The effect of the addition of adrenaline to pethidine for patient-controlled epidural analgesia after caesarean section.
We have investigated the addition of adrenaline to pethidine for patient-controlled epidural analgesia after elective Caesarean section. In a randomised, double-blind study, patients received patient-controlled epidural analgesia for 24 h using pethidine 5 mg.ml-1 with adrenaline 5 micrograms.ml-1 (adrenaline group, n = 40) or pethidine 5 mg.ml-1 without adrenaline (plain group, n = 38). Visual analogue scale pain scores at rest and on coughing measured 2 h, 6 h and 24 h after surgery were similar between the two groups. There was a trend towards lower mean total consumption of pethidine in the adrenaline group (231.5 mg; SD 140.5 mg) compared with the plain group (289.5 mg; SD 139.5 mg; p = 0.071). Patients in the adrenaline group had higher visual analogue scale scores for nausea at 2 h and 24 h and higher scores for pruritus at 2 h compared with the plain group. Addition of adrenaline to pethidine for patient-controlled epidural analgesia does not appear to have significant clinical advantages.


D-graph clusters flaviviruses and β-coronaviruses according to their hosts, disease type and human cell receptors.
There is a need for rapid and easy to use, alignment free methods to cluster large groups of protein sequence data. Commonly used phylogenetic trees based on alignments can be used to visualize only a limited number of protein sequences. DGraph, introduced here, is a dynamic programming application developed to generate 2D-maps based on similarity scores for sequences. The program automatically calculates and graphically displays property distance (PD) scores based on physico-chemical property (PCP) similarities from an unaligned list of FASTA files. Such "PD-graphs" show the interrelatedness of the sequences, whereby clusters can reveal deeper connectivities. PD-Graphs generated for flavivirus (FV), enterovirus (EV), and coronavirus (CoV) sequences from complete polyproteins or individual proteins are consistent with biological data on vector types, hosts, cellular receptors and disease phenotypes. PD-graphs separate the tick- from the mosquito-borne FV, clusters viruses that infect bats, camels, seabirds and humans separately and the clusters correlate with disease phenotype. The PD method segregates the β-CoV spike proteins of SARS, SARS-CoV-2, and MERS sequences from other human pathogenic CoV, with clustering consistent with cellular receptor usage. The graphs also suggest evolutionary relationships that may be difficult to determine with conventional bootstrapping methods that require postulating an ancestral sequence. DGraph is written in Java, compatible with the Java 5 runtime or newer. Source code and executable is available from the GitHub website ( https://github.com/bjmnbraun/DGraph/releases ). Documentation for installation and use of the software is available from the Readme.md file at ( https://github.com/bjmnbraun/DGraph ). firstname.lastname@example.com or firstname.lastname@example.com. Supplementary information Table S1 and Fig. S1 are online available.


The M-band: an elastic web that crosslinks thick filaments in the center of the sarcomere.
The sarcomere of striated muscle is an efficient molecular machine, characterized by perfect structural organization of contractile filaments. This order is ensured by the sarcomere cytoskeleton, an important element of which is the M-band, believed to maintain the thick filament lattice. We review here recent progress in understanding the M-band function and its structural organization. We explain how the M-band might reduce the intrinsic instability of thick filaments and help titin to maintain order in the sarcomeres. The M-band molecular structure has been clarified recently by biochemical and biophysical approaches that focused on the properties of the prominent M-band component myomesin. These have shown that antiparallel myomesin dimers might link the thick filaments in the M-band, a role analogous to that of alpha-actinin in the Z-disc. Furthermore, similar to titin, myomesin is a molecular spring with complex visco-elastic properties that can be modified by alternative splicing. M-band protein composition correlates with the expression of titin isoforms and appears to be a reliable marker for biomechanical conditions in contracting muscle. We propose that the M-band is in fact a dynamic structure that monitors the stress appearing in the thick filament lattice during contraction and quickly reorganizes to meet new physiological requirements.


Erratum: Long Intergenic Non-Coding RNA 01121 Promotes Breast Cancer Cell Proliferation, Migration, and Invasion via the miR-150-5p/HMGA2 Axis [Corrigendum].
[This corrects the article DOI: 10.2147/CMAR.S230367.].


[Two-stage orchidopexy--an alternative to orchiectomy in cryptorchidism].
Treatment of high undescended testes is a serious surgical problem. To analyze the two-stage orchidopexy performed and the early results obtained. Of 625 orchidopexy in 40 (6,4%) instances a two-stage orchidopexy was done for a 10 years period (1994-2003). The second operation is performed within 2 years after the first one. Scrotal fixation of the testis is achieved by Gross procedure. The final success rate is 83,3%, satisfactory results in 13,9% cases and failure in 2,8%. We always prefer for this reason the two-stage orchidopexy as an alternative to orchiectomy.


Pressure sensation by an anterior pagoda neuron population distributed in multiple ganglia in the leech, Whitmania pigra.
Sensory processing of pressure signals in the central nervous system of the leech, Whitmania pigra, was studied through the interaction between pressure sensory neurons and anterior pagoda neurons. The responses of anterior pagoda neurons to one pulse or a train of pulses in pressure sensory neurons were characterized by the latency and amplitude of excitatory postsynaptic potentials. Here we show that each pressure sensory neuron is able to activate all the anterior pagoda neurons throughout the leech central nervous system. The response patterns of all anterior pagoda neurons were appropriate to the pressure location: in the longitudinal direction the anterior pagoda neuron further away from the pressure sensory neuron had a smaller response with longer latency; inside each ganglion, the anterior pagoda neuron on the contralateral side had a larger response with shorter latency than that on the ipsilateral side. All anterior pagoda neurons excited by pressure sensory neurons comprised a parallel system in which each anterior pagoda neuron was independent from the others. The location information of pressure stimuli was represented through the response of all 40 anterior pagoda neurons covering the whole leech body with a specific pattern of latency and amplitude.


Role of bacterial toxins, bile acids, and free fatty acids in colonic water malabsorption in tropical sprue.
Colonic perfusion studies in 10 southern Indian patients with tropical sprue and nine matched healthy adults revealed a defect of water and sodium absorption from the colon in sprue. Heat-labile and heat-stable enterotoxin production was not detected in coliforms cultured from the feces of any of the 19 subjects. The 24-hr fecal bile acid output was increased in patients with sprue, but fecal aqueous bile acid concentrations remained within normal limits, and these did not correlate with defects in colonic water and sodium absorption. Fecal free fatty acid excretion was markedly increased in sprue. There was a negative correlation between fecal excretion of unsaturated free fatty acids and colonic water and sodium absorption.


AtAAH encodes a protein with allantoate amidohydrolase activity from Arabidopsis thaliana.
We report the identification and cloning of an allantoate amidohydrolase (allantoate deiminase, EC 18.104.22.168) cDNA from Arabidopsis thaliana (L.) Heynh. This sequence, which we term Arabidopsis thaliana Allantoate Amidohydrolase (AtAAH), was shown to be functional by complementation of Saccharomyces cerevisiae dal2 mutants, blocked in allantoate degradation. Following transfer to a medium containing allantoin as the sole nitrogen source, Ataah T-DNA insertion mutants were severely impaired and eventually died. Ataah mutants demonstrated higher allantoate levels than wild-type plants in the presence and absence of exogenous ureides, supporting a block in allantoate catabolism. AtAAH transcript was detected in all tissues examined by RT-PCR, consistent with a function in purine turnover in Arabidopsis. To our knowledge this is the first allantoate amidohydrolase gene identified in any plant species.


Machine learning approaches to drug response prediction: challenges and recent progress.
Cancer is a leading cause of death worldwide. Identifying the best treatment using computational models to personalize drug response prediction holds great promise to improve patient's chances of successful recovery. Unfortunately, the computational task of predicting drug response is very challenging, partially due to the limitations of the available data and partially due to algorithmic shortcomings. The recent advances in deep learning may open a new chapter in the search for computational drug response prediction models and ultimately result in more accurate tools for therapy response. This review provides an overview of the computational challenges and advances in drug response prediction, and focuses on comparing the machine learning techniques to be of utmost practical use for clinicians and machine learning non-experts. The incorporation of new data modalities such as single-cell profiling, along with techniques that rapidly find effective drug combinations will likely be instrumental in improving cancer care.


Apoptosis and autophagy markers predict survival in neoadjuvant treated oesophageal adenocarcinoma patients.
Less than 20 % of patients with resectable oesophageal adenocarcinoma obtain a pathological response following neoadjuvant chemotherapy. Studies using oesophageal cancer cell lines have shown that drug sensitive tumour cells undergo apoptosis in response to drug treatment, whereas resistant cells induce autophagy and can recover following withdrawal of drug. In this study, we evaluated markers of apoptosis (active/cleaved caspase-3) and autophagy (LC3B) to establish whether these markers are useful prognostic indicators following neoadjuvant therapy. Oesophageal adenocarcinoma tumour tissue from the Northern Ireland Biobank at Queens University Belfast was examined retrospectively. Tumours from 144 patients treated with platinum-based neoadjuvant chemotherapy followed by surgical resection were assembled into tissue microarrays prior to immunohistochemical analysis. Kaplan-Meier survival curves and log-rank tests were used to assess the impact of cleaved caspase-3 and LC3B expression on survival. Cox regression was used to examine association with clinical risk factors. High levels of cleaved caspase-3 were found in 14.6 % of patients and this correlated with a significantly better overall survival (p = 0.03). 38.9 % of patients had high cytoplasmic LC3B expression, which correlated with poor overall survival (p = 0.041). In addition, a distinct globular pattern of LC3B expression was identified in 40.3 % of patients and was also predictive of overall survival (p < 0.001). LC3B globular structures are also associated with tumour recurrence (p = 0.014). When these markers were assessed in combination, it was found that patients who showed low/negative cleaved caspase-3 staining and high/positive staining for both patterns of LC3B had the worst overall survival (p < 0.001). Multi-variate analysis also indicated that this marker combination was an independent predictor of poor prognosis (p = 0.008; HR = 0.046, 95% CI = (0.005-0.443). The expression of cleaved caspase-3 and specific LC3B staining patterns are associated with overall survival following neoadjuvant treatment. The combination of these markers is an independent indicator of outcome in neoadjuvant chemotherapy treated oesophageal adenocarcinoma.


Reversed spin of a ratchet motor on a vibrating water bed.
A ratchet gear on a vibrating water bed exhibits a one-way spin. However, the spinning direction is opposite to that of the gear placed on the granular bed. The one-way spin is caused by the surface waves of water. Surface deformation causes transportation of the water element to rotate the gear. The spatial symmetry of the surface wave and gear geometry regulates the rotational torque. In this study, the same ratchet shows reversed motion between the granular and water beds, and the direction is not determined only by the ratchet geometry. The self-organization of the fluid medium caused by small agitation induces a nontrivial inversion of the spinning direction.


