A population cytogenetic study of a common fragile site, fra(3)(p14), in a healthy population.
A population survey of a common folate-sensitive fragile site, fra(3)(p14), was carried out on PHA-stimulated peripheral lymphocytes of 1,078 healthy subjects. Fra(3)(p14) was expressed more frequently in the younger than in the older, and in males than in females. It also showed some seasonal variation. The age difference of the expression frequency was also observed by aphidicolin treatment. A positive correlation of the expression frequency was found, though not so strongly, between both culture conditions of folate deprivation and aphidicolin treatment, These findings suggest that the inter-individual variation in the expressivity of common fragile sites is not only ascribable to chance, but to some physiological conditions of blood donors such as response rate of lymphocyte to PHA stimulation and blood concentration of folic acid.


T Cell Metabolism in a State of Flux.
Our knowledge of T cell metabolism relies primarily on studies performed in vitro that may not fully recapitulate physiological conditions in vivo. In this issue of Immunity, Ma et al. find that the in vivo environment dictates the metabolic phenotype of effector CD8+ T cells-particularly their glucose utilization.


Excess all-cause mortality in the USA and Europe during the COVID-19 pandemic, 2020 and 2021.
Both the USA and Europe experienced substantial excess mortality in 2020 and 2021 related to the COVID-19 pandemic. Methods used to estimate excess mortality vary, making comparisons difficult. This retrospective observational study included data on deaths from all causes occurring in the USA and 25 European countries or subnational areas participating in the network for European monitoring of excess mortality for public health action (EuroMOMO). We applied the EuroMOMO algorithm to estimate excess all-cause mortality in the USA and Europe during the first two years of the COVID-19 pandemic, 2020-2021, and compared excess mortality by age group and time periods reflecting three primary waves. During 2020-2021, the USA experienced 154.5 (95% Uncertainty Interval [UI]: 154.2-154.9) cumulative age-standardized excess all-cause deaths per 100,000 person years, compared with 110.4 (95% UI: 109.9-111.0) for the European countries. Excess all-cause mortality in the USA was higher than in Europe for nearly all age groups, with an additional 44.1 excess deaths per 100,000 person years overall from 2020-2021. If the USA had experienced an excess mortality rate similar to Europe, there would have been approximately 391 thousand (36%) fewer excess deaths in the USA.


Strategies for successful promotion for clinical track nursing faculty.
Successful promotion of faculty yields multiple benefits including career advancement, recognition for productivity and contributions to the organization, and an increase in financial compensation for the individual. In academic settings, particularly in research intensive institutions, time and resources often are focused on supporting tenure track faculty to be successful in obtaining promotion and tenure. Although most nursing programs have substantial numbers of clinical track faculty (CTF), there may be less emphasis around planning and resources for performing activities that will lead to successful promotion for nontenure track faculty. Consequently, at the time of initial faculty appointment, CTF must begin promotion planning. This paper provides practical advice for CTF preparing for promotion including planning the promotion trajectory and identifying and facilitating the collection of evidence supporting the areas of teaching, scholarship, practice, and service. Examples are provided of activities engaged in by CTF that would serve as evidence to support promotion.


Printer center nanoparticles alter the DNA repair capacity of human bronchial airway epithelial cells.
Nano-enabled, toner-based printing equipment emit nanoparticles during operation. The bioactivity of these nanoparticles as documented in a plethora of published toxicological studies raises concerns about their potential health effects. These include pro-inflammatory effects that can lead to adverse epigenetic alterations and cardiovascular disorders in rats. At the same time, their potential to alter DNA repair pathways at realistic doses remains unclear. In this study, size-fractionated, airborne particles from a printer center in Singapore were sampled and characterized. The PM0.1 size fraction (particles with an aerodynamic diameter less than 100 nm) of printer center particles (PCP) were then administered to human lung adenocarcinoma (Calu-3) or lymphoblastoid (TK6) cells. We evaluated plasma membrane integrity, mitochondrial activity, and intracellular reactive oxygen species (ROS) generation. Moreover, we quantified DNA damage and alterations in the cells' capacity to repair 6 distinct types of DNA lesions. Results show that PCP altered the ability of Calu-3 cells to repair 8oxoG:C lesions and perform nucleotide excision repair, in the absence of acute cytotoxicity or DNA damage. Alterations in DNA repair capacity have been correlated with the risk of various diseases, including cancer, therefore further genotoxicity studies are needed to assess the potential risks of PCP exposure, at both occupational settings and at the end-consumer level.


Expedient synthesis of the pentasaccharide repeating unit of the O-antigen of Escherichia coli O86 and its conformational analysis.
Synthesis of the pentasaccharide with a 2-aminoethyl linker attached to the reducing end corresponding to the cell wall O-antigen of Escherichia coli O86 strain is reported. The synthetic strategy involves sequential glycosylation of suitably protected monosaccharide intermediates under similar glycosylation reaction conditions. Thioglycosides have been used as glycosyl donor throughout the synthetic strategy. Conformational analysis of the synthesized pentasaccharide has been carried out using 2D ROESY NMR spectral analysis and all atom explicit molecular dynamics (MD) simulation technique. Graphical abstract Facile synthesis of the pentasaccharide with a 2-aminoethyl linker attached to the reducing end corresponding to the cell wall O-antigen of Escherichia coli O86 strain is reported. Conformational analysis of the synthesized pentasaccharide has been carried out using 2D ROESY NMR spectral analysis and all atom explicit molecular dynamics (MD) simulation technique.


The Relationship Between Caregiver Burden and Resilience and Quality of Life in a Turkish Pediatric Rehabilitation Facility.
To investigate the effect of caregiver burden, resilience, and quality of life of the parents of patients who are followed-up in a tertiary pediatric rehabilitation clinic. This is a correlational cross-sectional study. Parents of patients who attend to utilize pediatric rehabilitation outpatient clinics of a tertiary center on a regular basis were invited to participate. All participants filled in the Zarit Caregiver Burden (ZCB) scale, Family Resilience scale (FRS) and Nottingham Health Profile (NHP). A total of 107 patient and caregiver dyads were included. Fifty-five (51%) patients had cerebral palsy, 10 (9%) had spina bifida and 42 (39%) had other neurodevelopmental disorders. Eighty-one (75%) of the caregivers were mothers. There was a significant difference in the caregiver burden between ambulatory children (Mean ZCB score 30.11 ± 13.56) and non-ambulatory patients (Mean ZCB score 37.22 ± 13.91) (p = .01). There were moderate negative correlations between caregiver burden and FRS commitment to life and FRS self-sufficiency subscales. Caregiver burden significantly positively correlated with all NHP domains. Caregiver burden is significantly higher in parents of non-ambulatory children when compared to ambulatory children in the pediatric rehabilitation setting. Caregiver burden and resilience correlated on moderate levels, but the factors influencing them are still unclear. Healthcare and social support should be given to all caregivers in pediatric rehabilitation setting, but more so to the caregivers of non-ambulatory patients.


Treatment of port-wine stain birthmarks using the 1.5-msec pulsed dye laser at high fluences in conjunction with cryogen spray cooling.
The majority of port-wine stain (PWS) patients treated with the pulsed dye laser (PDL) do not achieve complete blanching. Safe administration of higher fluences has been proposed as a means of improving treatment efficacy. To determine the safety and efficacy of PWS treatment with the 1.5-msec PDL at high fluences in conjunction with cryogen spray cooling. Twenty PWS patients were treated with the PDL in combination with cryogen spray cooling utilizing a 7 or 10 mm spot size and fluences ranging from 6 to 15 J/cm2. Before and after treatment photographs were compared on a blinded basis. No scarring or skin textural changes occurred. Blanching scores were as follows: 20% of patients achieved 75% or greater blanching after an average of 3.3 treatments, 30% achieved 50-74% blanching, 20% achieved 25-49% blanching, and 30% achieved less than 25% blanching. In conjunction with cryogen spray cooling, the PDL can be safely used at high fluences. At this time it is not clear that the use of higher fluences improves treatment efficacy; however, as other aspects of PWS laser treatment are optimized, safe administration of higher fluences is likely to be advantageous.


Determination of nanogram amounts of primary aromatic amines and nitro compounds in blood and plasma.
A rapid and highly sensitive method, based on the direct fluorimetric scanning of thin-layer chromatograms, is described for the quantitative determination of flunitrazepam and its main metabolites in human blood or plasma. This method is generally applicable to aromatic nitro compounds that are reducible with tin(II) chloride. In particular, it is possible to determine primary amines in nanogram amounts. Fluorescamine is used as a regent to produce fluorescent derivatives. The method is suitable for pharmacokinetic studies of flunitrazepam and its main metabolites in human blood and plasma.


High-density electron anions in a nanoporous single crystal: [Ca24Al28O64]4+(4e-).
We removed approximately 100% of clathrated oxygen ions from the crystallographic cages in a single crystal of 12CaO.7Al2O3, leading to the formation of high-density (approximately 2 x 10(21) cm-3) electrons highly localized in the cages. The resulting electron forms a structure that we interpret as an F+ center and migrates throughout the crystal by hopping to a neighboring cage with conductivity approximately 100 siemens per centimeter, demonstrating that the encaged electron behaves as an anion. The electron anions couple antiferromagnetically with each other, forming a diamagnetic pair or singlet bipolaron. The resulting [Ca24Al28O64]4+(4e-) may be regarded as a thermally and chemically stable single crystalline "electride."


Imaging the field inside nanophotonic accelerators.
Controlling optical fields on the subwavelength scale is at the core of nanophotonics. Laser-driven nanophotonic particle accelerators promise a compact alternative to conventional radiofrequency-based accelerators. Efficient electron acceleration in nanophotonic devices critically depends on achieving nanometer control of the internal optical nearfield. However, these nearfields have so far been inaccessible due to the complexity of the devices and their geometrical constraints, hampering the design of future nanophotonic accelerators. Here we image the field distribution inside a nanophotonic accelerator, for which we developed a technique for frequency-tunable deep-subwavelength resolution of nearfields based on photon-induced nearfield electron-microscopy. Our experiments, complemented by 3D simulations, unveil surprising deviations in two leading nanophotonic accelerator designs, showing complex field distributions related to intricate 3D features in the device and its fabrication tolerances. We envision an extension of our method for full 3D field tomography, which is key for the future design of highly efficient nanophotonic devices.


