Influence of sex and gonadal status of sheep on cortisol secretion in response to ACTH and on cortisol and LH secretion in response to stress: importance of different stressors.
There are sex differences in the response to stress and in the influence of stress on reproduction which may be due to gonadal steroids but the nature of these differences and the role of the gonads are not understood. We tested the hypotheses that sex and the presence/absence of gonads (gonadal status) will influence the cortisol response to injection of ACTH, insulin-induced hypoglycaemia and isolation/restraint stress, and that sex and gonadal status will influence the secretion of LH in response to isolation/restraint stress. Four groups of sheep were used in each of three experiments: gonad-intact rams, gonadectomised rams, gonad-intact ewes in the mid-luteal phase of the oestrous cycle and gonadectomised ewes. In Experiment 1 (n=4/group), jugular blood samples were collected every 10 min for 6 h; after 3 h, two animals in each group were injected (i.v.) with ACTH and the remaining two animals were injected (i.v.) with saline. Treatments were reversed 5 days later so that every animal received both treatments. Experiment 2 (n=4/group) used a similar schedule except that insulin was injected (i.v.) instead of ACTH. In Experiment 3 (n=5/group), blood samples were collected every 10 min for 16 h on a control day and again 2 weeks later when, after 8 h of sampling, all sheep were isolated and restrained for 8 h. Plasma cortisol was significantly (P<0.05) elevated following injection of ACTH or insulin and during isolation/restraint stress. There were no significant differences between the sexes in the cortisol response to ACTH. Rams had a greater (P<0.05) cortisol response to insulin-induced hypoglycaemia than ewes while ewes had a greater (P<0.05) cortisol response to isolation/restraint stress than rams. There was no effect of gonadal status on these parameters. Plasma LH was suppressed (P<0.05) in gonadectomised animals during isolation/restraint stress but was not affected in gonad-intact animals, and there were no differences between the sexes. Our results show that the sex that has the greater cortisol response to a stressor depends on the stressor imposed and that these sex differences are likely to be at the level of the hypothalamo-pituitary unit rather than at the adrenal gland. Since there was a sex difference in the cortisol response to isolation/restraint, the lack of a sex difference in the response of LH to this stress suggests that glucocorticoids are unlikely to be a major mediator of the stress-induced suppression of LH secretion.


Dichapetalin-type triterpenoids from Dichapetalum longipetalum and their anti-inflammatory activity.
A phytochemical research on the twigs of Dichapetalum longipetalum (Turcz.) Engl. Resulted in five undescribed dichapetalin-type triterpenoids 1-5. Their chemical structures were determined by spectroscopic analysis of HR-ESIMS and NMR spectra and the absolute configuration of compound 1 was completely elucidated by single crystal X-ray crystallography. Through preliminary anti-inflammatory activity assessment, compound 1 exhibited inhibitory effect on LPS-induced NO production in RAW264.7 murine macrophages with an IC50 value of 2.09 μM.


Membrane-bound hemichrome in density-separated cohorts of normal (AA) and sickled (SS) cells.
The presence of bound heme pigment was compared in membranes of AA and SS cells. Spectophotometric study of membranes prepared by hypotonic lysis and washed free of hemoglobin revealed the presence of an irreversibly oxidized hemoglobin derivative, HCh. SS cell membranes contained significantly more HCh than did the AA cell membranes. When red cells were separated into cohorts of various density on a discontinuous density gradient of Stractan, washed membranes from the highest-density AA cells had significantly more HCh than did the remainder. In contrast, when density-separated SS cells were studied, no significant difference could be demonstrated in the HCh content of membranes from various cohorts.


The language phenotype of children and adolescents with Noonan syndrome.
This study presents an analysis of language skills in individuals with Noonan syndrome (NS), an autosomal dominant genetic disorder. We investigated whether the language impairments affecting some individuals arise from deficits specifically within the linguistic system or whether they are associated with cognitive, perceptual, and motor factors. Comparisons of language abilities among the different NS genotypes were also conducted. Sixty-six children and adolescents with NS were evaluated using standardized speech, language, and literacy assessments. Additional cognitive, perceptual, and motor tasks were administered to examine the relation of these factors to language development. Genotype was noted for those who underwent genetic testing. Language impairments were more frequent in NS than in the general population and were associated with higher risk for reading and spelling difficulties. Language was significantly correlated with nonverbal cognition, hearing ability, articulation, motor dexterity, and phonological memory. Genotype analyses suggest that the higher performance of SOS1-positive than PTPN11-positive individuals on language tasks was largely mediated by differences in cognitive ability. Our results indicate that variation in language skill in NS is closely related to cognitive, perceptual, and motor factors. It does not appear that specific aspects of language are selectively affected in this syndrome.


Narcissism and the self-evaluation maintenance model: effects of social comparison threats on relationship closeness.
When threatened with an upward social comparison with a close other in a self-relevant domain, people may reduce either the self-relevance of the ability being compared or their perceived closeness to the other person (Tesser, 1988). Those high in the trait of narcissism may be more likely to push away others who outperform them. Participants and nominated close others completed online measures of narcissism, contingent self-worth, and relationship closeness. Subsequently, participants heard that their friend performed better (or equivalently) on a "competitive spirit" test. Participants higher in narcissism significantly reduced the closeness of their relationships after a threat but did not reduce the relevance of competitiveness to their self-worth.


Validity of the Michaelis-Menten equation--steady-state or reactant stationary assumption: that is the question.
The Michaelis-Menten equation is generally used to estimate the kinetic parameters, V and K(M), when the steady-state assumption is valid. Following a brief overview of the derivation of the Michaelis-Menten equation for the single-enzyme, single-substrate reaction, a critical review of the criteria for validity of the steady-state assumption is presented. The application of the steady-state assumption makes the implicit assumption that there is an initial transient during which the substrate concentration remains approximately constant, equal to the initial substrate concentration, while the enzyme-substrate complex concentration builds up. This implicit assumption is known as the reactant stationary assumption. This review presents evidence showing that the reactant stationary assumption is distinct from and independent of the steady-state assumption. Contrary to the widely believed notion that the Michaelis-Menten equation can always be applied under the steady-state assumption, the reactant stationary assumption is truly the necessary condition for validity of the Michaelis-Menten equation to estimate kinetic parameters. Therefore, the application of the Michaelis-Menten equation only leads to accurate estimation of kinetic parameters when it is used under experimental conditions meeting the reactant stationary assumption. The criterion for validity of the reactant stationary assumption does not require the restrictive condition of choosing a substrate concentration that is much higher than the enzyme concentration in initial rate experiments.


Acrylamide-induced effects on general and neurospecific cellular functions during exposure and recovery.
Basal cytotoxicity, morphological changes and alterations in cell physiological and neurochemical functions were studied in differentiated human neuroblastoma (SH-SY5Y) cells during exposure to acrylamide and during a subsequent recovery period after cessation of exposure. Acrylamide induced a 20% reduction in the number of neurites per cell at 0.21 mmol/L and 20% decrease in the protein synthesis rate at 0.17 mmol/L after 72 h of exposure. Furthermore, the basal level of intracellular calcium concentration ([Ca2+]i) and receptor-activated (carbachol, 0.1 mmol/L) Ca2+ fluxes increased by 49% and 21%, respectively, at 0.25 mmol/L. These observations were made at noncytotoxic acrylamide concentrations, signifying specific neurotoxic alterations. Forty-eight hours after cessation of acrylamide exposure, the SH-SY5Y cells had recovered, i.e., the number of neurites per cell as well as the basal level of [Ca2+]i and rate of protein synthesis were comparable to those of control cells. The general calpain inhibitor calpeptin decreased the acrylamide-induced (0.5 mmol/L) neurite degeneration, determined as reduction in number of neurites per cell, from 52% to 17% as compared to control cells, which further supports the hypothesis that an increased [Ca2+]i plays a significant role for acrylamide-induced axonopathy.


Platelet fibrinogen binding in diabetes mellitus. Differences between binding to platelets from nonretinopathic and retinopathic diabetic patients.
While it is known that platelets from diabetic patients bind more fibrinogen than do platelets from normal subjects, there has been no study comparing this phenomenon in platelets from nonretinopathic and retinopathic patients. We have made such a comparison and have found the following. In agreement with previous reports, platelets from nonretinopathic diabetic patients bind abnormally high amounts of fibrinogen. No differences in the amount of fibrinogen bound to platelets (stimulated by collagen or thrombin) were found when data from nonretinopathic and retinopathic patients were compared. However, while aspirin (an inhibitor of thromboxane synthesis) reduced the abnormally high fibrinogen binding of platelets from nonretinopathic patients to normal control levels, it did not normalize the high fibrinogen binding of platelets from retinopathic diabetic patients. The combination of aspirin plus apyrase (an ADP scavenger) almost suppressed fibrinogen binding and aggregation of platelets from normal or nonretinopathic diabetic subjects, whereas it had a somewhat lesser effect on binding and aggregation of platelets from retinopathic subjects. By using a monoclonal antibody (B59.2) to the platelet receptor for fibrinogen, we determined that this receptor was the same in platelets from normal as well as nonretinopathic diabetic subjects and that this antibody could suppress the binding of fibrinogen and the aggregation of platelets from both types of patients just as it did in platelets from normal subjects. Thus, our data indicate that, while platelets from both retinopathic and nonretinopathic patients are hyperaggregable and show abnormally high binding of fibrinogen, they differ in that these abnormalities can be normalized in platelets from nonretinopathic patients by suppressing prostaglandin/thromboxane formation and scavenging ADP, but not in those from retinopathic patients.


The role of cough and hyperventilation in perpetuating airway inflammation in asthma.
Air flowing through a pipe exerts frictional stress on the walls of the pipe. Frictional stress of more than 40 N/m2 (velocity equivalent of air 113 m/s) is known to cause acute endothelial damage in blood vessels. The frictional stress in airways during coughing may be much greater, however, since the velocity of air may be as high as speed of sound in air. We suggest that high levels of frictional stress perpetuate airway inflammation in airways which are already inflamed and vulnerable to frictional stress-induced trauma in patients with asthma. Activities associated with rapid ventilation and higher frictional stress (e.g. exercise, hyperventilation, coughing, sneezing and laughing) cause asthma to worsen whilst activities that reduce frictional stress (Yoga 'Pranayama', breathing a helium-oxygen mixture and nasal continuous positive airway pressure) are beneficial. Therefore control of cough may have anti-inflammatory benefits in patients with asthma.


Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression.
The hormonal form of vitamin D(3), 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), is an immune system modulator and induces expression of the TLR coreceptor CD14. 1,25(OH)(2)D(3) signals through the vitamin D receptor, a ligand-stimulated transcription factor that recognizes specific DNA sequences called vitamin D response elements. In this study, we show that 1,25(OH)(2)D(3) is a direct regulator of antimicrobial innate immune responses. The promoters of the human cathelicidin antimicrobial peptide (camp) and defensin beta2 (defB2) genes contain consensus vitamin D response elements that mediate 1,25(OH)(2)D(3)-dependent gene expression. 1,25(OH)(2)D(3) induces antimicrobial peptide gene expression in isolated human keratinocytes, monocytes and neutrophils, and human cell lines, and 1,25(OH)(2)D(3) along with LPS synergistically induce camp expression in neutrophils. Moreover, 1,25(OH)(2)D(3) induces corresponding increases in antimicrobial proteins and secretion of antimicrobial activity against pathogens including Pseudomonas aeruginosa. 1,25(OH)(2)D(3) thus directly regulates antimicrobial peptide gene expression, revealing the potential of its analogues in treatment of opportunistic infections.


[Stability of shortcut nitrification-denitrification].
The effects of temperature and aeration time on the stability of shortcut nitrification-denitrification are studied specially in some experiments are carried on a sequencing batch reactor (SBR) fed with soybean wastewater. Results show that shortcut nitrification-denitrification achieved by controlling temperature was not stable until the temperature was more than 28 degrees C. In addition, for the first time strong effect of excess aeration on shortcut nitrification-denitrification is observed. When the system run under excess aeration for twelve days, the type of nitrification turned from shortcut nitrification which nitrosation rate (NO2(-)-N/NOx(-) -N) was more than 96% to complete nitrification which nitrosation rate (NO2(-) -N/NOx(-) -N) was less than 39.3%. So, in order to make shortcut nitrification-denitrification run stably, real-time process control must be used.


Anaerobic acquisition of [4FE 4S] clusters by the inactive FNR(C20S) variant and restoration of activity by second-site amino acid substitutions.
The FNR protein of Escherichia coli controls the transcription of target genes in response to anoxia. The anaerobic incorporation of oxygen-sensitive [4Fe 4S] clusters promotes dimerization, which in turn enhances DNA binding. Four potential iron ligands (C20, C23, C29 and C122) are essential for normal FNR activity in vivo. Three FNR variants (C20S, C23G and C29G) retained the ability to incorporate oxygen-sensitive [4Fe 4S] clusters and to bind target DNA with essentially unimpaired affinity, suggesting that their failure to function normally in vivo resides at a later stage in the signal transduction pathway. The C122 variant failed to assemble iron-sulphur clusters and to bind DNA. Second-site substitutions that partially restore activity to FNR(C20S) were generated by error-prone polymerase chain reaction and were located in the dimer interface, in the activating regions (AR1, 2 or 3) or close to C122. Substitutions at E47, R48, E123, I124, E127 or T128 allowed the extent of the FNR AR2 surface to be defined. Only one revertant, FNR(C20S Y69F G149S), specifically corrected the C20S defect. It was concluded that [4Fe 4S] cluster acquisition, dimerization and DNA binding are not sufficient to confer transcription regulatory activity on FNR: the iron-sulphur cluster must also be correctly liganded in order to establish effective activating contacts between FNR and RNA polymerase.


Rhodiola crenulata induces death and inhibits growth of breast cancer cell lines.
Diverse compounds from many different chemical classes are currently targeted in preclinical analyses for their ability to act as both chemopreventive and chemotherapeutic agents. Phenolic phytochemicals from Rhodiola crenulata has such potential. This Rhodiola species is a perennial plant that grows in the Tundra, Siberia, and high-elevation regions of Tibet. The phenolic secondary metabolites isolated from R. crenulata were recently analyzed in a preclinical setting for their ability to treat lymphosarcomas and superficial bladder cancers. However, the effects of R. crenulata have yet to be examined for its implications in breast cancer prevention or for its chemotherapeutic abilities. Therefore this study investigated the effects of R. crenulata on breast cancer both in vivo and in vitro. Experiments using aggressive human-derived MDA-MB-231 and mouse-derived V14 breast cancer cell lines demonstrated that phenolic-enriched R. crenulata extract was capable of inhibiting the proliferation, motility, and invasion of these cells. In addition, the extracts induced autophagic-like vesicles in all cell lines, eventually leading to death of the tumor cell lines but not the immortal or normal human mammary epithelial cells. Finally, an in vivo experiment showed that phenolic-enriched dietary R. crenulata is effective in preventing the initiation of tumors and slowing down the tumor growth in mice bearing tumor grafts, thereby further demonstrating its possible potential for treatment of breast cancer progression and metastasis.


Supplementary phages for the investigation of strains of methicillin-resistant Staphylococcus aureus.
Nineteen experimental phages were derived by mitomycin-C induction from methicillin-resistant strains of Staphylococcus aureus collected world-wide. They were assessed for their ability to distinguish isolates of a methicillin-resistant strain of S. aureus epidemic in the London area from other British strains, both sensitive and resistant to methicillin. The experimental phages were most active against strains of phage groups III and I + III. One phage was related to the phages of lytic group I. A typing pattern common to isolates of the epidemic strain was identified and used as an aid in the recognition of this strain. Ten of the phages were retained for further study.


Seasonal vaccination with RTS,S/AS01E vaccine with or without seasonal malaria chemoprevention in children up to the age of 5 years in Burkina Faso and Mali: a double-blind, randomised, controlled, phase 3 trial.
Seasonal vaccination with the RTS,S/AS01E vaccine combined with seasonal malaria chemoprevention (SMC) prevented malaria in young children more effectively than either intervention given alone over a 3 year period. The objective of this study was to establish whether the added protection provided by the combination could be sustained for a further 2 years. This was a double-blind, individually randomised, controlled, non-inferiority and superiority, phase 3 trial done at two sites: the Bougouni district and neighbouring areas in Mali and Houndé district, Burkina Faso. Children who had been enrolled in the initial 3-year trial when aged 5-17 months were initially randomly assigned individually to receive SMC with sulphadoxine-pyrimethamine and amodiaquine plus control vaccines, RTS,S/AS01E plus placebo SMC, or SMC plus RTS,S/AS01E. They continued to receive the same interventions until the age of 5 years. The primary trial endpoint was the incidence of clinical malaria over the 5-year trial period in both the modified intention-to-treat and per-protocol populations. Over the 5-year period, non-inferiority was defined as a 20% increase in clinical malaria in the RTS,S/AS01E-alone group compared with the SMC alone group. Superiority was defined as a 12% difference in the incidence of clinical malaria between the combined and single intervention groups. The study is registered with ClinicalTrials.gov, NCT04319380, and is complete. In April, 2020, of 6861 children originally recruited, 5098 (94%) of the 5433 children who completed the initial 3-year follow-up were re-enrolled in the extension study. Over 5 years, the incidence of clinical malaria per 1000 person-years at risk was 313 in the SMC alone group, 320 in the RTS,S/AS01E-alone group, and 133 in the combined group. The combination of RTS,S/AS01E and SMC was superior to SMC (protective efficacy 57·7%, 95% CI 53·3 to 61·7) and to RTS,S/AS01E (protective efficacy 59·0%, 54·7 to 62·8) in preventing clinical malaria. RTS,S/AS01E was non-inferior to SMC (hazard ratio 1·03 [95% CI 0·95 to 1·12]). The protective efficacy of the combination versus SMC over the 5-year period of the study was very similar to that seen in the first 3 years with the protective efficacy of the combination versus SMC being 57·7% (53·3 to 61·7) and versus RTS/AS01E-alone being 59·0% (54·7 to 62·8). The comparable figures for the first 3 years of the study were 62·8% (58·4 to 66·8) and 59·6% (54·7 to 64·0%), respectively. Hospital admissions for WHO-defined severe malaria were reduced by 66·8% (95% CI 40·3 to 81·5), for malarial anaemia by 65·9% (34·1 to 82·4), for blood transfusion by 68·1% (32·6 to 84·9), for all-cause deaths by 44·5% (2·8 to 68·3), for deaths excluding external causes or surgery by 41·1% (-9·2 to 68·3), and for deaths from malaria by 66·8% (-2·7 to 89·3) in the combined group compared with the SMC alone group. No safety signals were detected. Substantial protection against malaria was sustained over 5 years by combining seasonal malaria vaccination with seasonal chemoprevention, offering a potential new approach to malaria control in areas with seasonal malaria transmission. UK Joint Global Health Trials and PATH's Malaria Vaccine Initiative (through a grant from the Bill & Melinda Gates Foundation). For the French translation of the abstract see Supplementary Materials section.


Streptomyces spp. as efficient expression system for a D,D-peptidase/D,D-carboxypeptidase involved in glycopeptide antibiotic resistance.
VanYn, encoded by the dbv7 gene (also known as vanYn) of the biosynthetic cluster devoted to A40926 production, is a novel protein involved in the mechanism of self-resistance in Nonomuraea sp. ATCC 39727. This filamentous actinomycete is an uncommon microorganism, difficult-to-handle but biotechnologically valuable since it produces the glycopeptide antibiotic A40926, which is the precursor of the second-generation dalbavancin in phase III of clinical development. In order to investigate VanYn role in glycopeptide resistance in the producer actinomycete an appropriate host-vector expression system is required. The cloning strategy of vanYn gene (G-C ratio 73.3%) in the expression vector pIJ86 yielded a recombinant protein with a tag encoding for a histidine hexamer added at the C-terminus (C-His6-vanYn) or at the N-terminus (N-His6-vanYn). These plasmids were used to transform three Streptomyces spp., which are genetically-treatable high G-C content Gram-positive bacteria taxonomically related to the homologous producer Nonomuraea sp.. Highest yield of protein expression and purification (12 mg of protein per liter of culture at 3 L bioreactor-scale) was achieved in Streptomyces venezuelae ATCC 10595, that is a fast growing streptomyces susceptible to glycopeptides. VanYn is a transmembrane protein which was easily detached and recovered from the cell wall fraction. Purified C-His6-VanYn showed d,d-carboxypeptidase and d,d-dipeptidase activities on synthetic analogs of bacterial peptidoglycan (PG) precursors. C-His6-VanYn over-expression conferred glycopeptide resistance to S. venezuelae. On the contrary, the addition of His6-tag at the N-terminus of the protein abolished its biological activity either in vitro or in vivo assays. Heterologous expression of vanYn from Nonomuraea sp. ATCC 39727 in S. venezuelae was successfully achieved and conferred the host an increased level of glycopeptide resistance. Cellular localization of recombinant VanYn together with its enzymatic activity as a d,d-peptidase/d,d-carboxypeptidase agree with its role in removing the last d-Ala from the pentapeptide PG precursors and reprogramming cell wall biosynthesis, as previously reported in glycopeptide resistant pathogens.