Genome-wide heritability analysis of severe malaria resistance reveals evidence of polygenic inheritance.
Estimating single nucleotide polymorphism (SNP)-heritability (h2g) of severe malaria resistance and its distribution across the genome might shed new light in to the underlying biology. We investigated h2g of severe malaria resistance from a genome-wide association study (GWAS) dataset (sample size = 11 657). We estimated the h2g and partitioned in to chromosomes, allele frequencies and annotations using the genetic relationship-matrix restricted maximum likelihood approach. We further examined non-cell type-specific and cell type-specific enrichments from GWAS-summary statistics. The h2g of severe malaria resistance was estimated at 0.21 (se = 0.05, P = 2.7 × 10-5), 0.20 (se = 0.05, P = 7.5 × 10-5) and 0.17 (se = 0.05, P = 7.2 × 10-4) in Gambian, Kenyan and Malawi populations, respectively. A comparable range of h2g [0.21 (se = 0.02, P < 1 × 10-5)] was estimated from GWAS-summary statistics meta-analysed across the three populations. Partitioning analysis from raw genotype data showed significant enrichment of h2g in genic SNPs while summary statistics analysis suggests evidences of enrichment in multiple categories. Supporting the polygenic inheritance, the h2g of severe malaria resistance is distributed across the chromosomes and allelic frequency spectrum. However, the h2g is disproportionately concentrated on three chromosomes (chr 5, 11 and 20), suggesting cost-effectiveness of targeting these chromosomes in future malaria genomic sequencing studies. We report for the first time that the heritability of malaria resistance is largely ascribed by common SNPs and the causal variants are overrepresented in protein coding regions of the genome. Further studies with larger sample sizes are needed to better understand the underpinning genetics of severe malaria resistance.


Ethnicity and first-rank symptoms in patients with psychosis.
Previous studies suggested that African-American patients with psychotic disorders present more commonly with first-rank symptoms. However, it was unclear whether these results reflected true differences among African- and Euro-Americans in symptom presentation or instead resulted from raters being more likely to assign first-rank symptoms to African-American patients. In this study, a total of 195 African- and Euro-American patients presenting for hospitalization with psychosis were evaluated using structured diagnostic and symptom rating instruments; this evaluation was audiotaped. The tapes were transcribed and all cues indicating the patient's ethnicity were edited from the transcript and from medical records. Two board-certified psychiatrists then evaluated the transcripts and medical records in order to make consensus expert diagnosis and rate first-rank symptoms. Ratings of first-rank symptoms in African- and Euro-American patients were compared between ethnicity-blinded expert consensus assessments and the unblinded structured interview. African-American men received higher first-rank symptom ratings than the remaining patient groups by both ethnicity-blinded expert consensus and unblinded structured interview. African-American men also had significantly more total psychotic symptoms than Euro-American men. However, the ethnically blinded expert consensus did not find an increased rate of schizophrenia in the African-American men. These findings indicate that psychotic symptom presentation should be evaluated in the context of other symptoms (e.g., affective symptoms) in diagnostic assessments in order to prevent misdiagnoses of schizophrenia.


MRI safety management in patients with cardiac implantable electronic devices: Utilizing failure mode and effects analysis for risk optimization.
Cardiac implantable electronic devices (CIEDs) are increasing in prevalence. Exposing patients with CIEDs to magnetic resonance imaging (MRI) can lead to adverse outcomes. This has led certain radiology departments to not accept MRI referrals related to patients with CIEDs. Patients with MR-conditional CIEDs can be safely scanned under specific conditions. Our institution has accepted such referrals since 2014. The aim of this study was to systematically identify and reduce risk in our CIED-MRI protocol using failure mode and effects analysis (FMEA). A multidisciplinary FMEA team was assembled and included senior stakeholders from the CIED-MRI protocol. A process map was constructed followed by risk analysis and scoring. Targeted interventions were formulated and implemented; high-risk failure modes were prioritized. A new process map and protocol were drafted and repeat risk analysis was performed. Monitoring and re-evaluation of the CIED-MRI pathway were instigated at departmental quality assurance (QA) meetings. Interventions included direct CIED characterization using wireless technology pre-MRI, CIED programming and reprogramming in the MRI suite before and immediately after MRI reducing device downtime and continuous patient monitoring during MRI by a cardiac physiologist. The cumulative risk priority number (RPN) decreased from 1190 pre-FMEA to 492 post-FMEA. Despite the risk of exposing CIEDs to the MR environment, patients with MR-conditional CIEDs can be safely scanned with an appropriate multidisciplinary support. We found FMEA an indispensable tool in identifying and minimizing risk with no adverse events recorded since FMEA recommendations were implemented.


Embryo morphologic quality in relation to the metabolic and cognitive development of singletons conceived by in vitro fertilization and intracytoplasmic sperm injection: a matched cohort study.
Embryos with higher morphologic quality grading may have a greater potential to achieve clinical pregnancy that leads to a live birth regardless of the type of cleavage-stage embryos or blastocysts. Few studies have investigated the impacts of embryo grading on the long-term health of the offspring. This pilot study aimed to examine the associations between embryo morphologic quality and the physical, metabolic, and cognitive development of singletons conceived by in vitro fertilization and intracytoplasmic sperm injection at preschool age. This matched cohort study included singletons born to infertile couples who underwent fresh cleavage-stage embryo transfer cycles with good- or poor-quality embryos from 2014 to 2016 at the reproductive center of the Women's Hospital, School of Medicine, Zhejiang University. A total of 144 children, aged 4 to 6 years, participated in the follow-up assessment from 2020 to 2021, and the response rate of poor-quality embryo offspring was 39%. Singletons in the good-quality embryo group were matched with singletons in the poor-quality embryo group at a 2:1 ratio according to the fertilization method and the children's age (±1 year). We measured the offspring's height, weight, body mass index, blood pressure, thyroid hormone levels, and metabolic indicators. Neurodevelopmental assessments were performed using the Chinese version of the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition, and the Adaptive Behavior Assessment System, Second Edition. We also collected data from the medical records. A linear regression model was used to analyze the association between embryo morphologic quality and offspring health outcomes. A total of 48 singletons conceived with poor-quality embryo transfer and 96 matched singletons conceived with good-quality embryo transfer were included in the final analysis. Age, sex, height, weight, body mass index, blood pressure, thyroid function, and metabolic indicators were comparable between the 2 groups. After adjustment for potential risk factors by linear regression model 1 and model 2, poor-quality embryo offspring exhibited a tendency toward higher free thyroxine levels than offspring of good-quality embryo transfers (beta, 0.22; 95% confidence interval, 0.09-0.90; beta, 0.22; 95% confidence interval, 0.09-0.91, respectively), but this difference was not clinically significant. Regarding neurodevelopmental assessments, there was no difference in the full-scale intelligence quotient based on the Wechsler Preschool and Primary Scale of Intelligence (109.96±12.42 vs 109.60±14.46; P=.88) or the general adaptive index based on the Adaptive Behavior Assessment System (108.26±11.70 vs 108.08±13.44; P=.94) between the 2 groups. The subindices of the 2 tests were also comparable. These findings remained after linear regression analysis. At 4 to 6 years of age, singletons born from poor-quality embryo transfers have comparable metabolic and cognitive development as those born from good-quality embryo transfers using fresh cleavage-stage embryos. The results of this pilot study indicate that poor-quality embryos that can survive implantation and end in live birth are likely to have a developmental potential comparable to that of good-quality embryos.


Field measurements reveal exposure risk to microplastic ingestion by filter-feeding megafauna.
Microparticles, such as microplastics and microfibers, are ubiquitous in marine food webs. Filter-feeding megafauna may be at extreme risk of exposure to microplastics, but neither the amount nor pathway of microplastic ingestion are well understood. Here, we combine depth-integrated microplastic data from the California Current Ecosystem with high-resolution foraging measurements from 191 tag deployments on blue, fin, and humpback whales to quantify plastic ingestion rates and routes of exposure. We find that baleen whales predominantly feed at depths of 50-250 m, coinciding with the highest measured microplastic concentrations in the pelagic ecosystem. Nearly all (99%) microplastic ingestion is predicted to occur via trophic transfer. We predict that fish-feeding whales are less exposed to microplastic ingestion than krill-feeding whales. Per day, a krill-obligate blue whale may ingest 10 million pieces of microplastic, while a fish-feeding humpback whale likely ingests 200,000 pieces of microplastic. For species struggling to recover from historical whaling alongside other anthropogenic pressures, our findings suggest that the cumulative impacts of multiple stressors require further attention.


Circulating class II transplantation antigen-expressing T lymphocytes in children with insulin-dependent diabetes mellitus at diagnosis.
The occurrence of circulating class II antigen-expressing T lymphocytes was examined in 25 children with insulin-dependent diabetes mellitus using an indirect double immunofluorescence assay on prefixed cell samples. In order to exclude sensitization to heterologous insulin as a possible factor affecting the results, the patients were investigated at the day of clinical onset, before receiving insulin. An increased percentage of T cells (CD3+ cells) expressing class II antigens was seen in 19 out of 25 patients and class II expression was observed on cells within both the CD4+ and CD8+ T cell subsets. No correlation was found between the levels of class II expressing T cells and the individual degree of metabolic derangement or indicators of recent infection. Re-testing of 16 patients after one year on insulin treatment revealed a significant decrease of class II expressing T cell levels. Our data suggest that the increased levels of class II expressing T cells seen in IDDM of recent onset directly reflects immune reactions that are related to the disease process.


Quantitative magnetization transfer by trains of radio frequency pulses in human brain: extension of a free evolution model to continuous-wave-like conditions.
A theoretical model of free evolution between repeated magnetic transfer (MT) pulses was extended to continuous-wave (CW)-like conditions showing that only the repetitive "direct" saturation of bulk water changes the transient and stationary behavior. The influence of the pulse repetition period (PR) on progressive saturation was studied in cortical gray matter (GM) and central white matter (WM) under conditions of short periods of free evolution and strong macromolecular saturation. Interpulse delays of 3 ms were achieved in vivo on a 1.5-T MR system with bell-shaped MT pulses of 12-ms duration and nominal flip angles of up to 1440 degrees and single-shot readout by a stimulated echo acquisition mode localization sequence. The frequency offset was chosen between 1 and 3 kHz to avoid excessive direct saturation. The stationary MT ratio (MTR) followed an inverse linear PR dependence, showing a consistent partial saturation of about 90% at zero PR for both WM and GM. Comparison to a relaxation-matched liquid indicated the presence of MT, but not necessarily of direct saturation. The transient behavior indicated considerable direct saturation, but this could also be explained by MT. These inconsistencies showed that the intervals of time evolution in our experiments were too long to be modeled by CW-like conditions. Free evolution takes place during the whole PR rather than during the interpulse delay only. Quantification using the rates of free evolution theory yielded the saturations and rate constants necessary to explain the observed behavior. The theory of rapid CW-like pulsing provides an upper limit for the rate of progressive saturation. This limit is approached at PR below an estimated value of 5 ms. The phenomenological PR dependence of the steady-state MTR may indicate that MT exceeded the direct saturation. Unlike to an idealized CW experiment, the extrapolated value at zero PR is subject to direct effects and not a physically meaningful constant.