Open clavicle fractures: patterns of trauma and associated injuries.
To describe the demographic distribution, mechanism of injury, and associated injuries of patients sustaining open clavicle fractures. Retrospective case series. Level I trauma center. Trauma registry data from all patients who required admission to the hospital from October 1995 through January 2010, specifically patients with open clavicle fractures. Not applicable. The patterns of open clavicle fractures and their association with severe, nonorthopaedic injuries (head, thoracic, and great vessel). Fifty-three patients with open clavicle fractures were identified, and they were organized by mechanism of injury: 21 sustained blunt injuries, 26 penetrating injuries, and six not specified. No difference between blunt and penetrating injuries existed with respect to age, Injury Severity Score, inpatient days, or mortality rates. Blunt injuries were more likely associated with head injuries (52%) versus penetrating injuries (22%), but penetrating injuries were more likely associated with a great vessel injury (27% vs 7%, respectively), all statistically significant (P = 0.0487). Open clavicle fractures are rare injuries. Patients often have associated head, thoracic, and great vessel injuries. Penetrating injuries have higher rates of great vessel injuries and that blunt force injuries have higher rates of head injuries.


Oral disease in relation to future risk of dementia and cognitive decline: prospective cohort study based on the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) trial.
Examine the association of oral disease with future dementia/cognitive decline in a cohort of people with type 2 diabetes. A total of 11,140 men and women aged 55-88 years at study induction with type 2 diabetes participated in a baseline medical examination when they reported the number of natural teeth and days of bleeding gums. Dementia and cognitive decline were ascertained periodically during a 5-year follow-up. Relative to the group with the greatest number of teeth (more than or equal to 22), having no teeth was associated with the highest risk of both dementia (hazard ratio; 95% confidence interval: 1.48; 1.24, 1.78) and cognitive decline (1.39; 1.21, 1.59). Number of days of bleeding gums was unrelated to these outcomes. Tooth loss was associated with an increased risk of both dementia and cognitive decline.


Glyoxalase I polymorphism in Catalonia (Spain).
Blood samples from two Catalonian populations (North-East of Spain) were analysed for glyoxalase (GLO) I polymorphism. Gene frequencies of GLO1 (0.46 and 0.41) are comparable to those reported for Central-European Caucasoid populations.


Effect of Biologics in Subgroups of Axial Spondyloarthritis Based on Magnetic Resonance Imaging and C-Reactive Protein: A Systematic Review and Meta-Analysis.
To determine if the efficacy of biologics differ based on magnetic resonance imaging (MRI) and C-reactive protein (CRP) findings. We compared four subgroups (MRI+/CRP+, MRI+/CRP-, MRI-/CRP+, MRI-/CRP-) from randomized controlled trials (RCTs). A comprehensive database search was performed to include axial spondylarthritis (axSpA; both radiographic axSpA [r-axSpA] and nonradiographic axSpA [nr-axSpA]) RCTs with treatment efficacy reported by different MRI and CRP subgroups. Study-specific disease activity scores (at 12-16 weeks) were pooled using a random-effects model and compared between the four subgroups. Five trials (all nr-axSpA) were included: three with tumor necrosis factor inhibitors (TNFi, N = 729) and two with interleukin-17 inhibitors (IL-17i, N = 794). TNFi and IL-17i showed efficacy based on the Assessment of Spondyloarthritis International Society 40 (ASAS40) and Bath Ankylosing Spondylitis Disease Activity Index 50 (BASDAI50) in all MRI and CRP subgroups, except the CRP-/MRI- subgroup, which had a single study with only 39 patients. There was no statistically significant difference between the four subgroups in terms of patients achieving ASAS40 (P = 0.60, I2 = 0%) or BASDAI50 (P = 0.27, I2 = 23.9%). The number needed to treat was three for the CRP+/MRI+ and CRP+/MRI- subgroups and six for the CRP-/MRI+ and CRP-/MRI- subgroups. All trials had a low risk of bias. Between-study heterogeneity was low to moderate. Sensitivity analyses comparing TNFi or IL-17i versus placebo similarly showed no difference between subgroups in terms of ASAS40 (TNFi, P = 0.57; IL-17i, P = 0.28) and BASDAI50 (TNFi, P = 0.37; IL-17i, P = 0.18). In this systematic review, there was no statistically significant difference between the four subgroups in terms of efficacy based on ASAS40 or BASDAI50.


Water balance profiles, humidity preference and survival of two sympatric cockroach egg parasitoids Evania appendigaster and Aprostocetus hagenowii (Hymenoptera: Evaniidae; Eulophidae).
The impact of desiccation on habitat selection, foraging and survival has been characterized for many insects. However, limited information is available for parasitic wasps. In this study, water balance, relative humidity (RH) preference, and effect of humidity on survival of solitary Evania appendigaster (L.) (Hymenoptera: Evaniidae) and gregarious Aprostocetus hagenowii (Ratzeburg) (Hymenoptera: Eulophidae) were examined. These species are both oothecal parasitoids of the American cockroach Periplaneta americana (L.) (Dictyoptera: Blattidae). E. appendigaster had significantly higher cuticular permeability (CP) and a lower surface area to volume ratio but a similar percentage of total body water content compared to A. hagenowii. No differences in these attributes were found between sexes of each parasitoid species. The percentage of total body water loss rates among E. appendigaster males and females and A. hagenowii females were similar but significantly lower than that of A. hagenowii males. All parasitoids except E. appendigaster males exhibited reduced survival times as the RH of their enclosure decreased from 87% to 38%, but this phenomenon did not occur when parasitoids were given a sugar solution. In environmental chambers with a 44-87% RH gradient, both sexes of E. appendigaster resided significantly more often in the 87% RH chamber than in the 44% RH chamber. For A. hagenowii, females preferred both the driest and the wettest chambers and males preferred the driest ones. These results demonstrate the water balance profile and its relationship to life history traits and differential responses to RH in these competing parasitoid wasps, suggesting the role of physiological and behavioral adaptations in shaping their ecological niche.


The role of protein restriction and interaction with antibiotics in the regulation of compensatory growth in pigs: growth performance, serum hormone concentrations, and messenger RNA levels in component tissues of the endocrine growth axis.
The present study investigated the effects of protein restriction and antibiotics on the hypothalamus-pituitary-liver growth axis during the compensatory growth of growing and finishing pigs. Growth performance, serum hormones, and messenger RNA (mRNA) levels of hormones and their receptors in growth axis tissues were recorded for analyses. A total of 64 piglets (large white × Landrace × Duroc cross) with an initial weight of 10.07 ± 0.14 kg were randomly divided into 4 treatment groups of 16 piglets per group. The dietary treatments consisted of 2 protein levels (14% and 20%) and 2 antibiotic levels (no antibiotics and 20 mg/kg colistin sulfate with 50 mg/kg kitasamycin) in a 2 × 2 factorial arrangement. The study was performed over 30 d for the first stage (S1, restriction phase) and 74 d for the second stage (S2, realimentation phase). The 4 treatment diets were maintained throughout the duration in the restriction phase. The 4 groups were fed the same diet in the realimentation phase. The trial period totaled 104 d. Protein restriction decreased BW, average daily food intake, and ADG in weaning pigs (P < 0.01) and induced compensatory growth after feeding a normal diet during the growth of finishing pigs. Average daily gain increased during the last phase of compensatory growth (P < 0.01). Protein restriction increased serum GH and leptin (LEP) and the mRNA levels of liver IGF-1 receptor (IGF-1-R; P < 0.01) but decreased serum IGF-1 (P < 0.01) and the mRNA levels of liver GH receptor (GH-R; P < 0.01) and IGF-1 (P < 0.05) in weaning piglets. Serum GH was increased, but serum IGF-1 was decreased during the realimentation phase (P < 0.05). Antibiotics increased the mRNA levels of GHRH (P < 0.05) and decreased somatostatin (P < 0.01) in the hypothalamus of weaning pigs. Protein restriction and antibiotics had no interactions across the entire trial. In conclusion, the slowing of growth caused by early protein restriction may be compensated for in the later stages of pig raising, and the mechanism of compensation is related to the regulation of GH, IGF-1, GH-R, and IGF-1-R.


Expression of L-CCR in HEK 293 cells reveals functional responses to CCL2, CCL5, CCL7, and CCL8.
It has become clear in the past years that chemokines and chemokine receptors are pivotal regulators of cellular communication and trafficking. In addition to the approximately 20 chemokine receptors that have been cloned and described, various orphan receptors with a chemokine receptor-like structure are known. We have investigated the orphan mouse chemokine receptor (L-CCR) in HEK 293 cells, a receptor that was originally described in a mouse macrophage cell line. Cells expressing this receptor show pertussis toxin-sensitive chemotaxis and small intracellular calcium transients in response to the chemokines CCL2, CCL7, CCL8, and CCL5. Biotinylated CCL2 binds to L-CCR-expressing cells, and transfection experiments with an L-CCR-green fluorescent protein fusion protein showed L-CCR expression in the membranes of recombinant HEK 293 cells. Although radioligand binding was not detected, it is suggested that L-CCR is a functional chemokine receptor.


Inhibition of neuronal nicotinic acetylcholine receptor channels expressed in Xenopus oocytes by beta-amyloid1-42 peptide.
Neuronal nicotinic acetylcholine receptors (nAChRs) are involved in a variety of physiological processes, including cognition and development. Dysfunctions in nAChRs have been linked to Alzheimer's disease (AD), a human neurological disorder that is the leading cause of dementia. AD is characterized by an increasing loss of cognitive function, nAChRs, cholinergic neurons, and choline acetyltransferase activity. A major hallmark of AD is the presence of extracellular neuritic plaques composed of the beta-amyloid (Abeta1-42) peptide; however, the link between Abeta1-42 and the loss of cognitive function has not been established. Many groups have shown direct interactions between Abeta1-42 and nAChR function, however, with differing results. For example, in rat hippocampal CA1 interneurons in slices, we found that Abeta1-42 inhibits nAChR channels directly, and non-alpha7 receptors were more sensitive to block than alpha7 receptors. However, some groups have found that alpha7 subtypes were potently blocked by Abeta1-42, whereas other groups reported that Abeta1-42 can activate nAChRs (i.e., both alpha7 and non-alpha7 subtypes). To further investigate the link between nAChR function and Abeta1-42, we expressed various subtypes of nAChRs in Xenopus oocytes (e.g., alpha4beta2, alpha2beta2, alpha4alpha5beta2, and alpha7) and found that Abeta1-42 blocked these various non-alpha7 nAChRs, without any effect on alpha7 nAChRs. Furthermore, none of these channels was activated by Abeta1-42. The relative block by Abeta1-42 was dependent on the subunit makeup and apparent stoichiometry of these receptors. These data further support our previous findings that Abeta1-42 directly and preferentially inhibits non-alpha7 nAChRs.


