Long-Term Durability and Recurrence Patterns After Endovascular Treatment for Basilar Tip Aneurysms.
Treating recurrence after coil embolization of basilar tip aneurysm remains challenging even with the development of endovascular procedures. The present study evaluated long-term durability and recurrence patterns after endovascular treatment of basilar tip aneurysms. Data of 116 consecutive patients treated with endovascular therapy at 3 regional hospitals from 2002-2019 were retrospectively analyzed. Aneurysms were ruptured in 51 cases and unruptured in 65 cases, with a mean maximal diameter of 7.8 mm (>15 mm in 14 patients) and a mean follow-up period of 5.8 ± 4.3 years. Recurrence was observed in 24 of the 116 patients (21%), and 14 patients were retreated. The 5-year recurrence-free survival rate was 75.3%. Cox proportional hazards analysis found that recurrence correlated significantly with maximal aneurysm diameter >10 mm (P = 0.001; hazard ratio: 3.95, 95% confidence interval: 1.76-8.90) and incomplete occlusion (P = 0.003; hazard ratio: 4.43, 95% confidence interval: 1.63-12.00). Recurrence pattern was classified into 3 types: neck type (9 patients), regrowth type (10 patients), and regrowth type of initially thrombosed aneurysms (3 patients). Rerupture occurred in neck type with de novo aneurysm formation adjacent to the neck (n = 3) and regrowth type with dome filling (n = 4). Recurrence after coil embolization for basilar tip aneurysms is associated with large aneurysms and incomplete occlusion at initial embolization. Understanding the patterns of recurrence is useful for predicting recurrence and selecting treatment strategies.


The effects of some bronchodilator and anti-inflammatory drugs on prostaglandin F2alpha-induced contraction of guinea-pig isolated trachea.
1. The bronchodilator drugs isoprenaline, salbutamol, theophylline and prostaglandin E1 (PGE1) relaxed the guinea-pig isolated tracheal chain preparation dose-dependently and their potencies were compared by EC50 values. 2. The non-steroid anti-inflammatory drugs flufenamate, mefenamate and phenylbutazone also relaxed the preparation dose-dependently, but were less potent than the sympathomimetic drugs and PGE1. 3. The contractile response to a submaximal concentration of prostaglandin F2alpha (PGF2alpha) was antagonized by flufenamate, mefenamate, phenylbutazone, aspirin, theophylline, isoprenaline, salbutamol and PGE1, at concentrations similar to or less than the clinical peak plasma levels in man. A relatively higher concentration of indomethacin was required. 4. The antagonism was relatively specific for PGF2alpha in the case of the fenamates, which did not cause comparable reductions in responses to equi-effective concentrations of histamine and carbachol. The other anti-inflammatory drugs, theophylline and the sympathomimetic drugs were less or non-specific. 5. The nature of the shifts in the long dose-response curve for PGF2alpha caused by increasing concentration levels of flufenamate indicates a dual competitive/non-competitive type of antagonism.


Effect of nanostructure lipid carrier of methylene blue and monoterpenes as enzymes inhibitor for Culex pipiens.
Solid lipid nanoparticles second generation, nanostructure lipid carrier (NLC), is one of the most important biodegradable nanoparticles. Nanostructure Lipid carrier (NLC) was used to encapsulate methylene blue (MB) dye, carvacrol and citronellal and their efficacy as insecticidal against Culex pipiens (Cx. pipiens) were distinguished. The prepared nanoformulation revealed very good physicochemical properties, especially the homogeneity of the particle size. Transmission electron microscope showed spherical shaped nanoparticles within range less than 200 nm. The prepared NLC-MB-MT system showed a very competitive insecticidal activity and high virulence against the mosquito larvae with higher mortality rate of LC50 of 0.141 µl/mL, in addition to high level of Oxidative stress parameters obtained through all the tested enzymes including hydrogen peroxide (4.8 ppm), protein carbonyl amount (0.12 OD/mg protein), ascorbic acid (0.15 mg) and Superoxide dismutase (SOD) showed strong increasing (0.09 OD/mg protein/min) at 6 µg/mL, respectively. Whereas paradoxical results of the oxidative stress enzymes were obtained from different concentration of nanoformulation that introduce a convenient reason for their potential insecticidal effect. The cytotoxic effect of NLC-MB-MT was evaluated using WI38 human lung cell lines, the LC50 was 6.4 mg/mL. The low cytotoxic reactivity towards the tested cell line makes the NLC-MB-MT nanoformulation has its promising insecticidal efficacy. Molecular docking study for each component were done against acetylcholine esterase protein and accepted binding modes achieved by the three compounds.


Recovery from coronary artery bypass grafting at home: is your nursing practice current?
This article provides a comprehensive approach to caring for the patient who has experienced coronary artery bypass grafting and is recovering at home. Using the National Nursing Practice Guidelines for the Cardiac Home Care Patient as a guide, specific assessment guidelines and nursing interventions are discussed.


Differential Diagnosis of Acquired Esotropia in the Elderly.
To provide an overview of the differential diagnoses of acquired esotropia that occur in the elderly and to facilitate their differentiation in everyday clinical practice. The data of all patients who presented in our outpatient university department for strabology and neuroophthalmology from March 2014 to October 2015 due to esotropia with diplopia with onset after age 50 were evaluated retrospectively. Exclusion criteria were a known strabismus before the age of 50 and/or vertical deviations in the primary position. Anamnestic characteristics, accompanying findings and orthoptic parameters, were analysed. 85 patients were included in the study, 42 of them female and 43 male. The following diagnoses were made: abducens nerve palsy (n = 34, 3 of them both sides), esotropia due to myopia magna (n = 12), esotropia with accompanying neurological symptoms (n = 6) and other etiology (n = 5). In 4 cases, the diagnosis was still unclear at the end of the study. In 24 patients, none of the above diagnoses existed and the diagnosis of "sagging eye syndrome" (ETSAG) was made. The abducens nerve palsy typically showed a sudden onset of double vision, slowed abduction saccades and asymmetrical abduction ability. With unilateral abducens nerve palsy, the esotropia increased continuously from the view to the unaffected side through the primary position to the view to the affected side. Patients with ETSAG and myopia-associated esotropia, on the other hand, reported a gradual onset of double vision, showed normal abduction saccades and a slightly reduced abduction ability. The squint angle often increased slightly to both sides. Esotropia with accompanying neurological symptoms was rare and was seen in various underlying diseases. The kind of onset of the double vision, the quality of the saccades, the incomitance pattern and the ability to abduct are important parameters for the etiological assignment of an esotropia in the elderly. The characteristics of the individual diagnoses are described and differential diagnostic aspects are discussed.


Increased T-cell reactivity and elevated levels of CD8+ memory T-cells in Alzheimer's disease-patients and T-cell hyporeactivity in an Alzheimer's disease-mouse model: implications for immunotherapy.
Neuroinflammation is observed in neurodegenerative diseases like Alzheimer's disease (AD). However, a little is known about the mechanisms of neural-immune interactions. The involvement of peripheral T-cell function in AD is still far from clear, though it plays an important role in immunotherapy. The aim of this study was to determine peripheral T-cell reactivity in AD patients and in an AD mouse model. Mitogenic activation via ligation of the T-cell receptor (TCR) with PHA-L was measured in T lymphocytes from AD patients and Thy1(APP 751SL) x HMG(PS1 M146L)-transgenic mice (APP x PS1). In order to uncover failures in TCR signaling, the TCR was also bypassed by PMA and ionomycin treatment. All patients were sporadic late onset cases and the transgenic mice expressed no mutant APP in lymphocytes, so that direct interactions of mutant APP on T-cell function can be excluded. CD4+ and CD8+ T-cell showed increased reactivity (tyrosine phosphorylation, CD69 expression, and proliferation) in AD, while APP x PS1 transgenic mice displayed hyporeactive CD8+ T-cells after TCR ligation. Increased levels of CD8+ T memory cells and down regulation of CD8 receptor were found in AD and the animal model. Anergic TCR uncoupling was associated with loss of MAPK signaling (p38, ERK1 and ERK2) in APP x PS1. Our data implicate the generation of reactive memory T-cell in AD and of anergic memory T-cells in transgenic mice and should be taken into concern when designing immunotherapy.


Attitude ambivalence, social norms, and behavioral intentions: Developing effective antitobacco persuasive communications.
This study assessed the moderating effects of attitude ambivalence on the relationship between social norms, attitudes, and behavioral intentions to use tobacco. It was predicted that people would use social norms to reduce attitude ambivalence, and that reduced ambivalence would lead to changes in attitudes and behavioral intentions. To test this hypothesis, participants (N = 152) were exposed to persuasive communications designed to influence attitude ambivalence and perceived social norms regarding tobacco use. Analysis indicated that providing a social norm antagonistic to tobacco use significantly reduced ambivalence among participants reading the ambivalence message (p < .001). Examining changes in tobacco attitudes from pre- to postpersuasive communications demonstrated a significant decrease in tobacco attitudes only for participants reading the ambivalence message who were provided with the antitobacco use norm (p < .001). Ambivalent message participants also expressed significantly lower intentions to use tobacco when provided with social norms indicating antitobacco sentiments (p < .02), and this significant decrease in intentions was associated with changes in attitudes toward tobacco. These results point to the important role of social norms in mediating the effects of attitude ambivalence on subsequent behavior in preventative programs targeting tobacco use.


Adrenocorticotrophic hormone, cortisol and catecholamine concentrations during insulin hypoglycaemia in dogs anaesthetized with thiopentone.
Glucose homeostasis is maintained by complex neuroendocrine control mechanisms. Increases in plasma concentrations of various glucose-raising hormones such as glucagon, catecholamines, adrenocorticotrophic hormone (ACTH), and cortisol are observed under certain conditions associated with stress (haemorrhage and hypoglycaemia). The purpose of this study was to determine the effect of thiopentone anaesthesia on the catecholamine, ACTH and cortisol response to insulin hypoglycaemia in dogs. Blood sugar (BS), plasma catecholamine, and ACTH, and serum cortisol concentrations were measured during the course of (1) an intravenous insulin test (ITT) and (2) an ACTH test in conscious and in anaesthetized fasted dogs. During the ITT, the anaesthetized dogs showed a moderate resistance, compared with conscious dogs, to the hypoglycaemic action induced by insulin (blood sugar concentration 30 min after insulin injection: 2.91 +/- 0.25 vs 1.93 +/- 0.12 mM.L-1; P < 0.01). In addition, decreased epinephrine (220 +/- 27 vs 332 +/- 32 pg.ml-1), ACTH (65 +/- 6 vs 90 +/- 5 pg.ml-1) and cortisol (4.48 +/- 0.3 vs 6.25 +/- 0.5 micrograms.ml-1) concentrations were detected 60 min after insulin injection (P < 0.01). The norepinephrine response to hypoglycaemia was not altered by anaesthesia (273 +/- 33 vs 325 +/- 25 pg.ml-1). Anaesthetized dogs showed a decreased cortisol response to ACTH at 45 min (5.68 +/- 0.54 vs 8.87 +/- 0.47 micrograms.ml-1) when compared with control dogs (P < 0.001). Haemodynamic variables during anaesthesia showed little changes (P < NS); while respiratory rate was altered (P < 0.01 between 60 and 105 min).(ABSTRACT TRUNCATED AT 250 WORDS)


Author Correction: Metabolic GWAS of elite athletes reveals novel genetically-influenced metabolites associated with athletic performance.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


Arylation Using Sulfonamides: Phenylacetamide Synthesis through Tandem Acylation-Smiles Rearrangement.
A range of electron-poor and heterocyclic sulfonamides react with phenylacetyl chlorides to produce benzhydryl derivatives in a single step. The reaction proceeds via tandem amide bond formation/Dohmori-Smiles rearrangement under the simple conditions of an aqueous base. In the case of o-nosylamides, a further reaction takes place at the nitro group to yield indazoles.