Direct repair of chronic distal biceps tendon tears.
To present the results from direct tendon repair using EndoButton and interference screws in patients with lesions of the distal biceps that had evolved over a period of more than 28 days. Between January 2012 and November 2013, eleven patients (all male) with a torn distal biceps and a time interval between injury and surgery of more than 28 days were evaluated. The patients' mean age was 46 years and the most common mechanism of injury was eccentric loading with the elbow flexed and supinated. A subjective analysis on pain and function was conducted using a visual analog scale of pain (VAS) and the Mayo Elbow Performance Score (MEPS), before and after surgery. The VAS showed a decrease of 5 points to 0.8 points on average. The MEPS improved from 69.3 points before the operation to 97.5 points afterwards. The mean flexion was 133.1° on the operated side, versus 134.3°. The mean extension was -2.5° and 0° (operated side versus non-operated). Supination was 88.2° versus 89.5° and pronation was 82.5° versus 84.1°, comparing the operated side versus the non-operated side. Flexion and supination strengths were evaluated with the aid of a dynamometer, and the mean flexion and supination strengths were found to be respectively 78.57% and 89.65% of the strength of the non-operated limb. Use of the technique of direct tendon repair using EndoButton and interference screws was shown to be a safe and effective alternative for repairing chronic lesions of the distal biceps.


Glucocorticoid dexamethasone reversibly complements EJ-RAS oncogene to transform mouse embryo BALB-3T3 cells.
EJ-A is a Balb-3T3 transfectant cell line that bears a small number of EJ-ras oncogene copies/cell, has low EJ-ras expression, and resembles the parental cell line in displaying a non-transformed phenotype. The glucocorticoid hormone dexamethasone reversibly induces transformation traits in EJ-A cells, namely: 1) morphological transformation; 2) increased growth rate and saturation density; 3) reduced G1 length; and 4) independence of the FGF requirement to initiate DNA synthesis. Western blot analysis revealed that dexamethasone does not increase the p21ras protein intracellular level. beta-IFN, added to the culture medium, does not suppress the dexamethasone-induced growth stimulation and morphological transformation. Therefore, glucocorticoid hormones can complement low EJ-ras expression to transform Balb-3T3 cells, by a mechanism that is likely to be independent of p21ras increase and beta-IFN decrease.


Insights into the anomalous heme pocket of rainbow trout myoglobin.
Rainbow trout myoglobin (Mb) is characterized by an unusually low affinity for oxygen, having a P(50) of 4.92±0.29 mm Hg at 25 °C which is the highest ever reported for any vertebrate Mb at the same temperature (Helbo and Fago, (2011) Am. J. Physiol. Regul. Integr. Comp. Physiol. 300, R101-R108). In order to gain insight into the structural factors of the heme pocket that may be important determinants for this atypical oxygen affinity, we have carried out an electronic absorption and resonance Raman characterization of the ferric and ferrous protein with and without exogenous ligands (O(2), CO, F(-)) and compared the results with those of other Mbs. While the ν(Fe-His) stretch appears at a frequency similar to other vertebrate Mbs, the resonance Raman frequencies of the Fe-ligand stretching modes reveal significant variations in the interaction of iron-bound ligands with distal residues. In particular, the spectroscopic characterization highlights two exceptional properties of rainbow trout Mb, a significantly higher level of reversed heme and reduced hydrogen bonding interactions between ligands and the distal HisE7 residue compared with other Mbs. The weakening of the hydrogen bond interaction is proposed to be the primary cause of the significantly reduced oxygen affinity.


A cytochrome c from a lupanine-transforming Pseudomonas putida strain is expressed in Escherichia coli during aerobic cultivation and efficiently exported and assembled in the periplasm.
We have cloned, sequenced, and heterologously expressed a periplasmic cytochrome c from a lupanine-utilizing Pseudomonas putida strain. Aerobic batch cultivation of Escherichia coli TB1 harboring the cytochrome c gene placed downstream of the lac promoter in pUC9 vector resulted in significant production of the holo-cytochrome c in the periplasm ( approximately 4 mg of hemoprotein/liter of culture). The recombinant cytochrome c was purified to homogeneity and was found to be functional in accepting electrons from lupanine hydroxylase while catalyzing hydroxylation of lupanine. Comparison of the N-terminal amino acid sequence of the isolated cytochrome c with that deduced from the DNA sequence indicated that the signal sequence was processed at the bond position predicted by the SigPep program. The molecular size of the cytochrome c determined by electrospray mass spectrometry (9,595) was in precise agreement with that predicted from the nucleotide sequence.


Fatty acid specificity in the inhibition of cell proliferation and its relationship to lipid peroxidation and prostaglandin biosynthesis.
Primary cultures of smooth muscle cells were established from the medial layer of guinea pig aorta. Cells at passage level 4 were treated with different series of fatty acids belonging to the n-9, n-6 and n-3 families. Lipid peroxidation was measured by the thiobarbituric acid assay and prostaglandin biosynthesis was measured by the radioimmunoassay of PGE and 6-keto-PGF1 alpha. Cell proliferation was estimated from the total cell number of cultures seeded at low density. 18:1(n-9) did not form lipid peroxides and this fatty acid stimulated cell proliferation. All fatty acids which generated lipid peroxides inhibited cell proliferation, but inhibition was correlated with the degree of lipid peroxidation only in the n-9 fatty acid family. 22:4(n-6) and 22:6(n-3) inhibited prostaglandin biosynthesis. 18:2(n-6), 18:2(n-9), 18:3(n-3), 20:2(n-9), 20:3(n-3) and 20:5(n-3) had no effect on prostaglandin biosynthesis. 18:3(n-6), 20:3(n-6) and 20:4(n-6) generated prostaglandins. 20:3(n-9) generated metabolites with prostaglandin immunoreactivity. The inhibition of cell proliferation did not correlate with enhanced or inhibited prostaglandin synthesis. The inhibition of cell proliferation was related to the structures of the different polyunsaturated fatty acid families decreasing in the order n-9 greater than n-6 greater than n-3. Eicosatrienoic acids were the most effective inhibitors of cell proliferation in each fatty acid family and 20:3(n-9) was the most potent eicosatrienoic acid. These data show that specific as yet unrecognized products of fatty acid metabolism are responsible for the inhibition of cell proliferation.


A method for direct in vivo measurement of drug concentrations from a single 2H NMR spectrum.
The use of 2H-labeled drugs provides a measure of drug concentration in situ directly from a single 2H NMR spectrum obtained with any antenna by correcting only for differential saturation effects. The limit of detection for a drug labeled with three equivalent deuterons is roughly 0.5 mM.


N6-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling.
Accumulating evidence suggests that the primary and acquired resistance of hepatocellular carcinoma (HCC) to sorafenib is mediated by multiple molecular, cellular, and microenvironmental mechanisms. Understanding these mechanisms will enhance the likelihood of effective sorafenib therapy. In vitro and in vivo experiments were performed and clinical samples and online databases were acquired for clinical investigation. In this study, we found that a circular RNA, circRNA-SORE, which is up-regulated in sorafenib-resistant HCC cells, was necessary for the maintenance of sorafenib resistance, and that silencing circRNA-SORE substantially increased the efficacy of sorafenib-induced apoptosis. Mechanistic studies determined that circRNA-SORE sequestered miR-103a-2-5p and miR-660-3p by acting as a microRNA sponge, thereby competitively activating the Wnt/β-catenin pathway and inducing sorafenib resistance. The increased level of circRNA-SORE in sorafenib-resistant cells resulted from increased RNA stability. This was caused by an increased level of N6-methyladenosine (m6A) at a specific adenosine in circRNA-SORE. In vivo delivery of circRNA-SORE interfering RNA by local short hairpin RNA lentivirus injection substantially enhanced sorafenib efficacy in animal models. This work indicates a novel mechanism for maintaining sorafenib resistance and is a proof-of-concept study for targeting circRNA-SORE in sorafenib-treated HCC patients as a novel pharmaceutical intervention for advanced HCC.


Floral nectar reabsorption and a sugar concentration gradient in two long-spurred Habenaria species (Orchidaceae).
Floral nectar is the most common reward flowers offered to pollinators. The quality and quantity of nectar produced by a plant species provide a key to understanding its interactions with pollinators and predicting rates of reproductive success. However, nectar secretion is a dynamic process with a production period accompanied or followed by reabsorption and reabsorption remains an understudied topic. In this study, we compared nectar volume and sugar concentration in the flowers of two long-spurred orchid species, Habenaria limprichtii and H. davidii (Orchidaceae). We also compared sugar concentration gradients within their spurs and rates of reabsorption of water and sugars. Both species produced diluted nectar with sugar concentrations from 17 to 24%. Analyses of nectar production dynamics showed that as flowers of both species wilted almost all sugar was reabsorbed while the original water was retained in their spurs. We established a nectar sugar concentration gradient for both species, with differences in sugar concentrations at their spur's terminus and at their spur's entrance (sinus). Sugar concentration gradient levels were 1.1% in H. limprichtii and 2.8% in H. davidii, both decreasing as flowers aged. We provided evidence for the reabsorption of sugars but not water occurred in wilted flowers of both Habenaria species. Their sugar concentration gradients vanished as flowers aged suggesting a slow process of sugar diffusion from the nectary at the spur's terminus where the nectar gland is located. The processes of nectar secretion/reabsorption in conjunction with the dilution and hydration of sugar rewards for moth pollinators warrant further study.


Modification of cardiopulmonary hemodynamics and vasoactive mediators by extracorporeal membrane oxygenation in newborn lambs.
We asked if prolonged venoarterial extracorporeal membrane oxygenation (ECMO) causes alterations in cardiopulmonary hemodynamics that might be reflected in arbiters of vascular tone: thromboxane, prostacylin, norepinephrine, and epinephrine. Newborn lambs undergoing ECMO demonstrated significant augmentation of systemic and pulmonary arterial blood pressure that was temporally related to rises in all vasoactive mediators measured. Although the prostanoids returned to baseline within 30 minutes, the catecholamines remained elevated significantly throughout bypass. Long-term bypass, however, was not associated with sustained systemic hypertension. Pulmonary hypertension was achieved only after 6 hours of bypass. These acute and chronic changes may exacerbate a pathological state for which ECMO is indicated.


