Persistent Detwinning of Iron-Pnictide EuFe_{2}As_{2} Crystals by Small External Magnetic Fields.

Our comprehensive study on EuFe_{2}As_{2} reveals a dramatic reduction of magnetic detwinning fields compared to other AFe_{2}As_{2} (A=Ba, Sr, Ca) iron pnictides by indirect magnetoelastic coupling of the Eu^{2+} ions. We find that only ∼0.1 T are sufficient for persistent detwinning below the local Eu^{2+} ordering; above T_{Eu}=19 K, higher fields are necessary. Even after the field is switched off, a significant imbalance of twin domains remains constant up to the structural and electronic phase transition (190 K). This persistent detwinning provides the unique possibility to study the low temperature electronic in-plane anisotropy of iron pnictides without applying any symmetry-breaking external force.

The effect of surgically assisted rapid maxillary expansion on sleep architecture: an exploratory risk study in healthy young adults.

Maxillary transverse deficiencies (MTD) cause malocclusions. Rapid maxillary expansion treatment is commonly used treatment for correcting such deficiencies and has been found to be effective in improving respiration and sleep architecture in children with obstructive sleep apnoea (OSA). However, thus far, the effect of surgically assisted rapid maxillary expansion (SARME) treatment on sleep architecture and breathing of normal subjects has not been assessed. We hypothesised that sleep quality will improve after maxillary expansion treatment. The objective of this study is to access the effect of maxillary expansion treatment on sleep structure and respiratory functions in healthy young adults with severe MTD. This is a prospective and exploratory clinical study. Twenty-eight consecutive young adult patients (15 males and 13 females, mean age 20·6 ± 5·8 years) presenting with severe MTD at the orthodontic examination were recruited into the study. All the participants underwent a standardised SARME procedure (mean expansion 6·5 ± 1·8 and 8·2 ± 1·8 mm, intercanine and intermolar distance, respectively) to correct malocclusion caused by MTD. An overnight in-laboratory polysomnography, before and after the treatment, was performed. The mean follow-up time was 9 months. The main outcome parameters were the changes in sleep architecture, including sleep stages, arousals, slow-wave activity (SWA) and respiratory variables. Before surgery, young adult patients with MTD presented no evidence of sleep breathing problems. At baseline sleep recording, 7 of 28 (25%) had apnoea-hypopnoea index (AHI) ≥ 5 events per hour. No negative effect of the SARME was observed in questionnaires or sleep laboratory parameters. In the patients with a higher baseline AHI (AHI ≥ 5 h of sleep), we observed a reduction in AHI after surgical treatment (P = 0·028). SARME did not have a negative effect on any sleep or respiration parameters in healthy young individuals with MTD. It normalised the breathing index in the patients with a mild AHI index.

Ultrafast strain propagation and acoustic resonances in nanoscale bilayer systems.

Ultrafast structural probing has greatly enhanced our understanding of the coupling of atomic motion to electronic and phononic degrees-of-freedom in quasi-bulk materials. In bi- and multilayer model systems, additionally, spatially inhomogeneous relaxation channels are accessible, often governed by pronounced interfacial couplings and local excitations in confined geometries. Here, we systematically explore the key dependencies of the low-frequency acoustic phonon spectrum in an elastically mismatched metal/semiconductor bilayer system optically excited by femtosecond laser pulses. We track the spatiotemporal strain wave propagation in the heterostructure employing a discrete numerical linear chain simulation and access acoustic wave reflections and interfacial couplings with a phonon mode description based on a continuum mechanics model. Due to the interplay of elastic properties and mass densities of the two materials, acoustic resonance frequencies of the heterostructure significantly differ from breathing modes in monolayer films. For large acoustic mismatch, the spatial localization of phonon eigenmodes is derived from analytical approximations and can be interpreted as harmonic oscillations in decoupled mechanical resonators.

Allogeneic human umbilical cord-derived mesenchymal stem/stromal cells for chronic obstructive pulmonary disease (COPD): study protocol for a matched case-control, phase I/II trial.

