Accuracy and feasibility of dynamic contrast-enhanced 3D MR imaging in the assessment of lung perfusion: comparison with Tc-99 MAA perfusion scintigraphy.
The aim of this study was to correlate findings of perfusion magnetic resonance imaging (MRI) and perfusion scintigraphy in cases where there was a suspicion of abnormal pulmonary vasculature, and to evaluate the usefulness of MRI in the detection of perfusion deficits of the lung. In all, 17 patients with suspected abnormality of the pulmonary vasculature underwent dynamic contrast-enhanced MRI. T1-weighted 3D fast-field echo pulse sequences were obtained (TR/TE 3.3/1.58 ms; flip angle 30 degrees; slice thickness 12 to 15 mm). The dynamic study was acquired in the coronal plane following administration of 0.1 mmol/kg gadopentetate dimeglumine. A total of 8 to 10 sections repeated 20 to 25 times at intervals of 1s were performed. Perfusion lung scintigraphy was carried out a maximum of 48 h before the MR examination in all cases. Two radiologists, who were blinded to the clinical data and results of other imaging methods, reviewed all coronal sections. MR perfusion images were independently assessed in terms of segmental or lobar perfusion defects in the 85 lobes of the 17 individuals, and the findings were compared with the results of scintigraphy. Of the 17 patients, 8 were found to have pulmonary emboli, 2 chronic obstructive pulmonary disease with emphysema, 2 bullous emphysema, 2 Takayasu arteritis and 1 had a hypoplastic pulmonary artery. Pulmonary perfusion was completely normal in 2 cases. In 35 lobes, perfusion defects were detected using both methods, in 4 with MR alone and in 9 only with scintigraphy. There was good agreement between MRI and scintigraphy findings (kappa=0.695). Pulmonary perfusion MRI is a new alternative to scintigraphy in the evaluation of pulmonary perfusion for various lung disorders. In addition, this technique allows measurement and quantification of pulmonary perfusion abnormalities.


Soil bacterial diversity, structure, and function of Suaeda salsa in rhizosphere and non-rhizosphere soils in various habitats in the Yellow River Delta, China.
Soil microorganisms play a key role in regulating the biogeochemical cycles of ecosystems. However, studies that quantitatively examine bacterial metabolic groups to predict the environmental and biological impacts are limited. In this research, we employed 16S rRNA gene sequencing on an Illumina MiSeq platform to analyze bacterial diversity, structure, function, and driving factors of Suaeda salsa in rhizosphere and non-rhizosphere soils in intertidal and supratidal habitats in the Yellow River Delta, China. Results showed that bacterial richness and Shannon diversity index of the rhizosphere soil were greater in the intertidal than in the supratidal habitat. Although the bacteria of the two habitats changed extremely in community structure, the bacterial groups related to carbohydrate metabolism (CM) and amino acid metabolism (AAM) had higher abundance than the other groups in both habitats. Furthermore, they were higher in the supratidal than the intertidal habitats, and bacterial groups associated with energy metabolism (EM) are opposite. Furthermore, bacterial diversity showed no significant difference between the rhizosphere and non-rhizosphere soils. In the intertidal habitat, the rhizosphere soil had higher EM but lower AAM and CM than the non-rhizosphere soil, which indicated that bacterial structure and function were obviously influenced by the root exudates of S. salsa under flooding and salt stresses. Redundancy analysis showed that the dominant phyla were significantly affected by available phosphorus (51.0%), total potassium (32.2%), moisture content (28.1%), available potassium (25.3%), electrical conductivity (24.2%), total nitrogen (22.8%), total carbon (21.9%), and soil organic matter (21.0%). Overall, the findings provide important insights into the roles of bacterial groups in coastal wetland under climate changes.


Genetically determined proteolytic cleavage modulates alpha7beta1 integrin function.
The dystrophin-glycoprotein complex and the alpha7beta1 integrin are trans-sarcolemmal linkage systems that connect and transduce contractile forces between muscle fibers and the extracellular matrix. alpha7beta1 is the major laminin binding integrin in skeletal muscle. Different functional variants of this integrin are generated by alternative splicing and post-translational modifications such as glycosylation and ADP-ribosylation. Here we report a species-specific difference in alpha7 chains that results from an intra-peptide proteolytic cleavage, by a serine protease, at the 603RRQ605 site. Site-directed mutagenesis of RRQ to GRQ prevents this cleavage. This RRQ sequence in the alpha7 integrin chain is highly conserved among vertebrates but it is absent in mice. Protein structure modeling indicates this cleavage site is located in an open region between the beta-propeller and thigh domains of the alpha7 chain. Compared with the non-cleavable alpha7 chain, the cleaved form enhances cell adhesion and spreading on laminin. Cleavage of the alpha7 chain is elevated upon myogenic differentiation, and this cleavage may be mediated by urokinase-type plasminogen activator. These results suggest proteolytic cleavage is a novel mechanism that regulates alpha7 integrin functions in skeletal muscle, and that the generation of such cleavage sites is another evolutionary mechanism for expanding and modifying protein functions.


Highly accelerated submillimeter resolution 3D GRASE with controlled T2 blurring in T2 -weighted functional MRI at 7 Tesla: A feasibility study.
To achieve highly accelerated submillimeter resolution T2 -weighted functional MRI at 7T by developing a three-dimensional gradient and spin echo imaging (GRASE) with inner-volume selection and variable flip angles (VFA). GRASE imaging has disadvantages in that (a) k-space modulation causes T2 blurring by limiting the number of slices and (b) a VFA scheme results in partial success with substantial SNR loss. In this work, accelerated GRASE with controlled T2 blurring is developed to improve a point spread function (PSF) and temporal signal-to-noise ratio (tSNR) with a large number of slices. To this end, the VFA scheme is designed by minimizing a trade-off between SNR and blurring for functional sensitivity, and a new GRASE-optimized random encoding, which takes into account the complex signal decays of T2 and T2∗ weightings, is proposed by achieving incoherent aliasing for constrained reconstruction. Numerical and experimental studies were performed to validate the effectiveness of the proposed method over regular and VFA GRASE (R- and V-GRASE). The proposed method, while achieving 0.8 mm isotropic resolution, functional MRI compared to R- and V-GRASE improves the spatial extent of the excited volume up to 36 slices with 52%-68% full width at half maximum (FWHM) reduction in PSF but approximately 2- to 3-fold mean tSNR improvement, thus resulting in higher BOLD activations. We successfully demonstrated the feasibility of the proposed method in T2 -weighted functional MRI. The proposed method is especially promising for cortical layer-specific functional MRI.


An exon junction complex-independent function of Barentsz in neuromuscular synapse growth.
The exon junction complex controls the translation, degradation, and localization of spliced mRNAs, and three of its core subunits also play a role in splicing. Here, we show that a fourth subunit, Barentsz, has distinct functions within and separate from the exon junction complex in Drosophila neuromuscular development. The distribution of mitochondria in larval muscles requires Barentsz as well as other exon junction complex subunits and is not rescued by a Barentsz transgene in which residues required for binding to the core subunit eIF4AIII are mutated. In contrast, interactions with the exon junction complex are not required for Barentsz to promote the growth of neuromuscular synapses. We find that the Activin ligand Dawdle shows reduced expression in barentsz mutants and acts downstream of Barentsz to control synapse growth. Both barentsz and dawdle are required in motor neurons, muscles, and glia for normal synapse growth, and exogenous Dawdle can rescue synapse growth in the absence of barentsz. These results identify a biological function for Barentsz that is independent of the exon junction complex.


Production of recombinant human factor VIII in different cell lines and the effect of human XBP1 co-expression.
Recombinant factor VIII is one of the most complex mammalian proteins and a biotechnology venture required for the treatment of hemophilia A. The complexity of the protein, post-translational modifications and limitations of expression elements make the production of active recombinant FVIII a challenge. Here we report the production of biologically active Factor VIII in two different cell lines, CHO and HepG2, by transient transfection. Two expression vectors based on the CMV promoter were used: one harboring CMV Intron A (InA) and the other without it. To bypass difficulties in secretion, we also studied the influence of co-expression of the human splice isoform of the XBP1 gene. We report the production of recombinant FVIII possessing bioengineered FVIII heavy and light chains, linked by a minimal B domain. In our study, HepG2, a human hepatocyte cell line, expressed Factor VIII ten-fold more than a CHO cell line, and in HepG2 cells, the expression of XBP1 improved Factor VIII activity. For CHO cells, expression was improved by the presence of InA, but no further improvement was noted with XBP1 co-expression. These data suggest that the minimal B domain rFVIII preserves Factor VIII biological activity and that different expression elements can be used to improve its production.


Lichen planus and liver diseases: a multicentre case-control study. Gruppo Italiano Studi Epidemiologici in Dermatologia (GISED).
To assess the association of lichen planus with liver complaints and with known aetiological factors of liver diseases. Multicentre case-control study. Interviews were conducted by trained medical investigators on the basis of a structured questionnaire. At the interview patients and controls were asked for consent to blood samples being taken to determine transaminase activities and the presence of hepatitis B virus surface antigen. Outpatient departments of 27 Italian general and teaching hospitals that were collaborating in the Gruppo Italiano Studi Epidemiologici in Dermatologia (GISED). Incident cases and controls were eligible. A total of 577 patients with lichen planus and 1031 controls with dermatological diseases other than lichen planus were interviewed. Less than 1% of the people contacted refused to participate. Patients and controls were matched for sex and age in five year intervals. The risk of lichen planus was higher in patients with a history of liver diseases requiring hospital admission or specialist consultation (relative risk = 1.6; 95% confidence interval = 1.2 to 2.2), those who had had liver biopsy (5.5; 1.9 to 15.6), and those with a history of viral hepatitis (1.9; 1.1 to 3.1). High activities of liver enzymes and positive results of tests for hepatitis B virus surface antigen were also associated with lichen planus. The association with alcohol consumption was not clearly confirmed by a dose-risk relation. This study adds quantitative epidemiological evidence to the clinical observation that liver disease is a risk factor for lichen planus although not a specific marker of it.


The role of percutaneous vertebral augmentation in patients with metastatic breast cancer: Literature review including report of two cases.
Patients with metastatic breast cancer are at high risk for developing vertebral compression fractures due to underlying bone metastases and bone density loss. Vertebral augmentation techniques including percutaneous vertebroplasty and percutaneous balloon kyphoplasty are techniques used to stabilize compression fractures and improve pain. However, rare complications from these interventions have been observed, including spinal cord compression, nerve root compression, venous cement embolism, and pulmonary cement embolism. These complications pose unique potential challenges for patients with cancer who may already have decreased lung function and potential for venous thromboembolism. In this review, we first describe the role of percutaneous vertebral augmentations in patients with metastatic cancer, with a particular focus on patients with breast cancer. Then, we describe complications of vertebral augmentation in two patients with metastatic breast cancer including long-term symptomatic and radiographic follow-up.


