Pre-operative templating in THA. Part I: a classification of architectural hip deformities.
While numerous classifications of hip arthritis have been proposed, none considered the magnitude and direction of femoral head translation relative to the native acetabulum. A more precise classification of architectural hip deformities is necessary to improve preoperative templating and anticipate surgical challenges of total hip arthroplasty (THA). The purpose of the present study was to introduce a classification system to distinguish different types of architectural hip deformities, based on femoral head translation patterns, and to evaluate its repeatability using plain radiographs (qualitative) and Computed Tomography (CT) measurements (quantitative). We studied pre-operative frontal and lateral hip radiographs and CT scans of 191 hips (184 patients) that received primary THA. The distance between the femoral head center (FC) and the acetabular center (AC) was measured, as well as femoral offset, acetabular offset, head center height, acetabular floor distance and femoral neck angle. The hips were classified qualitatively using frontal plain radiographs, and then quantitatively using CT scans (with an arbitrary threshold of 3 mm as Centered, Medialized, Lateralized, Proximalized or Proximo-lateralized. The agreement between qualitative and quantitative classification methods was compared for applying the same classification. Qualitative classification identified 120 centered (63%), 8 medialized (4%), 49 lateralized (26%), 3 proximalized (2%), and 11 proximo-lateralized (6%) hips, while quantitative classification identified 116 centered (61%), 8 medialized (4%), 51 lateralized (27%), 5 proximalized (3%), and 11 proximo-lateralized (6%) hips. The agreement between the two methods was excellent (0.94; CI 0.90-0.98). Medialization reached 9.7 mm, while lateralization reached 10.9 mm, and proximalization reached 8.5 mm. Proximalized and proximo-lateralized hips had more valgus necks, while medialized hips had more varus necks (p = 0.003). The classification system enabled repeatable distinction of 5 types of architectural hip deformities. The excellent agreement between quantitative and qualitative methods suggests that plain radiographs are sufficient to classify architectural hip deformities.


Surgical and orthodontic treatment of skeletal Class III featuring severe transversal and sagittal discrepancy.
Anterior cross-bite is a difficult malocclusion to treat in adult patients, especially if compounded by skeletal discrepancy. The present study describes a dentoskeletal Class III case and aims to provide the clinician with rational guidelines for presurgical orthodontic preparation and postsurgical finishing. In this case, a 20-year-old male patient, R.M, was treated for severe dental and skeletal Class III malocclusion on both the transversal and anteroposterior planes via combined orthodontics and surgery. Initially, the treatment involved surgically-assisted expansion of the upper jaw (total 1 month), followed by a fixed-orthodontics phase to decompensate for the malocclusion in preparation for movement of the osseous bases with the aim of achieving maximum coordination of the dental arches. After 19 months of orthodontic preparation, the patient underwent combined orthognathic surgery (upper and lower jaws). In the subsequent 4 months, orthodontic stabilization and finishing were performed, and debonding was carried out 24 months after the start of active treatment. The combined orthodontic and surgical treatment adequately corrected the severe Class III over a period of 2 years, leading to a satisfactory occlusal, functional and aesthetic result. Thorough diagnosis and close communication between the orthodontist and maxillofacial surgeon, operating as an interdisciplinary team, ensures good outcomes, even in complex orthodontic and surgical cases.


The association between workers' compensation claims involving neck pain and future health care utilization: a population-based cohort study.
To describe the health care utilization of injured workers who made a workers' compensation claim for neck pain. We conducted a cohort study of injured workers who made an incident claim involving neck pain to the Ontario Workplace Safety and Insurance Board between 1997 and 1998. We linked their workers' compensation and Ontario Health Insurance Plan files to collect all health care services accrued during the year prior to and 2 years after the claim was initiated. We report the 7 day simple moving average of health care services per 1,000 claimants per day. We stratified our analysis by age, sex, the pre-claim level of health care utilization, diagnostic category and health care specialty. 58.1 % of claimants were males and 35.1 % were between the ages of 35 and 44 years. The cumulative rate of health care utilization was stable (mean = 60.80 services/1,000 claimants/day; 95 % CI: 59.7-62.0) throughout the year prior to the claim. However, it peaked during the first 4 days following the onset of the claim (mean = 473.3 services/1,000 claimants/day) and remained on average 311 % higher than baseline during the first month post-claim. On average in our sample, the health care utilization remained 11 % higher in the second year after the claim compared to the pre-claim level. This sustained increase was attributable to 6 % of claimants. We report a long-term increase in the average number of health care services utilized by injured workers who make a workers' compensation claim involving neck pain. This increase was attributable to a minority of claimants. The health reasons for this increase deserve further investigation.


Introduction of a model of skin lesions on rats and testing of dissolving microneedles containing 5-aminolevulinic acid.
Topical photodynamic therapy (PDT) is widely used to treat non melanoma skin cancers. It consists of topically applying on the skin lesions a cream containing a prodrug (5-aminolevulinic acid (5-ALA) or methyl aminolevulinate (MAL)) that is then metabolized to the photosensitizer protoporphyrin IX (PpIX). Light irradiation at PpIX excitation wavelength combined with oxygen then lead to a photochemical reaction inducing cell death. Nevertheless, this conventional PDT treatment is currently restricted to superficial skin lesions since the penetration depth of the prodrug is limited and hampers the production of PpIX in deep seated lesions. To overcome this problem, dissolving microneedles (MNs) included in a square flexible patch were developed. This easy-to-handle MN-patch is composed of 5-ALA mixed with hyaluronic acid (HA) and has the ability to dissolve after skin application. To evaluate the efficiency of this MN-patch in vivo, a skin lesion model has been developed on rats by applying UV-B illuminations. After 40 UV-B illuminations, histological and pharmacokinetic controls confirmed that the rats presented skin lesions. Once the rat skin lesion model has been validated, it was demonstrated that the MNs penetrated into the skin and fully dissolved in one hour on most of the rats. After one hour, the fluorescence images showed that the MN-patch produced a consequent and homogeneous level of PpIX. Overall, the dissolving MN-patch is a recent technology that has interesting features and several preclinical investigations should be led to compare its efficiency to that of the conventional treatment for PDT of non melanoma skin cancers.


Efficacy of Speech-language Pathology Therapy in Chronic Cough: Systematic Review With Meta-analysis.
To analyze the efficacy of speech-language pathology therapy in the self-assessment, in the cough frequency, and the vocal quality of adults with chronic cough. This is a systematic review with meta-analysis that answered the clinical question: "In adults with chronic cough, what is the effect of the speech-language pathology therapy in the self-assessment, in the cough frequency, and the vocal quality, compared to another intervention?" (PROSPERO 2021/CRD42021226729). An electronic search (MEDLINE, Web of Science, EMBASE, SCOPUS, Cochrane Library, and Lilacs), and a manual search (Journal of Voice, Brazilian Library of Theses and Dissertations, Open Grey and Clinical Trials) with specific search strategies was performed. The risk of bias was assessed using the Cochrane Collaboration's tool for assessing the risk of bias in randomized trials. Meta-analysis (standardized difference of means, Inverse Variance, and random effects model) and heterogeneity analysis (Chi², Tau², and I²) were performed. We found 610 studies and selected three. There was an uncertain risk of detection bias. The data were heterogeneous, and there was no difference between interventions in self-perception of cough severity (z = 0.09, P = 0.930; tau² = 0.65, I² = 90%) and in the self-perception of the effects of chronic cough on health status (z = 0.30, P = 0.77; tau² = 0.99, I² = 97%). The estimated mean difference was 0.97 to cough frequency, and it was differ significantly from zero (z = 4.47, P < 0.001) but the results are heterogeneous (Chi² (1) = 22.22, P < 0.001, I² = 95%). The speech-language pathology therapy had a greater effect size than the control interventions on cough frequency. However, in the subjects' perception, there were no differences between the interventions.


Erratum to "Circulating Anti-Elastin Antibody Levels and Arterial Disease Characteristics: Associations with Arterial Stiffness and Atherosclerosis" by Lee SH, et al. (Yonsei Med J 2015;56:1545-51.).
[This corrects the article DOI: 10.3349/ymj.2015.56.6.1545.].


Role of oxygen-dependent mechanisms in monoclonal antibody-induced lysis of normal T cells by phagocytes. I.--Human Phagocytes.
The present study investigates the lytic potential of the reactive oxygen species (ROS) which, as previously shown in our laboratory, are generated within the first minutes following the Fc-receptor-mediated interaction between phagocytic cells and anti-T-cell monoclonal-antibody (mAb)-coated T lymphocytes. A comparative study of ROS production (measured by chemiluminescence (CL] and the cytotoxic effect (evaluated in a 51Cr release antibody-dependent cellular cytotoxicity (ADCC) assay) of human polymorphonuclear (PMN) and mononuclear (MN) cells against mAb-coated autologous, allogeneic and xenogeneic (murine) thymocytes showed that the two reactions were closely interdependent for PMN and co-existed without significant correlation for MN cells. Catalase and superoxide dismutase did not modify ADCC results, suggesting that these ROS scavengers could not diffuse into the target cell destruction area. Colchicine treatment of PMN and MN cells at a dose inhibiting phagocytosis consistently impaired their CL generation and, in parallel, strongly reduced PMN-mediated ADCC but only weakly reduced that of MN cells. PMN and MN cells from 14 patients with chronic granulomatous disease (CGD) were not capable of producing CL after contact with mAb-coated T cells and showed significantly reduced ADCC activities, while PMN and MN cells from mothers carrying the X-linked type of CGD exhibited ADCC and oxidative responses of an intermediate level. We conclude that ADCC mediated by human PMN cells against T cells is mainly dependent upon the generation of ROS, whereas that induced by MN cells is most likely effected by both oxidative and non-oxidative events.


Improved mitral valve coaptation and reduced mitral valve annular size after percutaneous mitral valve repair (PMVR) using the MitraClip system.
Improved mitral valve leaflet coaptation with consecutive reduction of mitral regurgitation (MR) is a central goal of percutaneous mitral valve repair (PMVR) with the MitraClip® system. As influences of PMVR on mitral valve geometry have been suggested before, we examined the effect of the procedure on mitral annular size in relation to procedural outcome. Geometry of the mitral valve annulus was evaluated in 183 patients undergoing PMVR using echocardiography before and after the procedure and at follow-up. Mitral valve annular anterior-posterior (ap) diameter decreased from 34.0 ± 4.3 to 31.3 ± 4.9 mm (P < 0.001), and medio-lateral (ml) diameter from 33.2 ± 4.8 to 32.4 ± 4.9 mm (P < 0.001). Accordingly, we observed an increase in MV leaflet coaptation after PMVR. The reduction of mitral valve ap diameter showed a significant inverse correlation with residual MR. Importantly, the reduction of mitral valve ap diameter persisted at follow-up (31.3 ± 4.9 mm post PMVR, 28.4 ± 5.3 mm at follow-up). This study demonstrates mechanical approximation of both mitral valve annulus edges with improved mitral valve annular coaptation by PMVR using the MitraClip® system, which correlates with residual MR in patients with MR.