The importance of creating a social business to produce low-cost hearing aids.
The World Health Organization (WHO) estimates that about 280 million people worldwide have a bilateral hearing loss, mostly living in poor countries. Hearing loss causes heavy social burdens on individuals, families, communities and countries. However, due to the lack of accessibility and affordability, the vast majority of people in the world who need hearing aids do not have access to them. Low-income countries are thus pulled into a disability/poverty spiral. From this standpoint, the production of available, accessible and affordable hearing aids for the poorest populations of our planet should be one of the main issues in global hearing healthcare. Designing and producing a brand new low-cost hearing aid is the most effective option. Involving a large producer of hearing aids in the creation of a social business to solve the problem of access to affordable hearing aids is an essential step to reduce hearing disability on a large scale globally. Today's technology allows for the creation of a "minimal design" product that does not exceed $100-$150, that can be further lowered when purchased in large quantities and dispensed with alternative models. It is conceivable that by making a sustainable social business, the low cost product could be sold with a cross-subsidy model in order to recover the overhead costs. Social business is an economic model that has the potential to produce and distribute affordable hearing aids in low- and middle-income countries. Rehabilitation of hearing impaired children will be carried out in partnership with Sahic (Society of Assistance to Hearing Impaired Children) in Dhaka, Bangladesh and the ENT Department of Ospedale Burlo di Trieste, Dr. Eva Orzan.


Hsp70-1: upregulation via selective phosphorylation of heat shock factor 1 during coxsackieviral infection and promotion of viral replication via the AU-rich element.
Coxsackievirus B3 (CVB3) is the primary pathogen of viral myocarditis. Upon infection, CVB3 exploits the host cellular machineries, such as chaperone proteins, to benefit its own infection cycles. Inducible heat shock 70-kDa proteins (Hsp70s) are chaperone proteins induced by various cellular stress conditions. The internal ribosomal entry site (IRES) within Hsp70 mRNA allows Hsp70 to be translated cap-independently during CVB3 infection when global cap-dependent translation is compromised. The Hsp70 protein family contains two major members, Hsp70-1 and Hsp70-2. This study showed that Hsp70-1, but not Hsp70-2, was upregulated during CVB3 infection both in vitro and in vivo. Then a novel mechanism of Hsp70-1 induction was revealed in which CaMKIIγ is activated by CVB3 replication and leads to phosphorylation of heat shock factor 1 (HSF1) specifically at Serine 230, which enhances Hsp70-1 transcription. Meanwhile, phosphorylation of Ser230 induces translocation of HSF1 from the cytoplasm to nucleus, thus blocking the ERK1/2-mediated phosphorylation of HSF1 at Ser307, a negative regulatory process of Hsp70 transcription, further contributing to Hsp70-1 upregulation. Finally, we demonstrated that Hsp70-1 upregulation, in turn, stabilizes CVB3 genome via the AU-rich element (ARE) harbored in the 3' untranslated region of CVB3 genomic RNA.


Recent Insights on the Role of PPAR-β/δ in Neuroinflammation and Neurodegeneration, and Its Potential Target for Therapy.
Peroxisome proliferator-activated receptor (PPAR) β/δ belongs to the family of hormone and lipid-activated nuclear receptors, which are involved in metabolism of long-chain fatty acids, cholesterol, and sphingolipids. Similar to PPAR-α and PPAR-γ, PPAR-β/δ also acts as a transcription factor activated by dietary lipids and endogenous ligands, such as long-chain saturated and polyunsaturated fatty acids, and selected lipid metabolic products, such as eicosanoids, leukotrienes, lipoxins, and hydroxyeicosatetraenoic acids. Together with other PPARs, PPAR-β/δ displays transcriptional activity through interaction with retinoid X receptor (RXR). In general, PPARs have been shown to regulate cell differentiation, proliferation, and development and significantly modulate glucose, lipid metabolism, mitochondrial function, and biogenesis. PPAR-β/δ appears to play a special role in inflammatory processes and due to its proangiogenic and anti-/pro-carcinogenic properties, this receptor has been considered as a therapeutic target for treating metabolic syndrome, dyslipidemia, carcinogenesis, and diabetes. Until now, most studies were carried out in the peripheral organs, and despite of its presence in brain cells and in different brain regions, its role in neurodegeneration and neuroinflammation remains poorly understood. This review is intended to describe recent insights on the impact of PPAR-β/δ and its novel agonists on neuroinflammation and neurodegenerative disorders, including Alzheimer's and Parkinson's, Huntington's diseases, multiple sclerosis, stroke, and traumatic injury. An important goal is to obtain new insights to better understand the dietary and pharmacological regulations of PPAR-β/δ and to find promising therapeutic strategies that could mitigate these neurological disorders.


Survey of acute hospital infection control resources and services in the Republic of Ireland.
Following the development of national guidelines on the control of antimicrobial resistance in 2001, a survey was carried out in 2003 of all 68 acute hospitals in the Republic of Ireland on resources available and current practice to control and prevent nosocomial infection. Completed questionnaires were received from 66 hospitals (97%). The median number of acute inpatient beds per hospital was 156; this was 522 in regional/tertiary referral centres. Only 31 (47%) hospitals had on-site consultant microbiologist sessions, and there was an infection control nurse in 56 (85%) hospitals. Eighteen (29%) hospitals had an occupational health physician, and 48 (73%) hospitals had an infection control committee. There was a median of one isolation room for every 16 acute beds, and a median of five rooms with en-suite bathroom facilities per hospital in those hospitals that provided data. All hospitals had documented infection control policies, and these were available in electronic format in 25 (38%) hospitals. Fifty-five (83%) hospitals undertook surveillance of nosocomial infection, and alcohol-based hand hygiene facilities were available, either at a handwashing sink or at the entrance to a ward, in 57 (86%) hospitals. In the Republic of Ireland, there remains a significant shortage of microbiologists/infection control doctors, occupational health physicians and infection control nurses. Isolation facilities are also inadequate. Although there is much agreement internationally on the importance of nosocomial infection and the priorities for surveillance, there are no agreed basic minimum standards for the resources and facilities necessary to control and prevent nosocomial infection.


Crystal structure of 3-(benzo[d]thia-zol-2-yl)-6-methyl-2H-chromen-2-one.
The mol-ecule of the title compound, C17H11NO2S, is almost planar, with an inter-planar angle of 3.01 (3)° between the benzo-thia-zole and chromene ring systems. A short intra-molecular S⋯O=C contact of 2.727 (2) Å is observed. The crystal packing involves a layer structure parallel to (211), containing dimeric inversion-symmetric units connected by a 'weak' C-H⋯O=C hydrogen bond.


Enhanced deposition of predominantly type I collagen in myocardial disease.
The myocardium consists of a muscle fibre array surrounded and interspersed by a network of connective tissue, principally collagen, which maintains the functional integrity of the heart. Changes in collagen composition may therefore contribute to altered ventricular function. Collagen composition was examined in cardiac tissue from 15 patients undergoing orthotopic cardiac transplantation. Of these, 10 had severely impaired left ventricular function due to coronary artery disease. The remaining five had dilated cardiomyopathy. Normal heart tissue was taken at autopsy from 25 patients who died of causes unrelated to cardiovascular disease. Left ventricular collagen concentration, estimated from hydroxyproline levels, increased from 48.6 +/- 4.1 mg/g dry weight of tissue in the control group to 95.3 +/- 9.7 mg/g (P less than 0.01) in patients with dilated cardiomyopathy and to 63.5 +/- 9.8 mg/g in the coronary artery disease group. This increase was attributable to an increase in absolute concentrations of both type I and III collagen, determined by separation of cyanogen bromide peptides by sodium dodecyl sulphate polyacrylamide gel electrophoresis. However, there was a significant decrease in the proportion of type III collagen (compared with type I plus III) from 41.8 +/- 1.1% in controls, to 34.6 +/- 1.5% (P less than 0.01) in the coronary artery disease group and 35.8 +/- 2.8% (P less than 0.05) in the dilated cardiomyopathy group. These results suggest that excessive collagen production, with a preponderance of type I, occurs in these forms of myocardial disease, indicative of a remodelling of the collagen matrix, which, by increasing passive myocardial stiffness may contribute to impaired heart function seen in these groups of patients.


Randomized trial of prophylactic phototherapy in the infant with very low birth weight.
Twenty-two preterm infants (birth weight 850 +/- 220 gm) were randomly assigned to receive phototherapy either soon after birth or after the serum bilirubin concentration reached 5 mg/dl. Infants receiving prophylactic phototherapy were placed under lights at a significantly earlier age and lower serum bilirubin concentration than infants in the routine group (P less than 0.001). There was no significant difference between groups in peak serum bilirubin concentration, age at which it peaked, rate of rise in serum bilirubin concentration, or serum bilirubin concentration at any time during the study. Infants assigned to the prophylactic phototherapy group were under lights for a significantly longer time than those in the routine group (P less than 0.05). There was a significant rise in both configurational and structural photo-isomers (P less than 0.005) independent of serum bilirubin concentration after phototherapy in all patients. These data suggest that the clinical course of hyperbilirubinemia is not altered in infants with very low birth weight receiving prophylactic phototherapy compared with infants with phototherapy begun at a bilirubin concentration of 5 mg/dl.


