In vivo labelling of the mouse dopamine uptake complex with the phencyclidine derivative [3H]BTCP.
[3H]BTCP ([3H]N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine), a phencyclidine (PCP) derivative which binds with a high affinity to the dopamine (DA) uptake complex in vitro, has been tested for in vivo binding to mouse brain. Using [3H]BTCP as a tracer (5 microCi, i.v.) we found the striatum as the region which accumulated the largest amount of radioactivity (58 dpm/mg tissue). In other brain regions the radioactive level (about 20 dpm/mg tissue) was close to the non-specific binding determined by an injection of unlabeled BTCP (40 mg/kg, s.c.) 2 h prior to the [3H]BTCP injection. In the striatum [3H]BTCP binding was inhibited in a dose-dependent manner by unlabeled BTCP (ID50 = 6.34 mg/kg) and nomifensine (ID50 = 11.06 mg/kg). It was unaffected by the DA receptor antagonist haloperidol and by PCP or its analog TCP at doses of 10 mg/kg. These results suggest that [3H]BTCP binds to the dopamine uptake complex in the mouse brain in vivo. Thus, although PCP has no effect on [3H]BTCP binding in these experimental conditions, this in vivo binding model will be useful for the determination of the precise interaction of PCP and its derivatives with the striatal dopamine uptake complex in vivo independently of their interaction with the N-methyl-D-aspartate receptor-channel complex.


Toward the creation of an ontology for the coupling of atmospheric electricity with biological systems.
Atmospheric electric fields (AEFs) are produced by both natural processes and electrical infrastructure and are increasingly recognized to influence and interfere with various organisms and biological processes, including human well-being. Atmospheric electric fields, in particular electromagnetic fields (EMFs), currently attract a lot of scientific attention due to emerging technologies such as 5G and satellite internet. However, a broader retrospective analysis of available data for both natural and artificial AEFs and EMFs is hampered due to a lack of a semantic approach, preventing data sharing and advancing our understanding of its intrinsic links. Therefore, here we create an ontology (ENET_Ont) for existing (big) data on AEFs within the context of biological systems that is derived from different disciplines that are distributed over many databases. Establishing an environment for data sharing provided by the proposed ontology approach will increase the value of existing data and facilitate reusability for other communities, especially those focusing on public health, ecology, environmental health, biology, climatology as well as bioinformatics.


Tetra-carbonyldi-μ-chlorido-di-chlorido-bis-(η5-cyclo-penta-dien-yl)diirondigallium(2 Fe-Ga).
The title compound, [Fe2Ga2(C5H5)2Cl4(CO)4], has an iron-gallium bond distance of 2.3028 (3) Å. The gallium atoms are connected by two bridging chlorine atoms, each gallium also has one terminal chlorine. The mol-ecule has an inversion center located between the gallium atoms. The cyclo-penta-dienyl ligand is disordered over two sites with an occupancy of 0.57 (2) for the major occupied site.


Omicron BA.1-containing mRNA-1273 boosters compared with the original COVID-19 vaccine in the UK: a randomised, observer-blind, active-controlled trial.
The omicron BA.1 bivalent booster is used globally. Previous open-label studies of the omicron BA.1 (Moderna mRNA-1273.214) booster showed superior neutralising antibody responses against omicron BA.1 and other variants compared with the original mRNA-1273 booster. We aimed to compare the safety and immunogenicity of omicron BA.1 monovalent and bivalent boosters with the original mRNA-1273 vaccine in a large, randomised controlled trial. In this large, randomised, observer-blind, active-controlled, phase 3 trial in the UK (28 hospital and vaccination clinic sites), individuals aged 16 years or older who had previously received two injections of any authorised or approved COVID-19 vaccine, with or without an mRNA vaccine booster (third dose), were randomly allocated (1:1) using interactive response technology to receive 50 μg omicron BA.1 monovalent or bivalent vaccines or 50 μg mRNA-1273 administered as boosters via deltoid intramuscular injection. The primary outcomes were safety and immunogenicity at day 29, including prespecified non-inferiority and superiority of booster immune responses, based on the neutralising antibody geometric mean concentration (GMC) ratios of the monovalent and bivalent boosters compared with mRNA-1273. Safety was assessed in all participants who received first or second boosters, and primary immunogenicity outcomes were assessed in all participants who received the planned booster dose, had pre-booster and day 29 antibody data, had no major protocol deviations, and who were SARS-CoV-2-negative. The study is registered with EudraCT (2022-000063-51) and ClinicalTrials.gov (NCT05249829) and is ongoing. Between Feb 16 and March 24, 2022, 724 participants were randomly allocated to receive omicron BA.1 monovalent (n=366) or mRNA-1273 (n=357), and between April 2 and June 17, 2022, 2824 participants were randomly allocated to receive omicron BA.1 bivalent (n=1418) or mRNA-1273 (n=1395) vaccines as second boosters. Median durations (months) between the most recent COVID-19 vaccine and study boosters were similar for omicron BA.1 monovalent (4·0 months [IQR 3·6-4·7]) and mRNA-1273 (4·1 [3·5-4·7]), and for the omicron BA.1 bivalent (5·5 [4·8-6·2]) and mRNA-1273 (5·4 [4·8-6·2]) boosters. The omicron BA.1 monovalent and bivalent boosters elicited superior neutralising GMCs against the omicron BA.1 variant compared with mRNA-1273, with GMC ratios of 1·68 (99% CI 1·45-1·95) and 1·53 (1·41-1·67) at day 29 post-booster doses in participants without previous SARS-CoV-2 infection. Both boosters induced non-inferior ancestral SARS-CoV-2 (Asp614Gly) immune responses with GMCs that were similar for the bivalent (2987·2 [95% CI 2814·9-3169·9]) versus mRNA-1273 (2911·3 [2750·9-3081·0]) and lower for the monovalent (2699·7 [2431·3-2997·7] vs 3020·6 [2776·5-3286·2]) boosters, with respective GMC ratios of 1·05 (99% CI 0·96-1·15) and 0·82 (95% CI 0·74-0·91). Results were comparable regardless of previous SARS-CoV-2 infection status. Incidences of solicited adverse reactions with the omicron BA.1 monovalent (335 [91·3%] of 367 participants) and omicron BA.1 bivalent (1285 [90·4%] of 1421 participants) boosters were similar to those observed previously for mRNA-1273, with no new safety concerns identified and no occurrences of fatal adverse events. Omicron-containing booster vaccines generated superior immunogenicity against omicron BA.1 and comparable immunogenicity against the original strain with no new safety concerns. It remains important to continuously monitor the immune responses and real-world vaccine effectiveness as divergent SARS-CoV-2 variants emerge. Moderna.


Reflux from ileum to colon in the dog. Role of external ligamentous attachments.
In four dogs we quantified the role of external ("coloileal") ligaments in preventing coloileal reflux. All animals were tested under control conditions, and then two had all external ligamentous attachments between ileum and colon divided; the other pair underwent a sham operation. Coloileal reflux was quantified scintigraphically at colonic pressures of 20, 40, and 60 mm Hg, and ileal motility was recorded concurrently. During control experiments and after sham operations, no dogs showed coloileal reflux at colonic pressures of 20 and 40 mm Hg. At a colonic pressure of 60 mm Hg, two control experiments and one in a dog after sham operation resulted in reflux of 9%, 4%, and 8% of counts, respectively. In contrast, both test dogs (after division of the ligaments) refluxed 30-70% of colonic content in all of four experiments at pressure below 20 mm Hg. In control dogs and in those with a continent ileocolonic junction, ileal motility consisted of scattered clusters of phasic contractions. In dogs with coloileal reflux, these clusters occurred with a similar frequency, but they lasted longer (P less than 0.005). Four weeks later, ileal motility indices in control dogs were significantly less (P less than 0.02) than in animals with divided coloileal ligaments. These observations establish an experimental model for coloileal reflux, support the hypothesis that external ligamentous attachments help maintain continence at the ileocolonic junction, and imply that coloileal reflux changes the motor pattern of the terminal ileum.


Interleukin-10 haplotype associated with total serum IgE in atopic dermatitis patients.
The genetic background of atopic dermatitis (AD) is not clearly understood. Interleukin (IL)-10 is a powerful Th-2 cell cytokine produced by lymphoid cells that exerts its function by inhibiting macrophage/monocyte and T-cell lymphocyte replication and secretion of inflammatory cytokines [IL-1, tumour necrosis factor-alpha (TNFA), IL-6, IL-8 and IL-12]. In an effort to discover additional polymorphism(s) in genes whose variant(s) have been implicated in total immunoglobulin E (IgE) level in AD patients, we scrutinized the single nucleotide polymorphisms (SNPs) in the IL10 gene as a potent candidate for contributing to the level of IgE in serum. We recruited 334 AD patients and assayed their serum total IgE levels using the LIPA-200 system. Four SNPs in the IL10 gene were genotyped using the single-base extension (SBE) method. Logistic regression analyses were performed with single polymorphisms and haplotypes (ht) to determine their association with the level of serum total IgE. Genetic association analysis of total serum IgE in AD patients revealed that one of the IL10 ht, IL10-ht2, was associated with decreased serum total IgE in gene dose-dependent manner (P = 0.02-0.001). It was predicted that the inhibition of innate immunity by increased IL-10 production in IL10-ht2-bearing individuals might be associated with decreased total serum IgE levels among AD patients. The greater effects of IL10 ht on decreased total serum IgE levels suggest that the effect of IL-10 polymorphism might be the result of a combined genotype (ht) rather than single polymorphisms.


A β-glucuronidase-responsive albumin-binding prodrug for potential selective kinase inhibitor-based cancer chemotherapy.
We report on the synthesis and in vitro biological evaluations of a nanomolar protein kinase inhibitor (PKI) and its β-glucuronidase-responsive albumin-binding prodrug. The highly potent PKI is 400-3400 times more cytotoxic than the well-known PKI Roscovitine. The prodrug is able to bind covalently to human serum albumin through Michael addition and release the cytotoxic PKI in the presence of β-glucuronidase, an enzyme over-expressed in the microenvironment of solid tumours.