INTRODUCTION: The global prevalence of chronic obstructive pulmonary disease (COPD) is increasing, and it has become a major public health burden worldwide, including in Vietnam. A large body of preclinical and clinical studies supports the safety of mesenchymal stem/stromal cells (MSCs) in the treatment of lung injury, including COPD. The aim of this trial is to investigate the safety and potential therapeutic efficacy of allogeneic administration of umbilical cord-derived MSCs (UC-MSCs) as a supplementary intervention in combination with standard COPD medication treatments in patients with moderate-to-severe COPD based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2019 and Vietnam Ministry of Health's guidelines. METHODS AND ANALYSIS: This matched case-control phase I/II trial is conducted at Vinmec Times City International Hospital, Hanoi, Vietnam between June 2020 and December 2021. In this study, 40 patients will be enrolled and assigned into two age-matched, gender-matched and COPD condition-matched groups, including a UC-MSC group and a control group. Both groups will receive standard COPD medication treatment based on the GOLD 2019 guidelines and the Vietnam Ministry of Health protocol. The UC-MSC group will receive two doses of thawed UC-MSC product with an intervention interval of 3 months. The primary outcome measures will include the incidence of prespecified administration-associated adverse events and serious adverse events. The efficacy will be evaluated based on the absolute changes in the number of admissions, arterial blood gas analysis, lung function and lung fibrosis via CT scan and chest X-ray. The clinical evaluation will be conducted at baseline and 3, 6 and 12 months postintervention. ETHICS AND DISSEMINATION: Ethical approval was secured from the Ethical Committee of Vinmec International Hospital (number:166/2019/QD-VMEC) and Vietnam Ministry of Health (number:2002/QD-BYT). The results will be reported to trial collaborators, publication in peer-reviewed academic journals. TRIAL REGISTRATION NUMBER: NCT04433104.

[Acral circumscribed hypokeratosis of plantar and dorsum of the finger localization: two cases]. / Hypokératose acrale circonscrite : forme plantaire et forme du dos du doigt (deux cas).

INTRODUCTION: Palmar or plantar circumscribed hypokeratosis is a remarkable clinicopathologic entity described in 2002. It consists in a well demarcated decrease in thickness of the stratum corneum, that can be clinically mistaken for Bowen's disease or porokeratosis. We present a classical plantar localisation and a more original case on the dorsum of the finger, together with a microscopic and immunohistochemical study. CASE REPORTS: Case 1. A 65-year-old man was seen 15 years after a first consultation for a well demarcated 1.5cm erythematous lesion localised on the border of his left foot. The biopsy, then misinterepreted as keratosis sulcata, was reviewed. It showed a sudden and well demarcated decrease in thickness of the stratum corneum, overlying a slightly acanthotic epidermis, associated with dilated capillaries in the papillary dermis. HPV immunostaining was negative. Case 2. A 75-year-old woman had a well demarcaated erythematous lesion of the dorsum of her right index finger, lasting for months without significant evolution. A first biopsy showed pale and haloed keratinocytes that could be interpreted as koilocytes. She was therefore treated by cryotherapy, 5-fluro-uracile and imiquimod, that proved unsuccessful. A second biopsy showed a sudden and major decrease in thickness of the stratum corneum, overlying an area containing a few pale keratinocytes with perinuclear halo. HPV immunostaing was negative and Ki67 positive cells were slightly decreased in number when compared to lateral normal skin. DISCUSSION: Our first case is typical of plantar hypokeratosis characterised by its long evolution, typical semiology and well demarcated anomaly of the stratum corneum. Our second case is original as it shows that the disease can also affect the dorsum of the fingers. Acral circumscribed hypokeratosis is therefore a better name for this condition. We did not find any arguments in favor of a viral cause or an increased proliferation of keratinocytes. As often described in other cases, the lesion can remain unchanged for decades, which confirm its benign evolution. Topical treatments are generally ineffective. The pathogenesis of this localised hypokeratosis remains mysterious.

Activity of 6-methyl-8-substituted ergolines against the 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma.

The ability of a series of 8-beta-carboxamido ergolines, 8-formamido ergolines, and 8-methyl ergolines to cause regressions of established dimethylbenz[a]anthracene-induced mammary carcinomas was compared to some ergot alkaloids. Although most of the ergoline derivatives depressed serum prolactin concentrations in rats, only a few had pronounced effects against the dimethylbenz[a]anthracene-induced mammary carcinoma in rats. Some derivatives from each of the three groups of substituted ergolines gave comparable activities against the dimethylbenz[a]anthracene-induced mammary carcinoma.

Synthesis and biological activity of 8-arylergolines.

9,10-Didehydro-6-methyl-8beta-arylergolines 2, in which the carboxyl group of lysergic acid and isolysergic acid is replaced by various aryl groups, were prepared in two steps by alkylation of aromatic substrates with the tetracyclic allylic alcohol 3, followed by aromatization with MnO2. The new ergolines 2 have modest prolactin-inhibiting and rat antimuricidal activities and possess significant alpha-blocking and antiserotonin properties.

