfamily PL7_4 glucuronan lyases.


Novel germline mutations in the PTEN tumour suppressor gene found in women with multiple cancers.
Germline mutations in PTEN can predispose people to Cowden syndrome (CS) and Bannayan-Ruvalcaba-Riley (BRR) syndrome, rare, autosomal dominantly inherited neoplastic disorders. To determine whether germline mutations in PTEN contribute to genetic predisposition to multiple primary tumours within the general population, we conducted a nested case-control study, among 32 826 members of the prospective Nurses' Health Study cohort; cases were women with more than one primary tumour at different anatomical sites. We screened all nine exons of PTEN and flanking intronic splice sites for all 103 eligible cases using SSCP and sequencing. We observed two novel germline heterozygous missense mutations in exon 5 in five of the cases; three were V119L and two were V158L. Neither mutation was observed in 115 controls free of diagnosed cancer (p = 0.02). Both mutants showed partial tumour suppressor activity when compared to wild type PTEN when transfected into a PTEN null breast cancer cell line. The phenotype was cell line specific suggesting that genetic background affects growth suppression activity of the mutants. These data provide evidence that germline mutations in PTEN may be a more frequent predisposing factor for cancers in women than previously suggested.


Biochemical and pharmacological characterization of the human lymphocyte antigen B-associated transcript 5 (BAT5/ABHD16A).
Human lymphocyte antigen B-associated transcript 5 (BAT5, also known as ABHD16A) is a poorly characterized 63 kDa protein belonging to the α/β-hydrolase domain (ABHD) containing family of metabolic serine hydrolases. Its natural substrates and biochemical properties are unknown. Amino acid sequence comparison between seven mammalian BAT5 orthologs revealed that the overall primary structure was highly (≥95%) conserved. Activity-based protein profiling (ABPP) confirmed successful generation of catalytically active human (h) and mouse (m) BAT5 in HEK293 cells, enabling further biochemical characterization. A sensitive fluorescent glycerol assay reported hBAT5-mediated hydrolysis of medium-chain saturated (C14:0), long-chain unsaturated (C18:1, C18:2, C20:4) monoacylglycerols (MAGs) and 15-deoxy-Δ12,14-prostaglandin J2-2-glycerol ester (15d-PGJ2-G). In contrast, hBAT5 possessed only marginal diacylglycerol (DAG), triacylglycerol (TAG), or lysophospholipase activity. The best MAG substrates were 1-linoleylglycerol (1-LG) and 15d-PGJ2-G, both exhibiting low-micromolar Km values. BAT5 had a neutral pH optimum and showed preference for the 1(3)- vs. 2-isomers of MAGs C18:1, C18:2 and C20:4. Inhibitor profiling revealed that β-lactone-based lipase inhibitors were nanomolar inhibitors of hBAT5 activity (palmostatin B > tetrahydrolipstatin > ebelactone A). Moreover, the hormone-sensitive lipase inhibitor C7600 (5-methoxy-3-(4-phenoxyphenyl)-3H-[1], [3], [4]oxadiazol-2-one) was identified as a highly potent inhibitor (IC50 8.3 nM). Phenyl and benzyl substituted analogs of C7600 with increased BAT5 selectivity were synthesized and a preliminary SAR analysis was conducted to obtain initial insights into the active site dimensions. This study provides an initial characterization of BAT5 activity, unveiling the biochemical and pharmacological properties with in vitro substrate preferences and inhibitor profiles. Utilization of glycerolipid substrates and sensitivity to lipase inhibitors suggest that BAT5 is a genuine lipase with preference for long-chain unsaturated MAGs and could in this capacity regulate glycerolipid metabolism in vivo as well. This preliminary SAR data should pave the way towards increasingly potent and BAT5-selective inhibitors.


Production of the phytohormone indole-3-acetic acid by estuarine species of the genus Vibrio.
Strains of Vibrio spp. isolated from roots of the estuarine grasses Spartina alterniflora and Juncus roemerianus produce the phytohormone indole-3-acetic acid (IAA). The colorimetric Salkowski assay was used for initial screening of IAA production. Gas chromatography-mass spectroscopy (GC-MS) was then employed to confirm and quantify IAA production. The accuracy of IAA quantification by the Salkowski assay was examined by comparison to GC-MS assay values. Indole-3-acetamide, an intermediate in IAA biosynthesis by the indole-3-acetamide pathway, was also identified by GC-MS. Multilocus sequence typing of concatenated 16S rRNA, recA, and rpoA genes was used for phylogenetic analysis of environmental isolates within the genus Vibrio. Eight Vibrio type strains and five additional species-level clades containing a total of 16 environmental isolates and representing five presumptive new species were identified as IAA-producing Vibrio species. Six additional environmental isolates similar to four of the Vibrio type strains were also IAA producers. To our knowledge, this is the first report of IAA production by species of the genus Vibrio or by bacteria isolated from an estuarine environment.


Active choice, implicit defaults, and the incentive to choose.
Home-delivered prescriptions have no delivery charge and lower copayments than prescriptions picked up at a pharmacy. Nevertheless, when home delivery is offered on an opt-in basis, the take-up rate is only 6%. We study a program that makes active choice of either home delivery or pharmacy pick-up a requirement for insurance eligibility. The program introduces an implicit default for those who don't make an active choice: pharmacy pick-up without insurance subsidies. Under this program, 42% of eligible employees actively choose home delivery, 39% actively choose pharmacy pick-up, and 19% make no active choice and are assigned the implicit default. Individuals who financially benefit most from home delivery are more likely to choose it. Those who benefit least from insurance subsidies are more likely to make no active choice and lose those subsidies. The implicit default incentivizes people to make an active choice, thereby playing a key role in choice architecture.


The knotted1-like homeobox gene BREVIPEDICELLUS regulates cell differentiation by modulating metabolic pathways.
Members of the KNOX gene family have important roles in plant meristems by regulating cell division and differentiation. BREVIPEDICELLUS (BP), one of seven KNOX genes in Arabidopsis, has a primary role in internode patterning. We carried out a comparison of RNA expression profiles between wild-type seedlings and bp mutants at a developmental stage prior to a visible phenotypic difference. Transcript differences were found for a number of genes in cell wall biosynthesis, especially genes in the lignin pathway. The regulation of lignin biosynthesis by BP was demonstrated by observing increased lignin deposition in bp mutants following bolting, decreased lignification in plants overexpressing BP, and aberrant lignin deposition in discrete regions of the bp stem. Furthermore, we showed that BP binds promoters of some genes in the lignin pathway. Our results provide a metabolic fingerprint for BP and identify the lignin pathway as one of the coordinate processes that BP regulates.


Staying Quit After Release (SQuARe) trial protocol: a randomised controlled trial of a multicomponent intervention to maintain smoking abstinence after release from smoke-free prisons in Victoria, Australia.
Smoke-free policies have been introduced in prisons internationally. However, high rates of relapse to smoking after release from prison indicate that these policies typically result in short-term smoking cessation only. These high rates of relapse, combined with a lack of investment in relapse prevention, highlight a missed opportunity to improve the health of a population who smoke tobacco at two to six times the rate of the general population. This paper describes the rationale and design of a randomised controlled trial, testing the effectiveness of a caseworker-delivered intervention promoting smoking cessation among former smokers released from smoke-free prisons in Victoria, Australia. The multicomponent, brief intervention consists of behavioural counselling, provision of nicotine spray and referral to Quitline and primary care to promote use of government-subsidised smoking cessation pharmacotherapy. The intervention is embedded in routine service delivery and is administered at three time points: one prerelease and two postrelease from prison. Control group participants will receive usual care. Smoking abstinence will be assessed at 1 and 3 months postrelease, and confirmed with carbon monoxide breath testing. Linkage of participant records to survey and routinely collected administrative data will provide further information on postrelease use of health services and prescribed medication. Ethical approval has been obtained from the Corrections Victoria Research Committee, the Victorian Department of Justice Human Research Ethics Committee, the Department of Human Services External Request Evaluation Committee and the University of Melbourne Human Research Ethics Committee. Results will be submitted to major international health-focused journals. In case of success, findings will assist policymakers to implement urgently needed interventions promoting the maintenance of prison-initiated smoking abstinence after release, to reduce the health disparities experienced by this marginalised population. ACTRN12618000072213; Pre-results.