Association of gastroesophageal reflux disease symptoms with stable chronic obstructive pulmonary disease.
Patients with various chronic respiratory diseases have a higher incidence of gastroesophageal reflux disease (GERD)-related symptoms, but the mechanisms of the relationship between GERD symptoms and chronic obstructive pulmonary disease (COPD) remain unclear. The aim of the present study was to explore the association of GERD symptoms with impaired pulmonary function and other factors in patients with COPD. Patients with clinically stable COPD were consecutively recruited, and a pulmonary function test, visual analogue scale (VAS), and Reflux Diagnostic Questionnaire (RDQ) were administered. The patients were categorized into GERD-positive and GERD-negative groups according to the RDQ. Univariate and multivariate analyses were performed to evaluate the factors associated with the incidence of GERD symptoms in COPD. A total of 1,486 patients with COPD were enrolled. There was no difference in age, gender proportion, body mass index, tobacco exposure, and the use of respiratory medications between the GERD-positive and GERD-negative groups. The respiratory pattern, the values of forced expiratory volume in 1 s, inspiratory capacity (IC), and residual volume, and VAS scores were significantly different between the groups (all P<0.05). Multivariate logistic regression analysis revealed that the decreased IC (odds ratio (OR) =1.56; 95% CI=1.32-2.27; P<0.001) and increased VAS scores (OR=1.38; 95% CI=1.19-1.68; P=0.011) were independent risk factors of GERD symptoms in patients with COPD. The severity of hyperinflation and dyspnea may be important associated risk factors for the incidence of GERD symptoms in patients with clinically stable COPD.


Response of atrial fibrillation to pulmonary vein antrum isolation is directly related to resumption and delay of pulmonary vein conduction.
The role of pulmonary vein (PV) isolation in ablative treatment of atrial fibrillation (AF) has been debated in conflicting reports. We sought to compare PV conduction in patients who had no AF recurrence (group I), patients who could maintain sinus rhythm on antiarrhythmic medication (group II), and patients who had recurrent AF despite antiarrhythmic medication (group III) after PV antrum isolation (PVAI). PV conduction was examined in consecutive patients undergoing second PVAI for AF recurrence. We also recruited some patients cured of AF to undergo a repeat, limited electrophysiological study at >3 months after PVAI. All patients underwent PVAI with an intracardiac echocardiography (ICE)-guided approach with complete isolation of all 4 PV antra (PVA). The number of PVs with recurrent conduction and the shortest atrial to PV (A-PV) conduction delay was measured with the use of consistent Lasso positions defined by ICE. Late AF recurrence was defined as AF >2 months after PVAI with the patient off medications. Patients in groups I (n=26), II (n=37), and III (n=44) did not differ at baseline (38% permanent AF; ejection fraction 53+/-6%). Recurrence of PV-left atrial (LA) conduction was seen in 1.7+/-0.8 and 2.2+/-0.8 PVAs for groups II and III but only in 0.2+/-0.4 for group I (P=0.02). In patients with recurrent PV-LA conduction, the A-PV delay increased from the first to second procedure by 69+/-47% for group III, 267+/-110% for group II, and 473+/-71% for group I (P<0.001). When pacing was at a faster rate, A-PV block developed in all 5 of the group I patients with recurrent PV-LA conduction. The majority of patients with drug-free cure show no PV-LA conduction recurrence. Substantial A-PV delay is seen in patients able to maintain sinus rhythm on antiarrhythmic medication or cured of AF compared with patients who fail PVAI.


Evaluation of Outer Membrane Vesicles Obtained from Predominant Local Isolate of Boredetella pertussis as a Vaccine Candidate.
Pertussis is a current contagious bacterial disease caused by Bordetella pertussis (Bp). Given the prevalence of pertussis, development of new vaccines is important. This study was attempted to evaluate the expression of main virulence factors (pertussis toxin [PTX], PRN [pertactin], and filamentous hemagglutinin [FHA]) from Bp predominant strains and also compare the expression of these factors in the outer membrane vesicles (OMVs) obtained from predominant circulating Bp isolate. The physicochemical features of the prepared OMVs were analyzed by electron microscopy and SDS-PAGE. The presence of the mentioned virulence factors was confirmed by Western blotting. BALB/c mice (n = 21) immunized with characterized OMVs were challenged intranasally with sublethal doses of Bp, to examine their protective capacity. Electron microscopic examination of the OMVs indicated vesicles within the range of 40 to 200 nm. SDS-PAGE and Western blotting demonstrated the expression of all three main protective immunogens (PTX, PRN, and FHA), prevalent in the predominant, challenge, and vaccine strains, and OMVs of the predominant IR37 strain and BP134 vaccine strain. Significant differences were observed in lung bacterial counts between the immunized mice with OMV (30 CFU/lung) compared to the negative control group ((6 104 CFU/lung; p < 0.001). In mice immunized with OMVs (3 µg), the number of lungs recovered colonies after five days dropped at least five orders of magnitude compared to the control group. OMVs obtained from circulating isolates with the predominant profile may constitute a highly promising vaccine quality. They also can be proposed as a potential basic material for the development of new pertussis vaccine candidate.


Removal of trichloroethylene DNAPL trapped in porous media using nanoscale zerovalent iron and bimetallic nanoparticles: direct observation and quantification.
Direct trichloroethylene (TCE) dense non-aqueous phase liquid (DNAPL) removal inside pore areas using nanoscale zerovalent iron (NZVI) and bimetallic nanoparticles were first investigated in a water-saturated porous glass micromodel. Effects of nitrate, aqueous ethanol co-solvent, humic substance, and elapsed time on TCE DNAPL removal using NZVI were studied by direct visualization. The removal efficiency was then quantified by directly measuring the remaining TCE DNAPL blobs area using an image analyzer. As ethanol content of co-solvent increased, TCE DNAPL removal by NZVI was also increased implying sequential TCE DNAPL removal mechanisms: as dissolved TCE was degraded by NZVI, TCE dissolution from TCE blobs would be then facilitated and the TCE blob areas would be eventually reduced. The presence of nitrate and humic substance hindered the NZVI reactivity for the TCE DNAPL removal. In contrast, the TCE DNAPL removal efficiency was enhanced using bimetallic nanoparticles in a short-term reaction by generating atomic hydrogen for catalytic hydro-dechlorination. However, all TCE DNAPL removal efficiencies reached the same level after long-term reaction using both NZVI and bimetallic nanoparticles. Direct TCE DNAPL observation clearly implied that TCE blobs existed for long time even though all TCE blobs were fully exposed to NZVI and bimetallic nanoparticles.


Effect of atebrine on glucose blood levels and on flavinic nucleotides content in rat liver in deficiency state and in satisfied demand of riboflavine.
Changes in glucose levels in blood, excretion of riboflavine in urine, FAD and FMN flavinic nucleotides and a total riboflavine content in liver homogenates were determined in rats. Both riboflavine deficiency and atebrine do not effect the glucose, blood levels. Atebrine (ATB) significantly inhibits the urinary excretion of riboflavine both in deficiency state and in satisfied demand of this vitamin. The lack of riboflavine in food results in a decrease of total riboflavine and FA- in liver, while during the first period of deficiency the amount of FMN increases. When the riboflavine demand is satisfied, low doses of ATP do not influence the total riboflavine and flavinic nucleotides content in the liver, while at high doses, the total riboflavine increases and the amount of FMN initially significantly exceeds the amount of FAD. ATB markedly inhibits the growth of rats both in the deficiency state and in the satisfied demand of riboflavine.


Differences in noun and verb processing in lexical decision cannot be attributed to word form and morphological complexity alone.
It has been suggested that the effect of word category in noun and verb processing reflects typical word class properties, which can be characterized in terms of semantic as well as syntactic and morphological features. The present study is aimed at differentiating and discussing the relative contribution of these aspects with a main focus on syntactic and morphological processing. Experiment 1 established a processing advantage for nouns in German visual lexical decision, using nouns denoting biological and man-made objects as compared to transitive and intransitive verbs. Experiment 2 showed that the noun advantage persisted even when the morphological differences between word categories were reduced by using identical suffixes in nouns and verbs. Overall results suggest that the processing differences cannot be reduced to variables such as frequency, word form, or morphological complexity. Reaction time differences between transitive and intransitive verbs strengthen the role of syntactic information. In line with previous accounts the observed effects are discussed in terms of a category-specific combination of linguistic parameters.


Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia.
ABT-199, a potent and selective small-molecule antagonist of BCL-2, is being clinically vetted as pharmacotherapy for the treatment of acute myeloid leukemia (AML). However, given that prolonged monotherapy tends to beget resistance, we sought to investigate the means by which resistance to ABT-199 might arise in AML and the extent to which those mechanisms might be preempted. Here we used a pathway-activating genetic screen to nominate MCL-1 and BCL-XL as potential nodes of resistance. We then characterized a panel of ABT-199-resistant myeloid leukemia cell lines derived through chronic exposure to ABT-199 and found that acquired drug resistance is indeed driven by the upregulation of MCL-1 and BCL-XL. By targeting MCL-1 and BCL-XL, resistant AML cell lines could be resensitized to ABT-199. Further, preemptively targeting MCL-1 and/or BCL-XL alongside administration of ABT-199 was capable of delaying or forestalling the acquisition of drug resistance. Collectively, these data suggest that in AML, (1) the selection of initial therapy dynamically templates the landscape of acquired resistance via modulation of MCL-1/BCL-XL and (2) appropriate selection of initial therapy may delay or altogether forestall the acquisition of resistance to ABT-199.


Comparing contractile properties within an integrated group of muscles: The abdominal wall.
The abdominal wall (external oblique (EO), internal oblique (IO), rectus abdominis (RA), and transverse abdominis (TrA)) is a functionally and anatomically integrated group of muscles. While the passive mechanical properties of the individual abdominal muscles have been studied previously, their contractile properties have yet to be described. Muscle samples were taken from the EO, IO, RA, and TrA of 6 Sprague-Dawley rats. Single muscle fibres were isolated from each sample, chemically permeabilized and tested in a Ca2+ (pCa 4.2) bath to determine their contractile properties: specific force, active modulus, unloaded shortening velocity, and rate of force redevelopment. Myosin heavy chain (MHC) isoforms were identified by gel electrophoresis to determine the fibre type of each tested fibre, as well as larger bundles of fibres. No type I fibres and only two type IIa fibres were tested, therefore type IIx and IIb fibres were combined for statistical analysis. There were no significant differences between muscles for specific force, active modulus, and unloaded shortening velocity (p > 0.05). Rate of force redevelopment was statistically significant (p = 0.029), with TrA being 62 % greater than EO, suggesting faster cross-bridge transitioning between low and high force-generating states in the TrA. The functional significance of this difference is unclear and will need to be studied further.


Effect of pollution on some freshwater species. I. histochemical and biochemical features of lead pollution on some organs of Viviparus viviparus L. (Mollusca Gastropoda).
Experimental lead pollution was studied in some organs (foot, mantle and digestive gland) of Viviparus viviparus L. The amount of lead contained after 48h, 96 h and one week of pollution were established using an atomic absorption spectrophotometer. On the basis of physicochemical determination, it turns out that lead is mainly concentrated in the mantle. The biochemical tests (cholesterol, sulpholipids and phospholipids) were aimed at evaluating the lipids involved in the membranes. The histochemical research was carried out chiefly to evaluate the modifications of polysaccharides and proteins. Some hydrolytic enzymes (Na+ and K+ dependent ATPase) and some ooreductive enzymes (NADH+ and NADPH+ dependent diaphorases, D-lactate dehydrogenase, succinate dehydrogenase and glucose-6-P-dehydrogenase) were also tested. The digestive gland is the most severely damaged organ as proved by histomorphological and biochemical analyses.