Conversion of ergolines to hexahydro- and octahydrobenzo[f]quinolines (depyrroloergolines).

A general method has been developed for removal of the pyrrole ring from the ergolines. Oxidation of various ergolines at the 2,3 double bond gave formamido ketones 10, which afforded the amino ketones 11. These were deaminated to give the ketones 12, from which the carbonyl group was removed by reduction. The resulting depyrroloergolines (9) have, in contrast to the ergolines, little or no dopamine agonist activity in two tests.

Bicyclic and tricyclic ergoline partial structures. Rigid 3-(2-aminoethyl)pyrroles and 3- and 4-(2-aminoethyl)pyrazoles as dopamine agonists.

It is proposed, based upon comparisons with apomorphine, that the rigid pyrroleethylamine moiety of the ergolines is the portion of the molecule responsible for dopamine agonist activity. In support of this hypothesis, bicyclic and tricyclic ergoline partial structures 6, 11, 25, and 35 have been synthesized. In addition, some pyrazole isosters (37, 38, 40, and 45) of these rigid pyrroleethylamines have been made. All of the classes show dopaminergic activity in prolactin inhibition and in lesioned rat turning assays. The most potent drugs, the linear tricyclic pyrazoles 38 (R = Pr) and 40 (R = Pr), are comparable in potency with the highly active ergoline pergolide (41).

Synthetic and structure/activity studies on acid-substituted 2-arylphenols: discovery of 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5- hydroxyphenoxy]-propoxy]phenoxy]benzoic acid, a high-affinity leukotriene B4 receptor antagonist.

Structural derivatives of LY255283 have been studied as receptor antagonists of leukotriene B4. Substitution of the 2-hydroxyacetophenone subunit of 1 (LY255283) with a 2-arylphenol group provided entry into several new series that feature various mono- and diacidic core functionality. These new analogues, the subject of a broad structure-activity investigation, displayed significantly increased in vitro and in vivo activity as receptor antagonists of LTB4. A series of diaryl ether carboxylic acids demonstrated especially interesting activity and led to the discovery of compound 43b, 2-[2-propyl-3-[3-[2-ethyl-4-(4- fluorophenyl)-5-hydroxyphenoxy]-propoxy]phenoxy]benzoic acid (LY293111), a 2-arylphenol-substituted diaryl ether carboxylic acid which displayed potent binding to human neutrophils (IC50 = 17 +/- 4.6 nM) and guinea pig lung membranes (IC50 = 6.6 +/- 0.71 nM), inhibition of LTB4-induced expression of the CD11b/CD18 receptor on human neutrophils (IC50 = 3.3 +/- 0.81 nM), and inhibition of LTB4-induced contraction of guinea pig lung parenchyma (pKB = 8.7 +/- 0.16). In vivo, 43b demonstrated potent activity in inhibiting LTB4-induced airway obstruction in the guinea pig when dosed by the oral (ED50 = 0.40 mg/kg) or intravenous (ED50 = 0.014 mg/kg) routes. A specific LTB4 receptor antagonist, 43b had little effect on inhibiting contractions of guinea pig lung parenchyma induced by leukotriene D4 (LTD4), histamine, carbachol, or U46619. Compound 43b has been chosen as a clinical candidate and is currently in phase I studies for a variety of inflammatory diseases.

Indole inhibitors of human nonpancreatic secretory phospholipase A2. 1. Indole-3-acetamides.

Phospholipases (PLAs) produce rate-limiting precursors in the biosynthesis of various types of biologically active lipids involved in inflammatory processes. Increased levels of human nonpancreatic secretory phospholipase A2 (hnps-PLA2) have been detected in several pathological conditions. An inhibitor of this enzyme could have therapeutic utility. A broad screening program was carried out to identify chemical structures which could inhibit hnps-PLA2. One of the lead compounds generated by the screening program was 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid (13a). We describe the syntheses, structure--activity relationships, and pharmacological activities of a series of indole-3-acetamides and related compounds derived from this lead. This SAR was undertaken with the aid of X-ray crystal structures of complexes between the inhibitors and hnps-PLA2 which were of great value in directing the SAR.

Indole inhibitors of human nonpancreatic secretory phospholipase A2. 2. Indole-3-acetamides with additional functionality.