A secreted placental alkaline phosphatase-based reporter assay system for screening of compounds acting at an octopamine receptor stably expressed in a mammalian cell line.
Octopamine receptors are attractive insecticide targets. To screen compounds acting at octopamine receptors simply and rapidly, we constructed a chemiluminescent reporter gene assay system that detects secreted placental alkaline phosphatase transcriptionally regulated by the cAMP response element for a silkworm octopamine receptor. This system proved useful in high-throughput screening to develop octopamine receptor-specific insecticides.


[Different treatments on the prognosis of poor-grade aneurysmal subarachnoid hemorrhage patients].
To compare the outcomes of surgical clipping, interventional treatment and conservative treatment of poor-grade aneurysm patients. A total of 119 patients of WFNS (World Federation of Neurosurgical Societies) grades IV (n=73) and V (n=46) from June 2004 from to December 2011 were analyzed. There were 51 males and 68 female with a mean age of 55.2 years (range: 32-77). The approaches included surgical clipping (n=57), interventional embolization (n=40) and conservative treatment (n=22). Their outcome were assessed with a 3-month follow-up according to the Glasgow outcome score (GOS). In surgical clipping group, the prognoses were excellent (5-4 points, n=22), poor prognosis (3-2 points, n=30) and death (1 point, n=5); excellent (n=26), poor (n=1) and death (n=13) in interventional embolization group; excellent (n=0), poor (n=3) and death (n=19) in conservative treatment. The excellent outcome of interventional embolism was better than those of surgical clipping and conservative treatment (P<0.05), but it had higher mortality than surgical clipping (P<0.05). In conservative treatment group, mortality was significantly higher than the first two groups (P<0.05). For patients of grade IV, surgical clipping and interventional embolization may be selected; for those of grade V, interventional embolization can be used as a first choice; for those of grade IV/V with large intracerebral hematoma (hematoma volume>30 ml), surgical clipping is preferred.


Pregnancy and birth outcomes following fresh or vitrified embryo transfer according to blastocyst morphology and expansion stage, and culturing strategy for delayed development.
How do live birth rates (LBRs), following fresh and vitrified/warmed embryo transfer, compare according to morphological grade, developmental stage and culturing strategy of human blastocysts in vitro? Equivalent LBRs were obtained after fresh embryo transfer and after vitrified/warmed embryo transfer of blastocysts of top or non-top quality, while vitrification after prolonged embryo culture of blastocysts with delayed development had a positive impact on LBR. Blastocyst morphology correlates with clinical outcome; however, few data are available on vitrified/warmed embryo transfer using non-top quality blastocysts. The aim of this study was to determine clinical outcomes of non-top quality blastocysts and blastocysts with delayed development that underwent vitrified/warmed embryo transfer. This retrospective, single-centre study (conducted January 2009 to June 2013) compared 1010 fresh embryo transfer and 1270 vitrified/warmed embryo transfer of blastocysts originating from the same stimulation cycle. Furthermore, 636 fresh embryo transfers and 304 vitrified/warmed embryo transfer after delayed expansion or blastulation in the same period were also analysed. Clinical outcomes after fresh and vitrified/warmed embryo transfer according to blastocyst morphology were compared in both groups. Similar LBRs after fresh embryo transfer or after vitrified/warmed embryo transfer of top or non-top quality blastocysts were observed. A statistically significant improvement in clinical outcomes was obtained after vitrified/warmed embryo transfer of Day 5 embryos with delayed expansion or blastulation when applying prolonged culture. Our study suggests that vitrification of non-top quality blastocysts as well as delayed cavitating and blastulating Day 5 embryos should be considered in autologous IVF cycles. Given that the present retrospective study used aseptic vitrification of blastocysts, the results, particularly the survival rates, may not be fully applicable to other vitrification protocols. The retrospective nature of the study has to be mentioned. Restriction of vitrification to top quality blastocysts may result in discarding potentially viable embryos. This study was not externally funded. There are no conflicts of interest to declare.


Protective effects of Devosia sp. ANSB714 on growth performance, immunity function, antioxidant capacity and tissue residues in growing-finishing pigs fed with deoxynivalenol contaminated diets.
This study aimed to investigate the toxic effects of deoxynivalenol (DON) and the effectiveness of Devosia sp. ANSB714 for alleviation of DON toxicosis in growing-finishing pigs. A total of twenty pigs were allocated equally to four treatments for 18 days: CON (basal diet formulated with normal rice), Devosia sp. ANSB714 (CON + Devosia sp. ANSB714), DON (toxic diet formulated with DON-contaminated rice), and DON + Devosia sp. ANSB714. The treatments of Devosia sp. ANSB714 and DON + Devosia sp. ANSB714 were given the fermentation liquor of Devosia sp ANSB714 by drinking water. DON-contaminated diet significantly decreased the average daily gain of growing-finishing pigs. Serum IgA content was significantly increased in DON treatment compared with that in CON. Besides, DON in diet also significantly reduced the activities of GSH-Px in the liver and serum of pigs. Supplementation of Devosia sp. ANSB714 in drinking water effectively prevented these adverse effects of DON on pigs. Moreover, the DON residues in the serum, liver and kidney were significantly decreased with the addition of Devosia sp. ANSB714 to diet contaminated with DON. Taken together, it is effective to feeding Devosia sp. ANSB714 to pigs fed with diet contaminated with DON and ameliorating DON toxicosis of pigs.


Self-amplifying mRNA vaccines: Mode of action, design, development and optimization.
The mRNA-based vaccines are quality-by-design (QbD) immunotherapies that provide safe, tunable, scalable, streamlined and potent treatment possibilities against different types of diseases. The self-amplifying mRNA (saRNA) vaccines, as a highly advantageous class of mRNA vaccines, are inspired by the intracellular self-multiplication nature of some positive-sense RNA viruses. Such vaccine platforms provide a relatively increased expression level of vaccine antigen(s) together with self-adjuvanticity properties. Lined with the QbD saRNA vaccines, essential optimizations improve the stability, safety, and immunogenicity of the vaccine constructs. Here, we elaborate on the concepts and mode-of-action of mRNA and saRNA vaccines, articulate the potential limitations or technical bottlenecks, and explain possible solutions or optimization methods in the process of their design and development.


An update on microcrystalline cellulose in direct compression: Functionality, critical material attributes, and co-processed excipients.
Microcrystalline cellulose (MCC) is one of the most popular cellulose derivatives in the pharmaceutical industry. Thanks to its outstanding tabletability, MCC is generally included in direct compression (DC) tablet formulations containing poor-tabletability active pharmaceutical ingredients. Nowadays, numerous grades of MCC from various brands are accessible for pharmaceutical manufacturers, leading to variability in MCC properties. Hence, it seems to be worthy and urgent to evaluate the influences of MCC variability on tablet quality and to identify critical material attributes (CMAs) based on the idea of Quality by Control. Besides, MCC-based co-processed excipients can effectively combine the functions of the filler, binder, disintegrant, lubricant, glidant, or flavor, and thus have drawn extensive interest. In this review, we focused specifically on the recent advances and development of MCC on DC tableting, including the functions in tablet formulations, potential CMAs, and MCC-based co-possessed excipients, therefore providing a reference for further studies.


Laboratory monitoring to reduce adverse drug-related events: a mixed methods study.
BACKGROUND: Therapy with angiotensinconverting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) requires laboratory monitoring to avoid hyperkalemia and acute kidney failure. OBJECTIVE: To assess the frequency of recommended annual serum potassium and creatinine monitoring and determine potential factors associated with care gaps among adults dispensed an ACEI or ARB. METHODS: This mixed-methods study integrated findings from a retrospective cohort study and individual patient interviews. Adults aged 21 years and over within Kaiser Permanente Southern California with at least 180 treatment days of an ACEI and/or ARB in 2015 were included. Patients invited for qualitative interviews included those who did and did not complete the recommended laboratory tests. We assessed the proportion of patients completing both recommended laboratory tests, factors associated with not receiving laboratory monitoring, and patients' insights into barriers and facilitators of recommended monitoring. RESULTS: Of 437,544 patients who received an ACEI or ARB, 9.0% did not receive both a serum potassium and creatinine laboratory test during treatment (defined as a care gap). Lower risk of a care gap was observed for patients with increasing age (rate ratio [RR] per 10-year increase = 0.78, 95% CI = 0.77-0.79); diabetes mellitus (RR = 0.62, 95% CI = 0.60-0.64); hypertension (RR = 0.71, 95% CI = 0.71-0.74); Charlson Comorbidity Index score of at least 2 (RR = 0.62, 95% CI = 0.60-0.64); those who changed medication classes (RR = 0.53, 95% CI = 0.51-0.56); and patients with a cardiologist (RR = 0.81, 95% CI = 0.73-0.90) or nephrologist (RR = 0.60, 95% CI = 0.52-0.69) as their prescribing provider. Twenty-five patients completed the qualitative interviews. Patients often lacked knowledge about the need for laboratory monitoring, cited logistical barriers to accessing the laboratory, and deemed the reminders they received through an outpatient safety program as a facilitator to completing tests. CONCLUSIONS: Given the large patient population on ACEI and ARB medications, monitoring and support strategies such as electronic clinical surveillance could be important in addressing care gaps and potentially reducing adverse drug effects. DISCLOSURES: This project was supported by grant number R01HS024437 from the Agency for Healthcare Research and Quality. The funder had no role in the design of the study; collection, analyses, or interpretation of the data, or decision to submit this manuscript for publication. Harrison, Reynolds, Hahn, Munoz-Plaza, Yi, Fischer, Luong, Sim, Brettler, Handler, and Mittman are employees of the Southern California Permanente Medical Group. Danworth was employed by the Southern California Permanente Medical Group at the time of this study. Singh was partially supported by the Houston VA HSR&D Center for Innovations in Quality, Effectiveness and Safety (CIN13-413). Reynolds reports grants from Novartis, Amgen Inc., and Vital Strategies, Resolve to Save Lives, unrelated to this work. Yi reports grants from Novartis unrelated to this work. Kanter has nothing to disclose.


Effects of Echinostoma trivolvis (trematoda) infection on metallic ions in the host snail Helisoma trivolvis (gastropoda).
Flame and graphite-furnace atomic absorption spectrometry and inductively coupled plasma atomic emission spectrometry were used to study the metallic ions in the digestive gland-gonad complex (DGG) of Helisoma trivolvis snails infected with the daughter rediae of Echinostoma trivolvis and in uninfected DGG. Seven metals were found to be present in infected and uninfected DGG at concentrations above the detection limits of the analytical methods. Of these, sodium was present in significantly higher amounts (Student's t-test, confidence level of 95%) in the infected versus uninfected DGG; magnesium and manganese occurred in significantly lower amounts in the infected DGG. Our results were compared with those from a Bulgarian study in which neutron activation analysis was used to determine elements in Lymnaea stagnalis snails infected with the intramolluscan stages of the 37-collar-spined echinostome E. revolutum. The Bulgarian study also reported a significant elevation of sodium but reduction of zinc in the hepatopancreas (i.e., digestive gland) of infected snails. Other differences between the two studies are discussed.