Resistance and cross-resistance of the IgM immunocytoma in the LOU/M Wsl rat for cisplatin, carboplatin, and iproplatin.
We investigated the antitumor activity of cis-diammine[1,1-cyclobutanedicarboxylato]platinum(II) (CBDCA, JM8) and cis-dichloro-trans-dihydroxybis(isopropylammine)platinum(IV) (CHIP, JM9) for the cis-DDP-sensitive and -resistant IgM immunocytoma in the LOU/M Wsl rat. The optimal dose for the antitumor effect of cis-diamminedichloroplatinum (cis-DDP) in this tumor model is 1 mg/kg body weight. In order to determine the dose range for antitumor activity of JM8 and JM9, tumor-bearing rats were treated i.p. (twice weekly) with 2, 4, 8, 16, or 32 mg/kg JM8 or with 2, 4, or 8 mg/kg JM9. The maximal antitumor activity of JM8 was found at a dose of 4-8 mg/kg and that of JM9, at 4 mg/kg. Doses of 16 or 32 mg/kg JM8 did not increase the antitumor activity. Recurrence of tumors was observed in JM8- and JM9-treated rats. It was demonstrated that these relapses during treatment with JM8 or JM9 involved tumor cell populations almost completely resistant against therapy with the respective drugs. The growth of cis-DDP-resistant tumors was not influenced by the analog JM9 (4 and 8 mg/kg). Only a high dose of JM8 (32 mg/kg) caused growth retardation of the cis-DDP-resistant IgM subline. The JM8-resistant tumor was resistant to treatment with cis-DDP (1 and 2 mg/kg). The JM9-resistant tumor was also resistant to this treatment (1 mg/kg); however, at a dose of 2 mg/kg cis-DDP, growth retardation of the tumor occurred. We conclude that cis-DDP, JM8, and JM9 induce resistance in the IgM immunocytoma tumor system; tumors resistant for cis-DDP were not sensitive to the treatment with JM8 or JM9. Although JM9 reacts in vitro distinctly differently with DNA than cis-DDP and JM8, no differences were found in the induction of Pt resistance. In this study tumor cells were readily made resistant, which allows us to study in more detail the induction of (cross-) resistance by cis-DDP, JM8, and JM9.


Strong expression of NETRIN-G2 in the monkey claustrum.
The claustrum is a phylogenetically conserved structure, with extensive reciprocal connections with cortical regions, and has thus been considered important for sensory, motor, emotional, and mnemonic coordination or integration. Here, we show by in situ hybridization that the adult monkey claustrum is strongly positive for NETRIN-G2, a gene encoding a glycosyl phosphatidyl-inositol-linked membrane protein, which constitutes a subfamily with NETRIN-G1 within the netrin/UNC6 family. There is a conspicuous dorsal/ventral differentiation, where the label is stronger in the ventral claustrum. NETRIN-G2 positive neurons are not GABAergic, but rather correspond to claustrocortical projection neurons, as demonstrated by retrograde transport of Fast Blue from cortical injections and by double in situ hybridization for NETRIN-G2 and GAD67. Since NETRIN-G2 is known to be preferentially expressed in cortex, in contrast with the thalamically expressed NETRIN-G1, these results raise the possibility of some functional similarity in regulation of excitatory neural transmission in the claustrum and cortex.


Faster and cleaner real-time pure shift NMR experiments.
Real-time pure shift experiments provide highly resolved proton NMR spectra which do not require any special processing. Although being more sensitive than their pseudo 2D counterparts, their signal intensities per unit time are still far below regular NMR spectra. In addition, scalar coupling evolution during the individual data chunks produces decoupling sidebands. Here we show that faster and cleaner real-time pure shift spectra can be obtained through the implementation of two parameter alterations. Variation of the FID chunk lengths between individual transients significantly suppresses decoupling sidebands for any kind of real-time pure shift spectra and thus allows for example the analysis of minor components in compound mixtures. Shifting the excitation frequency between individual scans of real-time slice-selective pure shift spectra increases their sensitivity obtainable in unit time by allowing faster repetitions of acquisitions.


I Am Right for Your Child! : Tactics for Manipulating Potential Parents-In-Law.
Parents and children have converging as well as diverging interests with respect to the latter's mate choices. Diverging interests frequently result in children choosing mates who do not gain the approval of their parents. Manipulation then arises wherein parents try to drive away undesirable prospective sons- and daughters-in-law, and the latter employ counter manipulation to make the former to change their minds. The present research aims to identify and measure the effectiveness of manipulation tactics that individuals employ to influence their partners' parents to accept them as mates for their daughters and sons. Study 1 recruited a sample of 106 Greek-Cypriots and, using open-ended questionnaires, identified 41 acts that individuals employ on their partners' parents. Using principal-components analysis, in a sample of 738 Greek-Cypriots, Study 2 classified these acts into seven broader manipulation tactics and identified the ones that are more and the ones that are less likely to be employed. Study 3 examined in a sample of 414 Greek-Cypriots the effectiveness of these tactics in altering parents' minds and finds a moderate effectiveness, with some tactics being more effective than others. The implications of these findings are discussed.


Predicting Opioid Overdose Deaths Using Prescription Drug Monitoring Program Data.
Prescription Drug Monitoring Program data can provide insights into a patient's likelihood of an opioid overdose, yet clinicians and public health officials lack indicators to identify individuals at highest risk accurately. A predictive model was developed and validated using Prescription Drug Monitoring Program prescription histories to identify those at risk for fatal overdose because of any opioid or illicit opioids. From December 2018 to July 2019, a retrospective cohort analysis was performed on Maryland residents aged 18-80 years with a filled opioid prescription (n=565,175) from January to June 2016. Fatal opioid overdoses were identified from the Office of the Chief Medical Examiner and were linked at the person-level with Prescription Drug Monitoring Program data. Split-half technique was used to develop and validate a multivariate logistic regression with a 6-month lookback period and assessed model calibration and discrimination. Predictors of any opioid-related fatal overdose included male sex, age 65-80 years, Medicaid, Medicare, 1 or more long-acting opioid fills, 1 or more buprenorphine fills, 2 to 3 and 4 or more short-acting schedule II opioid fills, opioid days' supply ≥91 days, average morphine milligram equivalent daily dose, 2 or more benzodiazepine fills, and 1 or more muscle relaxant fills. Model discrimination for the validation cohort was good (area under the curve: any, 0.81; illicit, 0.77). A model for predicting fatal opioid overdoses was developed using Prescription Drug Monitoring Program data. Given the recent national epidemic of deaths involving heroin and fentanyl, it is noteworthy that the model performed equally well in identifying those at risk for overdose deaths from both illicit and prescription opioids.


Cancer associated fibroblast derived gene signature determines cancer subtypes and prognostic model construction in head and neck squamous cell carcinomas.
Head and neck squamous cell carcinomas (HNSCC) are the most common type of head and neck cancer with an unimproved prognosis over the past decades. Although the role of cancer-associated-fibroblast (CAF) has been demonstrated in HNSCC, the correlation between CAF-derived gene expression and patient prognosis remains unknown. A total of 528 patients from TCGA database and 270 patients from GSE65858 database were contained in this study. After extracting 66 CAF-related gene expression data from TCGA database, consensus clustering was performed to identify different HNSCC subtypes. Limma package was used to distinguish the differentially expression genes (DEGs) between these subtypes, followed by Lasso regression analysis to construct a prognostic model. The model was validated by performing Kaplan-Meier survival, ROC and risk curve, univariate and multivariate COX regression analysis. GO, KEGG, GSEA, ESTIMATE and ssGSEA analyses was performed to explort the potential mechanism leading to different prognosis. Based on the 66 CAF-related gene expression pattern we stratitied HNSCC patients into two previously unreported subtypes with different clinical outcomes. A prognostic model composed of 15 DEGs was constructed and validated. In addition, bioinformatics analysis showed that the prognostic risk of HNSCC patients was also negatively correlated to immune infiltration, implying the role of tumor immune escape in HNSCC prognosis and treatment option. The study develops a reliable prognostic prediction tool and provides a theoretical treatment guidance for HNSCC patients.


Interactive control of graphic output devices.
A software package for the support of graphic output was developed. The main feature is the capability to draw graphs in a Cartesian coordinate system. With up to 60 variable parameters, it is problematic to change them interactively. Classical program languages do not support interaction. Subroutines for various kinds of input had to be written. Most important are other subroutines for reading, writing or erasing datasets at runtime, the name of which need not be known before starting a program. According to the problems, different appropriate methods of dialogue were used: the simple sequential dialoque, command languages and, for more complex input, a syntax analyser. The resulting dialogue is very simple and self-explanatory. The users need not have previous experience with computers; the package was accepted quickly and is now in extensive use.


Cement Plug Fragmentation Following Percutaneous Cementoplasty of the Bony Pelvis: Is it a Frequent Finding in Clinical Practice?
To report the rate of fragmentation of the cement plug following percutaneous cementoplasty with polymethylmethacrylate (PMMA) in the bony pelvis (i.e., pelvic bones or sacrum). Post-interventional and follow-up CT scans of 56 patients (36 men; mean age of 68.4 ± 15.4) with a total of 98 percutaneous cementoplasty procedures were analyzed. Indications for treatment included painful malignant tumors (42.9%; 42/98) and insufficiency fractures (57,1%; 56/98). Fragmentation of PMMA was recorded for each cement plug. Mean interval between the procedure and the last available CT scan was 29.3 ± 18.8 months. There was no significant difference between the length of follow-up of malignant lesions (27.6 ± 15.1 months) and insufficiency fractures (29 ± 20.5 months) (p = 0.69). Fragmentation was diagnosed following 2/98 (2%) procedures, both in the malignant lesions group. The time intervals between the procedure and the first visualization of cement fragmentation were 6 for the first and 24 months for the second patient. Fragmentation of the PMMA plug following percutaneous cementoplasty in the bony pelvis is a rare finding at midterm follow-up. It was only observed in cementoplasty performed in malignant lesions and seems to be more a consequence of local mechanical stresses than as a result of porosity.


