Effect of gamma-interferon on lectin-binding glycoproteins in cultured human keratinocytes.
We report the effect of exposure of human keratinocyte cultures to human recombinant gamma-interferon (g-IFN) on the expression of glycoproteins. Concanavalia ensiformis agglutinin (Con-A), and Arachis hypogaea agglutinin (PNA) were used to investigate expression of glycoproteins. NP-40 extracts from cultures grown with or without 100 U/ml g-IFN were analyzed by incubation of SDS-polyacrylamide gels with 125I-labeled lectins. Comparison of Con-A binding glycoprotein profiles showed both qualitative and quantitative changes related to the effect of g-IFN. Differences were also apparent after labeling of the gels with PNA. A limited number of components were labeled, with most of the reactivity falling within a couple of diffuse bands with high molecular weight (300 to 360 kDa). These components were strongly labeled in extracts from cells grown in the presence of g-IFN, but weakly reactive in control cultures. Neuraminidase treatment unmasked a 205 kDa PNA binding molecule only when cells were cultured in the absence of g-IFN. These changes are interpreted in terms of increased keratinocyte differentiation induced by g-IFN and demonstrate that glycoproteins bearing carbohydrate residues available to lectins Con-A and PNA have to be taken into account to better understand the complex action of this lymphokine. In inflammatory lesions, such changes in the glycoproteins of keratinocytes expressing HLA-DR antigens remain to be explored.


A simple whole cell based high throughput screening protocol using Mycobacterium bovis BCG for inhibitors against dormant and active tubercle bacilli.
This study aimed at developing a whole cell based high throughput screening protocol to identify inhibitors against both active and dormant tubercle bacilli. A respiratory type of nitrate reductase (NarGHJI), which was induced during dormancy, could reflect the viability of dormant bacilli of Mycobacterium bovis BCG in microplate adopted model of in vitro dormancy. Correlation between reduction in viability and nitrate reductase activity was seen clearly when dormant stage inhibitor metronidazole and itaconic anhydride were applied in this in vitro microplate model. Active replicating stage could also be monitored in the same assay by measuring the A(620) of the culture. MIC values of 0.08, 0.075, 0.3 and 3.0 microg/ml, determined through monitoring A(620) in this assay for rifampin, isoniazid, streptomycin and ethambutol respectively, were well in agreement with previously reported by BACTEC and Bio-Siv assays. S/N ratio and Z' factor for the assay were 8.5 and 0.81 respectively which indicated the robustness of the protocol. Altogether the assay provides an easy, inexpensive, rapid, robust and high content screening tool to search novel antitubercular molecules against both active and dormant bacilli.


Perceived disability but not pain is connected with autonomic nervous function among patients with chronic low back pain.
To assess the association of cardiovascular autonomic balance with perceived functional impairment and pain among patients with chronic low back pain. A cross-sectional analysis of working patients with chronic low back pain. Forty-six consecutive patients aged 24-45 years with chronic low back pain fulfilling the inclusion criteria. A total of 39 subjects had technically acceptable electrocardiographic recordings during periods of rest and standard provocations. Perceived functional disability was assessed with the Oswestry disability index and pain with a numerical rating scale. Autonomic nervous function was assessed by measuring heart rate variability with short recordings. The total power of heart rate variability was lower among those with moderate perceived disability (Oswestry 20-40%) compared with those with minimal disability (Oswestry < 20%). However, heart rate variability did not differ significantly among those with numerical rating scale values < or = 5/10 from those with values > 5/10. The power of the high-frequency component (0.15-0.4 Hz) of heart rate variability was lower among those with moderate perceived functional impairment. A significant association existed between heart rate variability and perceived physical impairment, but not between heart rate variability and pain. Proportionally reduced high-frequency activity was found to reflect decreased parasympathetic activity or increased sympathetic activity. This resulted in sympathetic dominance among the patients with higher subjective disability. The possible clinical implications of this observation are discussed.


Simultaneous determination of femtogram levels of 237Np, 239Pu, and 240Pu in environmental solid samples using extraction chromatography and ICP-MS/MS.
An analytical method based on triple quadrupole inductively coupled plasma mass spectrometry (ICP-MS/MS) was developed for simultaneous determination of femtogram levels of 237Np, 239Pu, and 240Pu in environmental samples. By carefully controlling the valence states of Np and Pu in the entire separation procedure using a simple single extraction chromatographic column (TK200), the consistent behavior of Np and Pu was achieved, allowing for the reliable application of 242Pu as the chemical yield tracer for 237Np, 239Pu, and 240Pu. A high decontamination factor of 3.2 × 107 for the most critical interfering element, uranium, was achieved in the chemical separation step. The interferences of 238U1H+ and peak tailing of 238U+ during the measurement of plutonium isotopes were effectively eliminated by utilizing 7.5 mL/min He-1.1 mL/min CO2 as reaction gases in the octupole collision/reaction cell and employing sequential quadrupole mode for mass separation in ICP-MS/MS. Specifically, the interference of 238U1H+ was reduced to 10-6 and the peak tailing of 238U+ to 10-10, surpassing the performance of measurement method without reaction gases by 3 orders of magnitude. The developed method enables the accurate determination of femtogram levels of 237Np, 239Pu, and 240Pu in the samples with U/Np and U/Pu atom ratios of up to 1017 and 1012, respectively. The developed method was validated by analyzing standard reference materials and spiked soil samples.


Facial Palsy-Specific Quality of Life in 920 Patients: Correlation With Clinician-Graded Severity and Predicting Factors.
To investigate the correlation between facial palsy severity and quality of life in a broad cohort of facial palsy patients and to elucidate factors that influence this relationship. Retrospective study. Records of patients presenting with a clinician-graded facial function (eFACE) and facial palsy-specific quality-of-life patient-reported outcome measure (FaCE) scale from the same moment were reviewed. Multiple linear regression was performed to study the effect of various variables on FaCE total score. A total of 920 of 1,304 patients were included, 59.9% female with a mean (standard deviation) age of 48.6 (16.7) years and a median (interquartile range palsy duration of 9.6 [2.2; 42.2] months. A multiple linear regression model predicting FaCE total score was established, finding 10 significant variables: eFACE; viral, malignant, and congenital etiologies; overweight status; anxiety; chronic pain; previous treatment; radiotherapy; and duration of palsy (R2 = 0.261, P < 0.001). Gender, age, laterality, surgical etiology, depression, and timing of evaluation (at initial intake or at follow up) were not found to predict FaCE total scores. A correlation between facial palsy severity and quality of life was found in a large cohort of patients comprising various etiologies. Additionally, novel factors that predict quality of life in facial palsy were revealed. This information may help specialists to predict which facial palsy patients are at higher risk of a poorer quality of life, regardless of severity. 4 Laryngoscope, 129:100-104, 2019.


Activation of bovine liver glycerol kinase by ethanol.
The crystallization of bovine glycerol kinase (ATP:glycerol 3-phosphotransferase EC 220.127.116.11) is reported along with a study on the unusual activation of this enzyme by ethanol. The enzyme was extracted from calf lever andusual activation of this enzyme by ethanol. The enzyme was extracted from calf liver and purified 5900-fold giving crystals with a 5% yield. The kinetics of the enzyme with regard to glycerol and ATP were studied by varying the concentration of one substrate while keeping the other at saturating levels, and the effect of ethanol was observed by adding it at levels of 5% (v/v). Ethanol increased the V in both cases almost 2-fold. The apparent Km of ATP was 3.5 - 10(-6) and was increased to 7.6 - 10(-6) in the presence of ethanol. The apparent Km for glycerol was 3 - 10(-5) and was increased to 12 - 10(-5) when ethanol was added. A number of other alcohols had a similar activating effect except for 1,2-diols which only inhibited the enzyme. These findings are consistent with the explanation that alcohols compete with glycerol (hence also with the glycerophosphate product) for a hydroxy binding site on the enzyme. This leads to more rapid dissociation of the glycerophosphate (i.e. an increase in the steady-state constant, "k+2" resulting in an increased V).


Steroid hormone effects on picrotoxin-induced seizures in female and male rats.
Picrotoxin (1 mg/kg, i.p.), evoked a single generalized seizure in 75% of ovariectomized rats. Pretreatment of matched pairs with silastic implants containing 100% estradiol had an anticonvulsant effect; it protected all rats against such seizures. Implants containing 10% estradiol in cholesterol were less effective in protecting against picrotoxin-induced seizures. With 2 mg/kg picrotoxin, 85% of the seizure-affected ovariectomized controls had multiple seizures. The incidence of seizures and the ratio of single to multiple seizures induced by the higher dose of picrotoxin were unaffected by estradiol silastic implants, intraperitoneal injections of progesterone (0.5 mg, 4-5 h before convulsant) or the combination of both hormones. At the 2 mg/kg dose, 8/8 intact males had no seizures while all paired ovariectomized females had seizures. By contrast, the incidence of seizures in pairs of gonadectomized males and females did not differ. Testosterone treatment improved the ratio of single to multiple seizures in males but not in females. Males had statistically fewer multiple seizures than did females after testosterone treatment. The distribution of latencies to a single seizure is statistically different from the distribution of latencies to the first of multiple seizures irrespective of dose, sex and hormone treatment. This suggests that the population of rats responding with a single seizure at the higher dose of picrotoxin have a higher threshold for acquiring multiple seizures and that testosterone predisposes males but not females to this population.


Identification of genetic factors controlling kernel hardness and related traits in a recombinant inbred population derived from a soft × 'extra-soft' wheat (Triticum aestivum L.) cross.
Kernel hardness or texture, used to classify wheat (Triticum aestivum L.) into soft and hard classes, is a major determinant of milling and baking quality. Wheat genotypes in the soft class that are termed 'extra-soft' (with kernel hardness in the lower end of the spectrum) have been associated with superior end-use quality. In order to better understand the relationship between kernel hardness, milling yield, and various agronomic traits, we performed quantitative trait mapping using a recombinant inbred line population derived from a cross between a common soft wheat line and a genotype classified as an 'extra-soft' line. A total of 47 significant quantitative trait loci (QTL) (LOD ≥ 3.0) were identified for nine traits with the number of QTL affecting each trait ranging from three to nine. The percentage of phenotypic variance explained by these QTL ranged from 3.7 to 50.3%. Six QTL associated with kernel hardness and break flour yield were detected on chromosomes 1BS, 4BS, 5BS, 2DS, 4DS, and 5DL. The two most important QTL were mapped onto orthologous regions on chromosomes 4DS (Xbarc1118-Rht-D1) and 4BS (Xwmc617-Rht-B1). These results indicated that the 'extra-soft' characteristic was not controlled by the Hardness (Ha) locus on chromosome 5DS. QTL for eight agronomic traits occupied two genomic regions near semi-dwarf genes Rht-D1 on chromosome 4DS and Rht-B1 on chromosome 4BS. The clustering of these QTL is either due to the pleiotropic effects of single genes or tight linkage of genes controlling these various traits.