Syndrome of inappropriate antidiuretic hormone secretion: a story of duloxetine-induced hyponatraemia.
Hyponatraemia is the most commonly encountered electrolyte abnormality in clinical practice. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) accounts for nearly 60% of all hyponatraemias. Selective serotonin reuptake inhibitors (SSRIs) are well known to have side effects of SIADH. There have been few reported cases of serotonin norepinephrine reuptake inhibitors (SNRIs) causing SIADH-induced hyponatraemia. Duloxetine is one type of SNRI used to treat several conditions, including depression and diabetic neuropathy. We present a case of a 76-year-old woman with a history of fibromyalgia who had recently been prescribed duloxetine for her condition. On admission to the hospital, her sodium decreased to a low of 118 mmol/L. Evaluation for other causes of hyponatraemia yielded negative results. Duloxetine was discontinued and after 3 days the patient's sodium increased to 130 mmol/L. The purpose of this case report is to highlight the importance of having suspicion for rare but real side effects of medications such as duloxetine.


The species distribution, antimicrobial resistance and risk factors for poor outcome of coagulase-negative staphylococci bacteraemia in China.
Coagulase-negative staphylococci (CoNS) are one of the major opportunistic pathogens and the incidence of CoNS bacteraemia is increasing. However, most of the CoNS-positive blood cultures are contaminants rather than true CoNS bacteraemia. In order to minimize contamination, we defined true CoNS bacteraemia as the patient that has two or more identical CoNS-positive blood cultures drawn within 48 h in this study and the objective of this study was to analyse the species distribution and antibiotic resistance and to identify risk factors for 30-day mortality of the true CoNS-bacteraemia. By reviewing the electronic medical database, this study retrospectively analysed patients diagnosed as CoNS bacteraemia by blood cultures in a comprehensive tertiary care hospital in China from January 1, 2014, to December 31, 2017. A total of 1241 patients with 1562 episodes of CoNS-positive blood cultures were recorded in the database but only 157 patients were finally diagnosed as true CoNS bacteraemia after contaminants were excluded. All these 157 patients (12.7%, 157/1241) had bacteraemia-related clinical symptoms. Among the 157 patients, the most common species were Staphylococcus hominis (40.8%), Staphylococcus epidermidis (36.3%) and Staphylococcus capitis (11.5%). The antimicrobial susceptibility tests showed that all CoNS had a high rate of resistance to penicillin (94.9%), oxacillin (93.6%) and erythromycin (92.4%). Resistance to gentamicin (22.3%) and rifampicin (10.8%) was low, and none of the bacteria were resistant to vancomycin or linezolid. The 30-day mortality of patients with CoNS bacteraemia was up to 12.7% (20/157), and the multivariate logistics regression analysis showed that chronic renal failure (OR 5.9, 95% CI 1.6-21.5, p = 0.007) and chronic liver failure (OR 4.0, 95% CI 1.2-13.1, p = 0.024) were both the significant independent risk factors for the 30-day mortality of CoNS bacteraemia. Staphylococcus hominis and Staphylococcus epidermidis were the most common species in CoNS bacteraemia. All CoNS had high multi-drug resistance, but gentamicin and rifampicin had a relatively lower resistance and could be considered as alternative antibiotics for anti-CoNS bacteraemia in addition to vancomycin and linezolid. Additionally, patients with chronic renal failure or chronic liver failure have a higher 30-day mortality after the onset of CoNS bacteraemia.


[Immunotoxicity of aluminum chloride].
Aluminum chloride was tested for its effect on primary T-dependent humoral immune response. The administration of aluminum chloride in the genotoxic dose (0.04 M) caused in mice a profound immunosuppressive effect accompanied by diminished thymic and splenic cellularity. The findings suggest that aluminum chloride possesses marked immunotoxic properties.


A management algorithm for patients with intracranial pressure monitoring: the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC).
Management algorithms for adult severe traumatic brain injury (sTBI) were omitted in later editions of the Brain Trauma Foundation's sTBI Management Guidelines, as they were not evidence-based. We used a Delphi-method-based consensus approach to address management of sTBI patients undergoing intracranial pressure (ICP) monitoring. Forty-two experienced, clinically active sTBI specialists from six continents comprised the panel. Eight surveys iterated queries and comments. An in-person meeting included whole- and small-group discussions and blinded voting. Consensus required 80% agreement. We developed heatmaps based on a traffic-light model where panelists' decision tendencies were the focus of recommendations. We provide comprehensive algorithms for ICP-monitor-based adult sTBI management. Consensus established 18 interventions as fundamental and ten treatments not to be used. We provide a three-tier algorithm for treating elevated ICP. Treatments within a tier are considered empirically equivalent. Higher tiers involve higher risk therapies. Tiers 1, 2, and 3 include 10, 4, and 3 interventions, respectively. We include inter-tier considerations, and recommendations for critical neuroworsening to assist the recognition and treatment of declining patients. Novel elements include guidance for autoregulation-based ICP treatment based on MAP Challenge results, and two heatmaps to guide (1) ICP-monitor removal and (2) consideration of sedation holidays for neurological examination. Our modern and comprehensive sTBI-management protocol is designed to assist clinicians managing sTBI patients monitored with ICP-monitors alone. Consensus-based (class III evidence), it provides management recommendations based on combined expert opinion. It reflects neither a standard-of-care nor a substitute for thoughtful individualized management.


The quick extraction of chitin from an epizoic crustacean species (Chelonibia patula).
Chitin was isolated from the shells of Chelonibia patula (barnacle, Crustacea), which lives on blue crab epizoically, following a 10-min demineralisation process through HCl and a 20-min deproteinisation process through NaOH. Due to the low-crystalline structure, and mineral-rich and low-protein content of the shells, chitin isolation was convenient. It was observed that the shell structure of C. patula contains 3.11% chitin per its dry weight. Following characterisation of the isolated chitin by using Fourier transform infrared spectroscopy, thermogravimetric analysis, X-ray diffractometry, elemental analysis and scanning electron microscopy, it was determined that there was close similarity with the α-chitin isolated from crabs, shrimps and insects in various studies. It was observed that chitin was composed of nanofibres with a width of 10-20 nm. It was concluded that this was an economically advantageous chitin resource compared with crustaceans such as shrimp, crayfish and crab, because it is possible to isolate chitin in a significantly shorter time.


Lysophosphatidic acid-operated K+ channels.
Lysophosphatidic acid (LPA) is an abundant cellular lipid with a myriad of biological effects. It plays an important role in both inter- and intracellular signaling. Activation of the LPA1-3 G-protein-coupled receptors explains many of the extracellular effects of LPA, including cell growth, differentiation, survival, and motility. However, LPA also acts intracellularly, activating the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma that regulates gene transcription. This study shows that the novel subfamily of mechano-gated K2P channels comprising TREK-1, TREK-2, and TRAAK is strongly activated by intracellular LPA. The LPA-activated 2P domain K+ channels are intracellular ligand-gated K+ channels such as the Ca2+- or the ATP-sensitive K+ channels. LPA reversibly converts these mechano-gated, pH- and voltage-sensitive channels into leak conductances. Gating conversion of the 2P domain K+ channels by intracellular LPA represents a novel form of ion channel regulation. Thus, the TREK and TRAAK channels should be included in the LPA-associated physiological and disease states.


Regulating the Active Sites of Cs2 AgBiCl6 by Doping for Efficient Coupling of Photocatalytic CO2 Reduction and Benzyl Alcohol Oxidation.
Halide perovskites exhibit outstanding optoelectronic properties, which make them an ideal choice for photocatalytic CO2 reduction and benzyl alcohol (BA) oxidation. Nevertheless, the simultaneous realization of the above redox coupling reactions on halide perovskites remains a great challenge, as it requires distinct catalytic sites for different target reactions. Herein, the catalytic sites of Cs2 AgBiCl6 (CABC) are regulated by doping Fe for efficient coupling of photocatalytic CO2 reduction and BA oxidation. The Fe-doped CABC (Fe: CABC) exhibits an enhanced visible-light response and effective charge separation. Experimental results and theoretical calculations reveal a synergistic interplay between Bi and Fe sites, where the Bi and Fe sites have lower activation energies toward CO2 reduction and BA oxidation. Further investigations demonstrate that electrons and holes prefer to accumulate at the Bi site and Fe site under light irradiation, respectively, which creates favorable conditions for facilitating CO2 reduction and BA oxidation. The resultant Fe: CABC achieves a high photocatalytic performance toward CO (18.5 µmol g-1 h-1 ) and BD (1.1 mmol g-1 h-1 ) generation, which surpasses most of the state-of-the-art halide photocatalysts. This work demonstrates a facile strategy for regulating the catalytic site for redox coupling reactions, which will pave a new way for designing halide perovskites for photocatalysis.