Isolation of a polyethylene degrading Paenibacillus sp. from a landfill in Brazil.
The annual production of plastics has doubled over the past 15 years and, consequently, a large amount of plastic has accumulated in the environment generating ecological problems. In this study, a Paenibacillus sp. isolate was obtained from a landfill from Brazil and it presented the alkane hydroxylase gene (alkB). Weight loss of low-density polyethylene (LDPE) was measured and a significant difference in final weight compared to initial weight was assessed. Some chemical characteristics, such as bond scissions and formation of new functional groups [carboxylic acids (3300-2500 cm-1), esters (1210-1163 cm-1), and ethers (1075-1020 cm-1)], were detected by Fourier-transform infrared spectroscopy. Bacterial colonization on the plastic surface and physical changes, as formation of cracks and pits, was visualized by scanning electron microscopy. This isolate was susceptible to all the antimicrobials tested. Therefore, this isolate possesses great potential to degrade polyethylene and become an option for LDPE bioremediation.


Assessment of a new modified soft jelly capsule containing nonoxynol as spermicide contraceptive.
The mean rupture time, after its vaginal insertion, of a new modified soft jelly capsule containing nonoxynol-9 (DF-486) was investigated in 40 women. The subjects were randomly allocated to 8 study groups. The capsules remained in the vagina from 2-13 minutes. Vaginal infection, vaginal dryness, and multiparity, were recorded. Capsule rupture was not observed at minute 2; 20% of capsules that remained in the vagina 3 minutes suffered rupture, as did 80% of capsules that remained 4, 5 and 7 minutes, and 100% of those remaining 9 minutes or more. The mean rupture time of the studied capsules was 8.2 minutes with 95% confidence limits of 6.2 and 8.8 minutes. At minutes 2-7, vaginal infection, dryness and tone diminution probably accounted for lack of rupture; after minute 7, these factors did not influence capsule rupture.


Hybrid System of an Optical Nanofibre and a Single Quantum Dot Operated at Cryogenic Temperatures.
Recent progress in quantum nanophotonics brings novel ways for manipulating single photons in various nano-waveguides. Among them, one promising approach is to use optical nanofibres (ONFs), tapered optical fibres with sub-wavelength diameter waists. Here, we develop a hybrid system of an ONF and a single quantum dot (QD) operated at cryogenic temperatures. We deposit a single colloidal CdSe QD on an ONF waist and observe emitted photons through the fibre guided modes. We systematically investigate emission characteristics for both the neutral exciton and charged exciton (trion) for one specific QD. We quantitatively show that the trion at cryogenic temperatures acts as an excellent quantum emitter for the ONF and QD hybrid system. The present ONF/QD hybrid system at cryogenic temperatures paves the way for quantum information technologies for manipulating single photons in fibre networks.


Multiple sclerosis and the neurogenic bladder.
Most patients with progressive MS will develop voiding dysfunction. In order to properly manage these patients, it is imperative to have a basic understanding of normal and abnormal bladder function. Based on history, physical examination, urinalysis, and renal function, diagnostic evaluation can be tailored to the individual. Empiric therapy without urologic consultation may be appropriate in some patients. In others, referral for full urodynamic evaluation will be necessary to best manage neurogenic voiding dysfunctions. Although there are many treatment options for patients with neurogenic bladders, it is imperative that therapy remain conservative and initially reversible because symptoms from MS tend to wax and wane over time. Long-term follow-up for patients with MS and neurogenic bladders is required to preserve renal function and avoid infections. A urologic program should be designed to promote continent, low-pressure bladder storage and controlled emptying while minimizing symptoms in a manner that promotes improved quality of life and self-esteem.


Abatacept therapy and safety management.
To develop and/or update fact sheets about abatacept treatment, in order to assist physicians in the management of patients with inflammatory joint disease. 1. selection by a committee of rheumatology experts of the main topics of interest for which fact sheets were desirable 2. identification and review of publications relevant to each topic 3. development and/or update of fact sheets based on three levels of evidence: evidence-based medicine, official recommendations, and expert opinion. The experts were rheumatologists and invited specialists in other fields (dermatologist, cardiologist, pediatric rheumatologist, endocrinologist, hematologist, immunologist, infectiologist), and they had extensive experience with the management of chronic inflammatory diseases, such as rheumatoid arthritis (RA). They were members of the CRI (Club Rhumatismes et Inflammation), a section of the French Rheumatology Society (Societe Francaise de Rhumatologie). Each fact sheet was revised by several experts and the overall process was coordinated by three experts. Several topics of major interest were selected: contraindications of abatacept treatment; management of adverse effects and concomitant diseases that may develop during abatacept treatment; and management of common situations such as pregnancy, surgery, patient older than 75 years of age, and patients with co-morbidities (such as dialysis, hemoglobinopathy, or splenectomy). After a review of the literature and discussion among experts, a consensus was developed about the content of the fact sheets presented here. These fact sheets focus on several points: 1. in RA, initiation and monitoring of the abatacept treatment, management of patients with specific past histories, and specific clinical situations such as pregnancy 2. diseases other than RA, such as juvenile idiopathic arthritis, spondylarthropathies, or autoimmune diseases (systemic lupus erythematosus and other systemic autoimmune diseases) 3. models of letters for informing the rheumatologist and general practitioner 4. patient information about the use of abatacept in RA 5. and data on the new abatacept formulation for subcutaneous administration (approved by the FDA in August 2011 for patients with moderate-to-severe RA). These fact sheets built on evidence-based medicine and expert opinion will serve as a practical tool for assisting physicians who manage patients on abatacept. They will be available continuously on www.cri-net.com and will be updated at appropriate intervals.


Sixty years of experimental studies on the blastogenesis of the colonial tunicate Botryllus schlosseri.
In the second half of the eighteenth century, Schlosser and Ellis described the colonial ascidian Botryllus schlosseri garnering the interest of scientists around the world. In the 1950's scientists began to study B. schlosseri and soon recognized it as an important model organism for the study of developmental biology and comparative immunology. In this review, we summarize the history of B. schlosseri studies and experiments performed to characterize the colony life cycle and bud development. We describe experiments performed to analyze variations in bud productivity, zooid growth and bilateral asymmetry (i.e., the situs viscerum), and discuss zooid and bud removal experiments that were used to study the cross-talk between consecutive blastogenetic generations and vascular budding. We also summarize experiments that demonstrated that the ability of two distinct colonies to fuse or reject is controlled by a single polymorphic gene locus (BHF) with multiple, codominantly expressed alleles. Finally, we describe how the ability to fuse and create chimeras was used to show that within a chimera somatic and germline stem cells compete to populate niches and regenerate tissue or germline organs. Starting from the results of these 60 years of study, we can now use new technological advances to expand the study of B. schlosseri traits and understand functional relationships between its genome and life history phenotypes.


The impact of putative methyltransferase overexpression on the Trichoderma harzianum cellulolytic system for biomass conversion.
Trichoderma harzianum has attracting attention for its potential alternative use in biofuel production, due to a recognized competence for high diversity glycoside hydrolases (GH) enzyme complex, including higher β-glucosidases and auxiliary proteins, using low-cost carbon sources. This strain constitutively overexpressed the global regulator putative methyltransferase - LAE1, in order to improve the GHs production. The recombinant strain achieved 79-fold increase in lae1 expression and high GHs productivity. The evaluation of the LAE1 impact to induce the GHs used soluble and lignocellulose inexpensive carbon sources in a stirred-tank bioreactor. Using sugarcane bagasse with sucrose, the overexpression of lae1 resulted in significantly increment of gh61b (31x), cel7a (25x), bgl1(20x) and xyn3 (20x) genes expression. Reducing sugar released from pretreated sugarcane bagasse, which hydrolyzed by recombinant crude enzyme cocktail, achieved 41% improvement. Therefore, lae1 overexpression effectively is a promising improving GHs target for biomass degradation by T. harzianum.


The Hidden Curriculum and Integrating Cure- and Care-Based Approaches to Medicine.
Although current literature about the "cure versus care" issue tends to promote a patient-centered approach, the disease-centered approach remains the prevailing model in practice. The perceived dichotomy between the two approaches has created a barrier that could make it difficult for medical students and physicians to integrate psychosocial aspects of patient care into the prevailing disease-based model. This article examines the influence of the formal and hidden curricula on the perception of these two approaches and finds that the hidden curriculum perpetuates the notion that "cure" and "care" based approaches are dichotomous despite significant changes in formal curricula that promote a more integrated approach. The authors argue that it is detrimental for clinicians to view the two approaches as oppositional rather than complementary and attempt to give recommendations on how the influence of the hidden curriculum can be reduced to get a both-cure-and-care-approach, rather than an either-cure-or-care-approach.


Detection of Circulating BRAF(V600E) in Patients with Papillary Thyroid Carcinoma.
BRAF(V600E) is a common mutation in papillary thyroid carcinoma (PTC) correlated with aggressive features. Our objective was to assess the feasibility and accuracy of a novel RNA-based blood assay to identify individuals with a high-risk tumor mutation in patients with PTC. Patients with benign or malignant thyroid disorders were included between September 2013 and July 2014 before either thyroidectomy (n = 62) or treatment of recurrent or metastatic PTC (n = 8). RNA was isolated from peripheral blood lymphocytes and reverse transcribed and followed by two rounds of nested PCR amplification with a restriction digest specific for wild-type BRAF. BRAF(V600E) levels were quantified with standardization curves. Circulating BRAF(V600E) levels were compared with BRAF mutation status from surgical pathologic DNA-based tissue assays. Testing characteristics and receiving-operator curve using tissue results as the gold standard were assessed. Matched blood and tissue assays for BRAF(V600E) were performed on 70 patients with PTC (stages I to IV, n = 48) or other (n = 22) thyroid tumors. Sixty-three percent of PTC patients tested positive for BRAF(V600E) with conventional tissue assays on surgical specimens. The correlation between the RNA-based blood assay and tissue BRAF status was 0.71. PTC patients harbor detectable BRAF(V600E) circulating tumor cells. This blood assay is feasible and has potential as a biomarker for prognosis, surveillance, clinical decision making, and assessment of treatment response to BRAF-targeted therapies.


ATP increases the migration of microglia across the brain endothelial cell monolayer.
The cerebral microcapillary endothelium, known as the blood-brain barrier (BBB), acts as a barrier between the blood and the interstitial fluid of the brain. The BBB therefore controls the passage of nutrients into the central nervous system (CNS). Microglia show a specific affinity for migration into the CNS, and this migration appears to occur independently of BBB integrity. To study the migration of microglia across the BBB, we developed an in vitro co-culture system of mouse brain endothelial cells (MBECs) and Ra2 microglia using Transwell inserts. We first investigated the influence of microglia or ATP, a microglial chemotactic factor, on MBEC barrier integrity. The addition of microglia or ATP led to the disruption of the MBEC monolayer and significantly decreased barrier function as measured by trans-endothelial electrical resistance (TEER) and electric cell-substrate impedance sensing (ECIS). Furthermore, ATP promoted the migration of microglia but not macrophages across the MBEC monolayer. An inhibitor of matrix metalloproteinases (MMPs) decreased the transmigration of microglia in our system, indicating that MMPs play a role in microglial chemotaxis. We specifically identify a role for microglia-derived MMP-2. In conclusion, we offer evidence that microglia migration across the brain endothelial cell monolayer is increased in the presence of ATP in a manner that involves MMP secretion.