Trem2 deficiency impairs recovery and phagocytosis and dysregulates myeloid gene expression during virus-induced demyelination.
Triggering receptor expressed on myeloid cells 2 (Trem2) plays a protective role in neurodegenerative diseases. By contrast, Trem2 functions can exacerbate tissue damage during respiratory viral or liver infections. We, therefore, investigated the role of Trem2 in a viral encephalomyelitis model associated with prominent Th1 mediated antiviral immunity leading to demyelination. Wild-type (WT) and Trem2 deficient (Trem2-/-) mice were infected with a sublethal glia tropic murine coronavirus (MHV-JHM) intracranially. Disease progression and survival were monitored daily. Leukocyte accumulation and pathological features including demyelination and axonal damage in spinal cords (SC) were determined by flow cytometry and tissue section immunofluorescence analysis. Expression of select inflammatory cytokines and chemokines was measured by RT-PCR and global myeloid cell gene expression in SC-derived microglia and infiltrated bone-marrow-derived macrophages (BMDM) were determined using the Nanostring nCounter platform. BMDM recruited to SCs in response to infection highly upregulated Trem2 mRNA compared to microglia coincident with viral control. Trem2 deficiency did not alter disease onset or severity, but impaired clinical recovery after onset of demyelination. Disease progression in Trem2-/- mice could not be attributed to altered virus control or an elevated proinflammatory response. A prominent difference was increased degenerated myelin not associated with the myeloid cell markers IBA1 and/or CD68. Gene expression profiles of SC-derived microglia and BMDM further revealed that Trem2 deficiency resulted in impaired upregulation of phagocytosis associated genes Lpl and Cd36 in microglia, but a more complex pattern in BMDM. Trem2 deficiency during viral-induced demyelination dysregulates expression of other select genes regulating phagocytic pathways and lipid metabolism, with distinct effects on microglia and BMDM. The ultimate failure to remove damaged myelin is reminiscent of toxin or autoimmune cell-induced demyelination models and supports that Trem2 function is regulated by sensing tissue damage including a dysregulated lipid environment in very distinct inflammatory environments.


A proposal concerning the origin of life on the planet earth.
The widely accepted Oparin thesis for the origin and early evolution of life seems sufficiently far from the true state of affairs as to be considered incorrect. It is proposed that life on earth actually arose in the planet's atmosphere, however an atmosphere very different from the present one. Because of an extremely warm surface, the early earth may have possessed no liquid surface water, its water being partitioned between a motten crust and a fairly dense atmosphere. Early preliving systems are taken to arise in the droplet phase in such an atmosphere. The early earth, which resembled Venus then and to some extent now, underwent a transition to its present condition largely as a result of the evolution of methanogenic metabolism.


Characterization of an emerging porcine respirovirus 1 isolate in the US: A novel viral vector for expression of foreign antigens.
Porcine respirovirus 1 (PRV1) is widely spread in many countries. In this study, we isolated an emgerging PRV1 strain (KS17-258) from a US swine farm. A full-length genome sequence of the virus was obtained, and the mRNA editing mechanism utilized for the expression of V/W proteins by P gene was confirmed. The virus shares 91.3-98% nucleotide sequence identity with the other PRV1 genomes reported previously. Phylogenetic analysis showed that KS17-258 forms a clade with the other US isolates. Infectious clone of the KS17-258 isolate was constructed, which was further explored as a viral vector to express enhanced green fluorescent protein (EGFP). The expression cassette of EGFP in the recombinant virus remained stable for 10 passages in cell culture. The availability of PRV1 infectious clone provides an important tool for study the basic PRV1 replication mechanisms. It also provides a novel platform for potential development of vectored vaccines against swine diseases.


Successful repair of interrupted aortic arch with aortopulmonary window associated with long gap oesophageal atresia and Type C tracheoesophageal fistula: challenging and rare case report.
Congenital heart diseases are most common anomalies associated with tracheoesophageal fistula (TEF) and oesophageal atresia (EA). The physiology and anatomy of heart disease is major determinant factor influencing outcome in patients with TEF/EA. We present a successfully treated case of complex congenital heart anomaly of interrupted aortic arch (IAA) with aortopulmonary window (APW) with TEF/EA.


[Proposals for common definitions of reference points in gynecological brachytherapy (author's transl)].
In May 1975 the report of European Curietherapy Group recommended in gynecological Dosimetry by computer. Use of reference points = lymphatic trapezoid figure with 6 points, Pelvic wall, all points are refering to bony structures. Use of critical organ reference points = maximum rectum dose, bladder dose mean rectal dose. Use of 6,000 rads reference isodose described by height, width, and thickness dimensions. These proposals are the basis of a common language in gynecological brachytherapy.


On collapsibility and confounding bias in Cox and Aalen regression models.
We study the situation where it is of interest to estimate the effect of an exposure variable [Formula: see text] on a survival time response [Formula: see text] in the presence of confounding by measured variables [Formula: see text]. Quantifying the amount of confounding is complicated by the non-collapsibility or non-linearity of typical effect measures in survival analysis: survival analyses with or without adjustment for [Formula: see text] typically infer different effect estimands of a different magnitude, even when [Formula: see text] is not associated with the exposure, and henceforth not a confounder of the association between exposure and survival time. We show that, interestingly, the exposure coefficient indexing the Aalen additive hazards model is not subject to such non-collapsibility, unlike the corresponding coefficient indexing the Cox model, so that simple measures of the amount of confounding bias are obtainable for the Aalen hazards model, but not for the Cox model. We argue that various other desirable properties can be ascribed to the Aalen model as a result of this collapsibility. This work generalizes recent work by Janes et al. (Biostatistics 11:572-582, 2010).


Implementing a training intervention to support caregivers after stroke: a process evaluation examining the initiation and embedding of programme change.
Medical Research Council (MRC) guidance identifies implementation as a key element of the development and evaluation process for complex healthcare interventions. Implementation is itself a complex process involving the mobilization of human, material, and organizational resources to change practice within settings that have pre-existing structures, historical patterns of relationships, and routinized ways of working. Process evaluations enable researchers and clinicians to understand how implementation proceeds and what factors impact on intended program change. A qualitative process evaluation of the pragmatic cluster randomized controlled trial; Training Caregivers after Stroke was conducted to examine how professionals were engaged in the work of delivering training; how they reached and involved caregivers for whom the intervention was most appropriate; how did those on whom training was targeted experience and respond to it. Normalization Process Theory, which focuses attention on implementing and embedding program change, was used as a sensitizing framework to examine selected findings. Contextual factors including organizational history and team relationships, external policy, and service development initiatives, impinged on implementation of the caregiver training program in unintended ways that could not have been predicted through focus on mechanisms of individual and collective action at unit level. Factors that facilitated or impeded the effectiveness of the cascade training model used, whether and how stroke unit teams made sense of and engaged individually and collectively with a complex caregiver training intervention, and what impact these factors had on embedding the intervention in routine stroke unit practice were identified. Where implementation of complex interventions depends on multiple providers, time needs to be invested in reaching agreement on who will take responsibility for delivery of specific components and in determining how implementation and its effectiveness will be monitored. This goes beyond concern with intervention fidelity; explicit consideration also needs to be given to the implementation process in terms of how program change can be effected at organizational, practice, and service delivery levels. Normalization Process Theory's constructs help identify vulnerable features of implementation processes in respect of the work involved in embedding complex interventions.


Improved health outcomes in integrative medicine visits may reflect differences in physician and patient behaviors compared to standard medical visits.
To identify differences in patient-physician interactions associated with improvements in GERD symptoms in a randomized controlled trial comparing integrative medicine and primary care/standard visits. We analyzed video recordings of 2-minute excerpts (thin slices) from the beginning, middle, and end of 21 study visits (11 standard, 10 integrative medicine). According to blind coders' analysis of the excerpts, prospective improvement in GERD symptoms was most highly correlated with patients appearing pleased (r = 0.71, p < 0.01) and friendly (r = 0.67, p < 0.01) at the end of the visit, controlling for visit type. The combination of patient and physician smiling at the end of the visit was associated with improvement in GERD symptoms (r2 = 0.45, p = 0.004). The physician in the integrative visits was more engaged (p = 0.009), friendly (p = 0.005), relaxed (p = 0.002), smiled longer (p = 0.006), gazed longer (p = 0.02), and gestured more (p = 0.007), compared to standard visits. Patients in integrative visits also smiled longer (p = 0.004). The expanded history-taking questions asked by integrative clinicians may enhance relationship building, modifying patients' responses and improving patient-centered behaviors from clinicians,ultimately facilitating symptom improvement. Analysis of nonverbal behaviors may facilitate a better understanding of patient-clinician interactions in integrative medicine visits and yield insights to improve clinical interactions in conventional medicine.


Integrated microbiology and metabolomics analysis reveal responses of cotton rhizosphere microbiome and metabolite spectrum to conventional seed coating agents.
Fludioxonil (FL) and metalaxyl-M·fludioxonil·azoxystrobin (MFA) are conventional seed coating agents for controlling cotton seedling diseases. However, their effects on seed endophytic and rhizosphere microecology are still poorly understood. This study aimed to assess the effects of FL and MFA on cotton seed endophytes, rhizosphere soil enzymatic activities, microbiome and metabolites. Both seed coating agents significantly changed seed endophytic bacterial and fungal communities. Growing coated seeds in the soils originating from the Alar (AL) and Shihezi (SH) region inhibited soil catalase activity and decreased both bacterial and fungal biomass. Seed coating agents increased rhizosphere bacterial alpha diversity for the first 21 days but decreased fungal alpha diversity after day 21 in the AL soil. Seed coating reduced the abundance of a number of beneficial microorganisms but enriched some potential pollutant-degrading microorganisms. Seed coating agents may have affected the complexity of the co-occurrence network of the microbiome in the AL soil, reducing connectivity, opposite to what was observed in the SH soil. MFA had more pronounced effects on soil metabolic activities than FL. Furthermore, there were strong links between soil microbial communities, metabolites and enzymatic activities. These findings provide valuable information for future research and development on application of seed coatings for disease management.