Efficacy and safety of sertraline treatment of posttraumatic stress disorder: a randomized controlled trial.
Despite the high prevalence, chronicity, and associated comorbidity of posttraumatic stress disorder (PTSD) in the community, few placebo-controlled studies have evaluated the efficacy of pharmacotherapy for this disorder. To determine if treatment with sertraline hydrochloride effectively diminishes symptoms of PTSD of moderate to marked severity. Twelve-week, double-blind, placebo-controlled trial preceded by a 2-week, single-blind placebo lead-in period, conducted between May 1996 and June 1997. Outpatient psychiatric clinics in 8 academic medical centers and 6 clinical research centers. A total of 187 outpatients with a Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition diagnosis of PTSD and a Clinician Administered PTSD Scale Part 2 (CAPS-2) minimum total severity score of at least 50 at baseline (mean age, 40 years; mean duration of illness, 12 years; 73% were women; and 61.5% experienced physical or sexual assault). Patients were randomized to acute treatment with sertraline hydrochloride in flexible daily dosages of 50 to 200 mg/d, following 1 week at 25 mg/d (n=94); or placebo (n=93). Baseline-to-end-point changes in CAPS-2 total severity score, Impact of Event Scale total score (IES), and Clinical Global Impression-Severity (CGI-S), and CGI-Improvement (CGI-I) ratings, compared by treatment vs placebo groups. Results Sertraline treatment yielded significantly greater improvement than placebo on 3 of the 4 primary outcome measures (mean change from baseline to end point for CAPS-2 total score, -33.0 vs -23.2 [P =.02], and for CGI-S, -1.2 vs -0.8 [P=.01]; mean CGI-I score at end point, 2.5 vs 3.0 [P=.02]), with the fourth measure, the IES total score, showing a trend toward significance (mean change from baseline to end point, -16.2 vs -12.1; P=.07). Using a conservative last-observation-carried-forward analysis, treatment with sertraline resulted in a responder rate of 53% at study end point compared with 32% for placebo (P=.008, with responder defined as >30% reduction from baseline in CAPS-2 total severity score and a CGI-I score of 1 [very much improved], or 2 [much improved]). Significant (P<.05) efficacy was evident for sertraline from week 2 on the CAPS-2 total severity score. Sertraline had significant efficacy vs placebo on the CAPS-2 PTSD symptom clusters of avoidance/numbing (P=.02) and increased arousal (P=.03) but not on reexperiencing/intrusion (P=.14). Sertraline was well tolerated, with insomnia the only adverse effect reported significantly more often than placebo (16.0% vs 4.3%; P=.01). Our data suggest that sertraline is a safe, well-tolerated, and effective treatment for PTSD.


An investigation of "We" agency in co-operative joint actions.
Sense of agency refers to the sense that I am controlling an action or outcome, and is associated with a perceived compression of the temporal interval between these events known as intentional binding (IB). Though most IB studies focus on individually performed actions, some reveal the existence of shared implicit agency among joint actors, suggesting the formation of a shared "we" identity that may be sensitive to the intentions and actions of all actors. While current understanding of this shared agentic identity is far from clear, the present study used variants of the IB paradigm involving truly co-operative actions to investigate (1) the relative strength of individual and joint agency, and (2) whether different complementary roles modulate the sense of agency among joint actors. Experiment 1 compared the strength of agency for actions performed alone or with a partner, by instructing pairs of participants to press a key simultaneously to produce an auditory tone. Here, binding was weaker when performing jointly, but this may have been influenced by the demands of temporally co-ordinating actions. Experiment 2 removed these task demands by implementing joint actions that were not identical but complementary, and assessed the impact of varying roles (moving versus clicking a mouse) on agency. Here, binding was similar for independent and joint actions, and across all roles. These results support the notion of a shared "we" identity, suggesting that the joint sense of agency is as strong as individual agency and represents the intentions and actions of all co-actors.


Differential acid stabilities of citraconylated amino groups of glucagon. Preparation of N alpha-citraconyl glucagon and evaluation of its biological properties.
Acylation of the alpha- and epsilon-amino groups of histidine-1 and lysine-12 in glucagon with citraconic anhydride resulted in the formation of amide bonds which displayed different stabilities to hydrolysis under mild acid conditions. Treatment of N alpha,epsilon-dicitraconyl glucagon at pH 4.0 and room temperature regenerated the free epsilon-amino group within 16 h, while the citraconyl-alpha-amino group was stable. N alpha-Citraconyl glucagon was purified by anion-exchange chromatography and was a weak partial agonist in stimulating adenylate cyclase in rat liver plasma membranes. The derivative exhibited 1% of the biological potency and 35-40% of the maximal stimulation of glucagon. Binding affinity to plasma membranes was also reduced, but not to as great an extent as adenylate cyclase activity. Removal of the alpha-citraconyl group by treatment with 10 mM HCl at 40 degrees C restored full potency and stimulation to glucagon. These results suggest that the N-terminal histidine of glucagon is involved in both binding to plasma membranes and transduction of the signal to adenylate cyclase.


Autophagy in cellular transformation, survival and communication with the tumor microenvironment.
Autophagy describes several metabolic pathways, by which cytoplasmic constituents are imported into lysosomes for degradation. These pathways and in particular macroautophagy play an important role during oncogenesis by apparently inhibiting cellular transformation initially, but then ensuring tumor cell survival in established cancers. Furthermore, the conditioning of the tumor microenvironment, including the cross-talk with the immune system, is influenced by autophagy. These multiple facets of autophagy regulation in tumors will be discussed in the series of review articles of this issue of Seminars in Cancer Biology. A comprehensive understanding of this pathway in oncology is needed to efficiently apply autophagy regulating tumor therapies, which are already in use.


Quantitative LC-MS/MS analysis of seven ginsenosides and three aconitum alkaloids in Shen-Fu decoction.
Shen-Fu decoction is a traditional Chinese medicine prescription with a 3:2 ratio of Radix Ginseng and Fuzi (Radix Aconiti lateralis praeparata). Ginsenosides and alkaloids are considered to be the main active components of Shen-Fu decoction. However, no analytical methods have been used to quantitatively analyse both components in Shen-Fu decoction simultaneously. We successfully developed a rapid resolution liquid chromatography coupled with tandem mass spectrometry (RRLC-MS/MS) method for the simultaneous analysis of seven ginsenosides and three aconitum alkaloids in Shen-Fu decoction, the decoction of Radix ginseng and Fuzi (Radix Aconiti lateralis praeparata). Chromatogrpahic separation by RPLC was achieved using a reversed-phase column and a water/acetonitrile mobile phase, containing 0.05% formic acid and using a gradient system. The method was optimized to allow for simultaneous analysis of all analytes in 11minutes without the need for baseline resolution of the components. Furthermore, the separation demonstrated good linearity (r > 0.9882), repeatability (RSD < 7.01%), intra- and inter-day precisions (RSD < 5.06%) and high yields of recovery (91.13-111.97%) for ten major constituents, namely ginsenoside-Re, Rg1, Rb1, Rc, Rb2, Rd, Rf, aconitine, hypacoitine and mesaconitine. The developed method could be used as a rapid and reliable approach for assessment of the quantity of the major constituents in Shen-Fu decoction.


Substance and Alcohol use in Young Adults in Turkey as Indicated by the CAGE Questionnaire and Drinking Frequency.
The purpose of this study was to determine drinking problems and to analyze the socio-demographic factors associated with problematic alcohol use in young adults. The study included 262 students who were surveyed for substance use problems in a postgraduate program using the Cut down, Annoyed, Guilty, Eye opener (CAGE) Questionnaire. The relationships between socio-demographic variables and alcohol use were assessed using both univariate and multivariate analyses. Of the whole sample, 56.11% reported that they had tried drinking alcohol and 1.91% had tried cannabis. The prevalence of problematic alcohol use was 15.3% and 29.7% according to CAGE1+ and past-year drinking frequency, respectively. Alcohol use by mothers was an important differentiating factor for alcohol use by their daughters. Graduating from a university located in the Eastern/Southeastern Anatolia regions, graduating from a private high school, and having average academic performance levels were determinants of problematic alcohol use according to CAGE1+ and frequency of drinking. This study suggests there is need for early intervention to prevent exposure to the risk factors for problematic alcohol use in young adults, emphasizing that probable presence of an alcohol use disorder and high frequency of drinking are related to socio-demographic factors (high school type, geographical location of the university, and family structure).


The assessment clock: A model to prioritize the principles of the utility of assessment formula in emergency situations, such as the COVID-19 pandemic.
This article was migrated. The article was marked as recommended. Many concerns have been raised regarding the impact of the changes to medical education as a result of the coronavirus disease 2019 (COVID-19) pandemic, particularly the impact of these changes on student assessments. This paper suggests an assessment clock as a conceptual model to enable medical educators to decide which assessment method is suitable under challenging circumstances, such as the COVID-19 pandemic. The assessment clock has five numbers, representing the five principles of the utility of assessment formula, which are arranged from the principle with the lowest weight (cost = 1) to the principle with the highest weight (validity = 5). The numbers are repeated in each half of the clock, and the clock is placed in the middle of two overlapping axes. The vertical axis is related to exam stakes (high or low). The low stakes condition, which represents the normal situation of running assessments at the beginning of each academic year, is placed at the top of the clock. The horizontal axis is related to the type of situation (normal or crisis). The high stakes condition is placed at the bottom of the clock. The right half of the clock represents the normal situation of planning and conducting assessments, while the left half represents an emergency situation, such as the current COVID-19 pandemic. The assessment clock offers assessment planners insights into how to determine the most important assessment principles on which they should focus during a crisis situation. Moreover, it provides practical guidance for educators to help them decide which assessment tool is suitable for use in which situation.


Racial and ethnic trends in unintentional carbon monoxide poisoning deaths.
Government programs have attempted to impact a recognized elevated risk for carbon monoxide (CO) poisoning among minority racial and ethnic groups. This study sought to describe U.S. mortality due to unintentional, non-fire-related CO poisoning, examining the distribution and trends by race and ethnicity. CDC Wonder was used to extract and analyze data on all U.S. resident deaths from unintentional CO poisoning from 2000-2017, categorizing them by year, race, ethnic origin and gender. The absolute number of unintentional CO deaths decreased from about 450 to 380 per year during the period studied, a number near totally accounted for by the decrease in deaths occurring among non-Hispanic/Latino whites. The number of deaths among the remainder of the population did not significantly change. However, greater growth in minority populations resulted in a similar decline in the mortality rate between non-Hispanic/Latino whites and the combined minority population. The decline in combined minority death rate resulted from a decrease in the Hispanic/Latino white rate. Death rate did not decline in the black or African American population. All minority groups continue to display a disproportionate number of unintentional non-fire-related CO poisoning deaths compared to non-Hispanic/Latino whites. The decrease in U.S. deaths from unintentional non-fire-related carbon monoxide poisoning from 2000-2017 is accounted for by a decrease in non-Hispanic/Latino white deaths. While numbers of such deaths among minority groups have not changed since 2000, increases in the size of minority populations have resulted in a declining crude death rate for Hispanic/Latino whites.