Segregation and coactivation of developing neocortical layer 1 neurons.
Layer 1 in the developing cerebral cortex is populated by two basic neuronal cell types, Cajal-Retzius (CR) cells and non-CR cells. We generated transgenic mice in which green fluorescent protein (GFP) was driven by the promoter of metabotropic glutamate receptor subtype 2 and expressed specifically in CR cells during cortical development. On the basis of the precise identification of CR cells with GFP fluorescence, we pursued developmental changes and synaptic mechanisms of both CR and non-CR cells during the postnatal period. Immunostaining in combination with GFP fluorescence imaging showed that GFP and reelin, a protein involved in corticogenesis, completely overlap in CR cells at postnatal day 0. At the subsequent postnatal stage, reelin-positive neurons are segregated and categorized into GFP-positive/GABA-negative CR cells and GFP-negative/GABA-positive non-CR cells. Individual and simultaneous whole-cell recordings of CR and non-CR cells in developing cerebral slices revealed that spontaneous and electrically evoked postsynaptic currents (sPSCs and ePSCs) measured in CR and non-CR cells are differentially mediated by GABA(A) receptors versus GABA(A), AMPA, and NMDA receptors, respectively. Furthermore, CR and non-CR cells show synchronized repetitive barrages of sPSCs that reflect a network-driven activity in the developing cerebral cortex. These findings imply that the layer 1 neurons dynamically change and play a distinct and integral role in the postnatal developing neocortex.


Jasmonic Acid Inhibits Auxin-Induced Lateral Rooting Independently of the CORONATINE INSENSITIVE1 Receptor.
Plant root systems are indispensable for water uptake, nutrient acquisition, and anchoring plants in the soil. Previous studies using auxin inhibitors definitively established that auxin plays a central role regulating root growth and development. Most auxin inhibitors affect all auxin signaling at the same time, which obscures an understanding of individual events. Here, we report that jasmonic acid (JA) functions as a lateral root (LR)-preferential auxin inhibitor in Arabidopsis (Arabidopsis thaliana) in a manner that is independent of the JA receptor, CORONATINE INSENSITIVE1 (COI1). Treatment of wild-type Arabidopsis with either (-)-JA or (+)-JA reduced primary root length and LR number; the reduction of LR number was also observed in coi1 mutants. Treatment of seedlings with (-)-JA or (+)-JA suppressed auxin-inducible genes related to LR formation, diminished accumulation of the auxin reporter DR5::GUS, and inhibited auxin-dependent DII-VENUS degradation. A structural mimic of (-)-JA and (+)-coronafacic acid also inhibited LR formation and stabilized DII-VENUS protein. COI1-independent activity was retained in the double mutant of transport inhibitor response1 and auxin signaling f-box protein2 (tir1 afb2) but reduced in the afb5 single mutant. These results reveal JAs and (+)-coronafacic acid to be selective counter-auxins, a finding that could lead to new approaches for studying the mechanisms of LR formation.


Pretreatment with high-dose statin, but not low-dose statin, ezetimibe, or the combination of low-dose statin and ezetimibe, limits infarct size in the rat.
Statins reduce infarct size by upregulating nitric oxide synthases and PGI2 production. In this article, the infarct size-limiting effect of low-dose simvastatin + ezetimibe, ezetimibe, and high-dose statins were compared. Rats received 3-day water, atorvastatin (10 mg/kg/d), simvastatin (10 mg/kg/d), simvastatin (2 mg/kg/d), simvastatin (2 mg/kg/d) + ezetimibe (1 mg/kg/d), or ezetimibe. Rats underwent 30-minute coronary artery occlusion and 4-hour reperfusion. Atorvastatin and simvastatin 10 reduced infarct size, whereas simvastatin 2, ezetimibe, and simvastatin 2 + ezetimibe had no effect. Atorvastatin and simvastatin 10 increased nitric oxide synthases activity, whereas simvastatin-2, ezetimibe, and simvastatin-2 + ezetimibe had only a small effect. Atorvastatin and simvastatin 10 significantly increased myocardial 6-ketoprostaglandin F(1 alpha) levels, whereas simvastatin 2, ezetimibe, and simvastatin 2 + ezetimibe had no effect. High-dose statin is required to decrease infarct size, upregulate myocardial nitric oxide synthases activities, and increase 6-keto prostaglandin F(1 alpha) levels. Combination of ezetimibe and low-dose statin is ineffective in modulating myocardial biochemical changes associated with cardioprotection.


Herpes simplex virus type 1 pathogenicity in footpad and ear skin of mice depends on Langerhans cell density, mouse genetics, and virus strain.
Skin Langerhans cells have been shown to be very efficient in presenting antigens to T-helper cells and stimulating the immune response. The present study demonstrates their essential role in the control of primary herpetic infections in the skin. Two unrelated stimuli (abrasion and steroids) were shown to cause depletion of the Langerhans cells in the murine epidermis, and both caused enhancement of the virulence of herpes simplex type 1 (HSV-1) in the skin. The Langerhans cell density was found to be lower in the skin of the ear than in the footpad. HSV-1 was consistently more virulent when injected into the ear epidermis than in the footpad. Thus, HSV-1 pathogenicity in mouse skin depends on the mouse age and strain, the virus strain, and the state of the epidermal Langerhans cells. These findings are discussed in relation to the antigen-presenting cell function of the Langerhans cells.


Similar success rate in proximal and distal colonic stent placement: a retrospective multi-center study.
Stenting of malignant colon obstruction is used as a bridge to surgery or as an alternative to surgical colostomy in a palliative setting. Current guidelines recommend stent placement as the first line of treatment in colonic obstruction in both curative and palliative settings. However, it is unclear whether the location of the malignant obstruction influences the outcome of the stenting procedure. The goal of this study was to compare the outcomes of colonic stents between proximal and distal colonic strictures with regard to technical and clinical success and the risk of adverse events. A multi-center retrospective cohort was composed of patients who underwent a colonic stent placement at two tertiary hospitals between 2013 and 2021. The technical and clinical outcome, stent type used, duration of post-procedural hospital stay and complications were noted. A total of 148 patients who underwent colonic stenting were identified. 41 patients underwent stent placement in the proximal colon and 107 patients underwent a distal stent placement. There was no difference in technical success (100% vs 96.3%, p = 0.209), clinical success (97.0% vs 89.6%, p = 0.199) or complications (24.4% vs 37.4%, p = 0,135). Technical success and clinical success rates are high and do not differ between stent locations. There is no significant difference in complication rates between proximal and distal colonic stents.


Investigation of opioid use and long-term oncologic outcomes for non-small cell lung cancer patients treated with surgery.
Opioids are commonly used for postoperative pain control in cancer patients. In addition to pain control, an association between opioid use and long-term oncologic outcomes, such as recurrence or overall survival, has been postulated. The aim of this study was to determine whether postoperative opioid use in patients with non-small cell lung cancer is associated with long-term oncologic outcomes, including recurrence and death. Data obtained from 1009 medical records of patients who underwent curative resection at the National Cancer Center, Korea between January 2006 and December 2010 were retrospectively analyzed. Seven-day opioid use was divided into four quartiles to analyze probability of recurrence and death. Multivariate regression analyses of recurrence and death was conducted, including the calculation of odds ratios. A total of 871 patients were analyzed. When opioid dosage was examined by quartiles, the probability of death and recurrence increased gradually with increasing opioid use. However, in the multivariate regression analysis, the amount of opioid usage did not affect the risk of recurrence or death of lung cancer (P = 0.520 for recurrence; P = 0.659 for death). Opioid use was correlated with outcome when stratified by lung cancer stage (P = 0.004 for recurrence; P = 0.049 for death); however, the odds ratios only slightly increased (1.001 for stage IA-IIIA) for both outcomes. In non-small cell lung cancer patients, the amount of opioid usage does not affect the risk of recurrence and death of lung cancer. There was an association with stage (IA-IIIA), but the effect was negligible. A well-designed prospective study is needed.


Validity of self-reported smoking status: Comparison of patients admitted to hospital with acute coronary syndrome and the general population.
Many studies rely on self-reported smoking status. We hypothesized that patients with acute coronary syndrome (ACS), a smoking-related condition, would be more prone to misclassify themselves as ex-smokers, because of pressure to quit. We compared patients admitted with ACS with a general population survey conducted in the same country at a similar time. We determined whether ACS patients who classified themselves as ex-smokers (n = 635) were more likely to have cotinine levels suggestive of smoking deception than self-reported ex-smokers in the general population (n = 289). On univariate analysis, the percentage of smoking deceivers was similar among ACS patients and the general population (11% vs. 12%, p = .530). Following adjustment for age, sex and exposure to environmental tobacco smoke, ACS patients were significantly more likely to misclassify themselves (adjusted OR = 14.06, 95% CI 2.13-93.01, p = .006). There was an interaction with age whereby the probability of misclassification fell significantly with increasing age in the ACS group (adjusted OR = 0.95, 95% CI 0.93-0.97, p<.001), but not in the general population. Overall, smoking deception was more common among ACS patients than the general population. Studies comparing patients with cardiovascular disease and healthy individuals risk introducing bias if they rely solely on self-reported smoking status. Biochemical confirmation should be undertaken in such studies.