Expression of hes, iha, and tpsA codified in locus of adhesion and autoaggregation and their involvement in the capability of shiga toxin-producing Escherichia coli strains to adhere to epithelial cells.
Shiga toxin-producing Escherichia coli strains LAA-positive are important cause of human infection. The capability to adhere to epithelial cells is a key virulence trait, and genes codified in LAA pathogenicity island could be involved in the adhesion during the pathogenesis of LAA-positive STEC strains. Thus, our objectives were to compare hes-negative and hes-positive STEC strains in their adherence capability to epithelial cells (HEp-2) and to evaluate the expression levels of the hes, iha, and tpsA in the bacteria adhered and non-adhered to HEp-2 cells. These genes are encoded in LAA, and are virulence factors that participate in adhesion and autoaggregation. We could not observe differences between the adhesion of strains but also in the expression level of of hes, iha, and tpsA. Genes encoded in LAA contribute to the adhesion phenotype though the expression of STEC adhesins is a coordinated event that depends not only the strain but also on the environment as well as its genetic background. Therefore, the results of this study suggest that LAA ,the most prevalent PAI among LEE-negative STEC strains, plays a role in pathogenesis.


Recent Advances in Thyroid Cancer Research.
This Special Issue (SI) "Recent Advances in Thyroid Cancer Research" covers research articles and reviews in the field of thyroid cancer research [...].


2,4,6-Triphenyl-N-{(3E)-3-[(2,4,6-tri-phenyl-phen-yl)imino]-butan-2-yl-idene}aniline.
The title compound, C52H40N2, is disposed about a centre of inversion and the conformation about the imine bond [1.268 (3) Å] is E. The terminal benzene ring is approximately perpendicular to the central 1,4-di-aza-butadiene mean plane, forming a dihedral angle of 81.2 (3)°. Weak C-H⋯π and π-π [inter-centroid distance = 4.021 (5) Å] inter-actions help to consolidate the packing.


Crystal structure of diethyl 2-acet-oxy-2-[3-(4-nitro-phen-yl)-3-oxo-1-phenyl-prop-yl]malonate.
In the racemic title compound, C24H25NO9, the dihedral angle between the planes of the two benzene-ring systems is 80.16 (6)°, while the side-chain conformation is stabilized by a methyl-ene-carboxyl C-H⋯O hydrogen bond. Weak inter-molecular C-H⋯O hydrogen bonds form inversion dimers [graph set R 2 (2)(16)] which are linked into chains extending along a. Further C-H⋯O hydrogen bonding extends the structure along b through cyclic R 2 (2)(10) motifs. Although no π-π aromatic ring inter-actions are present in the structure, C-H⋯π ring inter-actions across c generate an overall three-dimensional supra-molecular structure.


Varenicline for smoking cessation among methadone-maintained smokers: a randomized clinical trial.
With smoking rates far exceeding the general population, methadone-maintained (MMT) opiate-dependent smokers experience high rates of tobacco-related health consequences. Previous treatment studies have used nicotine replacement and produced low quit rates. We test, using a three-group randomized design, the efficacy of varenicline versus placebo, in comparison with nicotine replacement therapy (NRT) that combines nicotine patch prescription plus ad libitum nicotine rescue, for smoking cessation. We recruited methadone-maintained smokers from nine treatment centers in southern New England and provided six months of treatment, and a minimal behavioral intervention at baseline (NCI's 5A's). Outcomes included carbon monoxide (CO) confirmed 7-day point smoking cessation prevalence at 6 months and self-reported change in mean cigarettes per day. The 315 participants had a mean age of 40, with 50% male and 79% non-Hispanic White, smoked an average of 19.6 (± 10.4) cigarettes/day, and had a mean daily methadone dose of 109 mg. Intent-to-treat analyses, with missing considered to be smoking, showed the rate of CO-confirmed 7-day abstinence at 6-months was 5.4% overall, with varenicline 3.7% compared to placebo 2.2%, and NRT 8.3% (p>.05). Adherence rates during the 7-days immediately prior to 6-month assessment were 34.2% in varenicline, 34.4% in placebo, and 48.8% in NRT. Between baseline and 6-months there was an overall self-reported mean reduction of 8.3 cigarettes/day. Varenicline did not increase quit rates over placebo. Smoking cessation rates in methadone-maintained smokers are low and novel treatment strategies are required.


Long-term experience with pergolide therapy of advanced parkinsonism.
Nine patients with idiopathic Parkinson's disease were treated with pergolide to a daily maintenance dose of 2.2 +/- 0.9 mg (mean +/- SD) for 17.3 +/- 8.3 months. After 1 month, there was an average 68% increase in mobile on-time, but the improvement declined to 30% by 6 months, 23% by 1 year, and virtually disappeared by 18 months of therapy. Pergolide was discontinued in seven patients because of loss of efficacy (4 patients), confusion (1 patient), or myocardial infarction or ventricular ectopy (2 patients). Partial but temporary restoration of mobility was observed in seven patients who were switched to an alternate-day dosing schedule after 9.2 +/- 2.4 months. Two patients with advanced Shy-Drager syndrome were treated with pergolide without benefit.


Donor catch-up growth after laser surgery for twin-twin transfusion syndrome.
To assess fetal growth after laser surgery for TTTS at the time of prenatal diagnosis, birth, and at 2years of age. Growth data were collected from surviving children treated between 2007 and 2010 as part of a study to assess neurodevelopment at 24months (±6weeks) corrected age. Fetal weights were obtained via ultrasound using Hadlock's formula at the time of preoperative assessment for laser surgery. Birth weights were recorded by the staff at the delivering institutions. Weights at 2years corrected age were recorded at the time of neurodevelopmental testing. Weights were converted into percentiles according to standard growth curves. Growth restriction was defined as <10th percentile for given age. Multilevel latent growth curve models in Mplus (twins nested in families) examined weight change over time as a function of donor status, and repeated measures ANOVA was utilized to assess in donor-recipient weight discordance over time for twin pairs. 99 of 206 children (56 of 130 families) were studied. There were no differences between enrolled and non-enrolled patients in donor/recipient status and survival rates, fetal demise, intrauterine growth restriction, Quintero stage, and gestational age of surgery or delivery. 48.5% were donors. The median fetal, birth, and 2-year weights for all twins were 288g, 1.9kg, and 11.8kg, respectively, and the overall prevalence of growth restriction was 28%, 22%, and 3%, respectively. Growth restriction rates at prenatal diagnosis were 56% in donors vs. 2% in recipients (OR=64.3, p<0.001); at birth, 35% vs. 10% (OR=5.0, p<0.01); and at 2years, 6% vs. 0%. Donors showed significant gains in weight percentile (B=13.1, p<0.001) and a significant decrease in growth restriction rates over time (B=-1.6, p<0.001). Weight discordance between donor and recipient pairs also significantly decreased over time (linear F(1,42)=54.34, p<0.001). After laser surgery for TTTS, donor twins exhibit significant catch-up growth by two years of age.


Oxidative stress induces Z-DNA-binding protein 1-dependent activation of microglia via mtDNA released from retinal pigment epithelial cells.
Oxidative stress, inflammation, and aberrant activation of microglia in the retina are commonly observed in ocular pathologies. In glaucoma or age-related macular degeneration, the chronic activation of microglia affects retinal ganglion cells and photoreceptors, respectively, contributing to gradual vision loss. However, the molecular mechanisms that cause activation of microglia in the retina are not fully understood. Here we show that exposure of retinal pigment epithelial (RPE) cells to chronic low-level oxidative stress induces mitochondrial DNA (mtDNA)-specific damage, and the subsequent translocation of damaged mtDNA to the cytoplasm results in the binding and activation of intracellular DNA receptor Z-DNA-binding protein 1 (ZBP1). Activation of the mtDNA/ZBP1 pathway triggers the expression of proinflammatory markers in RPE cells. In addition, we show that the enhanced release of extracellular vesicles (EVs) containing fragments of mtDNA derived from the apical site of RPE cells induces a proinflammatory phenotype of microglia via activation of ZBP1 signaling. Collectively, our report establishes oxidatively damaged mtDNA as an important signaling molecule with ZBP1 as its intracellular receptor in the development of an inflammatory response in the retina. We propose that this novel mtDNA-mediated autocrine and paracrine mechanism for triggering and maintaining inflammation in the retina may play an important role in ocular pathologies. Therefore, the molecular mechanisms identified in this report are potentially suitable therapeutic targets to ameliorate development of ocular pathologies.


Pre-targeted immunoscintigraphy of murine tumors with indium-111-labeled bifunctional haptens.
A method of tumor imaging utilizing the nonspecific accumulation of antibody through leaky capillaries is described, in which the antibody and the radiolabel are administered separately. Nonradioactive antibody is given first (pre-targeted), and allowed adequate time to reach maximum tumor concentration. Depending on the antibody, this may take several days. At the time of maximum tumor concentration of nonradioactive antibody, the blood is quickly cleared of excess circulating nonradioactive antibody using a special i.v. "chase". The radiolabel then is given and imaging done in 1 to 3 hr. The use of short lived tracers (hours) to image antibodies that localize slowly (days) in-vivo is made possible by this method.


FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons.
A missense mutation in the fibroblast growth factor 14 (FGF14) gene underlies SCA27, an autosomal dominant spinocerebellar ataxia in humans. Mice with a targeted disruption of the Fgf14 locus (Fgf14(-/-)) develop ataxia resembling human SCA27. We tested the hypothesis that loss of FGF14 affects the firing properties of Purkinje neurons, which play an important role in motor control and coordination. Current clamp recordings from Purkinje neurons in cerebellar slices revealed attenuated spontaneous firing in Fgf14(-/-) neurons. Unlike in the wild type animals, more than 80% of Fgf14(-/-) Purkinje neurons were quiescent and failed to fire repetitively in response to depolarizing current injections. Immunohistochemical examination revealed reduced expression of Nav1.6 protein in Fgf14(-/-) Purkinje neurons. Together, these observations suggest that FGF14 is required for normal Nav1.6 expression in Purkinje neurons, and that the loss of FGF14 impairs spontaneous and repetitive firing in Purkinje neurons by altering the expression of Nav1.6 channels.


Treatment of posttraumatic bone defects by the induced membrane technique.
Among bone reconstruction techniques, the induced membrane technique, proposed in 1986 by Masquelet, has rarely been studied or evaluated in the surgical literature until recently. The 2010 French Society of Orthopaedic Surgery and Traumatology (SoFCOT) Annual Convention symposium was the occasion to evaluate a large cases series having used this technique. This retrospective study included 84 posttraumatic diaphyseal long bone reconstructions using the induced membrane technique (1988-2009). The series included 79 men and five women (mean age 32-year-old). In 89% of cases, the initial trauma was an open fracture. The leg was involved in 70% of cases. The mean delay between the accident and treatment of bone defects (BD) was 8 months. In 50% of the cases, infection was present. Bone defects were larger than 5cm in 57% of the cases. Union was obtained in 90% of cases, a mean 14.4 months after the first stage of the reconstruction. A mean 6.11 interventions were necessary to obtain union. Malalignment was present in 17% of cases. Delayed interventions to correct deformities mostly of the foot were necessary in 16% of the cases. Eight failures (10%) involved severe leg traumas associating extensive bone defects, soft tissue lesions and infection and required amputation in six cases. This series emphasizes the severity of open fractures of the leg, especially those with primary or secondary infection. The induced membrane technique has been shown to be effective in treating bone defects, regardless of their magnitude. In a two-step procedure, this simple but demanding technique, which may be more complicated when repair of soft tissue is necessary, provides successful treatment in case of initial infection and fulfills the goal of controlling infection before bone reconstruction. Moreover, the induced membrane technique can be integrated in hybrid reconstruction procedures. Level IV. Retrospective study.