Asters, vortices, and rotating spirals in active gels of polar filaments.
We develop a general theory for active viscoelastic materials made of polar filaments. This theory is motivated by the dynamics of the cytoskeleton. The continuous consumption of a fuel generates a nonequilibrium state characterized by the generation of flows and stresses. Our theory applies to any polar system with internal energy consumption such as active chemical gels and cytoskeletal networks which are set in motion by active processes at work in cells.


Force interactions between Yersiniae lipopolysaccharides and monoclonal antibodies: An optical tweezers study.
This article reports the force spectroscopy investigation of interactions between lipopolysaccharides (LPSs) of two species from Yersinia genus and complementary (or heterologous) monoclonal antibodies (mAbs). We have obtained the experimental data by optical trapping on the "sensitized polystyrene microsphere - sensitized glass substrate" model system at its approach - retraction in vertical plane. We detected non-specific interactions in low-amplitude areas on histograms mainly due to physicochemical properties of abiotic surface and specific interactions in complementary pairs "antigen - antibodies" in high-amplitude areas (100-120 pN) on histograms. The developed measurement procedure can be used for detection of rupture forces in other molecular pairs.


Disturbances of micturition in patients with a spinal arteriovenous malformation.
Neuro-urological studies were performed on 9 patients with a spinal arteriovenous malformation (S-AVM). The micturitional history revealed that all 9 patients had voiding symptoms, obstructive in 9 and irritative in 3 patients. All patients still had obstructive symptoms after treatment of S-AVM. Six of the 9 patients had a large volume of residual urine before treatment; 5 showed urinary retention. Four of the 5 patients (80%) for whom urodynamic studies were performed before treatment had micturitional dysfunction; 2 patients had detrusor hyperreflexia, 1 with detrusor external urethral sphincter dyssynergia (DSD) and 1 with a normal sphincter, 1 patient had an autonomous bladder with DSD and 1 patient had an atonic bladder with DSD. Only 1 patient had a normal bladder and sphincter. Findings of the urodynamic studies after treatment in 9 patients showed detrusor hyperreflexia in 3 patients (2 with DSD and 1 with normal sphincter), autonomous bladder in 1 patient with DSD, atonic bladder in 4 patients (2 with DSD, 1 with incompetent sphincter and 1 with normal sphincter) and normal bladder with normal sphincter in 1 patient. Lower urinary function after treatment of S-AVM was improved in 2 patients, unchanged in 4 patients and worsened in 3 patients. The above results showed 80% of S-AVM had a severe neuropathic bladder manifested mainly by disturbance of micturition. Treatment of S-AVM does not necessarily improve the lower urinary tract function.


Accelerated superfractionated radiotherapy with concomitant boost for locally advanced head-and-neck squamous cell carcinomas.
A growing body of evidence supports the efficacy of accelerated superfractionated radiotherapy with concomitant boost for advanced head-and-neck carcinomas. This study represents a single-institution experience, performed to identify the factors influencing tumor control, survival, and toxicity. Between 1988 and 1999, 133 patients with primary squamous cell head-and-neck carcinoma underwent accelerated superfractionated radiotherapy using a concomitant boost. The concomitant boost in this regimen was delivered using reduced fields delivered 3 times weekly in a twice-daily schedule during the final phase. The total radiation dose ranged from 64.8 Gy to 76.5 Gy (mean 71.1). Patients were evaluated in follow-up for local control and late toxicity. Multivariate analysis of treatment and patient parameters was performed to evaluate their influence on toxicity, local control, and overall survival. With a mean follow-up of 37 months, the actuarial overall survival rate for the entire group at 5 years was 24% and the local control rate was 57%. The tumor volume was the most significant predictor of local control, such that each 1-cm(3) increase in volume was associated with a 1% decrease in local control. For patients with tumor volumes </=30 cm(3) vs. >30 cm(3), the 5-year disease-specific survival rate was 52% and 27% (p = 0.004) and locoregional control rate was 76% and 26% (p <0.001), respectively. Seventy-six patients with a minimum of 12 months and median of 39 months toxicity follow-up were studied for late effects. None of these patients experienced Grade 4 or 5 toxicity. The actuarial rate of significant toxicity (Grade III or greater) was 32% at 5 years. Of the toxicities observed, xerostomia (19%) was the most common. Multivariate analysis revealed N stage and dose as independent predictors of Grade 3 effects. The locoregional control and survival for patients in this institutional experience compare favorably to other published reports. Tumors of the larynx had the best prognosis. Larger volume tumors were associated with significantly lower local control and survival. Significant late effects were related to dose and nodal status.


Direct optical activation of skeletal muscle fibres efficiently controls muscle contraction and attenuates denervation atrophy.
Neural prostheses can restore meaningful function to paralysed muscles by electrically stimulating innervating motor axons, but fail when muscles are completely denervated, as seen in amyotrophic lateral sclerosis, or after a peripheral nerve or spinal cord injury. Here we show that channelrhodopsin-2 is expressed within the sarcolemma and T-tubules of skeletal muscle fibres in transgenic mice. This expression pattern allows for optical control of muscle contraction with comparable forces to nerve stimulation. Force can be controlled by varying light pulse intensity, duration or frequency. Light-stimulated muscle fibres depolarize proportionally to light intensity and duration. Denervated triceps surae muscles transcutaneously stimulated optically on a daily basis for 10 days show a significant attenuation in atrophy resulting in significantly greater contractile forces compared with chronically denervated muscles. Together, this study shows that channelrhodopsin-2/H134R can be used to restore function to permanently denervated muscles and reduce pathophysiological changes associated with denervation pathologies.


Acute idiopathic pericarditis and calcific aortic stenosis: unusual fatal disease combination.
Acute idiopathic pericarditis with massive pericardial effusion complicated left ventricular enlargement due to calcific aortic stenosis and led to intractable congestive heart failure and death during aortic valve replacement in a 42-year-old white male. This unusual combination of acute and chronic diseases is lethal due to their combined deleterious effect upon myocardial function.


Behavior of silica particles introduced into an isolated rat heart as potential drug carriers.
Silica powders consisting of small spherical particles (50-200 nm) have been obtained by the sol-gel method. A suspension of such particles in the Krebs-Hanseleit solution has been introduced into the coronary circulation of a beating perfused rat heart. The influence of the suspension on the heart muscle and the coronary vessels in the rat body has been histopathologically examined. The particles have not left the lumen of the vessels and have not caused any side effects. These observations suggest the possibility of using such silica particles as a carrier for selected drugs.


Experiences and Perceptions of Pharmacy Students on Practical Skills and Education During Clinical Rotations in India.
Objective. To investigate the overall experience of pharmacy students in India during their clinical rotations and their assessment of primary mentors in imparting the intended clinical skills. Methods. A prospective cross-sectional study using a self-administered survey instrument containing 34 items to obtain feedback from senior PharmD students in the latter three years of their six-year program from November 2014 to February 2015. Results. Of the 415 PharmD students invited for this survey, 261(63% response rate) completed the survey (54% males and 46% females). Of the surveyed participants, 74% were fifth- and final-year interns undertaking clinical training in private hospitals (60.9%). Interestingly, 37.9% of the students ranked their clinical training as "least satisfactory" and remarked that their clinical pharmacy services were not recognized or appreciated in their respective hospitals (42.9%). However, 20% of the students expressed that their site "definitely" provided them with the opportunity to hone clinical pharmacy skills. Only 10% of the students strongly agreed that their mentors encouraged them to use resource materials and learn on their own, met with them regularly to review their work and to provide feedback, and encouraged them to express their opinion in patient-care issues. Conclusion. Majority of PharmD students who completed the survey were "least satisfied" with their clinical training program. Mentors should take more effort to demonstrate practice-based clinical training and provide patient-centered education to PharmD students at their clinical sites.


Housekeeping and tissue-specific genes differ in simple sequence repeats in the 5'-UTR region.
SSRs (simple sequence repeats) have been shown to have a variety of effects on an organism. In this study, we compared SSRs in housekeeping and tissue-specific genes in human and mouse, in terms of SSR types and distributions in different regions including 5'-UTRs, introns, coding exons, 3'-UTRs, and upstream regions. Among all these regions, SSRs in the 5'-UTR show the most distinction between housekeeping genes and tissue-specific genes in both densities and repeat types. Specifically, SSR densities in 5'-UTRs in housekeeping genes are about 1.7 times higher than those in tissue-specific genes, in contrast to the 0.8-1.2 times differences between the two classes of genes in other regions. Tri-SSRs in 5'-UTRs of housekeeping genes are more GC rich than those of tissue-specific genes and CGG, the dominant type of tri-SSR in 5'-UTR, accounts for 74-79% of the tri-SSRs in housekeeping genes, as compared to 42-57% in tissue-specific genes. 75% of the tri-SSRs in the 5'-UTR of housekeeping genes have 4-5 repeat units, versus the 86-90% in tissue-specific genes. Taken together, our results suggest that SSRs may have an effect on gene expression and may play an important role in contributing to the different expression profiles between housekeeping and tissue-specific genes.


Engineered bacterial swarm patterns as spatial records of environmental inputs.
A diverse array of bacteria species naturally self-organize into durable macroscale patterns on solid surfaces via swarming motility-a highly coordinated and rapid movement of bacteria powered by flagella. Engineering swarming is an untapped opportunity to increase the scale and robustness of coordinated synthetic microbial systems. Here we engineer Proteus mirabilis, which natively forms centimeter-scale bullseye swarm patterns, to 'write' external inputs into visible spatial records. Specifically, we engineer tunable expression of swarming-related genes that modify pattern features, and we develop quantitative approaches to decoding. Next, we develop a dual-input system that modulates two swarming-related genes simultaneously, and we separately show that growing colonies can record dynamic environmental changes. We decode the resulting multicondition patterns with deep classification and segmentation models. Finally, we engineer a strain that records the presence of aqueous copper. This work creates an approach for building macroscale bacterial recorders, expanding the framework for engineering emergent microbial behaviors.