Differential sensitivity of a mouse myeloid leukemia cell line and normal mouse bone marrow cells to X-ray-induced chromosome aberrations.
Cell line ML-1 was established from a myelogenous leukemia of an RFM mouse. The ML-1 cells and in vitro normal mouse bone marrow cells were analyzed to determine if there was a differential sensitivity to X-ray-induced chromosome aberrations in G1 cells and/or differences in postirradiation cell cycle progression. Cells identified as being in G1 at the time of irradiation by their staining pattern after replication in 5-bromodeoxyuridine were analyzed for all types of chromosomal aberrations following X-ray doses of 0.5, 1.0, 1.5, and 2.0 Gy. ML-1 cells showed a greater sensitivity to the induction of both chromosome-type aberrations (dicentrics and terminal deletions) and chromatid-type aberrations (exchanges and deletions) compared to normal mouse bone marrow cells, which only contained chromosome-type aberrations. The presence of chromatid-type aberrations in the ML-1 cells and not normal bone marrow cells suggested a differential progression through the cell cycle for the two cell types after irradiation. Mitotic index and flow cytometric analyses were performed and showed that both cell types have a delay in progression from G2 into mitosis, but only the normal mouse bone marrow cells have a delay in progression from G1 into S, as well as delayed progression through the S phase following X-irradiation. These results indicate that the ML-1 leukemia cells have an increased radiosensitivity. This may be due to a defect in their ability to respond to DNA damage as evidenced by their lack of a G1- and S-phase delay which allows normal cells an increased time to repair DNA damage before replication. These same characteristics have been observed in ataxia telangiectasia cells and may well represent a general feature of cells with increased radiosensitivity.


The active management of impending cephalopelvic disproportion in nulliparous women at term: a case series.
The Active Management of Risk in Pregnancy at Term (AMOR-IPAT) protocol has been associated in several studies with significant reductions of group cesarean delivery rate. Present within each of these studies were nulliparous women with risk factors for cephalopelvic disproportion. Risk factors for cephalopelvic disproportion in nulliparous women are especially important because they represent the precursors for the most common indication for primary cesarean delivery. Three examples of exposure of urban nulliparous women to the AMOR-IPAT protocol are presented. Each woman's risk factor profile for Cephalopelvic Disproportion (CPD) was used to estimate her Upper Limit of Optimal Time of Vaginal Delivery for CPD (UL-OTDcpd). Labor management and clinical outcomes for each case are presented. A simple table summarizing induction rates and birth outcome rates of exposed versus nonexposed nulliparous women is also presented. Because the mode of delivery of the first birth substantially impacts birth options in later pregnancies, the impact of AMOR-IPAT on nulliparous patients is particularly important. Determining the UL-OTDcpd in nulliparous patients, and carefully inducing each patient who has not entered labor by her UL-OTDcpd, may be an effective way of lowering rates of cesarean delivery in nulliparous women.


Hybridization arrest of globin synthesis in rabbit reticulocyte lysates and cells by oligodeoxyribonucleoside methylphosphonates.
Oligodeoxyribonucleoside methylphosphonates which are complementary to the 5' end, the initiation codon regions, or the coding regions of rabbit globin mRNA were synthesized. These oligomers were shown to interact with their complementary mRNA binding sites by their ability to serve as primers for reverse transcriptase. In several cases, the priming efficiency of the oligomers was enhanced when the oligomer was preannealed with the mRNA. This behavior correlates with the predicted secondary structure of the mRNA and suggests that some oligomer binding sites occur in hydrogen-bonded stem regions of the mRNA. Methylphosphonate oligomers inhibit translation of globin mRNA in reticulocyte lysates. Inhibition is due to the interaction of the oligomers with mRNA. The extent of inhibition is affected by the sequence and chain length of the oligomer, the location of the oligomer binding site on the mRNA, and the secondary structure of the binding site. Oligomers which bind to the 5' end and initiation codon regions of beta-globin mRNA inhibit both alpha- and beta-globin synthesis whereas oligomers which bind to the coding region of alpha-globin mRNA or the coding region of beta-globin mRNA inhibit translation of their target mRNA in a specific manner. Oligodeoxyribonucleoside methylphosphonates inhibit globin synthesis in rabbit reticulocytes. The effects of various oligomers on cellular globin synthesis are similar to those in the lysate system and suggest that the conformation of globin mRNA is the same in both systems during translation.


Cytokinins: Wide-Spread Signaling Hormones from Plants to Humans with High Medical Potential.
Nature is a rich source of biologically active novel compounds. Sixty years ago, the plant hormones cytokinins were first discovered. These play a major role in cell division and cell differentiation. They affect organogenesis in plant tissue cultures and contribute to many other physiological and developmental processes in plants. Consequently, the effect of cytokinins on mammalian cells has caught the attention of researchers. Many reports on the contribution and potential of cytokinins in the therapy of different human diseases and pathophysiological conditions have been published and are reviewed here. We compare cytokinin effects and pathways in plants and mammalian systems and highlight the most important biological activities. We present the strong profile of the biological actions of cytokinins and their possible therapeutic applications.


Suppression of PTEN expression is essential for antiapoptosis and cellular transformation by oncogenic Ras.
Ras is one of the most commonly mutated oncogenes in the array of human cancers. The mechanism by which Ras induces cellular transformation is, however, not fully elucidated. We present here evidence that oncogenic Ras suppresses the expression of the tumor suppressor phosphatase and tensin homologue deleted from chromosome 10 (PTEN), and this action of oncogenic Ras is mediated by the Raf-mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway via up-regulation of c-Jun. Jun(+/+) cells undergo cellular transformation by oncogenic Ras, and restoration of wild-type PTEN, but not a phosphate-defective mutant of PTEN, induces apoptosis in these cells. Conversely, in Jun(-/-) cells, oncogenic Ras neither suppresses PTEN nor causes transformation, but rather it induces PTEN-dependent apoptosis. An apoptotic response to oncogenic Ras in Jun(-/-) cells can be prevented by suppressing PTEN expression. These findings imply that oncogenic Ras suppresses the apoptotic gene PTEN via the Raf-MEK-ERK-c-Jun pathway to induce antiapoptosis and cellular transformation. Together, our findings identify a novel molecular interface between the oncogenic and tumor suppressor pathways that regulates cellular transformation and survival.


Alcaptonuria and ochronotic arthritis.
The rare hereditary metabolic disorder alcaptonuria is characterized by the inability to metabolize homogentisic acid, an intermediary compound in the catabolism of the aromatic amino acids phenylalanine and tyrosine. The essentially complete deficiency of homogentisic acid oxidase causes a striking accumulation of homogentisic acid and a derived melanin-like pigment in the connective tissues; the latter is termed ochronosis. Urinary homogentisic acid is oxidized rapidly and becomes a brown or black pigment if alkali is added. Older alcaptonurics have intensely pigmented (ochronotic) connective tissues, primarily the cartilaginous joint surfaces, ribs, intervertebral disks, ear cartilage, etc. They also have an unusual type of arthritis affecting the large weight-bearing joints, i.e. hips, knees and spine, but not the small joints of the hands and feet, as in rheumatoid arthritis. A mechanistic explanation for ochronotic arthritis has not been worked out, but it is clear that accumulation of homogentisic acid in the connective tissues directly or indirectly leads to the arthritic changes. A detailed analysis of the events leading to alcaptonuric arthritis should be worthwhile since it is a model form of arthritis secondary to a well-defined metabolic disorder that must persist for many years before the arthritic complications appear. Possibly other, more common types of arthritis, develop secondarily to metabolic disturbances that involve chemical mediators less obvious, or less easily detected, than homogentisic acid.


Vascular endothelial growth factor (VEGF)-C differentially affects tumor vascular function and leukocyte recruitment: role of VEGF-receptor 2 and host VEGF-A.
Unlike vascular endothelial growth factor (VEGF)-A, the effect of VEGF-C on tumor angiogenesis, vascular permeability, and leukocyte recruitment is not known. To this end, we quantified in vivo growth and vascular function in tumors derived from two VEGF-C-overexpressing (VC+) and mock-transfected cell lines (T241 fibrosarcoma and VEGF-A-/- embryonic stem cells) grown in murine dorsal skinfold chambers. VC+ tumors grew more rapidly than mock-transfected tumors and exhibited parallel increases in tumor angiogenesis. Furthermore, VEGF-C overexpression elevated vascular permeability in T241 tumors, but not in VEGF-A-/- tumors. Surprisingly, unlike VEGF-A, VEGF-C did not increase leukocyte rolling or adhesion in tumor vessels. Administration of VEGF receptor (VEGFR)-2 neutralizing antibody DC101 reduced vascular density and permeability of both VC+ and mock-transduced T241 tumors. These data suggest that VEGFR-2 signaling is critical for tumor angiogenesis and vascular permeability and that VEGFR-3 signaling does not compensate for VEGFR-2 blockade. An alternate VEGFR, VEGFR-1 or neuropilin-1, may modulate adhesion of leukocytes to tumor vessels.