Quantitation of escitalopram and its metabolites by liquid chromatography-tandem mass spectrometry in psychiatric patients: New metabolic ratio establishment.
Therapeutic drug monitoring (TDM) is used to determine the concentration of drug in plasma/serum to adjust the dose of the therapeutic drug. Selective and sensitive analytical methods are used to determine drug and metabolite levels for the successful application of TDM. The aim of the study was to develop and validate using LC-MS/MS to analyse quantitative assay of escitalopram (S-CT) and metabolites in human plasma samples. In order to provide a convenient and safe treatment dose, it was aimed to determine the levels of S-CT and its metabolites in the patients' plasma. A new method with short sample preparation and analysis time was developed and validated using LC-MS/MS to analyse quantitative assay of S-CT and its metabolites in plasma. Also, plasma samples of 30 patients using 20 mg S-CT between the ages of 18 and 65 years were analysed by the validated method. The mean values of S-CT, demethyl escitalopram and didemethyl escitalopram in plasma of patients were 27.59, 85.52 and 44.30 ng/mL, respectively. At the end of the analysis, the metabolic ratio of S-CT and metabolites was calculated. It is considered that the method for the quantitative analysis of S-CT and its metabolites in human plasma samples may contribute to the literature on account of its sensitive and easy application. Additionally, the use of our data by physicians will contribute to the effective drug treatment for their patients who take S-CT.


Environmental risk assessment of priority biocidal substances on Polish surface water sample.
The EU directive 2013/39/EU has incorporated four biocidal compounds as priority substances: diuron, isoproturon, cybutryne, and terbutryn. The research was undertaken to determine the concentration of biocides in surface waters in three locations in southern Poland: the Wisła River in Kraków, the Wisłoka River in Mielec, and the drainage ditch draining water from arable fields located near Mielec. Environmental samples were taken in two series: winter (February) and spring (May and June). The analyses were carried out using gas chromatography with mass spectrometry. The seasonality of biocides in surface waters was observed. In winter samples, the concentrations were below MQL, while in spring, they ranged from a few to several dozen nanograms per liter. The highest concentrations of all analyzed compounds were recorded in water taken from the Wisła River. According to directive 2013/39/EU, the maximum allowable concentration was exceeded only in the case of cybutryne in water from the Wisła, both in May and in June. The assessment of the toxicity with the tested compounds was defined based on the Environmental Risk Assessment method. Low risk was estimated for diuron and isoproturon, while moderate risk for terbutryn and cybutryne.


Distributed data analysis in a multicenter study: the CARDIA Study.
Unlike distributed data entry, which is used in many large epidemiologic studies and multicenter clinical trials, distributed data analysis is a relatively new concept. This paper reports on the usefulness of such a system in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. CARDIA distributes the entire examination dataset to participating centers soon after completion of each round of data collection. The process was designed to encourage more numerous, diverse, and rapid publications, and to allow for more efficient use of the manpower and expertise in centers. Responsibilities of the coordinating center have changed from a conventional coordinating center but remain substantial due to the need for collating, monitoring, verifying, and documenting the distributed data analysis (DDA) system. DDA is successful from the standpoint of implementation and operation--21 manuscripts representing work analyzed at six participating centers had been submitted for publication within 3.5 years of the completion of the baseline examination.


Tumour-lysis-related elevation of intraocular pressure following high-dose rate brachytherapy for choroidal melanoma.
To describe the clinical course and management of acute tumour lysis-related intraocular pressure (IOP) elevation, which is a rare late complication of brachytherapy for choroidal melanoma. Seven patients out of 36 treated with Iodine-125 brachytherapy were identified who had in common: an uneventful latent period with continuing tumour regression, ended by a sudden massive release of pigmented debris in association with elevated IOP without iris neovascularization. Medications that reduce aqueous production (timolol, dorzolamide, betaxolol, and acetozolamide) were used in combinations to lower IOP. Tumour lysis developed after a mean period of 17.4 months. IOPs ranged between 28 and 35 mmHg, which normalized in a mean period of 10.7 months under topical medications. The seven patients were inadvertently prescribed apical dose rates ranging between 118.3 to 289.16 cGy/h that were significantly higher than the rest of the group (P = 0.000). This complication did not develop in patients whose apical dose rates did not exceed 109 cGy/h. Acute tumour lysis associated with an elevated IOP after brachytherapy appears to be related to large tumour size and high dose rates. IOP can be lowered by topical medications but visual prognosis is poor. There is no evidence of any effect on overall prognosis of tumour lysis, elevation of IOP, or its treatment.


[Epidemiological and prognostic profile of acute heart failure: experience in the emergency department at the Charles Nicole Hospital of Tunis from 2013 to 2014].
Acute Heart Failure (AHF) is a specific syndromic disorder grouping several heterogeneous clinical conditions frequently seen in the emergency department. This study aimed to describe the epidemiological, clinical, therapeutic and prognostic features of patients with AHF admitted to the emergency department. We conducted a prospective, descriptive study in the emergency department. It included all patients admitted with AHF. We studied the epidemiological, clinical, therapeutic and prognostic features of these patients. The study enrolled 180 patients with AHF admitted to the emergency department. Sex ratio was 1.27. The average age of patients was 66±12 years. Eighty-two percent of patients were hypertensive and 69% were known diabetic patients. The causes of decompensation included primarily hypertensive crisis (61.7% of patients), acute coronary syndrome (24% of patients). Respiratory support was mainly provided by CPAP (Continuous Positive Airway Pressure) in 73.3% of cases. Pharmacological treatment was based on nitrate derivatives (70% of cases) and diuretic (40.5% of cases). Acute heart failure incidence at one month was 21.7% (n=39 patients) and mortality rate at 3 months was 13.3%. Patients with AHF treated in the emergency department mainly had hypertensive crisis. Treatment is primarily based on CPAP, vasodilators and diuretics. Recurrence rate and mortality rate were high.


Defining predictive values using three different platelet function tests for CYP2C19 phenotype status on maintenance dual antiplatelet therapy after PCI.
Published data suggests that the presence of CYP2C19*2 or *3 loss of function (LOF) alleles is indicative of increased platelet aggregation and a higher risk of adverse cardiovascular events after clopidogrel administration. We sought to determine cut-off values using three different assays for prediction of the CYP2C19 phenotype in Korean percutaneous coronary intervention (PCI) patients. We enrolled 244 patients with drug-eluting stent implantation who were receiving clopidogrel and aspirin maintenance therapy for one month or more. Platelet reactivity was assessed with light transmittance aggregometry (LTA), multiple electrode aggregometry (MEA) and the VerifyNow P2Y12 assay (VN). The CYP2C19 genotype was analyzed by polymerase chain reaction (PCR) and snapshot method. The frequency of CYP2C19 LOF allele carriers was 58.6%. The cut-off values from LTA, MEA and VerifyNow for the identification of LOF allele carriers were as follows: 10 µM ADP-induced LTA ≥ 48 %, VN>242 PRU and MEA ≥ 37 U. Between the three tests, correlation was higher between LTA vs. VN assays (r=0.69) and LTA vs. MEA (r=0.56), with moderate agreement (κ=0.46 and κ=0.46), but between VN assay and MEA, both devices using whole blood showed a lower correlation (r=0.42) and agreement (κ=0.3). Our results provide guidance regarding cut-off levels for LTA, VerifyNow and MEA assays to detect the CYP2C19 LOF allele in patients during dual antiplatelet maintenance therapy.


Development of epidural abscess following surgical drainage of perianal abscess: report of a case.
A case of epidural abscess originating from a perianal abscess is reported. The history of the patient, erythrocyte sedimentation rate, magnetic resonance imaging, and bacteriological tests were used to reach a diagnosis and the possible mechanism. Epidural abscess was suspected because the patient had a fever and intense low back pain following drainage of a perianal abscess. Magnetic resonance imaging was used to correctly diagnose the epidural abscess and bacteriologic studies disclosed the pathophysiologic mechanism. Epidural abscess is an extremely rare complication of perianal abscess. It should always be suspected in a patient with acute onset of back pain, fever, history of recent infection, and an elevated erythrocyte sedimentation rate, because delay in diagnosis can cause neurologic compromise and even death.


Relationship between baseline systolic blood pressure and long-term outcomes in acute heart failure patients treated with TRV027: an exploratory subgroup analysis of BLAST-AHF.
TRV027, a 'biased' ligand of the angiotensin II type 1 receptor (AT1R), did not affect a composite clinical outcome at 30 days in a phase 2b acute heart failure (AHF) trial (BLAST-AHF). Post-hoc analyses from BLAST-AHF (n = 618) examined the effects of TRV027 by baseline systolic blood pressure (SBP) on changes in renal function and 180-day outcomes. Interactions between baseline SBP and select endpoints were identified utilizing a subpopulation treatment effect pattern plots (STEPP) analysis, then grouping of patients by SBP tertile: < 127, ≥ 127 to < 140, and ≥ 140 mmHg. A trend towards increased creatinine in the first 3 days was noted in the lower SBP tertile, while in those in the higher two tertiles, TRV027, especially the 1 mg/h dose, reduced creatinine at days 5 and 30. Beneficial effects on 180-day all-cause mortality and cardiovascular (CV) death or readmission were observed in the two higher SBP tertiles (SBP ≥ 127 mmHg) in the TRV027 1 mg/h dose group (all-cause mortality HR 0.39, 95% CI 0.14-1.06, p = 0.056; CV death or HF/RF rehospitalization HR 0.53, 95% CI 0.28-1.01, p = 0.049), while more adverse outcomes were observed in patients in the lower SBP tertile. This post-hoc analysis of the BLAST-AHF study suggests contrasting effects of TRV027 by baseline SBP, with trends towards lower 180-day event rates in patients enrolled with higher baseline SBP, especially when given lower doses of TRV027.


EasyMEG: An easy-to-use toolbox for MEG analysis.
Magnetoencephalography (MEG) is an advanced magnetic source imaging technology that measures the magnetic fields produced by neural activities. It has been extensively used in scientific research and clinical diagnosis due to its high temporal and spatial resolution. Considering the special nature of MEG data, it needs to perform a series of processes and analysis to obtain valuable information. Therefore, the identification of data processing is a key point of MEG studies. At present, the software for MEG analysis such as FieldTrip has no Graphic User Interface (GUI) and users must write their own script to perform concrete analysis. It brings the difficulties to researchers like the doctors without experience in programming or newcomers to MEG. Thus, an open-sourced software-EasyMEG was developed. It has friendly interface with highly functions-integration. The functions of EasyMEG are developed based on MATLAB language to ensure the consistency of the user interface under different operating systems. EasyMEG is a highly integrated software that contains a set of functions for preprocessing, time-lock analysis, time-frequency analysis, source analysis, and plotting. EasyMEG provides a friendly GUI and allows users to complete analyses through a simple and clean interface. This toolbox has been released as an open-source software on GitHub under the GNU General Public License: https://tonywu2018.github.io/EasyMEG/. We hope to improve this toolbox by the power of community and wish to make EasyMEG a simple and powerful toolbox for further MEG studies.