Zootherapeutic practices in Aquismón, San Luis Potosí, México.
Animal derived products have been a source of medicinal compounds since ancient times. This work documents the use of animal species in traditional medicine in the municipality of Aquismón, San Luis Potosí, México. Direct interviews were performed with inhabitants from Aquismón. The interviews were analyzed with two quantitative tools: (a) the informant consensus (ICF) that estimates the level of agreement about which animals may be used for each category and (b) the relative importance (RI) that determines the extent of potential utilization of each species. A total of 24 animal species used for medicinal purposes, belonging to 22 families and 4 taxonomic categories, were reported by interviewees. Nine medicinal species had not been reported in scientific literature. The results of the IFC showed that diseases of the respiratory systems had the greatest agreement. The most versatile species according to their RI are Crotalus atrox and Mephitis macroura. Further studies with medicinal fauna from Aquismón are required for the experimental validation of their traditional uses, especially with Mephitis macroura and Crotalus atrox.


Copper-catalyzed free-radical C-H arylation of pyrroles.
A room temperature copper-catalyzed radical arylation of pyrroles with anilines, through in situ generated aryl diazonium salts, has been developed under neutral conditions. Experimental and theoretical studies explain the crucial role of CaCO3 and the high regioselectivity observed.


Biomembrane cooperative enzymes. In vivo modulation of rat erythrocyte acetylcholinesterase by insulin in normal and diabetic conditions.
The present study investigated the effect of insulin in vivo on the changes in the cooperativity of a membrane-bound enzyme. The allosteric inhibition by F- of the erythrocyte membrane acetylcholinesterase (acetylcholine hydrolase, EC 188.8.131.52) was studied during intravenous glucose tolerance tests in control and alloxan-induced diabetic rats. In the former group, the value of n decreased from 1.6 to 1.0 whereas it remained about 1.6 in the latter groups. Intravenous injection of insulin (30 U/kg) decreased the values of n in both groups. It is suggested that the in vivo insulin action on membrane cooperative enzymes could also take place in insulin target cells.


Pulmonary Venous Gradients in Healthy Controls and Following the Repair of Total Anomalous Pulmonary Venous Return.
The percent of children who can achieve a normal and physiologic pulmonary venous gradient and flow following the repair of Total Anomalous Pulmonary Venous Return (TAPVR) is not known. Pulmonary venous confluence gradients from infants with supra-, infra-, or mixed TAPVR, repaired using a direct anastomotic connection were measured. Data from age, weight, and gender-matched controls established the normal pulmonary venous gradient range (0.30-0.94 mmHg). TAPVR subjects were divided into three groups: (I) pulmonary venous gradient < 2 × normal with multiphasic flow (II) pulmonary venous gradient > 2 × normal with multiphasic flow, and (III) pulmonary venous gradient > 2 × normal with monophasic flow. From 63 children following TAPVR repair and 63 matched controls, pulmonary venous gradients were significantly lower [0.5 mmHg (IQR:0.4, 0.6) vs 1.6 mmHg (IQR:1.0, 2.4); p < 0.001], and multiphasic flow more frequent (100 vs. 84.1%; p = 0.001) within the control group. There were 38 children (60.3%) in group I, 15 (23.8%) in group II, and 10 (15.8%) in group III. Children in Group I were significantly older at the time of repair, had shorter cardiopulmonary bypass times, and did not utilize deep hypothermic circulatory arrest (DHCA). Multivariate analysis confirmed that avoiding DHCA [Odds Ratio 0.931 (0.913,0.994; p = 0.002)] and shorter cardiopulmonary bypass times [Odds Ratio 0.962 (0.861,0.968; p = 0.02)] during repair were associated with the lowest pulmonary venous gradients and multiphasic flow. Following TAPVR repair with a direct anastomosis, the majority of children can achieve a gradient two times normal or less with multiphasic pulmonary venous flow.


CD44, SHH and SOX2 as novel biomarkers in esophageal cancer patients treated with neoadjuvant chemoradiotherapy.
Neoadjuvant chemoradiotherapy (nCRT) improves survival in esophageal cancer (EC) patients, but the response to treatment is heterogeneous and little is known regarding prognostic and predictive markers in these patients. CD44, SOX2 and SHH have been implicated in resistance to CRT, possibly through an association with a cancer stem cell phenotype. 101 EC patients treated with nCRT and surgery were included. Sufficient pre-treatment biopsy material was present in 71 patients, of which 53 patients were non-complete responders on nCRT (nCR). Protein expression was examined using immunohistochemistry (IHC). Prognostic factors were determined using Cox regression analysis for disease free survival (DFS) and cause specific survival (CSS) in the complete cohort, the pre-treatment biopsies group and post-treatment nCR group. Low CD44 expression in the nCR group was an independent prognostic factor for both DFS and CSS (DFS HR 2.81, p=0.002 and CSS HR 3.48, p=0.002). Absent SOX2 expression in pretreatment biopsies was related to systemic recurrence (p=0.029) while low SHH in pretreatment biopsies was an independent prognostic factor for a poor DFS (HR 2.27, p=0.036). No relation between marker expression and response to nCRT was observed. Low expression of CD44 and SHH are associated with a poor survival outcome in EC patients treated with nCRT.


Porous silica and polymer monolith architectures as solid-state optical chemosensors for Hg2+ ions.
We demonstrate a simple strategy to concoct a competent solid-state opto-chemosensor for the selective and sensitive visual detection of Hg2+ ions. The sensor fabrication involves the utilization of indigenously prepared mesoporous silica and polymer monoliths as probe anchoring templates and 8-hydroxy-7-(4-n-butylphenylazo) quinoline (HBPQ) as the chromo-ionophoric probe for Hg2+ sensing. Both the monoliths are designed with discrete structural and morphological features to serve as efficient host templates. The structural and surface features of the monoliths are characterized using p-XRD, TEM, SEM, SAED, EDAX, XPS, and N2 isotherm analysis. The synergetic features of monolith structural hierarchy along with the probe's selective chelating ability enable rapid signal response and remarkable ion selectivity for Hg2+. The solid-state sensors evince a linear signal response from 0.6 to 150 μg/L for Hg2+ recognition, with superior data authenticity and replication that is preceded by an RSD value of ≤ 2.25% when tested with real water samples.Graphical abstract Mesoporous silica and polymer monolith architects hosting HBPQ probe molecules demonstrate an excellent visual sensing of ultra-trace (μg/L) Hg2+ in various water samples with a striking color transition from light orange to dark red upon complexation of probe with Hg2+. The solid-state sensors are Hg2+ ion selective, super-responsive, real-time applicable, and also reusable.


Quantitative blood flow measurements in gliomas using arterial spin-labeling at 3T: intermodality agreement and inter- and intraobserver reproducibility study.
QUASAR is a particular application of the ASL method and facilitates the user-independent quantification of brain perfusion. The purpose of this study was to assess the intermodality agreement of TBF measurements obtained with ASL and DSC MR imaging and the inter- and intraobserver reproducibility of glioma TBF measurements acquired by ASL at 3T. Two observers independently measured TBF in 24 patients with histologically proved glioma. ASL MR imaging with QUASAR and DSC MR imaging were performed on 3T scanners. The observers placed 5 regions of interest in the solid tumor on rCBF maps derived from ASL and DSC MR images and 1 region of interest in the contralateral brain and recorded the measured values. Maximum and average sTBF values were calculated. Intermodality and intra- and interobsever agreement were determined by using 95% Bland-Altman limits of agreement and ICCs. The intermodality agreement for maximum sTBF was good to excellent on DSC and ASL images; ICCs ranged from 0.718 to 0.884. The 95% limits of agreement ranged from 59.2% to 65.4% of the mean. ICCs for intra- and interobserver agreement for maximum sTBF ranged from 0.843 to 0.850 and from 0.626 to 0.665, respectively. The reproducibility of maximum sTBF measurements obtained by methods was similar. In the evaluation of sTBF in gliomas, ASL with QUASAR at 3T yielded measurements and reproducibility similar to those of DSC perfusion MR imaging.


Heterogeneity in presynaptic regulation of GABA release from hippocampal inhibitory neurons.
Release of GABA from the terminals of hippocampal inhibitory neurons is inhibited by activation of GABAB autoreceptors and mu opioid receptors. However, it is not known whether these presynaptic processes affect all inhibitory synapses equally. We examined the effects of the GABAB receptor agonist baclofen and the mu opioid receptor agonist DAGO on postsynaptic currents evoked by minimal stimulation of inhibitory fibers (meIPSCs) in area CA3. Baclofen reversibly depressed approximately half of the meIPSCs evoked in the stratum pyramidale. The remaining meIPSCs were unaffected despite a coincident depression of spontaneous IPSCs. In contrast, all meIPSCs were depressed by DAGO. In addition, minimal stimulation in the stratum radiatum evoked meIPSCs that were always depressed by baclofen. These results indicate that regulation of GABA release by GABAB autoreceptors occurs at a subset of inhibitory synapses and that GABAB-resistant inhibitory synapses are located on pyramidal neuron somata. Hippocampal inhibitory neurons may be heterogeneous with respect to presynaptic receptor-mediated regulation of GABA release.


Surgical Resection and Interstitial Iodine-125 Brachytherapy for High-Grade Meningiomas: A 25-Year Series.
Atypical and malignant meningiomas can recur despite resection and radiation. To determine outcomes of patients with recurrent atypical or malignant meningioma treated with repeat resection and permanent iodine-125 ( 125 I) brachy-therapy. Charts of patients who underwent surgical resection and 125 I brachyther-apy implantation for atypical and malignant meningiomas between 1988 and 2013 were retrospectively reviewed. The Kaplan-Meier actuarial method was used to calculate progression-free and overall survival. The log-rank test was used to compare groups. Significance was set at P < .05. Forty-two patients underwent 50 resections with 125 I brachytherapy im-plantations. All patients had undergone previous resections and 85% had previously undergone radiation. Median follow-up was 7.5 years after diagnosis and 2.3 years after brachytherapy. Median time to progression after resection with 125 I brachytherapy was 20.9 months for atypical meningioma, 11.4 months for malignant meningioma, and 11.4 months for the combined groups. Median survival after re-resection and 125 I brachytherapy was 3.5 years for atypical meningioma, 2.3 years for malignant menin-gioma, and 3.3 years for all subjects. Median overall survival after diagnosis was 11.1 years for atypical meningioma, 9.1 years for malignant meningioma, and 9.4 years for all subjects. Complications occurred in 17 patients and included radiation necrosis (n = 8, 16%), wound breakdown (n = 6, 12%), hydrocephalus (n = 4, 8%), infection (n = 3, 6%), and a pseudomeningocele (n = 2, 5%). This is the largest experience with adjuvant 125 I brachytherapy for recurrent high-grade meningiomas. The outcomes support the use of adjuvant brachytherapy as an option for these aggressive tumors.