Variations of urinary iodine during the first trimester of pregnancy in an iodine-replete area. Comparison with non-pregnant women.
To assess variations of urinary iodine concentration (UIC) during a 4-week period among pregnant and non-pregnant women in an iodine-replete area. Pregnant (in their first trimester of pregnancy) and non-pregnant women referred to two maternity hospitals in Tehran were consecutively recruited from September 2005 to March 2006. Urine samples (5-10 mL) were collected on an every-other-day basis for 4 weeks (i.e., 12 samples for each individual). UIC was determined using a modified Sandell-Kolthoff method. Thirty-six pregnant and 32 non-pregnant women completed the study. Mean±SD age of pregnant women was 27.4±6.4 and of non-pregnant women 27.6±4.5 years (P=0.897). Mean±SD gestational age was 11±3.3 weeks in pregnant participants. Median UIC of <100, 100-149, 150-249, and ≥250 µg/L was present in 19.4, 25, 30.6, and 25% of pregnant, 15.6, 37.5, 34.4, and 12.5% of non-pregnant, and 17.6, 30.9, 32.4, and 19.1% of total individuals, respectively. Median UIC values of samples numbers 1 to 12 were not significantly different either in pregnant (P=0.591) or in non-pregnant subjects (P=0.745). Except for sample number 11, median UIC was not significantly different between pregnant versus non-pregnant women (P values >0.05). Mean SD values for UIC in samples numbers 1 to 12 in pregnant women was 138.4 (24.1-404) and in non-pregnant women 118 (29.5-272.4) µg/L (P=0.286). There was a wide intrapersonal variation in UIC values among pregnant and non-pregnant women residing in an iodine-replete area, supporting the notion that casual UIC would not reflect the iodine status of the individual.


An unusual case of radioactive seed migration to the vertebral venous plexus and renal artery with nerve root compromise.
We report a case of prostate brachytherapy seed migration to the vertebral venous plexus and subsequently to the renal artery with corresponding dosimetry analysis describing nerve doses. A 52-year-old male with low-risk prostate carcinoma (clinical stage T1c; Gleason score=6; prostate-specific antigen level of 5.5) underwent transperineal permanent prostate seed implant. Postimplantation routine imaging had failed to locate the missing seed, but he subsequently presented with back pain and parathesia with radiation down the leg. CT with bony windows and MRI had located the seed in the left L5 vertebral venous plexus. Neurosurgical intervention failed to locate and remove the migrated seed. Postsurgery, the left lower limb parathesia persisted but had normal nerve conduction studies. Dose to the spinal nerve roots and nearby structures were estimated using a GEANT4 Monte Carlo simulation. Serial X-ray imaging and CT had found that the seed had further migrated to left renal hilum. Seed migration to vertebral venous plexus is uncommon and to our knowledge this is the third reported case. Its subsequent migration to the renal hilum is most unusual. CT with bony windows or MRI are required if this is suspected. There is risk of spinal or nerve root damage and dose to these structures has to be estimated using GEANT4, although the tissue tolerance in the setting of low-dose rates are unknown and long-term followup of this patient is required.


Magnetic resonance imaging following the demonstration of a normal common bile duct on ultrasound in children with suspected choledocholithiasis: what is the benefit?
The role of MRI in evaluating children with an in situ gallbladder and suspected choledocholithiasis following a negative or inconclusive US is unclear. To determine whether MRI benefits children with suspected choledocholithiasis and a normal common bile duct (CBD) without stones on US. We conducted a retrospective 10-year review of paired US and MRI (within 10 days) in children 18 years or younger with suspected choledocholithiasis. With MRI as a reference standard, two reviewers independently evaluated the images for CBD diameter, choledocholithiasis, cholelithiasis and pancreatic edema. Serum lipase was recorded. We calculated exact binomial confidence limits for test positive predictive values (PPVs) and negative predictive values (NPVs) using R library epiR. Of 87 patients (46 female, 41 male; mean age 14 years, standard deviation [SD] 4.6 years; mean interval between US and MRI 1.6 days, SD 1.8 days), 55% (48/87) had true-negative US, without CBD dilation/stones confirmed on MRI; 5% (4/87) had false-positive US showing CBD dilatation without stones, not confirmed on MRI; 33% (29/87) had true-positive US, with MRI confirming CBD dilatation; and 7% (6/87) had false-negative US, where MRI revealed CBD stones without dilatation (2 patients) and CBD dilatation with or without stones (4 patients). Patients with false-negative US had persistent or worsening symptoms, pancreatitis or SCD. The overall US false-negative rate was 17% (6/35). Normal-caliber CBD on US without stones had an NPV of 89% (48/54, 95% confidence interval: 0.77-0.96). MRI adds little information in children with a sonographically normal CBD except in the setting of pancreatitis or worsening clinical symptoms. Further evaluation is warranted in children with elevated risk of stone disease.


Methods for studying store-operated calcium entry.
Activation of surface membrane receptors coupled to phospholipase C results in the generation of cytoplasmic Ca2+ signals comprised of both intracellular Ca2+ release, and enhanced entry of Ca2+ across the plasma membrane. A primary mechanism for this Ca2+ entry process is attributed to store-operated Ca2+ entry, a process that is activated by depletion of Ca2+ ions from an intracellular store by inositol 1,4,5-trisphosphate. Our understanding of the mechanisms underlying both Ca2+ release and store-operated Ca2+ entry have evolved from experimental approaches that include the use of fluorescent Ca2+ indicators and electrophysiological techniques. Pharmacological manipulation of this Ca2+ signaling process has been somewhat limited; but recent identification of key molecular players, STIM and Orai family proteins, has provided new approaches. Here we describe practical methods involving fluorescent Ca2+ indicators and electrophysiological approaches for dissecting the observed intracellular Ca2+ signal to reveal characteristics of store-operated Ca2+ entry, highlighting the advantages, and limitations, of these approaches.


The mGluR2/3 agonist LY379268 attenuates context- and discrete cue-induced reinstatement of sucrose seeking but not sucrose self-administration in rats.
We recently reported that systemic injections of the mGluR(2/3) agonist LY379268, which decreases evoked glutamate release, attenuate context- and discrete cue-induced reinstatement of heroin seeking, but not heroin self-administration. Here, we report that systemic injections of LY379268 attenuate context- and discrete cue-induced reinstatement of sucrose seeking, but not sucrose self-administration. These results suggest that similar neuronal mechanisms mediate cue-induced relapse to opiate- and palatable food seeking.


First-dose hypotension after angiotensin-converting enzyme (ACE) inhibitors in chronic heart failure: a comparison of enalapril and perindopril. Slovak Investigator Group.
First-dose hypotension refers to an observed reduction in blood pressure after the administration of the first dose of ACE inhibitors in patients with congestive heart failure. To compare the first-dose responses of low-dose enalapril and perindopril in patients with stable symptomatic chronic heart failure. Single blind, randomised, multicenter, parallel, prospective study. Patients (N=298) with chronic heart failure due to ischemic heart disease or dilated cardiomyopathy, NYHA II-IV, ejection fraction<40%, age>18 years, naive to ACE inhibitors or ATI-receptor blocker, were randomised to receive a single dose of 2. 5 mg enalapril or 2.0 mg perindopril. Baseline laboratory and clinical examinations were performed before entry into the study. Ambulatory blood pressure monitoring started 2 h before the study medication was given, and continued for at least 10 h after the medication. The maximum drop in blood pressure appeared approximately 4 h after dose administration in both groups, and was more pronounced in the enalapril group. Patients in the enalapril group had a significantly higher incidence of asymptomatic hypotension. No symptomatic hypotension requiring a change in medication or a prolongation of hospitalisation was observed. A low dose of perindopril is well-tolerated at initiation of ACE inhibitor therapy in patients with chronic heart failure and causes less first-dose hypotension than a low dose of enalapril.


Myelinated axon as a plastic cable regulating brain functions.
Each oligodendrocyte (OC) forms myelin approximately in around 10 different axons to coordinate information transfer by regulating conduction velocity in the central nervous system (CNS). In the classical view, myelin has been considered a static structure that rarely turns over under healthy conditions because myelin tightly holds axons by their laminar complex structure. However, in recent decades, the classical views of static myelin have been renewed with pioneering studies that showed plastic changes in myelin throughout life with new experiences, such as the acquisition of new motor skills and the formation of memory. These changes in myelin regulate conduction velocity to optimize the temporal pattern of neuronal circuit activity among distinct brain regions associated with skill learning and memory. Here, we introduce pioneering studies and discuss the implications of plastic myelin on neural circuits and brain function.


CT appearance of primary pleural lymphoma.
We report a case of primary pleural lymphoma. The CT appearance was of hemorrhagic pleural effusion with thickened membranes. The CT evaluation of pleural disease is discussed.


The role of cardiac transcription factor NKX2-5 in regulating the human cardiac miRNAome.
MicroRNAs (miRNAs) are translational regulatory molecules with recognised roles in heart development and disease. Therefore, it is important to define the human miRNA expression profile in cardiac progenitors and early-differentiated cardiomyocytes and to determine whether critical cardiac transcription factors such as NKX2-5 regulate miRNA expression. We used an NKX2-5eGFP/w reporter line to isolate both cardiac committed mesoderm and cardiomyocytes. We identified 11 miRNAs that were differentially expressed in NKX2-5 -expressing cardiac mesoderm compared to non-cardiac mesoderm. Subsequent profiling revealed that the canonical myogenic miRNAs including MIR1-1, MIR133A1 and MIR208A were enriched in cardiomyocytes. Strikingly, deletion of NKX2-5 did not result in gross changes in the cardiac miRNA profile, either at committed mesoderm or cardiomyocyte stages. Thus, in early human cardiomyocyte commitment and differentiation, the cardiac myogenic miRNA program is predominantly regulated independently of the highly conserved NKX2-5 -dependant gene regulatory network.


Hidden sources of galactose in the environment.
A galactose-restricted diet free of lactose is lifesaving in patients with galactose-1-phosphate uridyl transferase (GALT) deficiency, but does not prevent long-term complications such as developmental delay, abnormal speech, poor growth and, in females, ovarian failure. Lactose, found in dairy products and as an extender in drugs, has been considered the primary source of galactose in the diet. Two recent publications reported that small amounts of galactose are present in many fruits and vegetables. We report the presence of considerable amounts of free galactose in some legumes (dried beans and peas) and the presence of bound galactose in many food plants. Galactose, in various glycosidic linkages, such as alpha-1,6, beta-1,3 and beta-1,4, and as a component of lipids, is ubiquitous in animals and plants. The bioavailability of alpha-1,6 and beta-1,3 linked galactose in foods is unknown. However, alpha-galactosidases found in plant and animal tissues may release galactose in alpha-1,6 linkage, and from diagalactosyldiacylglycerol. Galactose in beta-1,4 linkage and as monogalactosyldiacylglycerol may be released by beta-galactosidases in animal and plant tissues. Foods fermented by microorganisms for preparation or preservation purposes may contain free galactose. The role of free and bound galactose in cereals, fruits, legumes, nuts, organ meats, seeds, and vegetables in the poor outcome seen in some patients with GALT deficiency is unknown. It is certain that no patients with GALT deficiency have ever ingested a galactose-free diet.