CNS macrophages and peripheral myeloid cells in brain tumours.
Primary brain tumours (gliomas) initiate a strong host response and can contain large amounts of immune cells (myeloid cells) such as microglia and tumour-infiltrating macrophages. In gliomas the course of pathology is not only controlled by the genetic make-up of the tumour cells, but also depends on the interplay with myeloid cells in the tumour microenvironment. Especially malignant gliomas such as glioblastoma multiforme (GBM) are notoriously immune-suppressive and it is now evident that GBM cells manipulate myeloid cells to support tumour expansion. The protumorigenic effects of glioma-associated myeloid cells comprise a support for angiogenesis as well as tumour cell invasion, proliferation and survival. Different strategies for inhibiting the pathological functions of myeloid cells in gliomas are explored, and blocking the tropism of microglia/macrophages to gliomas or manipulating the signal transduction pathways for immune cell activation has been successful in pre-clinical models. Hence, myeloid cells are now emerging as a promising target for new adjuvant therapies for gliomas. However, it is also becoming evident that some myeloid-directed glioma therapies may only be beneficial for distinct subclasses of gliomas and that a more cell-type-specific manipulation of either microglia or macrophages may improve therapeutic outcomes.


An easy and economically viable route for the decoration of carbon nanotubes by magnetite nanoparticles, and their orientation in a magnetic field.
A simple, cheap and tunable approach for the decoration of carbon nanotubes by magnetite nanoparticles and their orientation in a magnetic field is reported.


Coconut fatty acids exhibit strong repellency and week-long efficacy against several urban pest arthropods of the southwestern United States.
The southwestern United States is home to a variety of arthropods including Turkestan cockroaches, Blatta lateralis (Walker); hematophagous kissing bugs, Tritoma rubida (Uhler); and Arizona bark scorpions, Centruroides sculpturatus Ewing. These arthropods cause medical concern when they become established around homes and/or invade indoors. Traditionally, the management of these pests has relied primarily on the use of chemical insecticides; however, they offer poor prospects for control owing to their lack of efficacy as well as the effects of insecticides on humans and the environment. Botanical repellents are an option that has not been fully investigated for the management of these pests. Here, we investigated the behavioral responses of common urban pests of the southwestern USA to recently discovered coconut fatty acids (CFAs), to establish the potential use of these compounds as repellents. Fresh residues of CFA mixture (CFAm) and their constituents caprylic acid, capric acid, capric acid methyl ester, lauric acid, and lauric acid methyl ester, tested at a concentration of 1 mg cm-2 , strongly repelled all arthropods. The repellent activity of CFAm lasted for at least 7 days, and the addition of lavender oil, used as an odor-masking agent, did not decrease this effect. Concentrations of CFAm ten times lower (0.1 mg cm-2 ) still repelled Turkestan cockroaches, and concentrations 100 times lower (0.01 mg cm-2 ) repelled T. rubida and scorpions. CFAm and some of their constituents are efficacious, economical, and logistically feasible for inclusion in integrated pest management programs for these important urban pests of the southwestern USA. © 2023 Society of Chemical Industry.


Hydroxybenzoic acids and their derivatives as peroxynitrite scavengers.
A social challenge of the 21(st) century is to reduce the incidence of chronic diseases. A balanced diet rich in polyphenols could contribute to reduce the risk and to the prevention of diabetes, coronary heart disease, cancer, Alzheimer's diseases and cataract(1). Hydroxybenzoic acids (HBA) and their derivatives, which are one of the substances responsible for these beneficial properties, are known mainly due to their antioxidant properties(2). They are effective scavengers of free radicals and reactive nitrogen species, such as peroxynitrite. Peroxynitrite is resulting from the reaction of nitric oxide with superoxide, causes lipid peroxidation and subsequent cellular damage and is responsible for the inactivation of many enzymes, activation of stress signalling pathways, release of proapoptotic factors, as well as cardiovascular dysfunction in septic schock(3). In this study we have tested 2-HBA, 3-HBA, 4-HBA, acetylsalicylic acid, 4-HBA methyl and propyl esters, 2,3-dihydroxybenzoic acid (DHBA), 2,5-DHBA, 2,4-DHBA, 2,6-DHBA, 3,5-DHBA, 3,4-DHBA, gallic acid and caffeic acid, by UV/VIS spectroscopy. The best ability to scavenge peroxynitrite was observed for gallic acid, 2,4-DHBA, 3,5-DHBA and caffeic acid. Improved comprehension of the complex relationship between the antioxidant properties of substances and their structure is important to understand their proper use in the prevention and treatment of diseases and for the detection of pathological processes. Monitoring and improved understanding of the antioxidant properties of hydroxybenzoic acid derivatives are important due to their frequent use in modern medical nutrition therapies.


Atrocities exposure in Vietnam combat veterans with chronic posttraumatic stress disorder: relationship to combat exposure, symptom severity, guilt, and interpersonal violence.
Vietnam combat veterans (N = 151) with chronic posttraumatic stress disorder (PTSD) completed measures of atrocities exposure, combat exposure, PTSD symptom severity, guilt and interpersonal violence. PTSD symptom severity, guilt and interpersonal violence rates were similar to previously reported studies that examined treatment seeking combat veterans with PTSD. Controlling for combat exposure, endorsement of atrocities exposure was related to PTSD symptom severity, PTSD B (reexperiencing) symptoms, Global Guilt, Guilt Cognitions, and cognitive subscales of Hindsight-Bias/Responsibility and Wrongdoing. These results are discussed in the context of previous research conducted regarding atrocities exposure and PTSD.


Anti-acetylcholine receptor response achieved by immunization with a synthetic peptide from the receptor sequence.
A synthetic peptide corresponding to the first twenty amino acids of the N-terminal region from the alpha-subunit of the Torpedo acetylcholine receptor cross reacts with antibodies to the receptor. A conjugate of this peptide to bovine serum albumin elicits in rabbits an immune response towards the synthetic peptide as well as towards the acetylcholine receptor. Blotting experiments demonstrate that the antipeptide antibodies react exclusively with the alpha-subunit of the acetylcholine receptor. Antibodies against synthetic peptides from various regions of the receptor sequence may provide useful reagents for structural and developmental analysis of the acetylcholine receptor as well as for the regulation of experimental autoimmune myasthenia gravis.


Sialic acids Neu5Ac and KDN in adipose tissue samples from individuals following habitual vegetarian or non-vegetarian dietary patterns.
Sialic acids (Sias) are a class of sugar molecules with a parent nine-carbon neuraminic acid, generally present at the ends of carbohydrate chains, either attached to cellular surfaces or as secreted glycoconjugates. Given their position and structural diversity, Sias modulate a wide variety of biological processes. However, little is known about the role of Sias in human adipose tissue, or their implications for health and disease, particularly among individuals following different dietary patterns. The goal of this study was to measure N-Acetylneuraminic acid (Neu5Ac), N-Glycolylneuraminic acid (Neu5Gc), and 2-keto-3-deoxy-D-glycero-D-galacto-nononic acid (KDN) concentrations in adipose tissue samples from participants in the Adventist Health Study-2 (AHS-2) and to compare the abundance of these Sias in individuals following habitual, long-term vegetarian or non-vegetarian dietary patterns. A method was successfully developed for the extraction and detection of Sias in adipose tissue. Sias levels were quantified in 52 vegans, 56 lacto-vegetarians, and 48 non-vegetarians using LC-MS/MS with Neu5Ac-D-1,2,3-13C3 as an internal standard. Dietary groups were compared using linear regression. Vegans and lacto-ovo-vegetarians had significantly higher concentrations of Neu5Ac relative to non-vegetarians. While KDN levels tended to be higher in vegans and lacto-ovo-vegetarians, these differences were not statistically significant. However, KDN levels were significantly inversely associated with body mass index. In contrast, Neu5Gc was not detected in human adipose samples. It is plausible that different Neu5Ac concentrations in adipose tissues of vegetarians, compared to those of non-vegetarians, reflect a difference in the baseline inflammatory status between the two groups. Epidemiologic studies examining levels of Sias in human adipose tissue and other biospecimens will help to further explore their roles in development and progression of inflammatory conditions and chronic diseases.


'Click' assembly of selective inhibitors for MAO-A.
In this Letter, an efficient strategy for the fast construction of 108 compounds library was developed using click chemistry. The fingerprint of inhibitory activity toward MAO-A/B against this library was obtained, and four hit compounds were identified as selective inhibitors toward MAO-A. Docking study was carried out to demonstrate the binding mode between a9 and MAO-A/B, and the result reveals that a9 localized in the 'aromatic cage' and oriented to establish π-π stacking interactions with Tyr407, Tyr444 and FAD in MAO-A rather than in MAO-B.


Pedestrian injuries near disabled vehicles.
Six cases of pedestrians injured near disabled vehicles and treated at Denver General Hospital are reviewed, with special attention paid to their cause. All occurred next to disabled or stopped vehicles. The serious injuries sustained could be avoided with public education.


Electrochemical charge storage performance of mesoporous MoO3@Co3O4nanocomposites as electrode materials.
Constructing a novel nanocomposite structure based on Co3O4is of the current interest to design and develop efficient electrochemical capacitors. The capacitive performance of MoO3@Co3O4nanocomposite is compared with pristine Co3O4nanoparticles, both of them being synthesized by hydrothermal technique. A BET surface area of ∼41 m2g-1(almost twice that of Co3O4) and average pore size of 3.6 nm is found to be suitable for promoting Faradaic reactions in the nanocomposite. Electrochemical measurements conducted on both samples predict capacitive behavior with quasi-reversible redox reactions. MoO3@Co3O4nanocomposite is capable of delivering a superior specific capacitance of 1248 F g-1at 0.5 A g-1along with notable stability of 92% even after 2000 cycles of charge-discharge and Coulombic efficiency approaching 100% at 10 A g-1. The outstanding results obtained in this work assure functional adequacy of MoO3@Co3O4nanocomposite in fabricating high-performance electrochemical capacitors.


Complexity of acclimatization substrate affects anaerobic digester microbial community response to organic load shocks.
This study elucidated the changes in the short-term response to organic load shocks of the anaerobic digestion (AD) microbiome acclimatized to a simple substrate and a complex substrate. Batch vial reactors were inoculated with AD sludge acclimatized to either a simple (starch and hipolypeptone) or a complex (dog food and starch) substrate, both with carbon-to-nitrogen ratio of 25. Organic loads in the form of an easily degradable substrate mix (starch and hipolypeptone) with concentrations varying from 0 to 5 g VS/L were applied to the reactors. Runs utilizing the inoculum acclimatized to a complex substrate sustained its methane productivity despite the high organic load shocks which the inoculum acclimatized to a simple substrate was unable to handle efficiently. The alpha-diversity of the microbiome decreased with increase in organic load for inoculum acclimatized with a simple substrate but was unaffected for the case of the inoculum acclimatized with a complex substrate. LactobacillalesandCloacimonadales were inferred to be major players in starch degradation pathways for the inoculum acclimatized using a simple substrate as predicted by the bioinformatics package PICRUSt2. However, acclimatizing using a complex substrate did not support their growth and were replaced by Coriobacteriales which provided higher flexibility in terms of the predicted regulated metabolic functions. The predicted functional regulation of Synergistales and Syntrophales increased with acclimatization using a complex substrate which also showed increase in the flexibility of the microbiome towards handling organic load shocks. Acetoclastic pathway was upregulated with increase in organic load regardless of the acclimatization substrate while the hydrogenotrophic pathway was downregulated. Overall, acclimatization using a complex substrate increased the robustness and flexibility of the microbiome towards organic load shocks.