Assessment of variations in productive performance of two different plumage color varieties of Japanese quail and their reciprocal crosses.
This study aimed to detect the phenotypic differences between the brown (BB) and white (WW) feathered quails and their reciprocal crosses (BW and WB) over two successive generations. The WW and cross quails, especially the BW, had the heaviest body weights, throughout the studied period, with significant variations between the two studied generations (P<0.05). Moreover, the WW and BW possessed the largest egg production during the F1, while in the F2, the BB had superiority among the studied quails with a prominent superiority of the F2 over the F1 (P<0.05). However, the F1 had higher egg weights than F2 with superiority of WW quails compared to the others (P<0.05). Also, the WW quails had the lowest lipid contents of the eggs. These phenotypic variations among the studied quails might be preliminarily explained by the results of the analyzed microsatellite markers despite the few markers used. The high variability among the BW and WB quails might be due to the larger number of alleles (NA and Ne) and the lower values of FIS with low heterozygosity levels (HO and He). Moreover, the BW and BB were the closest, while WB and WW were the farthest because of the high and low genetic identities and the high and low genetic distance between them, respectively. So the obtained results might introduce an initial scientific basis for evaluating and employing the genetic properties of BB, WW, BW, and WB quails in further genetic improvement program, and more microsatellite markers are recommended.


Reactive, infectious, or postinfectious arthritis?
The issue of reactive arthritis belongs to one of the most complex problems in rheumatology. Although the original concept of reactive arthritis as a "sterile arthritis" has already been overcome, much remains unclear. Non-uniform terminology, classification and diagnostic criteria as well as treatment guidelines leave room for different interpretations of this issue. Therefore it is difficult for non-rheumatologists (internal medicine physicians and general practitioners) to find their way around this topic. Our comprehensive report discusses the latest findings from etiology to treatment of reactive arthritis. It also addresses the aforementioned controversies from terminology to the latest list of causative pathogens, including viruses, parasites and vaccines.


Efficacy of smoking cessation intervention delivered through mobile tele-counseling among smokers with tuberculosis in a Revised National Tuberculosis Control Program.
India has high burden of tuberculosis and smokers. Prevalence of tuberculosis is three times higher in smokers than non-smokers. Active smoking causes severe disease, delay in seeking treatment, lost to treatment follow up, delayed sputum conversion and drug resistance. WHO advocates mobile phone technology to improve health outcomes (mHealth). We used mobile tele-counseling as a smoking cessation intervention in smokers with tuberculosis (TB) receiving treatment under tuberculosis control program. To determine smoking quit rate at six months of TB treatment among smokers receiving mobile tele-counseling versus brief advice and to estimate smoking quit rates and relapse rates during the tele-counseling period. Open label randomized controlled trial. Newly detected pulmonary tuberculosis or pleural effusion patients received brief advice on smoking cessation as per The UNION's guiding framework. Subjects were then randomly allocated to intervention or control group. Intervention group was contacted telephonically at 2,3,4,5 and 6 months to assess smoking quit rates and provide continued smoking cessation advice. Intervention group had 80 and 82 in the control group, mean (SD) age was 40.6(12.6), 43.5(12.7) p = 0.53. Quit rate at six months was 54 (67.5%) in intervention group versus 34 (42%) in control group; RR 1.60 (95% CI 1.19, 2.16) p = 0.001. Trend in smoking quit rates in intervention group was 81.3%, 61.3%, 55%, 73.8% at 2,3,4 and 5 months respectively. Smoking relapse rate was 43.1%, 53.1%, 20.5%,15.3% at 3,4,5 and 6 months respectively. 27.5%, 43.8% were abstinent for last three, two months. Mobile tele-counseling is an effective strategy for smoking cessation among TB patients.


mlpB, a gene encoding a new lipoprotein in Myxococcus xanthus.
To search for and study the genes involved in the regulation of phosphate in the soil developmental bacterium Myxococcus xanthus. The mlpB gene encoding a 149 residue polypeptide was identified while screening for genes with products related to phosphate metabolism. The amino terminal 19 residues of MlpB encode a typical prokaryotic signal sequence with a putative lipoprotein cleavage site. In this study, a new myxobacterial putative lipoprotein is reported. The data suggest that MlpB may be involved in the secretion of phosphate-related proteins. Soil bacteria have complex regulatory systems for using inorganic phosphate. This nutrient is limiting in the environment, and has a critical importance for growth and in the initiation of differentiation for developmental bacteria. A number of proteins are involved in all these processes, including membrane lipoproteins, which are being increasingly studied in M. xanthus.


Comparing the hyper-variable V4 and V9 regions of the small subunit rDNA for assessment of ciliate environmental diversity.
The hyper-variable V4 and V9 regions of the small subunit (SSU) rDNA have been targeted for assessing environmental diversity of microbial eukaryotes using next generation sequencing technologies. Here, we explore how the genetic distances among these short fragments compare with the distances obtained from near full-length SSU-rDNA sequences by comparing all pairwise estimates, as well as within and among species of ciliates. Results show that pairwise distances from V4 more closely match the near full-length SSU-rDNA and are more comparable with previous studies based on much longer SSU-rDNA fragments, then pairwise distances from V9. Thus, studies that use the V4 will estimate similar values of phylotype richness and community structure as would have been estimated using the full-length SSU-rDNA.


Compound of Cynanchum wilfordii and Humulus lupulus L. Ameliorates Menopausal Symptoms in Ovariectomized Mice.
Cynanchum wilfordii and Humulus lupulus L. have been used for their various pharmacological properties in South Korea as a traditional medicine or health functional food, respectively, and their intake may relieve menopausal symptoms. The purpose of current study was to determine the effect of compound of Cynanchum wilfordii and Humulus lupulus L. (CWHL) in menopausal symptoms of ovariectomized (OVX) mice. OVX mice received CWHL or caudatin (an active ingredient of CWHL) once daily for 7 weeks. Values for hypothalamic serotonin (5-HT), dopamine, norepinephrine, estrogen receptor (ER)-β, 5-HT1A, and 5-HT2A were significantly enhanced, while value for hypothalamic monoamine oxidase A was reduced in CWHL and caudatin groups compared with the OVX group. CWHL and caudatin significantly reduced tail skin temperature and rectal temperature of OVX mice through partial recovering of the levels of serum estrogen, nitric oxide, follicle-stimulating hormone, luteinizing hormone, and receptor-activator of the NF-κB ligand (RANKL). Moreover, CWHL and caudatin improved bone mineral density via decreasing levels of serum RANKL, tartrate-resistant acid phosphatase, and collagen type 1 cross-linked N-telopeptide and improving levels of serum alkaline phosphatase, osteoprotegerin, and osteocalcin compared with the OVX group without adverse effects such as dyslipidemia. CWHL increased uterine ER-β levels but did not change uterus and vaginal weights. Taken together, the results indicate that CWHL may relieve menopausal symptoms by controlling depression-, hot flashes-, and osteoporosis-associated biomarkers. Therefore, we propose that CWHL might be a safe and potential candidate for management of menopause as a health functional food.


Activation of interleukin-1 beta (IL-1 beta) signaling in the spinal cord in the rats with experimental cardiac injury.
The involvement of central nervous system (CNS) interleukin-1 beta (IL-1 beta) in the pathogenesis of acute cardiac injury is still an unexplored issue. The present study was aimed to investigate whether cardiac injury could induce the activation of IL-1 beta in the spinal cord. Cardiac injury model in rats was established by intra-myocardial injection of formalin through the diaphragm. Western blot showed that IL-1 beta was upregulated in the upper thoracic spinal cord following cardiac injury. The upregulated IL-1 beta was distributed in the dorsal and ventral horns in the thoracic spinal cord as determined by immunohistochemistry. In situ hybridization demonstrated that IL-1 beta mRNA localized in the neurons was elevated in response to cardiac injury. The DNA binding activities of two IL-1 beta transcription factors, activator protein (AP)-1 and nuclear factor kappa B (NF-kappaB), were enhanced after cardiac injury. In correlated with the upregulation of the spinal IL-1 beta, the circulating IL-1 beta level was also increased following cardiac injury. Acute cardiac injury could activate the spinal IL-1 beta signaling, which, in turn, may contribute to disease progression in the acute phase of cardiac injury in clinical practice.


Exchange of phosphatidylcholine between small unilamellar liposomes and human plasma high-density lipoprotein involves exclusively the phospholipid in the outer monolayer of the liposomal membrane.
By making use of the capacity of phospholipase A2 to degrade selectively the phospholipid in the outer half of the lipid bilayer of small unilamellar phospholipid/cholesterol vesicles without affecting the retention of a vesicle-encapsulated solute, we demonstrated that the exchange of phosphatidylcholine between such vesicles and human high density lipoprotein involves exclusively the phosphatidylcholine present in the outer monolayer of the vesicle membrane.


fMRI mapping of cortical centers following visual stimulation in postnatal pigs of different ages.
Classical studies have demonstrated that the visual centers in primates consist of cortical areas V1, V2 and V4 and their branches. However, nothing is known about how these visual areas change in postnatal development. In the present studies, therefore, pigs aged 2, 4, and 6 months old, were stimulated visually with a colored checker board and the active sites in the cortex, cerebellum and brainstem recorded using functional magnetic resonance imaging (fMRI). In pigs aged 2 months old, visual stimulation induced an increase in activation of sites in the V2 and V4 cortical areas, as well as in the areas of the inferior aspect of the parietal and middle aspect of the temporal cortices, but not in the medial and caudal occipital cortex (V1 area). At 4 months old, the V1 area was also activated, and by 6 months old, an inferior sector in the prefrontal cortex was also activated. As the pigs aged, functional active sites were further demonstrated in the cerebellum and the brainstem, which probably had to do with action memory, and the control of the ocular muscles, respectively. It is concluded that the visual pathway of the pig mainly involves cortical areas that mature at 6 months of age.


Reduced host plant growth and increased tyrosine-derived secondary metabolites under climate change and negative consequences on its specialist herbivore.
Compositive changes in climatic factors, e.g., carbon dioxide (CO2) and precipitation frequency and intensity, affect the strength of species interactions via responses in plants. Therefore, understanding the effects of climate change on plant-herbivore interactions is important to maintain biodiversity as about 70% of insects are herbivorous. However, the interactive effects of CO2 and precipitation on plants and consequences for herbivores are poorly understood. Here, we examined how elevated CO2 and increased watering frequency affect the growth and resistance responses of Aristolochia contorta and the growth performance of its specialist herbivore, Sericinus montela. Elevated CO2 suppressed growth with decreased photosynthesis ability, and increased resistance in plants. In contrast, increased watering frequency partly ameliorated the negative effects of high CO2. Growth performance of specialist herbivores decreased under elevated CO2 condition as a consequence of increased resistance in plants. Due to the significant effects of CO2, we suggest that both the quantity and the quality of host plants as a food would decline, and the growth performance of its specialist herbivore might be threatened as climate change progresses.