Altered androstenedione and estrone dynamics associated with abnormal hormonal profiles in amenorrheic subjects with weight loss or obesity.
The present study was designed for exploration of hormonal disturbances underlying common forms of amenorrhea. Polycystic ovary syndrome (PCO) patients and obese amenorrheic subjects had significantly elevated estrone (E1) levels, elevated luteinizing hormone/follicle-stimulating hormone ratios, and an exaggerated luteinizing hormone response to luteinizing hormone-releasing hormone. However, androstenedione (delta 4A), the precursor of E1, was elevated only in PCO. Thus, the E1/delta 4A ratio, which provides an indirect index of aromatase activity in extraglandular sites, was raised in obese subjects as a group but not in PCO subjects. These findings suggest that elevated E1 levels, which give rise to abnormal gonadotropin secretion, arise from increased available androgens in PCO but from an increased effect of aromatase (present in adipose tissue) in obese subjects. Measurement of androgens and the E1/delta 4A ratio provides insights into the relative contributions of hyperandrogenemia and enhanced aromatase activity to the genesis of amenorrhea in these groups. In patients with suppressed estradiol levels associated with hyperprolactinemia or weight loss, follicle-stimulating hormone levels were suppressed, while luteinizing hormone was not elevated. Prolactin excess explains these findings in hyperprolactinemia. Plasma E1 levels and the E1/delta 4A ratio were suppressed in patients with weight loss, possibly as a consequence of reduced adiposity. This finding suggests that hypothesis that a minimum level of E1, dependent upon adequate adiposity, is critical for the normal mature function of the hypothalamic-pituitary-ovarian axis. Abnormal E1/delta 4A ratios, high in obesity-associated amenorrhea and suppressed in weight loss-associated amenorrhea, may provide specific markers for these groups of patients.


Echocardiographic studies of dobutamine-induced ST-segment elevation before and after coronary artery bypass grafting in patients with old Q-wave myocardial infarction.
There is a controversy regarding the functional significance of stress-induced ST-segment elevation (STE) in Q leads. However, the effect of revascularization on the induction of STE was not investigated. We studied 35 patients with old Q-wave myocardial infarction who underwent coronary artery bypass grafting (CABG) of the infarct-related artery with dobutamine (up to 40 microg/kg per minute) stress echocardiography before and 3 months after CABG. Ischemia was defined as new or worsened wall motion abnormalities. Functional recovery was defined as a reduction of regional wall motion score of 1 or more in 2 or more segments from the pre-CABG to post-CABG resting echocardiogram with the use of the 16-segment/5-grade score model. STE (>/=0.1 mV J-point elevation lasting 80 ms in >/=2 Q leads) occurred in 20 (57%) patients. There was no significant difference between patients with and those without STE before CABG with regard to the prevalence of peri-infarction ischemia (85% vs 80%) or index of improvement of regional function after CABG (0.26 +/- 0.26 vs 0.29 +/- 0.33). STE was reinduced to the same level in 4 patients after CABG, whereas 16 patients showed absent reinduction (8 patients) or reduced level (8 patients) of STE. Functional changes associated with absent reinduction or less STE after CABG were absence of reinduction of regional ischemia in 13 patients, improvement of resting regional function in 5 patients, and resection of scarred segments in 4 patients. Among the 4 patients with persistent dobutamine-induced STE, 1 patient had persistent ischemia and 2 showed worsening of resting regional function. Although dobutamine-induced STE in patients with old Q-wave infarction referred for CABG cannot identify patients with a higher prevalence of ischemia, the lack of reinduction of this pattern after CABG correlates with absent reinduction of ischemia in most of patients.


The efficacy of 9-cis retinoic acid in experimental models of cancer.
9-cis retinoic acid (9-cis RA) is a retinoid receptor pan-agonist that binds with high affinity to both retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Using a variety of in vivo and in vitro cancer models, we present experimental data that 9-cis RA has activity as a potential chemotherapeutic agent. Treatment of the human promyelocytic leukemia cell line HL-60 with 9-cis RA decreases cell proliferation, increases cell differentiation, and increases apoptosis. Induction of apoptosis correlates with an increase in tissue transglutaminase (type II) activity. In vivo, 9-cis RA induces complete tumor regression of an early passage human lip squamous cell carcinoma xenograft. Finally, 9-cis RA inhibits the anchorage-independent growth of the human breast cancer cell lines MCF-7 and LY2 (an antiestrogen-resistant MCF-7 variant). Transient co-transfection assays indicate that 9-cis RA inhibits estrogen receptor transcription of an ERE-tk-LUC reporter through RAR or RXR receptors. These data suggest that retinoid receptors can antagonize estrogen-dependent transcription and provides one possible mechanism for the inhibition of cell growth by 9-cis RA in breast cancer cell lines. In summary, these findings present evidence that 9-cis RA has a wide range of activities in human cancer models.


The association of platelets with failed patent ductus arteriosus closure after a primary course of indomethacin or ibuprofen: a systematic review and meta-analysis.
To conduct a meta-analysis of the association of platelet counts and pharmacotherapeutic failure in preterms with a patent ductus arteriosus (PDA). MEDLINE, Embase, Science Citation Index, abstracts and conference proceedings were searched, and principal authors contacted. Included studies reported indomethacin or ibuprofen use for PDA closure, compared a group which failed treatment versus a group which did not and reported the association between platelet counts and indomethacin or ibuprofen failure. Two reviewers independently screened results and assessed methodological quality using the Newcastle-Ottawa Scale. Results are expressed as mean difference in platelet counts and summary odds ratios (OR) using a random effects model. 1105 relevant studies were identified; eight involving 1087 preterms were included. Platelet counts were significantly lower in infants who failed pharmacotherapy (Meandifference:-30.88 × 109/L; 95% CI:-45.69 × 109,-16.07 × 109/L; I2 = 24%; pheterogeneity = 0.24). Similar results were obtained based on either pharmacotherapeutic agent. Treatment failure was also significantly associated with pre-treatment thrombocytopenia (summary OR:1.75; 95% CI:1.23-2.49, I2 = 36%, pheterogeneity = 0.20). Platelet counts are significantly lower in preterms who fail primary treatment for PDA. Pre-treatment thrombocytopenia is associated with higher odds of failure. Further cohort studies reporting platelet counts in prostaglandin inhibitor failure are needed for meta-analyses to firmly establish or refute a stronger association.


Recommendations for Psychosocial Evaluation of VAD candidates: Adoption, completion, and barriers to implementation.
Recommendations exist to guide clinicians on a comprehensive psychosocial (PS) evaluation prior to Mechanical Circulatory Support (MCS) implantation. Assess adoption, beliefs, methodologies, and barriers to completion of the 2018 ISHLT/APM/AST/ICCAC/STSW Recommendations for Psychosocial evaluation of adult cardiothoracic transplant and long term mechanical circulatory support. Cross-sectional survey distributed to all 183 implanting LVAD centers in North America via mail and email. Total of 58 Programs (35.6% response rate) representing 29 states and all regions of the United States responded. Respondents reported implanting 1,183 adults (range 0 - 85; mean = 21.5, SD = 18) in 2018. A majority (n = 55, 94.8%) reported that the 2018 Recommendations were consistent with their clinical practice and most (n = 51, 87.9%) had adopted the recommendations. The Stanford Integrated Psychosocial Assessment for Transplant (SIPAT) (n = 25, 47.1%) was the most commonly cited assessment tool in the use, although 15 centers reported utilizing more than one tool during the assessment process. Most common barriers influencing completion of the PS evaluation include patient too ill (total responses = 104), lack of time (total responses = 89), patient poor candidate (total responses = 44), and lack of Insurance coverage/reimbursement (total responses = 41). The 2018 ISHLT Recommendations for PS evaluation of LVAD Candidates are widely adopted by respondents in clinical practice, although barriers are still reported to their implementation. Additional research is needed to understand strategies to reduce barriers to implementation and maintenance of the recommendations in clinical practice.


Effect of metformin taken in the 'fresh' in vitro fertilization/intracytoplasmic sperm injection cycle upon subsequent frozen embryo replacement in women with polycystic ovary syndrome.
We aimed to determine whether metformin when taken during a fresh in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycle affects live birth rate (LBR) in subsequent frozen embryo replacement cycles (FERC). A retrospective database analysis of women with polycystic ovary syndrome (PCOS) undergoing FERC at a university teaching hospital between 2002 and 2007 (n = 142). The outcome of FERC in women who had taken metformin in the 'fresh' IVF/ICSI cycle (group A, n = 28) and those who had not (group B, n = 114) were compared. In the first FERC there was a significantly higher LBR (A = 28.6%, B = 12.3%, OR 2.86 95% CI 1.06-7.71). Women who had elective cryopreservation due to ovarian hyperstimulation syndrome risk were found to have significantly higher LBRs if metformin was taken in the fresh IVF/ICSI cycle (A = 44.4%, B = 7.9%, OR 9.33 95% CI 1.60-54.58). Women with PCOS who take metformin during IVF/ICSI may have a higher LBR in subsequent FERC, especially in those who have elective cryopreservation for OHSS risk. The findings of this study are limited by its retrospective design and small sample size and require confirmation in an adequately powered prospective randomized controlled trial.


Investigating the suitability of online eye tracking for psychological research: Evidence from comparisons with in-person data using emotion-attention interaction tasks.
The future is bound to bring rapid methodological changes to psychological research. One such promising candidate is the use of webcam-based eye tracking. Earlier research investigating the quality of online eye-tracking data has found increased spatial and temporal error compared to infrared recordings. Our studies expand on this work by investigating how this spatial error impacts researchers' abilities to study psychological phenomena. We carried out two studies involving emotion-attention interaction tasks, using four participant samples. In each study, one sample involved typical in-person collection of infrared eye-tracking data, and the other involved online collection of webcam-based data. We had two main findings: First, we found that the online data replicated seven of eight in-person results, although the effect sizes were just 52% [42%, 62%] the size of those seen in-person. Second, explaining the lack of replication in one result, we show how online eye tracking is biased toward recording more gaze points near the center of participants' screen, which can interfere with comparisons if left unchecked. Overall, our results suggest that well-powered online eye-tracking research is highly feasible, although researchers must exercise caution, collecting more participants and potentially adjusting their stimulus designs or analytic procedures.