Nucleation of biomimetic Ca-P coatings on ti6A14V from a SBF x 5 solution: influence of magnesium.
Biomimetic Calcium-Phosphate (Ca-P) coatings were applied by using 5 times concentrated Simulated Body Fluid (SBF x 5) using Carbon Dioxide gas. This process allows the deposition of a uniform Ca-P coating within 24 h. A previous study of our process emphasized the importance of hydrogenocarbonate ions (HCO-3), a crystal growth inhibitor. The aim of the present study was to investigate the role of the other crystal growth inhibitor present in SBF x 5, Magnesium (Mg2+), on the Ca-P coating formation. Several SBF x 5 solutions were prepared with various Mg2+ and HCO3 contents. No Ca-P deposits were detected on Ti6A14V substrate soaked for 24h in a Mg-free SBF x 5 solution, whereas by increasing HCO-3 content in a Mg-free SBF x 5 solution, a Ca-P coating developed on Ti6A14V substrate. Therefore, it appeared that Mg2+ has a stronger inhibitory effect on apatite crystal growth than HCO-3. Nevertheless, Mg2+ plays also another important role as suggested by depth profile X-ray Photoelectron Spectroscopy (XPS) of the Ca-P coating obtained from SBF x 5 solution. Ca2+ and Mg2+ contents increased significantly at the titanium/coating interface. Therefore, Ca2+ and Mg2+ initiated Ca-P coating from SBF x 5 solution. The relatively high interfacial concentration in Mg2+ favors heterogeneous nucleation of tiny Ca-P globules onto the substrate. So physical adhesion is enhanced at the early stage of the coating formation.


Early warning signs of fatal heart attacks 'being missed' in hospitals.
Symptoms may have been missed in up to one in six patients who died of a heart attack in hospital in England, new study results suggest.


Autogenous internal iliac artery bypass in the surgical treatment of renovascular hypertension: a case report.
A 24 year old female with severe renovascular hypertension resulting from bilateral fibromuscular dysplasia was successfully treated surgically. The internal iliac artery was used for a left aortorenal grafts. The right renal artery was dilated through the amputated left renal stump. Although saphenous vein graft is most commonly used, the autogenous internal iliac artery is considered a satisfactory graft in aortorenal reconstruction, especially for a young patient.


Phytoextraction potential of Pteris vittata L. co-planted with woody species for As, Cd, Pb and Zn in contaminated soil.
The objective of this study was to determine the phytoextraction potential of a hyperaccumulator co-planted with a large biomass of woody plant in metal(loid)-contaminated soil. A pot experiment was conducted for 270 days (d) to study the growth, physiological responses, and metal(loid)s accumulation characteristics of plants, which included a shade-requiring, As-hyperaccumulator perennial herb, Pteris vittata L., co-planted with a woody tree, namely Morus alba L. or Broussonetia papyrifera L., for soil contaminated with arsenic (As), cadmium (Cd), lead (Pb), and zinc (Zn). The results showed that the biomass, photosynthetic pigment contents, antioxidant enzyme activity, and uptake of As in P. vittata L. were significantly enhanced by co-planting with M. alba L. or B. papyrifera L. Especially, the uptake of As by P. vittata L. was significantly (p < 0.05) increased by 80.0% and 64.2% when it was co-planted with M. alba L. or B. papyrifera L., respectively, while the As, Cd, Pb, and Zn contents of both M. alba L. and B. papyrifera L. were not significantly promoted by the co-planting. The comprehensive phytoextraction of metal(loid)s could be optimized by the co-planting of P. vittata L. with M. alba L. or B. papyrifera L. The total amount of As in the shoots from co-planting species was significantly (p < 0.05) higher than that of the monoculture with M. alba L. or B. papyrifera L., and that of Cd and Zn in the shoots was significantly (p < 0.05) higher than that of the monoculture with P. vittata L. The results showed that the co-planting of P. vittata L. with M. alba L. or B. papyrifera L. can alleviate the toxic effects of metal(loid)s on plant growth and improve the comprehensive phytoextraction amounts of metal(loid)s, and is a promising strategy for remediation of metal(loid)-contaminated soil.


Correction: Associations of sexually transmitted infections and bacterial vaginosis with abnormal cervical cytology: A cross-sectional survey with 9090 community women in China.
[This corrects the article DOI: 10.1371/journal.pone.0230712.].


Senolytic agent Quercetin ameliorates intervertebral disc degeneration via the Nrf2/NF-κB axis.
Intervertebral disc degeneration (IDD) represents major cause of low back pain. Quercetin (QUE) is one of the approved senolytic agents. In this study, we evaluated the protective effects of QUE on IDD development and its underlying mechanism. Effects of senolytic agent QUE on the viability of nucleus pulposus cells (NPCs) were measured by CCK-8 assays and EdU staining. The senescence associated secreted phenotype (SASP) factors expressions were measured by qPCR, western blot, and ELISA; and NF-κB pathway was detected by immunofluorescence and western blot. Molecular docking was applied to predict the interacting protein of QUE; while Nrf2 was knocked down by siRNAs to confirm its role in QUE regulated senescence phenotype. X-ray, MRI, Hematoxylin-Eosin and Safranin O-Fast green staining were performed to evaluate the therapeutic effects of QUE on IDD in the puncture-induced rat model. In in vitro experiments, QUE inhibited SASP factors expression and senescence phenotype in IL-1β-treated NPCs. Mechanistically, QUE suppressed IL-1β induced activation of the NF-κB pathway cascades; it was also demonstrated in molecular docking and knock down studies that QUE might bind to Keap1-Nrf2 complex to suppress NF-κB pathway. In vivo, QUE ameliorated the IDD process in the puncture-induced rat model. Together the present work suggests that QUE inhibits SASP factors expression and senescence phenotype in NPCs and ameliorates the progression of IDD via the Nrf2/NF-κB axis, which supports senolytic agent QUE as a potential therapeutic agent for the treatment of IDD.


Atorvastatin therapy may reduce the incidence of sudden cardiac death in patients with advanced chronic heart failure.
In retrospective studies, statin therapy has been related to decreased incidence of sudden cardiac death (SCD) in heart failure. We sought to prospectively investigate a relation between atorvastatin therapy and SCD in patients with advanced chronic heart failure. We enrolled 110 patients with heart failure with a left ventricular ejection fraction less than 30% and cholesterol level greater than 150 mg/dL. Fifty-five patients were randomized to atorvastatin (10 mg/day) (statin group); the remaining 55 patients received no statins (controls). Patients were followed for 1 year. At baseline, the two groups did not differ in age, sex, left ventricular ejection fraction, cholesterol, B-type natriuretic peptide, heart rate variability, or QT variability. During follow-up, 29 patients died (26%) and 2 patients (2%) underwent heart transplantation. Of the 29 deaths, 13 were attributed to pump failure, 15 were attributed to SCD, and 1 was attributed to noncardiac causes. All-cause mortality was lower in the statin group (9/55, 16%) than in controls (20/55, 36%) (P = .017). The same was true of the SCD rate (3/55 [5%] vs. 12/55 [22%], P = .012), but not of the pump failure (5/55 [9%] vs. 8/55 [15%], P = .38). SCD-free survival was 2.3-times higher in the statin group than in controls (P = .01). Atorvastatin therapy seems to be associated with decreased incidence of SCD in patients with advanced chronic heart failure. Larger studies are ongoing to confirm this hypothesis.


MicroRNA and gynecological cancers: Focus on miR-195.
Different cancer types have been shown to have down-regulated expression levels of miR-195 as an anti-tumor agent. MiR-195 family members can inhibit cancer cell proliferation, angiogenesis, epithelial-mesenchymal transition and metastases, immunosuppression, glycolysis, drug resistance, and cancer stem cell development by targeting the 3'-UTR of the mRNA of different pro-tumor genes. MiR-195 identified as a tumor suppressor miR in a variety of cancers, most notably gynecological malignancies such as cervical, endometrial, and ovarian carcinoma. As a result, restoring miR-195 expression should be regarded as a potential therapy for either prevention or treatment of gynecological cancers. This review will present the most recent data about miR-195-mediated anti-tumor effects in gynecological malignancies, emphasizing its downstream signaling pathways and target genes, as well as prospective treatment techniques.


Personality characteristics of father/perpetrators and nonoffending mothers in incest families: individual and dyadic analyses.
Clinical reports suggest that mothers and fathers in incestuous families exhibit characteristic personality traits. Typically the father/perpetrator is described as powerful and domineering, the mother weak and submissive. The present study examined individual personality characteristics of 65 nonoffending mothers and 94 father/perpetrators, and used canonical correlations and multiple regression analyses to examine patterns of personality traits occurring in 63 pairs of fathers and mothers in which there was acknowledged child sexual abuse by the fathers. At the individual level, a minority of both mothers and offenders differed from norms on traits reflecting social inadequacy, but no personality deviations were prototypical in either group. At the dyadic level, no evidence for a pervasive "dominant-submissive" pairing was found. Results indicated that father/perpetrator traits tended to be similar to traits of nonoffending mothers. Forensic, clinical, and research implications of the findings are discussed.


Arsenic removal from water employing heterogeneous photocatalysis with TiO2 immobilized in PET bottles.
Arsenic oxidation (As(III) to As(V)) and As(V) removal from water were assessed by using TiO2 immobilized in PET (polyethylene terephthalate) bottles in the presence of natural sunlight and iron salts. The effect of many parameters was sequentially studied: TiO2 concentration of the coating solution, Fe(II) concentration, pH, solar irradiation time; dissolved organic carbon concentration. The final conditions (TiO2 concentration of the coating solution: 10%; Fe(II): 7.0 mg l(-1); solar exposure time: 120 min) were applied to natural water samples spiked with 500 microg l(-1) As(III) in order to verify the influence of natural water matrix. After treatment, As(III) and total As concentrations were lower than the limit of quantitation (2 microg l(-1)) of the voltammetric method used, showing a removal over 99%, and giving evidence that As(III) was effectively oxidized to As(V). The results obtained demonstrated that TiO2 can be easily immobilized on a PET surface in order to perform As(III) oxidation in water and that this TiO2 immobilization, combined with coprecipitation of arsenic on Fe(III) hydroxides(oxides) could be an efficient way for inorganic arsenic removal from groundwaters.


