Stroke Lesion Segmentation in FLAIR MRI Datasets Using Customized Markov Random Fields.
Robust and reliable stroke lesion segmentation is a crucial step toward employing lesion volume as an independent endpoint for randomized trials. The aim of this work was to develop and evaluate a novel method to segment sub-acute ischemic stroke lesions from fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) datasets. After preprocessing of the datasets, a Bayesian technique based on Gabor textures extracted from the FLAIR signal intensities is utilized to generate a first estimate of the lesion segmentation. Using this initial segmentation, a customized voxel-level Markov random field model based on intensity as well as Gabor texture features is employed to refine the stroke lesion segmentation. The proposed method was developed and evaluated based on 151 multi-center datasets from three different databases using a leave-one-patient-out validation approach. The comparison of the automatically segmented stroke lesions with manual ground truth segmentation revealed an average Dice coefficient of 0.582, which is in the upper range of previously presented lesion segmentation methods using multi-modal MRI datasets. Furthermore, the results obtained by the proposed technique are superior compared to the results obtained by two methods based on convolutional neural networks and three phase level-sets, respectively, which performed best in the ISLES 2015 challenge using multi-modal imaging datasets. The results of the quantitative evaluation suggest that the proposed method leads to robust lesion segmentation results using FLAIR MRI datasets only as a follow-up sequence.


Drug-induced endocrine disorders in the intensive care unit.
The neuroendocrine response to critical illness is key to the maintenance of homeostasis. Many of the drugs administered routinely in the intensive care unit significantly impact the neuroendocrine system. These agents can disrupt the hypothalamic-pituitary-adrenal axis, cause thyroid abnormalities, and result in dysglycemia. Herein, we review major drug-induced endocrine disorders and highlight some of the controversies that remain in this area. We also discuss some of the more rare drug-induced syndromes that have been described in the intensive care unit. Drugs that may result in an intensive care unit admission secondary to an endocrine-related adverse event are also included. Unfortunately, very few studies have systematically addressed drug-induced endocrine disorders in the critically ill. Timely identification and appropriate management of drug-induced endocrine adverse events may potentially improve outcomes in the critically ill. However, more research is needed to fully understand the impact of medications on endocrine function in the intensive care unit.


[Mechanism of the interaction of the anticancer antibiotic adriamycin (doxorubicin) with the anion radical O2].
Interaction of the O2. anion radical with adriamycin in water-acetonitrile mixtures was studied by UV-spectroscopy. It was shown that with changing of the water content in the reaction mixture from 0 to 90 per cent O2. practically irreversibly reacted with adriamycin to form the same product. The spectrum of the reaction product was shifted to the long-wave region as compared to that of adriamycin and depended on the solvent composition. In the presence of the proton donors the "regeneration" of the absorption spectrum of the starting antibiotic was observed. To investigate the mechanism of the reaction product formation, electrochemical reduction of adriamycin and its reaction with benzosemiquinone and alkali were studied. Formation of the same compound under the different conditions showed that the primary step of O2. interaction with adriamycin was one electron reduction of the antibiotic. The study suggested the reaction mechanism involving formation of adriamycin semiquinone as a result of the electron transfer from the O2. molecule, splitting out of the sugar moiety and reduction of deoxyaglycone semiquinone into anion of deoxyaglycone tautomer. The possible role of the oxygen anion radical in the mechanism of activation of adriamycin and other anthracycline antibiotics is discussed.