Longitudinal Associations Between Maternal Glucose Levels and Ultrasonographic Fetal Biometrics in a Shanghai Cohort.
Evidence on the timing of fetal growth alterations associated with gestational diabetes or on the association of the maternal glycemic trajectory with fetal growth during pregnancy remains lacking. To examine the associations between maternal glucose levels and offspring intrauterine growth. This cohort study used data from 4574 eligible pregnant women and their offspring in the Shanghai Maternal-Child Pairs Cohort collected from April 10, 2016, to April 30, 2018. Group-based trajectory modeling was used to classify fasting plasma glucose levels during pregnancy into 3 glycemic trajectories (trajectory 1, consistently normal glucose levels in all 3 trimesters; trajectory 2, hyperglycemia only in late pregnancy; and trajectory 3, hyperglycemia in all 3 trimesters [ie, consistently high glucose levels]). Statistical analysis was performed from April 25, 2020, to October 1, 2021. Gestational diabetes, which was defined using the results of an oral glucose tolerance test. Longitudinal fetal biometrics during gestational weeks 11 to 40 and birth outcomes were obtained from medical records. Pregnancy was partitioned into 3 periods (<24, 24-34, and >34 weeks' gestational age). The differences in offspring growth (log-transformed) and maternal glucose levels were compared using generalized linear mixed models. A total of 4121 pregnant women had oral glucose tolerance test results (mean [SD] age, 28.8 [4.1] years), 3746 of whom had glycemic trajectory data (mean [SD] age, 28.6 [4.1] years); 983 women (23.8%) had gestational diabetes. Throughout the pregnancy period and compared with the women without gestational diabetes or with women in the trajectory 1 group, the fetal biometrics for the women with gestational diabetes or for those in the trajectory 3 group were significantly higher (except for biparietal diameter), with an estimated increase in fetal weight in the group with gestational diabetes (β = 1.82; 95% CI, 1.03-2.61) and in the trajectory 3 group (β = 1.50; 95% CI, 0.54-2.47; P = .002). Fetal biometric alterations among women with gestational diabetes appeared before 24 weeks' gestational age, with neonatal birth weight significantly higher than in the group without gestational diabetes at 40.4 g (95% CI, 9.8-71.1 g) along with an increased risk of large size for gestational age (odds ratio, 1.36; 95% CI, 1.05-1.75) and macrosomia (odds ratio, 1.47; 95% CI, 1.12-1.94). However, pregnant women in the trajectory 2 group manifested significantly reduced fetal biometrics, and abdominal circumference was significantly augmented after 34 weeks' gestational age (increase, β = 1.92; 95% CI, 0.87-2.99). In this cohort study, pregnant women who received a diagnosis of gestational diabetes in midpregnancy or had hyperglycemia during all 3 trimesters showed an association with altered fetal growth patterns, including increased estimated fetal weight that appeared before 24 weeks' gestational age, increased birth weight, and the risk for large size for gestational age and macrosomia.


Oleic acid lung injury increases plasma prostaglandin levels.
To determine whether lung injury causes increased plasma prostaglandin (PG) levels, 35 rabbits received oleic acid and 35 served as controls. Half of each group also received 4 ml/kg of Intralipid over one hour and at least five in each subgroup received indomethacin 7.5 mg/kg. Arterial and venous plasma concentrations of PGE2, 6-keto-PGF1 alpha, and PGF2 alpha-M were measured. Venous PGE2 was significantly higher in the oleic acid-injured than in the normal lung group, 1560 +/- 270 (Mean +/- SEM) versus 880 +/- 140 pg/ml (p less than .05). Plasma levels were reduced by 50% with indomethacin, but PGE2 levels remained significantly higher than in the normal lung group, 850 +/- 180 versus 480 +/- 60 for arterial (p less than .05) and 820 +/- 140 versus 480 +/- 80 for venous (p less than .05), respectively. PGF2 alpha-M levels were significantly higher in the lung injury group, 240 +/- 50 versus 50 +/- 40 pg/ml for arterial (p less than .05) and 220 +/- 50 versus 95 +/- 40 for venous (p less than .05), respectively. These lung injury-related increases in PGE2 and PGF2 alpha-M appear related both to increased pulmonary production and to decreased pulmonary clearance. With Intralipid infusion, however, arterial PGE2 increased by 500 +/- 260 pg/ml compared to baseline (p less than .05) with no change in venous PGE2, indicating in this instance that the increase in arterial PGE2 levels is related to increased pulmonary production.


Mechanisms of DHEA-induced AMH increase in the ovarian tissues of PCOS rat.
The present study aimed to build a DHEA-induced polycystic ovary syndrome (PCOS) rat model to evaluate the potential mechanism of DHEA-induced AMH rise in these rat ovarian tissues. A total of 36 female 3-week-old rats were allocated into two groups at random. The control group received merely the same amount of sesame oil for 20 days while the experimental group received 0.2 mL of sesame oil Plus DHEA 6 mg/100 g daily. Both groups' vaginal opening times were noted, and vaginal smears were taken. By using RT-qPCR and Western blot, the mRNA and protein expression of AMH, GATA4, SF1, and SOX9 in the ovarian tissues of the two groups was investigated.The rats in the experimental group appeared to have obvious disorders of the estrus cycle, as evidenced by the ratio of estrus being significantly higher than that in the control group (P < 0.05); HE staining revealed that the ovarian volume, follicular vacuoles, and follicular lumen of the rats in the experimental group increased significantly.The ELISA results revealed that T and AMH in the experimental group were higher than those in the control group at day 15 and 20. AMH、GATA4 and SF1 mRNA and protein expression were higher in the experimental group than in the control group on day 15 and 20 (P < 0.05). On day 20, the experimental group outperformed the control group (P < 0.05). In the DHEA-induced PCOS rat model, androgen may have enhanced AMH expression via increasing the expression of genes associated to the AMH promoter binding site (GATA4, SF1, SOX9).


Regulation of 17β-hydroxysteroid dehydrogenases in cancer: regulating steroid receptor at pre-receptor stage.
Increased intracelullar hormone concentration levels have been shown to be the cause of several endocrine-related cancers including breast, prostate, endometrial, ovarian, cervix, testicular, thyroid, and osteosarcoma. Deregulated expression of steroidogenic enzymes in these tumors seems to be the source of a positive balance in active steroids that bind to the corresponding nuclear receptor, thus ultimately stimulating cell proliferation. Among these enzymes, 17β-hydroxysteroid dehydrogenases catalyze the interconversion between 17-ketosteroids and 17-hydroxysteroids on the last steps of sex hormones biosynthesis and metabolism. To date, 14 isoforms have been identified in vertebrates although only 13 are present in humans. Development and clinical evaluation of specific inhibitors to block their activity is currently under progress especially against the best characterized members 1 to 5. Selectivity and potency of these drugs constitute the main challenge in this new approach to cancer and steroid-dependent diseases treatment at the "pre-receptor level". Here we review the current state of knowledge regarding the deregulation of the expression of some of these enzymes in endocrine-related tumors.


Retrospective analysis and prospective validation of an AI-based software for intracranial haemorrhage detection at a high-volume trauma centre.
Rapid detection of intracranial haemorrhage (ICH) is crucial for assessing patients with neurological symptoms. Prioritising these urgent scans for reporting presents a challenge for radiologists. Artificial intelligence (AI) offers a solution to enable radiologists to triage urgent scans and reduce reporting errors. This study aims to evaluate the accuracy of an ICH-detection AI software and whether it benefits a high-volume trauma centre in terms of triage and reducing diagnostic errors. A peer review of head CT scans performed prior to the implementation of the AI was conducted to identify the department's current miss-rate. Once implemented, the AI software was validated using CT scans performed over one month, and was reviewed by a neuroradiologist. The turn-around-time was calculated as the time taken from scan completion to report finalisation. 2916 head CT scans and reports were reviewed as part of the audit. The AI software flagged 20 cases that were negative-by-report. Two of these were true-misses that had no follow-up imaging. Both patients were followed up and exhibited no long-term neurological sequelae. For ICH-positive scans, there was an increase in TAT in the total sample (35.6%), and a statistically insignificant decrease in TAT in the emergency (- 5.1%) and outpatient (- 14.2%) cohorts. The AI software was tested on a sample of real-world data from a high-volume Australian centre. The diagnostic accuracy was comparable to that reported in literature. The study demonstrated the institution's low miss-rate and short reporting time, therefore any improvements from the use of AI would be marginal and challenging to measure.


Health benefits for women staying with their husbands during a long-term trip to a hot springs spa.
The authors collected saliva samples from 15 married couples and 13 women staying with a female companion (N = 43) during an 8-day stay at a spa resort in Nagano, Japan. To examine changes in endocrinological stress markers, the authors evaluated participants' levels of salivary cortisol and chromogranin A (CgA) by enzyme-linked immunosorbent assay. By the eighth day, women staying with their husbands had significantly increased levels of cortisol and CgA. During the protocol, the authors observed no significant variation in levels of cortisol or CgA for either the women who were staying with same-sex companions or the male spouses. These findings suggest that the effects of long-term stays in a spa resort are more beneficial for married women staying with their husbands than for either married men or women staying with female companions.


Protein kinase Cδ oxidation contributes to ERK inactivation in lupus T cells.
CD4+ T cells from patients with active lupus have impaired ERK pathway signaling that decreases DNA methyltransferase expression, resulting in DNA demethylation, overexpression of immune genes, and autoimmunity. The ERK pathway defect is due to impaired phosphorylation of T(505) in the protein kinase Cδ (PKCδ) activation loop. However, the mechanisms that prevent PKCδ T(505) phosphorylation in lupus T cells are unknown. Others have reported that oxidative modifications, and nitration in particular, of T cells as well as serum proteins correlate with lupus disease activity. We undertook this study to test our hypothesis that nitration inactivates PKCδ, contributing to impaired ERK pathway signaling in lupus T cells. CD4+ T cells were purified from lupus patients and controls and then stimulated with phorbol myristate acetate (PMA). Signaling protein levels, nitration, and phosphorylation were quantitated by immunoprecipitation and immunoblotting of T cell lysates. Transfections were performed by electroporation. Treating CD4+ T cells with peroxynitrite nitrated PKCδ, preventing PKCδ T(505) phosphorylation and inhibiting ERK pathway signaling similar to that observed in lupus T cells. Patients with active lupus had higher nitrated T cell PKCδ levels than did controls, which correlated directly with disease activity, and antinitrotyrosine immunoprecipitations demonstrated that nitrated PKCδ, but not unmodified PKCδ, was refractory to PMA-stimulated T(505) phosphorylation, similar to PKCδ in peroxynitrite-treated cells. Oxidative stress causes PKCδ nitration, which prevents its phosphorylation and contributes to the decreased ERK signaling in lupus T cells. These results identify PKCδ as a link between oxidative stress and the T cell epigenetic modifications in lupus.


Dependence of coronary 3-dimensional dose maps on coronary topologies and beam set in breast radiation therapy: a study based on CT angiographies.
In left-side breast radiation therapy (RT), doses to the left main (LM) and left anterior descending (LAD) coronary arteries are usually assessed after delineation by prior anatomic knowledge on the treatment planning computed tomography (CT) scan. In this study, dose sensitivity due to interindividual coronary topology variation was assessed, and hot spots were located. Twenty-two detailed heart models, created from heart computed tomography angiographies, were fitted into a single representative female thorax. Two breast RT protocols were then simulated into a treatment planning system: the first protocol comprised tangential and tumoral bed beams (TGs_TB) at 50 + 16 Gy, the second protocol added internal mammary chain beams at 50 Gy to TGs_TB (TGs_TB_IMC). For the heart, the LAD, and the LM, several dose indicators were calculated: dose-volume histograms, mean dose (Dmean), minimal dose received by the most irradiated 2% of the volume (D2%), and 3-dimensional (3D) dose maps. Variations of these indicators with anatomies were studied. For the LM, the intermodel dispersion of Dmean and D2% was 10% and 11%, respectively, with TGs_TB and 40% and 80%, respectively, with TGs_TB_IMC. For the LAD, these dispersions were 19% (Dmean) and 49% (D2%) with TGs_TB and 35% (Dmean) and 76% (D2%) with TGs_TB_IMC. The 3D dose maps revealed that the internal mammary chain beams induced hot spots between 20 and 30 Gy on the LM and the proximal LAD for some coronary topologies. Without IMC beams, hot spots between 5 and 26 Gy are located on the middle and distal LAD. Coronary dose distributions with hot spot location and dose level can change significantly depending on coronary topology, as highlighted by 3D coronary dose maps. In clinical practice, coronary imaging may be required for a relevant coronary dose assessment, especially in cases of internal mammary chain irradiation.