Diagnostic strategies for the management of patients with clinically suspected deep-vein thrombosis.
Given the perceived inaccuracy of clinical diagnosis, patients with suspected deep vein thrombosis should have objective testing. Due to the inherent limitations of the reference method (contrast venography), several diagnostic strategies using noninvasive tests have been developed. These strategies share two components: anticoagulant therapy is initiated only in patients with an abnormal test, and serial testing is performed in patients with an initial normal test result. A thorough search of the literature was done to identify all studies that have evaluated the feasibility, accuracy, and safety of diagnostic strategies in patients with clinically suspected deep vein thrombosis. The safety of the individual diagnostic strategies was expressed as the total rate of venous thromboembolic complications. Feasibility was expressed as the mean number per patient of extra visits to the hospital and additional tests per patient. A total of 12 reports qualified for the analysis. The diagnostic strategies included venography, serial impedance plethysmography with and without 125I-fibrinogen leg scanning, serial ultrasound imaging with and without D-dimer determination, serial ultrasound imaging in combination with a clinical score, and a diagnostic work-up including ultrasound imaging, impedance plethysmography, D-dimer determination, and a clinical score. The observed venous thromboembolic complication rates varied between 0.4% and 2.6%. Feasibility was lowest for the initial serial impedance plethysmography strategy (mean number of extra hospital visits and mean number of additional tests, 4.1 per patient). Strategies that used the D-dimer test complimentary to ultrasound imaging or the combination of impedance plethysmography and a clinical score performed best (mean number of extra hospital visits and mean number of additional tests, approximately 0.3 per patient). All available noninvasive diagnostic strategies are as accurate and safe as contrast venography for the treatment of patients with clinically suspected deep vein thrombosis. The recently introduced simplified diagnostic strategies allow treatment decisions to be made on the day of presentation in most patients.


Mixed urinary incontinence: greater impact on quality of life.
We compared the impact of mixed, stress and urge urinary incontinence on quality of life in middle-aged or older women. We analyzed cross-sectional data from a population based cohort of 2,109 ethnically diverse middle-aged or older women. Among participants reporting weekly incontinence, clinical type of incontinence was assessed by self-reported questionnaires and disease specific quality of life impact was evaluated using the Incontinence Impact Questionnaire. Multivariable logistic regression was used to compare the odds of greater quality of life impact from incontinence, defined as an Incontinence Impact Questionnaire score in the 75th percentile or greater in women with stress, urge and mixed incontinence. More than 28% (598) of women reported weekly incontinence, including 37% with stress, 31% with urge and 21% with mixed incontinence. Unadjusted Incontinence Impact Questionnaire scores were higher for women with mixed vs urge or stress incontinence (median score 29 vs 17 and 13, respectively, p <0.01). Adjusting for age, race/ethnicity, health status and clinical incontinence severity, women with mixed incontinence were more likely to report a greater overall quality of life impact compared to those with stress incontinence (OR 2.5, 95% CI 1.4-4.3), as well as a greater specific impact on travel (OR 2.2, 95% CI 1.3-3.7) and emotional (OR 1.8, 95% CI 1.0-3.4) Incontinence Impact Questionnaire domains. The overall impact of urge incontinence did not differ significantly from that of stress (urge vs stress OR 1.6, 95% CI 0.9-2.7) or mixed incontinence (mixed vs urge OR 1.6, 95% CI 0.9-2.8) in adjusted models. In middle-aged or older women mixed incontinence is associated with a greater quality of life impact than stress incontinence independent of age, race, health or incontinence severity. Identification of women with mixed incontinence symptoms may be helpful in discovering which women are most likely to experience functional limitations and decreased well-being from incontinence.


Increase of plasma acetaldehyde. An objective indicator of the chlorpropamide alcohol flush.
Chlorpropamide alcohol flushing (CPAF) in non-insulin-dependent diabetics (NIDDs) has been reported to be associated with a lower tendency to develop late complications. The flush was thought to be mediated by enkephalins and prostaglandins. Early studies could not correlate CPAF to increased levels of acetaldehyde in blood and the flush was not regarded as an antabuse-like reaction. In this study, the increase of plasma acetaldehyde during the flush in 13 CPAF positive diabetics was significantly (P less than 0.005) higher than in the 13 CPAF negative diabetics during a CPAF challenge test. The increase of plasma acetaldehyde was reduced to the level of CPAF negative diabetics in three CPAF positive diabetics when they were exposed to alcohol without premedication with chlorpropamide and they did not flush. The normal breakdown of ethanol to acetic acid via acetaldehyde appears to be inhibited by chlorpropamide in the flushers. Acetaldehyde measurement is an objective method to study the chlorpropamide alcohol flush and it appears superior to the measurement of skin temperature.


The effect of propofol and fentanyl as compared with sevoflurane on postoperative vomiting in children after adenotonsillectomy.
Postoperative vomiting (PV) after adenotonsillectomy in children is a common problem with an incidence as high as 40-80%. Only few studies in the recent literature compared the effect of different anesthetic techniques concerning PV in children. The aim of this study was to compare the incidence of PV in two groups of children who underwent two different general anesthesia techniques in order to determine what type of anesthetic technique is more related to less PV. The clinical trial included 50 children (physical status ASA I, 3-12 years old) divided into 2 groups and monitored for PV 24 hours following the surgery. Group one (G1) consisted of 25 children who underwent general anesthesia with gas mixture 60% nitrous oxide and 40% oxygen and anesthetic propofol, opioid fentanyl and muscle relaxant vecuronium intravenously and group two (G2) included 25 children to whom volatile anesthesia with sevoflurane in the same gas mixture was given. Demographic characteristics (gender, age, weight, history of motion sickness and earlier PV) as well as surgical data (length of surgery and anesthesia, intraoperative blood loss) were recorded. There were no significant differences considering demographic characteristics and surgical data between the investigated groups. The incidence of PV was relatively low 3 children (12%) in G1 group and 5 children (20%) in G2 group. Statistically there was no significant difference between the groups regarding the incidence of PV and both anesthetic techniques can be used equally safe regarded to PV.


Cannabidiol Inhibits In Vitro Human Liver Microsomal Metabolism of Remdesivir.
Introduction: The year 2020 began with the world being flounced with a wave of novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) disease, named COVID-19. Based on promising pre-clinical and clinical data, remdesivir (RDV) was the first drug to receive FDA approval and so far, it is the most common therapy for treatment of SARS-CoV-2/MERS-CoV. However, following intravenous administration, RDV metabolizes majorly by human liver carboxylesterase 1 (CES1) and marginally by the CYP3A4 enzyme in merely less than an hour. Its resultant active metabolite is a hydrophilic nucleoside with very limited accumulation within lung tissues. Therefore, there is a need to investigate strategies to overcome such premature metabolism issues and improve the antiviral efficacy of RDV at the target site. Objective: Considering the major CES1-mediated metabolism of RDV on systemic administration, we intend to explore the remarkable CES1 plus CYP3A4 inhibitory activity of cannabidiol (CBD) against in vitro microsomal metabolism of RDV to indicate its therapeutic potential as an adjuvant to RDV in the treatment and management of COVID-19. Methods: We investigated the in vitro human liver microsomal metabolism of RDV in the presence of two potential CES1 inhibitors-CBD and nelfinavir, and two standard CYP3A4 inhibitors-ritonavir (RITO) and cyclosporin A. The microsomal metabolism assay was further validated by using a well-characterized CYP3A4-selective substrate, midazolam (MDZ), in the presence of CBD and RITO. Results: Our findings depicted that RDV was rapidly and completely metabolized by human liver microsomes within 60 min. Coincubation with CBD substantially reduced microsomal metabolism of RDV and prolonged its in vitro half-life from 8.93 to 31.07 min. CBD showed significantly higher inhibition of RDV compared with known CES1 and CYP3A4 inhibitors. Inhibition of MDZ metabolism by CBD and RITO further validated the assay. Conclusions: The current study strongly suggests that CBD significantly inhibits human liver microsomal metabolism of RDV and extends its in vitro half-life. Thus, concomitant administration of CBD with RDV intravenous injection could be a promising strategy to prevent premature metabolism in COVID-19 patients.


Vancomycin-Associated Hemorrhagic Occlusive Retinal Vasculitis: Clinical Characteristics of 36 Eyes.
To expand understanding of presentation, diagnosis, and outcomes of hemorrhagic occlusive retinal vasculitis (HORV). Retrospective case series. Thirty-six eyes of 23 patients. The American Society of Cataract and Refractive Surgery (ASCRS) and the American Society of Retina Specialists (ASRS) formed a joint task force to define clinical characteristics of HORV and to study its prevalence, cause, treatment, and outcomes. An online registry was established on both societies' web sites. Surveys were e-mailed to members of both societies soliciting cases of suspected HORV. A literature search was performed to uncover additional cases. Historical data including intraoperative characteristics, images, treatment regimens, and visual and anatomic outcomes. Characteristic findings of HORV included unremarkable postoperative day 1 undilated examination, delayed-onset painless vision loss, mild anterior chamber and vitreous inflammation, sectoral retinal hemorrhages in areas of ischemia, and predilection for venules and peripheral involvement. Based on predetermined diagnostic criteria, 36 eyes of 23 patients were diagnosed with HORV. All eyes received intraocular vancomycin via intracameral bolus (33/36), via intravitreal injection (1/36), or through the irrigation bottle (2/36). Patients sought treatment with HORV 1 to 21 days after surgery or intravitreal injection. Visual results usually were poor: 22 of 36 eyes (61%) had 20/200 or worse visual acuity and 8 of 36 eyes (22%) had no light perception (NLP). Neovascular glaucoma developed in 20 of 36 eyes (56%). Seven eyes received additional intravitreal vancomycin after surgery; 5 of these 7 eyes had NLP visual acuity at the most recent examination. Three eyes received intravitreal corticosteroids and had final visual acuities of 20/40, 20/70, and hand movements. Hemorrhagic occlusive retinal vasculitis is a rare, potentially devastating condition that can develop after cataract surgery or intraocular injection. All cases in this series were associated with intraocular vancomycin. Disease course and findings suggest that HORV is caused by a delayed hypersensitivity reaction to vancomycin. Early treatment with corticosteroids likely is beneficial. Subsequently, anti-vascular endothelial growth factor injections and panretinal photocoagulation are important to prevent neovascular glaucoma, a common complication. Avoidance of additional intravitreal vancomycin is recommended if HORV is suspected.