Disease-specific, neurosphere-derived cells as models for brain disorders.
There is a pressing need for patient-derived cell models of brain diseases that are relevant and robust enough to produce the large quantities of cells required for molecular and functional analyses. We describe here a new cell model based on patient-derived cells from the human olfactory mucosa, the organ of smell, which regenerates throughout life from neural stem cells. Olfactory mucosa biopsies were obtained from healthy controls and patients with either schizophrenia, a neurodevelopmental psychiatric disorder, or Parkinson's disease, a neurodegenerative disease. Biopsies were dissociated and grown as neurospheres in defined medium. Neurosphere-derived cell lines were grown in serum-containing medium as adherent monolayers and stored frozen. By comparing 42 patient and control cell lines we demonstrated significant disease-specific alterations in gene expression, protein expression and cell function, including dysregulated neurodevelopmental pathways in schizophrenia and dysregulated mitochondrial function, oxidative stress and xenobiotic metabolism in Parkinson's disease. The study has identified new candidate genes and cell pathways for future investigation. Fibroblasts from schizophrenia patients did not show these differences. Olfactory neurosphere-derived cells have many advantages over embryonic stem cells and induced pluripotent stem cells as models for brain diseases. They do not require genetic reprogramming and they can be obtained from adults with complex genetic diseases. They will be useful for understanding disease aetiology, for diagnostics and for drug discovery.


Pacing therapy for atrial tachyarrhythmias.
The use of pacing techniques for the treatment of atrial tachyarrhythmias has been advocated for more than 30 years. Although it has played a beneficial role in the management of paroxysmal supraventricular tachycardia (PSVT) in drug-refractory patients, tachycardia acceleration and development of atrial fibrillation has been the major drawback. With the availability of radiofrequency catheter ablation therapy, the use of implantable antitachycardia devices for PSVT is currently negligible. From retrospective and small control studies it has been shown that atrial or dual-chamber pacing in patients with sick sinus syndrome has been associated with a lower incidence of paroxysmal atrial flutter or fibrillation than in those who received a ventricular pacemaker. Furthermore, recent studies have reported the potential benefit of reducing frequency of paroxysmal atrial flutter and fibrillation with multisite atrial pacing. As a result, there is a resurgence of research interest in antitachycardia pacing for prevention of atrial tachyarrhythmias. This paper briefly describes the basic aspects of antitachycardia pacing, reviews the data on the use of implantable antitachycardia devices for PSVT and the selection of patients, and assesses the current status of research on atrial pacing for prevention of paroxysmal atrial flutter and fibrillation.


Use of damage control and the open abdomen in combat.
Despite the well-documented use of damage control laparotomy (DCL) in civilian trauma, its use has not been well described in the combat setting. Therefore, we sought to document the use of DCL and to investigate its effect on patient outcome. Prospective data were collected on 1603 combat casualties injured between April 2003 and January 2009. One hundred seventy patients (11%) underwent an exploratory laparotomy (ex lap) in theater and comprised the study cohort. DCL was defined as an abbreviated ex lap resulting in an open abdomen. Patients were stratified by age, Injury Severity Score (ISS), Glasgow Coma Score (GCS), mechanism of injury, and blood product administration. Multivariate regression analyses were used to determine risks factors for intensive care unit length of stay (ICU LOS), hospital length of stay (HLOS), and the need for DCL. Mean age of the cohort was 24 ± 5 years, ISS was 21 ± 11, and 94 per cent sustained penetrating injury. Patients with DCL comprised 50.6 per cent (n = 86) of the study cohort and had significant increases in ICU admission (P < 0.001), ICU LOS (P < 0.001), HLOS (P < 0.05), ventilator days (P < 0.001), abdominal complications (P < 0.05), but not mortality (P = 0.65) compared with patients without DCL. When compared with the non-DCL group, patients undergoing DCL required significantly more blood products (packed red blood cells, fresh-frozen plasma, platelets, and cryoprecipitate; P < 0.001). Multivariate regression analyses revealed blood transfusion and GCS as significant risk factors for DCL (P < 0.05). Patients undergoing DCL had increased complications and resource use but not mortality compared with patients not undergoing DCL. The need for combat DCL may be different compared with civilian use. Prospective studies to evaluate outcomes of DCL are warranted.