Real-time 3D reconstruction from single-photon lidar data using plug-and-play point cloud denoisers.
Single-photon lidar has emerged as a prime candidate technology for depth imaging through challenging environments. Until now, a major limitation has been the significant amount of time required for the analysis of the recorded data. Here we show a new computational framework for real-time three-dimensional (3D) scene reconstruction from single-photon data. By combining statistical models with highly scalable computational tools from the computer graphics community, we demonstrate 3D reconstruction of complex outdoor scenes with processing times of the order of 20 ms, where the lidar data was acquired in broad daylight from distances up to 320 metres. The proposed method can handle an unknown number of surfaces in each pixel, allowing for target detection and imaging through cluttered scenes. This enables robust, real-time target reconstruction of complex moving scenes, paving the way for single-photon lidar at video rates for practical 3D imaging applications.


Relation between the faecal concentration of various potentially pathogenic microorganisms and infections in individuals (mice) with severely decreased resistance to infection.
Lethally irradiated conventional mice were killed at daily intervals after irradiation. A high correlation was found between the occurrence of bacterial overgrowth in the digestive tract and invasion into the regional lymph nodes the spleen and the blood. By oral contamination of mice with quite high doses of either an exogenous or an endogenous biotype of an Enterobacteriaceae species at day 4 after irradiation, it was attempted to induced such condition of intestinal overgrowth. In all animals such an abnormal colonization of the contaminant was indeed achieved in this way and the mice died from an infection caused by the biotype used for the contamination. The interval between contamination and death was different when different biotypes were used for contamination and occurred sooner after irradiation when an endogenous biotype was used for (re)contamination. It is concluded that oral contamination with exogenous as well as with endogenous potentially pathogenic bacteria during a period of severely decreased resistance to infections must be avoided. The colonization resistance of the digestive tract of these animals should be maintained as high as possible.


Time related decay in prey antigens ingested by the predator Podisus maculiventris (Hemiptera, Pentatomidae) as detected by ELISA.
Individual nymphs of the predaceous pentatomid Podisus maculiventris Say were each fed a single first instar Douglas Fir tussock moth larva, Orgyia pseudotsugata McDunnough, and held without further feeding at constant temperature for a known number of days before being frozen. Enzyme-linked immunosorbent assay, ELISA, was used to examine these predators for the presence of prey antigens. The concentration of prey antigens in these predators declined at a linear rate over the 7 days they were held post-feeding. Detectable antigens remained in 50% of the predators after three days at 24°C. On the day in which the prey was consumed (day 0) only 80% of the unstarved predators had detectable prey antigens which suggests the possibility of instinctive killing of prey with little or no subsequent ingestion. The amount of prey antigen in molted and unmolted predators was not statistically distinguishable; although molting interrupts feeding, digestion of the antigen(s) employed in this study seems to be continuous.


I-Impute: a self-consistent method to impute single cell RNA sequencing data.
Single-cell RNA-sequencing (scRNA-seq) is becoming indispensable in the study of cell-specific transcriptomes. However, in scRNA-seq techniques, only a small fraction of the genes are captured due to "dropout" events. These dropout events require intensive treatment when analyzing scRNA-seq data. For example, imputation tools have been proposed to estimate dropout events and de-noise data. The performance of these imputation tools are often evaluated, or fine-tuned, using various clustering criteria based on ground-truth cell subgroup labels. This limits their effectiveness in the cases where we lack cell subgroup knowledge. We consider an alternative strategy which requires the imputation to follow a "self-consistency" principle; that is, the imputation process is to refine its results until there is no internal inconsistency or dropouts from the data. We propose the use of "self-consistency" as a main criteria in performing imputation. To demonstrate this principle we devised I-Impute, a "self-consistent" method, to impute scRNA-seq data. I-Impute optimizes continuous similarities and dropout probabilities, in iterative refinements until a self-consistent imputation is reached. On the in silico data sets, I-Impute exhibited the highest Pearson correlations for different dropout rates consistently compared with the state-of-art methods SAVER and scImpute. Furthermore, we collected three wetlab datasets, mouse bladder cells dataset, embryonic stem cells dataset, and aortic leukocyte cells dataset, to evaluate the tools. I-Impute exhibited feasible cell subpopulation discovery efficacy on all the three datasets. It achieves the highest clustering accuracy compared with SAVER and scImpute. A strategy based on "self-consistency", captured through our method, I-Impute, gave imputation results better than the state-of-the-art tools. Source code of I-Impute can be accessed at https://github.com/xikanfeng2/I-Impute .


Comparison of the distribution of calcium-binding proteins and intrinsic connectivity in the lateral nucleus of the rat, monkey, and human amygdala.
A large amount of anatomic, electrophysiologic, pharmacologic, and behavioral data published over the past decade has provided novel insight into the function of the amygdala in the rat. An important question remains as to how well the data obtained in the rat amygdala can be extrapolated to primates. To address this issue from a functional neuroanatomic point of view, we compared the recently published data on the distribution of calcium-binding proteins (parvalbumin, calbindin-D(28k), calretinin) and intrinsic connectivity in the rat, monkey, and human amygdala. The aim of our ongoing analysis is twofold: (1) to determine whether the nuclei with the "same name" in the three species are chemoarchitectonically similar and (2) to determine whether the intradivisional, interdivisional, and internuclear connectivity is similarly organized in the rat and monkey. We focused on the lateral nucleus, which is the major recipient of thalamic and cortical sensory information directed to the amygdala and provides the most widespread intraamygdaloid connections. Our analysis suggests many similarities in the organization of chemoarchitectonics and intrinsic connectivity of the different subdivisions of the lateral nucleus of the rat, monkey, and human amygdala. There are also dissimilarities, however, which might relate to differences in the function of the amygdala in rodents and primates.


Ocular dominance in cataract surgery: research status and progress.
Ocular dominance (OD), a commonly used concept in clinical practice, plays an important role in optometry and refractive surgery. With the development of refractive cataract surgery, the refractive function of the intraocular lens determines the achievement of the postoperative full range of vision based on the retinal defocus blur suppression and binocular monovision principle. Therefore, OD plays an important role in cataract surgery. OD is related to the visual formation of the cerebral cortex, and its plasticity suggests that visual experience can influence the visual system. Cataract surgery changes the visual experience and transforms the dominant eye, which confirms the plasticity of the visual system. Based on the concept and mechanism of OD, this review summarizes the application of OD in cataract surgery.


Corrigendum to "Pulsed Radiofrequency of the Trigeminal Ganglion for Treating Postherpetic Neuralgia of the Ophthalmic Branch".
[This corrects the article DOI: 10.1155/2021/6638392.].


Botulinum toxin in upper limb spasticity after acquired brain injury: a randomized trial comparing dilution techniques.
To compare the efficacy of two different volume preparations of the same dose of botulinum toxin-A in relieving spasticity in wrist and finger flexors secondary to acquired brain injury. Thirteen adult patients who had modified Ashworth scale scores of 3 for both wrist and finger flexors were included in this randomized, controlled trial. Wrist and finger flexors were each injected. Blinded modified Ashworth scale ratings of wrist and finger flexor spasticity were measured. Spasticity in both muscles decreased significantly in both treatment groups. However, the high-volume and low-volume groups did not differ significantly in spasticity reduction. Because this preliminary study found no difference in spasticity reduction between high- and low-volume preparations of a 60-unit dose of botulinum toxin-A, a larger-sample study seems warranted to compare the efficacy of high-volume and low-volume preparations.


Discovery of an O-mannosylation pathway selectively serving cadherins and protocadherins.
The cadherin (cdh) superfamily of adhesion molecules carry O-linked mannose (O-Man) glycans at highly conserved sites localized to specific β-strands of their extracellular cdh (EC) domains. These O-Man glycans do not appear to be elongated like O-Man glycans found on α-dystroglycan (α-DG), and we recently demonstrated that initiation of cdh/protocadherin (pcdh) O-Man glycosylation is not dependent on the evolutionary conserved POMT1/POMT2 enzymes that initiate O-Man glycosylation on α-DG. Here, we used a CRISPR/Cas9 genetic dissection strategy combined with sensitive and quantitative O-Man glycoproteomics to identify a homologous family of four putative protein O-mannosyltransferases encoded by the TMTC1-4 genes, which were found to be imperative for cdh and pcdh O-Man glycosylation. KO of all four TMTC genes in HEK293 cells resulted in specific loss of cdh and pcdh O-Man glycosylation, whereas combined KO of TMTC1 and TMTC3 resulted in selective loss of O-Man glycans on specific β-strands of EC domains, suggesting that each isoenzyme serves a different function. In addition, O-Man glycosylation of IPT/TIG domains of plexins and hepatocyte growth factor receptor was not affected in TMTC KO cells, suggesting the existence of yet another O-Man glycosylation machinery. Our study demonstrates that regulation of O-mannosylation in higher eukaryotes is more complex than envisioned, and the discovery of the functions of TMTCs provide insight into cobblestone lissencephaly caused by deficiency in TMTC3.


One-step processing of highly viscous multiple Pickering emulsions.
Solid-stabilized Pickering emulsions have attracted a lot of attention recently due to their surfactant-free character, and exceptional stability. At the moment, how the viscosities of the liquid phases impact the processing of Pickering emulsions remain to be clearly understood - it is however an important parameter to consider when developing chemical engineering processes employing these multiphase liquids. Our first assumption was that the amount of emulsified dispersed phase would drastically decrease as viscosity increases. In this work, we demonstrate that double water-in-oil-in-water (W/O/W) Pickering emulsions are obtained in a single processing step when using very high viscosity silicone oils (≥10,000 cSt) and a single type of sub-μm silica particles modified with two grafted silanes and sodium alginate. The formation of water sub-inclusions proceeds via a phase-inversion mechanism. These sub-inclusions are subsequently stabilized and retained in the oil phase due to its viscosity, limiting sub-inclusions mobility, and the presence of adsorbed particles forming dense layers at oil-water interfaces, acting as barriers. The process we present is simple, requires a minimum number of components, and allows the preparation of multiple emulsions which could then be used to efficiently protect and/or transport a variety of sensitive encapsulated compounds.


Production of Cyr61 protein is modulated by extracellular acidification and PI3K/Akt signaling in prostate carcinoma PC-3 cells.
High expression of Cyr61, an extracellular cysteine-rich heparin-binding protein, has been associated with a malignant cell phenotype and poor outcome in prostate cancers. Although Cyr61 was found by us to be overproduced in androgen-independent PC-3 cells treated with N-acetylcysteine (NAC), its significance is still unclear. We therefore aimed to determine how and why Cyr61 protein is overexpressed in NAC-treated cells. Here, we found that Cyr61 protein level markedly increased in cells treated with NAC at high cell seeding density. Silencing of Cyr61 by siRNA induced enhanced activity of caspase-3/7, upregulation of the proapototic Bok, BimL and BimS, cleavage of apoptosis hallmarkers such as Bax, PARP and caspase-3, and downregulation of antiapoptotic Bcl2, Bcl-xL and Mcl-1 proteins. NAC treatment caused a reduction of extracellular medium pH to acidic and an increase in Akt phosphorylation, after which the replacement with NAC-free medium returned them to control levels within 24h. Acid stimulation increased the levels of Cyr61 and p-Akt proteins, whereas it suppressed the induction of proapoptotic and antiapoptotic proteins. Overall, our data indicate that PC-3 cells overproduce Cyr61 protein via activation of the PI3K/Akt signaling as a part of the survival mechanisms under the conditions causing extracellular acidity and further cytotoxicity.