Complete Mitochondrial Genome of Three Species of the Genus Microtus (Arvicolinae, Rodentia).
The 65 species of the genus Microtus have unusual sex-related genetic features and a high rate of karyotype variation. However, only nine complete mitogenomes for these species are currently available. We describe the complete mitogenome sequences of three Microtus, which vary in length from 16,295 bp to 16,331 bp, contain 13 protein-coding genes (PCGs), two ribosomal RNA genes, 22 transfer RNA genes and a control region. The length of the 13 PCGs and the coded proteins is the same in all three species, and the start and stop codons are conserved. The non-coding regions include the L-strand origin of replication, with the same sequence of 35 bp, and the control region, which varies between 896 bp and 930 bp in length. The control region includes three domains (Domains I, II and III) with extended termination-associated sequences (ETAS-1 and ETAS-2) in Domain I. Domain II and Domain III include five (CSB-B, C, D, E and F) and three (CSB-1, CSB-2, and CSB-3) conserved sequence blocks, respectively. Phylogenetic reconstructions using the mitochondrial genomes of all the available Microtus species and one representative species from another genus of the Arvicolinae subfamily reproduced the established phylogenetic relationships for all the Arvicolinae genera that were analyzed.


Endothelial TNF receptor 2 induces IRF1 transcription factor-dependent interferon-β autocrine signaling to promote monocyte recruitment.
Endothelial-dependent mechanisms of mononuclear cell influx are not well understood. We showed that acute stimulation of murine microvascular endothelial cells expressing the tumor necrosis factor receptors TNFR1 and TNFR2 with the soluble cytokine TNF led to CXCR3 chemokine generation. The TNF receptors signaled through interferon regulatory factor-1 (IRF1) to induce interferon-β (IFN-β) and subsequent autocrine signaling via the type I IFN receptor and the transcription factor STAT1. Both TNFR2 and TNFR1 were required for IRF1-IFNβ signaling and, in human endothelial cells TNFR2 expression alone induced IFN-β signaling and monocyte recruitment. In vivo, TNFR1 was required for acute renal neutrophil and monocyte influx after systemic TNF treatment, whereas the TNFR2-IRF1-IFN-β autocrine loop was essential only for macrophage accumulation. In a chronic model of proliferative nephritis, IRF1 and renal-expressed TNFR2 were essential for sustained macrophage accumulation. Thus, our data identify a pathway in endothelial cells that selectively recruits monocytes during a TNF-induced inflammatory response.


Films based on neutralized chitosan citrate as innovative composition for cosmetic application.
In this work, citrate and acetate buffers, were investigated as neutralizers to chitosan salts in order to provide biocompatible and stable films. To choose the appropriate film composition for this study, neutralized chitosan citrate and acetate films, with and without the plasticizer glycerol, were prepared and characterized by thickness, moisture content, degree of swelling, total soluble matter in acid medium, simultaneous thermal analysis and differential scanning calorimetry. Chitosan films neutralized in citrate buffer showed greater physical integrity resulted from greater thicknesses, lower moisture absorbance, lower tendency to solubility in the acid medium, and better swelling capacities. According to thermal analyses, these films had higher interaction with water which is considered an important feature for cosmetic application. Since the composition prepared in citrate buffer without glycerol was considered to present better physical integrity, it was applied to investigate hyaluronic acid release in a skin model. Skins treated with those films, with or without hyaluronic acid, show stratum corneum desquamation and hydration within 10min. The results suggest that the neutralized chitosan citrate film prepared without glycerol promotes a cosmetic effect for skin exfoliation in the presence or absence of hyaluronic acid.


Reduction of liver Fas expression by an antisense oligonucleotide protects mice from fulminant hepatitis.
Aberrant apoptosis-mediated cell death is believed to result in a number of different human diseases. For example, excessive apoptosis in the liver can result in fulminant and autoimmune forms of hepatitis. We have explored the possibility that inhibition of Fas expression in mice would reduce the severity of fulminant hepatitis. To do this, we have developed a chemically modified 2'-O-(2-methoxy)ethyl antisense oligonucleotide (ISIS 22023) inhibitor of mouse Fas expression. In tissue culture, this oligonucleotide induced a reduction in Fas mRNA expression that was both concentration- and sequence-specific. In Balb/c mice, dosing with ISIS 22023 reduced Fas mRNA and protein expressions in liver by 90%. The ID50 for this response was 8-10 mg kg-1 daily dosing, and the reduction was highly dependent on oligonucleotide sequence, oligonucleotide concentration in liver, and treatment time. Pretreatment with ISIS 22023 completely protected mice from fulminant hepatitis induced by agonistic Fas antibody, by a mechanism entirely consistent with an oligonucleotide antisense mechanism of action. In addition, oligonucleotide-mediated suppression of Fas expression reduced the severity of acetaminophen-mediated fulminant hepatitis, but was without effect on concanavalin A-mediated hepatitis. Our results demonstrate that 2'-O-(2-methoxy)ethyl containing antisense oligonucleotides targeting Fas can exert in vivo pharmacological activity in liver, and suggest that oligonucleotide inhibitors of Fas may be useful in the treatment of human liver disease.


Novel mutant phenotypes of a dark-germinating mutant dkg1 in the fern Ceratopteris richardii.
The mutant dark-germinating 1 ( dkg1) of the fern Ceratopteris richardii was originally characterized by two phenotypes, germination in the dark and inhibition of germination by light. In this work, we examined whether other phenotypes are present in the gametophytic generation of the dkg1 mutant. Although dkg1 prothalli grown in darkness were elongated as in the case of the wild type, some developmental processes were found to proceed even in complete darkness: (1) the apical and subapical zones developed largely by forming a lateral meristem; (2) asymmetric cell division for rhizoid differentiation occurred in the subapical elongation zone; (3) an archegonium was formed in the proximity of the meristem; and (4) chloroplast relocation could occur without de novo protein synthesis. Furthermore, these processes were shown to be under the control of phytochrome in the wild-type gametophytes on the basis of red/far-red reversibility. These results indicate that the DKG1 gene is pleiotropic and is involved in several phytochrome-mediated responses in the gametophyte development of C. richardii.


Translation and adaptation of Theory of Mind tasks into Brazilian portuguese.
Theory of mind (ToM) is a field of social cognition that deals with the individual's cognitive ability to interpret or infer the mental states of others based on previous knowledge. Recently, research has shown that this ability is compromised in patients with some psychopathologies, e.g., schizophrenia and autistic disorder. Investigators have also shown that deficits in ToM have impacts on social functioning and, consequently, on quality of life. Even though ToM studies have recently grown in number, some problems still remain (e.g., the difficulty of standardized tools to assess ToM in different languages). To describe the translation and adaptation into Brazilian Portuguese of two of the most important and widely used ToM tasks, namely, the Theory of Mind Stories and the Hinting Task. The process included the following steps: 1) translation; 2) production of a single translated version and review by specialists; 3) back-translation into English; 4) review by an English-speaking specialist; 5) adaptation of marked corrections; and 6) pilot application in a group representative of the target population (people with schizophrenia). A final translated version was obtained for each of the tasks. Both instruments were well understood by participants and can now be used in the Brazilian experimental setting. The availability of two major ToM tasks in Brazilian Portuguese facilitates the conduction of research on the topic in Brazil. In the future, this could help design clinical interventions aimed at people with social and cognitive difficulties.


Nasal carriage of Staphylococcus aureus in children with grass pollen-induced allergic rhinitis and the effect of polyvalent mechanical bacterial lysate immunostimulation on carriage status: A randomized controlled trial.
Numerous studies indicate that Staphylococcus aureus (S. aureus) colonizing the nasal cavity plays a role in the pathogenesis of allergic rhinitis (AR). This bacterium is able to produce a variety of toxins with superantigenic properties that can exacerbate allergic inflammation. The objective of the study was to evaluate the ability of polyvalent mechanical bacterial lysate (PMBL) to eliminate S. aureus nasal carriage in children with grass pollen-induced AR. This randomized, double-blind, placebo-controlled study included 80 children aged 5-17 years with seasonal AR (SAR). At the randomization visit and after 12 weeks of the study, a swab was taken from the region of the middle nasal meatus. Standard microbiology culture and identification techniques were used to analyze the swab contents. Nasal colonization by S. aureus was confirmed in 29 children (42%), with Moraxella catarrhalis in three participants (4.4%). Physiological flora was detected in 37 children. No statistically significant differences were observed between the two measurement points in both the PMBL and placebo groups with respect to the number of patients whose nasal swab cultures showed a growth of S. aureus (p = 1). Both groups also showed no significant changes in the mean number of S. aureus colonies in nasal swab cultures taken at baseline and after 12 weeks of the study (PMBL group p = .41; placebo group p = .16). Almost every second child with SAR is S. aureus nasal carrier. Sublingual administration of PMBL in children with grass pollen-induced AR did not affect S. aureus nasal colonization. Therefore, PMBL should not be used for the eradication of S. aureus from the nasal cavity.


DNA-AuNP networks on cell membranes as a protective barrier to inhibit viral attachment, entry and budding.
Viral infections have caused numerous diseases and deaths worldwide. Due to the emergence of new viruses and frequent virus variation, conventional antiviral strategies that directly target viral or cellular proteins are limited because of the specificity, drug resistance and rapid clearance from the human body. Therefore, developing safe and potent antiviral agents with activity against viral infection at multiple points in the viral life cycle remains a major challenge. In this report, we propose a new modality to inhibit viral infection by fabricating DNA conjugated gold nanoparticle (DNA-AuNP) networks on cell membranes as a protective barrier. The DNA-AuNPs networks were found, via a plaque formation assay and viral titers, to have potent antiviral ability and protect host cells from human respiratory syncytial virus (RSV). Confocal immunofluorescence image analysis showed 80 ± 3.8% of viral attachment, 91.1 ± 0.9% of viral entry and 87.9 ± 2.8% of viral budding were inhibited by the DNA-AuNP networks, which were further confirmed by real-time fluorescence imaging of the RSV infection process. The antiviral activity of the networks may be attributed to steric effects, the disruption of membrane glycoproteins and limited fusion of cell membrane bilayers, all of which play important roles in viral infection. Therefore, our results suggest that the DNA-AuNP networks have not only prophylactic effects to inhibit virus attachment and entry, but also therapeutic effects to inhibit viral budding and cell-to-cell spread. More importantly, this proof-of-principle study provides a pathway for the development of a universal, broad-spectrum antiviral therapy.