[Reconstruction of the anterior chamber in posttraumatic epithelial ingrowths and epithelial anterior chamber cysts].
The pathology of penetrating injuries of the cornea and corneal-scleral area with the ingrowth of epithelium and formation of anterior chamber cysts is characterized by polymorphism and can be defined by two main kinds: 1) plane ingrowth of epithelium along the posterior surface of the cornea involving the iris and the lens, and partially or totally obliterating the anterior chamber; 2) formation of cysts with a locked cavity and clear content. In 42 patients with epithelial ingrowths as a result of penetrating injuries of the cornea and corneal-scleral area, the following kinds of interventions were used: 1) transplantation of posterior layers of the cornea with dissection of epithelial growth; 2) dissection of anterior chamber cysts; 3) cystectomy; 4) dissection of the cite of epithelial ingrowth by means of corneal transplantation with removal of the cyst or reconstruction of the anterior chamber. Immediate and remote results of surgical treatment, complications in various forms of the mentioned pathology are described.


Ingestion of Casein Hydrolysate Induces Oral Tolerance and Suppresses Subsequent Epicutaneous Sensitization and Development of Anaphylaxis Reaction to Casein in Mice.
Casein is the most dominant causal allergen in cow's milk allergy (CMA). Casein hydrolysates are frequently applied in infant formulas for children with a risk or history of CMA. However, there is limited information on the oral tolerance-inducing ability of casein hydrolysates. The aim of this study was to investigate whether the ingestion of casein hydrolysate induces tolerance to casein, ultimately preventing subsequent epicutaneous sensitization and development of an anaphylaxis reaction. BALB/c mice were orally administered casein or a casein hydrolysate (CNH) via the drinking water and were then epicutaneously sensitized by repeated exposure of casein on tape-stripped skin. Sensitization was assessed by basophil activation tests, the serum levels of casein-specific antibodies, and cytokine production from casein-stimulated spleen and mesenteric lymph node (MLN) cells. Occurrence of an anaphylaxis reaction was evaluated by measuring rectal temperature and the plasma level of mouse mast cell protease-1 (mMCP-1) after oral casein challenges. The T cell population in the spleen and MLN was assessed by flow cytometry. Intestinal mast cells and basophils were analyzed histologically. Sensitization and anaphylaxis reaction to casein were significantly suppressed in casein- or CNH-fed mice compared to controls. Prior ingestion of casein or CNH had no effect on the population of regulatory T cells and activated T cells in lymphoid tissues. Intestinal basophils increased by the epicutaneous sensitization of casein, which was suppressed in casein- or CNH-fed mice. Although the increase in the plasma level of mMCP-1 after oral challenge was suppressed in casein- or CNH-fed mice, there was no change in the number of intestinal mast cells. Prior ingestion of casein or CNH induced oral tolerance and suppressed subsequent epicutaneous sensitization and development of systemic anaphylaxis to casein.


A Systematic Review of Urban Navigation Systems for Visually Impaired People.
Blind and Visually impaired people (BVIP) face a range of practical difficulties when undertaking outdoor journeys as pedestrians. Over the past decade, a variety of assistive devices have been researched and developed to help BVIP navigate more safely and independently. In addition, research in overlapping domains are addressing the problem of automatic environment interpretation using computer vision and machine learning, particularly deep learning, approaches. Our aim in this article is to present a comprehensive review of research directly in, or relevant to, assistive outdoor navigation for BVIP. We breakdown the navigation area into a series of navigation phases and tasks. We then use this structure for our systematic review of research, analysing articles, methods, datasets and current limitations by task. We also provide an overview of commercial and non-commercial navigation applications targeted at BVIP. Our review contributes to the body of knowledge by providing a comprehensive, structured analysis of work in the domain, including the state of the art, and guidance on future directions. It will support both researchers and other stakeholders in the domain to establish an informed view of research progress.


Bi-layered α-tocopherol acetate loaded membranes for potential wound healing and skin regeneration.
With an increase in the demand for skin regeneration products, there is a noticeable increase in developing materials that encourage, wound healing and skin regeneration. It has been reported that antioxidants play an important role in anti-inflammatory reactions, cellular proliferation and remodeling phase of wound healing. While consideration all these factors, a novel α-tocopherol acetate (vitamin E) (VE) loaded bi-layered electrospun membrane, based on lower polycaprolactone (PCL) layer and upper polylactic acid (PLA) layer, was fabricated through electrospinning. Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), in-vitro degradation studies, swelling studies and VE release studies were performed to evaluate structural, physical and in-vitro behavior of membranes. Biological properties of membranes were evaluated through cell proliferation assay, cell adhesion studies, live/dead cell assay and CAM assay. SEM images showed that the average diameter of nanofibers ranged from 1 to 6 μm, while addition of VE changed the diameter and morphology of fibers. Bi-layered membranes showed significant swelling behavior through water uptake, membranes loaded with 30% VE showed 8.7% and 6.8% degradation in lysozyme and H2O2 respectively. 20% and 30% VE loaded membranes followed Korsmeyer-Peppas and first order drug release kinetics followed by non-fickian drug release kinetics. Membranes showed non-toxic behavior and supported cell proliferation via alamar blue assay, cell adhesion via SEM, cell viability via live/dead assay and wound healing by scratch assay. CAM assay showed that membranes having VE supported angiogenesis and showed significant formation of blood vessels making it suitable for skin regeneration and wound healing. Results showed that large surface area of nanofibers, porous structure and biocompatible nature are suitable for targeted clinical applications.


The Golden Mirror in the imperial court of the Qianlong emperor, 1739-1742.
In the last month of 1739, the third f the Manchu rulers, the Qianlong emperor (r. 1736-1795), ordered the compilation of a treatise on medicine "to rectify medical knowledge" throughout the empire. By the end of 1742, eighty participants chosen from several offices within the palace bureaucracy based in Beijing completed the Golden Mirror of the Orthodox Lineage of Medicine, the only imperially commissioned medical text the Qing government's Imperial Printing Office published. The Golden Mirror represents both the limitations in the power of the Qianlong emperor and the dominance in the Manchu court of Chinese scholarship from the Jiangnan region during the first decade of his reign. Chinese scholars participating in the compilation of the Golden Mirror fashioned a medical orthodoxy for the empire in the mid-eighteenth century from regional trends since the sixteenth century. The Golden Mirror is an illuminating example of how medical scholars participated in the formation of evidential scholarship in early-modern China and why Manchu patronage, southern Chinese scholarship, and medical orthodoxy, coalesced in the imperial court of the Qianlong emperor.


A biomarker-based age, biomarkers, clinical history, sex (ABCS)-mortality risk score for patients with coronavirus disease 2019.
Early identification and timely therapeutic strategies for potential critical patients with coronavirus disease 2019 (COVID-19) are of crucial importance to reduce mortality. We aimed to develop and validate a prediction tool for 30-day mortality for these patients on admission. Consecutive hospitalized patients admitted to Tongji Hospital and Hubei Xinhua Hospital from January 1 to March 10, 2020, were retrospective analyzed. They were grouped as derivation and external validation set. Multivariate Cox regression was applied to identify the risk factors associated with death, and a nomogram was developed and externally validated by calibration plots, C-index, Kaplan-Meier curves and decision curve. Data from 1,717 patients at the Tongji Hospital and 188 cases at the Hubei Xinhua Hospital were included in our study. Using multivariate Cox regression with backward stepwise selection of variables in the derivation cohort, age, sex, chronic obstructive pulmonary disease (COPD), as well as seven biomarkers (aspartate aminotransferase, high-sensitivity C-reactive protein, high-sensitivity troponin I, white blood cell count, lymphocyte count, D-dimer, and procalcitonin) were incorporated in the model. An age, biomarkers, clinical history, sex (ABCS)-mortality score was developed, which yielded a higher C-index than the conventional CURB-65 score for predicting 30-day mortality in both the derivation cohort {0.888 [95% confidence interval (CI), 0.869-0.907] vs. 0.696 (95% CI, 0.660-0.731)} and validation cohort [0.838 (95% CI, 0.777-0.899) vs. 0.619 (95% CI, 0.519-0.720)], respectively. Furthermore, risk stratified Kaplan-Meier curves showed good discriminatory capacity of the model for classifying patients into distinct mortality risk groups for both derivation and validation cohorts. The ABCS-mortality score might be offered to clinicians to strengthen the prognosis-based clinical decision-making, which would be helpful for reducing mortality of COVID-19 patients.