Curcumin and Boswellia serrata gum resin extract inhibit chikungunya and vesicular stomatitis virus infections in vitro.
Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes chikungunya fever and has infected millions of people mainly in developing countries. The associated disease is characterized by rash, high fever, and severe arthritis that can persist for years. CHIKV has adapted to Aedes albopictus, which also inhabits temperate regions including Europe and the United States of America. CHIKV has recently caused large outbreaks in Latin America. No treatment or licensed CHIKV vaccine exists. Traditional medicines are known to have anti-viral effects; therefore, we examined whether curcumin or Boswellia serrata gum resin extract have antiviral activity against CHIKV. Both compounds blocked entry of CHIKV Env-pseudotyped lentiviral vectors and inhibited CHIKV infection in vitro. In addition, vesicular stomatitis virus vector particles and viral infections were also inhibited to the same extent, indicating a broad antiviral activity. Although the bioavailability of these compounds is rather poor, they might be used as a lead structure to develop more effective antiviral drugs or might be used topically to prevent CHIKV spread in the skin after mosquito bites.


ADAM and ADAMTS disintegrin and metalloproteinases as major factors and molecular targets in vascular malfunction and disease.
A Disintegrin and Metalloproteinase (ADAM) and A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) are two closely related families of proteolytic enzymes. ADAMs are largely membrane-bound enzymes that act as molecular scissors or sheddases of membrane-bound proteins, growth factors, cytokines, receptors and ligands, whereas ADAMTS are mainly secreted enzymes. ADAMs have a pro-domain, and a metalloproteinase, disintegrin, cysteine-rich and transmembrane domain. Similarly, ADAMTS family members have a pro-domain, and a metalloproteinase, disintegrin, and cysteine-rich domain, but instead of a transmembrane domain they have thrombospondin motifs. Most ADAMs and ADAMTS are activated by pro-protein convertases, and can be regulated by G-protein coupled receptor agonists, Ca2+ ionophores and protein kinase C. Activated ADAMs and ADAMTS participate in numerous vascular processes including angiogenesis, vascular smooth muscle cell proliferation and migration, vascular cell apoptosis, cell survival, tissue repair, and wound healing. ADAMs and ADAMTS also play a role in vascular malfunction and cardiovascular diseases such as hypertension, atherosclerosis, coronary artery disease, myocardial infarction, heart failure, peripheral artery disease, and vascular aneurysm. Decreased ADAMTS13 is involved in thrombotic thrombocytopenic purpura and microangiopathies. The activity of ADAMs and ADAMTS can be regulated by endogenous tissue inhibitors of metalloproteinases and other synthetic small molecule inhibitors. ADAMs and ADAMTS can be used as diagnostic biomarkers and molecular targets in cardiovascular disease, and modulators of ADAMs and ADAMTS activity may provide potential new approaches for the management of cardiovascular disorders.


Rabbit models to study atherosclerosis and its complications - Transgenic vascular protein expression in vivo.
Animal models of atherosclerosis often present limitations of transferability, since important hallmarks of human disease are not completely reproduced in other species. Rabbits have been used in several approaches: 1) inbred strains: Watanabe hereditary hyperlipidemic animals which express a defect in the LDL receptor, 2) transgenic rabbits, which overexpress human lipoproteins, and first knock-out rabbits. 3) native New Zealand white rabbits (NZW) fed with cholesterol-rich diet for at least 8 weeks represent the quickest way to establish arteriosclerosis. Rabbits are arguably the most sensitive animal species to cholesterol overload. Interventions in native or arteriosclerotic arteries are used to induce local thrombus formation, e.g. endothelial denudation or photochemical injury. In contrast to smaller animals, catheterisation of coronary arteries is feasible, whose external ligation serves to induce myocardial infarction. As biological endpoints, arterial vasoreactivity/endothelial dysfunction can be studied in analogy to measurements of brachial artery vasomotion in humans in response to increasing doses of acetylcholine or volume challenges. Tissue fixation allows studying vascular morphology, plaque sizes and thrombi after local interventions. Macrophage and T lymphocyte invasion can be investigated histologically. Positron emission tomography (PET/MRI) offers to measure plaques and content in vivo serially in the same animals. Local virally mediated gene transfer to atherosclerotic rabbit arteries has been established as a rapid and reproducible method to test interesting transgenes. Histological plaque features correspond well to alterations in patients (inflammation and lipid load). Thus, effects of any proteins can be studied directly in the arteriosclerotic disease background - much quicker than after germline transgenesis and cross-breeding.


Corrigendum: OIT3 serves as a novel biomarker of hepatocellular carcinoma by mediating ferroptosis via regulating the arachidonic acid metabolism.
[This corrects the article DOI: 10.3389/fonc.2022.977348.].


Extracts of Phellinus gilvus and Phellinus baumii inhibit pulmonary inflammation induced by lipopolysaccharide in rats.
Compared to saline-challenged rats, rats exposed to 50 microg intratracheal lipopolysaccharide showed an increase of total white cells (from 0.3 x 10(6) to 2.4 x 10(6)), neutrophils (from 0.09 x 10(6) to 1.8 x 10(6)), the levels of tumor necrosis factor (TNF)-alpha (from 200 pg ml(-1) to 1200 pg ml(-1)), and interleukin (IL)-1beta (from 220 pg ml(-1) to 650 pg ml(-1)) in the bronchial lavage fluid. However, after pretreatment with extracts of Phellinus gilvus and Phellinus baumii, the total white cells, neutrophils, and the level of IL-1beta in lipopolysaccharide-challenged rats were similar to those in saline-challenged rats, except for TNF-alpha. The results indicate that extracts of P. gilvus and P. baumii may be useful in preventing acute pulmonary inflammation in human diseases.


Brain structure and function in patients after metal-on-metal hip resurfacing.
Hip prostheses that use a metal-on-metal articulation expose the brain to elevated metal concentrations that, in acute excess due to prosthesis malfunction, is associated with neurologic damage, including visual and hearing loss and motor deficits. Here, we examined whether chronic exposure to lower elevated metal levels, typical of well-functioning prostheses, also affects brain structure and function. We compared brain volumes, metal deposition, and gray matter attenuation by MR imaging and clinical neurologic function in patients 8 years after receiving a metal-on-metal hip resurfacing versus a matched group of patients with the same duration exposure to a conventional hip prosthesis. Twenty-nine patients (25 men; mean, age 59±7 years) after metal-on-metal hip resurfacing and 29 patients (25 men; 59±8 years) after total hip arthroplasty were compared. Whole blood cobalt and chromium concentrations were 5-10 times higher in the metal-on-metal hip resurfacing group (P<.0001). Occipital cortex gray matter attenuation tended to be lower (P<.005 uncorrected, P>.05 corrected), and the optic chiasm area tended to be lower (mean difference, -2.7 mm2; P=.076) in the metal-on-metal hip resurfacing group. Subgroup analyses in 34 patients (17 per group), after exclusion of primary ocular pathology, showed the same trend in gray matter attenuation in the occipital cortex and basal ganglia and a smaller optic chiasm in the metal-on-metal hip resurfacing group (mean difference, -3.9 mm2; P=.048). No other structural or functional differences were found between the groups. Chronic exposure to metal-on-metal hip resurfacing is associated with subtle structural change in the visual pathways and the basal ganglia in asymptomatic patients.


Nitric oxide and angiotensin II receptors mediate the pressor effect of angiotensin II: a study in conscious and zoletil-anesthetized rats.
The circumventricular structures of the central nervous system and nitric oxide are involved in arterial blood pressure control, and general anesthesia may stimulate the central renin-angiotensin system. We therefore investigated the central role of angiotensin II and nitric oxide on the regulation of systemic arterial blood pressure in conscious and anesthetized rats. Rats with stainless steel cannulae implanted into their lateral ventricle were studied. We injected the AT1 and AT2 angiotensin II receptor antagonists, losartan and PD123319, L-NAME, 7-nitroindazole (nitric oxide synthetase inhibitors), and FK409 (nitric oxide donor agent) into the lateral ventricles. Mean arterial blood pressure (MAP) was recorded in conscious and zoletil-anesthetized rats. Mean +/- sem baseline MAP was 117.5 +/- 2 mm Hg. Angiotensin II injected into the brain lateral ventricle increased MAP from 136.5 +/- 2 mm Hg to 138.5 +/- 4 mm Hg (Delta16 +/- 3 mm Hg to Delta21 +/- 3 mm Hg) for all experimental groups versus control from 116 +/- 2 mm Hg to 120 +/- 3 mm Hg (Delta3 +/- 1 mm Hg to Delta5 +/- 2 mm Hg) (P < 0.05). L-NAME or 7-nitroindazole enhanced the angiotensin II pressor effect (P < 0.05). Prior injection of losartan and PD123319 decreased the angiotensin II pressor effect and the enhancement effect of L-NAME and 7-nitroindazole (P < 0.05). Zoletil anesthesia did not interfere with the effects of angiotensin II, AT1, AT2 antagonists, or nitric oxide synthetase inhibitors. Endogenous nitric oxide functions tonically as a central inhibitory modulator of the angiotensinergic system. AT1 and AT2 receptors influence the angiotensin II central control of arterial blood pressure. Zoletil anesthesia did not interfere with these effects.


Oncolysis of multifocal hepatocellular carcinoma in the rat liver by hepatic artery infusion of vesicular stomatitis virus.
Hepatocellular carcinoma (HCC) is a lethal malignancy with poor prognosis and few effective treatments, as well as ever-increasing frequencies in the Western world. Viruses that replicate selectively in cancer cells hold considerable promise as novel therapeutic agents for the treatment of malignancy. Vesicular stomatitis virus (VSV) is a negative-strand RNA virus with intrinsic oncolytic specificity due to significantly attenuated antiviral responses in many tumor cells. The aim of this study was to evaluate the potential of VSV, administered via the hepatic artery, as an effective and safe therapeutic agent for treating "multifocal" HCC in the rat liver. Recombinant VSV vector expressing beta-galactosidase (rVSV-beta-gal) was generated by reverse genetics and infused into the hepatic artery of Buffalo rats bearing orthotopically implanted multifocal HCC. Access by the virus to multifocal HCC lesions in the liver, as well as the kinetic profiles of intratumoral viral replication and spread, was established by X-gal staining of liver and tumor sections. Plaque assays were also performed to determine the infectious viral yields in tumor and normal liver tissues. Pharmacotoxicology studies, including serum chemistries and proinflammatory cytokine production, as well as organ histopathology, were performed. Buffer- or vector-treated tumor-bearing rats were followed for survival and the results were analyzed by the Kaplan-Meier method and the log-rank test. Hepatic arterial infusion of rVSV-beta-gal at the maximum tolerated dose in tumor-bearing rats resulted in efficient viral transduction of multifocal HCC lesions in their livers, tumor-selective viral replication, and extensive oncolysis. Importantly, no significant vector-associated toxicities were noted and, in particular, no damage to the hepatic parenchyma was seen. Finally, survival of vector-treated rats was substantially prolonged over that of animals in the control treatment group (p < 0.028). Thus, hepatic arterial administration of VSV is both effective and safe in an orthotopic animal model of multifocal HCC. The results suggest that oncolytic VSV can be developed into an effective and safe therapeutic modality for patients with multifocal HCC in the future.