Doppler echocardiographic comparison of haemodynamic results of one- and two-stage anatomic correction of complete transposition.
Eighteen children who had single-stage and 18 who had two-stage anatomic correction of complete transposition between the ages of 1 week and 3 years (mean 6.5 months) were investigated with pulsed and continuous wave Doppler ultrasound. Peak mitral flow velocities showed no significant difference from normal after single-stage correction, but were significantly higher than normal after two-stage correction (P less than 0.05). Peak tricuspid flow velocities were significantly higher than normal in both groups (P less than 0.02 and P less than 0.001). There was no significant difference in pulmonary artery flow velocities between the two groups, which were means (SD) of 214 (84) cm/sec after single-stage and 179 (87) cm/sec after two-stage repair. Peak velocities in the ascending aorta were within normal limits after single-stage correction, but were lower than normal in the two-stage group (P less than 0.02). Mild aortic regurgitation was detected in 22% of single-stage and 55% of two-stage patients (P = 0.043, 2P = 0.085). Both types of repair are associated with higher peak tricuspid flow velocities than normal and have a similar incidence of mild supravalvar pulmonary stenosis. Mitral flow velocities are higher than normal only after two-stage correction. Velocities in the ascending aorta are lower than normal and the incidence of mild aortic regurgitation appears to be increased after two-stage repair, probably due to dilatation of the aortic root following banding of the pulmonary trunk.


Incidence of amikacin ototoxicity: a sigmoid function of total drug exposure independent of plasma levels.
A sigmoid curve was found to closely describe the relationship between the incidence of amikacin ototoxicity (greater than or equal to 15 dB hearing loss at a given frequency) and either (1) total dose, or (2) the area under the curve (AUC) describing plasma drug concentration v time over the total period of amikacin administration (total AUC) in continuously infused guinea pigs. Total dose or total AUC estimates of the drug exposure required to produce ototoxicity in 50% of the animals (ED50s) were not significantly different over an eight-fold range of dosing rates or plasma concentrations. A theoretical explanation for this result is that ototoxicity occurs only when a critical amount of drug is accumulated at the ototoxic site by an essentially unidirectional process with a rate that is slow and linearly related to the extracellular drug concentration. The sigmoid relationships for pooled data were parallel in slope for all hearing frequencies from 2 to 32 kHz, and the ED50s showed a strong negative linear relationship to the log of the hearing frequency over this range. The magnitude of ototoxicity expressed as the number of octaves (frequency ratios of 2) for which hearing loss damage was continuous from 32 kHz downward, was correlated to both total dose (r = .605) and total AUC (r = 0.703). No relationship between ototoxicity and plasma level or dosing rate was found. The extreme steepness of the dose-effect curve for the incidence of ototoxicity greatly amplified the variability between individuals and offers an explanation for the unpredictability of aminoglycoside ototoxicity in human patients. The results indicate that either total dose or total AUC (in cases of highly unpredictable blood levels), and not peak or trough serum levels, should be used as an index of ototoxic risk and that the safety limits of drug exposure should be set conservatively.


Abnormal activator protein 1 transcription factor expression in CD30-positive cutaneous large-cell lymphomas.
CD30+ cutaneous large-cell lymphomas (CLCL) represent a heterogeneous subgroup of skin lymphomas including primary cutaneous CD30+ anaplastic large-cell lymphoma (C-ALCL), lymphomatoid papulosis (LyP), transformed mycosis fungoides (T-MF) and Hodgkin's lymphoma (HL) with cutaneous involvement. The activator protein 1 (AP-1) transcription factor consists of JUN, FOS and other protein families. Recent studies have revealed upregulation of JUNB in both MF and C-ALCL and overexpression of JUNB and CD30 in systemic HL and ALCL. To assess systematically the expression pattern of AP-1 transcription factors in CLCL. We analysed paraffin tissue sections from 27 patients with LyP, 10 with C-ALCL, eight with T-MF and two with cutaneous HL by immunohistochemistry with antibodies against c-JUN, JUNB, JUND, c-FOS and RAF-1. We also stained samples from 10 patients with C-ALCL, seven with Sézary syndrome (SS), six with T-MF, three with cutaneous HL, two with LyP and control samples with total and phosphorylated mitogen-activated protein kinase (MAPK) antibodies. Results Positive staining for JUND (++) was observed in 13 cases of LyP (48%), 10 C-ALCL, six T-MF (75%) and two cutaneous HL cases. Positive JUNB protein expression was present in four cases of T-MF (50%), four C-ALCL (44%), three LyP (11%) and two cutaneous HL. Expression of total (p44/42) MAP kinase and phosphorylated p44/42 MAP kinase were detected in nine cases of C-ALCL (90%), seven SS (88%), five T-MF (89%) and three cutaneous HL. Most of these samples also showed positive staining for JUNB. These results suggest the presence of abnormal AP-1 protein expression in CLCL, which may be relevant to CLCL.


Label-Free Semiquantitative Liquid Chromatography-Tandem Mass Spectrometry Proteomics Analysis of Laryngeal/Hypopharyngeal Squamous Cell Carcinoma on Formalin-Fixed, Paraffin-Embedded Tissue Samples - a Pilot Study.
Squamous cell carcinoma (SCC) of the head and neck region is the sixth most frequent malignancy with high mortality rate. Due to its poor prognosis it is considered a growing public health problem worldwide inspite of existing treatment modalities. Thus, early diagnosis of new diseases and recurrences is emerging on one hand, but on the other hand troublesome in the lack of reliable tumor markers in this field. The rapid development of proteomics has opened new perspectives in tumor marker discovery. Liquid chromatography/mass spectrometry (LC/MS) as the gold standard in proteomics enables the semi-quantitative analysis of proteins within various tissues. Abundance differences between tumor and normal tissue also can be interpreted as tumor specific changes. The aim of this study was to identify potential tumor markers of laryngeal/hypopharyngeal SCC by revealing abundance changes between cancerous and the surrounding phenotypically healthy tissue. After separating the phenotypically cancerous and healthy parts of formalin-fixed paraffin-embedded tissues, each sample underwent protein recovery process and tryptic digestion for label-free semi-quantitative LC/MS analysis. Eight proteins showed significantly higher abundance in tumor including tenascin, transmembrane emp24 domain-containing protein 2, cytoplasmic dynein light chain 1, coactosin-like protein, small proline-rich protein 2D, nucleolin, U5 small nuclear RNP 200-kDa helicase and fatty aldehyde dehydrogenase. Desmoglein-1 and keratin type I cytoskeletal 9 were down-regulated in tumor. Using Ingenuity Pathway Analysis we mapped the signaling pathways these proteins play role in regarding other tumors. Based on these findings these proteins may serve as promising biomarkers in the fight against laryngeal/hypopharyngeal SCCs.


Widening or narrowing income inequalities in myocardial infarction? Time trends in life years free of myocardial infarction and after incidence.
Despite substantial improvements in prevention and therapy, myocardial infarction (MI) remains a frequent health event, causing high mortality and serious health impairments. Previous research lacks evidence on how social inequalities in incidence and mortality risks developed over time, and on how these developments affect the lifespan free of MI and after MI in different social subgroups. This study investigates income inequalities in MI-free life years and life years after MI and whether these inequalities widened or narrowed over time. The analyses are based on claims data of a large German health insurance provider insuring approximately 2.8 million individuals in the federal state Lower Saxony. Trends in income inequalities in incidence and mortality were assessed for all subjects aged 60 years and older by comparing the time periods 2006-2008 and 2015-2017 using multistate survival models. Trends in the number of life years free of MI and after MI were calculated separately for income groups by applying multistate life table analyses. MI incidence and mortality risks decreased over time, but declines were strongest among men and women in the higher-income group. While life years free of MI increased in men and women with higher incomes, no MI-free life years were gained in the low-income group. Among men, life years after MI increased irrespective of income group. Income inequalities in the lifespan spent free of MI and after MI widened over time. In particular, men with low incomes are disadvantaged, as life years spent after MI increased, but no life years free of MI were gained.


Quantification of seven apolipoproteins in human plasma by proteotypic peptides using fast LC-MS/MS.
We investigated different sample pretreatment strategies and developed a standardized sample pretreatment protocol for absolute quantification of seven apolipoproteins (Apos) in human serum by LC-MS/MS using proteotypic peptides and corresponding stable isotope-labeled peptides as internal standards. Micro-LC was coupled with quadrupole-linear ion trap MS for quantification and peptide confirmation. Denaturation, reduction, alkylation, and tryptic digestion including ultrasound and microwave assistance were investigated. Method comparison of 50 plasma samples with an immunoassay was performed for Apo A-I and Apo B. Tryptic digestion times ranged between 5 min (Apo A-I, Apo E, Apo A-IV) and 16 h (Apo A-II). Ultrasound and microwave assistance did not improve the digestion yield. Linearity was found between 0.1 nmol/L and 100 mmol/L. The lower limits of quantification were ≤ 0.4 μmol/L for Apo A-I, Apo A-IV, Apo B-100, Apo C-I, Apo C-III, Apo E, and <1.4 μmol/L for Apo A-II. CV <13% were determined. Comparison with immunoassays showed a good agreement for Apo A-I and Apo B. The validated preanalytical protocol enables a reliable simultaneous analysis of seven Apos in human serum without depletion. The method can now be applied in clinical studies to investigate the Apo distributions in cardiovascular diseases.