Evaluation on the applied value of the dot immunogold filtration assay (DIGFA) for rapid detection of anti-Schistosoma japonicum antibody.
The dot immunogold filtration assay (DIGFA) is a rapid technique for the detection of anti-Schistosoma japonicum antibody. Its sensitivity with regard to sera obtained from patients with acute or chronic schistosomiasis was shown to be 100 and 96.9%, respectively. The specificity when using sera of people living in an area non-endemic for schistosomiasis japonica was 100%. Cross-reaction rates for paragonimiasis and clonorchiasis patients were 14.3% and 0%, respectively. Parallel serum tests of 1091 residents from an area endemic for S. japonicum by means of DIGFA, enzyme-linked immunosorbent assay and indirect haemagglutination test resulted in positive rates of 9.3%, 11.5% and 11.0%, respectively. Thus, there was a high level of agreement between the sets of results (P>0.05). In conclusion, DIGFA holds considerable promise for rapid and accurate diagnosis of S. japonicum, as it does not require any specific instruments and can be applied with ease. DIGFA has therefore several advantages over conventional diagnostic approaches and is useful not only for screening and sero-epidemiological surveys in the field, but also in clinical settings.


PEGylated substrates of NSP4 protease: A tool to study protease specificity.
Herein we present the synthesis of a novel type of peptidomimetics composed of repeating diaminopropionic acid residues modified with structurally diverse heterobifunctional polyethylene glycol chains (abbreviated as DAPEG). Based on the developed compounds, a library of fluorogenic substrates was synthesized. Further library deconvolution towards human neutrophil serine protease 4 (NSP4) yielded highly sensitive and selective internally quenched peptidomimetic substrates. In silico analysis of the obtained peptidomimetics revealed the presence of an interaction network with distant subsites located on the enzyme surface.


Oxytocin receptor pattern of expression in primary lung cancer and in normal human lung.
In order to assess if oxytocin- and vasopressin-induced mitogenic effects detected on small-cell lung carcinoma (SCLC) cell lines could be transposed on primary SCLC, the aim of the present work was to identify mediators of these mitogenic actions on primary tumours samples. This was addressed on normal human lung tissue, on SCLC and on non-SCLC (NSCLC). Herein, we observe, in normal human lung, that OTR is colocalized with vascular endothelial cells of the lung and is not expressed by lung cells of epithelial nature. We detected mRNA amplification of V1aR, V2R and of a V2R variant. We observed that 86% of SCLC biopsies analyzed expressed at least the OTR and that 71% expressed the OTR, the V1aR and the V2R altogether. Comparatively, 50% of NSCLC biopsies tested expressed at least the OTR and 32% expressed the OTR, the V1aR and the V2R altogether. The occurrence of the V1bR/V3R is of 28 and 18% for SCLC and NSCLC, respectively. Nevertheless, for the SCLC biopsies analyzed in this study, V1bR/V3R expression correlates, in all cases, with the expression of all the other neurohypophysial peptide receptors. Our results suggest that neurohypophysial peptide antagonists may offer promise as a potential new therapeutic modality for the treatment of lung cancer expressing at least one of the neurhypophysial peptide receptor subtypes.


ERP correlates of pitch error detection in complex tone and voice auditory feedback with missing fundamental.
Previous studies have shown that the pitch of a sound is perceived in the absence of its fundamental frequency (F0), suggesting that a distinct mechanism may resolve pitch based on a pattern that exists between harmonic frequencies. The present study investigated whether such a mechanism is active during voice pitch control. ERPs were recorded in response to +200 cents pitch shifts in the auditory feedback of self-vocalizations and complex tones with and without the F0. The absence of the fundamental induced no difference in ERP latencies. However, a right-hemisphere difference was found in the N1 amplitudes with larger responses to complex tones that included the fundamental compared to when it was missing. The P1 and N1 latencies were shorter in the left hemisphere, and the N1 and P2 amplitudes were larger bilaterally for pitch shifts in voice and complex tones compared with pure tones. These findings suggest hemispheric differences in neural encoding of pitch in sounds with missing fundamental. Data from the present study suggest that the right cortical auditory areas, thought to be specialized for spectral processing, may utilize different mechanisms to resolve pitch in sounds with missing fundamental. The left hemisphere seems to perform faster processing to resolve pitch based on the rate of temporal variations in complex sounds compared with pure tones. These effects indicate that the differential neural processing of pitch in the left and right hemispheres may enable the audio-vocal system to detect temporal and spectral variations in the auditory feedback for vocal pitch control.


A framework for resolving the transboundary water allocation conflict conundrum.
This paper describes a methodology for resolving transboundary water disputes that arise when people/states/nations sharing a resource that crosses legal/political jurisdictions disagree about the use of the resource. Laws and treaties written in an attempt to settle disputes are frequently neither enforced nor effective, and disagreements continue. Crises, arising through resource overuse or shortages, worsen the conflict and typically result in further discord, lawsuits, depletion of the resource, and even open-armed hostility. Many water management experts call for either private/market-based or state/command-and-control resource management systems, but these eventually break down during crisis. The crises therefore necessitate the adoption of a more effective institutional arrangement to address and resolve present and future problems. A better alternative to management by private or state entities and the resolution of conflicts by the mere application of law is a cooperative approach. The Rowland-Ostrom Framework, introduced in this paper, incorporates Ostrom's eight design principles for sustainable common pool resource management within the context of crisis that involves an urgent threat to the quantity or quality of a resource such as water, as described by the author. This paper demonstrates that although established 15 years ago, Ostrom's design principles remain applicable today for effective, sustainable transboundary water management, and the Rowland-Ostrom Framework is a model for the equitable use of shared water resources throughout the world.


Oligopeptide inhibitors of metalloendoprotease activity inhibit catecholamine secretion from bovine adrenal chromaffin cells by modulating intracellular calcium homeostasis.
Synthetic oligopeptide inhibitors of metalloendoprotease activity were found to inhibit catecholamine release from intact bovine adrenal chromaffin cells. The efficiency of these compounds in blocking secretion was dependent on the type and dose of the secretagogues employed. By contrast, catecholamine release from digitonin-permeabilized cells stimulated with micromolar calcium was virtually not affected. Using a different model system mimicking protein-mediated membrane fusion during exocytosis (Bental, M., Lelkes, P.I., Scholma, J., Hoekstra, D., and Wilschut, J. (1984) Biochim. Biophys. Acta 774, 296-300) we found that exposure of chromaffin granules to a genuine metalloendoprotease, thermolysin, impaired their fusion competence with liposomes. The same oligopeptide inhibitors of metalloendoprotease activity that interfered with secretion from the intact cells were also found to cause an increase in 45Ca2+ efflux concomitant with a slight elevation of the free intracellular calcium concentration [( Ca2+]i) to levels not sufficient to elicit secretion. Subsequent stimulation of the cells in the presence of the potent inhibitors resulted in a reduced increase in the cytosolic calcium concentration, as compared to nontreated control cells. The reduction in the secretagogue-evoked rise in [Ca2+]i was also dependent on the time of pretreatment of the cells with the metalloendoprotease inhibitors. Consistently, none of these effects were seen with structurally similar oligopeptides that are not metalloendoprotease substrates/inhibitors. We conclude that potent inhibitors of metalloendoprotease activity and hence, presumably, the enzymes per se modulate stimulus-secretion coupling by interfering with calcium homeostasis rather than directly with membrane fusion.


Distribution of free N-acetylneuraminic acid in rat organs.
The concentration of free N-acetylneuraminic acid in various rat organs was estimated by gas chromatography/mass spectrometry. Its concentration was in the range of 3.95 to 104.72 micrograms/g wet tissues, being particularly high in the endocrine glands. The ratio of free N-acetylneuraminic acid to total N-acetylneuraminic acid varied from 0.031 to 0.183, being especially high in the adrenal gland (0.181) and heart (0.183).


Immunogenicity and safety of quadrivalent human papillomavirus types 6/11/16/18 recombinant vaccine in chronic kidney disease stage IV, V and VD.
Up to >80% of sexually active adults will become infected with human papillomavirus (HPV) during their lifetime. Persistent HPV infection can result in cervical, vulvovaginal, penile and anogenital cancer. Clinical studies have shown the efficacy of three doses of quadrivalent HPV-6/11/16/18 L1 virus-like particle (VLP) vaccination, at Day 0, Month 2 and Month 6, to lower the occurrence of HPV infection and its complications. However, immunogenicity and safety of the HPV vaccine have not been proven in the chronic kidney disease (CKD) population. Sixty CKD stage IV, V and VD patients were enrolled for quadrivalent HPV-6/11/16/18 vaccination. A dose of vaccine was given at Day 0, Month 2 and Month 6. Each dose contained 20 μg HPV-6 L1 VLP, 40 μg HPV-11 L1 VLP, 40 μg HPV-16 L1 VLP and 20 μg HPV-18 L1 VLP, along with 225 μg of amorphous aluminum hydroxyphosphate sulfate adjuvant. HPV type-specific antibody response to neutralizing epitopes on HPV-6/11/16/18 was performed by multiplexed, competitive Luminex® immunoassays (cLIA) at Day 0 and Month 7. At Day 0, anti-HPV seropositivity was 0-6.6% depending on HPV genotype. Patients who received three doses of vaccine had 98.2, 100, 100 and 98.2% seropositivity for genotypes 6/11/16/18, respectively. The average cLIA at Month 7 for genotypes 6/11/16/18 were 928.4 ± 231.1, 1136.1 ± 264.6, 6951.0 ± 1872.3 and 2196.3 ± 761.2 milliMerck units (mMu)/mL, respectively. No serious vaccine-related adverse events were observed. Quadrivalent HPV vaccine has been well tolerated, is safe and provides excellent immunogenicity in late-stage CKD.


Regeneration of the pulmonary vascular endothelium after viral pneumonia requires COUP-TF2.
Acute respiratory distress syndrome is associated with a robust inflammatory response that damages the vascular endothelium, impairing gas exchange. While restoration of microcapillaries is critical to avoid mortality, therapeutic targeting of this process requires a greater understanding of endothelial repair mechanisms. Here, we demonstrate that lung endothelium possesses substantial regenerative capacity and lineage tracing reveals that native endothelium is the source of vascular repair after influenza injury. Ablation of chicken ovalbumin upstream promoter-transcription factor 2 (COUP-TF2) (Nr2f2), a transcription factor implicated in developmental angiogenesis, reduced endothelial proliferation, exacerbating viral lung injury in vivo. In vitro, COUP-TF2 regulates proliferation and migration through activation of cyclin D1 and neuropilin 1. Upon influenza injury, nuclear factor κB suppresses COUP-TF2, but surviving endothelial cells ultimately reestablish vascular homeostasis dependent on restoration of COUP-TF2. Therefore, stabilization of COUP-TF2 may represent a therapeutic strategy to enhance recovery from pathogens, including H1N1 influenza and SARS-CoV-2.