Stathmin expression alters the antiproliferative effect of eribulin in leiomyosarcoma cells.
Uterine leiomyosarcoma is an aggressive soft tissue tumor. Stathmin, a phosphoprotein that modulates microtubule dynamics, is highly expressed in many malignancies including leiomyosarcoma. The microtubule-depolymerizing agent eribulin has been recently approved for treating malignant soft tissue tumors. Although eribulin inhibits microtubule polymerization, little is known about the relationship between eribulin treatment and stathmin dynamics. In this study, we explored the role of stathmin expression in the action of eribulin in leiomyosarcoma cells. Eribulin induced phosphorylation of stathmin and reduced expression of subunits A and C of protein phosphatase 2A (PP2A) in a leiomyosarcoma cell line. The PP2A activator FTY720 reduced levels of phosphorylated stathmin. Eribulin decreased stathmin protein levels without affecting stathmin mRNA expression. Furthermore, stathmin knockdown attenuated the inhibitory effects of eribulin on cell viability, whereas stathmin overexpression enhanced the anti-proliferative effect of eribulin. Eribulin-resistant leiomyosarcoma cell lines had enhanced expression of the class Ⅰ β-tubulin TUBB1, multi-drug resistance 1 protein MDR1 and breast cancer-resistance protein BCRP, and decreased expression of stathmin. Taken together, these results suggest that stathmin expression modulates the pharmacological efficacy of eribulin in uterine leiomyosarcoma cells.


Evaluation of the effects of a preparation containing asiaticoside on periocular wrinkles of human volunteers.
Skin ageing is accompanied by wrinkle formation. In particular, periorbital wrinkle formation is a relatively early sign of skin ageing. We evaluated the effects of a preparation containing asiaticoside on the periorbital wrinkles of a group of volunteers. The effectiveness of the active compound, asiaticoside, in a base-cream preparation for the treatment of temporal periorbital wrinkles was tested on 27 female volunteers as follows: the women applied the cream twice a day to the region of interest for 12 weeks. Same women also applied a vehicle control cream to the periorbital skin around the other eye. Negative replicas were taken of the periorbital skin before treatment and 4, 8, and 12 weeks after application of the cream. The results were evaluated by semi-automated morphometry of the plastic replicas. After 12 weeks of treatment, there was a significant improvement of the periorbital wrinkles in majority of the volunteers who tested the cream. Of the 27 women examined with periocular wrinkles, 65% showed an improvement at the end of the treatment. In three cases, the improvement was 100% (disappearance of the crow's feet), 75% +/- 1.97 and 79% +/- 2.82. On six eyes, there was no significant change after the treatment. With 12 weeks of treatment with the asiaticoside-containing cream, most of the periorbital wrinkles were attenuated to some degree, and some women experienced a significant improvement of the periorbital wrinkles on one of their eyes.


The recognition by monoclonal antibodies of various portions of a major antigenic site of human growth hormone.
The reactivities of five mouse monoclonal antibodies against human growth hormone (hGH) were defined by either a competitive radioimmunoassay with insolubilized antibodies or by an agglutination-inhibition method with hGH-coated polystyrene particles. The five antibodies reacted significantly but to various degrees with human placental lactogen and at least three antibodies reacted with human prolactin and three synthetic peptides extending from residues 19 to 128, 73 to 128 and 98 and 128 of hGH. Four tested monoclonal antibodies failed to react with bovine growth hormone and with hGH oxidized by performic acid. The antibodies were further distinguished by their different reactions with hGH modified by reduction and alkylation or by adsorption on a polystyrene surface. The unique specificity of each antibody was confirmed for most of them by an agglutination method in which the agglutinating activity of hGH was tested on latex particles coated with various paired combinations of the monoclonal antibodies. The lack of agglutination with certain combinations suggested that the specificities of such a pair of antibodies overlapped each other. These results suggest that the sequences corresponding to the synthetic peptides participate in the structure of a major antigenic site of which various portions are recognized by the monoclonal antibodies.


Gastric fluid volume and pH in elective inpatients. Part II: Coffee or orange juice with ranitidine.
In order to assess the effect of preoperative oral fluids, with and without ranitidine, on gastric fluid volume and pH 300 elective surgical inpatients, ASA physical status I and II, were randomly allocated to one of six groups. The three ranitidine groups (Groups 4, 5, and 6) are discussed in this paper (Part II), and the three placebo groups (Groups 1, 2, and 3) in Part I. Between two and three hours before the scheduled time of surgery, patients received 150 ml coffee with oral ranitidine 150 mg (Group 4), 150 ml orange juice with oral ranitidine 150 mg (Group 5), or oral ranitidine alone (Group 6). No opiate or belladonna premedication was given. Immediately following induction of anaesthesia a # 18 Salem sump tube was passed and its position in the stomach confirmed by auscultation of insufflated air. The volume of residual gastric fluid, which was aspirated into a 60 ml syringe, was recorded, and its pH was measured. There were no statistically significant differences between groups with respect to volume (Group 4: 14.3 +/- 15.4; Group 5: 14.8 +/- 17.0; Group 6: 9.7 +/- 12.6 ml). The mean pH in all groups was greater than 5.40 (Group 4: 5.65 +/- 2.12; Group 5: 5.41 +/- 2.12; Group 6: 6.21 +/- 1.51).


Modeling adult COX-2 cerebrospinal fluid pharmacokinetics to inform pediatric investigation.
Hysteresis is reported between plasma concentration and analgesic effect from nonsteroidal anti-inflammatory drugs. It is possible that the temporal delay between plasma and CSF nonsteroidal anti-inflammatory drugs mirrors this hysteresis. The temporal relationship between plasma and CSF concentrations of COX-inhibitors (celecoxib, rofecoxib, valdecoxib) has been described. The purpose of this secondary data analysis was to develop a compartmental model for plasma and CSF disposition of these COX-2 inhibitors. Plasma and CSF concentration-time profiles and protein binding data in 10 adult volunteers given oral celecoxib 200 mg, valdecoxib 40 mg and rofecoxib 50 mg were available for study. Nonlinear mixed effects models with a single plasma compartment were used to link a single CSF compartment with a transfer factor and an equilibration rate constant (Keq). To enable predictive modeling in pediatrics, celecoxib pharmacokinetics were standardized using allometry. Movement of all three unbound plasma COX-2 drugs into CSF was characterized by a common equilibration half-time (T1/2 keq) of 0.84 h. Influx was faster than efflux and a transfer scaling factor of 2.01 was required to describe conditions at steady-state. Estimated celecoxib clearance was 49 (95% CI 34-80) L/h/70 kg and the volume of distribution was 346 (95% CI 237-468) L/70 kg. The celecoxib absorption half-time was 0.35 h with a lag time of 0.62 h. Simulations predicted a 70-kg adult given oral celecoxib 200 mg with maintenance 100 mg twice daily would have a mean steady-state total (bound and unbound) plasma concentration of 174 μg L-1 and CSF concentration of 1.1 μg L-1 . A child (e.g., 25 kg, typically 7 years) given oral celecoxib 6 mg kg-1 with maintenance of 3 mg kg-1 twice daily would have 282 and 1.7 μg L-1 mean plasma and CSF concentrations, respectively. Transfer of unbound COX-2 inhibitors from plasma to CSF compartment can be described with a delayed effect model using an equilibration rate constant to collapse observed hysteresis. An additional transfer factor was required to account for passage across the blood-brain barrier. Use of a target concentration strategy for dose and consequent plasma (total and unbound) and CSF concentration prediction could be used to inform pediatric clinical studies.


D-Stellate Neurons of the Ventral Cochlear Nucleus Decrease in Auditory Nerve-Evoked Activity during Age-Related Hearing Loss.
Age-related hearing loss (ARHL) is associated with weakened inhibition in the central auditory nervous system including the cochlear nucleus. One of the main inhibitory neurons of the cochlear nucleus is the D-stellate neuron, which provides extensive glycinergic inhibition within the local neural network. It remains unclear how physiological activities of D-stellate neurons change during ARHL and what are the underlying mechanisms. Using in vitro whole-cell patch clamp technique, we studied the intrinsic membrane properties of D-stellate neurons, the changes of their firing properties, and the underlying mechanisms in CBA/CaJ mice at the ages of 3-4 months (young), 17-19 months (middle age), and 27-33 months (aged). We found that the intrinsic membrane properties of D-stellate neurons were unchanged among these three age groups. However, these neurons showed decreased firing rate with age in response to sustained auditory nerve stimulation. Further investigation showed that auditory nerve-evoked excitatory postsynaptic currents (EPSCs) were significantly reduced in strength with age. These findings suggest that D-stellate neurons receive weakened synaptic inputs from the auditory nerve and decreased sound driven activity with age, which are expected to reduce the overall inhibition and enhance the central gain in the cochlear nucleus during ARHL.


Mycobacterium kansasii and human immunodeficiency virus co-infection in London.
although Mycobacterium kansasii infection has long been endemic in the U.K., the disease burden and characteristics of infection in the HIV-seropositive population has not been well documented. This study addresses these issues in an inner city population that comprises a quarter of all cases of acquired immunodeficiency syndrome (AIDS) reported in the U.K. retrospective review of case notes from two inner London specialist HIV Units. twenty-nine cases of M. kansasii infection were identified, with case notes available for review in 26. Ten had pulmonary disease and nine had disseminated infection: a further seven patients appeared simply to be colonized (two respiratory and five gastrointestinal): M. kansasii was isolated from stool in over a third (nine of 26) of cases. Disseminated M. kansasii infection occurred in 0.44% of AIDS cases seen in our two units and all isolates were resistant to isoniazid ion vitro. A clinical response achieved in 11 of the 13 patients with M. kansasii-related disease who received anti-mycobacterial therapy. All four patients who relapsed following initial clinical response to therapy had received sub-optimal treatment. the incidence of disseminated M. kansasii infection in HIV-infected individuals in the U.K. is similar to that seen in those from high prevalence regions of the U.S.A., and anti-mycobacterial therapy leads to a clinical response in the majority of patients with HIV and M. kansasii co-infection. The frequent isolation of M. kansasii from the stool suggests that the gastrointestinal tract may be a significant source of disseminated infection.