Human herpesvirus-6 reactivation and disease after allogeneic haematopoietic cell transplantation in the era of letermovir for cytomegalovirus prophylaxis.
Letermovir for cytomegalovirus (CMV) prophylaxis in allogeneic haematopoietic cell transplant (HCT) recipients has decreased anti-CMV therapy use. Contrary to letermovir, anti-CMV antivirals are also active against human herpesvirus-6 (HHV-6). We assessed changes in HHV-6 epidemiology in the post-letermovir era. We conducted a retrospective cohort study of CMV-seropositive allogeneic HCT recipients comparing time periods before and after routine use of prophylactic letermovir. HHV-6 testing was at the discretion of clinicians. We computed the cumulative incidence of broad-spectrum antiviral initiation (foscarnet, (val)ganciclovir, and/or cidofovir), HHV-6 testing, and HHV-6 detection in blood and cerebrospinal fluid within 100 days after HCT. We used Cox proportional-hazards models with stabilized inverse probability of treatment weights to compare outcomes between cohorts balanced for baseline factors. We analysed 738 patients, 376 in the pre-letermovir and 362 in the post-letermovir cohort. Broad-spectrum antiviral initiation incidence decreased from 65% (95% CI, 60-70%) pre-letermovir to 21% (95% CI, 17-25%) post-letermovir. The cumulative incidence of HHV-6 testing (17% [95% CI, 13-21%] pre-letermovir versus 13% [95% CI, 10-16%] post-letermovir), detection (3% [95% CI, 1-5%] in both cohorts), and HHV-6 encephalitis (0.5% [95% CI, 0.1-1.8%] pre-letermovir and 0.6% [95% CI, 0.1-1.9%] post-letermovir) were similar between cohorts. First HHV-6 detection occurred at a median of 37 days (interquartile range, 18-58) in the pre-letermovir cohort and 27 (interquartile range, 25-34) in the post-letermovir cohort. In a weighted model, there was no association between the pre-versus post-letermovir cohort and HHV-6 detection (adjusted hazard ratio, 1.08; 95% CI, 0.44-2.62). Despite a large decrease in broad-spectrum antivirals after the introduction of letermovir prophylaxis in CMV-seropositive allogeneic HCT recipients, there was no evidence for increased clinically detected HHV-6 reactivation and disease.


Psychometric properties of the Spanish version of the academic help seeking scale in a sample of adults.
Although academic help-seeking is an important variable in the academic context, as it is related to academic achievement, college adjustment and teacher support, among other variables, no instruments evaluate it in the Spanish adult population. The main goal of the current study was to develop an adaptation of the Academic Help-Seeking Scale for the Spanish adult population with suitable psychometric properties. The sample consisted of 536 adults with an average age of 24.98 (SD = 8.55). The exploratory factor analysis in the first half of the sample suggested that only one factor was underlying the data, and the confirmatory factor analysis in the second half showed that the factor structure replicated in a different sample. The results suggest that this adaptation has appropriate psychometric properties, and adequate reliability and convergent validity. We also found the expected relationships with gender and academic achievement. Therefore, this instrument may be useful for researchers and education professionals who need to assess this behaviour in adults so that they can help them improve their academic performance. The study also contributes to a better understanding of academic help-seeking as an adaptative learning strategy and the variables it is related to.


Presence and characterization of methicillin-resistant Staphylococcus aureus co-carrying the multidrug resistance genes cfr and lsa(E) in retail food in China.
Staphylococcus aureus is an important food-related pathogen associated with bacterial poisoning that is difficult to treat due to its multidrug resistance. The cfr and lsa(E) genes both cause multiple drug resistance and have been identified in numerous Staphylococcus species, respectively. In this study, we found that a methicillin-resistant S. aureus (MRSA) strain, 2868B2, which was isolated from a sample of frozen dumplings in Hangzhou in 2015, co-carried these two different multidrug resistance genes. Further analysis showed that this strain was resistant to more than 18 antibiotics and expressed high-level resistance to florfenicol, chloramphenicol, clindamycin, tiamulin, erythromycin, ampicillin, cefepime, ceftazidime, kanamycin, streptomycin, tetracycline, trimethoprim-sulfamethoxazole and linezolid (MIC = 8 μg/mL). Whole genome sequencing was performed to characterize the genetic environment of these resistance genes and other genomic features. The cfr gene was located on the single plasmid p2868B2 (39,159 bp), which demonstrated considerable similarity to many plasmids previously identified in humans and animals. p2868B2 contained the insertion sequence (IS) element IS21-558, which allowed the insertion of cfr into Tn558 and played an important role in the mobility of cfr. Additionally, a novel multidrug resistance region (36.9 kb) harbouring lsa(E) along with nine additional antibiotic resistance genes (ARGs) (aadD, aadE, aacA-aphD, spc, lnu(B), lsa(E), tetL, ermC and blaZ) was identified. The multidrug resistance region harboured four copies of IS257 that were active and can mediate the formation of four circular structures containing ARGs and ISs. In addition, genes encoding various virulence factors and affecting multiple cell adhesion properties were identified in the genome of MRSA 2868B2. This study confirmed that the cfr and lsa(E) genes coexist in one MRSA strain and the presence of plasmid and IS257 in the multi-ARG cluster can promote both ARG transfer and dissemination. Furthermore, the presence of so many ARGs and virulence genes in food-related pathogens may seriously compromise the effectiveness of clinical therapy and threaten public health, its occurrence should pay public attention and the traceability of these genes in food-related samples needs further surveillance.


Sodium vanadate, a tyrosine phosphatase inhibitor, affects expression of hematopoietic growth factors and extracellular matrix RNAs in SV40-transformed human marrow stromal cells.
Protein tyrosine kinases represent a subset of proteins that mediate signal transduction between the extracellular environment and the nucleus. We have previously described a coordinated upregulation between RNA transcripts of a tyrosine kinase, c-abl, and those of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 6 (IL-6) in human marrow stromal cells (SVMSC). Moreover, an inverse relationship exists between expression of c-abl transcripts and those of extracellular matrix proteins such as type collagen I transcripts. In the present study, these inverse relationships were again seen in SVMSC when tyrosine kinase effects were enhanced by treatment of the cells with the tyrosine phosphatase inhibitor sodium orthovanadate. This suggests that tyrosine kinases are involved in the coordinate regulation of these genes.


Resolution of Precapillary Pulmonary Hypertension After Liver Transplantation for Hereditary Hemorrhagic Telangiectasia: Systematic Review and Case Report.
Pulmonary hypertension (PH) is a known complication of hereditary hemorrhagic telangiectasia (HHT) in patients with hepatic arteriovenous malformations (HAVM). Orthotopic liver transplantation (OLT) is a recognized treatment of HAVM in HHT, but its effect on PH has not been reported in detail before. Systematic review on HHT patients with pre- or postcapillary PH who underwent OLT and report of a case. Twenty-one patients were included from 7 articles, all case reports or case series. All had high-output cardiac failure prior to OLT. Two patients had precapillary PH, both related to ALK1 mutations. All patients but 1 showed significant improvement or complete resolution of PH after transplantation. One patient died of acute cardiac failure postoperatively. We also report the case of a 72-year-old woman with type 3 HHT and severe mixed pre- and postcapillary PH. The patient presented with multiple HAVM, left-to-right shunting, and severe but partially reversible combined pre- and postcapillary PH, without ALK1 mutation. After recurrent cholangitis episodes, liver abscesses, and severe obstruction of the right-sided biliary tree, an interdisciplinary decision was taken to proceed with OLT despite PH. Intraoperatively, PH resolved almost instantly after hepatic artery ligation and hepatectomy. In our patient, OLT completely abrogated mixed pre- and postcapillary PH. Based on this systematic review, we suggest that OLT should be considered a viable treatment option in patients with HHT, HAVM, and mixed pre- and postcapillary PH, featuring cardiac failure and drug responsive PH, rather than being seen as a major risk factor for cardiopulmonary complications.


Subchronic dermal toxicity study of triethanolamine in C3H/HeJ mice.
Triethanolamine (TEA) was applied to the skin of male and female C3H mice (15 per sex per dose group) three times weekly for 95 days (37 applications). TEA was administered at concentrations of 0 (acetone vehicle), 10, 33 and 100% (undiluted) in a volume of 50 microliters. The approximate daily doses of TEA were 0.14, 0.46 or 2.0 g/kg per male and 0.16, 0.54 or 2.3 g/kg per female, respectively. The animals were weighted weekly and observed for clinical signs including skin irritation. 10 mice per sex per dose group were designated for clinical chemistry and haematology at terminal killing. Complete autopsies were performed, and the liver, kidneys, brain, heart, spleen, thymus and testes were weighted. Histopathology was performed on tissues from control and high-dose mice and on target organs. Treatment-related effects were limited to a slight epidermal hyperplasia at the site of application at all TEA concentrations. The results indicate that TEA caused a mild local reaction at all concentrations tested, but did not cause systemic toxicity under these conditions.


An atretic parietal cephalocele associated with multiple intracranial and eye anomalies.
We present the cranial MRI findings in a 4-month-old girl with an atretic parietal cephalocele associated with multiple cerebral and ocular anomalies including lobar holoprosencephaly, a Dandy-Walker malformation, agenesis of the corpus callosum, grey-matter heterotopia, extra-axial cysts in various locations, bilateral microphthalmia and a retroocular cyst.


Expression and characterization of styrene monooxygenases of Rhodococcus sp. ST-5 and ST-10 for synthesizing enantiopure (S)-epoxides.
Styrene monooxygenase (StyA, SMOA)- and flavin oxidoreductase (StyB, SMOB)-coding genes of styrene-assimilating bacteria Rhodococcus sp. ST-5 and ST-10 were successfully expressed in Escherichia coli. Determined amino acid sequences of StyAs and StyBs of ST-5 and ST-10 showed more similarity with those of Pseudomonas than with self-sufficient styrene monooxygenase (StyA2B) of Rhodococcus. Recombinant enzymes were purified from E. coli cells as functional proteins, and their properties were characterized in detail. StyBs (flavin oxidoreductase) of strains ST-5 and ST-10 have similar enzymatic properties to those of Pseudomonas, but StyB of strain ST-10 exhibited higher temperature stability than that of strain ST-5. StyAs of strains ST-5 and ST-10 catalyzed the epoxidation of vinyl side-chain of styrene and its derivatives and produced (S)-epoxides from styrene derivatives and showed high stereoselectivity. Both StyAs showed higher specific activity on halogenated styrene derivatives than on styrene itself. Additionally, the enzymes could catalyze the epoxidation of short-chain 1-alkenes to the corresponding (S)-epoxides. Aromatic compounds including styrene, 3-chlorostyrene, styrene oxide, and benzene exhibited marked inhibition of SMO reaction, although linear 1-alkene showed no inhibition of SMO activity at any concentration.


Retinal electrophysiological results in patients receiving lamotrigine monotherapy.
To evaluate the effects on vision in patients receiving lamotrigine (LTG) monotherapy. Twenty-four consecutive patients taking LTG for partial seizures were referred for a routine ophthalmologic examination including visual acuity testing, tonometry, slit lamp, and fundus examination. Automated kinetic perimetry, electrooculogram (EOG), and electroretinogram were performed after informed consent was obtained. In 18 patients finally included, the clinical ophthalmologic examination showed no abnormality. Four patients complained of blurring; among them, one patient had a visual field constriction in both eyes, which, however, was of unclear clinical significance (poor compliance) and a reduced light/dark ratio of the electrooculogram. One other patient with blurred vision had a reduced EOG, but the visual field was normal. Two patients had a reduced EOG but no visual symptoms. Considering the whole group of patients receiving LTG therapy, the light/dark ratio of the EOG was reduced in a dose-dependent fashion (p < 0.0001). The electroretinogram was normal in all patients. No irreversible visual field impairment in patients treated with LTG was encountered, although a dose-dependent retinal toxicity may have been present. The exact cellular mechanism of the electrophysiologic changes in patients taking LTG remain to be explained.