Evidence for differential regulation of corticotropin-releasing factor and vasopressin immunoreactivities in parvocellular neurosecretory and autonomic-related projections of the paraventricular nucleus.
A combined retrograde transport-immunohistochemical method was used to compare the numbers of corticotropin-releasing factor (CRF) and vasopressin-immunoreactive neurons in the paraventricular nucleus of the hypothalamus (PVH) that could be retrogradely labeled after tracer injections in the dorsomedial medulla or the spinal cord in untreated, colchicine-treated, and adrenalectomized (ADX) male rats. In untreated animals, very few CRF-stained cells were retrogradely labeled after tracer injections in either target, while a modest number, comparable to that seen in previous studies, of vasopressinergic cells were found to project to one or both structures. Animals pretreated with colchicine, a non-specific inhibitor of axonal transport, displayed CRF immunoreactivity in a small percentage of retrogradely labeled neurons in the PVH; the number of retrogradely labeled vasopressin-immunoreactive cells was comparable to that seen in untreated rats. Despite the fact that ADX animals displayed enhanced immunostaining for both peptides in the parvocellular division of the PVH, the number of retrogradely labeled cells stained for each peptide was similar to that seen in controls. The results establish that CRF is contained within the long descending projections of the PVH, and are consistent with the view that adrenal steroid withdrawal preferentially enhances the expression of CRF and vasopressin in parvocellular neurosecretory neurons.


Studies on plasma fibrinogen level in pre-eclampsia and eclampsia.
The plasma fibrinogen level of maternal blood has been estimated in 30 cases of pre-eclampsia, 60 cases of eclampsia and 35 cases of normal pregnancy of 3rd trimester. The plasma fibrinogen value increased by about 70% and 145% in pre-eclampsia and eclampsia, respectively. In essential hypertension, the fibrinogen level remains more or less the same as in normal pregnancy.


Brain structural and functional connectivity in Parkinson's disease with freezing of gait.
To use a multimodal approach to assess brain structural pathways and resting state (RS) functional connectivity abnormalities in patients with Parkinson's disease and freezing of gait (PD-FoG). T1-weighted, diffusion tensor (DT) MRI and RS functional MRI (fMRI) were obtained from 22 PD-FoG patients and 35 controls on a 3.0 T MR scanner. Patients underwent clinical, motor, and neuropsychological evaluations. Gray matter (GM) volumes and white matter (WM) damage were assessed using voxel based morphometry and tract-based spatial statistics, respectively. The pedunculopontine tract (PPT) was studied using tractography. RS fMRI data were analyzed using a model free approach investigating the main sensorimotor and cognitive brain networks. Multiple regression models were performed to assess the relationships between structural, functional, and clinical/cognitive variables. Analysis of GM and WM structural abnormalities was replicated in an independent sample including 28 PD-FoG patients, 25 PD patients without FoG, and 30 healthy controls who performed MRI scans on a 1.5 T scanner. Compared with controls, no GM atrophy was found in PD-FoG cases. PD-FoG patients showed WM damage of the PPT, corpus callosum, corticospinal tract, cingulum, superior longitudinal fasciculus, and WM underneath the primary motor, premotor, prefrontal, orbitofrontal, and inferior parietal cortices, bilaterally. In PD-FoG, right PTT damage was associated with a greater disease severity. Analysis on the independent PD sample showed similar findings in PD-FoG patients relative to controls as well as WM damage of the genu and body of the corpus callosum and right parietal WM in PD-FoG relative to PD no-FoG patients. RS fMRI analysis showed that PD-FoG is associated with a decreased functional connectivity of the primary motor cortex and supplementary motor area bilaterally in the sensorimotor network, frontoparietal regions in the default mode network, and occipital cortex in the visual associative network. This study suggests that FoG in PD can be the result of a poor structural and functional integration between motor and extramotor (cognitive) neural systems.


Coronary vasospasm during anesthesia induction: awareness, recognition, possible mechanisms, anesthetic factors, and treatment.
We describe a patient who developed severe ST-segment elevation, pulseless ventricular tachycardia, and cardiac arrest during induction of general anesthesia. This transient ST-segment elevation may have been the result of coronary artery spasm. Awareness of this variant of coronary artery vasospasm--Prinzmetal angina--in patients without clear symptoms or established ischemic heart disease, is the key to successful outcome. Recommended preparations and treatments are preoperative calcium channel blockers, nitroglycerin available intraoperatively, reduction of endogenous or exogenous catecholamines, and vigilant monitoring.


Withaferin A suppresses breast cancer cell proliferation by inhibition of the two-pore domain potassium (K2P9) channel TASK-3.
Withaferin A (WFA), a C5,C6-epoxy steroidal lactone isolated from the medicinal plant Withania somnifera (L.) Dunal, inhibits growth of tumor cells in different cancer types. However, the mechanisms underlying the effect of WFA on tumor cells are not fully understood. In the present study, we evaluated the blockade of TASK-3 channels by WFA in TASK-3-expressing HEK-293 cells. Explore if the WFA-mediated TASK-3 blockade can be used as a pharmacological tool to decrease the cell viability in cancer cells. A combination of functional experiments (patch-clamp, gene downregulation, overexpression and pharmacological inhibition) and molecular docking analysis were used to get insights into the mechanism by which the inhibition of TASK-3 by WFA affects the growth and viability of cancer cells. Withaferin A was found to inhibit the activity of TASK-3 channels. The inhibitory effect of Withaferin A on TASK-3 potassium currents was dose-dependent and independent of voltage. Molecular modeling studies identified putative WFA-binding sites in TASK-3 channel involved the channel blockade. In agreements with the molecular modeling predictions, mutation of residues F125 to A (F125A), L197 to V (L197 V) and the double mutant F125A-L197 V markedly decreased the WFA-induced inhibition of TASK-3. Finally, the cytotoxic effect of WFA was tested in MDA-MB-231 human breast cancer cells transfected with TASK-3 or shRNA that decreases TASK-3 expression. Together, our results show that the cytotoxic effect of WFA on fully transformed MDA-MB-231 cells depends on the expression of TASK-3. Herein, we also provide insights into the mechanism of TASK-3 inhibition by WFA.


Structural conditions required for the bridge lithiation and substitution of a basic calix[4]arene.
Lithiation and subsequent reaction with CO(2) was applied to calix[4]arenes with different, equal or mixed, ether functions at the lower-rim site as well as tert-butylated or non-tert-butylated upper-rim positions. Whereas this reaction fails for symmetric calix[4]arene ethers with alkoxy residues greater than methoxy, the carboxylation of mixed methoxy-propoxy calixarene ethers is possible. In connection with this, several new monobridge-substituted calix[4]arenes were characterized with respect to their conformational behaviour in solution and the X-ray crystal structure of one key intermediate is taken into consideration.


Measurement of a 103Pd solution using the TDCR method by LSC.
Palladium 103 is a radionuclide used in brachytherapy sources for the treatment of prostate cancers and also for other medical applications. It decays through electron capture to excited levels of 103Rh. This paper describes the calculation method used to compute the detection efficiency in the framework of the triple to double coincidence ratio model. The calculation of the energy transferred to the scintillator is made by considering the various atomic events following the electron capture and the electron conversion. The energy deposited in the scintillator after the absorption of X-rays is calculated using the PENELOPE stochastic calculation code. The main contributors to the final uncertainty and their covariance matrix are discussed. As the calculation method cannot be reduced to an explicit function, this paper describes the Monte Carlo method used for the evaluation of uncertainties.


Novel protein-protein interactions between Entamoeba histolyticad-phosphoglycerate dehydrogenase and phosphoserine aminotransferase.
Physical interactions between d-phosphoglycerate dehydrogenase (EhPGDH) and phosphoserine aminotransferase (EhPSAT) from an enteric human parasite Entamoeba histolytica was observed by pull-down assay, gel filtration chromatography, chemical cross-linking, emission anisotropy, molecular docking and molecular dynamic simulations. The protein-protein complex had a 1:1 stochiometry with a dissociation constant of 3.453 × 10(-7) M. Ionic interactions play a significant role in complex formation and stability. Analysis of the energy minimized average simulated model of the protein complex show that the nucleotide binding domain of EhPGDH specifically interacts with EhPSAT. Denaturation studies suggest that the nucleotide binding domain (Nbd) and substrate binding domain (Sbd) of EhPGDH are independent folding/unfolding units. Thus the Nbd-EhPGDH was separately cloned over-expressed and purified to homogeneity. Fluorescence anisotropy study show that the purified Nbd interacts with EhPSAT. Forward enzyme catalyzed reaction for the EhPGDH-PSAT complex showed efficient Km values for 3-phosphoglyceric acid as compared to only EhPGDH suggesting a possibility of substrate channelling in the protein complex.


High-resolution discrimination of homologous and isomeric proteinogenic amino acids in nanopore sensors with ultrashort single-walled carbon nanotubes.
The hollow and tubular structure of single-walled carbon nanotubes (SWCNTs) makes them ideal candidates for making nanopores. However, the heterogeneity of SWCNTs hinders the fabrication of robust and reproducible carbon-based nanopore sensors. Here we develop a modified density gradient ultracentrifugation approach to separate ultrashort (≈5-10 nm) SWCNTs with a narrow conductance range and construct high-resolution nanopore sensors with those tubes inserted in lipid bilayers. By conducting ionic current recordings and fluorescent imaging of Ca2+ flux through different nanopores, we prove that the ion mobilities in SWCNT nanopores are 3-5 times higher than the bulk mobility. Furthermore, we employ SWCNT nanopores to discriminate homologue or isomeric proteinogenic amino acids, which are challenging tasks for other nanopore sensors. These successes, coupled with the building of SWCNT nanopore arrays, may constitute a crucial part of the recently burgeoning protein sequencing technologies.