Dlg4 and Vamp2 are involved in comorbid epilepsy and attention-deficit hyperactivity disorder: A microarray data study.
Children with epilepsy exhibit a significantly higher risk for attention-deficit hyperactivity disorder (ADHD), which is often associated with lower quality of life. In this study, we aimed to identify molecular mechanisms associated with both epilepsy and ADHD. Gene expression profiles of GSE12457 and GSE47752 were downloaded from the gene expression omnibus (GEO) database. Differentially expressed genes (DEGs) were separately screened in epilepsy and ADHD samples and compared with controls. Weighted gene coexpression network analysis (WGCNA) was used to identify candidate modules associated with the two disorders. Functional annotation and analysis of hub genes and molecular complex detection (MCODE) was also performed. Three modules closely related to epilepsy and ADHD were screened using WGCNA; DEGs in this module were involved in the synaptic vesicle cycle, axon and neuron regeneration, and neurotransmission. The Dlg4 and Vamp2 genes were selected as common candidate factors in epilepsy and ADHD pathogenesis. Dlg4 and Vamp2 could play essential roles in comorbidity between epilepsy and ADHD.


[Epidemiological study of intrapelvic venous congestion syndrome (IVCS) using new IVCS symptom score].
The pathophysiology of prostatodynia still remains unknown. Recently, it was reported using three dimentional magnetic resonance venography (3D-MRV) that intrapelvic venous congestion (IVC) was found predominantly in patients with prostatodynia, and was designated this condition as IVC syndrome (IVCS). The present study was designed to reveal the prevalence of IVCS in taki drivers and office workers. A total of 605 men (584 drivers and 21 office workers) in a taxi company in Kyoto city was enrolled in this study. They completed the IVCS symptom score, which was developed originally, including 5 questions (pain or discomfort at 1: the urethra during voiding, 2 lower abdomen, 3: perineal region, 4: inguinal region, 5: during ejaculation). The score of each question was graded from 0 to 5 points, and a total symptom score was obtained by adding these 5 scores to give a range of 0 to 25 points. 3D-MRV was performed to evaluate IVC. The diagnosis of IVC was determined based on the findings of the dilation of the prostatic capsular vein and/or the venous plexus of the lateral ligament of the bladder. Out of 603 men, 494 (81.9%), 40 (6.6%), 30 (5.0%) and 39 (6.5%) had a total symptom score of 0,1,2 and 3 or more. 3D-MRV was performed in 16 symptomatic men (scores of 3 or more), demonstrating IVC in 7 of them (43.8%). These 7 men were considered to have IVCS. In contrast, IVC was recognized in only one (6.3%) of 16 asymptomatic men (score of 0), were selected at random from 494 men scored 0 (p < 0.05). IVCS symptom score could be used as a screening tool for the detection of IVCS.


Partition of inorganic ions and phospholipids in isolated cell, membrane and matrix vesicle fractions: evidence for Ca-Pi-acidic phospholipid complexes.
Electrolytes and phospholipids of cartilage fractions were partitioned by extraction with organic and aqueous solvents into six solubility groups: Electrolytes I, II and III, and Lipids I, II and III. Of the total Ca, only 4% was water soluble (Electrolytes I); 4-12% was complexed with lipids (Electrolytes II); while the majority (84-92%) was insoluble (Electrolytes III). In contrast, nearly half of the Mg and Pi were water soluble. Of the neutral phospholipid, 95% was not complexed with mineral ions (Lipids I), but 30-45% of the acidic phospholipid was (Lipids II). Ca/Pi ratios were extremely low in the water-soluble phase, but were in the range of amorphous calcium phosphate (ACP) in the insoluble. Molar ratios of the lipid-mineral complex were: Ca:Mg:Pi:acidic phospholipid, 4:3:2:2. Mg/Ca ratios in the soluble fraction were high (5.5-8.9), sufficient to stabilize ACP. Kinetic studies revealed rapid turnover of soluble Ca, insoluble turning over much more slowly. Labeling of lipid-complexed Ca was rapid in cells, but occurred later in matrix vesicles, suggesting transfer. While lipid-Ca-Pi complexes can nucleate apatite in vitro, those present in vivo inside matrix vesicles apparently do not because of the excess Mg. We conclude therefore, that in vesicle-mediated calcification, lysis of the membrane may be essential to allow release of internal Mg.


Ventricular septal defect associated with left ventricular outlfow tract obstruction below the defect.
Muscular subaortic stenosis associated with ventricular septal defect (VSD) is a rare but important anomaly. Two types of left ventricular outflow tract (LVOT) obstruction should be distinguished on the basis of morphologic as well as hemodynamic differences, depending on whether the stenosis is localized above (Type I) or below (Type II) the defect. The five cases presented are all in the latter category. In the first two cases the correct diagnosis was not made until after repair of the VSD. Two patients had previously undergone banding of the pulmonary artery (PAB). Marked carotid shudder and a vertical QRS axis in the frontal plane were presented in all cases. For the diagnosis to be established by catheterization, the catheter tip must be maneuvered into the apical part of the left ventricular cavity in order to detect the stenosis on the withdrawal curve. It is difficult to visualize the stenosis by angiography. The surgical approach through the VSD via a right atriotomy is highly recommended for Type II subaortic stenosis.


Long-term efficacy of imatinib for treatment of metastatic GIST.
Imatinib is an effective and approved treatment for advanced gastrointestinal stromal tumor (GIST). Continuous imatinib treatment is recommended by current guidelines. This review summarizes the long-term efficacy and safety of imatinib for patients with metastatic GIST. Key clinical studies were reviewed-including B2222, S0033, and BFR14-with particular emphasis on recently reported results of the long-term clinical outcome of imatinib for metastatic GIST. The B2222 and S0033 studies recently reported 10-year follow-up results that demonstrate the long-term efficacy of imatinib. Furthermore, results from the BFR14 study demonstrate that imatinib treatment should not be interrupted and that the efficacy of imatinib following reintroduction is inferior compared with the continuous administration group. The S0033 study also supports the importance of dose optimization and dose escalation of imatinib in patients with KIT exon 9 mutations or progressive disease. These studies demonstrate that individual patient characteristics should be evaluated for optimal patient management. Managing adverse events proactively is very important to maintain compliance. The results from these studies demonstrate that long-term imatinib extends survival in patients with advanced GIST. Furthermore, these studies support the safety of long-term imatinib therapy in this patient population.


Wallenberg's lateral medullary syndrome with loss of pain and temperature sensation on the contralateral face: clinical, MRI and electrophysiological studies.
Thirteen patients with Wallenberg's lateral medullary syndrome (WLMS) were studied. Clinical and magnetic resonance imaging (MRI) evidence demonstrated infarction in the dorsolateral medulla which produced loss of pain and temperature sensation on one side of the face ipsilateral to the lesion in seven patients. However, in another six patients, the infarction in a similar location produced the same sensory loss on the contralateral face. This is the first report of an analysis comparing these two conditions in WLMS patients, confirmed by MRI. The finding of normal blink reflex and somatosensory evoked potentials (stimulation on median nerve) in the two groups of patients may indicate that the impulses travel along the central pathways of touch, vibration and joint position sensation instead of the pathways for pain and temperature, because the patients had normal sensation of touch, vibration and joint position but impairment of pain and temperature sensation. In addition, it is suggested that the pathways of late blink reflex (R2) pass through the medial lemniscus in the ventromedial medulla instead of the spinal trigeminal tract in the dorsolateral medulla. Further, the observation of the much longer lantencies (about 29 ms) of the normal R2 raises the possibility that the impulses may travel along the longer pathways through the opposite medial lemniscus and up to the thalamus or cortex where they project to bilateral motoneurons of the orbicularis oculi muscles. Although the alternative of R2 travelling only by the shorter pathways through the brain stem is not excluded, this is not supported by current data.


Multiple high-regional-incidence cardiac disease diagnosis with deep learning and its potential to elevate cardiologist performance.
Currently, due to lack of large-scale datasets containing multiple arrhythmias and acute coronary syndrome-related diseases, AI-aided diagnosis for cardiac diseases is limited in clinical scenarios. Whether AI-based ECG diagnosis can assist cardiologists to improve performance has not been reported. We constructed a large-scale dataset containing multiple high-regional-incidence arrhythmias and ACS-related diseases, including 162,622 12-lead ECGs collected between January 2018 and March 2021. We presented a deep learning model for clinical ECG diagnosis of multiple cardiac diseases. Results show that our model for diagnosing 15 cardiac abnormalities achieved 88.216% accuracy, and its average AUC ROC score reached 0.961. On the board-certified re-annotated dataset, its performance surpasses that of cardiologists in non-reference group. Moreover, with aid of labels given by our model, accuracy and efficiency for cardiologist increased by 13.5% and 69.9% than non-reference group. Our approach provides solutions for AI-aided diagnosis systems of cardiac diseases in applications.


Clonal specificity of concanavalin A-induced cytotoxic T lymphocytes.
The specificity of polyclonally induced cytotoxic T lymphocyte (CTL) precursors has been analyzed under clonal conditions. Primary clones of concanavalin A-inducible CTL, if tested on different targets, revealed that they could distinguish between (a) two different allogeneic tumor targets; (b) allogeneic and syngeneic tumor targets, and (c) syngeneic B blasts and tumor targets. No "nonspecific" CTL clones were generated under these culture conditions, and all clones were found to display classical immunological specificity.


Catastrophic kinesins: piecing together their mechanism by 3D reconstruction.
Kin Is, kinesins with an internal catalytic domain, de-polymerize microtubules from both ends, and the KIF2C crystal structure presented by ([this issue of Cell]) provides provocative evidence to support the theory that the highly conserved sequences are critical structural elements in these catastrophic kinesins.


scGAD: single-cell gene associating domain scores for exploratory analysis of scHi-C data.
Quantitative tools are needed to leverage the unprecedented resolution of single-cell high-throughput chromatin conformation (scHi-C) data and integrate it with other single-cell data modalities. We present single-cell gene associating domain (scGAD) scores as a dimension reduction and exploratory analysis tool for scHi-C data. scGAD enables summarization at the gene unit while accounting for inherent gene-level genomic biases. Low-dimensional projections with scGAD capture clustering of cells based on their 3D structures. Significant chromatin interactions within and between cell types can be identified with scGAD. We further show that scGAD facilitates the integration of scHi-C data with other single-cell data modalities by enabling its projection onto reference low-dimensional embeddings. This multi-modal data integration provides an automated and refined cell-type annotation for scHi-C data. scGAD is part of the BandNorm R package at https://sshen82.github.io/BandNorm/articles/scGAD-tutorial.html. Supplementary data are available at Bioinformatics online.