Serious maternal complications after early preterm delivery (24-33 weeks' gestation).
We sought to describe the prevalence of serious maternal complications following early preterm birth by gestational age (GA), delivery route, and type of cesarean incision. Trained personnel abstracted data from maternal and neonatal charts for all deliveries on randomly selected days representing one third of deliveries across 25 US hospitals over 3 years (n = 115,502). All women delivering nonanomalous singletons between 23-33 weeks' gestation were included. Women were excluded for antepartum stillbirth and highly morbid conditions for which route of delivery would not likely impact morbidity including nonreassuring fetal status, cord prolapse, placenta previa, placenta accreta, placental abruption, and severe and unstable maternal conditions (cardiopulmonary collapse, acute respiratory distress syndrome, seizures). Serious maternal complications were defined as: hemorrhage (blood loss ≥1500 mL, blood transfusion, or hysterectomy for hemorrhage), infection (endometritis, wound dehiscence, or wound infection requiring antibiotics, reopening, or unexpected procedure), intensive care unit admission, or death. Delivery route was categorized as classic cesarean delivery (CCD), low transverse cesarean delivery (LTCD), low vertical cesarean delivery (LVCD), and vaginal delivery. Association of delivery route with complications was estimated using multivariable regression models yielding adjusted relative risks (aRR) controlling for maternal age, race, body mass index, hypertension, diabetes, preterm premature rupture of membranes, preterm labor, GA, and hospital of delivery. Of 2659 women who met criteria for inclusion in this analysis, 8.6% of women experienced serious maternal complications. Complications were associated with GA and were highest between 23-27 weeks of gestation. The frequency of complications was associated with delivery route; compared with 3.5% of vaginal delivery, 23.0% of CCD (aRR, 3.54; 95% confidence interval (CI), 2.29-5.48), 12.1% of LTCD (aRR, 2.59; 95% CI, 1.77-3.77), and 10.3% of LVCD (aRR, 2.27; 95% CI, 0.68-7.55) experienced complications. There was no significant difference in complication rates between CCD and LTCD (aRR, 1.37; 95% CI, 0.95-1.97) or between CCD and LVCD (aRR, 1.56; 95% CI, 0.48-5.07). The risk of maternal complications after early preterm delivery is substantial, particularly in women who undergo cesarean delivery. Obstetricians need to be prepared to manage potential hemorrhage, infection, and intensive care unit admission for early preterm births requiring cesarean delivery.


Sensitizing the interdisciplinary team to desensitizations: An alemtuzumab case report.
We describe a case of alemtuzumab (Campath®) hypersensitivity requiring desensitization within the medical intensive care unit (MICU) in a patient with T-cell prolymphocytic leukemia. We adopted a desensitization protocol from Gutierrez-Fernandez et al., which included three aliquots (0.15 mg intravenously (IV), 1.5 mg IV, and 28.5 mg IV) given approximately 1 h apart on day 1 followed by a full 30 mg dose IV on day 3. Unlike prior attempts to administer alemtuzumab to this patient, she tolerated the medication well and did not require any rescue medications. Successful plan development required a significant amount of strategic communication between hematology/oncology and MICU-related physicians, pharmacists, and nurses to ensure a safe and effective desensitization. The first step of planning required creation of a desensitization order set with directions for medication preparation and administration, premedications, and available medications in the event of an adverse reaction or anaphylaxis. Anaphylactoid-related medications were prepared at bedside and ready for administration prior to beginning the desensitization. Alemtuzumab was compounded in a chemotherapy-certified hood and verified by at least two chemotherapy-certified pharmacists. Foreword planning was also necessary to ensure multiple people were available or present at bedside for the desensitization, including a chemotherapy-certified nurse, a second chemotherapy-certified nurse for verification, a critical care-certified pharmacist, a pulmonary/critical care attending physician, and hematology attending physician. This case exemplifies the importance of clear and coordinated communication between different healthcare fields to safely and effectively complete extensive protocols such as desensitization strategies.


The ghosts of HeLa: How cell line misidentification contaminates the scientific literature.
While problems with cell line misidentification have been known for decades, an unknown number of published papers remains in circulation reporting on the wrong cells without warning or correction. Here we attempt to make a conservative estimate of this 'contaminated' literature. We found 32,755 articles reporting on research with misidentified cells, in turn cited by an estimated half a million other papers. The contamination of the literature is not decreasing over time and is anything but restricted to countries in the periphery of global science. The decades-old and often contentious attempts to stop misidentification of cell lines have proven to be insufficient. The contamination of the literature calls for a fair and reasonable notification system, warning users and readers to interpret these papers with appropriate care.


Deamination of 4-aminopyrimidine nucleosides by extracts of rye grass (Lolium perenne).
A deaminase specific for 4-aminopyrimidine nucleosides has been found in rye grass. Lolium perenne. The pH optimum, temperature stability, Km values and specificity was determined.A new and more accurate method for following the course of deamination is reported. This method depends on the shift in maximum absorbance wavelength of the mixture containing the 4-aminopyrimidine nucleoside and its deaminated product.


[Papanicolaou smear screening: coverage in two home surveys applied in the city of São Paulo in 1987 and 2001-2002].
To compare the coverage of conventional Papanicolaou cytology in women aged 15 to 59 years between two home surveys, related to some personal attributes and to the tendency to die from cervical cancer. We analyzed data collected in two home surveys, with complex sampling, in the city of São Paulo, Brazil, over the years from 1987 to 2001 and 2002. The self-reported answers of 968 women in the first inquiry and of 1,125 women in the second inquiry were compared regarding the reply to the question about the execution of the Papanicolaou test "sometimes in a lifetime" in relation to age distribution, black skin, marital status, years of education and tendency to die because cervical cancer during the period from 1980 to 2007. The Fisher exact test was used to compare the sample regarding each item, with the level of significance set at p value >5%. From the first to the second inquiry there was a 24% increase in the execution of conventional Papanicolaou cytology (from 68.8% to 85%). The greatest variations in the increased coverage related to the personal attributes of the women were detected in black skin color, among single women and among women of lower schooling. Regarding the tendency to mortality rates due to cervical cancer, no clear ascending or declining tendency was observed along the 28 years studied (1980 to 2007). There was an increase in access to the cytological Papanicolaou test among the most vulnerable women. Since 2001 and 2002, the 85% coverage already reached WHO recommendation, although without a clear trend of decline in mortality due to cervical cancer in the following years, indicating that screening is only part of an effective and organized program for the control of cervical cancer, whose model must guarantee full women's health care.


Chapter 2: Skin testing in allergy.
Skin tests are used in addition to a directed history and physical exam to exclude or confirm IgE-mediated diseases such as allergic rhinitis, asthma, and anaphylaxis to aeroallergens, foods, insect venoms, and certain drugs. There are two types of skin testing used in clinical practice. These include percutaneous testing (prick or puncture) and intracutaneous testing (intradermal). Prick testing involves introducing a needle into the upper layers of the skin through a drop of allergen extract and gently lifting the epidermis up. Other devices are available for prick testing. Intracutaneous (intradermal) testing involves injecting a small amount of allergen (0.01-0.02 mL) into the dermis. The release of preformed histamine from mast cells causes increased vascular permeability via smooth muscle contraction and development of a wheal; inflammatory mediators initiate a neural reflex causing vasodilatation, leading to erythema (the flare). Prick testing methods are the initial technique for detecting the presence of IgE. They may correlate better with clinical sensitivity and are more specific but less sensitive than intradermal testing. Sites of skin testing include the back and the volar aspect of the arm. Although the back is more reactive, the difference is minimal. By skin testing on the arm, the patient can witness the emergence and often sense the pruritus of the skin test reaction. Because more patients are sensitized (have IgE antibodies and positive skin test reactions) than have current symptoms, the diagnosis of allergy can be made only by correlating skin testing results with the presence of clinical symptoms.


Stage-specific disruption of Stat3 demonstrates a direct requirement during both the initiation and promotion stages of mouse skin tumorigenesis.
Constitutive activation of signal transducer and activator of transcription 3 (Stat3) has been found in a variety of human malignancies and has been suggested to play an important role in carcinogenesis. Recently, our laboratory demonstrated that Stat3 is required for the development of skin tumors via two-stage carcinogenesis using skin-specific loss-of-function transgenic mice. To investigate further the role of Stat3 in each stage of chemical carcinogenesis in mouse skin, i.e. initiation and promotion stages, we generated inducible Stat3-deficient mice (K5.Cre-ER(T2) x Stat3(fl/fl)) that show epidermal-specific disruption of Stat3 following topical treatment with 4-hydroxytamoxifen (TM). The epidermis of inducible Stat3-deficient mice treated with TM showed a significant increase in apoptosis induced by 7,12-dimethylbenz[a]anthracene (DMBA) and reduced proliferation following exposure to 12-O-tetradecanoylphorbol-13-acetate. In two-stage skin carcinogenesis assays, inducible Stat3-deficient mice treated with TM during the promotion stage showed a significant delay of tumor development and a significantly reduced number of tumors compared with control groups. Inducible Stat3-deficient mice treated with TM before initiation with DMBA also showed a significant delay in tumor development and a significantly reduced number of tumors compared with control groups. Finally, treatment of inducible Stat3-deficient mice that had existing skin tumors generated by the two-stage carcinogenesis protocol with TM (by intraperitoneal injection) led to inhibition of tumor growth compared with tumors formed in control groups. Collectively, these results directly demonstrate that Stat3 is required for skin tumor development during both the initiation and promotion stages of skin carcinogenesis in vivo.


Management of clavicle fractures.
Fractures of the clavicle are relatively common injuries that can occur in patients of all ages. The history and physical examination remain the primary means of diagnosing this injury. Plain radiographs are helpful to confirm the diagnosis and to provide information regarding fracture classification, prognosis, and treatment options. The emphasis of this article is on the management of these injuries. Historically, only unstable distal clavicle fractures were treated operatively. However, recent well-conducted studies demonstrate that plate fixation of displaced midshaft clavicle fractures may result in improved functional outcome and a lower rate of malunion and non-union, compared with non-operative treatment. For clavicle fractures managed non-operatively, the sling-and-swathe or figure-of-eight splints remain appropriate options. Multiple factors should be considered when counseling an athlete on the appropriate time to return to sports participation after a clavicle fracture.