Phase 1, open-label study of MEDI-547 in patients with relapsed or refractory solid tumors.
Targeting the cell-surface receptor EphA2, which is highly expressed in some solid tumors, is a novel approach for cancer therapy. We aimed to evaluate the safety profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of MEDI-547, an antibody drug conjugate composed of the cytotoxic drug auristatin (toxin) linked to a human anti-EphA2 monoclonal antibody (1C1), in patients with solid tumors relapsed/refractory to standard therapy. In this phase 1, open-label study with planned dose-escalation and dose-expansion cohorts, patients received a 1-h intravenous infusion of MEDI-547 (0.08 mg/kg) every 3 weeks. Six patients received 0.08 mg/kg; all discontinued treatment. Dose escalation was not pursued. The study was stopped before cohort 2 enrollment due to treatment-related bleeding and coagulation events (hemorrhage-related, n = 3; epistaxis, n = 2). Therefore, lower doses were not explored and an MTD could not be selected. The most frequently reported treatment-related adverse events (AEs) were increased liver enzymes, decreased hemoglobin, decreased appetite, and epistaxis. Three patients (50%) experienced treatment-related serious AEs, including conjunctival hemorrhage, pain (led to study drug discontinuation), liver disorder, and hemorrhage. Best response included progressive disease (n = 5; 83.3%) and stable disease (n = 1; 16.7%). Minimal or no dissociation of toxin from 1C1 conjugate occurred in the blood. Serum MEDI-547 concentrations decreased rapidly, ~70% by 3 days post-dose. No accumulation of MEDI-547 was observed at 0.08 mg/kg upon administration of a second dose 3 weeks following dose 1. The safety profile of MEDI-547 does not support further clinical investigation in patients with advanced solid tumors.


P53 mutation correlates with cisplatin sensitivity in head and neck squamous cell carcinoma lines.
A critical factor for successful organ preservation treatment in head and neck cancer may be selecting tumors that respond to chemotherapy and radiation. Previous results in patients indicated that tumors that overexpressed p53 were more sensitive to chemotherapy than those that did not overexpress p53. To determine the relationship of p53 mutations to sensitivity to cisplatin in vitro, 23 head and neck squamous cell carcinoma (HNSCC) cell lines were analyzed for cisplatin sensitivity, p53 expression, and p53 mutation status. Mutations of the p53 gene were identified in 13 of 23 of the cell lines tested. Mutation of the p53 gene was significantly associated with high levels of expression of the p53 protein. The average ID(50) (drug dose required to inhibit 50% of cell growth) for cell lines with mutant p53 was 6.8 microM, whereas the average ID(50) for cell lines with wild-type p53 was 13.7 microM. These in vitro data support a role for mutation of the p53 tumor suppressor gene as a marker for response to cisplatin in HNSCC.


Behavior of Trichogramma atopovirilia Oatman & Platner and T. pretiosum Riley (Hymenoptera: Trichogrammatidae) on Spodoptera frugiperda (J. E. Smith) (Lepidoptera: Noctuidae) egg masses.
In this study we analyzed the impact of physical barriers of Spodoptera frugiperda (J. E. Smith) egg-masses on the behavior of Trichogramma atopovirilia Oatman & Platner and Trichogramma pretiosum Riley. The duration of drumming, drilling, oviposition, period spent over the egg-mass, and interval between parasitized eggs were timed, and the number of parasitized eggs were recorded. The presence of scales on the egg-masses caused a significant increase in the time spent by both parasitoids on each process and a decrease in the residence time over the egg-mass and in the number of parasitized eggs, with an increase in the number of egg layers. There was a significant decrease in the number of parasitized eggs in relation to egg-masses with one layer and no scales. We observed that the physical barriers in fall armyworm egg-masses changed the behavior of T. atopovirilia and T. pretiosum, affecting their parasitization capacity.


Dissecting endophytic lifestyle along the parasitism/mutualism continuum in Arabidopsis.
Mutualistic interactions between plants and fungi often occur in the rhizosphere, although examples exist where shoot-endophytes support host growth and increase resistance to pathogens and herbivores. Fungal endophytes which colonize their hosts without any visible disease symptoms have been recognized to be fundamental components of various ecosystems. Initial efforts have been taken to decipher the genetic basis of beneficial plant-fungus interactions and of lifestyle transitions. This review gives a short overview on well established experimental systems amenable to genetic manipulation and of known genome sequence for dissecting plant-fungal endophyte interactions with a special focus on Arabidopsis thaliana associations.


Do response time advantage and interference reflect the order of processing of global- and local-level information?
Navon's (1977) global precedence hypothesis was based primarily on the joint occurrence of two effects: a response time (RT) advantage for identifying global targets, and interference by global distractors on responding to local targets. Although the hypothesis has been questioned on the basis of experiments in which it has been shown that a local RT advantage and local interference can occur, it is still frequently assumed that these two effects are a valid measure of the order in which local and global levels of structure are processed. In the present experiment, this assumption was examined. Subjects identified target letters that occurred randomly at the global or local level in a divided-attention task. The visual angle subtended by the stimulus pattern was varied, a manipulation known to affect the relative speed of response to local- or global-level information. Local targets were identified faster than global targets at the larger visual angles, but there was no difference in RT at the smallest visual angle. Despite this change in RT advantage, the interference effect did not change as a function of the visual angle of the stimulus pattern. Moreover, global distractors interfered with responding to local targets but local targets had no effect on responding to global targets, which is exactly the opposite of the finding one would expect if RT advantage and interference reflected order of processing. These findings are not consistent with the assumption that RT advantage and interference reflect order of processing in a simple way.


The effect of moisture on the mechanical and powder flow properties of microcrystalline cellulose.
This study determined the effects of moisture on the mechanical and powder flow properties of microcrystalline cellulose. A variety of mechanical properties were determined as a function of solid fraction at moisture levels ranging from 0 to 12.2% and included: compaction pressure required to form a compact, dynamic indentation hardness, quasi-static indentation hardness, tensile strength, best case and worst case Bonding Index, Brittle Fracture Index, Strain Index, Compressibility Index and shear cell index. Significant changes were observed as the moisture level of microcrystalline cellulose increased. The compaction pressure required to produce a compact at a solid fraction of 0.6 decreased with increasing moisture content. The permanent deformation pressure and tensile strength of compacts were observed to be relatively independent of moisture content below about 5% moisture and then decrease as the moisture content increased further. The "best case" Bonding Index was also observed to be independent of moisture content below 5% and then increase with increasing moisture. The Brittle Fracture Index and "worst case" Bonding Index, however, did not appear to be affected by changes in moisture content. Powder flow was shown to decrease with increasing moisture content. These mechanical property data are consistent with the hypothesis that water acts as a plasticizer and influences the mechanical properties of microcrystalline cellulose. At moisture levels above about 5%, the material exhibits significant changes consistent with a transition from the glassy state to the rubbery state.


Climacteric symptom control after the addition of low-dose esterified conjugated estrogens to raloxifene standard doses.
Hormone therapy (HT) is one the best options for climacteric symptom control; however when women are switched to raloxifene, after several years of HT, they restart with symptoms. To evaluate the effect of the addition of low-dose esterified conjugated estrogens to the conventional dose of raloxifene in the control of climacteric symptoms. 14 healthy postmenopausal patients were studied. Climacteric symptoms were evaluated at baseline and 3 months after the beginning of treatment by the Kupperman's index (KI) and by the sum of the symptom evaluations carried out with an analog visual scale called SUMEVA. In all the anthropometric variables were documented, as well as time since menopause and endometrial thickness. At random they were distributed in some of the following groups: I) Raloxifene 60 mg/day (n=7) and II) Raloxifene 60 mg/day plus esterified conjugated estrogens 0.312 mg/day (n=7). Differences among the groups, as well as those among baseline and those at the end of treatment, were determined by student's t test for independent samples and paired samples respectively. There were no differences in anthropometric variables, nor in the time since menopause. After three months of treatment the libido alterations vertigo and vaginal dryness were significantly greater in group I. In group II a significant decrease in hot flushes, insomnia, nervousness, vaginal dryness, KI, and SUMEVA were found, as was a significant increase in endometrial thickness. The treatment that is proposed in this study can constitute a temporary alternative during the period of transition from HT to raloxifene.


Cognitive therapy for depression: a comparison of individual psychotherapy and bibliotherapy for depressed older adults.
Thirty-one community-residing older adults age 60 or over either received 16 sessions of individual cognitive psychotherapy (Beck, Rush, Shaw, & Emery, 1979) or read Feeling Good (Bums, 1980) for bibliotherapy. Posttreatment comparisons with the delayed-treatment control indicated that both treatments were superior to a delayed-treatment control. Individual psychotherapy was superior to bibliotherapy at posttreatment on self-reported depression, but there were no differences on clinician-rated depression. Further, bibliotherapy participants continued to improve after posttreatment. and there were no differences between treatments at 3-month follow-up. Results suggest that bibliotherapy and that individual psychotherapy are both viable treatment options for depression in older adults.


[Toxic shock syndrome toxin-1 producing strains of Staphylococcus aureus in vaginal smears].
21 Staphylococcus aureus strains were isolated from 391 vaginal swabs. This corresponds to a frequency of 5.3%. In females using tampons this frequency was 7%, in users of napkins 2.4%. 2 out of these 21 S. aureus strains produced toxic shock syndrome toxin-1 (TSST-1). Both strains originated from women using tampons. Therefore, 5 out of 1000 women must be expected to carry TSST-1-producing S. aureus strains within their vagina.


The mitochondrial protease LONP1 maintains oocyte development and survival by suppressing nuclear translocation of AIFM1 in mammals.
Oogenesis is a fundamental process of human reproduction, and mitochondria play crucial roles in oocyte competence. Mitochondrial ATP-dependent Lon protease 1 (LONP1) functions as a critical protein in maintaining mitochondrial and cellular homeostasis in somatic cells. However, the essential role of LONP1 in maintaining mammalian oogenesis is far from elucidated. Using conditional oocyte Lonp1-knockout mice, RNA sequencing (RNA-seq) and coimmunoprecipitation/liquid chromatography-mass spectrometry (Co-IP/LC-MS) technology, we analysed the functions of LONP1 in mammalian oogenesis. Conditional knockout of Lonp1 in mouse oocytes in both the primordial and growing follicle stages impairs follicular development and causes progressive oocyte death, ovarian reserve loss, and infertility. LONP1 directly interacts with apoptosis inducing factor mitochondria-associated 1 (AIFM1), and LONP1 ablation leads to the translocation of AIFM1 from the cytoplasm to the nucleus, causing apoptosis in mouse oocytes. In addition, women with pathogenic variants of LONP1 lack large antral follicles (>10 mm) in the ovaries, are infertile and present premature ovarian insufficiency. We demonstrated the function of LONP1 in regulating oocyte development and survival, and in-depth analysis of LONP1 will be crucial for elucidating the mechanisms underlying premature ovarian insufficiency. This work was supported by grants from the National Key Research and Development Program of China (2018YFC1004701), the National Nature Science Foundation of China (82001629, 81871128, 81571391, 81401166, 82030040), the Jiangsu Province Social Development Project (BE2018602), the Jiangsu Provincial Medical Youth Talent (QNRC2016006), the Youth Program of the Natural Science Foundation of Jiangsu Province (BK20200116) and Jiangsu Province Postdoctoral Research Funding (2021K277B).