Search for quantitative trait loci of atopy-associated immune responses using allergen-specific IgG1 as an "endophenotype".
Inherited atopic diseases of humans arise from adverse adaptive humoral responses to noninfectious environmental allergens. We previously reported that allergen-specific IgG1 provides more reliable heritability estimates for responses to allergens than total IgE. Genome scans were done for 91 Caucasian nuclear families with history of atopy for total IgE and IgG1 produced against a common major allergen from house dust mite, Der p 1. Suggestive associations for Der p 1-IgG1 production were found at 7 quantitative trait loci (QTL) (logarithm of the odds, LOD > or = 1.23; p < or = 0.009) with QTL-specific heritabilities of 73%-80%. Scans using total IgE found suggestive associations for 12 QTLs (LOD > or = 1.44; p < or = 0.004), but QTL-specific heritabilities only in the range of 30%-35%. Allergen-specific IgG1 is a suitable "endophenotype" to be used in searches for genes associated with atopy-associated humoral immune responses to common aeroallergens.


The spatial distribution dynamic and convergence of CO2 emissions in Iran's provinces.
It is essential to study CO2 emissions intensity as the most critical factor affecting temperature increase and climate change in a country like Iran, which ranked seven regarding CO2 emissions intensity. Investigating the convergence of CO2 emissions intensity is essential in recognizing its dynamics in identifying the effectiveness of government environmental policies. In this paper, using the Markov chain and spatial Markov chain methods, the convergence of CO2 emissions intensity from fossil-fuel consumption has been investigated in 28 provinces of Iran from 2002 to 2016. The empirical results showed that convergence clubs and neighbors significantly influenced the transition probability of regions to clubs with high and low CO2 emissions. Therefore, if a province had a neighbor with low (high) CO2 emissions intensity, the transition probability of this province to the club with low (high) CO2 intensity increased. Therefore, in provinces that have neighbors with low (high) CO2 emissions intensity, the transition probability to the club with low (high) CO2 intensity increases.


Tissue distortion in three-dimensional reconstruction of wax or plastic embedded microscopic structures.
Three-dimensional reconstruction at the light microscopic level depends on obtaining reliable serial sections without "distortion" i.e., expansion and compression during section preparation. We have studied the extent of such distortion in serial sections from paraffin and resin embedded blocks of brain, kidney, liver and lung, using an IBAS 2000 Image Analyser. We found that, taking the uncut block as 100%, the section area, perimeter and minimum diameter varied by no more than 8%, except for the lung sections which varied up to 14%. There was no progressive compression due to knife bluntening. Resin sections also varied up to 8% (16% for lungs) but in addition creasing was a problem. We conclude that, provided the serial sectioning is carefully standardised for block shape and orientation, floating out temperature and time, serial paraffin sections are more suitable for three dimensional reconstruction than resin sections.


Curcumin/xanthan-galactomannan hydrogels: rheological analysis and biocompatibility.
Curcumin, a lipophilic compound found in the plant Curcuma longa L., exhibits a wide range of pharmacological activity; however, its therapeutic use has been limited because of its low bioavailability following oral administration. The aim of this study was to evaluate the viscoelastic characteristics and biocompatibility of a curcumin/xanthan:galactomannan hydrogel (X:G) system after topical application on chick embryo chorioallantoic membrane (CAM), a system established with a view toward curcumin nasal or topical pharmaceutical applications or possible administration in cosmetics or foods. A rheological analysis indicated that incorporation of curcumin did not alter the viscoelastic characteristics of the X:G hydrogel, suggesting that there was no change in the structure of the gel network. X:G hydrogels did not induce CAM tissue injury and the curcumin/X:G hydrogel system was also highly biocompatible. We conclude that the X:G hydrogel represents a potential matrix for curcumin formulations.


Is male breast cancer similar or different than female breast cancer?
To determine if male breast carcinogenesis was similar to its more common female counterpart, we compared incidence patterns among men and women with breast cancer. Breast cancer records were obtained from the SEER database. Women were stratified by age < 50 and > or = 50 years to simulate premenopausal and postmenopausal breast cancer. Age-adjusted incidence trends were stable among men but increased among women. Male to female breast cancer ratio was higher for blacks than for whites. Favorable prognostic factors reflective of tumor biology (nuclear grade and hormone receptor expression) were more common for men and postmenopausal women than for premenopausal women. For example, low nuclear grade, estrogen and progesterone receptor-positive expression were more common among men and postmenopausal women than among premenopausal women. The age-specific incidence rate curve for men increased steadily for all ages with a constant slope. On the other hand, age-specific rates for women increased rapidly until age 50 years then rose at a slower rate for postmenopausal women. Age-frequency distribution for male breast cancer was unimodal, with peak incidence at age 71 years. Age-frequency distribution for women was bimodal with early-onset and late-onset incidence at 52 and 71 years, respectively. Gender-specific incidence trends differed, most likely reflective of female-related changes in surveillance and/or reproductive risk factors. On the other hand, similar prognostic factor profiles reflective of tumor biology, age-specific incidence rate patterns, and age-frequency distributions suggested that male breast cancer was more like postmenopausal than premenopausal female breast cancer.


Selective and automated sample pretreatment by molecularly imprinted polymer for the analysis of the basic drug alfuzosin from plasma.
A molecularly imprinted polymer synthesized in dichloromethane, was evaluated for the selective extraction of a pharmaceutical compound from human plasma and integrated on-line with liquid chromatography. The target drug is an alpha-blocker called alfuzosin widely used for the treatment of benign prostatic hyperplasia. By a comprehensive approach of the retention mechanism, a selective extraction procedure was established by exploiting the development of electrostatic interactions between the target analyte and the selective support in LC compatible solvents. By applying this method to plasma, extraction recoveries close to 100% were obtained for alfuzosin while various pharmaceutical compounds currently found in biological fluids were not retained on the support. The high selectivity of the support coupled to the chromatographic system permitted an easy and fast analysis of the drug with a limit of quantification of 15 microg L(-1) by UV detection.


Clinical predictors of accurate prehospital stroke recognition.
Prehospital activation of in-hospital stroke response hastens treatment but depends on accurate emergency medical services (EMS) stroke recognition. We sought to measure EMS stroke recognition accuracy and identify clinical factors associated with correct stroke identification. Using EMS and hospital records, we assembled a cohort of EMS-transported suspect, confirmed, or missed ischemic stroke or transient ischemic attack cases. The sensitivity and positive predictive value (PPV) for EMS stroke recognition were calculated using the hospital discharge diagnosis as the gold standard. We used multivariable logistic regression analysis to determine the association between Cincinnati Prehospital Stroke Scale use and EMS stroke recognition. During a 12-month period, 441 EMS-transported patients were enrolled; of which, 371 (84.1%) were EMS-suspected strokes and 70 (15.9%) were EMS-missed strokes. Overall, 264 cases (59.9%) were confirmed as either ischemic stroke (n=186) or transient ischemic attack (n=78). The sensitivity of EMS stroke recognition was 73.5% (95% confidence interval, 67.7-78.7), and PPV was 52.3% (95% confidence interval, 47.1-57.5). Sensitivity (84.7% versus 30.9%; P<0.0001) and PPV (56.2% versus 30.4%; P=0.0004) were higher among cases with Cincinnati Prehospital Stroke Scale documentation. In multivariate analysis, Cincinnati Prehospital Stroke Scale documentation was independently associated with EMS sensitivity (odds ratio, 12.0; 95% confidence interval, 5.7-25.5) and PPV (odds ratio, 2.5; 95% confidence interval, 1.3-4.7). EMS providers recognized 3 quarters of the patients with ischemic stroke and transient ischemic attack; however, half of EMS-suspected strokes were false positives. Documentation of a Cincinnati Prehospital Stroke Scale was associated with higher EMS stroke recognition sensitivity and PPV.


Association between mismatch negativity and global functioning is specific to duration deviance in early stages of psychosis.
Mismatch negativity (MMN) is a candidate biomarker for early stages of psychosis. Although an association among duration MMN (dMMN), cognitive deficits, and functional outcome in chronic schizophrenia has been shown by a large-scale study, the effects of deviant type and clinical stages have not been investigated. We investigated the relationships among dMMN, frequency MMN (fMMN), global functioning, and cognitive function in early stages of psychosis. The participants included 26 individuals with recent-onset schizophrenia (ROSZ), 30 individuals with ultra-high risk (UHR), and 20 healthy controls. The correlational analyses revealed that dMMN amplitude, which was impaired in the ROSZ group compared to the healthy controls, correlated with global functioning (Global Assessment of Functioning-Functioning scale) in the ROSZ (r=-0.45) and UHR (r=-0.37) groups. The amplitude of fMMN, which did not differ among the groups, correlated with working memory (r=-0.57) only in the ROSZ group. The path analyses indicated that dMMN had a direct effect on global functioning in the ROSZ and UHR groups while fMMN had a direct effect on working memory only in the ROSZ group. Our findings suggested that the association between MMN and global functioning was specific to the duration deviant and was already present in early stages of psychosis. These findings confirm the usefulness of dMMN as a biological marker of early psychosis to guide treatment interventions.


Climbing plants beat trees to soil nutrient patches.
Charles Darwin reasoned that because climbing plants are freed from the need to be mechanically self-supporting, their stems can remain thin, elongate quickly, and efficiently colonize and display leaves in well-illuminated areas where trellises are available1. Herein, I report that this tremendous exploratory capacity also applies below-ground - roots of woody climbers (i.e., lianas) consistently beat tree roots to fertilized soil patches, apparently because lianas do not invest in thick roots. This claim is based on results of a greenhouse experiment in which individual seedlings (N = 5 individuals per species) of four liana and four tree species were planted in the centers of 60 x 15 cm rectangular sand-filled boxes. In the direction of a usually covered Plexiglas end wall, a nutrient gradient was established by adding increasing amounts of slow-release fertilizer in four 6 cm-wide vertical bands; no nutrients were added in the other direction. Entire plants were harvested by section when their first root reached the end wall. Roots from all four liana species reached the highly fertilized end of the planting box faster than all tree roots (Figure 1A; for statistical results, see the Supplementary Information). A Vitis rotundifolia root arrived after just 67 days, a Campsis radicans root after 84 days, another Vitis root after 91 days, and then a Wisteria sinensis root after 94 days, and the fastest root of Gelsemium sempervirens grew the 24 cm to the end wall in 149 days. In contrast to the liana species, the fastest tree roots reached the end wall in 235 days for Magnolia grandiflora, 253 days for Quercus hemisphaerica, 263 days for Nyssa sylvatica, and 272 days for Liquidambar styraciflua. This capacity to explore soil rapidly may help explain why lianas are such potent below-ground competitors2 and why their removal substantially increases tree growth rates3,4.