Novel antiproliferative agents bearing substituted thieno[2,3-d]pyrimidine scaffold as dual VEGFR-2 and BRAF kinases inhibitors and apoptosis inducers; design, synthesis and molecular docking.
A series of novel thieno[2,3-d]pyrimidine derivatives was designed and synthesized based on multitarget directed drug design strategy. All the newly synthesized compounds were evaluated for their antiproliferative activity in the National Cancer Institute (NCI) against a panel of 60 tumor cell lines. Compounds 4a and 4b showed a significant antiproliferative activity at 10 µM dose, and were accordingly evaluated at five dose concentrations. They showed potent and broad-spectrum antiproliferative activity, with GI50 values in the micromolar range of 1.44-6.93 µM and 1.66-5.82 µM, respectively. They also showed TGI values in the cytostatic range of 3.49-97.3 µM and 3.33-77.3 µM respectively. These two compounds potently inhibited VEGFR-2 with IC50 = 0.111 ± 0.006 and 0.049 ± 0.003 µM, BRAFV600E with IC50 = 0.089 ± 0.005 and 0.063 ± 0.003 µM and BRAFWT IC50 = 0.071 ± 0.004 and 0.05 ± 0.003 µM, respectively in comparison to sorafenib IC50 values of 0.031 ± 0.002, 0.035 ± 0.002 and 0.021 ± 0.001 µM against VEGFR-2, BRAFV600E and BRAFWT, respectively. Compounds 4a and 4b showed also potent down-regulation of total VEGFR-2 and phosphorylated VEGFR-2. In addition, the HUVECs migratory potential was greatly reduced resulting in significantly disrupted wound healing patterns after treatment with compounds 4a and 4b for 72 h. Furthermore, Compounds 4a and 4b induced apoptosis by 22.82- and 25.81-fold increase in the total apoptosis percentage in breast cancer MCF7 cell line. This apoptotic activity was supported by an increase in the level of apoptotic caspase-9 by 6.17- and 9.07-fold, respectively. Moreover, the cell cycle analysis showed that compounds 4a and 4b arrested the cell cycle mainly in the G1 and G1/S phases, respectively. The molecular modeling studies were performed to assess the binding pattern and affinity of derivatives 4a and 4b toward the VEGFR-2 and BRAF active sites.


Slow rhythmic oscillations of EEG slow-wave amplitudes and their relations to midbrain reticular discharge.
The amplitude of anterior neocortical EEG slow-waves (0.5-4 Hz) measured during quiet waking, drowsy (WS) and synchronized sleep (S) states showed slow rhythmic oscillations in WS and S similar to those previously reported in midbrain reticular neurons (periods of 8-12 s). Abrupt changes in slow rhythms of unit discharge was reflected by similar changes in the amplitude of EEG slow-waves. Analyses on grouped data from many WS leads to S transitions showed no common phase relation between oscillations of EEG slow-wave amplitudes prior to S onset, but showed signs of a common phase relationship after. These findings, together with a significantly lower EEG synchronization level just before S onset in grouped data, suggest that the beginning of S is phase-related to oscillations of slow-wave amplitudes in WS.


Delta oscillations induced by ketamine increase energy levels in sleep-wake related brain regions.
Neuronal signaling consumes much of the brain energy, mainly through the restoration of the membrane potential (MP) by ATP-consuming ionic pumps. We have reported that, compared with waking, ATP levels increase during the initial hours of natural slow-wave sleep, a time with prominent electroencephalogram (EEG) delta oscillations (0.5-4.5 Hz). We have hypothesized that there is a delta oscillation-ATP increase coupling, since, during delta waves, neurons exhibit a prolonged hyperpolarizing phase followed by a very brief phase of action potentials. However, direct proof of this hypothesis is lacking, and rapid changes in EEG/neuronal activity preclude measurement in the naturally sleeping brain. Thus, to induce a uniform state with pure delta oscillations and one previously shown to be accompanied by a similar pattern of neuronal activity during delta waves as natural sleep, we used ketamine-xylazine treatment in rats. We here report that, with this treatment, the high-energy molecules ATP and ADP increased in frontal and cingulate cortices, basal forebrain, and hippocampus compared with spontaneous waking. Moreover, the degree of ATP increase positively and significantly correlated with the degree of EEG delta activity. Supporting the hypothesis of decreased ATP consumption during delta activity, the ATP-consuming Na+-K+-ATPase mRNA levels were significantly decreased, whereas the mRNAs for the ATP-producing cytochrome c oxidase (COX) subunits COX III and COX IVa were unchanged. Taken together, these data support the hypothesis of a cortical delta oscillation-dependent reduction in ATP consumption, thus providing the brain with increased ATP availability, and likely occurring because of reduced Na+-K+-ATPase-related energy consumption.


First principles prediction of the gas-phase precursors for AlN sublimation growth.
Using a new, parameter-free first principles strategy for modeling sublimation growth, we show that while Al and N2 dominate gas concentrations in AlN sublimation growth chambers under typical growth conditions, N2 is undersaturated with respect to the crystal and therefore cannot be a growth precursor. Instead, our calculations predict that the nitrogen-containing precursors are Al(n)N (n=2,3,4), in stark contrast to assumptions used in all previous modeling studies of this system.


Intracellular concentrations of micafungin in different cellular compartments of the peripheral blood.
Whilst micafungin serum concentrations are well studied, little is known about its concentrations within cellular compartments of the peripheral blood. Hence, in this study blood samples were collected from patients receiving micafungin (n=26). These samples were separated by double-discontinuous Ficoll-Hypaque density gradient centrifugation. Intracellular concentrations within the obtained cells, i.e. peripheral blood mononuclear cells (PBMCs), polymorphonuclear leukocytes (PMNs) and red blood cells (RBCs), were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Within PBMCs and PMNs, the intracellular micafungin concentration was significantly increased compared with the concentration in plasma (P<0.001). The intracellular concentration within RBCs did not significantly differ from the plasma concentration. Micafungin reaches high concentrations in human PBMCs and PMNs and is present in RBCs. In vitro data showed that intracellular uptake of micafungin by PBMCs depends on the albumin concentration of the surrounding medium, but only at non-physiological protein concentrations.


Pollinator abundance, morphology, and flower visitation rate: analysis of the "quantity" component in a plant-pollinator system.
Abundance and flower visitation rate of the pollinators of Lavandula latifolia (Labiatae), an insect-pollinated shrub, were studied over a 6-year period. The objective was to elucidate interspecific patterns in the "quantity" component of the plant-pollinator interaction. A total of 54 insect taxa are considered in the analyses, including hynenopterans, dipterans and lepidopterans. Most pollinators were comparatively scarce, with a few taxa acounting collectively for the majority of individuals. Pollinators differed broadly in flower visitation rate (0.2-30 flowers/min). Most of this variation was explained by differences in flower handling time (HT). Regardless of proboscis length, hymenopterans had intrinsically shorter handling times than lepidopterans. Within each group, HT decreased exponentially with increasing proboscis length. Abundance and visitation rate were uncorrelated across pollinator taxa. The total number of visits that each pollinator contributed to the plant (NFV) was estimated as the product of abundance x visitation rate. NFV values spanned four orders of magnirade. A small, taxonomically diverse group of species (1 moth, 1 butterfly, 4 bees) accounted for most visits and thus could effectively exert some selection on floral features. Nevertheless, the morphological diversity represented in this group of dominant pollinators probably constrains plant specialization, as they will most likely select for different floral features or in opposing directions on the same traits.


Family interventions in schizophrenia and related disorders: a critical review of clinical trials.
To update evidence from studies on family intervention in schizophrenia looking carefully at methodological issues. Twenty-five studies were reviewed, using specific outcome criteria, and computing effect sizes whenever possible. Effect on relapse is relatively well assessed, although differences emerged particularly in comparison with poor control treatments and disappeared in recent studies. Findings on patient's symptoms, social functioning or family variables are limited and affected by methodological pitfalls. No difference between intervention models emerged, although behavioural/psycho-educational approaches were better investigated. Patients' inclusion, greater frequency and length of treatment led to better results. The main flaws were: poor control of standard treatment, small sample sizes, failure in evaluating clinical significance in continuous outcome variables. It remains unclear whether the effect depends on family treatment or on more intensive care. The failure to relate outcome to family-mediating variables is a challenge to the rationale underlying family interventions.


Phase I Study of Lenalidomide and Sorafenib in Patients With Advanced Hepatocellular Carcinoma.
Combination therapies in patients with hepatocellular carcinoma can be associated with overlapping toxicity and are therefore poorly tolerated.Using sorafenib at the maximum tolerated dose can lead to a higher incidence of toxicities. Consequently, combination studies might evaluate sorafenib at alternative schedules or doses to improve tolerance, recognizing this could affect sorafenib efficacy.Although this combination was poorly tolerated, it does not exclude further evaluation of new-generation immunomodulator drugs or immune checkpoint inhibitors in the hope of optimizing tolerance and safety. Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC), and to date, no combination therapy has demonstrated superior survival compared with sorafenib alone. The immunosuppressive microenvironment in HCC is a negative predictor for survival. Lenalidomide is an immunomodulator and antiangiogenic agent, with limited single-agent efficacy in HCC. Based on these data, we designed a phase I study of sorafenib plus lenalidomide to determine the safety and preliminary antitumor activity of this combination. This was an open-label, phase I study with a 3+3 dose escalation/de-escalation design. The starting dose of sorafenib was 400 mg p.o. b.i.d. and of lenalidomide was 15 mg p.o. daily with a planned dose escalation by 5 mg per cohort up to 25 mg daily. Dose de-escalation was planned to a sorafenib dose of 400 mg p.o. daily combined with two doses of lenalidomide: 10 mg p.o. daily for a 28-day cycle (cohort 1) and 10 mg p.o. daily for a 21- or 28-day cycle (cohort 2). Patients with cirrhosis, a Child-Pugh score of A-B7, and no previous systemic therapy were eligible. Five patients were enrolled. Their median age was 56 years (range 39-61), and the ECOG status was 0-2. Four patients were treated at dose level (DL) 1. Because of the poor tolerance to the combination associated with grade 2 toxicities, one more patient was treated at DL -1. No dose-limiting toxicity was observed as specified per protocol. The most common toxicities were nausea, anorexia, pruritus, elevated liver enzymes, and elevated bilirubin. Three patients experienced one or more of the following grade 3 toxicities: fatigue (DL 1), increased bilirubin (DL 1), skin desquamation (DL -1), and elevated transaminase levels (DL 1). The median duration of therapy was 1 cycle (range 1-3). All patients discontinued the study, 4 because of progressive disease and 1 by patient preference. The best confirmed response was progressive disease. The median progression-free survival was 1.0 month (95% confidence interval 0.9-2.8), and the median overall survival was 5.9 months (95% confidence interval 3.68-23.4). In our small study, the combination of lenalidomide and sorafenib was poorly tolerated and showed no clinical activity. Although the study was closed early because of toxicity concerns, future studies assessing combinations of sorafenib with new-generation immunomodulator drugs or other immunomodulatory agents, should consider lower starting doses of sorafenib to avoid excessive toxicity.