Bovine lactoferrin inhibits SARS-CoV-2 and SARS-CoV-1 by targeting the RdRp complex and alleviates viral infection in the hamster model.
Breast milk has been found to inhibit coronavirus infection, while the key components and mechanisms are unknown. We aimed to determine the components that contribute to the antiviral effects of breastmilk and explore their potential mechanism. Lactoferrin (Lf) and milk fat globule membrane inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related coronavirus GX_P2V and transcription- and replication-competent SARS-CoV-2 virus-like particles in vitro and block viral entry into cells. We confirmed that bovine Lf (bLf) blocked the binding between human angiotensin-converting enzyme 2 and SARS-CoV-2 spike protein by combining receptor-binding domain (RBD). Importantly, bLf inhibited RNA-dependent RNA polymerase (RdRp) activity of both SARS-CoV-2 and SARS-CoV in vitro in the nanomolar range. So far, no biological macromolecules have been reported to inhibit coronavirus RdRp. Our result indicated that bLf plays a major role in inhibiting viral replication. bLf treatment reduced viral load in lungs and tracheae and alleviated pathological damage. Our study provides evidence that bLf prevents SARS-CoV-2 infection by combining SARS-CoV-2 spike protein RBD and inhibiting coronaviruses' RdRp activity, and may be a promising candidate for the treatment of coronavirus disease 2019.


Segmental vs. extended colectomy: measurable differences in morbidity, function, and quality of life.
The colon coordinates fecal elimination while reabsorbing excess fluid. Extended colonic resection removes synchronous and prevents metachronous disease but may adversely alter bowel function and health-related quality of life to a greater degree than segmental resection. This study examined the short-term morbidity and long-term function and quality of life after colon resections of different extents. Patients undergoing extended resections (n = 201, subtotal colectomy with ileosigmoid or total abdominal colectomy with ileorectal anastomosis) and segmental colonic resections (n = 321) during 1991 to 2003 were reviewed for perioperative outcomes and surveyed for bowel function and quality of life using an institutional questionnaire and a validated quality of life instrument (response rate: 70 percent). The most common indication for extended resections was multiple polyps, and for segmental resections, single malignancy. The complication-free rate was 75.4 percent after segmental resections, 42.8 percent after ileosigmoid anastomosis, and 60 percent after ileorectal anastomosis. Median daily stool frequency was two after segmental resections, four after ileosigmoid anastomosis, and five after ileorectal anastomosis, despite considerable dietary restrictions (55.6 percent) and medication use (19.6 percent daily) after ileorectal anastomosis. Significant proportions of patients felt restricted from preoperative social activity (31.5 percent), housework (20.4 percent), recreation (31.5 percent), and travel (42.6 percent) after ileorectal anastomosis. The overall quality of life after segmental resection, ileosigmoid anastomosis, and ileorectal anastomosis was 98.5, 94.9, and 91.2, respectively. Measurable compromises in long-term bowel function and quality of life were observed after extended vs. segmental resections. The relative differences in patient-related outcomes should be deliberated against the clinical benefits of extended resection for the individual patient.


Dose rate calculations at beam tube no. 5 of the JSI TRIGA mark II research reactor using Monte Carlo method.
Monte Carlo N-Particle (MCNP) transport code accelerated by AutomateD VAriaNce reducTion Generator (ADVANTG) code was used to simulate neutron and prompt gamma particles emitted from TRIGA research reactor during operation. Firstly, the method was validated by measuring dose rates around open beam port number 5 was unplugged. Neutron and gamma dose rates inside the reactor hall in the vicinity of the beam port were calculated and compared to the measurements. Due to the satisfactory agreement, the method was later used to design external shielding for the same beam port when it was upgraded - special mechanism was installed that allows irradiation of larger samples. Computational analysis of the proposed shielding configuration provided acceptable dose rate levels inside the reactor hall. When the shield was constructed, calculated dose rates were confirmed by the actual measurements. No modifications were needed.


Effects of melatonin on luteinizing hormone secretion in anestrous ewes following dopamine and opiate receptor blockade.
In the present investigation we have examined the ability of melatonin to modify the pulsatile LH secretion induced by treatment with a DA antagonist (sulpiride, SULP) or opioid antagonist (naloxone, NAL) in intact mid-anestrous ewes. The experimental design comprised the following treatments-in experiment 1: (1) intracerebroventricular (i.c.v.) infusion of vehicle (control I); (2) pretreatment with SULP (0.6 mg/kg subcutaneously) and then i.c.v. infusion of vehicle (SULP + veh); (3) pretreatment with SULP and then i.c.v. infusion of melatonin (SULP + MLT, 100 microg per 100 microl/h, total 400 microg). In experiment 2: (4) i.c.v. infusion of vehicle (control II); (5) i.c.v. infusion of NAL (NAL-alone, 100 microg per 100 microl/h, total 300 microg); (6) i.c.v. infusion of NAL in combination with MLT (NAL + MLT, 100 microg + 100 microg per 100 microl/h). All infusions were performed during the afternoon hours. Pretreatment with SULP induced a significant (P < 0.01) increase in LH pulse frequency, but not in mean LH concentration, compared with control I. In SULP + MLT-treated animals, the LH concentration was significantly (P < 0.01) higher during MLT infusion, but due to highly increased LH secretion in only one ewe. The significant changes in the SULP + MLT group occurred in LH pulse frequency. A few LH pulses were noted after melatonin administration compared with the number during the infusion (P < 0.05) and after vehicle infusion in the SULP + MLT group (P < 0.05). The i.c.v. infusion of NAL evoked a significant increase in the mean LH concentration (P < 0.001) and amplitude of LH pulses (P < 0.01) compared with these before the infusion. The enhanced secretion of LH was also maintained after i.c.v. infusion of NAL (P < 0.01) with a concomitant decrease in LH pulse frequency (P < 0.05). In NAL + MLT-treated ewes, mean plasma LH concentrations increased significantly during and after the infusion compared with that noted before ( P < 0.001). No difference in the amplitude of LH pulses was found in the NAL + MLT group, but this parameter was significantly higher in ewes during infusion of both drugs than during infusion of the vehicle (P < 0.01). The LH pulse frequency differed significantly (p < 0.05), increasing slightly during NAL + MLT administration and decreasing after the infusion. In conclusion, these results demonstrate that: (1) in mid-anestrous ewes EOPs, besides DA, are involved in the inhibition of the GnRH/LH axis; (2) brief administration of melatonin in long-photoperiod-inhibited ewes suppresses LH pulse frequency after the elimination of the inhibitory DA input, but seems to not affect LH release following opiate receptor blockade.


Being (past and present) President of the ERS: interview about the role, perspectives on career development, and vision for the Society.
This article presents the views of the past and current Presidents of the ERS regarding their role, perspectives on career development and vision for the Society, along with important messages to inspire ECMs to build their own successful career. https://bit.ly/3kAvxIM.


Manifestation pattern of early-late vaginal morbidity after definitive radiation (chemo)therapy and image-guided adaptive brachytherapy for locally advanced cervical cancer: an analysis from the EMBRACE study.
Brachytherapy in the treatment of locally advanced cervical cancer has changed substantially because of the introduction of combined intracavitary/interstitial applicators and an adaptive target concept, which is the focus of the prospective, multi-institutional EMBRACE study (www.embracestudy.dk) on image-guided adaptive brachytherapy (IGABT). So far, little has been reported about the development of early to late vaginal morbidity in the frame of IGABT. Therefore, the aim of the present EMBRACE analysis was to evaluate the manifestation pattern of vaginal morbidity during the first 2 years of follow-up. In total, 588 patients with a median follow-up time of 15 months and information on vaginal morbidity were included. Morbidity was prospectively assessed at baseline, every 3 months during the first year, and every 6 months in the second year according to the Common Terminology Criteria for Adverse Events, version 3, regarding vaginal stenosis, dryness, mucositis, bleeding, fistula, and other symptoms. Crude incidence rates, actuarial probabilities, and prevalence rates were analyzed. At 2 years, the actuarial probability of severe vaginal morbidity (grade ≥3) was 3.6%. However, mild and moderate vaginal symptoms were still pronounced (grade ≥1, 89%; grade ≥2, 29%), of which the majority developed within 6 months. Stenosis was most frequently observed, followed by vaginal dryness. Vaginal bleeding and mucositis were mainly mild and infrequently reported. Severe vaginal morbidity within the first 2 years after definitive radiation (chemo)therapy including IGABT with intracavitary/interstitial techniques for locally advanced cervical cancer is limited and is significantly less than has been reported from earlier studies. Thus, the new adaptive target concept seems to be a safe treatment with regard to the vagina being an organ at risk. However, mild to moderate vaginal morbidity is still pronounced with currently applied IGABT, and it needs further attention.


Clinicopathologic significance of cystatin C expression in gliomas.
Cathepsin B, one of the lysosomal cysteine proteases, has been related to tumor invasiveness. Cystatin C is the strongest inhibitor of cathepsin B. Knowledge of its participation in the progression of gliomas is limited. We investigated the expression of cystatin C and its association with the clinicopathologic features of 57 gliomas. Cystatin C and cathepsin B expressions were evaluated by immunohistochemical methods and by semiquantitative real-time polymerase chain reaction analysis for the corresponding messenger RNA. Disease-free survival was analyzed by the Kaplan-Meier method. Tumors with low cystatin C protein expression and high cathepsin B protein expression were significantly more likely to be of high grade, and this pattern was significantly correlated with high Ki-67 LI and tumor recurrence. Depressed expression of cystatin C messenger RNA in glioblastomas compared with low-grade astrocytomas was demonstrated. Multivariate analysis demonstrated high tumor grade, high Ki-67 labeling index, high cathepsin B expression, and low cystatin C expression correlated significantly with shorter disease-free survival. These results suggest that gliomas in patients with an unfavorable clinical outcome are characterized by depressed expression of cystatin C. Evaluation of cystatin C expression in gliomas provides useful clinical information, especially as a prognostic indicator.