Evolution of LuxR solos in bacterial communication: receptors and signals.
Cell-cell communication in bacteria needs chemical signals and cognate receptors. Many Gram-negative bacteria use acyl-homoserine lactones (AHLs) and cognate LuxR-type receptors to regulate their quorum sensing (QS) systems. The signal synthase-receptor (LuxI-LuxR) pairs may have co-evolved together. However, many LuxR solo (orphan LuxR) regulators sense more signals than just AHLs, and expand the regulatory networks for inter-species and inter-kingdom communication. Moreover, there are also some QS regulators from the TetR family. LuxR solo regulators might have evolved by gene duplication and horizontal gene transfer. An increased understanding of the evolutionary roles of QS regulators would be helpful for engineering of cell-cell communication circuits in bacteria.


The relationship between big five personality traits, coping strategies, and emotional problems through the COVID-19 pandemic.
Considering the impact of pandemic condition on mental health and functioning in daily life, the main purpose of this study was to investigate the relationship between Big Five personality traits, coping strategies and emotional problems such as symptoms of depression and anxiety, during the COVID-19 pandemic period. Specifically, the purpose of this study is to create a model of the impact of coping strategies as mediating factors in the relationship between Big Five personality traits personality traits and emotional problems. For the purposes of this study, a sample of 200 Kosovar respondents was used, where the age of the participants varies from 18 to 54 years. As a result of the pandemic situation created, the method of data collection for this study was done in the form of self-reporting, divided into physical questionnaires and online ones. The BFI Personality Inventory is used to classify Big Five personality traits, the Coping Control Checklist (WCCL) to classify coping strategies, and the Adult Self-Reporting Questionnaire (ASR) used to identify emotional problems. The analysis of the results in this study was done by means of the statistical package of SPSS and R program. After the analysis, it is seen that there is a significant correlation between Big Five personality traits (extraversion and neuroticism) and coping strategies (seeking social support and avoidance), as well as there is a correlation between Big Five personality traits (compliance and neuroticism) and emotional problems (symptoms of anxiety and depression). An association was also found between coping strategies (avoidance) and emotional problems (anxiety symptoms). As for gender differences in experiencing anxiety and depression symptoms and using desired thoughts as coping strategies, it was found that women are more predisposed to experience anxiety symptoms and use desired thoughts than men. The findings highlighted the part that coping strategies are significant mediator factors in the relationship between Big Five personality traits and emotional problems.


Autoimmune response in cartilage-delivered peptides in a patient with osteoarthritis.
Whatever the initiating factor of osteoarthritis (OA), the process ultimately unmasks the immunogenic determinants of chondrocytes, proteoglycans and collagens, which then triggers autoimmune reactions. Although the precise mechanism of the immune responses in the pathogenesis of OA requires further investigation, here I postulate that the presence of autoimmunity to cartilage components has an important role in the process of cartilage degradation in OA. Current studies strongly suggest that a immunoregulatory therapeutic strategy should be established.


Pulmonary vein isolation in cases of difficult catheter placement: a new pacing maneuver to demonstrate complete isolation of the veins.
Pulmonary vein electrical isolation is the main goal of atrial fibrillation ablation. To ensure electrical isolation of the pulmonary veins, entrance and exit block should be demonstrated. However, this is sometimes challenging due to the complex anatomy of the pulmonary vein area and the anatomical variations that may preclude the correct position of the commonly used circular multielectrode catheter inside the veins. To describe a new pacing maneuver useful to demonstrate complete isolation of ipsilateral veins in cases of difficult catheter placement. Three representative cases illustrate the usefulness of the maneuver either at the right or left pulmonary veins. After the circumferential ablation of ipsilateral veins, the circular catheter is positioned in one vein and the ablation catheter in the other ipsilateral vein. When local capture in one vein can be demonstrated while pacing from the other vein and no conduction to the atria is observed, isolation of both veins can be assured. This novel maneuver might be of help in assessing complete isolation of the pulmonary veins in cases of difficult circular catheter placement.


Caries-preventive efficacy and retention of a resin-modified glass ionomer cement and a resin-based fissure sealant: a 3-year split-mouth randomised clinical trial.
This prospective clinical trial compared the retention rate and caries-preventive efficacy of two types of sealant modalities over a 3-year period. Using a split-mouth randomised design, 1280 sealants were randomly applied on sound permanent second molars of 320 young patients aged between 12 and 16 years. Half of the teeth (n = 640) were sealed with a resin-modified glass ionomer cement (RMGIC) (Vitremer™, 3M ESPE) and the other half (n = 640) with a conventional light-cure, resin-based fissure sealant (LCRB) (Fluoroshield®, Dentsply Caulk). Teeth were evaluated at baseline, 6-, 12-, 18-, 24-, 30- and 36-month intervals with regard to retention and new caries development. On the sealed occlusal surfaces after 3 years, 5.10% of RMGIC and 91.08% of LCRB sealants were totally intact and 6.37% of RMGIC and 7.65% of LCRB sealants were partially intact. New caries lesions were found in 20.06% of RMGIC sealed occlusal surfaces, compared to 8.91% for LCRB sealants. The findings of the present clinical study suggest that RMGIC should be used only as a transitional sealant that can be applied to newly erupting teeth throughout the eruptive process, whereas LCRB sealants are used to successfully prevent occlusal caries lesions once an effective rubber dam can be achieved. It can be concluded that there are differences between the RMGIC and LCRB sealants over a 3-year period in terms of the retention rate and caries-preventive efficacy. RMGIC can serve as a simple and economic sealing solution, however provisional. Due to its poor retention rate, periodic recalls are necessary, even after 6 months, to eventually replace the lost sealant.


Elaboration and surface modification of structured poly(L-lactic acid) thin film on various substrates.
Biosourced or biodegradable polymers like poly(lactic acid) (PLA) are often base-material for tissue-engineered scaffolds. However, in most of the cases, their bioadhesion properties are not satisfactory. Since the adhesion is controlled both by roughness and surface chemistry, PLA films were textured by applying the breath figure procedure and, then, plasma-treated. Depending on physicochemical characteristics of the breath figure technique, nice hexagonal structures were obtained. Their surface properties, i.e. hydrophobic-hydrophilic balance were controlled by plasma modification. However, their surface decoration could be only preserved with some specific plasma parameters depending on the applied energy and also on the induced surface chemistry.


Biomedical applications of MnO2 nanomaterials as nanozyme-based theranostics.
Manganese dioxide (MnO2) nanoenzymes/nanozymes (MnO2-NEs) are 1-100 nm nanomaterials that mimic catalytic, oxidative, peroxidase, and superoxide dismutase activities. The oxidative-like activity of MnO2-NEs makes them suitable for developing effective and low-cost colorimetric detection assays of biomolecules. Interestingly, MnO2-NEs also demonstrate scavenging properties against reactive oxygen species (ROS) in various pathological conditions. In addition, due to the decomposition of MnO2-NEs in the tumor microenvironment (TME) and the production of Mn2+, they can act as a contrast agent for improving clinical imaging diagnostics. MnO2-NEs also can use as an in situ oxygen production system in TME, thereby overcoming hypoxic conditions and their consequences in the progression of cancer. Furthermore, MnO2-NEs as a shell and coating make the nanosystems smart and, therefore, in combination with other nanomaterials, the MnO2-NEs can be used as an intelligent nanocarrier for delivering drugs, photosensitizers, and sonosensitizers in vivo. Moreover, these capabilities make MnO2-NEs a promising candidate for the detection and treatment of different human diseases such as cancer, metabolic, infectious, and inflammatory pathological conditions. MnO2-NEs also have ROS-scavenging and anti-bacterial properties against Gram-positive and Gram-negative bacterial strains, which make them suitable for wound healing applications. Given the importance of nanomaterials and their potential applications in biomedicine, this review aimed to discuss the biochemical properties and the theranostic roles of MnO2-NEs and recent advances in their use in colorimetric detection assays of biomolecules, diagnostic imaging, drug delivery, and combinatorial therapy applications. Finally, the challenges of MnO2-NEs applications in biomedicine will be discussed.


'True' bosonic coupling strength in strongly correlated superconductors.
Clarifying the coupling between electrons and bosonic excitations (phonons or magnetic fluctuations) that mediate the formation of Cooper pairs is pivotal to understand superconductivity. Such coupling effects are contained in the electron self-energy, which is experimentally accessible via angle-resolved photoemission spectroscopy (ARPES). However, in unconventional superconductors, identifying the nature of the electron-boson coupling remains elusive partly because of the significant band renormalization due to electron correlation. Until now, to quantify the electron-boson coupling, the self-energy is most often determined by assuming a phenomenological 'bare' band. Here, we demonstrate that the conventional procedure underestimates the electron-boson coupling depending on the electron-electron coupling, even if the self-energy appears to be self-consistent via the Kramers-Kronig relation. Our refined method explains well the electron-boson and electron-electron coupling strength in ruthenate superconductor Sr2RuO4, calling for a critical revision of the bosonic coupling strength from ARPES self-energy in strongly correlated electron systems.


Characterization of the ribosomal DNA from Trichinella spiralis.
Ribosomal DNA (rDNA) from three isolates of Trichinella was cloned into phage and sublcloned into the plasmid pBR322. The basic repeat unit of rDNA was variable in size, with the mapped clones ranging from 10-12 kb. There were differences in restriction sites within the genic region among the three isolates which were due to variations in the internal transcribed region (ITS) and the intergenic spacer (IGS). Three RsaI sites were mapped to the IGS repeat unit of the isolate AF1, and one RsaI site was mapped to the IGS repeat unit of Trichinella spiralis pseudospiralis (isolate Tp). The number of repetitive units in the IGS region varied markedly within and between the isolates. It was estimated that the basic repeat unit for the rDNA of isolate P1 was 10.6-28 kb, for AF1 10.7-37 kb, and for Tp it was 11-14.9 kb. There appeared to be a greater frequency of some sizes of the basic repeat unit in each of the populations, based on the relative intensity with which certain bands hybridize to the probe.