Cysteine Restriction in Murine L929 Fibroblasts as an Alternative Strategy to Methionine Restriction in Cancer Therapy.
Methionine restriction (MetR) is an efficient method of amino acid restriction (AR) in cells and organisms that induces low energy metabolism (LEM) similar to caloric restriction (CR). The implementation of MetR as a therapy for cancer or other diseases is not simple since the elimination of a single amino acid in the diet is difficult. However, the in vivo turnover rate of cysteine is usually higher than the rate of intake through food. For this reason, every cell can enzymatically synthesize cysteine from methionine, which enables the use of specific enzymatic inhibitors. In this work, we analysed the potential of cysteine restriction (CysR) in the murine cell line L929. This study determined metabolic fingerprints using mass spectrometry (LC/MS). The profiles were compared with profiles created in an earlier work under MetR. The study was supplemented by proliferation studies using D-amino acid analogues and inhibitors of intracellular cysteine synthesis. CysR showed a proliferation inhibition potential comparable to that of MetR. However, the metabolic footprints differed significantly and showed that CysR does not induce classic LEM at the metabolic level. Nevertheless, CysR offers great potential as an alternative for decisive interventions in general and tumour metabolism at the metabolic level.


[Deontologic problems in the medical treatment of tumors].
An attempt is made to discuss deontological problems, related with pharmacological treatment of malignant tumors, according to the traditions of N.N. Petrov, who always paid great attention to the problems of morality and ethics in oncology. The stages of experimental tests of new substances and recommendations for their clinical application are described. Nonscientific approach to the estimation and practical use of new substances is critisized. It is concluded that the problems of selection of the optimum method of treatment for each particular case should be considered by three specialists together: a surgeon, a radiologist and a therapeutist.


Using the General Linear Model to Improve Performance in fNIRS Single Trial Analysis and Classification: A Perspective.
Within a decade, single trial analysis of functional Near Infrared Spectroscopy (fNIRS) signals has gained significant momentum, and fNIRS joined the set of modalities frequently used for active and passive Brain Computer Interfaces (BCI). A great variety of methods for feature extraction and classification have been explored using state-of-the-art Machine Learning methods. In contrast, signal preprocessing and cleaning pipelines for fNIRS often follow simple recipes and so far rarely incorporate the available state-of-the-art in adjacent fields. In neuroscience, where fMRI and fNIRS are established neuroimaging tools, evoked hemodynamic brain activity is typically estimated across multiple trials using a General Linear Model (GLM). With the help of the GLM, subject, channel, and task specific evoked hemodynamic responses are estimated, and the evoked brain activity is more robustly separated from systemic physiological interference using independent measures of nuisance regressors, such as short-separation fNIRS measurements. When correctly applied in single trial analysis, e.g., in BCI, this approach can significantly enhance contrast to noise ratio of the brain signal, improve feature separability and ultimately lead to better classification accuracy. In this manuscript, we provide a brief introduction into the GLM and show how to incorporate it into a typical BCI preprocessing pipeline and cross-validation. Using a resting state fNIRS data set augmented with synthetic hemodynamic responses that provide ground truth brain activity, we compare the quality of commonly used fNIRS features for BCI that are extracted from (1) conventionally preprocessed signals, and (2) signals preprocessed with the GLM and physiological nuisance regressors. We show that the GLM-based approach can provide better single trial estimates of brain activity as well as a new feature type, i.e., the weight of the individual and channel-specific hemodynamic response function (HRF) regressor. The improved estimates yield features with higher separability, that significantly enhance accuracy in a binary classification task when compared to conventional preprocessing-on average +7.4% across subjects and feature types. We propose to adapt this well-established approach from neuroscience to the domain of single-trial analysis and preprocessing wherever the classification of evoked brain activity is of concern, for instance in BCI.


The Ukraine crisis: Mental health resources for clinicians and researchers.
The mental health consequences of the war in Ukraine will be enormous. Mental health professionals who are providing care for people in Ukraine, or those resettled elsewhere, may require access to standardized and validated assessment tools. We have developed a repository of mental health measures that are available in Ukrainian, Russian and English and can be accessed at www.traumameasuresglobal.com/ukraine.


Family accommodation in obsessive-compulsive disorder: Relation to symptom dimensions, clinical and family characteristics.
Family accommodation is the term used to indicate the process whereby family members of patients with obsessive-compulsive disorder (OCD) assist or participate in the patients' rituals. Family accommodation is a relatively under-researched phenomenon in OCD but an important one because it may be predictive of poor treatment outcome. This study systematically examined several socio-demographic and clinical variables that are associated with family accommodation in a well-characterized sample of adult patients and their healthy family members. Experienced clinicians administered the Family Accommodation Scale (FAS) to 141 psychopathology-free family members cohabiting with 97 patients with OCD. The items of the FAS were first subjected to principal component analysis (PCA) and the resulting domains of family accommodation (Participation, Modification, and Distress and Consequences) introduced as dependent variables in a series of multiple regression models assessing the relationship between family accommodation domains and a wide range of clinical variables, including Axis I and II psychopathology and symptom dimensions derived from the Yale-Brown Obsessive-Compulsive Scale (YBOCS) Symptom Checklist. The results showed that family accommodation was common, with the provision of reassurance, participation in rituals and assisting the patient in avoidance being the most frequent practices (occurring on a daily basis in 47%, 35%, and 43% of family members, respectively). The PCA of the YBOCS Symptom Checklist yielded four symptom dimensions, which were identical to those previously identified in the international literature. Multiple linear regression analyses showed that a higher score on the contamination/washing symptom dimension and a positive family history for an anxiety disorder other than OCD (referring to a family member other than the participant in this study) predicted greater scores on several domains of family accommodation. Our study confirms that family accommodation is frequent and distressing in psychopathology-free family members cohabiting with adult OCD patients. Family accommodation is particularly frequent and distressing when the patient has prominent contamination/washing symptoms and/or when another family member has a history of an anxiety disorder. Such families may be more likely to benefit from family-based interventions but this remains to be tested in controlled trials.


[Diagnosis of post-traumatic uveitis using ultrasonic dopplerography].
Changes in the brain biopotentials during early and remote periods after perforating wounds of the eyes were for the first time investigated in 55 patients with posttraumatic uveitis (PTU). Increased alpha-rhythmic activity of the brain was detected, its location and intensity depending on the severity of injury and PTU and course of PTU. The possibility of predicting the outcome of uveitis was demonstrated and diagnostic value of the method in evaluation of its severity was proven. In favorable outcomes of PTU, alpha-rhythm intensified in the anterior compartments of the brain. In severe uveitis and risk of sympathetic inflammation, brain activity increased in the posterior compartments presenting as sharp waves, being pronounced in both hemispheres or on the intact eye side.


Classic versus modified Blalock-Taussig shunts in neonates and infants.
Between July 1979 and October 1984, 61 systemic-pulmonary arterial shunts were created in 45 patients. Clinical and angiographic results with 23 classic Blalock-Taussig shunts (BTSs) and 35 modified Blalock-Taussig shunts (MBTSs) with polytetrafluoroethylene grafts between the subclavian and pulmonary arteries were compared. Forty-three of the patients studied were infants: 28 were less than 1 month old, and 19 were less than 1 week old. Weights were 1.1 to 19 kg (mean 2.9 kg). Diagnoses were complex tetralogy of Fallot (18 patients), transposition of the great arteries with small left ventricle or left ventricular outflow tract obstruction (six patients) pulmonary atresia (seven patients) with intact ventricular septum (three) and ventricular septal defect (four), tricuspid atresia (four patients), univentricular heart (six patients), atrioventricular septal defect (canal) with pulmonary stenosis (three patients), and double-outlet right ventricle (one patient). Comparison groups were concurrent and were equivalent for age, weight, and complexity of anomaly. Patients were removed from the study population at the time of subsequent open heart surgery or at death. All patients were followed for a minimum of 6 months and for up to 5 1/2 years (BTS 1 1/2 to 5 1/2 years, mean 33 months; MBTS 6 months to 3 years, mean 20 months). There were no intraoperative deaths in either group. Among the 23 BTSs, three failed at 1, 3, and 19 days, resulting in two deaths (17%). One premature infant died despite a second shunt, one died during attempted intracardiac repair at 13 days of age, and the other was well after revision of the shunt. Eight patients underwent subsequent intracardiac repair 1 to 5 years (mean 34 months) after the initial procedure. Another four patients died from complex intracardiac anomalies with patent shunts. Three patients are alive 2 to 4 years after receiving shunts and have not undergone subsequent surgery. Late postoperative angiograms demonstrate a disturbing incidence (21%) of stenosis and right pulmonary arterial deformity despite satisfactory immediate postoperative studies and good clinical function. Eight patients required a second shunt, two for anatomic discontinuity of the pulmonary arteries and six because of inadequate blood flow through the first shunt. Among the 35 patients receiving the MBTS, two required early revision (technical error and ductal tissue at the anastomosis). There were no shunt-related deaths, but three (6%) occurred within 30 days of operation from left ventricular infarct, cerebral hemorrhage, sepsis, and severe aortic stenosis with arrhythmias.(ABSTRACT TRUNCATED AT 400 WORDS)


Predicting pathological complete response based on weakly and semi-supervised joint learning from breast cancer MRI.
Neoadjuvant chemotherapy (NAC) is the standard treatment for breast cancer patients. Patients achieving complete pathological response (pCR) after NAC usually have a good prognosis. However, automatic pCR prediction has been a challenging problem due to lacking well annotations in 3D MRI. Thus far, unifying different annotation information to predict the tumor's early response to NAC has not been systematically addressed. This paper proposes a weakly and semi-supervised joint learning method that integrates attentional features from multi-parametric MRI with radiomic features for predicting pCR to NAC in breast cancer patients. The attention-based multi-instance learning (MIL) is first developed to generate informative MRI bag-level features and mine key instances. The mean-teacher framework is then employed to segment tumor regions in a semi-supervised setting for extracting radiomic features. We perform experiments on 442 patients' data and show that our method achieves an AUC value of 0.85 in pCR prediction, which is superior to comparative methods. It is also shown that learning from multi-parametric MRI outperforms that of single-parameter MRI in pCR prediction.