Designing super-fast trimodal sponges using recycled polypropylene for organics cleanup.
Sorbent pads and films have been commonly used for environmental remediation purposes, but designing their internal structure to optimize access to the entire volume while ensuring cost-effectiveness, ease of fabrication, sufficient strength, and reusability remains challenging. Herein, we report a trimodal sorbent film from recycled polypropylene (PP) with micropores, macro-voids, and sponge-like 3D cavities, developed through selective dissolution, thermally induced phase separation, and annealing. The sorbent has hundreds of cavities per cm2 that are capable of swelling up to twenty-five times its thickness, allowing for super-fast saturation kinetics (within 30 s) and maximum oil sorption (97 g/g). The sorption mechanism follows a pseudo-second-order kinetic model. Moreover, the sorbent is easily compressible, and its structure is retained during oil sorption, desorption, and resorption, resulting in 96.5% reuse efficiency. The oil recovery process involves manually squeezing the film, making the cleanup process efficient with no chemical treatment required. The sorbent film possesses high porosity for effective sorption with sufficient tensile strength for practical applications. Our integrated technique results in a strengthened porous polymeric structure that can be tailored according to end-use applications. This study provides a sustainable solution for waste management that offers versatility in its functionality.


Dynamic Bayesian networks as prognostic models for clinical patient management.
Prognostic models in medicine are usually been built using simple decision rules, proportional hazards models, or Markov models. Dynamic Bayesian networks (DBNs) offer an approach that allows for the incorporation of the causal and temporal nature of medical domain knowledge as elicited from domain experts, thereby allowing for detailed prognostic predictions. The aim of this paper is to describe the considerations that must be taken into account when constructing a DBN for complex medical domains and to demonstrate their usefulness in practice. To this end, we focus on the construction of a DBN for prognosis of carcinoid patients, compare performance with that of a proportional hazards model, and describe predictions for three individual patients. We show that the DBN can make detailed predictions, about not only patient survival, but also other variables of interest, such as disease progression, the effect of treatment, and the development of complications. Strengths and limitations of our approach are discussed and compared with those offered by traditional methods.


Adult cerebellar mutism and cognitive-affective syndrome caused by cystic hemangioblastoma.
Cerebellar mutism is a rare phenomenon often described in children following surgical intervention in the posterior fossa. In this report we present a very unusual case of pre-operative cerebellar mutism in an adult in the context of cognitive-affective syndrome caused by cystic hemangioblastoma.


Potential role of bone morphogenetic protein-15 in zebrafish follicle development and oocyte maturation.
Bone morphogenetic protein (BMP)-15 is a member of the transforming growth factor beta (TGF-beta) superfamily and is closely related to growth and differentiation factor (GDF)-9, both structurally and functionally. In mammals, BMP-15 is predominantly produced by oocytes and exerts important regulatory functions within the ovary, such as promoting early folliculogenesis, preventing premature luteinization and enhancing cumulus cell expansion. The role of BMP-15 in mammalian ovary differs between monoovulatory and polyovulatory species. Recent studies in zebrafish have provided initial evidence that BMP-15 is also an important regulator of ovarian functions. BMP-15 is produced by the zebrafish ovary throughout follicle development and maturation. In vitro studies using zebrafish follicles have revealed that incubation with recombinant human BMP-15 or over-expression of BMP-15 in oocytes results in an inhibition of gonadotropin- and maturation inducing hormone (MIH)-induced oocyte maturation. Conversely, immnunoneutralization with BMP-15 antiserum or silencing of BMP-15 expression using morpholino antisense oligonueclotides enhances oocyte maturation. A key step in BMP-15 action is the sensitivity of follicles to MIH. In vivo injection of BMP-15 antiserum causes a significant decrease in maturation-incompetent (insensitive to MIH) small early growth phase follicles and a concomitant increase in mature follicles. These findings support a role in BMP-15 in preventing precocious oocyte maturation in zebrafish. We propose that the suppression of premature oocyte maturation by BMP-15 may be important to maintain oocyte quality and subsequent ovulation and fertilization.


Chronic cold acclimation increases thermogenic capacity, non-shivering thermogenesis and muscle citrate synthase activity in both wild-type and brown adipose tissue deficient mice.
The purpose of this study was to determine whether chronic cold exposure would increase the aerobic capacity of skeletal muscle in UCP-dta mice, a transgenic line lacking brown adipose tissue (BAT). Wild type and UCP-dta mice were acclimated to either warm (23 °C), or cold (4 °C) conditions. Cold increased muscle oxidative capacity nearly equivalently in wild-type and UCP-dta mice, but did not affect the respiratory function of isolated mitochondria. Summit metabolism ( ̇V O2summit) and norepinephrine-induced thermogenesis ( ̇V O2NST) were significantly lower in UCP-dta mice relative to wild-type mice regardless of temperature treatment, but both were significantly higher in cold relative to warm acclimated mice. BAT mass was significantly higher in the cold relative to warm acclimated wild-type mice, but not in cold acclimated UCP-dta mice. BAT citrate synthase activity was lower in transgenic animals regardless of acclimation temperature and BAT citrate synthase activity per depot was significantly higher only in the cold acclimated wild-type mice. Muscle citrate synthase activity was increased in both genotypes. As defects in muscle oxidative function have been observed with obesity and type 2 diabetes, these results suggest that chronic cold exposure is a useful intervention to drive skeletal muscle oxidative capacity in mouse models of obesity.


Acute effects of sigma ligands on the electrophysiological activity of rat nigrostriatal and mesoaccumbal dopaminergic neurons.
The effects of acute i.v. administration of several sigma ligands on the single-unit activity of nigrostriatal and mesoaccumbal dopaminergic (DA) neurons were evaluated in chloral hydrate-anesthetized rats. DTG (1,3-di(o-tolyl)guanidine) did not alter DA neuronal activity at nontoxic doses and JO 1784 [(+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethylbut-3-en-1-+ ++ylamine] was inactive. (+)-Pentazocine was more effective in increasing mesoaccumbal vs. nigrostriatal DA cell firing rates. BMY 14802(alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-but anol) dose-dependently increased DA cell firing rate in both populations. The inhibition of nigrostriatal DA cell firing rate by (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)-3-PPP] was reversed by (-)-eticlopride and (+)-but not (-)-butaclamol, which supports previous evidence that (+)-3-PPP-induced inhibition is due to the DA agonist properties of the drug. From what is known of the pharmacological properties of these compounds, it is concluded that acute sigma receptor occupation does not markedly alter the firing rate of DA neurons. The dose-response curve for inhibition of nigrostriatal DA neuronal activity by the D2 DA agonist, quinpirole, was shifted to the right tenfold by BMY 14802 pretreatment (8 mg/kg, i.v.) and twofold by (+)-pentazocine (8 mg/kg, i.v.), but was not changed by DTG (2 mg/kg, i.v.). It is concluded that the marked effects of certain sigma ligands on DA cell electrophysiology are likely due to their non-sigma properties.


Novel ACOX1 mutations in two siblings with peroxisomal acyl-CoA oxidase deficiency.
Peroxisomal acyl-CoA oxidase (ACOX1) deficiency is a rare autosomal recessive single enzyme deficiency characterized by hypotonia, seizures, failure to thrive, developmental delay, and neurological regression starting from approximately 3 years of age. Here, we report two siblings with ACOX1 deficiency born to non-consanguineous Japanese parents. They showed mild global developmental delay from infancy and began to regress at 5 years 10 months and 5 years 6 months of age respectively. They gradually manifested with cerebellar ataxia, dysarthria, pyramidal signs, and dysphasia. Brain MRI revealed T2 high-intensity areas in the cerebellar white matter, bilateral middle cerebellar peduncle, and transverse tracts of the pons, followed by progressive atrophy of these areas. Intriguingly, the ratios of C24:0, C25:0, and C26:0 to C22:0 in plasma, which usually increase in ACOX1 deficiency were within normal ranges in both patients. On the other hand, whole exome sequencing revealed novel compound heterozygous variants in ACOX1: a frameshift variant (c.160delC:p.Leu54Serfs*18) and a missense variant (c.1259 T > C:p.Phe420Ser). The plasma concentration of individual very long chain fatty acids (C24:0, C25:0, and C26:0) was elevated, and we found that peroxisomes in fibroblasts of the patients were larger in size and fewer in number as previously reported in patients with ACOX1 deficiency. Furthermore, the C24:0 β-oxidation activity was dramatically reduced. Our findings suggest that the elevation of individual plasma very long chain fatty acids concentration, genetic analysis including whole exome analysis, and biochemical studies on the patient's fibroblasts should be considered for the correct diagnosis of ACOX1 deficiency.


Sialylation of lacto-N-neotetraosyl ceramide by a solubilized sialyltransferase(s) from chicken skeletal muscle: effect of phosphatidylcholine and sphingomyelin.
The sialytransferase(s) that transfers sialic acid to lacto-N-neotetraosylceramide and other glycosphingolipids with a galactose nonreducing terminus has been successfully solubilized from embryonic chicken skeletal muscle. The enzyme can be stored in 50 mM HEPES (pH 6.8), 1% Triton CF-54, and 20% glycerol at -70 degrees C for as long as six months. Addition of phosphatidylcholine or sphingomyelin (0.167%) readily reactivates the stored inactive enzymes and such activity persists for about two weeks at 0 degrees-4 degrees C with the peak activity occurring at 1 to 2 days. Sphingomyelin from chicken muscle, which contains mainly C16:0 and C18:0, is 2.1-fold more effective than bovine brain sphingomyelin at the same concentration (0.4%).


Right-sided approach to left bundle branch area pacing combined with atrioventricular node ablation in a patient with persistent left superior vena cava and left bundle branch block: a case report.
Left bundle branch area pacing (LBBAP) is an alternative to right ventricular (RV) and biventricular (BiV) pacing in patients scheduled for pace and ablate treatment strategy. However, current delivery sheaths are designed for left-sided implantation, making the right-sided LBBAP lead implantation challenging. We report a case of a right-sided LBBAP approach via right subclavian vein in a heart failure patient with a persistent left superior vena cava scheduled for pace and ablate treatment of refractory atrial flutter. To enable adequate lead positioning and support for transseptal screwing, the delivery sheath was manually modified with a 90-degree curve at the right subclavian vein and superior vena cava junction to allow right-sided implantation. The distance between the reshaping point and the presumed septal region was estimated by placing the sheath on the body surface under fluoroscopy. With the reshaping of the delivery sheath, we were able to achieve LBBAP with relatively minimal torque. Radiofrequency ablation of the atrioventricular node was performed the next day and the pacing parameters remained stable in short-term follow-up. With the modification of currently available tools, LBBAP can be performed with the right-sided approach.


Reoperative median sternotomy.
Sternal reentry for reoperative cardiac procedures poses a substantial risk of technical problems. A simple technique for sternal reentry is described that is both expeditious and safe.