RGS7/Gβ5/R7BP complex regulates synaptic plasticity and memory by modulating hippocampal GABABR-GIRK signaling.
In the hippocampus, the inhibitory neurotransmitter GABA shapes the activity of the output pyramidal neurons and plays important role in cognition. Most of its inhibitory effects are mediated by signaling from GABAB receptor to the G protein-gated Inwardly-rectifying K+ (GIRK) channels. Here, we show that RGS7, in cooperation with its binding partner R7BP, regulates GABABR-GIRK signaling in hippocampal pyramidal neurons. Deletion of RGS7 in mice dramatically sensitizes GIRK responses to GABAB receptor stimulation and markedly slows channel deactivation kinetics. Enhanced activity of this signaling pathway leads to decreased neuronal excitability and selective disruption of inhibitory forms of synaptic plasticity. As a result, mice lacking RGS7 exhibit deficits in learning and memory. We further report that RGS7 is selectively modulated by its membrane anchoring subunit R7BP, which sets the dynamic range of GIRK responses. Together, these results demonstrate a novel role of RGS7 in hippocampal synaptic plasticity and memory formation. DOI: http://dx.doi.org/10.7554/eLife.02053.001.


Glomerular angiotensin II receptor subtypes during development of rat kidney.
We used quantitative autoradiography to investigate distribution of angiotensin II (ANG II) receptor subtypes during development of the kidney in the rat. In fetal, newborn, and 3-day-old rats, immature glomeruli in the form of comma and S-shaped bodies, located in the nephrogenic zone of the renal cortex, expressed only the angiotensin AT2 receptor subtype. Conversely, the juxtamedullary glomeruli, in more advanced developmental stages, expressed only the AT1 subtype. Similarly, maturing and fully developed glomeruli, present in 1-, 2-, and 8-wk-old rats, expressed only AT1 receptors. In the kidney medulla, there was a similar change in ANG II receptor subtype expression, with the AT2 subtype expressed earlier and the AT1 subtype later during development. Our results demonstrate a selective expression of ANG II receptor subtypes during kidney development. We have found glomerular and medullary AT1 receptors only at developmental stages when kidney function has matured. Conversely, AT2 receptors are expressed only in immature structures, suggesting that they may have a role during kidney organogenesis.


Conformational cycle and ion-coupling mechanism of the Na+/hydantoin transporter Mhp1.
Ion-dependent transporters of the LeuT-fold couple the uptake of physiologically essential molecules to transmembrane ion gradients. Defined by a conserved 5-helix inverted repeat that encodes common principles of ion and substrate binding, the LeuT-fold has been captured in outward-facing, occluded, and inward-facing conformations. However, fundamental questions relating to the structural basis of alternating access and coupling to ion gradients remain unanswered. Here, we used distance measurements between pairs of spin labels to define the conformational cycle of the Na(+)-coupled hydantoin symporter Mhp1 from Microbacterium liquefaciens. Our results reveal that the inward-facing and outward-facing Mhp1 crystal structures represent sampled intermediate states in solution. Here, we provide a mechanistic context for these structures, mapping them into a model of transport based on ion- and substrate-dependent conformational equilibria. In contrast to the Na(+)/leucine transporter LeuT, our results suggest that Na(+) binding at the conserved second Na(+) binding site does not change the energetics of the inward- and outward-facing conformations of Mhp1. Comparative analysis of ligand-dependent alternating access in LeuT and Mhp1 lead us to propose that different coupling schemes to ion gradients may define distinct conformational mechanisms within the LeuT-fold class.


Time-dependent Inhibition of CYP2C8 and CYP2C19 by Hedera helix Extracts, A Traditional Respiratory Herbal Medicine.
The extract of Hedera helix L. (Araliaceae), a well-known folk medicine, has been popularly used to treat respiratory problems, worldwide. It is very likely that this herbal extract is taken in combination with conventional drugs. The present study aimed to evaluate the effects of H. helix extract on cytochrome P450 (CYP) enzyme-mediated metabolism to predict the potential for herb-drug interactions. A cocktail probe assay was used to measure the inhibitory effect of CYP. H. helix extracts were incubated with pooled human liver microsomes or CYP isozymes with CYP-specific substrates, and the formation of specific metabolites was investigated to measure the inhibitory effects. H. helix showed significant inhibitory effects on CYP2C8, CYP2C19 and CYP2D6 in a concentration-dependent manner. In recombinant CYP2C8, CYP2C19 and CYP2D6 isozymes, the IC50 values of the extract were 0.08 ± 0.01, 0.58 ± 0.03 and 6.72 ± 0.22 mg/mL, respectively. Further investigation showed that H. helix extract has a positive time-dependent inhibition property on both CYP2C8 and CYP2C19 with IC50 shift value of 2.77 ± 0.12 and 6.31 ± 0.25, respectively. Based on this in vitro investigation, consumption of herbal medicines or dietary supplements containing H. helix extracts requires careful attention to avoid any CYP-based interactions.


Apoptin nucleocytoplasmic shuttling is required for cell type-specific localization, apoptosis, and recruitment of the anaphase-promoting complex/cyclosome to PML bodies.
The chicken anemia virus protein Apoptin selectively induces apoptosis in transformed cells while leaving normal cells intact. This selectivity is thought to be largely due to cell type-specific localization: Apoptin is cytoplasmic in primary cells and nuclear in transformed cells. The basis of Apoptin cell type-specific localization and activity remains to be determined. Here we show that Apoptin is a nucleocytoplasmic shuttling protein whose localization is mediated by an N-terminal nuclear export signal (NES) and a C-terminal nuclear localization signal (NLS). Both signals are required for cell type-specific localization, since Apoptin fragments containing either the NES or the NLS fail to differentially localize in transformed and primary cells. Significantly, cell type-specific localization can be conferred in trans by coexpression of the two separate fragments, which interact through an Apoptin multimerization domain. We have previously shown that Apoptin interacts with the APC1 subunit of the anaphase-promoting complex/cyclosome (APC/C), resulting in G(2)/M cell cycle arrest and apoptosis in transformed cells. We found that the nucleocytoplasmic shuttling activity is critical for efficient APC1 association and induction of apoptosis in transformed cells. Interestingly, both Apoptin multimerization and APC1 interaction are mediated by domains that overlap with the NES and NLS sequences, respectively. Apoptin expression in transformed cells induces the formation of PML nuclear bodies and recruits APC/C to these subnuclear structures. Our results reveal a mechanism for the selective killing of transformed cells by Apoptin.


Methodological choices for the clinical development of medical devices.
Clinical evidence available for the assessment of medical devices (MDs) is frequently insufficient. New MDs should be subjected to high quality clinical studies to demonstrate their benefit to patients. The randomized controlled trial (RCT) is the study design reaching the highest level of evidence in order to demonstrate the efficacy of a new MD. However, the clinical context of some MDs makes it difficult to carry out a conventional RCT. The objectives of this review are to present problems related to conducting conventional RCTs and to identify other experimental designs, their limitations, and their applications. A systematic literature search was conducted for the period January 2000 to July 2012 by searching medical bibliographic databases. Problems related to conducting conventional RCTs of MDs were identified: timing the assessment, eligible population and recruitment, acceptability, blinding, choice of comparator group, and learning curve. Other types of experimental designs have been described. Zelen's design trials and randomized consent design trials facilitate the recruitment of patients, but can cause ethical problems to arise. Expertise-based RCTs involve randomization to a team that specializes in a given intervention. Sometimes, the feasibility of an expertise-based randomized trial may be greater than that of a conventional trial. Cross-over trials reduce the number of patients, but are not applicable when a learning curve is required. Sequential trials have the advantage of allowing a trial to be stopped early depending on the results of first inclusions, but they require an independent committee. Bayesian methods combine existing information with information from the ongoing trial. These methods are particularly useful in situations where the number of subjects is small. The disadvantage is the risk of including erroneous prior information. Other types of experimental designs exist when conventional trials cannot always be applied to the clinical development of MDs.