Radiation induced lipid oxidation in fish.
Oxidative rancidity in herring and redfish was studied as a function of the applied irradiation dose, the storage time and storage temperature and the packaging conditions.--Measurements of the TBA (thiobarbituric acid) value and the peroxide value were used to evaluate the degree of oxidation of lipids, and were related with sensory scores.--Especially for the fatty fish species (herring) irradiation accelerated lipid oxidation and induced oxidative rancidity. Irradiation of vacuum-packed herring fillets and subsequent storage at +2 degrees C seems to be an interesting process. For the experiments conducted on a semi-fatty fish (redfish), oxidative rancidity was never the limiting factor for organoleptic acceptability.


Plasma dopamine-beta-hydroxylase in childhood psychosis.
A previous report suggested that plasma dopamine-beta-hydroxylase (DBH) is elevated in childhood autism. We measured plasma DBH in 15 Children with functional psychosis and in 10 psychotic children with known organic etiology. DBH activity was significantly elevated in the children with functional psychoses and showed a significant correlation with age that is not reported for this age range in normals. It is possible that children with functional psychoses show an abnormal continuation of the rise in plasma DBH activity characteristic of infancy. No differences between children with functional psychoses and children with organic psychoses were found for red blood cell catechol-O-methyl-transferase, plasma monoamine oxidase, or plasma cyclic AMP.


Development of chemiluminescence monitored immunoassays for steroid hormones.
Solid-phase chemiluminescence based immunoassay methods for the measurement of steroids and urinary steroid conjugates are described. The assays incorporate the following features: (i) a steroid-chemiluminescent marker conjugate serves as the labeled ligand; (ii) polyclonal or monoclonal antibodies covalently coupled to polymer beads are utilized as the specific immunoadsorbent; and (iii) a centrifugation step after the binding reaction is used to remove interferring luminescent compounds along with unbound steroid. These assays proved satisfactory with respect to sensitivity, precision and accuracy and offer significant advantages over existing methods in speed, safety and economy. Moreover, the use of monoclonal antibodies provides optimal specifity and rigorous standardization.


IgE⁺ memory B cells and plasma cells generated through a germinal-center pathway.
Immunoglobulin E (IgE) antibodies are pathogenic in asthma and allergic diseases, but the in vivo biology of IgE-producing (IgE(+)) cells is poorly understood. A model of the differentiation of IgE(+) B cells proposes that IgE(+) cells develop through a germinal-center IgG1(+) intermediate and that IgE memory resides in the compartment of IgG1(+) memory B cells. Here we have used a reporter mouse expressing green fluorescent protein associated with membrane IgE transcripts (IgE-GFP) to assess in vivo IgE responses. In contrast to the IgG1-centered model of IgE switching and memory, we found that IgE(+) cells developed through a germinal-center IgE(+) intermediate to form IgE(+) memory B cells and plasma cells. Our studies delineate a new model for the in vivo biology of IgE switching and memory.


A bacteriologically controlled, randomized study comparing the efficacy of 2% mupirocin ointment (Bactroban) with oral erythromycin in the treatment of patients with impetigo.
Sixty patients participated in a bacteriologically controlled, randomized, parallel group comparison of 2% mupirocin ointment (Bactroban) and oral erythromycin ethylsuccinate for the treatment of impetigo. The trial included clinical and bacteriologic evidence and safety assessments. The Investigator's Global Evaluation, which compared the overall efficacy and safety of the trial drugs, demonstrated a more favorable performance for the mupirocin regimen. This difference was statistically and clinically significant. There were no significant differences between the trial regimens for any of the other efficacy variables examined. The bacteriologic success rate was 100% for both treatment groups. There was a clinically significant difference in adverse experience rates between treatment groups, with four (13%) of the erythromycin-treated patients reporting six adverse experiences versus none of the mupirocin-treated patients. The results of the trial indicate that 2% mupirocin ointment is as safe and effective as oral erythromycin ethylsuccinate in the treatment of patients with impetigo.


Wastewater-based epidemiology revealed in advance the increase of enterovirus circulation during the Covid-19 pandemic.
Wastewater-based epidemiology (WBE) was conducted to track Enteroviruses (EVs) circulation in the Milan metropolitan area (Northern Italy) during Covid-19 pandemic (March 2020-December 2022). 202 composite 24-hour wastewater samples (WWSs) were collected weekly from March 24, 2020, to December 29, 2022 at the inlet of two wastewater treatment plants (WWTP) in Milan (1.5 million inhabitants). EV-RNA was quantified and molecular characterization of non-polio EVs (NPEV) was performed by Sanger sequence analysis. Data from WWS were matched with virological data collected in the framework of Influenza-Like Illness (ILI) surveillance in the same place and time. EV-RNA was identified in 88.2 % of WWSs. The peak in EVs circulation was observed in late August 2020 (upon conclusion of the first national lockdown), in late August 2021, and in mid-April 2022. EV-RNA concentration in WWS (normalized as copies/d/1000 people) at peak of circulation presented a yearly increase (2020: 2.47 × 1010; 2021: 6.81 × 1010; 2022: 2.14 × 1011). This trend overlapped with trend in EV-positivity rate in ILI cases, expanded from 21.7 % in 2021 to 55.6 % in 2022. EV trends in WWS preceded clinical sample detections in 2021 and 2022 by eight and five weeks, respectively, acting as an early warning of outbreak. Although sequencing of EV-positive WWSs revealed the presence of multiple EV strains, typing remained inconclusive. Molecular characterization of EVs in clinical samples revealed the co-circulation of several genotypes: EV-A accounted for 60 % of EVs, EV-B for 16.7 %, EV-D68 for 23.3 %. EVs were circulating in Milan metropolitan area between March 2020 and December 2022. The epidemiological trends unfolded the progressive accumulation of EV transmission in the population after removal of Covid-19 restrictions. The increased circulation of EVs in 2021-2022 was identified at least 35 days in advance compared to the analysis of clinical data. The inconclusive results of Sanger sequencing lookout for improvement and innovative molecular approaches to deepen track EVs.


Triplets versus doublets, with or without cisplatin, in the first-line treatment of stage IIIB-IV non-small cell lung cancer (NSCLC) patients: a multicenter randomised factorial trial (FAST).
The FAST is a 2 × 2 factorial trial addressing two questions: (1) the role of replacing cisplatin (P) with a non-platinum agent, vinorelbine (N), and (2) the role of adding a third agent, ifosfamide (I), in a doublet based on gemcitabine (G). A total of 433 stage IIIB-IV non-small cell lung cancer (NSCLC) patients were randomised to one of four arms: gemcitabine-cisplatin (GP), gemcitabine-vinorelbine, gemcitabine-ifosfamide-cisplatin or gemcitabine-ifosfamide-vinorelbine. Two comparisons were performed: N- vs P-containing regimens and I-triplets vs non-I doublets. For N- vs P-containing regimens, adjusted overall survival was 9.7 vs 11.3 months (P=0.044), progression-free survival was 4.9 vs 6.4 months (P=0.020) and response rate was 24% vs 31% (P=0.124), respectively. No statistically significant difference was observed between doublets and triplets. Grade 3-4 haematological toxicity was significantly more frequent in P-containing therapy; grade 3-4 leucopenia was significantly more common in triplets. Concerning non-haematological toxicity, grade 3-4 nausea-vomiting was significantly increased in P-containing regimens. This trial provides evidence of a slight survival superiority of GP-containing regimens over platinum-free N-containing chemotherapy. This trial also confirms that the addition of a third chemotherapy agent (I) to a standard G-based doublet does not improve treatment outcome.


Effects of aldose reductase inhibitor and vitamin B12 on myocardial uptake of iodine-123 metaiodobenzylguanidine in patients with non-insulin-dependent diabetes mellitus.
This study was undertaken to examine the effects of aldose reductase inhibitor (ARI) and vitamin B12 (VB12) on myocardial uptake of iodine-123 metaiodobenzylguanidine (MIBG) in patients with diabetic autonomic disorder. Myocardial scintigraphy using 123I-MIBG was performed on 20 healthy volunteers (controls) and 56 patients with non-insulin-dependent diabetes mellitus (NIDDM), in order to obtain the heart/mediastinum ratio in the initial (HMi) and the delayed images (HMd), and the washout rate (%WR). Thirty-four of the 56 NIDDM patients could be diagnosed as having diabetic autonomic disorder by evaluating their scintigraphic findings in comparison with the controls. Seventeen of these 34 patients received 150 mg/day of doses before meals, and the other 17 received 1.5 mg/day of mecobalamin (VB12 group) in three divided doses after meals, for 3-5 months. According to the presence or absence of clinical symptoms of autonomic or peripheral somatic nerve disorder, the patients were subclassified into four groups. group 1=patients, with autonomic symptoms or somatosensory disorder in the ARI group; group 2=patients without autonomic symptoms or somatosensory disorder in the ARI group; group 3=patients with autonomic symptoms or somatosensory disorder in the VB12 group; and group 4=patients without autonomic symptoms or somatosensory disorder in the VB12 group. After completion of the treatment, myocardial scintigraphy was performed again. Comparing the results obtained before and after the treatment, it was seen that ARI improved only the HMi in group 1 (P=0.046), whereas VB12 significantly improved HMi in the group 3 (P=0.018) and HMi, HMd and %WR in group 4 (P=0.043, P=0.018 and P=0.043, respectively). We conclude that VB12 is more efficacious than ARI in the treatment of diabetic cardiovascular autonomic disorder.


Head circumference and brain size in autism spectrum disorder: A systematic review and meta-analysis.
Macrocephaly and brain overgrowth have been associated with autism spectrum disorder. We performed a systematic review and meta-analysis to provide an overall estimate of effect size and statistical significance for both head circumference and total brain volume in autism. Our literature search strategy identified 261 and 391 records, respectively; 27 studies defining percentages of macrocephalic patients and 44 structural brain imaging studies providing total brain volumes for patients and controls were included in our meta-analyses. Head circumference was significantly larger in autistic compared to control individuals, with 822/5225 (15.7%) autistic individuals displaying macrocephaly. Structural brain imaging studies measuring brain volume estimated effect size. The effect size is higher in low functioning autistics compared to high functioning and ASD individuals. Brain overgrowth was recorded in 142/1558 (9.1%) autistic patients. Finally, we found a significant interaction between age and total brain volume, resulting in larger head circumference and brain size during early childhood. Our results provide conclusive effect sizes and prevalence rates for macrocephaly and brain overgrowth in autism, confirm the variation of abnormal brain growth with age, and support the inclusion of this endophenotype in multi-biomarker diagnostic panels for clinical use.