Electrorotation of single microalgae cells during lipid accumulation for assessing cellular dielectric properties and total lipid contents.
Photosynthetic microalgae not only perform fixation of carbon dioxide but also produce valuable byproducts such as lipids and pigments. However, due to the lack of effective tools for rapid and noninvasive analysis of microalgal cellular contents, the efficiency of strain screening and culture optimizing is usually quite low. This study applied single-cell electrorotation on Scenedesmus abundans to assess cellular dielectric properties during lipid accumulation and to promptly quantify total cellular contents. The experimental electrorotation spectra were fitted with the double-shell ellipsoidal model, which considered varying cell wall thickness, to obtain the dielectric properties of cellular compartments. When the amount of total lipids increased from 15.3 wt% to 33.8 wt%, the conductivity and relative permittivity of the inner core (composed of the cytoplasm, lipid droplets, and nucleus) decreased by 21.7% and 22.5%, respectively. These dielectric properties were further used to estimate the total cellular lipid contents by the general mixing formula, and the estimated values agreed with those obtained by weighing dry biomass and extracted lipids with an error as low as 0.22 wt%. Additionally, the conductivity and relative permittivity of cell wall increased during nitrogen-starvation conditions, indicating the thickening of cell wall, which was validated by the transmission electron microscopy.


Commentary on: "Enzalutamide monotherapy in hormone-naive prostate cancer: primary analysis of an open-label, single-arm, phase 2 study." Tombal B, Borre M, Rathenborg P, Werbrouck P, Van Poppel H, Heidenreich A, Iversen P, Braeckman J, Heracek J, Baskin-Bey E, Ouatas T, Perabo F, Phung D, Hirmand M, Smith MR. Institut de Recherche Clinique, Université Catholique de Louvain, Brussels, Belgium. Electronic address: email@example.com. Aarhus University Hospital, Aarhus, Denmark. Herlev Hospital, Herlev, Denmark. AZ Groeninge Kortrijk, Kortrijk, Belgium. UZ Leuven, Leuven, Belgium. Klinik und Poliklinik für Urologie, RWTH University Aachen, Aachen, Germany. Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. UZ Brussel, Brussels, Belgium. Univerzita Karlova v Praze, Prague, Czech Republic. Astellas Pharma Global Development, Leiden, Netherlands. Astellas Pharma Global Development, Northbrook, IL, USA. Medivation Inc, San Francisco, CA, USA. Massachusetts General Hospital Cancer Center, Boston, MA, USA: Lancet Oncol. 2014 May;15(6):592-600; doi: 10.1016/S1470-2045(14)70129-9. [Epub 2014 Apr 14].
The androgen receptor inhibitor enzalutamide is approved for the treatment of metastatic castration-resistant prostate cancer that has progressed on docetaxel. Our aim was to assess the activity and safety of enzalutamide monotherapy in men with hormone-naive prostate cancer. This trial is an ongoing open-label, single-arm, phase 2 study, done across 12 European sites. Men aged over 18 years with hormone-naive prostate cancer for whom hormone therapy was indicated, and who had noncastration levels of testosterone and prostate-specific antigen (PSA) of 2ng/mL or greater at screening, and an Eastern Cooperative Oncology Group score of 0, received oral enzalutamide 160mg/day. The primary outcome was the proportion of patients with an 80% or greater decline in PSA at week 25. All analyses included all patients who had received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT01302041. 67 men were enrolled into the study. 62 patients (92.5%, 95% CI: 86.2-98.8) had a decline in PSA of 80% or greater at week 25. The most commonly reported treatment-emergent adverse events up to week 25 were gynaecomastia (n = 24), fatigue (n = 23), nipple pain (n = 13), and hot flush (n = 12), all of which were of mild to moderate severity. Overall, 9 patients had a treatment-emergent adverse event of grade 3 or higher, most of which were reported in one patient each, except for pneumonia (grade 3, two patients) and hypertension (grade 3, four patients). Five patients reported serious adverse events, none of which were deemed to be treatment related. Our findings suggest that enzalutamide monotherapy in men with hormone-naive prostate cancer of varying severity provides a level of disease suppression and was generally well tolerated. These findings provide a rationale for further investigation of clinical response and outcomes with enzalutamide in noncastrated men with prostate cancer.


Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the in vivo and in vitro dechlorination of pentachlorophenol.
The metabolism of pentachlorophenol has been studied in the rat after pretreatments with phenobarbital, 3-methyl cholanthrene or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In addition to the previously identified metabolite, tetrachloro-p-hydroquinone, trichloro-p-hydroquinone has been identified in urine as a metabolite. The formation of the latter represents a type dechlorination different from that of the formation of tetrachlorohydroquinone. The inducing agents, 3-methylcholanthrene and TCDD have similar effects on the dechlorination and increase the formation of tetrachloro-p-hydroquinone more pronounced than does phenobarbital. In contrast to phenobarbital they also increase the formation of trichloro-p-hydroquinone and the total elimination of pentachlorophenol and its metabolites. The in vivo findings are supported by in vitro studies with microsomes from rats pretreated with phenobarbital or TCDD. Use of the inhibitor beta-diethylaminoethyl-diphenyl propylacetate (SKF 525-A) in vitro showed a more pronounced inhibition on microsomes from phenobarbital-treated rats than on microsomes from untreated or TCDD-treated rats. Gas chromatography-mass spectrometry have been used for the identification and quantification of pentachlorophenol and its metabolites.


Re-laparotomy after cesarean section: operative complications in surgical delivery.
To determine the risk factors causing re-laparotomy and the indications, management and outcomes of re-laparotomy after a cesarean section. We had, during the study period of January 2002 to January 2007, 28,799 cesarean sections and 35 cases with re-laparotomy. We studied the patients' age, parity, indications for cesarean section and indications for re-laparotomy, time interval after cesarean section to reopening of the abdomen, type of surgery, need for blood transfusion and span of hospital stay. The incidence of re-laparotomy was 0.12%. Cases with placental abruption and previous cesarean > or =3 had a higher risk for re-laparotomy. Procedures that were performed at re-laparotomy were drainage and resuturing of hematomas (n = 8), resuturing of uterus and securing hemostasis with stitches (n = 10), bladder repair (n = 1), herniation repair (n = 1), total abdominal hysterectomy (n = 2), subtotal abdominal hysterectomy (n = 5), and draining and resuturing of broad ligament, parametrium, abdominal wound, and cutaneous and subcutaneous tissue due to infection and abscess formation (n = 8). Two cases required admission into the intensive care unit. We had one case with maternal mortality. Majority of the complications were revealed at an early period and these were hemorrhagic cases mostly. Although the rate of re-laparotomy after cesarean section is low, several actions must be undertaken to decrease the need for re-laparotomy. In particular, cases with placental abruption and previous cesarean > or =3 are with higher risk for re-laparotomy and have a 15-fold risk for re-laparotomy after cesarean section.


Detection of claudin-4 in salivary gland neoplasms (a study utilizing RT-PCR and immunohistochemistry).
Claudins are transmembrane proteins of tight junctions emerging as targets for diagnosis, prediction of prognosis, disease recurrence, and metastasis. Our goal was to evaluate expression of claudin-4 in the most common benign and malignant salivary gland neoplasms. Claudin-4 gene levels and protein expression were determined by real-time polymerase chain reaction (PCR), and immunohistochemistry in a total of 30 specimens containing normal salivary tissue, pleomorphic adenoma, Warthin's tumor, mucoepidermoid carcinoma, and adenoid cystic carcinoma. We identified down-regulation of claudin-4 gene levels and protein expression from normal control to benign salivary gland neoplasms and reached their lowest values in the malignant salivary gland neoplasms. Low claudin-4 expression could be considered as a sign of increasing cellular disorientation and invasion of salivary gland tumors.


Haemophilus pittmaniae respiratory infection in a patient with siderosis: a case report.
Haemophilus pittmaniae was described in 2005 as a new species distantly related to Haemophilus parainfluenzae. This member of the human saliva microbiota has also been further isolated from various body fluids without formal description of the patients. We report the case of H. pittmaniae isolate made from a sputum specimen collected from a 58-year-old Caucasian man with a massive fibrotic form of siderosis who was awaiting lung transplantation. Identification of the isolate was ascertained by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and 16S rRNA gene sequencing. H. pittmaniae was considered to be responsible for the worsening of the patient's chronic respiratory failure and was successfully treated with oral amoxicillin. H. pittmaniae should be regarded as a new pathogen responsible for respiratory tract infection in patients with chronic lung diseases.


Alteration of the visual evoked potential by macular holes: comparison with optic neuritis.
Nine patients with maculopathy (macular holes, macular cysts, and lamellar holes) and ten patients with optic neuritis were examined in order to determine changes in the visual evoked potential (VEP) in response to pattern-reversal stimulation. Eyes with lamellar holes had normal P100 latency, but eyes with macular cysts and macular holes had prolonged P100 latency. Eyes with optic neuritis exhibited greater prolongation of the P100 latency than eyes with macular holes. In contrast, eyes with macular holes had a greater reduction in the steady-state VEP amplitude than eyes with optic neuritis. The prolonged latency occurring in maculopathy may be due to a peculiar amplitude summation noted with half-field VEP, rather than to a true conduction delay like that seen in eyes with optic neuritis. The amplitude slope, which is usually positive in normal controls, was negative for 85.7% of eyes with macular holes and 69.2% of eyes with optic neuritis. The negative amplitude slope may represent a subtle defect in retinal ganglion X cells. Eyes with significantly lower values for four or more of the nine central test points on quantitative automated perimetry had negative amplitude slopes and prolonged P100 latency.


The influence of genetic counselors on the acceptance of mid-trimester amniocentesis.
To determine the effect of the genetic counselor on the acceptance of genetic amniocentesis. We studied women with singleton pregnancies who would be at least 35 years of age at the estimated date of delivery without fetal structural anomalies or family history of chromosomal abnormalities. The acceptance rate of genetic amniocentesis among women evaluated by each counselor was compared with the average acceptance rate for our population. Chi-square test, Fisher exact test and ANOVA were used for analysis. Of the 2,180 women met our inclusion criteria, 1,719 (78.9%) accepted genetic amniocentesis. The maternal age at estimated date of delivery, the proportion of women who conceived by in vitro fertilization, and the proportion with history of miscarriage were similar among women evaluated by each of the six genetic counselors. However, the acceptance rate of genetic amniocentesis was significantly lower in women evaluated by counselor C [115/170 (67.6%), P=0.001] and significantly higher in the group evaluated by counselor D [138/154 (89.6%), P=0.002] compared with the overall study population rate [1719/2180 (78.9%)]. The acceptance rate of 80.4% (210/261, P=0.52), 75.6 % (232/307, P=0.23), 80.9% (443/547, P=0.30] and 78.4% (581/741, P=0.83) for Counselors A, B, E and F respectively did not differ from the overall study population rate. Considerable variation exists in the acceptance rate of genetic amniocentesis among women based on the genetic counselor.