[A new oculo-dento-cutaneous syndrome (author's transl)].
A report is given about an 11-year-old girl with multiple anomalies - specially concerning the eye, followed by a comparison with other similar syndromes as presented in literature.


Pertubation of beta1 integrin function using anti-sense or function-blocking antibodies on corneal cells grown on fibronectin and tenascin.
During corneal development, neural crest derivatives from the periocular mesenchyme migrate into the cornea and differentiate into corneal fibroblasts. During this time, these cells interact with a variety of extracellular matrices for proper orientation and development. In the present studies, we have examined the interaction of beta(1) integrins on periocular mesenchyme cells (POM) and corneal fibroblasts (CF) with fibronectin and tenascin by perturbing the function of this integrin. POM and CF attached and spread to a much greater extent on fibronectin than on tenascin. An antibody against beta(1) integrin, CSAT, decreased spreading and attachment, and resulted in a lack of immuno-detectable beta(1) integrin in focal adhesions on fibronectin; few beta(1) positive focal adhesions were observed in cells grown on tenascin. An anti-sense retroviral construct decreased endogenous levels of beta(1) integrin protein, and caused decreased attachment and spreading as well as sparse, disorganized focal adhesions. These data indicate that in vitro, both POM and CF have beta(1) integrins that interact with fibronectin and allow them to attach and spread, while tenascin is anti-adhesive. Further studies using both of these experimental paradigms will clarify whether these interactions also occur in vivo.


The selective 5-HT6 receptor antagonists SB-271046 and SB-399885 potentiate NCAM PSA immunolabeling of dentate granule cells, but not neurogenesis, in the hippocampal formation of mature Wistar rats.
While there is now substantial evidence that 5-HT(6) antagonism leads to significantly improved cognitive ability, the mechanism(s) and/or pathway(s) involved are poorly understood. We have evaluated the consequence of chronic administration of the 5-HT(6) receptor antagonists SB-271046 and SB-399885 on neural cell adhesion molecule polysialylation state (NCAM PSA), a neuroplastic mechanism necessary for memory consolidation. Quantitative analysis of NCAM PSA immunopositive neurons in the dentate gyrus of drug-treated animals revealed a dose-dependent increase in polysialylated cell frequency following treatment with both SB-271046 and SB-399885. These effects could not be attributed to increased neurogenesis, as no difference in the rate of bromodeoxyuridine incorporation was apparent between the control and drug-treated groups. A substantial increase in the frequency of polysialylated cells in layer II of the entorhinal and perirhinal cortices was also observed, brain regions not previously associated with neurogenesis. Chronic treatment with SB-271046 or SB-399885 also significantly increased the activation of dentate polysialylation that is specific to learning. This effect does not occur with other cognition-enhancing drugs, such as tacrine, and this action potentially differentiates 5-HT(6) receptor antagonism as an unique neuroplastic mechanism for cognitive processes which may slow or reverse age/neurodegenerative related memory deficits.


On the strong field dependence and nonlinear response to gadolinium contrast agent of proton transverse relaxation rates in dairy cream.
Dairy cream, as a suspension of lipid droplets in water, is a potentially useful magnetic resonance imaging (MRI) phantom material and an interesting material for studying fundamental relaxation mechanisms. Here we report a strong increase in the transverse relaxation rates with field strength for both the water and lipid protons in dairy cream. Also, studies at 4.7 T reveal a nonlinear response of transverse relaxation rates with increasing concentration of a common gadolinium (Gd)-based contrast agent, including an initial decrease of water relaxation rates as measured with Hahn spin echoes at the lower Gd concentrations. The results are treated within the framework of a model in which the magnetic susceptibility difference between the lipid droplets and the aqueous phase plays the prominent role for transverse relaxation. Second-order polynomial fits of the water proton transverse relaxation rate dependence on field strength and on Gd concentration at 4.7 T provided experimental parameters from which model parameters are extracted and compared with expectations available from the literature.


Antidepressant-like activity of liposomal formulation containing nimodipine treatment in the tail suspension test, forced swim test and MAOB activity in mice.
Previous studies have shown that intracellular calcium ion dysfunction may be an etiological factor in affective illness. Nimodipine (NMD) is a Ca(2+) channel blocker that has been extensively investigated for therapy of central nervous system (CNS) disorders. In this work, we have evaluated the antidepressant-like activity of nimodipine encapsulated into liposomes (NMD-Lipo) in mice through tail suspension and forced swim assays, as well as MAOB activity. During the tail suspension test, the administration of NMD-Lipo at 0.1, 1 and 10mg/kg was able to promote a reduction in the immobility time of animals greater than the positive control (imipramine). In the forced swim test, the immobility time of mice treated with NMD-Lipo was reduced. This reduction was significantly greater than that found in the animals treated with imipramine and paroxetine. This may suggest that NMD-Lipo provides more antidepressant-like activity than in positive controls. The groups that received a combination of liposomal NMD and antidepressant drugs showed lower immobility time than the groups, which were treated only with imipramine or paroxetine. The mice treated with the combination of NMD-Lipo and reserpine presented an increase in the time of immobility compared with animals treated only with NMD-Lipo. There was a significant decrease in MAOB activity in animals treated with NMD-Lipo compared with untreated animals. The results of the tail suspension test, forced swim test and MAOB activity suggested that the antidepressant activity of NMD-Lipo may be related to an increase in the cerebral monoamine concentrations.


Characterization of cell-fate decision landscapes by estimating transcription factor dynamics.
Time-specific modulation of gene expression during differentiation by transcription factors promotes cell diversity. However, estimating their dynamic regulatory activity at the single-cell level and in a high-throughput manner remains challenging. We present FateCompass, an integrative approach that utilizes single-cell transcriptomics data to identify lineage-specific transcription factors throughout differentiation. By combining a probabilistic framework with RNA velocities or differentiation potential, we estimate transition probabilities, while a linear model of gene regulation is employed to compute transcription factor activities. Considering dynamic changes and correlations of expression and activities, FateCompass identifies lineage-specific regulators. Our validation using in silico data and application to pancreatic endocrine cell differentiation datasets highlight both known and potentially novel lineage-specific regulators. Notably, we uncovered undescribed transcription factors of an enterochromaffin-like population during in vitro differentiation toward ß-like cells. FateCompass provides a valuable framework for hypothesis generation, advancing our understanding of the gene regulatory networks driving cell-fate decisions.


From the ICU to the ward: cross-checking of the physician's transfer report by intensive care nurses.
To assess whether cross-checking of the physician ICU transfer report by ICU nurses may reduce transfer report errors. Prospective, observational study with random selection (according to patient registration code) of ICU transfer reports. Eight-bed multidisciplinary intensive care unit of a teaching hospital. ICU transfer reports of 123 patients were randomly selected at discharge from the ICU between November 2006 and February 2007. Physician ICU transfer reports were cross-checked by nurses using defined review criteria. Inter-rater agreement (between nurses and the head of ICU) was assessed by kappa-values, and was excellent overall (0.9). All intercepted errors (100%) were consequently corrected by the interns. Out of 123 transfer reports, 76 (62%) were affected by at least one error. Among 305 intercepted errors, 247 were prescription errors (26% of all prescriptions), 45 involved proposed procedures, and 13 were deficient in updating diagnoses. Most of the errors (248/305, 81%) were classified as simple, 43 (14%) as serious, or 14 (5%) as critical. Thirty-five (28%) transfer reports were considered potentially harmful (i.e., affected by at least one critical/serious error). In a multivariate model, only the number of medications included in the transfer report was associated with the occurrence of at least one critical/serious error. Errors in ICU transfer reports are frequent and may be potentially harmful. ICU nurses may help to effectively and accurately intercept those inaccuracies, and therefore reduce the exportation of errors from the ICU to the ward.


Evidence of normal hearing laterality in familial schizophrenic patients and their relatives.
Dichotic listening (DL) has been used as a tool to investigate possible left cerebral dysfunction in schizophrenia. However, the wide range of DL tests (e.g., words, emotions, sentences) as well as patient groups ("heterogeneity") has introduced several confounders. Assessing relatives of patients with schizophrenia may overcome some of these problems, and may be more useful in determining if loss of functional cerebral laterality in schizophrenia is a state or a trait phenomenon. The fused consonant-vowel DL test was administered to 114 subjects: 20 individuals with familial schizophrenia, 42 of their healthy relatives, and 52 healthy volunteers. We did this to investigate whether the normal language processing asymmetry-a right ear advantage (REA)-is present, and whether it could serve as a marker for genetic liability. General performance accuracy level was lower in schizophrenia patients and their relatives but the expected REA was present in all groups. Adjusting for age, accuracy, and obligate status made no difference. In conclusion, familial schizophrenic patients and their relatives have normal REA and hearing laterality on the fused DL test.


A sublethal dose of neonicotinoid imidacloprid precisely sensed and detoxified by a C-minus odorant-binding protein 17 highly expressed in the legs of Apis cerana.
As a native honeybee species in East Asia, Apis cerana is essential for the stability of local agricultural and plant ecosystems by its' olfactory system for searching nectar and pollen sources. Odorant-binding proteins (OBPs) existing in the insect's olfactory system can recognize environmental semiochemicals. It was known that sublethal doses of neonicotinoid insecticides could still cause a variety of physiological and behavioral abnormalities in bees. However, the molecular mechanism of A. cerana sensing and response for insecticide has not been further investigated. In this study, we found an A. cerana OBP17 gene significantly up-regulated expressed after exposure to sublethal doses of imidacloprid based on the transcriptomics results. The spatiotemporal expression profiles showed that OBP17 was highly expressed in the legs. Competitive fluorescence binding assays showed that OBP17 had the special and high binding affinity to imidacloprid among the 24 candidate semiochemicals, and the KA value of OBP17 binding with imidacloprid reached the maximum (6.94 × 104 L/mol) at low-temperature. Thermodynamic analysis showed that the quenching mechanism changed from dynamic to static binding interaction with the increasing temperature. Meanwhile, the force changed from hydrogen bond and van der Waals force to hydrophobic interaction and electrostatic force, indicating the interaction exhibits variability and flexibility. Molecular docking showed that Phe107 contributed the most energy. RNA interference (RNAi) results showed that OBP17 knockdown significantly enhanced the electrophysiological response of the bees' forelegs to imidacloprid. Our study indicated that OBP17 could precisely touch and sense sublethal doses of neonicotinoid imidacloprid in the natural environment through its high expression in legs, and the upregulation expression of OBP17 exposure to imidacloprid probably implied that it participate in the detoxification processes of A. cerana. Also, our research enriches the theoretical knowledge of the sensing and detoxifying activities of non-target insects' olfactory sensory system to environmental sublethal doses of systemic insecticides.