Wheat germ eIF2 and CoeIF2. Resolution and functional characterization in in vitro protein synthesis.
A factor that binds Met-tRNAiMet in a ternary complex (eucaryotic initiation factor (eIF2) ) and an auxiliary component that strongly stimulates the activity of the binding factor (CoeIF2) have been purified from extracts of wheat germ. The molecular weights of the two factors, as determined by glycerol gradient centrifugation and sodium dodecyl sulfate gel electrophoresis, are 88,000 and 20,000, respectively. Incubation of wheat germ eIF2 with gamma-[32P]ATP and alpha-subunit kinase results in the phosphorylation of a Mr = 40,500 subunit, while no specific phosphorylations are found when the eIF2 is incubated with the beta-kinase. These data are interpreted to suggest that CoeIF2 is a monomer of Mr = 20,000 while eIF2 may be a dimer, containing subunits of Mr = 40,000 and 50,000. Both eIF2 and CoeIF2 are strongly required for in vitro amino acid polymerization, providing the first direct demonstration of the function of CoeIF2 in protein synthesis.


Casein kinase 1α is required to maintain murine hypothalamic pro-opiomelanocortin expression.
Hypothalamic pro-opiomelanocortin (POMC) neuron development is considered to play an essential role in the development of obesity. However, the underlying mechanisms remain unclear. Casein kinase 1α (CK1α) was expressed in the embryonic mouse hypothalamus at high levels and colocalized with POMC neurons. CK1α deletion in POMC neurons caused weight gain, metabolic defects, and increased food intake. The number of POMC-expressing cells was considerably decreased in Csnk1a1fl/fl;POMCcre (PKO) mice from embryonic day 15.5 to postnatal day 60, while apoptosis of POMC neurons was not affected. Furthermore, unchanged POMC progenitor cells and a decreased POMC phenotype established CK1α function in hypothalamic POMC neuron development. CK1α deletion led to elevated Notch intracellular domain (NICD) protein expression, and NICD inhibition rescued the PKO mouse phenotype. In summary, CK1α is involved in hypothalamic POMC expression via NICD-POMC signaling, deepening our understanding of POMC neuron development and control of systemic metabolic functions.


Survival benefit of perioperative locoregional adjuvant treatment for hepatocellular carcinoma with portal vein tumor thrombosis: A systematic review and Bayesian network meta-analysis.
To identify the optimal strategy for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) by comparing the oncological prognosis of different perioperative locoregional adjuvant treatments. Electronic database were searched for relevant studies. Overall survival (OS) and recurrence-free survival (RFS) were pooled by pairwise and network meta-analysis. Fourteen eligible trials with 1927 patients and covering four adjuvant treatments were included. All adjuvant therapies in combination with surgery were shown to be superior to surgery alone. Adjuvant therapy with radiotherapy had the lowest hazard ratio (HR) for both OS (HR: 0.38, 95% CrI: 0.25-0.57) and RFS (HR: 0.27, 95% CrI: 0.11-0.65) compared with other combination treatments, with estimated surface under the cumulative ranking of 93.2% and 82.7%, respectively. Perioperative locoregional adjuvant therapy provides OS benefits and reduces the risk of recurrence for patients suffering from HCC with PVTT. Radiotherapy is likely to be the most effective adjuvant regimen.


Enhanced expression of common fragile site with occupational exposure to pesticides.
The expression of common fragile sites (FS), induced by aphidicolin, in subjects with occupational history of exposure to pesticides has been studied. Results showed a higher frequency of FS in exposed subjects; in particular, there was an elevated expression of FS at the cancer breakpoints 3p14, 5q31, 7q22, 7q32, 14q24, and 16q22, involved in leukemias and non-Hodgkin's lymphoma. Moreover, the frequency of breaks in chromosomal bands carrying oncogenes or tumor suppressor genes involved in aberrations was significantly higher in exposed subjects at sites 1q25, 3p25, 7p22, 8q24.1, and 13q14.


Prevalence of Listeria monocytogenes in milk in Africa: a generalized logistic mixed-effects and meta-regression modelling.
Listeria outbreaks and food recalls is on the raise globally. Milk particularly is highly susceptible to Listeria as its production and storage adequately support Listeria growth. The extent of milk contamination with Listeria monocytogenes (Lm) and preventative actions to halt milk associated outbreaks in Africa are unknown. Hence, this study aimed at assessing the national and subregional prevalence of Lm in milk in Africa and identify impacting factors via generalized logistic mixed-effects (GLMEs) and meta-regression modelling. Lm-milk-specific data acquired from primary studies according to standard protocol were fitted using a GLMEs. The GLMEs was subjected to leave-one-study-out-cross-validation (LOSOCV). Factors impacting Lm prevalence in milk were assayed via a 1000-permutation-assisted meta-regression-modelling. The pooled prevalence of Lm in milk in Africa was 4.35% [2.73-6.86] with a prediction interval (PI) of 0.14-59.86% and LOSOCV value of 2.43% [1.62-3.62; PI: 0.32-16.11%]. Western Africa had the highest prevalence [20.13%, 4.13-59.59], then Southern Africa [5.85%, 0.12-75.72], Northern Africa [4.67%, 2.82-7.64], Eastern Africa [1.91%, 0.64-5.55], and there was no record from Central Africa. In term of country, Lm prevalence in milk significantly (p < 0.01) varied from 0.00 to 90.00%. Whereas the Lm prevalence was negligibly different (p = 0.77) by milk type, raw-milk had the highest prevalence [5.26%], followed by fermented-milk [4.76%], boiled-milk [2.90%], pasteurized-milk [1.64%], and powdered-milk [1.58%]. DNA extraction approach did not significantly (p = 0.07) affect Lm prevalence (Boiling [7.82%] versus Kit [7.24%]) as well as Lm detection method (p = 0.10; (ACP [3.64%] vs. CP [8.92%] vs. CS [2.27%] vs. CSP [6.82%]). Though a bivariate/multivariate combination of all tested variables in meta-regression explained 19.68-68.75% (R2) variance in Lm prevalence in milk, N, nation, and subregion singly/robustly accounted for 17.61% (F1;65 = 7.5994; p = 0.005), 63.89% (F14;52 = 4.2028; p = 0.001), and 16.54% (F3;63 = 3.4743; p = 0.026), respectively. In conclusion, it is recommended that adequate sample size should be prioritized in monitoring Lm in milk to prevent spuriously high or low prevalence to ensure robust, plausible, and credible estimate. Also, national efforts/interests and commitments to Lm monitoring should be awaken.


Crowded bis ligand complexes of Ttz(Ph,Me) with first row transition metals rearrange due to ligand field effects: structural and electronic characterization (Ttz(Ph,Me) = tris(3-phenyl-5-methyl-1,2,4-triazolyl)borate).
The tris(3-phenyl-5-methyl-1,2,4-triazolyl)borate (Ttz(Ph,Me)) ligand provides intermediate steric bulk and forms predominantly bis(ligand) complexes of the form M(Ttz(Ph,Me))(2) with first row divalent transition metals (1(M), M = Zn, Cu, Ni, Co, Fe, Mn). Due to ligand field effects that are greatest with Ni and Cu, ligand rearrangement is favored with these metals and Cu(Ttz(Ph,Me)*)(2) (1(Cu)*) and (Ttz(Ph,Me)*)Ni(Ttz(Ph,Me)) (1(Ni)*) were isolated by selective recrystallization and fully characterized (* indicates a rearranged Ttz ligand with Ph and Me in swapped positions in one triazole ring). For comparison with Co(Ttz(Ph,Me))(2), the less bulky analogs (Ttz(H,H))(2)Co (4) and (Ttz(Me,Me))(2)Co (5) were studied by NMR and EPR spectroscopy, and 5 was crystallographically characterized. These complexes allow for a study of how slight changes in structure and electron donor properties (for Ni and Cu), as well as dramatic changes in steric bulk (for Co), influence the physical properties; specifically there are significant changes in the UV-Vis, EPR and NMR spectra. Bis(ligand) complexes predominate with all metals, but (Ttz(Ph,Me))Ni(OH(2))Cl (2) and (Ttz(Ph,Me))ZnBr (3) were also isolated and these show that Ttz(Ph,Me) is coordinatively flexible.


Mass transport and charge transfer through an electrified interface between metallic lithium and solid-state electrolytes.
All-solid-state Li-ion batteries are one of the most promising energy storage devices for future automotive applications as high energy density metallic Li anodes can be safely used. However, introducing solid-state electrolytes needs a better understanding of the forming electrified electrode/electrolyte interface to facilitate the charge and mass transport through it and design ever-high-performance batteries. This study investigates the interface between metallic lithium and solid-state electrolytes. Using spectroscopic ellipsometry, we detected the formation of the space charge depletion layers even in the presence of metallic Li. That is counterintuitive and has been a subject of intense debate in recent years. Using impedance measurements, we obtain key parameters characterizing these layers and, with the help of kinetic Monte Carlo simulations, construct a comprehensive model of the systems to gain insights into the mass transport and the underlying mechanisms of charge accumulation, which is crucial for developing high-performance solid-state batteries.


The influence of a carbon layer deposited on a zirconia surface on the retention of polar analytes in an organic rich mobile phase.
Hydrophilic interaction liquid chromatography (HILIC) represents a modern MS-friendly approach to the analysis of polar compounds. To date especially silica-based HILIC stationary phases are utilized. Recently the papers concerning retention of polar analytes on unmodified titania and zirconia as well as a polybutadiene modified zirconia stationary phase under HILIC conditions have been published. In this work the investigation of a highly hydrophobic carbon-coated zirconia column under HILIC conditions was reported. The influence of buffer concentration, buffer type, pH and temperature on the elution and chromatographic efficiency were studied. The processes participating on the retention of polar compounds showed a multimodal character. The retention was governed rather by surface adsorption than phase partition in high ACN mobile phases. The ligand exchange remained an important retention force although the access of the analytes to the active surface was significantly hindered by the carbon coating. Besides ligand exchange and hydrophilic interactions also the hydrophobic carbon layer was involved in the retention of carboxylic acids and especially xanthines in the organic rich mobile phase.