Monomeric and oligomeric complexes of the B cell antigen receptor.
The current structural model of the B cell antigen receptor (BCR) describes it as a symmetric protein complex in which one membrane-bound immunoglobulin molecule (mIg) is noncovalently bound on each side by an Ig-alpha/Ig-beta heterodimer. Using peptide-tagged Ig-alpha proteins, blue native polyacrylamide gel electrophoresis (BN-PAGE), and biosynthetical labeling of B cells, we find that the mIg:Ig-alpha/Ig-beta complex has a stoichiometry of 1:1 and not 1:2. An anti-Flag stimulation of B cells coexpressing Flag-tagged and wild-type Ig-alpha proteins results in the phosphorylation of both Ig-alpha proteins, suggesting that on the surface of living B cells, several BCR monomers are in contact with each other. A BN-PAGE analysis after limited detergent lysis provides further evidence for an oligomeric BCR structure.


Assessment of nerve excitability in toxic and metabolic neuropathies.
Measurement of nerve excitability by threshold tracking provides complementary information to conventional nerve conduction studies and may be used to infer the activity of a variety of ion channels, energy-dependent pumps, and ion exchange processes activated during the process of impulse conduction. This review highlights recent clinical excitability studies that have suggested mechanisms for nerve involvement in a range of metabolic and toxic neuropathies. While clinical nerve excitability studies are still in their infancy, and it is too early to know whether they have diagnostic value, there is growing evidence of their utility to provide novel insights into the pathophysiological mechanisms involved in a variety of neuropathic disturbances.


FOLFOX in patients aged between 76 and 80 years with metastatic colorectal cancer: an exploratory cohort of the OPTIMOX1 study.
Patients older than 75 years of age are usually excluded from metastatic colorectal cancer randomized studies. The OPTIMOX1 study evaluated FOLFOX7, a simplified (s) leucovorin (LV) and 5-fluorouracil (5FU) regimen (sLV5FU2) with high-dose oxaliplatin, in a new oxaliplatin stop-and-go strategy. An exploratory cohort of patients aged 76 to 80 years was included in the study. In all, 620 previously untreated patients were randomized between FOLFOX4 until progression (arm A), or FOLFOX7 for 6 cycles, maintenance without oxaliplatin for 12 cycles, and reintroduction of FOLFOX7 (arm B). A total of 37 patients aged 76 to 80 years were included, 20 in arm A and 17 in arm B. The overall response rate (ORR) was 59.4%, comparable to younger patients (59%). Median progression-free survival (PFS) was 9.0 months and median overall survival (OS) was 20.7 months. These results did not differ from that in younger patients < or =75 years in the OPTIMOX1 study with PFS 9.0 months (P = .63) and OS 20.2 months (P = .57). They experienced slightly more grade 3 of 4 toxicity than younger patients: 65% versus 48% (P = .06), mainly with more neutropenia (41% vs 24%, P = .03) and neurotoxicity (22% vs 11%, P = .06). Tolerability, however, was manageable and no toxic death occurred in this elderly population. The efficacy of FOLFOX-based treatment was maintained in patients >75 years with both FOLFOX regimens. The oxaliplatin stop-and-go management strategy performed well in this population.


Safety, Tolerability, and Pharmacokinetics of Crenezumab in Patients with Mild-to-Moderate Alzheimer's Disease Treated with Escalating Doses for up to 133 Weeks.
Crenezumab is a fully humanized, monoclonal anti-amyloid-β immunoglobulin G4 antibody. This Phase Ib study (NCT02353598) evaluated the safety, tolerability, and pharmacokinetics of crenezumabat doses of ≤120 mg/kg administered intravenously every 4 weeks (q4w). Immunogenicity and exploratory biomarkers were also evaluated. In this multicenter, double-blind study, participants (aged 50-90 years) with mild-to-moderate Alzheimer's disease (AD) and amyloid-positive positron emission tomography (PET) scan were randomized to receive crenezumab 30 or 45 mg/kg (Cohort 1, n = 21), 60 mg/kg (Cohort 2, n = 21), or 120 mg/kg (Cohort 3, n = 19) or corresponding placebo (n = 14) intravenously q4w for 13 weeks. Seventy-one participants were subsequently enrolled in an optional open-label extension (OLE) and received crenezumab at the originally assigned dose level, except for Cohort 3 (crenezumab 60 mg/kg during OLE). Participants received regular brain MRIs to assess amyloid-related imaging abnormalities (ARIA). Results up to Week 133 are reported. Approximately 94% of participants experienced ≥1 adverse event (AE). Most AEs were mild or moderate; 15.5% experienced a Grade ≥3 AE. No ARIA-edema/effusion (ARIA-E) events were observed. New ARIA-micro hemorrhages and hemosiderosis (ARIA-H) were reported in 4.9% (double-blind treatment period) and 9.9% (combined double-blind treatment and OLE periods) of participants. Steady-state trough concentrations of crenezumab were dose-proportional and maintained for each dose level. Crenezumab doses of ≤120 mg/kg intravenously q4w were well tolerated. The observed safety profile for ≤133 weeks of treatment in a mild-to-moderate AD population was similar to that seen in previous trials.


Evaluation of in vitro antioxidant effect of new mono and diselenides.
This study was designed to examine the antioxidant activity in vitro of novel mono- and diselenide compounds. We compared whether the formation of p-methyl-selenol from compounds 1-phenyl-3-(p-tolylselanyl)propan-2-amine (C1) and 1,2-dip-tolyldiselenide (C4) and o-methoxy-selenol from compounds 1-(2-methoxyphenylselanyl)-3-phenylpropan-2-amine (C2) and 1,2-bis(2-methoxyphenyl)diselenide (C3) may be involved in their antioxidant effects. The compounds were tested against Fe(II) and sodium nitroprusside (SNP)-induced lipid peroxidation in rat brain and liver homogenates. Likewise, the antioxidant capacity of the compounds was assessed by their ability to decolorize the DPPH radical as well as the Fe(II) chelating assay through the reduction of molybdenum(VI) (Mo6+) to molybdenum(V) (Mo5+). This colorimetric assay was also used to quantify thiol peroxidase (GPx) and oxidase activity and thioredoxin reductase (TrxR) activity. The results showed that the novel selenide compounds inhibit the thiobarbituric acid reactive species (TBARS) induced by different pro-oxidants, but the monoselenides effects were significant only at concentrations higher than the concentrations of the diselenides. Similarly, the total antioxidant activity was higher in the diselenides. Moreover, GPx and TrxR activity was only observed for the diselenides, which indicates that these compounds are more stable selenol molecules than monoselenides.


Natural abundance (17)O NMR spectroscopy of rat brain in vivo.
Oxygen is an abundant element that is present in almost all biologically relevant molecules. NMR observation of oxygen has been relatively limited since the NMR-active isotope, oxygen-17, is only present at a 0.037% natural abundance. Furthermore, as a spin 5/2 nucleus oxygen-17 has a moderately strong quadrupole moment which leads to fairly broad resonances (T(2)=1-4 ms). However, the similarly short T(1) relaxation constants allow substantial signal averaging, whereas the large chemical shift range (>300 ppm) improves the spectral resolution of (17)O NMR. Here it is shown that high-quality, natural abundance (17)O NMR spectra can be obtained from rat brain in vivo at 11.74 T. The chemical shifts and line widths of more than 20 oxygen-containing metabolites are established and the sensitivity and potential for (17)O-enriched NMR studies are estimated.


Role of Korean red ginseng total saponins in rat infertility induced by polycystic ovaries.
To investigate the effect of Korean red ginseng total saponins (GTS) on ovarian morphology and nerve growth factor (NGF) expression in the ovaries, pituitary, and hippocampus. Polycystic ovary (PCO) rat model induced by estradiol valerate (EV). University research laboratory. Thirty sexually mature female Sprague-Dawley rats weighing 190-210 g. Female Sprague-Dawley rats (190-210 g) were separated into three groups: EV control (n = 10), EV plus GTS (n = 10), and oil control (n = 10). Ovarian morphology and NGF protein expression. Polycystic ovary was fully developed in rats with a single intramuscular injection of EV. Increased expression of NGF was noted in the ovaries and the brain of rats with PCO. GTS administration attenuated NGF expression in the ovaries but not in the brain. Our findings suggest a role for GTS in the regulation of NGF expression in female rats with PCO.


The Correlation between Ferroptosis and m6A Methylation in Patients with Acute Kidney Injury.
The present research analyzed the correlation between N6-methyladenosine (m6A) methylation and ferroptosis associated genes (FAGs) in acute kidney injury (AKI) patients. Bioinformatics analysis of microarray profiles (GSE30718) was performed to select differential expression genes (DEGs). FAGs are derived from systematic analysis of the aberrances and functional implications. The m6A methylation related genes were derived from the molecular characterization and clinical significance of m6A modulators. The multi-gene correlation of ferroptosis and M6A methylation modification was displayed. Then, the CIBERSORT algorithm was used to analyze the proportions of 22 immune cell infiltration. In total, 349 DEGs were extracted between the AKI and control samples, among which 172 genes were upregulated and 177 were downregulated. FAGs (SLC1A5, CARS, SAT1, ACSL4, NFE2L2, TFRC, and MT1G) and m6A methylation related genes (YTHDF3, WTAP, and IGF2BP3) were significantly increased in AKI patients (p < 0.05). FAGs (SAT1, ACSL4, and NFE2L2) were positively correlated with the expression level of m6A methylation genes (p < 0.05). NFE2L2 has high diagnostic value, and the level of NFE2L2 was negatively correlated with the degree of follicular helper T (TFH) cell infiltration. Our research could provide a new theoretical basis for the pathogenesis and immune mechanism of AKI.