Insulin-like growth factor I (IGF-I) affects plasma lipid profile and inhibits the lipolytic action of growth hormone (GH) in isolated adipocytes.
The actions of insulin-like growth factor I (IGF-I) and growth hormone (GH) on lipid metabolism have been investigated in hormonally intact rats. The subcutaneous injection of IGF-I (100 micrograms) and GH (100 micrograms) lowered total cholesterol plasma levels. The in vitro assays on isolated rat adipocytes showed an antilipolytic effect of IGF-I on GH induced lipolysis. All these data support an important role for IGF-I and GH on the regulation of lipid metabolism.


Metabolically healthy and unhealthy obesity phenotypes in the general population: the FIN-D2D Survey.
The aim of this work was to examine the prevalence of different metabolical phenotypes of obesity, and to analyze, by using different risk scores, how the metabolic syndrome (MetS) definition discriminates between unhealthy and healthy metabolic phenotypes in different obesity classes. The Finnish type 2 diabetes (FIN-D2D) survey, a part of the larger implementation study, was carried out in 2007. The present cross-sectional analysis comprises 2,849 individuals aged 45-74 years. The MetS was defined with the new Harmonization definition. Cardiovascular risk was estimated with the Framingham and SCORE risk scores. Diabetes risk was assessed with the FINDRISK score. Non-alcoholic fatty liver disease (NAFLD) was estimated with the NAFLD score. Participants with and without MetS were classified in different weight categories and analysis of regression models were used to test the linear trend between body mass index (BMI) and various characteristics in individuals with and without MetS; and interaction between BMI and MetS. A metabolically healthy but obese phenotype was observed in 9.2% of obese men and in 16.4% of obese women. The MetS-BMI interaction was significant for fasting glucose, 2-hour plasma glucose, fasting plasma insulin and insulin resistance (HOMA-IR)(p < 0.001 for all). The prevalence of total diabetes (detected prior to or during survey) was 37.0% in obese individuals with MetS and 4.3% in obese individuals without MetS (p < 0.001). MetS-BMI interaction was significant (p < 0.001) also for the Framingham 10 year CVD risk score, NAFLD score and estimated liver fat %, indicating greater effect of increasing BMI in participants with MetS compared to participants without MetS. The metabolically healthy but obese individuals had lower 2-hour postload glucose levels (p = 0.0030), lower NAFLD scores (p < 0.001) and lower CVD risk scores (Framingham, p < 0.001; SCORE, p = 0.002) than normal weight individuals with MetS. Undetected Type 2 diabetes was more prevalent among those with MetS irrespective of the BMI class and increasing BMI had a significantly greater effect on estimates of liver fat and future CVD risk among those with MetS compared with participants without MetS. A healthy obese phenotype was associated with a better metabolic profile than observed in normal weight individuals with MetS.


Enhancement of the in vitro bioavailable carotenoid content of a citrus juice combining crossflow microfiltration and high-pressure treatments.
High-pressure treatments combined with crossflow microfiltration were used to obtain citrus concentrates enriched in carotenoids. The aim of this study was to investigate the effect of this process combination on carotenoid bioaccessibility and uptake by intestinal Caco-2 cells. Two high-pressure processes, high hydrostatic pressure treatment (HHP) and ultra-high-pressure homogenization (UHPH) were compared to conventional pasteurization. Processing effects on carotenoid content and bioaccessibility, on physicochemical and structural characteristics of the product, on methylation degree of pectins and micelle size after in vitro digestion were assessed. UHPH at 400 MPa drastically enhanced carotenoid bioaccessibility compared to HHP and pasteurization. Moreover, carotenoid uptake by Caco-2 cells was significantly improved by UHPH underlining the importance of the micelle size after in vitro digestion and the degree of methylation of pectins in this uptake. Finally, the in vitro bioavailable carotenoid content of different concentrates was evaluated, taking into account carotenoid content, bioaccessibility and uptake. Combining crossflow microfiltration with UHPH increased by 4-6 fold the bioavailable carotenoid content in the final product. The process led to a concentrate of high nutritional quality compared to the original juice, raw or pasteurized concentrates.


Epstein-Barr virus-associated primary B-cell lymphoproliferative disorder of the cerebellum in an immune competent man.
The role of the Epstein-Barr virus (EBV) in lymphoproliferative lesions has been widely accepted. Most of these lesions occur in patients who have deficiencies in their immune status. Lymphomatoid granulomatosis (LG) is a lymphoproliferative disorder originally characterized as an angiocentric, necrotizing, pleomorphic infiltrate of mononuclear cells. The etiology of LG is unknown. It was originally hypothesized that LG may represent an unusual lymphoid response to an infective organism, possibly EBV. Tissues from a previously healthy 60-year-old, healthy white man with primary cerebellar lymphomatoid granulomatosis were examined for the presence of EBV by nucleic acid hybridization. The original LG lesion was a polyclonal B-cell proliferation that contained detectable amounts of EBV. Peripheral blood leukocytes were negative for EBV by the same assay. After an 18-month remission, a tumor reappeared near the site of the primary lesion, which had the histologic appearance of a lymphoma. The cells showed restricted clonality and contained a similar amount of EBV-related DNA as the original lesion. Peripheral blood leukocytes at the time of recurrence were negative for EBV. The patient died approximately 2 months after the recurrent tumor was detected. This case demonstrated the development of a primary cerebellar B-cell lymphoproliferative disorder, histologically identical to lymphomatoid granulomatosis, that transformed into a lymphoma. The original tumor and the subsequent lymphoma contained, on average, several copies of EBV-related DNA per cell. Despite an extensive survey of the patient, no immune deficit was detected. Interpretation of the literature with the results of this case suggest that this instance of primary cerebellar LG arose as a consequence of an unusual EBV-associated B-cell lymphoproliferation. It is suggested that EBV may be a significant factor in the initiation of the abnormal proliferations of T-cells or B-cells reported in this disorder.


Totally extraperitoneal laparoscopic hernia repair.
Totally extraperitoneal laparoscopic hernia repair is the endoscopic equivalent of the open preperitoneal prosthetic approach. Results from a randomized trial confirm that it is less painful, associated with a more rapid return to normal activity, and associated with an insignificant increase in recurrence rates when compared with open tension-free hernia repair.


Corrigendum: Comprehensive transcriptomic analysis of critical RNA regulation associated with metabolism and prognosis in clear cell renal carcinoma.
[This corrects the article DOI: 10.3389/fcell.2021.709490.].


5α-Reduced glucocorticoids: a story of natural selection.
5α-Reduced glucocorticoids (GCs) are formed when one of the two isozymes of 5α-reductase reduces the Δ(4-5) double bond in the A-ring of GCs. These steroids are largely viewed inert, despite the acceptance that other 5α-dihydro steroids, e.g. 5α-dihydrotestosterone, retain or have increased activity at their cognate receptors. However, recent findings suggest that 5α-reduced metabolites of corticosterone have dissociated actions on GC receptors (GRs) in vivo and in vitro and are thus potential candidates for safer anti-inflammatory steroids. 5α-Dihydro- and 5α-tetrahydro-corticosterone can bind with GRs, but interest in these compounds had been limited, since they only weakly activated metabolic gene transcription. However, a greater understanding of the signalling mechanisms has revealed that transactivation represents only one mode of signalling via the GR and recently the abilities of 5α-reduced GCs to suppress inflammation have been demonstrated in vitro and in vivo. Thus, the balance of parent GC and its 5α-reduced metabolite may critically affect the profile of GR signalling. 5α-Reduction of GCs is up-regulated in liver in metabolic disease and may represent a pathway that protects from both GC-induced fuel dyshomeostasis and concomitant inflammatory insult. Therefore, 5α-reduced steroids provide hope for drug development, but may also act as biomarkers of the inflammatory status of the liver in metabolic disease. With these proposals in mind, careful attention must be paid to the possible adverse metabolic effects of 5α-reductase inhibitors, drugs that are commonly administered long term for the treatment of benign prostatic hyperplasia.


Evaluation of the urinary tract in children with myelomeningocele.
Of 43 children suffering from myelomeningocele, 2 died of obstructive nephropathy; 30 survived for more than 6 years and 12 of these developed upper urinary tract dilatation. A bladder compliance above 20 was only found in 4 patients, while in 11 with detrusor hyperreflexia, a low pressure amplitude was generally observed. Detrusor-sphincter dyssynergia accompanied by large residual volumes was found in 4 patients. Surveillance of the urological condition is discussed.


Identification of new selenocysteine tRNA[SER]SEC isoacceptors in human cell lines.
The selenocysteine tRNA population was examined in a human T-cell line and in a human monocytic cell line for the occurrence of additional species of selenocysteine tRNA. At least three additional (and possibly more) selenocysteine isoacceptors were found which occur in minor levels as compared to the two major selenocysteine isoacceptors previously characterized. The possible significance of these newly observed species are discussed.


CV risk prediction tools: Imperfect, Yes, but are they serviceable?
CVD risk prediction tools have largely been used to determine the advisability of statin therapy. They might be better used to counsel patients about across-the-board risk factor modification.


Medullary cavity application of tranexamic acid to reduce blood loss in tibial intramedullary nailing procedures-a randomized controlled trial.
Studies have shown an average postoperative hidden blood loss (HBL) of 473.29 ml and an average Hb loss of 16.71 g/l after intramedullary nailing. Reducing HBL has become a primary consideration for orthopaedic surgeons. Patients with only tibial stem fractures who visited the study clinic between December 2019 and February 2022 were randomized into two groups using a computer-generated form. Two grams of tranexamic acid (TXA) (20 ml) or 20 ml of saline was injected into the medullary cavity before implantation of the intramedullary nail. On the morning of the surgery, as well as on days one, three and five after surgery, routine blood tests and analyses of CRP and interleukin-6 were completed. The primary outcomes were total blood loss (TBL), HBL, and blood transfusion, in which the TBL and HBL were calculated according to the Gross equation and the Nadler equation. Three months after surgery, the incidence of wound complications and thrombotic events, including deep vein thrombosis and pulmonary embolism, was recorded. Ninety-seven patients (47 in the TXA group and 50 in the NS group) were analyzed; the TBL (252.10 ± 10.05 ml) and HBL (202.67 ± 11.86 ml) in the TXA group were significantly lower than the TBL (417.03 ± 14.60 ml) and HBL (373.85 ± 23.70 ml) in the NS group (p < 0.05). At the three month postoperative follow-up, two patients (4.25%) in the TXA group and three patients (6.00%) in the NS group developed deep vein thrombosis, with no significant difference in the incidence of thrombotic complications (p = 0.944). No postoperative deaths or wound complications occurred in either group. The combination of intravenous and topical TXA reduces blood loss after intramedullary nailing of tibial fractures without increasing the incidence of thrombotic events.