Sleep in hospitalized pediatric and adult patients - A systematic review and meta-analysis.
Sleep is essential for recovery from illness. As a result, researchers have shown a growing interest in the sleep of hospitalized patients. Although many studies have been conducted over the past years, an up to date systematic review of the results is missing. The objective of this systematic review was to assess sleep quality and quantity of hospitalized patients and sleep disturbing factors. A systematic literature search was conducted within four scientific databases. The search focused on synonyms of 'sleep' and 'hospitalization'. Papers written in English or Dutch from inception to April 25th,2022 were included for hospitalized patients >1 year of age. Papers exclusively reporting about patients receiving palliative, obstetric or psychiatric care were excluded, as well as patients in rehabilitation and intensive care settings, and long-term hospitalized geriatric patients. This review was performed in accordance with the PRISMA guidelines. Out of 542 full text studies assessed for eligibility, 203 were included, describing sleep quality and/or quantity of 17,964 patients. The median sample size of the studies was 51 patients (IQR 67, range 6-1472). An exploratory meta-analysis of the Total Sleep Time showed an average of 7.2 h (95%-CI 4.3, 10.2) in hospitalized children, 5.7 h (95%-CI 4.8, 6.7) in adults and 5.8 h (95%-CI 5.3, 6.4) in older patients (>60y). In addition, a meta-analysis of the Wake After Sleep Onset (WASO) showed a combined high average of 1.8 h (95%-CI 0.7, 2.9). Overall sleep quality was poor, also due to nocturnal awakenings. The most frequently cited external factors for poor sleep were noise and number of patients in the room. Among the variety of internal/disease-related factors, pain and anxiety were most frequently mentioned to be associated with poor sleep. Of all studies, 76% reported poor sleep quality and insufficient sleep duration in hospitalized patients. Children sleep on average 0.7-3.8 h less in the hospital than recommended. Hospitalized adults sleep 1.3-3.2 h less than recommended for healthy people. This underscores the need for interventions to improve sleep during hospitalization to support recovery.


Nutrigenomics: implications for breast and colon cancer prevention.
Nutrigenomics refers to the interaction between one's diet and his/her genes. These interactions can markedly influence digestion, absorption, and the elimination of bioactive food components, as well as influence their site of actions/molecular targets. Nutrigenomics comprises nutrigenetics, epigenetics, and transcriptomics, coupled with other "omic," such as proteomics and metabolomics, that apparently account for the wide variability in cancer risk among individuals with similar dietary habits. Multiple food components including essential nutrients, phytochemical, zoochemicals, fungochemical, and bacterochemicals have been implicated in cancer risk and tumor behavior, admittedly with mixed results. Such findings suggest that not all individuals respond identically to a diet. This chapter highlights the influence of single-nucleotide polymorphism, copy number, epigenetic events, and transcriptomic homeostasis as factors influencing the response to food components and ultimately health, including cancer risk. Both breast and colorectal cancers are reviewed as examples about how nutrigenomics may influence the response to dietary intakes. As the concept that "one size fits all" comes to an end and personalized approaches surface, additional research data will be required to identify those who will benefit most from dietary change and any who might be placed at risk because of an adjustment.


A genetic portrait of metastatic seeds in lung adenocarcinoma.
Patients with lung adenocarcinomas (LUAD) frequently develop metastasis. In this issue of Cancer Cell, Lengel et al. perform a comprehensive analysis of metastasis patterns in 2,532 LUAD samples to identify clinicopathologic and genomic features of LUAD tumors associated with metastatic development, burden, and organotropism.


A quality control study to assess the inter-laboratory variability of routine estrogen and progesterone receptor assays.
The steroid hormone receptor laboratories of Bern, Basel, Zürich, Locarno, Lausanne and Geneva have participated in a quality control study to assess potential inter-laboratory variability in results of tests for determination of steroid hormone receptor status in human breast tumor biopsies. Homogeneous breast tumor powders containing low, medium and high concentrations of estrogen receptors (ER) and progesterone receptors (PR) were prepared in Bern and dispatched on solid CO2 to each laboratory within 1 day of preparation. Each laboratory was requested to assay each powder for ER and PR by their usual procedures. The results revealed that the quantitative discrepancies in ER and PR binding values among the participants could be attributed in part to variations in the methods used for measuring cytosol protein content and also to the differences in hormone receptor assay methods. Nevertheless, all of the laboratories were able to identify the samples containing low, medium and high concentrations of ER and PR.


Liver fibrosis quantified by image analysis in methotrexate-treated patients with psoriasis.
Histopathologic monitoring of the liver is mandatory during methotrexate (MTX) treatment. Fibrosis is an important histologic feature of liver damage. Our purpose was to supply an independent measure to histopathologic grading of hepatic changes in MTX-treated patients with psoriasis. Forty-six liver biopsy specimens from 26 patients with psoriasis evaluated for or treated with MTX were histopathologically classified and their collagen content quantified by image analysis after staining with Sirius Red F3BA. Fibrosis in normal liver biopsy specimens (controls) amounted to 0.9% +/- 0.1% and in patients with psoriasis varied between 9.3% +/- 1.4% and 24.0% +/- 4.9%. An effect of MTX on liver fibrosis was not discerned. No correlation was obtained between fibrosis and histologic grades, intake of alcohol, lean tissue mass, or age of the patient. Two changes occurred in the psoriatic liver; the collagen content was increased at least tenfold when compared with controls, and significant heterogeneity in collagen content was present among patients (p < 0.001).


Localized hypertrophic neuropathy: magnetic resonance imaging findings and long-term follow-up.
Four patients with painless, progressive focal neurological deficits that localized to peripheral nerve or plexus were eventually found to have the relatively rare condition of localized hypertrophic neuropathy or intraneural perineurioma. Magnetic resonance imaging (MRI) was an excellent tool for aiding in the precise localization of the lesion, if specifically tailored with regard to imaging planes and specific MRI sequences. Fat-saturated T2-weighted and fat-saturated T1-weighted postgadolinium images provided the best visualization, particularly with a high-field magnet and phase array body coil. Two patients stabilized following resection of the lesion and sural nerve grafting, and 1 had partial improvement in a proximal muscle following neurolysis.


Evaluation of metabolic pathway activity in cultured skin fibroblasts and blood leukocytes.
Screening for a variety of blocked catabolic mutants can be achieved in cultured skin fibroblasts and in peripheral blood leukocytes with a simple radioisotope method that is reliable and convenient. The method measures the incorporation into trichloroacetic acid (TCA) insoluble macromolecules of a 14C-labelled intermediate in the pathway under question; incorporation of a 3H-labelled metabolite, not in the same pathway, is used as an internal control of metabolism in the cell population. The 14C/3H incorporation ratio is decreased in blocked pathways; use of the ratio method eliminates the delay required by radioautography (used in earlier adaptations of this method), the problems involved in CO2 collection, and the need to standardize cultures for cell number. This method has been used to identify cells with biochemical lesions in the oxidation of propionate, galactose, hypoxanthine and pyruvate; it has allowed us to identify a new variant of methylmalonicaciduria; we believe it can be extended to include other metabolites and pathways.


The safe minimally ischemic liver remnant for small-for-size syndrome in porcine hepatectomy.
The minimal functional remnant liver mass or graft after an ischemic injury in hepatectomy or living donor liver transplantation (LDLT) is not clear. This study sought to determine the minimal remnant liver (MRL) size after 20 minutes hepatic inflow occlusion (HIO) and the maximal portal flow with which the liver remnant can sustain in a porcine model. Twenty pigs that underwent massive hepatectomy were randomly divided into 3 groups: 30% group, the remnant constituted about 30% of total liver volume (TLV); 35%+O group, the remnant constitute about 35% of TLV with 20 minutes HIO, and 30%+O group, the remnant constituted about 30% of TLV with 20 minutes of HIO. We evaluated survival rates, kinetic portal vein pressures (PVP), hemodynamics, hepatocyte metabolism, and injury. The 14-day survival rate in the 30%+O group was significantly reduced compared with that of either the 30% group or the 35%+O group: l00% versus 28.6% versus 85.7% respectively (P = .009). The tissue, serum analyses, and PVP in the 30%+O group were significantly different compared with the measurements among the other groups (P < .05), revealing that the liver remnant in 30%+O group could not sustain more than 3 times baseline portal flow, whereas in 35%+O group it could sustain 2.8 times baseline portal flow. Intraoperative ischemia can injure the sinusoidal endothelium, decreasing its ability to regulate portal hyperperfusion, causing less than 30% to 35% of TLV to show small-for-size syndrome or postoperative liver failure.


Evidence that amplification of norepinephrine-induced LH release by morphine is indirectly due to suppression of tuberoinfundibular dopamine secretion.
We previously observed that morphine markedly amplifies LH secretion following intracerebroventricular (i.c.v.) norepinephrine (NE) infusions. Based on additional evidence, we hypothesized that perhaps these morphine effects were due to suppression of tuberoinfundibular dopamine (TIDA) secretion thus allowing NE to evoke a greater release of LHRH from axon terminals in the median eminence than would otherwise occur. In the present studies, we examined whether apomorphine (a DA receptor agonist) would suppress and haloperidol (a DA receptor antagonist) would mimic these enhancing effects of morphine on NE-induced LH secretion. Estrogen-treated ovariectomized rats were used in these studies. NE, when infused i.c.v. (45 micrograms) evoked a modest increase in plasma LH (1.1 +/- 0.2 to 2.2 +/- 0.2 ng/ml) within 15 min. When morphine sulfate (10 mg/kg s.c.) was given 15 min prior to NE, LH peak values of 11 +/- 2 ng/ml were obtained by 60 min. Treatment of rats with apomorphine (1.5 mg/kg s.c.) at -15 min, morphine at 0 min and i.c.v. NE at 15 min resulted in a significant blunting of morphine's effect on NE-induced LH release. Moreover, in all morphine-treated rats, plasma prolactin (PRL) increased significantly within 10 min, peaked at 30 min and declined towards basal values by 90 min. Apomorphine completely blocked this morphine effect of PRL release. Haloperidol (HAL; 2.5 mg/kg s.c.) treatment had no effect on basal LH release but resulted in a significant increase in PRL which remained elevated up to 180 min.(ABSTRACT TRUNCATED AT 250 WORDS)


Metal ion-promoted binding of proteins to immobilized triazine dye affinity adsorbents.
Low concentrations of metal ions, particularly those of the first row transition series such as Zn2+, Co2+, Mn2+, Ni2+, Cu2+, and, to a lesser extent, the group IIA ions, Ca2+ and Mg2+, promotes binding of carboxypeptidase G2, alkaline phosphatase and yeast hexokinase to immobilized Procion Red H-8BN, Procion Yellow H-A and Cibacron Blue F3G-A respectively. The binding of ovalbumin to immobilized Cibacron Blue F3G-A and Procion Orange MX-G is selectively enhanced in the presence of AI3+. With ovalbumin and alkaline phosphatase, the effect is almost totally specific for both the metal ion and dye, whereas with carboxypeptidase G2 and hexokinase, metal ions such as Co2+, Ni2+, Mn2+, Cu2+, Ca2+ and Mg2+ also promote binding to varying degrees. Almost all other monovalent and trivalent metal ions appear to be ineffective. Metal ion-bound enzymes can subsequently be eluted with appropriate chelating agents of the amine, aminocarboxylate or substituted pyridine classes.