Development of a specific and sensitive sandwich enzyme-linked immunosorbent assay for the quantification of dasatinib.
This study sought to develop a specific and sensitive sandwich enzyme-linked immunosorbent assay (ELISA) for pharmacokinetic studies of dasatinib, a tyrosine kinase inhibitor. Anti-dasatinib antibodies were obtained from mice or rabbits by using two partial structures of dasatinib as haptens: 2-amino-N-(2-chloro-6-methylphenyl)-thiazole-5-carboxamide and 2-{4-(2-hydroxyethyl)-1-piperazinyl}-isonicotinic acid. The best combination of two antibodies for sandwich ELISA of dasatinib was determined using four anti-dasatinib antibodies derived from mice and rabbits. Using two dasatinib-specific rabbit antibodies, we successfully developed an ultra-specific and highly sensitive sandwich ELISA that is hardly affected by the main metabolite of dasatinib. The sandwich ELISA showed a linear detection range from 320 pg/mL to 1000 ng/mL. Serum dasatinib concentrations lower than 320 pg/mL were reproducibly measurable using the sandwich ELISA. The ELISA was specific to dasatinib and there were no cross-reactivities with the major metabolites 4'-hydroxy dasatinib and dasatinib carboxylic acid. The developed sandwich ELISA will be a valuable tool for pharmacokinetic studies of dasatinib. Furthermore, this study revealed that rabbit antibodies can sandwich drug molecules of a smaller size than mouse antibodies in sandwich ELISA.


Determination of the antioxidant capacity of samples of different types of tea, or of beverages based on tea or other herbal products, using a superoxide dismutase biosensor.
Research was performed to experimentally evaluate the antioxidant capacity of different plant products sold by herbalists (ginger, dog rose, ginseng and camomile) and of several types of tea (ordinary tea, green tea, detheinated tea, lemon and peach flavoured tea) using a superoxide dismutase (SOD) biosensor recently developed by the present authors. Measurements were carried out by comparing biosensor response to the superoxide radical produced in solution using the xanthine-xanthine oxidase system, both in the presence and absence of the antioxidant sample considered. Precision of antioxidant capacity measures for herbal products and for non diluted samples was good, generally with a R.S.D.%< or =10% and a LOD value about 0.1 for relative antioxidant capacity. Also a "pool" of polyphenols from different tea samples was measured using a tyrosinase biosensor (LOD approximately 2 microM).


The Anaesthetic-ECT Time Interval in Electroconvulsive Therapy Practice--Is It Time to Time?
Because most common intravenous anaesthetics used in ECT have anticonvulsant properties, their plasma-brain concentration at the time of seizure induction might affect seizure expression. The quality of ECT seizure expression has been repeatedly associated with efficacy outcomes. The time interval between the anaesthetic bolus injection and the ECT stimulus (anaesthetic-ECT time interval) will determine the anaesthetic plasma-brain concentration when the ECT stimulus is administered. The aim of this study was to examine the effect of the anaesthetic-ECT time interval on ECT seizure quality and duration. The anaesthetic-ECT time interval was recorded in 771 ECT sessions (84 patients). Right unilateral brief pulse ECT was applied. Anaesthesia given was propofol (1-2 mg/kg) and succinylcholine (0.5-1.0 mg/kg). Seizure quality indices (slow wave onset, amplitude, regularity, stereotypy and post-ictal suppression) and duration were rated through a structured rating scale by a single blinded trained rater. Linear Mixed Effects Models analysed the effect of the anaesthetic-ECT time interval on seizure quality indices, controlling for propofol dose (mg), ECT charge (mC), ECT session number, days between ECT, age (years), initial seizure threshold (mC) and concurrent medication. Longer anaesthetic-ECT time intervals lead to significantly higher quality seizures (p < 0.001 for amplitude, regularity, stereotypy and post-ictal suppression). These results suggest that the anaesthetic-ECT time interval is an important factor to consider in ECT practice. This time interval should be extended to as long as practically possible to facilitate the production of better quality seizures. Close collaboration between the anaesthetist and the psychiatrist is essential.


Epstein-Barr virus DNA recombines via latent origin of replication with the human genome in the lymphoblastoid cell line RGN1.
We show here that in a lymphoblastoid cell line Epstein-Barr virus DNA recombines with the human genome. The genetic exchange involves the oriP region of the virus. A junction between viral and human DNA from this line has been cloned and sequenced. The results indicate that the integration of Epstein-Barr virus DNA involves a region of the human genome which contains internal short repetition. An 800-bp probe has been isolated from the human part of the junction. This probe has been used to show that the human region exists as a duplication in normal cells.


Flavins are source of visible-light-induced free radical formation in cells.
It has been hypothesized that reactive oxygen species (ROS) are created by an endogenous photosensitizer during low energy visible light illumination of tissue, and these ROS are responsible for reported biostimulative effects. This study aims to identify the endogenous photosensitizer responsible for ROS production by visible light. Electron paramagnetic resonance (EPR) spectroscopy was used to detect oxyradicals produced in cardiac and sperm cells during illumination by a halogen lamp. Oxyradical production was determined as a function of illumination wavelength, cell fraction, and molecular weight. Oxyradicals were created solely by the 400-500 nm range of visible light. The endogenous photosensitizer is found predominantly in the cytosol and is smaller than 12 kD. Flavin mononucleotide produces the same signal at concentrations consistent with reported intracellular free flavin concentrations. A small, water soluble photosensitizer active only at wavelengths shorter than 500 nm is consistent with a flavin, which reproduces cellular signals at physiological concentrations. Thus, flavins are responsible for the photosensitization of the observed oxyradicals in cells.


Treatment of long-segment congenital tracheal stenosis with congenital cardiovascular defects in infancy.
This study aims to evaluate the outcomes of simultaneous repair for infants with long-segment congenital tracheal stenosis (LSCTS) with congenital cardiovascular defects (CCD). We retrospectively reviewed the clinical data of infants aged less than 1 year with LSCTS and CCD who underwent simultaneous repair at Children's Hospital of Chongqing Medical University from January 2020 to March 2023. A systematic search of PubMed, Embase, and Cochrane Library for the relevant published studies that reported the simultaneous repair of CTS and CCD in infancy was conducted in March 2023. The inverse variance method of DerSimonian-Laird (D + L) was used for estimate synthesis. A total of thirteen infants with a mean age of 5.6 ± 3.1 months and a mean weight of 6.4 ± 0.9 Kg underwent slide tracheoplasty with modified procedures and cardiovascular operations. LSCTS was diagnosed in all thirteen patients. Nine infants were ventilator dependent, and four patients were operated on due to persistent wheezing and recurrent respiratory infections. Seven patients underwent pulmonary artery sling repair, and six underwent atrial septal defect repair. All infants were repaired utilizing cardiopulmonary bypass (CPB) support. Significant complications were recorded in three patients. In-hospital deaths were seen in one case. The median tracheal minimum diameter of hospital survivors was significantly larger than the preoperative minimum diameter (p < 0.001). The mean follow-up duration was 17.1 ± 7.1 months. There was no late mortality during the follow-up. Twelve studies were included based on our search strategy. The pooled estimate of mortality in the literature was 10.9% (95%CI, 5.3%-17.7%, I2 = 0). The pooled estimate of airway re-interventions was 28.8% (95%CI, 14.5%-43.2%, I2 = 74%). Simultaneous repair of LSCTS and CCD in infancy is safe and effective. Slide tracheoplasty with appropriate technical modifications may be valid for LSCTS repair without significant restenosis and reinterventions.


Gallstone ileus in the absence of the gallbladder: case report and review of the literature.
Although small-bowel obstruction due to gallstone ileus is uncommon, it assumes increasing importance with advancing age. The obstructing gallstone enters the bowel through an internal fistula between gallbladder and duodenum. The authors describe the case of a patient who had undergone cholecystectomy and in whom gallstone ileus occurred secondary to a stone that entered the bowel through a choledochoduodenal fistula. Treatment was traditional with removal of the obstructing stone, but the fistula was left undisturbed. The authors believe that further biliary tract symptoms are unlikely. The patient was well 8 weeks after operation and roentgenograms indicated that the internal biliary fistula was patent.


The ciliary necklace--a transmission electron microscopic study using tannic acid-containing fixation.
Human respiratory cilia, including those in seven cases of immotile cilia syndrome, were examined by transmission electron microscopy after tannic acid-containing fixation. This fixation method is useful for ultrastructural observation of unit membranes and of the dynein arms and protofilaments of cilia. In addition, intramembrane particles and electron-dense strands were also demonstrated in the neck of the cilia. These structures may correspond to the ciliary necklace, which has been demonstrated by the freeze-etch technique. In high-magnification electron micrographs, the intramembrane particles were 10 nm in diameter and the necklace spacing was about 30 nm in human respiratory cilia. Prior to this study, no reports on ultrastructural abnormalities of the ciliary necklace in humans had appeared, probably because of technical problems with tissue preparation. Therefore tannic acid-containing fixation appears to be useful for ultrastructural observation of the ciliary necklace.


Electrophysiologic findings in meningopolyneuritis of Garin-Bujadoux-Bannwarth.
Previous reports on neuropathy in Lyme disease and related disorders suggest predominant demyelination in most of the few cases investigated. We analysed retrospectively electrophysiologic data in 29 patients with MPN-GBB. In peripheral nerve involvement slowed NCV and/or prolonged DL was the prominent finding, concordant with primary demyelination. Distribution of pathology resembles mononeuritis. Facial nerve palsy was common and often bilateral.


Interactions of ErbB4 and Kap1 connect the growth factor and DNA damage response pathways.
ErbB4 is unusual among receptor tyrosine kinases because some isoforms can be efficiently cleaved at the plasma membrane to release a soluble intracellular domain. The cleavage product has high kinase activity and homes to the nucleus. A screen for proteins that associate with the ErbB4 intracellular domain identified candidate interactors including ITCH, WWP2, Nucleolin, and Krab-associated protein 1 (Kap1). Kap1 binds to multiple isoforms of ErbB4 but does not require ErbB4 kinase activity for binding, nor is it an ErbB4 substrate. Kap1 reduces ERBB4 transcription and either directly or indirectly modulates the expression of genes that are themselves regulated by ErbB4. Upregulation of ErbB4 and suppression of MDM2 jointly enhance and accelerate the accumulation of p21(CIP1) in response to DNA damage. Overall, these findings further substantiate the role of ErbB4 in conjoint regulation of growth factor signaling and DNA damage responses.