As reported in our previous paper, a series of indole-3-acetamides which possessed potency and selectivity as inhibitors of human nonpancreatic secretory phospholipase A2(hnps-PLA2) was developed. The design of these compounds was based on information derived from x-ray crystal structures determined for complexes between the enzyme and its inhibitors. We describe here the further implementation of this structure-based design strategy and continued SAR development to produce indole-3-acetamides with additional functionalities which provide increased interaction with important residues within the enzyme active site. These efforts led to inhibitors with substantially enhanced potency and selectivity.

Indole inhibitors of human nonpancreatic secretory phospholipase A2. 3. Indole-3-glyoxamides.

The preceding papers of this series detail the development of functionalized indole-3-acetamides as inhibitors of hnps-PLA2. We describe here the extension of the structure-activity relationship to include a series of indole-3-glyoxamide derivatives. Functionalized indole-3-glyoxamides with an acidic substituent appended to the 4- or 5-position of the indole ring were prepared and tested as inhibitors of hnps-PLA2. It was found that the indole-3-glyoxamides with a 4-oxyacetic acid substituent had optimal inhibitory activity. These inhibitors exhibited an improvement in potency over the best of the indole-3-acetamides, and LY315920 (6m) was selected for evaluation clinically as an hnps-PLA2 inhibitor.

Transgenic model for the discovery of novel human secretory non-pancreatic phospholipase A2 inhibitors.

Transgenic mice were created which overexpress human secretory non-pancreatic phospholipase A2 (sPLA2) pansomatically as a potential disease and drug-testing model. The mice were produced using a DNA construct in which the inducible mouse metallothionein gene promoter drives expression of a human sPLA2 minigene. High levels of sPLA2 were detected in several tissues by immunofluorescence localization. Expression in the testes caused hypospermia and male infertility. Circulating catalytically active sPLA2 could be induced to levels observed in patients undergoing a systemic inflammatory response but had no detectable effect on the mice. Therefore, these results suggest that sPLA2 hyperphospholipasemia alone may have only limited pathophysiological consequences. We further show that 3-[3-acetamide-1-benzyl-2-ethylindolyl-5-oxy]propane phosphonic acid LY311727), a potent new inhibitor of phospholipase A2 catalysis developed by our group, dramatically suppresses the circulating enzyme activity in these animals whereas 3-[3-acetamide-1-benzyl-2-propylindolyl-5-oxy]propane phosphonic acid (LY314024), a substantially less potent LY311727 analog, is without effect. These later results thus motivate the further development of this compound as a potential new therapeutic agent and valuable research tool.

Costimulation, tolerance and ignorance of cytolytic T lymphocytes in immune responses to tumor antigens.

Despite the fact that many tumors express MHC class I molecules presenting "foreign" peptide antigens, a vigorous tumor-destructing immune response is seldom detected. A possible explanation is that tumors cannot provide adequate costimulatory signals as provided by professional antigen presenting cells. CD28, upon interacting with B7, triggers costimulatory signals critical for the T-cell response. Transfection of tumor cells with B7 augments the immunogenicity of the tumor so that an anti-tumor immune response can be amplified. When B7-CD28 costimulation is provided CTL specific for otherwise silent epitopes can be activated. Therefore, unresponsiveness of T cells to many tumor antigens should be considered as ignorance rather than tolerance. Immunological ignorance may thus contribute to the failure of the immune system to respond against the tumor antigens.

Hepatocellular carcinoma associated with autoimmune chronic active hepatitis.

Primary hepatocellular carcinoma, one of the most common malignancies in the world, develops in chronic liver diseases of different etiologies. Hepatitis B and non-A, non-B infections, alcoholic cirrhosis, hemochromatosis, contamination with aflatoxins, and oral contraceptives are just a few of the conditions that have been associated with this carcinoma. To our knowledge, few cases of autoimmune chronic active hepatitis and hepatocellular carcinoma have been reported in the literature. We describe a patient who developed hepatocellular carcinoma 21 years after the onset of the autoimmune hepatitis.

The histologic effects of low-dose methotrexate therapy for primary biliary cirrhosis.