Evaluating individual genome similarity with a topic model.
Evaluating genome similarity among individuals is an essential step in data analysis. Advanced sequencing technology detects more and rarer variants for massive individual genomes, thus enabling individual-level genome similarity evaluation. However, the current methodologies, such as the principal component analysis (PCA), lack the capability to fully leverage rare variants and are also difficult to interpret in terms of population genetics. Here, we introduce a probabilistic topic model, latent Dirichlet allocation, to evaluate individual genome similarity. A total of 2535 individuals from the 1000 Genomes Project (KGP) were used to demonstrate our method. Various aspects of variant choice and model parameter selection were studied. We found that relatively rare (0.001<allele frequency < 0.175) and sparse (average interval > 20 000 bp) variants are more efficient for genome similarity evaluation. At least 100 000 such variants are necessary. In our results, the populations show significantly less mixed and more cohesive visualization than the PCA results. The global similarities among the KGP genomes are consistent with known geographical, historical and cultural factors. The source code and data access are available at: https://github.com/lrjuan/LDA_genome. Supplementary data are available at Bioinformatics online.


Effectiveness of pericapsular nerve group block with ultrasonography in patients diagnosed with hip fracture in the emergency department.
Hip fractures (HF) are among the most common fractures present in the emergency department and are very painful. Pericapsular nerve group block (PENG) is a new regional anesthesia technique developed for analgesia in total hip arthroplas-ties. We aimed to determine the effectiveness of PENG block used to reduce pain in patients with HF in the emergency department. This single-center, randomized, and prospective study was carried out in the emergency department. The patients in-cluded in the study were selected according to the suitability of the personnel who will perform the procedure. The sealed envelope system was used for randomization. Statistical analysis was performed with 39 patients (18 patients in the PENG group, 21 patients in the control group). Thir-teen (33.3%) of the patients were female and 26 (66.7%) were male. The mean age was 75.3. At rest post-procedure, the mean Numeric Rating Scale (NRS) scores of the patients at the 30th min, 2nd, 6th, and 24th h were 1.78±1.83, 0.00±0.00, 0.00±0.00, and 1.28±1.41 in the PENG group. On the other hand, it was 3.38±1.86, 0.05±0.22, 2.86±2.37, and 4.95±1.47 in the control group, respectively. The mean NRS scores of the patients at 15° elevation of the leg at the 30th min, 2nd, 6th, and 24th h were 3.06±1.80, 0.06±0.24, 0.22±0.43, and 2.44±1.50 in the PENG group and it was 5.24±1.81, 1.05±0.92, 4.29±2.35, and 7.14±1.24 in the control group, respectively. PENG block can reduce pain and the need for systemic analgesics as a practical option in patients with HF.


Effects of two putative endogenous digitalis-like factors, marinobufagenin and ouabain, on the Na+, K+-pump in human mesenteric arteries.
Recently, in rat aortae, two putative digitalis-like factors, marinobufagenin and ouabain, were shown to interact with alpha-1 (sarcolemma) and alpha-3 (nerve endings) subunits of the sodium pump, respectively, and elicit vasoconstriction via inhibition of the Na+,K+-pump in vascular smooth muscle or norepinephrine release. The purpose of the present study was to investigate the effects of ouabain and marinobufagenin on vascular tone, activity of Na+,K+-pump, and the expression of isoforms of the Na+,K+-ATPase alpha-subunit in human mesenteric arteries. Arteries were obtained from male patients undergoing surgery due to intestinal adenocarcinoma. Vasoconstrictor effects of both inhibitors were studied in isolated vascular rings. Na+,K+-pump activity was measured using the 86Rb technique. Membrane fractions of sarcolemma and nerve endings plasmalemma were prepared via differential centrifugation of membranes in a sucrose density gradient Specific antibodies to the alpha-1 and alpha-3 subunits of Na+,K+-ATPase were used to detect alpha-1 and alpha-3 isoforms in the membrane fractions by Western blotting. Marinobufagenin (EC50 = 88+/-15 nmoles/l) and ouabain (EC50 = 320+/-50 nmoles/l) elicited vasoconstriction in mesenteric artery rings. At a concentration of 1 nmol/l, both compounds stimulated the Na+,K+-pump, but inhibited its activity at 10-1000 nmoles/l. No stimulation of the Na+,K+-pump was observed in the presence of 5 micromol/l phentolamine; rather 1 nmol/l of marinobufagenin and ouabain inhibited the Na+,K+-pump by 30% and 13%, respectively. The alpha-1 polyclonal antibody detected alpha-1 isoform in membrane fractions from both sarcolemma and nerve endings. A monoclonal alpha-1 antibody detected the material in sarcolemmal membranes only. The alpha-3 isoform was detected in both membrane fractions by both antibodies, but staining for alpha-3 was more pronounced in the nerve endings. These results demonstrate that, in physiologically 'realistic' concentrations, marinobufagenin and ouabain can significantly affect the Na+,K+-pump in human mesenteric artery, and illustrate the importance of interaction of digitalis-like Na+,K+-pump inhibitors with the Na+,K+-ATPase localized to the intravascular adrenergic terminals. Present observations are in accord with the previous data suggesting that marinobufagenin and ouabain display greater affinity to alpha-1 and alpha-3 isoforms of the Na+,K+-pump, respectively, and support the view that the differential responsiveness to endogenous digitalis-like inhibitors is one of the features of alpha-isoforms of Na+,K+-ATPase.


Recent advances in municipal landfill leachate: A review focusing on its characteristics, treatment, and toxicity assessment.
Nowadays, sanitary landfilling is the most common approach to eliminate municipal solid waste, but a major drawback is the generation of heavily polluted leachates. These leachates must be appropriately treated before being discharged into the environment. Generally, the leachate characteristics such as COD, BOD/COD ratio, and landfill age are necessary determinants for selection of suitable treatment technologies. Rapid, sensitive and cost-effective bioassays are required to evaluate the toxicity of leachate before and after the treatment. This review summarizes extensive studies on leachate treatment methods and leachate toxicity assessment. It is found that individual biological or physical-chemical treatment is unable to meet strict effluent guidelines, whereas a combination of biological and physical-chemical treatments can achieve satisfactory removal efficiencies of both COD and ammonia nitrogen. In order to assess the toxic effects of leachate on different trophic organisms, we need to develop an appropriate matrix of bioassays based on their sensitivity to various toxicants and a multispecies approach using organisms representing different trophic levels. In this regard, a reduction in toxicity of the treated leachate will contribute to assessing the effectiveness of a specific remediation strategy.


Ventilation Monitoring in Severe Pediatric Traumatic Brain Injury at Nontrauma Centers.
Pediatric traumatic brain injury (TBI) guidelines should direct patient management. This retrospective study compared ventilation monitoring practices of nontrauma center (NTC) personnel and air medical crews (AMCs) in pediatric patients with severe TBI at NTCs after endotracheal intubation. Pediatric patient charts for level I trauma center admissions between 2008 and 2013 with severe TBI were screened. Inclusion criteria included admission Glasgow Coma Scale score ≤ 8, head Abbreviated Injury Scale score of ≥ 3, and secure airway initiated or managed at an NTC. A total of 30 patients were evaluated. The median head Abbreviated Injury Scale score was 4, and the trauma center mortality rate was 30%. NTC personnel and AMCs intubated 22 and 8 patients, respectively. AMCs monitored ventilation with much greater regularity (100 vs. 41%, P = .004), used continuous waveform capnography more often (75 vs. 14%, P = .003), and also initiated it quicker (17 vs. 37 minutes, = .001) after intubation. Unmonitored patients from NTC intubations waited on average 72.3 minutes before interfacility transport to the trauma center. AMCs showed superior ventilation monitoring after intubation in pediatric patients with severe TBI. Ventilation monitoring was not routinely conducted by NTC personnel, signifying areas to improve patient care.


Enhanced processivity of Dnmt1 by monoubiquitinated histone H3.
DNA methylation controls gene expression, and once established, DNA methylation patterns are faithfully copied during DNA replication by the maintenance DNA methyltransferase Dnmt1. In vivo, Dnmt1 interacts with Uhrf1, which recognizes hemimethylated CpGs. Recently, we reported that Uhrf1-catalyzed K18- and K23-ubiquitinated histone H3 binds to the N-terminal region (the replication focus targeting sequence, RFTS) of Dnmt1 to stimulate its methyltransferase activity. However, it is not yet fully understood how ubiquitinated histone H3 stimulates Dnmt1 activity. Here, we show that monoubiquitinated histone H3 stimulates Dnmt1 activity toward DNA with multiple hemimethylated CpGs but not toward DNA with only a single hemimethylated CpG, suggesting an influence of ubiquitination on the processivity of Dnmt1. The Dnmt1 activity stimulated by monoubiquitinated histone H3 was additively enhanced by the Uhrf1 SRA domain, which also binds to RFTS. Thus, Dnmt1 activity is regulated by catalysis (ubiquitination)-dependent and -independent functions of Uhrf1.


Network Analysis of Integrin Adhesion Complexes.
Cell-surface adhesion receptors mediate interactions with the extracellular matrix (ECM) to control many fundamental aspects of cell behavior, including cell migration, survival, and proliferation. Integrin adhesion receptors recruit structural and signaling proteins to form multimolecular adhesion complexes that link the plasma membrane to the actomyosin cytoskeleton. The assembly and turnover of adhesion complexes are tightly regulated, governed in part by the networks of physical protein interactions and functional signaling associations between components of the adhesome. Proteomic profiling of adhesion complexes has begun to reveal their molecular complexity and diversity. To interrogate the composition of cell-ECM adhesions, we detail herein an approach for the network analysis of adhesion complex proteomes. Integration of these proteomic data with adhesome databases in the context of predicted protein interactions enables the mapping of experimentally defined adhesion complex networks. Computational analysis of resultant network models can identify subnetworks of putative functionally linked adhesion protein communities. This approach provides a framework to predict functional adhesion protein relationships and generate new mechanistic hypotheses for further experimental testing.