Improving protein-ligand binding site prediction accuracy by classification of inner pocket points using local features.
Protein-ligand binding site prediction from a 3D protein structure plays a pivotal role in rational drug design and can be helpful in drug side-effects prediction or elucidation of protein function. Embedded within the binding site detection problem is the problem of pocket ranking - how to score and sort candidate pockets so that the best scored predictions correspond to true ligand binding sites. Although there exist multiple pocket detection algorithms, they mostly employ a fairly simple ranking function leading to sub-optimal prediction results. We have developed a new pocket scoring approach (named PRANK) that prioritizes putative pockets according to their probability to bind a ligand. The method first carefully selects pocket points and labels them by physico-chemical characteristics of their local neighborhood. Random Forests classifier is subsequently applied to assign a ligandability score to each of the selected pocket point. The ligandability scores are finally merged into the resulting pocket score to be used for prioritization of the putative pockets. With the used of multiple datasets the experimental results demonstrate that the application of our method as a post-processing step greatly increases the quality of the prediction of Fpocket and ConCavity, two state of the art protein-ligand binding site prediction algorithms. The positive experimental results show that our method can be used to improve the success rate, validity and applicability of existing protein-ligand binding site prediction tools. The method was implemented as a stand-alone program that currently contains support for Fpocket and Concavity out of the box, but is easily extendible to support other tools. PRANK is made freely available at http://siret.ms.mff.cuni.cz/prank.


Current status of small-bowel transplantation.
Patients who have lost such a large portion of their small bowel that they permanently require total parenteral nutrition for survival would greatly benefit by receiving a small-intestinal transplant. Over the past two decades, many experimental studies have delineated the specific problems surrounding small-bowel transplantation and provided strategies for their control. Control of rejection, the most difficult problem, may be achieved with a combination of cyclosporine, azathioprine, prednisone, antithymocyte globulin, and monoclonal antibodies. The threat of graft-versus-host disease originating from the allogeneic lymphatic tissues in the allograft is abolished by in vitro x-irradiation of the cold, nonperfused graft with 1000 rads. Monitoring of the intestinal allograft is possible with the combination of a function test (maltose absorption, glucose absorption, or any other function test) and repeated graft biopsy. Effective short-term preservation of small-bowel segments for up to 18 h is possible by intravascular flushing with a balanced electrolyte solution containing 3% fructose and by subsequent hypothermic storage. Clinical small-bowel transplantation is certainly not an imminent therapeutic tool. However, clinical trials in highly selected patients could be envisioned on the basis of our present understanding of small-bowel transplantation and of transplantation biology in general, and in view of the clinical successes achieved with duodenal grafts transplanted in conjunction with pancreatic grafts.


Bacterial Contamination of Mobile Phones Used by Healthcare Workers in Critical Care Units: A Cross-Sectional Study from Saudi Arabia.
Healthcare-associated infections (HAIs) present a formidable challenge for healthcare institutions, resulting in heightened mortality, morbidity, and economic burden. Within healthcare settings, various equipment and materials, including mobile phones, can potentially act as sources of infection. This study sought to examine the occurrence of bacterial contamination on mobile phones utilized by healthcare workers (HCWs) in intensive care units (ICUs), pediatric intensive care units (PICUs), neonatal intensive care units (NICUs), and cardiac care units (CCUs) within a central hospital (CH) and two peripheral hospitals (PHs) situated in the southwestern province of Saudi Arabia. We collected a total of 157 samples from mobile phones utilized by HCWs across all ICUs in the CH and PHs. These samples underwent bacteriological analysis to evaluate the degree of bacterial contamination. We found that 45 out of 55 samples from physicians (81.81%) and 58 out of 77 samples from nurses (75.32%) showed bacterial contamination. Contamination rates on HCWs' mobile phones in the ICU, PICU, and NICU departments of the CH were observed at 69.56%, 80.95%, and 70.27%, respectively. Furthermore, the overall contamination rates in the ICUs, NICUs, and CCUs of the PHs were 78.26%, 88.88%, and 66.66%, respectively. The overall contamination rates of mobile phones in the CH and PHs were 72.11% and 81.13%, respectively. These findings underscore the necessity of routinely disinfecting the mobile phones of HCWs to mitigate the risk of cross-contamination. Implementing robust disinfection protocols can significantly contribute to curtailing the propagation of bacterial pathogens and reducing the incidence of HAIs in healthcare settings.


All-FIT: allele-frequency-based imputation of tumor purity from high-depth sequencing data.
Clinical sequencing aims to identify somatic mutations in cancer cells for accurate diagnosis and treatment. However, most widely used clinical assays lack patient-matched control DNA and additional analysis is needed to distinguish somatic and unfiltered germline variants. Such computational analyses require accurate assessment of tumor cell content in individual specimens. Histological estimates often do not corroborate with results from computational methods that are primarily designed for normal-tumor matched data and can be confounded by genomic heterogeneity and presence of sub-clonal mutations. Allele-frequency-based imputation of tumor (All-FIT) is an iterative weighted least square method to estimate specimen tumor purity based on the allele frequencies of variants detected in high-depth, targeted, clinical sequencing data. Using simulated and clinical data, we demonstrate All-FIT's accuracy and improved performance against leading computational approaches, highlighting the importance of interpreting purity estimates based on expected biology of tumors. Freely available at http://software.khiabanian-lab.org. Supplementary data are available at Bioinformatics online.


Retracted: Changes in the impact factor of anesthesia/critical care journals within the past 10 years.
The impact factor (IF) is published by the Institute for Scientific Information (ISI). There is a tendency to assess quality of scientific journals with the help of the IE An analysis of the changes in the IF over time in the different specialities may help to further enlighten the worth and problems of the IE METHODS: The IFs listed under the subheadings Anesthesiology and Emergency Medicine & Critical Care in the Science Citation Index - Journal Citation Report were descriptively analysed over the past 10 years. Additionally, IFs of some other important journals (subheadings Surgery, Cardiovascular, General Medicine) were analysed. The IF of most of the journals showed a constant increase over the years (average in Anesthesiology: +65%; average in Emergency Medicine & Critical Care: +145%). IFs of the highest ranked journals of other specialities showed a similar increase over the years (average in surgical journals: +56%; average in cardiac journals: +59%; average in general journals: +40%). More Anesthesiology and Emergency Medicine & Critical Care journals originated from the USA show an IF >2.0 over the past 10 years than do European journals. Although the value of the IF is highly controversial, it is a frequently used tool to assess rating of a medical journal. Anesthesiology and Emergency Medicine & Critical Care journals showed a continuous increase in the IF over the past 10 years.


[Experimental evaluation of the combined effect of the noise and aerosols in the air of steel mills].
The analysis of 3 chronic experiments on white rats pertaining to the study of the combined effect of noise at 85 and 95 dBA and aerosols containing manganese, chromium, nickel oxides and SiO2 showed that there were noted the effects caused by their combined impact. The shifts were clearly marked in the state of the endocrine and cardiovascular systems.


Performance of alkali-activated slag individually incorporated with two nanozinc sources.
The role of nanozinc source (nanohydrozincite: nHZ; nanozinc oxide: nZO) on the performance of alkali-activated slag (AAS) was explored for the first time in the present work. The results showed that nHZ with different contents (0.5, 1.0, and 1.5 wt%) retards the early hydration rate of AAS, whereas nZO showed the lowest retardation effect. Zn(OH)2 is the main retarder inside AAS-nZO and AAS-nHZ, which consumes the dissolved Ca2+ (responsible for the early hardening of AAS) from slag to yield calcium zincate hydrate (CZH). The high retardation rate of nHZ is originated from its high affinity to consume much Ca2+ through the formation of additional pirssonite (Na2CO3.CaCO3.2H2O) double salt. Although adding nHZ induced the drying shrinkage of AAS, it improved the later compressive strengths (28 to 365 days), especially at low nHZ content (0.5 wt%), via the formation of CASH with lower Ca/Si ratio and higher binding capacity compared to that formed inside AAS and AAS-nZO. A further research is needed to reduce the drying shrinkage and to accelerate the early strength of AAS containing nHZ.


Long intergenic non-protein-coding RNA 1547 acts as a competing endogenous RNA and exerts cancer-promoting activity in non-small cell lung cancer by targeting the microRNA-195-5p/ homeobox C8 axis.
Long intergenic non-protein coding RNA 1547 (LINC01547) presents a notable relationship with prognosis in patients with ovarian cancer. Herein, we examined the expression of LINC01547 in non-small cell lung cancer (NSCLC) to ascertain its clinical significance. We also explored the detailed functions of LINC01547 in regulating the aggressive phenotype of NSCLC and the molecular mechanism of action underlying its carcinogenic activities events in NSCLC. Furthermore, we applied the data acquired from the tissue specimens and the Cancer Genome Atlas (TCGA) database to analyze the level of LINC01547 in NSCLC and conducted functional assays to address the regulatory effect of LINC01547. Further, we examined the mechanistic interaction among LINC01547, microRNA-195-5p (miR-195-5p), and homeobox C8 (HOXC8) using bioinformatics prediction and luciferase reporter assay. LINC01547 was noticeably overexpressed, as affirmed by data from TCGA and our own cohort; moreover, poor prognosis was associated with increased LINC01547 levels in patients with NSCLC. LINC01547 regulates cell proliferation, colony-forming, migration, and invasion, and its absence produced tumor-repressing effects in NSCLC. Mechanistically, as a competitive endogenous RNA, LINC01547 decoyed miR-195-5p and consequently resulted in the overexpression of HOXC8 in NSCLC cells. Using rescue experiments, we found that the regulatory activities of LINC01547 deficient in repressing the malignant properties of NSCLC cells could be counteracted by hindering miR-195-5p or overexpressing HOXC8. Conclusively, LINC01547 serves as a crucial component to worsen the oncogenicity of NSCLC cells by controlling the miR-195-5p/HOXC8 axis. Thus, the newly identified competing endogenous RNA pathway may potentially be an attractive therapeutic for NSCLC management.


PTEN-induction in U251 glioma cells decreases the expression of insulin-like growth factor binding protein-2.
PTEN is a tumor suppressor gene whose loss of function is observed in approximately 40-50% of human cancers. Although insulin-like growth factor binding protein-2 (IGFBP-2) was classically described as a growth inhibitor, multiple recent reports have shown an association of overexpression and/or high serum levels of IGFBP-2 with poor prognosis of several malignancies, including gliomas. Using an inducible PTEN expression system in the PTEN-null glioma cell line U251, we demonstrate that PTEN-induction is associated with reduced proliferation, increased apoptosis, and a substantial reduction of the high levels of IGFBP-2 expression. The PTEN-induced decrease in IGFBP-2 expression could be mimicked with the PI3-kinase inhibitor LY294002, indicating that the lipid phosphatase activity of PTEN is responsible for the observed effect. However, the rapamycin analog CCI-779 did not affect IGFBP-2 expression, suggesting that the PTEN-induced decrease in IGFBP-2 expression is not attributable to decreased mTOR signalling. Recombinant human IGFBP-2 was unable to rescue U251-PTEN cells from the antiproliferative effects of PTEN, and IGFBP-2 siRNA did not affect the IGF-dependent or -independent growth of this cell line. These results suggest that the clinical data linking IGFBP-2 expression to poor prognosis may arise, at least in part, because high levels of IGFBP-2 expression correlate with loss of function of PTEN, which is well known to lead to aggressive behavior of gliomas. Our results motivate translational research regarding the relationship between IGFBP-2 expression and loss of function of PTEN.