Model for conformational relaxation of flexible conjugated polymers: application to p-phenylenevinylene trimers in nonpolar solvents.
Photoexcitation of flexible conjugated polymers is invariably followed by a fast conformational/torsional relaxation towards a configuration favouring coplanarity of the conjugated segments. In general, the experimental relaxation rate constant (k(CR)) depends on the solvent viscosity (η) and temperature (T), and is not proportional to T/η. A theory capable of explaining the observed dependence of k(CR) on T and η over a wide range of these variables is not available. This gap is filled here by presenting a stochastic model that includes the participation of the oligomer side chain in storing and dissipating the stresses induced by photoexcitation. The model is able to account for the softening of solute-solvent interactions and its predictions are found to be in excellent agreement with the observed relaxation rate constants of a series of substituted p-phenylenevinylene trimers [ChemPhysChem 2009, 10, 448-454] on T, η and the size of the side-chains.


Unique case of granulomatous arteritis in a grey mouse lemur (Microcebus murinus) - first case description.
Overall, diseases of the vascular system are rarely observed entities among nonhuman primates that are commonly associated with systemic infections, septicemia or bacteremia. Rhesus monkeys infected with simian immunodeficiency virus (SIV) may develop a chronic occlusive arteriopathy of unknown etiology in late stages of the disease. This SIV associated arteriopathy is the only well-known specific vascular entity described in nonhuman primates. We herein report a unique case of granulomatous arteritis in a grey mouse lemur affecting multiple organs, which is not comparable to other disease entities formerly described in nonhuman primates. The features of the entity most closely resemble disseminated visceral giant cell arteritis in humans. A concise description of the disease is given, and the differential diagnoses are discussed. An idiopathic pathogenesis is suspected.


The binding of ethyl isocyanide to ferroperoxidase.
The equilibrium and kinetics of ethyl isocyanide binding to ferroperoxidase were studied. At pH9.1 the results of both studies are consistent with a single-process model with an affinity constant of 95m(-1) and combination and dissociation constants of 2.2x10(3)m(-1).s(-1) and 23s(-1) respectively. Ethyl isocyanide is not bound significantly at pH values lower than 6.0, and in this behaviour and the pH-dependence of the affinity constant, similarities exist between isocyanide and cyanide binding. The enthalpy of the process measured by equilibrium methods is -59kJ/mol (-14kcal/mol). At pH values below 9, the ethyl isocyanide adduct changes in a slow time-dependent manner, giving rise to a new species. These changes are reversible on increasing the pH. The results are discussed in relation to other known information about ligand binding to ferroperoxidase and to myoglobin.


An affinity label for alpha 2-adrenergic receptors in rat brain.
Clonidine, a potent and highly selective alpha 2-adrenergic agonist of the central nervous system, was modified. Insertion of the strong alkylating isothiocyanate group (NCS) group, at its aromatic residue, makes clonidine a potential affinity label of the alpha 2-adrenergic receptors. In displacement of [3H]clonidine and p-[3H]aminoclonidine from rat brain membrane preparations, clonidine-NCS demonstrates high affinity for the alpha 2-adrenergic receptors (Kd = 50 mM). The covalent labelling of the central alpha 2-receptors requires higher concentrations of the irreversible ligand (1-70 microM), thus indicating possible non-productive interactions at the environment of the receptor site. Only partial protection of the receptors is observed with a reversible alpha 2-agonist. The new clonidine analog appears to be a general ligand for the alpha 2-adrenergic receptors and might serve as a potential affinity probe for these receptors.


Dual roles for the variable domain in protein trafficking and host-specific recognition of Heterodera glycines CLE effector proteins.
*Soybean cyst nematodes (Heterodera glycines) produce secreted effector proteins that function as peptide mimics of plant CLAVATA3/ESR (CLE)-like peptides probably involved in the developmental reprogramming of root cells to form specialized feeding cells called syncytia. *The site of action and mechanism of delivery of CLE effectors to host plant cells by the nematode, however, have not been established. In this study, immunologic, genetic and biochemical approaches were used to reveal the localization and site of action of H. glycines-secreted CLE proteins in planta. *We present evidence indicating that the nematode CLE propeptides are delivered to the cytoplasm of syncytial cells, but ultimately function in the apoplast, consistent with their proposed role as ligand mimics of plant CLE peptides. We determined that the nematode 12-amino-acid CLE motif peptide is not sufficient for biological activity in vivo, pointing to an important role for sequences upstream of the CLE motif in function. *Genetic and biochemical analysis confirmed the requirement of the variable domain in planta for host-specific recognition and revealed a novel role in trafficking cytoplasmically delivered CLEs to the apoplast in order to function as ligand mimics.


The use of 3-bromopropionic acid for the determination of protein thiol groups.
S-Carboxymethylcysteine, formed by the reaction of iodoacetic acid with cysteine, was found to undergo intramolecular cyclization to yield 3-oxo-(2H,3H,5H,6H-1,4-thiazine)-5-carboxylic acid. The cyclization was studied under various conditions and the product was isolated and characterized. S-Carboxyethylcysteine, formed by the reaction of 3-bromopropionic acid with cysteine, did not undergo the cyclization reaction. The use of 3-bromopropionic acid was examined as an alternative to iodoacetic acid for the protection and determination of protein thiol groups.


Imaging Features of Primary Sclerosing Cholangitis: From Diagnosis to Liver Transplant Follow-up.
Primary sclerosing cholangitis (PSC) is a chronic progressive inflammatory disease of the bile ducts that leads to multifocal bile duct fibrosis, strictures, cholestasis, liver parenchymal changes, and ultimately cirrhosis. It more commonly occurs in young adults, with a variety of clinical and imaging manifestations. The cause of the disease is not known, but it has a strong association with inflammatory bowel disease and can overlap with other autoimmune diseases, including autoimmune hepatitis and immunoglobulin G4-related disease. Patients are predisposed to various hepatic and extrahepatic deteriorating complications, such as bile duct and gallbladder calculi, acute bacterial cholangitis, liver abscess, and portal hypertension, as well as malignancies including cholangiocarcinoma (CCA), gallbladder cancer, and colorectal carcinoma. Imaging has an essential role in diagnosis, surveillance, and detection of complications. MR cholangiopancreatography and endoscopic retrograde cholangiopancreatography have high specificity and sensitivity for detection of primary disease and assessment of disease progression. However, many patients with PSC are still diagnosed incidentally at US or CT. Novel imaging techniques such as transient elastography and MR elastography are used to survey the grade of liver fibrosis. Annual cancer surveillance is necessary in all PSC patients to screen for CCA and gallbladder cancer. Familiarity with PSC pathogenesis and imaging features across various classic imaging modalities and novel imaging techniques can aid in correct imaging diagnosis and guide appropriate management. The imaging features of the biliary system and liver parenchyma in PSC across various imaging modalities are reviewed. Imaging characteristics of the differential diagnosis of PSC, clinical associations, and complications are described. Finally, the role of imaging in evaluation of PSC progression, pre-liver transplant assessment, and post-liver transplant disease recurrence are discussed.©RSNA, 2019.


4-Nitroquinoline-1-oxide-induced mutagen sensitivity and risk of nonmelanoma skin cancer: a case-control analysis.
The UV radiation-mimetic chemical 4-nitroquinoline-1-oxide (4-NQO) is thought to induce squamous cell carcinoma (SCC) similar to those induced by UV radiation in animals. Therefore, we tested the hypothesis that cellular sensitivity to 4-NQO is associated with risk of developing skin cancer in a case-control study of 191 patients with nonmelanoma skin cancer (NMSC; 81 SCC and 110 basal cell carcinoma (BCC)) and 176 cancer-free controls. Short-term blood cultures were treated with 4-NQO at a final concentration of 10 microM for 24 hours and scored for chromatid breaks in 50 well-spread metaphases. We found that the mean frequency of chromatid breaks per cell (b/c) was significantly higher in the cases (mean+/-SD, 0.46+/-0.43 for SCC and 0.43+/-0.38 for BCC) than in the controls (0.25+/-0.25; P<0.001 for both comparisons) and were associated with more-than-twofold increased risk for both SCC and BCC after adjustment for known risk factors. Therefore, our findings support the notion that sensitivity to 4-NQO reflects susceptibility to UV-induced NMSC. However, there is a lack of correlation between UVB-induced b/c and 4-NQO-induced b/c in this study population. Therefore, these findings need to be verified by additional studies.


Extracellular matrix distribution and islet morphology in the early postnatal pancreas: anomalies in the non-obese diabetic mouse.
Previously, we reported elevated numbers of macrophages in the pancreas of NOD mice, a spontaneous animal model for T1D, during the early postnatal period. Extracellular matrix plays an important role in the tissue trafficking and retention of macrophages as well as in postnatal pancreas development. Therefore, we have examined the expression and distribution of laminin and fibronectin, two major extracellular matrix proteins and their corresponding integrin receptors, in the pre-weaning pancreases of NOD mice and control mouse strains. In addition, we have characterized the pancreas morphology during this period, since the morphology of the pre-weaning pancreas before the onset of lymphocytic peri-insulitis, when the pancreas is still subject to developmental changes, has been poorly documented. We show that laminin labeling is mainly associated with exocrine tissue, whereas fibronectin labeling was mostly localized at the islet-ductal pole, islet periphery and in intralobular septa. Moreover, the protein expression level of fibronectin was increased in NOD pancreases at the early stage of postnatal development, as compared to pancreases of C57BL/6 and BALB/c mouse strains. Interestingly, pancreatic macrophages were essentially found at sites of intense fibronectin labeling. The increased fibronectin content in NOD neonatal pancreas coincided with altered islet morphology, histologically reflected by enlarged and irregular shaped islets and increased percentages of total endocrine area as compared to that of control strains. In conclusion, increased levels of the extracellular matrix protein fibronectin were found in the early postnatal NOD pancreas, and this is associated with an enhanced accumulation of macrophages and altered islet morphology.


The use of carbon dioxide laser in pit and fissure caries prevention: clinical evaluation.
In this 4-year follow-up in vivo controlled study, 112 human permanent first molars from children between 6 and 11 years old were used to investigate the viability of the carbon dioxide (CO2) laser in promoting caries-free occlusal surfaces in permanent molars as an isolated form of treatment or associated with conventional fissure sealants. The findings suggest that occlusal caries prevention only by means of CO2 laser irradiation is not effective; that the utilization of photoactivated sealants, as well as its association with CO2 laser, applied over the occlusal fissures, are effective means of preventing occlusal caries, and that the application of CO2 laser over occlusal fissures prior to the application of a photoactivated fissure sealant improves the retention of the sealant.