Prevalence of suicidal thoughts and attempts in the transgender population of the world: a systematic review and meta-analysis.
The aim of this meta-analysis was to determine global pooled prevalence of suicide thoughts and attempts in transgender population. For doing comprehensive search strategy related to objectives in the presence meta-analysis, all international databases like PubMed (Medline), Scopus, Embase, Web of Sciences, PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature (CINHAL) were searched from January 1990 to December 2022. The quality of the final selected studies was evaluated according to Newcastle-Ottawa Quality Assessment Scale for cross-sectional studies. The subgroup analysis was done based on type of transgender (female to male, male to female) and prevalence (point, period, and lifetime), country, and criteria of diagnosis. All analysis was done in STATA version 17. From the total number of 65 selected studies, 71 prevalence of suicidal thoughts, including point, period, and lifetime prevalence were extracted and combined. After combining these values, the prevalence of suicidal thoughts in the transgender population in the world was 39% in the past month (pooled point prevalence: 39%; 95% CI 35-43%), 45% in the past year (pooled period prevalence: 45%; % 95 CI 35-54%) and 50% during lifetime (pooled lifetime prevalence: 50%; % 95 CI 42-57%). Also, the prevalence of suicide attempt in the transgender population of the world was 16% in the past month (pooled point prevalence: 16%; 95% CI 13-19%), 11% in the past year (pooled period prevalence: 11%; % 95 CI 5-19%) and 29% during lifetime (pooled lifetime prevalence: 29%; % 95 CI 25-34%). The present meta-analysis results showed the prevalence of suicidal thoughts and attempts in the transgender community was high, and more importantly, about 50% of transgenders who had suicidal thoughts, committed suicide.


Diversity, dynamics, direction, and magnitude of high-altitude migrating insects in the Sahel.
Long-distance migration of insects impacts food security, public health, and conservation-issues that are especially significant in Africa. Windborne migration is a key strategy enabling exploitation of ephemeral havens such as the Sahel, however, its knowledge remains sparse. In this first cross-season investigation (3 years) of the aerial fauna over Africa, we sampled insects flying 40-290 m above ground in Mali, using nets mounted on tethered helium-filled balloons. Nearly half a million insects were caught, representing at least 100 families from thirteen orders. Control nets confirmed that the insects were captured at altitude. Thirteen ecologically and phylogenetically diverse species were studied in detail. Migration of all species peaked during the wet season every year across localities, suggesting regular migrations. Species differed in flight altitude, seasonality, and associated weather conditions. All taxa exhibited frequent flights on southerly winds, accounting for the recolonization of the Sahel from southern source populations. "Return" southward movement occurred in most taxa. Estimates of the seasonal number of migrants per species crossing Mali at latitude 14°N were in the trillions, and the nightly distances traversed reached hundreds of kilometers. The magnitude and diversity of windborne insect migration highlight its importance and impacts on Sahelian and neighboring ecosystems.


Posterior circulation hyperperfusion syndrome after superficial temporal artery-superior cerebellar artery bypass for vertebral artery dissection.
A 68-year-old man was diagnosed with infarction of the cerebellum and medulla oblongata caused by vertebral artery dissection manifesting as severe stenosis with poor collateral flow. He underwent superficial temporal artery (STA)-superior cerebellar artery (SCA) bypass for the prevention of fatal brain stem infarction. He had consciousness disturbance 2 days postoperatively. Single-photon emission computed tomography revealed hyperperfusion in the posterior circulation. His consciousness improved as hyperperfusion improved. We report the first case of posterior circulation hyperperfusion syndrome after STA-SCA bypass and provide a review of the relevant literature.


Seizures and intracranial hemorrhage.
Seizures and intracranial hemorrhage are possible medical diseases that any obstetrician may encounter. This article reviews the cause, treatment, and medical management in pregnancy for seizures and intracranial hemorrhage, and how the two can overlap into preeclampsia or eclampsia. This article also highlights some challenging management issues from the obstetrician's perspective.


Correction: The bZIP transcription factor AREB3 mediates FT signalling and floral transition at the Arabidopsis shoot apical meristem.
[This corrects the article DOI: 10.1371/journal.pgen.1010766.].


The evolutionary history of the polyQ tract in huntingtin sheds light on its functional pro-neural activities.
Huntington's disease is caused by a pathologically long (>35) CAG repeat located in the first exon of the Huntingtin gene (HTT). While pathologically expanded CAG repeats are the focus of extensive investigations, non-pathogenic CAG tracts in protein-coding genes are less well characterized. Here, we investigated the function and evolution of the physiological CAG tract in the HTT gene. We show that the poly-glutamine (polyQ) tract encoded by CAGs in the huntingtin protein (HTT) is under purifying selection and subjected to stronger selective pressures than CAG-encoded polyQ tracts in other proteins. For natural selection to operate, the polyQ must perform a function. By combining genome-edited mouse embryonic stem cells and cell assays, we show that small variations in HTT polyQ lengths significantly correlate with cells' neurogenic potential and with changes in the gene transcription network governing neuronal function. We conclude that during evolution natural selection promotes the conservation and purity of the CAG-encoded polyQ tract and that small increases in its physiological length influence neural functions of HTT. We propose that these changes in HTT polyQ length contribute to evolutionary fitness including potentially to the development of a more complex nervous system.


Arousal by stimulation of deep-brain nuclei.
Schiff et al. show that deep-brain stimulation of the unspecific thalamocortical system through certain midline thalamic nuclei produces an alerting effect in a patient in a minimally conscious state. Such nuclei include the central lateral nucleus, paralaminar regions of the median dorsalis, and the posterior-medial aspect of the centromedian/parafascicularis nucleus complex.


Effects of pre, post, and simultaneous loading of natural organic matter on 2-methylisoborneol adsorption on superfine powdered activated carbon: Reversibility and external pore-blocking.
Three different natural organic matter (NOM)-loading methods were compared for the adsorptive removal of 2-methylisoborneol (MIB) by superfine powdered activated carbon (SPAC) and conventionally-sized powdered activated carbon (PAC). The three NOM-loading methods were: NOM adsorption followed by MIB (MIB adsorption on NOM-preloaded carbon), MIB adsorption followed by NOM (MIB adsorption on NOM post-loaded carbon), and simultaneous NOM and MIB loading (MIB adsorption on NOM-simultaneously loaded carbon). MIB removals were similar for the smaller-sized carbon (SPAC) at higher AC dosages and at lower initial NOM concentrations. The similar MIB removals indicate direct site competition between MIB and NOM with MIB adsorption reversibility (complete desorption of MIB by NOM). At lower AC doses, especially for PACs, and at higher initial NOM concentrations, the adsorption of MIBs depended on the sequence of MIB or NOM adsorption. MIB removal was lowest for the NOM-preloaded carbon, followed by NOM-simultaneously loaded carbon. The highest MIB removal was achieved by post-loading of NOM, indicating that the adsorption is irreversible. MIB adsorption on SPAC was more reversible than on PAC, although the pore size distributions of the two carbons were similar. The high degree of adsorption irreversibility for PAC compared with SPAC indicated that pore blocking occurs due to NOM loading at the PAC particle surface. Images of the external adsorption were obtained using isotope mapping and 15N-labeled effluent organic matter.


A Modified Delphi Process to Prioritize Experiences and Guidance Related to ICU Restricted Visitation Policies During the Coronavirus Disease 2019 Pandemic.
To create evidence-based consensus statements for restricted ICU visitation policies to support critically ill patients, families, and healthcare professionals during current and future pandemics. Three rounds of a remote modified Delphi consensus process. Online survey and virtual polling from February 2, 2021, to April 8, 2021. Stakeholders (patients, families, clinicians, researchers, allied health professionals, decision-makers) admitted to or working in Canadian ICUs during the coronavirus disease 2019 pandemic. During Round 1, key stakeholders used a 9-point Likert scale to rate experiences (1-not significant, 9-significant impact on patients, families, healthcare professionals, or patient- and family-centered care) and strategies (1-not essential, 9-essential recommendation for inclusion in the development of restricted visitation policies) and used a free-text box to capture experiences/strategies we may have missed. Consensus was achieved if the median score was 7-9 or 1-3. During Round 2, participants used a 9-point Likert scale to re-rate experiences/strategies that did not meet consensus during Round 1 (median score of 4-6) and rate new items identified in Round 1. During Rounds 2 and 3, participants ranked items that reached consensus by order of importance (relative to other related items and experiences) using a weighted ranking system (0-100 points). Participants prioritized 11 experiences (e.g., variability of family's comfort with technology, healthcare professional moral distress) and developed 21 consensus statements (e.g., communicate policy changes to the hospital staff before the public, permit visitors at end-of-life regardless of coronavirus disease 2019 status, creating a clear definition for end-of-life) regarding restricted visitation policies. We have formulated evidence-informed consensus statements regarding restricted visitation policies informed by diverse stakeholders, which could enhance patient- and family-centered care during a pandemic.


Correlation between Semi-Quantitative (18)F-FDG PET/CT Parameters and Ki-67 Expression in Small Cell Lung Cancer.
The aim of this study was to evaluate the relationship between semiquantitative parameters on (18)F-FDG PET/CT including maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) and the expression level of Ki-67 in small-cell lung cancer (SCLC). Ninety-four consecutive patients with SCLC were enrolled in this study. They underwent (18)F-FDG PET/CT for initial evaluation of SCLC, and we measured SUVmax, avgSUVmean, MTVsum, and TLGtotal on (18)F-FDG PET/CT images. The protein expression of Ki-67 was examined by immunohistochemical staining. Significant correlations were found between the MTVsum and Ki-67 labeling index (r = 0.254, p = 0.014) and the TLGtotal and Ki-67 labeling index (r = 0.239, p = 0.020). No correlation was found between the SUVmax and Ki-67 labeling index (r = 0.116, p = 0.264) and the avgSUVmean and Ki-67 labeling index (r = 0.031, p = 0.770). Dividing the Ki-67 expression level into three categories, it was suggested that increasing Ki-67 expression level caused a stepwise increase in the MTVsum and TLGtotal. (p = 0.028 and 0.039, respectively), but not the SUVmax and avgSUVmean (p = 0.526 and 0.729, respectively). In conclusion, the volume-based parameters of (18)F-FDG PET/CT correlate with immunohistochemical staining of Ki-67 in SCLC. Measurement of the MTVsum and TLGtotal by (18)F-FDG PET/CT might be a simple, noninvasive, and useful method to determine the proliferative potential of cancer cells.


Local effects of lysophosphatidylserine in rats.
To study the inflammatory properties of lysophosphatidylserine (a phospholipid acting as a histamine releaser), rats were subjected to local treatment with this compound. In the paw a rapid and dose-dependent edematous reaction occurred within 30-60 min (ED50 2.5 micrograms/rat). The effect was dependent on the intact configuration of serine head group since lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidic acid and N-acetimidyl-lysophosphatidylserine were uneffective. Indomethacin produced a weak inhibition but chlorpheniramine and cyproheptadine inhibited 50 and 70%, respectively. Consistently, the histamine stores of the paw were found to be decreased at the end of the lysophosphatidylserine effect. Increase in vascular permeability was observed also after the injection of lysophosphatidylserine into the dorsal skin and pleural cavity although the phospholipid was less effective in these regions. The fluid extravasation in the pleural cavity was 75% prevented by cyproheptadine. Parallel in vitro experiments showed that the effect of lysophosphatidylserine on isolated pleural and peritoneal mast cells is increased when a leukocyte lysate was also added. After centrifugation the activity was retained in the insoluble fraction. It is concluded that lysophosphatidylserine, injected locally, elicits an inflammatory reaction mediated by the components of mast cell granulus. The response may be amplified by the migration of other inflammatory cells into the exudate.