Serum N-terminal pro-brain natriuretic peptide level is a significant prognostic factor in patients with severe sepsis among Southwest Chinese population.
This study aimed to determine the predictive value of elevated N-terminal pro-brain natriuretic peptide (NTproBNP) for mortality in patients with severe sepsis. This was a retrospective study in Emergency Department of Sichuan Provincial People's Hospital, and patients were screened between January 1, 2009 and December 31, 2011. Demographic and clinical data as well as Acute Physiology And Chronic Health Evaluation II (APACHE II) and Sepsis Organ Failure Assessment (SOFA) scores were collected within the first day of admission. Survival was determined to establish its association with the NT-proBNP using logistic regression and receiver operating characteristic (ROC) curve. A total of 171 patients with severe sepsis were analyzed. The median APACHE IIⅡ and SOFA scores were 11 (IQR, 7-16) and 3 (IQR, 1-5), respectively. The median C-reactive protein (CRP), procalcitonin (PCT) and NT-proBNP was 10.3 mg/dL (IQR, 3.4-21.4 mg/dL), 0.4 ng/mL (IQR, 0.2-3.6 ng/mL), and 954 (321-1576) pg/mL, respectively. The median NT-proBNP in survivors was 584 pg/mL (IQR, 321-875 pg/mL) versus 1271 (IQR, 851-1576 pg/mL) in nonsurvivors (p < 0.001). In the ROC curves, the area value was 0.89 for serum NT-proBNP, and its potent cutoff value was 1500 pg/mL. After multivariate regression analysis, NT-proBNP was significantly correlated with the mortality of severe sepsis (OR = 1.58, 95% CI 1.36-1.77). Serum NT-proBNP is frequently increased in severe sepsis patients, and non-survivors have higher levels than survivors. High levels of admission NT-proBNP are associated with mortality.


[Risk factors for cesarean section: epidemiologic approach].
The increase in frequency of cesareans that has been noted through 70's, not diminished--like it was expected--perinatal morbidity and mortality. The most important indications to cesarean are distocias, previous cesarean and fetal stress. In 1998 frequency of cesarean deliveries in our hospital was 35% of the pregnancy attended. The claim of this study was to determine risks factors to cesarean in our hospital. A case-control study was performed, selecting 165 cases (cesareans) and 328 controls (via vaginal). It was determined OR of the risks factors and atribuible fraction. Data were analyzed by X2. The most important indications to cesarean delivery were: distocias (39%, n = 64); previous cesarean (23%, n = 41) and fetal stress (11%, n = 21). There was not significative differences in age, height and rupture membrane time in both groups. History of cesarean delivery gave major risk to another surgical intervention (OR = 12.7, p = < 0.0001, atribuible fraction 92%). Nuliparous (OR = 6.6, p < 0.00000, atribuible fraction 85%), second gestation (OR = 1.8, p = 0.002) or history of abortion (OR = 1.8, p = 0.04) were factors mainly associated to cesarean delivery. We concluded that the precise 'medications of this surgical intervention specially in nuliparous or previous cesarean delivery cases must be replanteated to diminish its elevated frequency.


A comparison of United Kingdom and Spanish general population time trade-off values for EQ-5D health states.
Few studies have compared preference values for health states obtained in different countries. The present study compared Spanish and United Kingdom (UK) time trade-off values for EuroQol-5D health states. The same preference elicitation protocol was followed in both countries. Differences in values for 43 health states rated directly were analyzed using t tests, and regression coefficients generated by random effects modeling were compared by aggregating the 2 value sets and using dummy variables to analyze country effect by dimension and level of severity. For the milder health states, Spanish and UK value assignation was similar; for intermediate health states, Spanish values were both higher and lower than UK values, whereas for health states worse than death, UK values were generally higher than Spanish values. There were statistically significant differences (P < 0.01) in values for 34.9% of health states rated directly, and some preference reversals between countries. UK raters ascribed greater importance to dimensions of pain/discomfort and anxiety/depression, whereas Spanish raters placed more importance on functional dimensions of mobility and self-care. Further analysis is required to determine how these differences affect cost-effectiveness and cost-utility analyses.


Calibrated automated thrombin generation measurement in clotting plasma.
Calibrated automated thrombography displays the concentration of thrombin in clotting plasma with or without platelets (platelet-rich plasma/platelet-poor plasma, PRP/PPP) in up to 48 samples by monitoring the splitting of a fluorogenic substrate and comparing it to a constant known thrombin activity in a parallel, non-clotting sample. Thus, the non-linearity of the reaction rate with thrombin concentration is compensated for, and adding an excess of substrate can be avoided. Standard conditions were established at which acceptable experimental variation accompanies sensitivity to pathological changes. The coefficients of variation of the surface under the curve (endogenous thrombin potential) are: within experiment approximately 3%; intra-individual: <5% in PPP, <8% in PRP; interindividual 15% in PPP and 19% in PRP. In PPP, calibrated automated thrombography shows all clotting factor deficiencies (except factor XIII) and the effect of all anticoagulants [AVK, heparin(-likes), direct inhibitors]. In PRP, it is diminished in von Willebrand's disease, but it also shows the effect of platelet inhibitors (e.g. aspirin and abciximab). Addition of activated protein C (APC) or thrombomodulin inhibits thrombin generation and reflects disorders of the APC system (congenital and acquired resistance, deficiencies and lupus antibodies) independent of concomitant inhibition of the procoagulant pathway as for example by anticoagulants.


First Two Imported Cases of Zika Virus Infections in Romania.
We report the first two cases of imported Zika virus (ZIKV) infection in Romanian patients returning from areas with ongoing outbreaks and challenges for laboratory diagnostic; first one with a classical pattern of acute flaviviral infection and the second one with an interesting pattern of a secondary flaviviral (ZIKV) infection in a yellow fever-vaccinated child living abroad in an endemic area.


Detecting the QTL-Allele System of Seed Oil Traits Using Multi-Locus Genome-Wide Association Analysis for Population Characterization and Optimal Cross Prediction in Soybean.
Soybean is one of the world's major vegetative oil sources, while oleic acid and linolenic acid content are the major quality traits of soybean oil. The restricted two-stage multi-locus genome-wide association analysis (RTM-GWAS), characterized with error and false-positive control, has provided a potential approach for a relatively thorough detection of whole-genome QTL-alleles. The Chinese soybean landrace population (CSLRP) composed of 366 accessions was tested under four environments to identify the QTL-allele constitution of seed oil, oleic acid and linolenic acid content (SOC, OAC, and LAC). Using RTM-GWAS with 29,119 SNPLDBs (SNP linkage disequilibrium blocks) as genomic markers, 50, 98, and 50 QTLs with 136, 283, and 154 alleles (2-9 per locus) were detected, with their contribution 82.52, 90.31, and 83.86% to phenotypic variance, corresponding to their heritability 91.29, 90.97, and 90.24% for SOC, OAC, and LAC, respectively. The RTM-GWAS was shown to be more powerful and efficient than previous single-locus model GWAS procedures. For each trait, the detected QTL-alleles were organized into a QTL-allele matrix as the population genetic constitution. From which the genetic differentiation among 6 eco-populations was characterized as significant allele frequency differentiation on 28, 56, and 30 loci for the three traits, respectively. The QTL-allele matrices were also used for genomic selection for optimal crosses, which predicted transgressive potential up to 24.76, 40.30, and 2.37% for the respective traits, respectively. From the detected major QTLs, 38, 27, and 25 candidate genes were annotated for the respective traits, and two common QTL covering eight genes were identified for further study.


Outpatient management of T and A procedure in children.
Present financial constraints make outpatient (day) surgery--provided it is proven to be safe--an attractive option for patients and surgeons as well as hospitals. The author had noticed some reluctance among surgeons at previous meetings to consider doing children's T and A surgery in this manner. Based on more than 3,000 cases, over a four year period, the safety of the procedure is shown. It is hoped that the 0% re-admission rate for primary hemorrhage will encourage those who have not so far felt comfortable with this method.


Ciguatera poisoning after ingestion of imported jellyfish: diagnostic application of serum immunoassay.
Ciguatera fish poisoning is an important public health problem wherever humans consume tropical and subtropical fish. It accounts for over half of fish-related poisonings in the United States but is uncommonly diagnosed and underreported. Produced by dinoflagellates, ciguatoxin accumulates up the food chain in herbivorous and carnivorous fishes. Cnidaria jellyfish and related invertebrates) have not previously been associated with direct ciguatera intoxication in humans. We report the first case of ciguatera fish poisoning associated with cnidarian ingestion. A 12-year-old Tongan female presented to our Emergency Department with mid-abdominal pain, nausea, change in mental status, and new-onset movement disorder after ingestion of jellyfish imported from American Samoa. Clinical diagnosis was confirmed by strongly positive serum identification of ciguatoxin and related polyether toxins (including okadaic acid) with a rapid extraction method (REM) and highly reliable solid-phase immunobead assay (S-PIA) performed by the Food Toxicology Research Group, University of Arizona. Ciguatera pathophysiology, clinical presentation, differential diagnosis (including consideration of palytoxin poisoning), and treatment are briefly reviewed. We emphasize the growing incidence of ciguatera fish poisoning outside "high-risk" areas. In regions with immigrant populations, privately imported exotic fish may be toxin vectors. Marine species other than carnivorous fish are now suspect in human ciguatera intoxication. Reliable tests can aid in premarket fish testing, diagnosis, and follow-up of ciguatera fish poisoning. The global prevalence of marine toxins demands fishermen, consumers, and physicians maintain a high index of suspicion for ciguatera fish poisoning.