Sex differences in the distribution of EEG frequencies during sleep: unipolar depressed outpatients.
Sex differences in period-amplitude-analysed (PAA) sleep EEG activity were evaluated in 20 symptomatic, unmedicated, unipolar, depressed outpatients. 19/20 PAA measures showed significant gender main effects or interactions. Overall, depressed females showed a higher incidence and amplitude of fast frequency, beta activity than males, particularly in the right hemisphere. Moreover, gender effects were also evident in sleep-stage-independent analysis of PAA measures. These findings are in striking contrast to normal controls for whom only slow-frequency activity differentiates males from females. These findings suggest that sex differences are stronger in depressed patients than those observed in normals and that these effects are more pronounced than age-related changes in sleep EEG activity.


The efficacy and safety of animal-derived nootropics in cognitive disorders: Systematic review and meta-analysis.
The animal-derived nootropics, Cerebrolysin, Actovegin and Cortexin, may have potential in treating neurocognitive disorders. Although these drugs have international usage, reports on their efficacy have been conflicting. These agents have been suggested for all dementia types, but may have particular utility in vascular cognitive impairment (VCI). We used systematic review and meta-analyses to summarize evidence of efficacy in all cause dementia, with a subgroup analysis restricted to VCI. We searched multidisciplinary, electronic databases from inception to August 2020. We assessed risk of bias using the Cochrane tool and framed results using GRADE criteria. We used random effects models to create summary estimates. Our primary outcome was change in cognition based on any quantitative cognitive assessment scale using standardized mean difference (SMD). We assessed various secondary efficacy outcomes and a safety outcome of serious adverse events. We performed subgroup analyses limited to VCI. Summary estimates suggested Cerebrolysin was potentially beneficial in improving cognition (8 trials,793 participants, SMD:-0.16, 95%CI:-0.30 to -0.03) and global function (4 trials,479 participants, OR:2.64, 95%CI:1.17 to 5.98) in the short term. There was no difference in incidence of serious adverse events (6 trials,1014 participants, RR:0.96, 95%CI:0.78 to 1.18). In our VCI subgroup, results were similar to the main analysis, with a beneficial effect on cognition (SMD:-0.22, 95%CI:-0.42 to -0.03) and clinical global impression (OR 2.99, 95%CI:1.02 to 8.73). The limited number of eligible studies for Actovegin (n = 2 trials,563 participants) and Cortexin, (n = 1 trial,80 participants) precluded meta-analyses but data suggested potential efficacy and no safety concerns. Across all included studies, risk of bias was moderate to high, there was imprecision, and certainty of evidence was considered low to very low. Although published data suggest potential benefits and relative safety of animal derived nootropics, the supporting evidence is weak. The size of the effects demonstrated were modest and probably less than would be considered clinically relevant.


Reproductive outcomes of Alpine goats primed with progesterone and treated with human chorionic gonadotropin during the anestrus-to-estrus transition season.
This study aimed to determine the possible effects of a single injection of human chorionic gonadotropin (hCG) as a means for estrus induction in acyclic French-Alpine goats during the reproductive transition period at 25°N, 103°W. The potential effects of hCG upon ovarian function and reproductive performance of goats were also assessed. Multiparous acyclic French-Alpine goats (n = 39; 37.4 ± 8 .5 kg) were primed with 20mg progesterone (P4) 1 day prior to hCG administration. Thereafter, does were treated either with saline (hCG-0; n = 10), 50 (hCG-50; n = 9), 100 (hCG-100; n = 10), or 300 IU of hCG (hCG-300; n = 10). Ovarian structures and pregnancy were monitored by transrectal ultrasonography. In addition, after hCG application, goats were monitored twice daily (0800 and 1800 h) to detect estrus signs, with the use of aproned, sexually active bucks treated with testosterone. Goats were bred 12h after the onset of estrus. Two days after hCG administration, the number of large follicles was higher (P < 0.05) in the hCG-50 and hCG-300 groups (1.7 ± 0.1 and 1.8 ± 0.2, respectively) compared with the hCG-100 and hCG-0 groups (1.4 ± 0.2 and 1.1 ± 0.1, respectively). Although none of the hCG-0-goats depicted estrus, the estrus response from the hCG-50, hCG-100, and hCG-300 groups over the 7-d breeding period was 67%, 100%, and 90%, respectively (P > 0.05), being always accompanied by ovulation. Pregnancy rate (67, 100, and 70%), kidding rate (55%, 80%, and 70%), and litter size (1.6 ± 0.5, 1.5 ± 0.5, and 1.5 ± 0.5) for hCG-50, hCG-100, and hCG-300, respectively, did not differ among the hCG-treated does. Therefore, the combined use of P4-priming plus a 100-IU hCG injection is an effective protocol for inducing estrus in non-cycling Alpine goats during the anestrus-to-estrus transition period, which is of key importance for both goat producers and industrializers.


Treatment beyond four cycles of first line Platinum and Etoposide chemotherapy in real-life patients with stage IV Small Cell Lung Cancer: a retrospective study of the Merseyside and Cheshire Cancer network.
Dose intensity and dose density of first line Platinum and Etoposide (PE) do not influence Overall Survival (OS) of Small Cell Lung Cancer (SCLC) patients. The effect of treatment length, however, remains unclear. Current guidelines recommend treating beyond 4 cycles -up to 6-, in patients that respond to and tolerate systemic treatment. This has led to variable practice both in clinical practice and clinical research. Here we aimed at quantifying the possible clinical benefit of the extended regimen in our real-life patients treated with PE doublet. Of all patients with SCLC treated in our network with non-concurrent first line PE chemotherapy between 2008 and 2015, we identified and described patients that received 4 cycles (4c) or more (> 4c), and analysed patients with stage IV disease. Two hundred forty-one patients with stage IV had 4c and 69 had > 4c. The latter were more likely to have sequential thoracic radiotherapy, which suggested a lower metastatic burden. Nevertheless, there were no statistically significant differences when comparing clinical outcomes. The median Duration of Response (DoR; time from last chemotherapy cycle to progression) was 5 months in both groups (HR 1.22; 95% CI 0.93-1.61). Median Progression Free Survival (PFS; time from diagnosis to radiological progression) was 8 months (4c) versus 9 months (> 4c) (HR 0.86; 95% CI 0.66-1.13) and median OS was 11 versus 12 months (HR 0.86, 95% CI 0.66-1.14). Our results highlight a lack of clinical benefit by extending first line PE treatment in stage IV disease, and support limiting treatment to 4 cycles until superiority of a longer regimen is identified in a randomised study.


Shunting during carotid endarterectomy.
The use of shunting during carotid endarterectomy (CEA) is controversial. While some surgeons advocate routine shunting, others prefer selective shunting or no shunting. Several large series have documented excellent results of CEA with routine shunting or without shunts. Others reported similar results with selective shunting using transcranial Doppler (TCD), electroencephalogram (EEG) monitoring, carotid stump pressure (SP), cervical block anesthesia (CBA), and somatosensory evoked potential (SSEP). In this study, we review the available evidence supporting shunting, nonshunting, and selective shunting during CEA. An electronic PubMed/MEDLINE search was conducted to identify all published CEA studies between January 1990 and December 2010, that analyzed the perioperative outcome of routine shunting, routine nonshunting, routine versus selective shunting, selecting shunting versus avoiding a shunt, and selective shunting based on EEG, TCD, SP, CBA, and SSEP. The mean reported perioperative stroke rate for CEAs with routine shunting was 1.4% and for routine nonshunt was 2%. Meanwhile, the mean perioperative stroke rates for selecting shunting were 1.6% using EEG, 4.8% using TCD, 1.6% using SP, 1.8% using SSEP, and 1.1% for CBA. Similar results were noted for perioperative stroke and death rates. The use of routine shunting and selective shunting was associated with a low stroke rate. Both methods are acceptable, and the individual surgeon should select the method with which they are more comfortable.


Antidepressant-like activity of sildenafil following acute and subchronic treatment in the forced swim test in mice: effects of restraint stress and monoamine depletion.
Sildenafil is a highly effective oral agent for the treatment of erectile dysfunction of multiple etiologies. Although in clinical practice sildenafil is often used in depressed patients, its influence on the pathophysiology of depression remains unclear. The aim of the present study was to evaluate the antidepressant-like activity following acute and subchronic treatment with sildenafil in naïve mice as well as in mice with reserpine- and restraint stress-induced depressive-like behavior. Since corticosterone is released in response to acute stress, we also aimed to assess the influence of sildenafil on serum corticosterone level in non-stressed and stressed animals. The antidepressant activity of sildenafil was assessed in the forced swim test. Corticosterone serum level was determined by using ELISA method, while brain and serum sildenafil level via HPLC method. Sildenafil administered acutely exerted an antidepressant-like effect. Subchronic (14 days) administration of sildenafil resulted only in a weak antidepressant-like effect when evaluated 24 h after the last dose. Acute but not subchronic sildenafil administration reversed the reserpine- and stress-induced immobility in the forced swim test. The lack of effects of sildenafil after subchronic treatment could have been related to its complete elimination from the brain within 24 h from the last injection. Interestingly, acute administration of sildenafil produced a marked increase in serum corticosterone level in both non-stressed and stressed animals. Sildenafil exerts differential effects in the forced swim test after acute and subchronic administration. Further studies on the antidepressant activity of sildenafil are required.


Expectations of new treatment in rheumatoid arthritis: developing a patient-generated questionnaire.
Service-user partnerships in research exist in mental health, but there have been few advances in other disciplines, apart from cancer. To develop a patient-generated expectancy measure for new treatments in rheumatoid arthritis (RA), using a participatory method. Stage 1: three repeated focus groups and two expert panels with patients with RA conducted by a patient researcher to generate items for the draft questionnaire. Stage 2: feasibility study of draft scale with consecutive outpatient attendees. Patients identified 21 dimensions of new treatment expectations, grouped into (i) physical, (ii) psycho-social and (iii) expectations relating to the impact of treatment. This resulted in a draft instrument assessed in a feasibility study. The participatory research method was useful in involving patients actively in research and to produce collaboratively a feasible, valid and acceptable measure in RA. The scale will be included in a longitudinal observational study, with newly diagnosed patients, to assess (i) whether the new scale demonstrates sensitivity to change for expectations when receiving new treatment and (ii) participants' completion rate of the new scale compared with five instruments included in the future study.