The subspine organization of actin fibers regulates the structure and plasticity of dendritic spines.
Synapse function and plasticity depend on the physical structure of dendritic spines as determined by the actin cytoskeleton. We have investigated the organization of filamentous (F-) actin within individual spines on CA1 pyramidal neurons in rat hippocampal slices. Using two-photon photoactivation of green fluorescent protein fused to beta-actin, we found that a dynamic pool of F-actin at the tip of the spine quickly treadmilled to generate an expansive force. The size of a stable F-actin pool at the base of the spine depended on spine volume. Repeated two-photon uncaging of glutamate formed a third pool of F-actin and enlarged the spine. The spine often released this "enlargement pool" into the dendritic shaft, but the pool had to be physically confined by a spine neck for the enlargement to be long-lasting. Ca2+/calmodulin-dependent protein kinase II regulated this confinement. Thus, spines have an elaborate mechanical nature that is regulated by actin fibers.


HMGB1 mediates homocysteine-induced endothelial cells pyroptosis via cathepsin V-dependent pathway.
Endothelial cells injury and pro-inflammation cytokines release are the initial steps of hyperhomocysteinemia (HHcy)-associated vascular inflammation. Pyroptosis is a newly identified pro-inflammation form of programmed cell death, causing cell lysis and IL-1β release, and characterized by the caspases-induced cleavage of its effector molecule gasdermins (GSDMs). However, the effect of homocysteine (Hcy) on endothelial cells pyroptosis and the underlying mechanisms have not been fully defined. We have previously reported that Hcy induces vascular endothelial inflammation accompanied by the increase of high mobility group box-1 protein (HMGB1) and lysosomal cysteine protease cathepsin V in endothelial cells, and other studies have shown that HMGB1 or cathepsins are involved in activation of NLRP3 inflammasome and caspase-1. Here, we investigated the role of HMGB1 and cathepsin V in the process of Hcy-induced pyroptosis. We observed an increase in plasma IL-1β levels in HHcy patients and mice models, cathepsin V inhibitor reduced the plasma IL-1β levels and cleavage of GSDMD full-length into GSDMD N-terminal in the thoracic aorta of hyperhomocysteinemia mice. Using cultured HUVECs, we observed that Hcy promoted GSDMD N-terminal expression, silencing GSDMD or HMGB1 rescued Hcy-induced pyroptosis. HMGB1 also increased GSDMD N-terminal expression, and silencing cathepsin V reversed HMGB1-induced pyroptosis. HMGB1 could increase lysosome permeability, and silencing cathepsin V attenuated HMGB1-induced activation of caspase-1. In conclusion, this study has delineated a novel mechanism that HMGB1 mediated Hcy-induced endothelial cells pyroptosis partly via cathepsin V-dependent pathway.


High plasma concentrations of desmethylclomipramine after chronic administration of clomipramine to a poor metabolizer.
A patient showed excessive concentrations of desmethylclomipramine after receiving normal daily doses of clomipramine (Anafranil) and the elimination kinetics of the desmethylated metabolite was zero-order/saturable. Investigation showed that she was a poor metabolizer of debrisoquine and that, in addition, she had been treated with allopurinol, an inhibitor of hepatic drug metabolism.


Pitfalls in scintigraphic detection of neuroendocrine tumours.
We report 4 cases of abnormal results using iodine-123 metaiodobenzylguanidine (123I-mIBG) or technetium-99m (V) dimercaptosuccinic acid (99mTc(V)-DMSA) scintigraphy in the diagnosis and follow-up of presumed neuroendocrine tumours. The present series consisted of 2 false-positive cases (1 adenomatous polyp of the caecum with mIBG and 1 follicular adenoma of the thyroid with DMSA) and 2 cases of anomalous uptake of (V)-DMSA in a non-neuroendocrine tissue.


Is there a timing for sensitivity to acute cerebral ischemia in migraine patients?
Migraine may be a factor of increased cerebral sensitivity to ischemia. Previous studies were conducted within 6 to 72 after stroke onset. We aimed to determine if an accelerated infarct growth exists in migraine patients within the first 4.5 h. A retrospective case-control study was conducted where all patients admitted for acute stroke started <4.5 h before and who underwent perfusion CT were assessed. The hypoperfusion and necrosis volumes on initial CT perfusion were analyzed, as well as the final infarct volume on MRI performed within 72 h after admission. A no-mismatch pattern was defined as a ratio necrosis/hypoperfusion volume > 83%. 24 patients with personal history of migraine were identified, 8 of them with aura. The control cohort included 51 patients. No difference was found between groups in terms of demographics, initial severity or outcome or presumed cause of stroke. Mean time to CT scan was 125 min in migraine patients and 127 min in the control group. A no-mismatch pattern was equally found in migraine patients and controls, even after adjustment for age, sex and presence of proximal occlusion (p = .22). The final infarct volume was also similar in both groups. Migraine patients did not display more no-mismatch pattern than controls within the 4.5 h of stroke onset. This deviates from previous studies and may be due to our earlier time from stroke onset to CT scan. A history of migraine may lead to malignant progression of ischemia but occurring only after several hours.


Influence of initial insulin dosage on blood glucose dynamics of children and adolescents with newly diagnosed type 1 diabetes mellitus.
To investigate the effect of initial insulin dosage on blood glucose (BG) dynamics, β-cell protection, and oxidative stress in type 1 diabetes mellitus. Sixty newly diagnosed type 1 diabetes mellitus patients were randomly assigned to continuous subcutaneous insulin infusions of 0.6 ± 0.2 IU/kg/d (group 1), 1.0 ± 0.2 IU/kg/d (group 2), or 1.4 ± 0.2 IU/kg/d (group 3) for 3 wk. BG was monitored continuously for the first 10 d and the last 2 d of wk 2 and 3. A total of 24-hour urinary 8-iso-PGF2α was assayed on days 8, 9, and 10. The occurrence and duration of the honeymoon period were recorded. Fasting C-peptide and glycosylated hemoglobin (HbA1c) were assayed after 1, 6, and 12 months of insulin treatment. BG decreased to the target range by the end of wk 3 (group 1), wk 2 (group 2), or wk 1 (group 3). The actual insulin dosage over the 3 wk, frequency of hypoglycemia on wk 1 and 2, and median BG at the end of wk 1 differed significantly, but not 8-iso-PGF2α and the honeymoon period in the three groups. No severe hypoglycemia event was observed in any patient, but there was significant difference in the first occurrence of hypoglycemia. Differences in initial insulin dosage produced different BG dynamics in wk 1, equivalent BG dynamics on wk 2 and 3, but had no influence on short- and long-term BG control and honeymoon phase. The wide range of initial insulin dosage could be chosen if guided by BG monitoring.


[Other methods: dilatation, T-tube (author's transl)].
In the Department of Surgery of the University of Mainz we prefer dilatation for treatment of stenosis of the papilla. In 1063 cases out of 4058 operations for cholelithiasis, we opened the choledochus. In 944 patients, a dilatation was performed; 40 were treated by papillotomy; in 79 cases, primarily in the past, we performed a biliodigestive anastomosis. In 106 patients we finished the procedure by inserting a T-tube; in 838 cases primary closure of the choledochus was performed. In 12 complications of the dilatation (perforation, pancreatitis, restenosis), there was no mortality; therefore we conclude that dilatation of the papilla is a safe, simple, and effective procedure.


The manner of death among fatalities where dextropropoxyphene caused or contributed to death.
Dextropropoxyphene (DXP) is one of the most prescribed analgesic compounds in Sweden. To investigate the manner of death among fatalities where DXP caused or contributed to death all medico-legal autopsies performed in Sweden in 1992-1996 were analysed on the bases of toxicological analyses and death certificates. DXP in peripheral blood was found in 1782 (7.5%) of the total 23,691 blood samples. According to the death certificates 956 (54%) of the 1782 cases were classified as fatal DXP poisoning. Among these, the manner of death was classified as accidental in 49 cases (5%), suicidal in 542 cases (57%) and undetermined in 365 cases (38%). The reported manner of death differed between the six forensic medicine districts in Sweden. The accident rate differed significantly between the district with the highest rate (9%) and the districts with the lowest rate (1%). One district had a significantly higher incidence of suicide (73%) than four of the other districts, while another district had a significantly lower incidence of suicide (33%) than all the other districts. The accident classification rate among the physicians performing ten or more autopsies varied from 0% to 17%, the suicide classification rate from 25% to 83% and the rate of undetermined manner of death from 8% to 71%. A major conclusion drawn from this study is that accidental DXP fatalities may be underestimated. This may have serious consequences, as under-reporting of accidental DXP fatalities will increase the risk that knowledge of the high toxicity of DXP will not reach the population consuming this drug. Since valid death statistics concerning the manner of death at DXP fatalities are needed to provide the base for preventive actions, special attention should be paid to the classification process, in order to increase the uniformity of the assessments among the different physicians, and to avoid under-reporting of accidents.


Polymerase chain reaction-based search for two alpha-globin gene mutations in India.
We have used restriction site-dependent polymerase chain reaction (PCR)-based methodology for detection of the alpha-globin polyadenylation (poly A) signal mutation, AATAAA>AATA- - and Hb Sun Prairie [alpha 130(H13)Ala-->Pro, GCT>CCT (alpha2)] mutation. The former mutation produces Hb H disease in the homozygous state and occurs frequently in the Indian population. It was detected in nine of 77 putative alpha-thalassemia (alpha-thal) patients and in three of 13 beta-thal intermedia patients tested. Four of the nine alpha-thal patients were homozygotes for the mutation. The Hb Sun Prairie mutation was confirmed in two alpha-thal patients, one of whom was a homozygote and the other a heterozygote.


Sequence confirmation of modified oligonucleotides using IRMPD in the external ion reservoir of an electrospray ionization Fourier transform ion cyclotron mass spectrometer.
Modified oligonucleotides continue to play an important role as antisense compounds that inhibit the expression of genes associated with metabolic disorders, cancer, and infectious diseases. Because the majority of modifications render these molecules refractory to standard enzymatic sequencing techniques, alternative sequencing methods which are fast and reliable are needed. In this work we explore how sugar and backbone modifications affect fragmentation patterns observed from oligonucleotides which are fragmented by infrared multiple photon dissociation in the external reservoir of an electrospray ionization Fourier transform ion cyclotron mass spectrometer. The modifications influence which fragment types (i.e., a(n)-B versus c(n)) dominate and the ease with which the oligonucleotides are fragmented. General observations for confirming the sequence of oligonucleotides are described.