Psychosocial assessments for HIV+ African adolescents: establishing construct validity and exploring under-appreciated correlates of adherence.
Psychosocial factors such as outcome expectancy, perceived stigma, socio-emotional support, consideration of future consequences, and psychological reactance likely influence adolescent adherence to antiretroviral treatments. Culturally-adapted and validated tools for measuring these factors in African adolescents are lacking. We aimed to identify culturally-specific factors of importance to establishing local construct validity in Botswana. Using in-depth interviews of 34 HIV+ adolescents, we explored how the psychosocial factors listed above are perceived in this cultural context. We evaluated six scales that have been validated in other contexts. We also probed for additional factors that the adolescents considered important to their HIV medication adherence. Analyses were conducted with an analytic framework approach using NVivo9 software. While the construct validity of some Western-derived assessment tools was confirmed, other tools were poorly representative of their constructs in this cultural context. Tools chosen to evaluate HIV-related outcome expectancy and perceived stigma were well-understood and relevant to the adolescents. Feedback from the adolescents suggested that tools to measure all other constructs need major modifications to obtain construct validity in Botswana. The scale regarding future consequences was poorly understood and contained several items that lacked relevance for the Batswana adolescents. They thought psychological reactance played an important role in adherence, but did not relate well to many components of the reactance scale. Measurement of socio-emotional support needs to focus on the adolescent-parent relationship, rather than peer-support in this cultural context. Denial of being HIV-infected was an unexpectedly common theme. Ambivalence about taking medicines was also expressed. In-depth interviews of Batswana adolescents confirmed the construct validity of some Western-developed psychosocial assessment tools, but demonstrated limitations in others. Previously underappreciated factors related to HIV medication adherence, such as denial and ambivalence, should be further explored.


Fatty acids and retinyl esters of rat milk: effects of diet and duration of lactation.
This study was initiated to explore the quantitative and qualitative differences in milk total fatty acids and milk retinyl esters when either hydrogenated or nonhydrogenated fat is fed during pregnancy and lactation. Rats were fed diets containing 10% by weight of corn oil or partially hydrogenated corn oil. Milk was collected on d 1, 8 and 14 of lactation and analyzed for protein, total fatty acids, fatty acid pattern, and retinyl ester pattern. Whereas diet produced no quantitative differences in milk protein or total fatty acids, the pattern of milk fatty acids varied significantly. Rats fed corn oil produced milk having more medium-chain saturated fatty acids, less long-chain monoenoic fatty acids, and more polyunsaturated fatty acids compared to those fed hydrogenated corn oil. Rats fed hydrogenated corn oil produced milk fat having 21-26% of the trans fatty acid, elaidic acid. Significant differences were also observed with duration of lactation: medium-chain fatty acids increased three to fourfold between d 1 and 8, where cis-monoenes and polyunsaturated fatty acids declined. The pattern of milk retinyl esters strongly reflected, but was not identical to, that of total milk fat. Comparing d 14 milk from rats fed corn oil with that from rats fed hydrogenated corn oil, medium-chain esters of retinol constituted 24 and 11% of total retinyl esters, whereas saturated long-chain fatty acid esters constituted 52 and 44%, respectively. trans Fatty acid esters of retinol comprised 24% of vitamin A esters in milk of rats fed hydrogenated fat. These data provide evidence that the composition of milk retinyl esters, as well as that of total milk fat, is determined both by the type of fatty acids from diet and from diet-related differences in de novo synthesis of fatty acids within the mammary gland and other tissues.


Shame and posttraumatic stress disorder.
Guilt about surviving a traumatic event is thought to be an associated feature of posttraumatic stress disorder (PTSD). Shame is an emotion closely related to guilt but is a distinct affective state. Little is known regarding the role of shame in PTSD and there are no studies of PTSD where shame and guilt are examined simultaneously. We used a measure of shame- and guilt-proneness in 107 community residing former prisoner of war veterans all of whom had been exposed to trauma. The measure of shame-proneness was positively correlated with PTSD symptom severity whereas guilt-proneness was not. This study provides the first empirical data regarding a possible role for shame in PTSD and may have important therapeutic and theoretical implications.


Serotonin1B receptors in the ventral tegmental area modulate cocaine-induced increases in nucleus accumbens dopamine levels.
Previous work has demonstrated that peripheral serotonin(1B) (5-HT(1B)) receptor agonist administration facilitates the behavioral and neurochemical effects of cocaine. This study used dual probe microdialysis to investigate whether activation of serotonin(1B) (5-HT(1B)) receptors in the ventral tegmental area (VTA) alters the ability of peripherally administered cocaine to elevate dopamine (DA) levels in the ipsilateral nucleus accumbens (NAcc) of drug-naive Wistar rats. Intra-VTA administration of the selective 5-HT(1B) agonist 1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo [3,2-b]pyridin-5-one dihydrochloride (CP 93,129) by reverse dialysis produced a dose-dependent (30 and 100 microM) potentiation of cocaine-induced (10 mg/kg i.p.) increases in NAcc DA efflux and concurrent cocaine-induced decreases in VTA GABA efflux. There was no effect of either local CP 93,129 or peripheral cocaine on VTA glutamate efflux. Intra-VTA administration of the 5-HT(1A/7) receptor agonist 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT; 100 microM) did not alter cocaine-induced alterations in NAcc DA or VTA GABA, suggesting that the effects of CP 93,129 were not mediated through 5-HT(1A) receptors. Moreover, the effects of intra-VTA CP 93,129 (100 microM) on both cocaine-induced increases in NAcc DA levels and cocaine-induced decreases in VTA GABA levels were reversed by coadministration of the selective 5-HT(1B) receptor antagonist 3-[3-(dimethylamine)propyl]-4-hydroxy-N-[4-(4-pyridinyl] phenyl] benzamide dihydrochloride (GR 55562; 300 microM). In the absence of cocaine, intra-VTA CP 93,139 produced an increase in NAcc DA and decrease in VTA GABA levels. However, intra-VTA GR 55562 alone had no effect on any of our neurochemical measures. These findings indicate that activation of VTA 5-HT(1B) receptors potentiates cocaine-induced increases in NAcc DA levels by enhancing the ability of cocaine to decrease VTA GABA efflux.


Root-Knot and Cyst Nematodes Activate Procambium-Associated Genes in Arabidopsis Roots.
Developmental plasticity is one of the most striking features of plant morphogenesis, as plants are able to vary their shapes in response to environmental cues. Biotic or abiotic stimuli often promote organogenesis events in plants not observed under normal growth conditions. Root-knot nematodes (RKNs) are known to parasitize multiple species of rooting plants and to induce characteristic tissue expansion called galls or root-knots on the roots of their hosts by perturbing the plant cellular machinery. Galls contain giant cells (GCs) and neighboring cells, and the GCs are a source of nutrients for the parasitizing nematode. Highly active cell proliferation was observed in galls. However, the underlying mechanisms that regulate the symptoms triggered by the plant-nematode interaction have not yet been elucidated. In this study, we deciphered the molecular mechanism of gall formation with an in vitro infection assay system using RKN Meloidogyne incognita, and the model plant Arabidopsis thaliana. By taking advantages of this system, we performed next-generation sequencing-based transcriptome profiling, and found that the expression of procambium identity-associated genes were enriched during gall formation. Clustering analyses with artificial xylogenic systems, together with the results of expression analyses of the candidate genes, showed a significant correlation between the induction of gall cells and procambium-associated cells. Furthermore, the promoters of several procambial marker genes such as ATHB8, TDR and WOX4 were activated not only in M. incognita-induced galls, but similarly in M. javanica induced-galls and Heterodera schachtii-induced syncytia. Our findings suggest that phytoparasitic nematodes modulate the host's developmental regulation of the vascular stem cells during gall formation.