Benzo[a]pyrene-induced multigenerational changes in gene expression, behavior, and DNA methylation are primarily influenced by paternal exposure.
Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon (PAH), is implicated in many developmental and behavioral adverse outcomes in offspring of exposed parents. The objective of this study was to investigate sex-dependent multigenerational effects of preconceptional effects of BaP exposure. Adult wild-type (5D) zebrafish were fed 708 μg BaP/g diet (measured) at a rate of 1% body weight twice/day (14 μg BaP/g fish/day) for 21 days. Fish were spawned using a crossover design, and parental (F0) behavior and reproductive indexes were measured. In offspring, behavioral effects were measured at 96 h post fertilization (hpf) in F1 & F2 larvae, and again when F1s were adults. Compared to controls, there was no significant effect on F0 adult behavior immediately following exposure, but locomotor activity was significantly increased in F1 adults of both sexes. Larval behavior (96 hpf, photomotor response assay) was significantly altered in both the F1 and F2 generations. To assess molecular changes associated with BaP exposure, we conducted transcriptome and DNA methylation profiling in F0 gametes (sperm and eggs) and F1 embryos (10 hpf) from all four crosses. Embryos resulting from the BaP male and control female cross had the most differentially expressed genes (DEGs) and differentially methylated regions (DMRs). Some DMRs were associated with genes encoding chromatin modifying enzymes suggesting regulation of chromatin conformation by DNA methylation. Overall, these results suggest that parental dietary BaP exposure significantly contributes to the multigenerational adverse outcomes.


A Perspective of the Comprehensive and Objective Assessment of Analytical Methods Including the Greenness and Functionality Criteria: Application to the Determination of Zinc in Aqueous Samples.
The recently proposed concept of White Analytical Chemistry (WAC), referring to the Red-Green-Blue color model, combines ecological aspects (green) with functionality (red and blue criteria), presenting the complete method as "white". However, it is not easy to carry out an overall quantitative evaluation of the analytical method in line with the WAC idea in an objective manner. This paper outlines the perspective of the future development of such a possibility by attempting to answer selected questions about the evaluation process. Based on the study consisting in the evaluation of selected model methods by a group of 12 independent analysts, it was shown how well individual criteria are assessed, whether the variability of assessments by different people is comparable for each criterion, how large it is, and whether averaging the scores from different researchers can help to choose the best method more objectively.


Anatomical location of the bifurcation of the sciatic nerve in the posterior thigh in infants and children: a formula derived from MRI imaging for nerve localization.
Sciatic nerve block is performed at the popliteal fossa for various surgical procedures in infants and children. The aim of this study is to review magnetic resonance imaging scans in children of various ages to assess the location of the division of the nerve in the posterior thigh. After Institutional Review Board approval was obtained, measurements of the bifurcation of the sciatic nerve in the posterior thigh were recorded from magnetic resonance images that were previously obtained in children of various ages. Data were recorded in a database and parametric and nonparametric statistical analysis was performed. Measurements were recorded from 59 patient images. Using a linear regression model, we were able to arrive at a formula for determining the point of bifurcation of the sciatic nerve at the posterior thigh. The mathematical formula derived from the linear regression equation was: We speculate that this knowledge will assist practitioners who use nerve stimulation techniques for sciatic nerve blocks in children of all ages.


BFRs (PBDEs and HBCDs) in freshwater species from Lake Trasimeno (Italy): The singular case of HBCDs in red swamp crayfish.
Eighty-six samples belonging to five different species (crucian carp, Carassius carassius; European perch, Perca fluviatilis; tench, Tinca tinca; eel, Anguilla anguilla; red swamp crayfish, Procambarus clarkii) collected from Lake Trasimeno (Italy) were analyzed to assess polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecanes (HBCDs) contamination. The Trasimeno is the largest Italian peninsular lake located in Umbria (Central Italy), in a rural area with low anthropogenic impact. All the samples were analyzed by an in-house developed analytical procedure involving a single sample preparation with dual detection: Gas- and Liquid-Chromatography coupled to tandem Mass Spectrometry (GC-MS/MS for PBDEs and LC-MS/MS for HBCDs). BFRs levels in crucian carp, tench and European perch were negligible and mostly below quantification limits (LOQs). In eel, the species with the higher fat content, PBDE sum (15 congeners) ranged from 0.269 to 0.916 ng/g w.w. BDE-47, -100 and -154 accounted for roughly 57%, 16% and 11% of the PBDE sum, respectively, while BDE-99 (usually one of the most abundant congeners in biota), only for 3%. HBCDs (sum of α-, β-, γ-isomers) were found between 0.157 and 1.14 ng/g w.w. with α- as predominant isomer (92% of the sum), followed by γ- (5%) and β- (2%). Peculiar was the contamination in red swamp crayfish characterized by negligible PBDEs and very high HBCDs levels with a singular contamination pattern. In female pools (n = 9) the mean HBCDs sum was 0.150 ng/g w.w., while in males higher concentrations were measured (mean = 2.77 ng/g w.w.). A significant correlation seems to exist between the contamination level and the seasonal cycle only in male crayfish. Interestingly, among the HBCDs, the γ-isomer was the highest (67% of the total) while α- contributes only for 20%.


Hydrochloric acid alters the effect of L-glutamic acid on cell viability in human neuroblastoma cell cultures.
l-Glutamic acid (l-glutamate) is used to induce excitotoxicity and test neuroprotective compounds in cell cultures. However, because l-glutamate powder is nearly insoluble in water, many manufacturers recommend reconstituting l-glutamate in hydrochloric acid (HCl) prior to successive dilutions. Nevertheless, HCl, even at low concentrations, may alter the pH of the cell culture medium and interfere with cell activity. Thus, the aim of this study was to evaluate whether the reconstitution of l-glutamate powder in HCl alters its capacity to induce neurotoxicity in different human neuroblastoma cell lines. SH-SY5Y, IMR-32 and SK-N-BE(2) cells were exposed to various concentrations of l-glutamate, which was either reconstituted in HCl (1M) or post re-equilibrated to the pH of the culture medium (7.5). After 24 and 48h of incubation, changes in the cell viability of treated versus untreated cells were evaluated. The effect of an identical amount of HCl present in the l-glutamate dilutions on neuroblastoma cell survival was also investigated. Our data showed that the neurotoxicity of glutamate reconstituted in HCl was comparable to that of HCl alone. Moreover, the pH variations induced by glutamate or HCl in the culture medium were similar. When the pH of the glutamate stock solution was re-equilibrated, l-glutamate induced variation in cell viability to a lower extent and after a longer incubation time. This study demonstrated that HCl used to reconstitute l-glutamate powder might alter the effect of glutamate itself in neuroblastoma cell cultures. Thus, this information might be useful to scientists who use l-glutamate to induce excitotoxicity or to test neuroprotective agents.


Spatial restriction of alpha4 integrin phosphorylation regulates lamellipodial stability and alpha4beta1-dependent cell migration.
Integrins coordinate spatial signaling events essential for cell polarity and directed migration. Such signals from alpha4 integrins regulate cell migration in development and in leukocyte trafficking. Here, we report that efficient alpha4-mediated migration requires spatial control of alpha4 phosphorylation by protein kinase A, and hence localized inhibition of binding of the signaling adaptor, paxillin, to the integrin. In migrating cells, phosphorylated alpha4 accumulated along the leading edge. Blocking alpha4 phosphorylation by mutagenesis or by inhibition of protein kinase A drastically reduced alpha4-dependent migration and lamellipodial stability. alpha4 phosphorylation blocks paxillin binding in vitro; we now find that paxillin and phospho-alpha4 were in distinct clusters at the leading edge of migrating cells, whereas unphosphorylated alpha4 and paxillin colocalized along the lateral edges of those cells. Furthermore, enforced paxillin association with alpha4 inhibits migration and reduced lamellipodial stability. These results show that topographically specific integrin phosphorylation can control cell migration and polarization by spatial segregation of adaptor protein binding.


A systematic review and meta-analysis of proton magnetic resonance spectroscopy and mismatch negativity in bipolar disorder.
Aberrant glutamate neurotransmission has been implicated in the pathophysiology of bipolar disorder with accumulating evidence from imaging, post-mortem and pathology studies. Studies investigating in vivo changes to the glutamatergic system have not been as consistent and warrant clarification. Studies utilizing proton-magnetic resonance spectroscopy ((1)H-MRS) have reported increased levels of combined glutamate and glutamine ("Glx"), which have been linked to impairments in N-methyl-d-aspartate (NMDA) receptor function. Similarly, neurophysiological studies utilising mismatch negativity (MMN) as an index of NMDA receptor function, have reported impairments in bipolar disorder. Here, we provide a systematic review of the literature in regards to the concentration of Glx and the magnitude of MMN in bipolar disorder. Separate meta-analyses revealed that bipolar disorder was associated with increased Glx concentration and decreased MMN-both measured frontally. The current findings corroborate previous evidence indicating that bipolar disorder is characterized by a perturbed frontal glutamate system. These observed changes in bipolar disorder might manifest as impairments in neuronal-glial interactions that lead to disrupted neuronal output and ultimately result in the characteristic neurocognitive sequelae associated with this disorder.


Usefulness of synaptophysin immunohistochemistry in an adult case of choroid plexus carcinoma.
Choroid plexus carcinoma in an adult case is a very rare tumor and difficult to differentiate from metastatic tumors. The authors report a case of a 49-year-old female with choroid plexus carcinoma who previously had multiple carcinomas. In this case, synaptophysin immunohistochemistry proved to be extremely helpful for the histological diagnosis.


Understanding the effect of non-surgical factors in a transcranial motor-evoked potential alert: A retrospective cohort study.
Intraoperative neuromonitoring (IONM) is important for detecting neurological dysfunction, allowing for intervention and reversal of neurological deficits before they become permanent. Of the several IONM modalities, transcranial electrical stimulation of motor-evoked potential (TES-MEP) can help monitor the activity in the pyramidal tract. Surgery- and non-surgery-related factors could result in a TES-MEP alert during surgery. Once the alert occurs, the surgeon should immediately intervene to prevent a neurological complication. However, TES-MEP monitoring does not provide sufficient data to identify the non-surgery-related factors. Therefore, this study aimed to identify and describe these factors among TES-MEP alert cases. In this multicenter study, data from 1934 patients who underwent various spinal surgeries for spinal deformities, spinal cord tumors, and ossification of the posterior longitudinal ligament of the spine from 2017 to 2019 were collected. A 70% amplitude reduction was set as the TES-MEP alarm threshold. All surgeries with alerts were categorized into true-positive (TP) and false-positive (FP) cases according to the assessment of immediate postoperative neurological deficits. In total, TES-MEP alerts were observed in 251 cases during surgery: 62 TP and 189 FP IONM cases. Overall, 158 cases were related to non-surgery-related factors. We observed 22 (35.5%) TP cases and 136 (72%) FP cases, which indicated cases associated with non-surgery-related factors. A significant difference was observed between the two groups regarding factors associated with TES-MEP alerts (p < 0.01). The ratio of TP and FP cases (related to non-surgery-related factors) associated with TES-MEP alerts was 13.9% (22/158 cases) and 86.1% (136/158 cases), respectively. Non-surgery-related factors are proportionally higher in FP than in TP cases. Although the surgeon should examine surgical procedures immediately after a TES-MEP alert, surgical intervention may not always be the best approach according to the results of this study.