A New Care Model Reduces Polypharmacy and Potentially Inappropriate Medications in Long-Term Care.
Assess the impact of a new pharmaceutical care model on (1) polypharmacy and (2) potentially inappropriate medication (PIM) use in long-term care facilities (LTCFs). Pragmatic quasi-experimental study with a control group. This multifaceted model enables pharmacists and nurses to increase their professional autonomy by enforcing laws designed to expand their scope of practice. It also involves a strategic reorganization of care, interdisciplinary training, and systematic medication reviews. Two LTCFs exposed to the model (409 residents) were compared to 2 control LTCFs (282 residents) in Quebec, Canada. All individuals were aged 65 years or older and residing in included LTCFs. Polypharmacy (≥10 medications) and PIM (2015 Beers criteria) were analyzed throughout 12 months between March 2017 and June 2018. Groups were compared before and after implementation using repeated measures mixed Poisson or logistic regression models, adjusting for potential confounding variables. Over 12 months, for regular medications, polypharmacy decreased from 42% to 20% (exposed group) and from 50% to 41% (control group) [difference in differences (DID): 13%, P < .001]. Mean number of PIMs also decreased from 0.79 to 0.56 (exposed group) and from 1.08 to 0.90 (control group) (DID: 0.05, P = .002). Compared with usual care, this multifaceted model reduced the probability of receiving ≥10 medications and the mean number of PIMs. Greater professional autonomy, reorganization of care, training, and medication review can optimize pharmaceutical care. As the role of pharmacists is expanding in many countries, this model shows what could be achieved with increased professional autonomy of pharmacists and nurses in LTCFs.


Cross-cultural validity of the Pulmonary Embolism Quality of Life questionnaire in the quality of life survey after pulmonary embolism: A Persian-speaking cohort.
The Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire is the first disease-specific scale for assessing the quality of life in patients with a history of pulmonary embolism (PE). To assess the cross-cultural validity and reliability of the disease-specific PEmb-QoL questionnaire. The Persian version was prepared through the forward and backward translation of the English questionnaire. Six months after the diagnosis of acute PE, consecutive Persian-speaking patients were asked to complete the PEmb-QoL, the generic 36-item Short Form (SF-36) questionnaires and undertake a 6-minute walk test (6MWT). Acceptability was assessed via item missing rate, reproducibility by the test-retest method, and internal consistency reliability by Cronbach's α and McDonald's ω coefficients. Convergence validity was assessed using the Spearman rank correlation between scores of PEmb-QoL, SF-36, and 6MWT. The questionnaire structure was evaluated through exploratory factor analysis. Ninety-six patients with a confirmed diagnosis of PE completed the questionnaires. The Persian version of PEmb-QoL had good internal consistency (α = 0.95, 3-factor ω = 0.96), inter-item correlation (0.3-0.62), item-total correlation (0.38-0.71), reproducibility (test-retest ICC with 25 participants = 0.92-0.99), and good discriminant validity. Convergence validity was confirmed by the moderate-to-high correlations between PEmb-QoL and SF-36 scores, and a good correlation between the "limitation in daily activities" dimension of the PEmb-QoL questionnaire and 6MWT results. Exploratory factor analysis suggested a 3-component structure with functional (items 1h, 4b-5d, 6, 8, 9i, and 9j), symptoms (1b-h, 7, and 8), and emotional (5a, 6, and 9a-h) components. The Persian version of the PEmb-QoL questionnaire is valid and reliable for measuring the disease-specific quality of life in patients with PE.


Benign paroxysmal vertigo of childhood: long-term outcome.
Benign paroxysmal vertigo (BPV) is characterized by recurrent attacks of dizziness in a healthy child. Complete recovery typically takes place during childhood, and an epidemiological link with migraine has been pointed out. Nevertheless, data concerning long-term patient outcome are scarce. We analyzed the clinical data of 17 patients diagnosed with BPV between 1991 and 2008 in our neuropediatric department; we particularly focused on family medical history and long-term patient outcome by reviewing their medical files and by interviewing the families with a standardized questionnaire administered by phone. Thirteen families responded to the questionnaire, performed 1.1 to 24.5 years after onset. Among 10 patients older than 11 years of age, five continue to suffer attacks of vertigo. Median age at recovery was six years. Nine subjects exhibited migraine, including all six aged 15 years or older. There was a first-degree history of migraine in eight out of 13 children. BPV may not be a homogeneous condition, as some children have a poorer prognosis than others. The strong link with migraine, already noticed by previous authors, led us to discuss the pathophysiology of this condition.


The association between early atrial arrhythmia and long-term return to sinus rhythm for patients following the Cox maze procedure for atrial fibrillation.
Observational studies identified increased age, left atrial (LA) size, type and duration of atrial fibrillation (AF) as independent predictors for failure of AF surgical ablation. Rhythm at discharge following the Cox maze (CM) procedure for AF was never considered a significant predictor of success. The purposes of this study were to: (i) Determine the association of sinus rhythm (SR) at discharge and maintenance of SR. (ii) Identify the variables associated with discharge rhythm. (iii) Identify the effects of discharge rhythm on health-related quality of life (HRQL) post-CM procedure. A prospective study (n = 534) of CM III/IV patients. Rhythm captured during hospitalization, discharge, 3, 6, 12 and 24 months and verified by electrocardiogram and 24-h holter. Subsequent SR interventions were captured. Logistic regression identified predictors of discharge rhythm. HRQL (Short-Form 12; AF symptom frequency and Severity Checklist V3) obtained during follow-up. Eighty-eight percent were discharged in SR (n = 469). LA size (OR = 1.36, CI: 1.02-1.82, P = 0.035) and long-standing AF type (OR = 2.68, CI: 1.31-5.50, P = 0.007) were the only independent predictors of non-SR at discharge. Lower rates of SR at 2 years were found in patients discharged in non-SR (75 vs 91%, P = 0.01). Patients discharged in SR had fewer perioperative morbidities [prolonged ventilation >24 h (6 vs 14%, P = 0.03), renal failure requiring dialysis (0.9 vs 5%, 0.04) and pneumonia (2 vs 9%, P = 0.005)]. During follow-up (mean = 43 ± 27 months), patients discharged in SR had fewer cardioversions (15 vs 29%, P = 0.006), similar percutaneous catheter ablations (6 vs 5%, P = 1.00) and no difference in late embolic strokes (1.5 vs 1.1%, P = 0.54). In this large prospective cohort study, rhythm at discharge was found to be clinically significant with predicting SR at 24 months. Surgeons should be aware that the prognosis of non-SR patients at discharge remains excellent with high rates of SR at 24 months if managed appropriately using rhythm rather than rate control strategies.


Mitochondrial superoxide targets energy metabolism to modulate epigenetic regulation of NRF2-mediated transcription.
Mitochondria are central to the metabolic circuitry that generates superoxide radicals/anions (O2•-) as a by-product of oxygen metabolism. By regulating superoxide levels, manganese superoxide dismutase plays important roles in numerous biochemical and molecular events essential for the survival of aerobic life. In this study, we used MitoParaquat (mPQ) to generate mitochondria-specific O2•- and stable isotope-resolved metabolomics tracing in primary human epidermal keratinocytes to investigate how O2•- generated in mitochondria regulates gene expression. The results reveal that isocitrate is blocked from conversion to α-ketoglutarate and that acetyl-coenzyme A (CoA) accumulates, which is consistent with a reduction in oxygen consumption rate and inactivation of isocitrate dehydrogenase (IDH) activity. Since acetyl-CoA is linked to histone acetylation and gene regulation, we determined the effect of mPQ on histone acetylation. The results demonstrate an increase in histone H3 acetylation at lysines 9 and 14. Suppression of IDH increased histone acetylation, providing a direct link between metabolism and epigenetic alterations. The activity of histone acetyltransferase p300 increased after mPQ treatment, which is consistent with histone acetylation. Importantly, mPQ selectively increased the nuclear levels and activity of the oxidative stress-sensitive nuclear factor erythroid 2-related factor 2. Together, the results establish a new paradigm that recognizes O2•- as an initiator of metabolic reprogramming that activates epigenetic regulation of gene transcription in response to mitochondrial dysfunction.


Visualization of Carbohydrate Uptake Using Fluorescent Polysaccharides.
Fluorescently labeled polysaccharides enable the visualization of carbohydrate-bacterial interactions and the quantification of carbohydrate hydrolysis rates in cultures and complex communities. Here, we present the method of generating polysaccharides conjugated to the fluorescent molecule, fluoresceinamine. Further, we describe the protocol of incubating these probes in bacterial cultures and complex environmental microbial communities, visualizing bacterial-probe interactions using fluorescence microscopy, and quantifying these interactions using flow cytometry. Finally, we present a novel approach for the in situ metabolic phenotyping of bacterial cells using fluorescently activated cell sorting coupled with omics-based analysis.


Mechanism and molecular basis for the sodium channel subtype specificity of µ-conopeptide CnIIIC.
Voltage-gated sodium channels (Na(V) channels) are key players in the generation and propagation of action potentials, and selective blockade of these channels is a promising strategy for clinically useful suppression of electrical activity. The conotoxin µ-CnIIIC from the cone snail Conus consors exhibits myorelaxing activity in rodents through specific blockade of skeletal muscle (Na(V) 1.4) Na(V) channels. We investigated the activity of µ-CnIIIC on human Na(V) channels and characterized its inhibitory mechanism, as well as the molecular basis, for its channel specificity. Similar to rat paralogs, human Na(V) 1.4 and Na(V) 1.2 were potently blocked by µ-CnIIIC, the sensitivity of Na(V) 1.7 was intermediate, and Na(V) 1.5 and Na(V) 1.8 were insensitive. Half-channel chimeras revealed that determinants for the insensitivity of Na(V) 1.8 must reside in both the first and second halves of the channel, while those for Na(V) 1.5 are restricted to domains I and II. Furthermore, domain I pore loop affected the total block and therefore harbours the major determinants for the subtype specificity. Domain II pore loop only affected the kinetics of toxin binding and dissociation. Blockade by µ-CnIIIC of Na(V) 1.4 was virtually irreversible but left a residual current of about 5%, reflecting a 'leaky' block; therefore, Na(+) ions still passed through µ-CnIIIC-occupied Na(V) 1.4 to some extent. TTX was excluded from this binding site but was trapped inside the pore by µ-CnIIIC. Of clinical significance, µ-CnIIIC is a potent and persistent blocker of human skeletal muscle Na(V) 1.4 that does not affect activity of cardiac Na(V) 1.5.