[Calcium channels in smooth muscle cells].
In smooth muscle cells, the electrophysiological properties of potential-dependent calcium channels are similar to those described in other excitable cells. The calcium current is dependent on the extracellular calcium concentration; it is insensitive to external sodium removal and tetrodotoxin application. Other ions (Ba2+, Sr2+, Na+) can flow through the calcium channel. This channel is blocked by Mn2+, Co2+, Cd2+ and by organic inhibitors. The inactivation mechanism is mediated by both the membrane potential and the calcium influx. Ca2+ ions can also penetrate into the cell through receptor-operated channels. These channels show a low ionic selectivity and are generally less sensitive to organic Ca-blockers than the potential-dependent calcium channels. The finding of specific channel inhibitors as well as the study of the biochemical pathways between receptor activation and channel opening are prerequisites to further characterization of receptor-operated channels.


Reduced social distancing early in the COVID-19 pandemic is associated with antisocial behaviors in an online United States sample.
Antisocial behaviors cause harm, directly or indirectly, to others' welfare. The novel coronavirus pandemic has increased the urgency of understanding a specific form of antisociality: behaviors that increase risk of disease transmission. Because disease transmission-linked behaviors tend to be interpreted and responded to differently than other antisocial behaviors, it is unclear whether general indices of antisociality predict contamination-relevant behaviors. In a pre-registered study using an online U.S. sample, we found that individuals reporting high levels of antisociality engage in fewer social distancing measures: they report leaving their homes more frequently (p = .024) and standing closer to others while outside (p < .001). These relationships were observed after controlling for sociodemographic variables, illness risk, and use of protective equipment. Independently, higher education and leaving home for work were also associated with reduced distancing behavior. Antisociality was not significantly associated with level of worry about the coronavirus. These findings suggest that more antisocial individuals may pose health risks to themselves and their community during the COVID-19 pandemic.


Mixed hematopoietic chimerism for preventing graft-versus-host disease in mice receiving rat bone marrow transplantation.
To find a method for preventing graft-versus-host disease (GVHD) in BALB/c mice receiving rat bone marrow transplantation. Firstly 12 SD rats were conditioned with 5.0 Gy sublethal total body irradiation(TBI), followed by infusion of 8 x 10(7) bone marrow cells from 28 BALB/c mice within 4 h and intraperitoneal administration of 100 mg/kg cyclophosphamide (Cy) 2 d later, for the purpose of inducing chimeric SD rats with specific immunological tolerance. Secondly, 24 BALB/c mice were exposed to 9.0 Gy lethal TBI and divided randomly into 3 equal groups designated respectively as groups A, B and C. Mice in group A were injected with 4 x 10(7) bone marrow cells from 4 normal rats, and mice in group B were injected with 4 x 10(7) bone marrow cells and 2 x 10(7) spleen cells from 4 normal rats, while those in group C were given 4 x 10(7) bone marrow cells and 2 x 10(7) spleen cells from 6 chimeric rats. The mice were then observed for 150 d for GVHD. In the second procedure, 2 mice in group A failed to survive due to infection and radiation injury respectively, and none of the rest mice presented signs of GVHD. The mice in group B all developed GVHD of varied degrees with symptoms as wasting, diarrhea, fur loss, arched body posture, and even bloody stool, and all died within 5 to 15 d with an average survival of 10.0 d (95% confidence interval 8,12). Pathological examination of the liver and intestinal tissues revealed inflammatory lymphocyte infiltration and necrosis. The majority of the mice in group C, in contrast, survived for more than 150 d with only two died on the postoperative days 18 and 31 respectively. The survival time of group B was significantly shorter than that of the other two groups. Donor/recipient chimerism may help prevent GVHD in xenogeneic bone marrow transplantation.


Comparison of vildagliptin and pioglitazone in patients with type 2 diabetes inadequately controlled with metformin.
To compare the tolerability and efficacy of vildagliptin to pioglitazone as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy over 1-year duration. This 52-week, multicentre, randomized, active-controlled study compared vildagliptin (50 mg b.i.d., n = 295) and pioglitazone (30 mg daily, n = 281) in patients with inadequate glycaemic control [haemoglobin A1c (HbA(1c)) 7.5-11%] receiving a stable dose of metformin (>or=1500 mg). The primary objective was to demonstrate non-inferiority of vildagliptin at 24 weeks in the change in HbA(1c) from baseline. The objective of the additional 28 weeks of the study was to assess long-term safety, while also assessing mean change from baseline to study end in HbA(1c), fasting plasma glucose and body weight. When added to a stable dose of metformin (mean baseline dose approximately 2 g/day), the non-inferiority of HbA(1c) lowering of vildagliptin to pioglitazone over 24 weeks was established at the non-inferiority margin of 0.3% (between-group difference = 0.1%). During the remaining 28 weeks, comparable HbA(1c) decreases were recorded in both groups. Overall adverse event (AE) rates were similar in both groups, as was the occurrence of peripheral oedema. Hypoglycaemia occurred rarely in both groups. Serious AEs occurred more frequently with pioglitazone group. While mean body weight increased significantly in the pioglitazone group (+2.6 kg) from baseline, there was no significant weight gain with vildagliptin (+0.2 kg). When added to metformin, vildagliptin demonstrates favourable safety and tolerability over 1 year. Vildagliptin provided additional HbA(1c) lowering to that achieved with metformin alone and comparable to that achieved with pioglitazone, with only pioglitazone causing weight gain.


[Cochlear implantation in patients with inner ear malformations].
To describe clinical experiences with multi-channel cochlear implantation in patients with bilateral inner ear malformations. Among 410 patients who received multi-channel cochlear implantations from 1996 to 2004 in Beijing Tongren Hospital, 82 patients were diagnosed with inner ear malformations and implanted. A retrospective analysis was performed about the surgical characteristics and mapping characteristics after implantation. (1) All patients had auditory sensations. (2) Gusher was more common than the normal cochlear implantation. (3) The electrodes were inserted in the "cochleostomy" in full length of 80 Patients, but 2 pairs of electrodes remained outside of "cochleostomy" in 2 patients. (4) No serious complications occurred after implantation. (5) The impedance of the electrodes, the T level and C level were similar with the normal cochlear implantation. The results had no significant difference in compare with normal cochlear group (P > 0. 05). (6) The abilities of speech discrimination and spoken language were improved through rehabilitation. The cochlear implantation can be performed safely in inner ear malformations. The outcome of hearing rehabilitation for patients with inner ear malformations are similar to those children with normal cochlear structure followed the multi-channel cochlear implantation.


Free amino acids in botanicals and botanical preparations.
Numerous studies were carried out about aminoacidic composition of vegetable proteins, but information about the free amino acid pool and the role of these substances is very incomplete. The aim of this paper was to contribute to the scarce knowledge concerning the composition of free amino acids in botanicals and botanical preparations widely used as food, in dietary supplements, and in pharmaceutical products. This work studied the composition of free amino acids, identified the major components of 19 species of plants, and evaluated the influence of different types of extraction on the amino acid profile. Amino acids were determined using an automatic precolumn derivatization with fluorenylmethyl-chloroformate and reversed-phase liquid chromatography with fluorescence and ultraviolet detection. The amounts of total free amino acids varied widely between plants, from approximately 12 g in 100 g of Echinacea pallida extract to less than 60 mg in the same amount of Coleus forskohlii, Garcinia cambogia, and Glycine max. In 13 plants arginine, asparagine, glutamine, proline, and gamma-aminobutyric acid were the free amino acids found in preponderant quantities. The levels of free amino acids above the quantification limit in 36 assayed samples of botanicals, extracts, and supplements are shown.


TGF-beta suppresses IFN-gamma induction of class II MHC gene expression by inhibiting class II transactivator messenger RNA expression.
Recently, a non-DNA binding protein, class II transactivator (CIITA), has been shown to be required for constitutive and IFN-gamma-inducible class II MHC transcription. The cytokine TGF-beta inhibits IFN-gamma-induced class II MHC expression at the transcriptional level. In this study, we provide evidence that TGF-beta blocks IFN-gamma-induced CIITA mRNA accumulation. TGF-beta down-regulates class II MHC and CIITA mRNA accumulation in human astroglioma and fibrosarcoma cell lines, but TGF-beta does not destabilize the CIITA message, suggesting an effect at the transcriptional level. In cells that stably overexpressed CIITA, leading to a constitutive class II MHC-positive phenotype, the inhibitory effect of TGF-beta on class II MHC was abrogated, but the cells remained responsive for expression of TGF-beta-inducible genes. Cell lines that possessed defects in TGF-beta signaling also became refractory to inhibition of IFN-gamma-induced CIITA and class II MHC expression. Our data indicate that TGF-beta suppresses IFN-gamma-induced class II MHC expression by inhibiting accumulation of CIITA mRNA.