OBJECTIVE: Primary biliary cirrhosis is a progressive liver disease that is believed to be autoimmune in nature. Treatment, at best, may slow the progression of the disease, although no therapy has been able to halt its progression. Preliminary data suggest a beneficial effect of methotrexate in the treatment of primary biliary cirrhosis. We evaluated the histologic effect of 2 years of treatment with methotrexate. DESIGN: Liver biopsies were obtained before methotrexate was started and after 2 years of therapy. Ninety-six paired biopsies from 48 patients with primary biliary cirrhosis were reviewed by a pathologist who was blinded to all clinical history and sequence of the biopsies. Variables examined included stage of the disease, degree of portal fibrosis, portal inflammation and piecemeal necrosis, bile duct injury or loss, bile ductular proliferation, lobular inflammation and necrosis, steatosis, granulomas, cholestasis, and nuclear pleomorphism of hepatocytes. RESULTS: In most categories, pretreatment and posttreatment biopsies did not reflect a change over the 2-year period of treatment. There was a trend toward progression of the stage of the disease, portal fibrosis, bile duct loss, fat, and pleomorphism over the 2 years and toward regression in piecemeal necrosis, bile duct injury, ductular proliferation, granulomas, and lobular inflammation and necrosis. CONCLUSION: After 2 years of treatment with methotrexate, the stage of disease and fibrosis of primary biliary cirrhosis continue to progress, although overall, inflammation and bile duct injury decrease with methotrexate treatment.

[Childhood infections: friends or foes?]. / Infections précoces dans l'enfance: amies ou ennemies?

Asthma prevalence has increased significantly; this increase appears to be relatively recent. The observed increases in this prevalence cannot be genetic in origin; on the other hand lifestyles have changed in many ways for environment or feeding. The hygiene hypothesis must be distinguished in terms whether one is addressing asthma or atopy. Although there are associations between asthma and atopy, they are not interchangeable. The pathogenic links between childhood infections and asthma require an undisputed definition of asthma. But many wheezing syndromes have been recognized in the pediatric age group, some overlap exists between these various phenotypes. The age at first severe infection seems to be crucial in determining the outcome of reinfection and suggests that the environment of the neonatal lung is a major determinant of disease and allergic patterns in later life.

[Role of viral infections and Chlamydia pneumoniae and Mycoplasma pneumoniae infections in asthma in infants and young children. Epidemiologic study of 118 children]. / Rôle des infections virales et des infections à Chlamydia pneumoniae et à Mycoplasma pneumoniae au cours de l'asthme du nourrisson et du jeune enfant. A propos d'une étude épidémiologique chez 118 enfants.

Wheezing associated with upper respiratory tract infections is common in children. Using conventional techniques (viral culture and immunofluorescence) and molecular techniques (PCR), we studied the prevalence of viral, Chlamydia pneumoniae (CP) and Mycoplasma pneumoniae (MP) infections in 118 children hospitalised for acute asthma exacerbation. A virus was identified by conventional techniques in 40 of the 118 nasal swabs (34%), while PCR allowed identification of virus CP and MP in 80 samples (68%). Combination of both techniques allowed identification of an infectious agent in 91 cases (77%). More than one agent was isolated in 15 cases (23%). Rhinovirus (RV) (45%) were prevalent, followed by respiratory syncytial virus (RSV) (28%) and enterovirus (8.5%). RV and RSV have a similar prevalence (42% and 36% respectively) before two years of age, as compared with 66% and 27% respectively in older children. CP and MP were identified by PCR in only 6 cases. Molecular techniques of identification demonstrated a clear advantage in sensitivity compared with conventional techniques. The high prevalence of RV and RSV infections is remarkable, while CP and MP do not seem particularly involved in children acute asthma exacerbation.

[Acute respiratory tract infections due to a human metapneumovirus in children: descriptive study and comparison with respiratory syncytial virus infections]. / Infections respiratoires aiguës à métapneumovirus humain chez l'enfant: études descriptive et comparative avec le virus respiratoire syncytial.

BACKGROUND: A new paramyxovirus, the human metapneumovirus was recently isolated. We report the first French cases collected between 2000 and 2002. MATERIAL AND METHODS: Samples were obtained from nasopharyngeal aspirates from children hospitalised for acute respiratory tract infection in hospitals of Caen and Flers in Basse-Normandie. Human metapneumovirus was studied by polymerase chain reaction on negative samples for respiratory syncytial virus, influenza A and B virus, parainfluenza (1, 2 and 3) virus, adenovirus, coronavirus and rhinovirus. Comparison between metapneumovirus virus and respiratory syncytial virus infections was done after matching sex, age and infection month. RESULTS: Twenty-six human metapneumovirus infections were identified. A comparative study of a matched group of children infected by respiratory syncytial virus found no significative difference for hospitalisation motive, clinical criteria and treatment. CONCLUSION: The human metapneumovirus is responsible for typical acute bronchiolitis in children.