Immune Response Following Quadrivalent Human Papillomavirus Vaccination in Women After Hematopoietic Allogeneic Stem Cell Transplant: A Nonrandomized Clinical Trial.
Human papillomavirus (HPV) infection is found in about 40% of women who survive allogeneic hematopoietic stem cell transplant and can induce subsequent neoplasms. To determine the safety and immunogenicity of the quadrivalent HPV vaccine (HPV-6, -11, -16, and -18) in clinically stable women post-allogeneic transplant compared with female healthy volunteers. Participants received the quadrivalent HPV vaccine in intramuscular injections on days 1 and 2 and then 6 months later. This prospective, open-label phase-1 study was conducted in a government clinical research hospital and included clinically stable women posttransplant who were or were not receiving immunosuppressive therapy compared with healthy female volunteers age 18 to 50 years who were followed up or a year after first receiving quadrivalent HPV vaccination. The study was conducted from June 2, 2010, until July 19, 2016. After all of the results of the study assays were completed and available in early 2018, the analysis took place from February 2018 to May 2019. Anti-HPV-6, -11, -16, and -18-specific antibody responses using L1 virus-like particle enzyme-linked immunosorbent assay were measured in serum before (day 1) and at months 7 and 12 postvaccination. Anti-HPV-16 and -18 neutralization titers were determined using a pseudovirion-based neutralization assay. Of 64 vaccinated women, 23 (35.9%) were receiving immunosuppressive therapy (median age, 34 years [range, 18-48 years]; median 1.2 years posttransplant), 21 (32.8%) were not receiving immunosuppression (median age, 32 years [range, 18-49 years]; median 2.5 years posttransplant), and 20 (31.3%) were healthy volunteers (median age, 32 years [range, 23-45 years]). After vaccine series completion, 18 of 23 patients receiving immunosuppression (78.3%), 20 of 21 not receiving immunosuppression (95.2%), and all 20 volunteers developed antibody responses to all quadrivalent HPV vaccine types (P = .04, comparing the 3 groups). Geometric mean antibody levels for each HPV type were higher at months 7 and 12 than at baseline in each group (all geometric mean ratios >1; P < .001) but not significantly different across groups. Antibody and neutralization titers for anti-HPV-16 and anti-HPV-18 correlated at month 7 (Spearman ρ = 0.92; P < .001 for both). Adverse events were mild and not different across groups. Treatment with the HPV vaccination was followed by strong, functionally active antibody responses against vaccine-related HPV types and no serious adverse events. These findings suggest that HPV vaccination may be safely administered to women posttransplant to potentially reduce HPV infection and related neoplasia. ClinicalTrials.gov Identifier: NCT01092195.


The relationship between lumbar lordosis and radiologic variables and lumbar lordosis and clinical variables in elderly, African-American women.
Several authors have hypothesized that there is a link between lumbar lordosis and low back pain. These relationships have not been previously described in a sample consisting exclusively of elderly, African-American women. The purpose of this study was to describe the relationship between lumbar lordosis and radiologic variables and lumbar lordosis and clinical variables in elderly, African-American women. A total of 475 African-American women enrolled in the multicenter Study of Osteoporotic Fractures participated in this ancillary, cross-sectional, study of lumbar lordosis. These women received lumbar spine radiographs and completed a questionnaire on low back pain and its impact on their daily lives. Lumbar lordosis tertiles were created based on radiographic measurements. Comparisons were made between the tertiles for differences in radiologic and clinical variables. Significant differences (p < 0.0025) were observed between the lordosis tertiles and the presence of spondylolisthesis, intervertebral disc space, and vertebral wedging. No significant differences were observed between the lordosis tertiles for the occurrence of low back pain, symptoms associated with low back pain, and disability experienced from low back pain. The degree of lumbar lordosis was associated with radiologic variables but was not associated with symptoms or decreased function from low back pain. These findings question the clinical utility of the lumbar lordosis measurement in elderly, African-American women.


Predicted influence of sample hematocrit on injected mass of internal standard in mass spectrometry assays utilizing simple protein precipitation for sample preparation.
The injected mass of internal standard is often monitored in mass spectrometry assays to flag aberrant specimen processing. When simple protein precipitation is used for sample preparation, the protein volume (solids fraction) of the specimen is in principle a variable affecting the final concentration of the internal standard in the liquid phase. We examined the predicted extent of this variation for an example of protein precipitation for sample preparation used in a mass spectrometry assay for immunosuppressants in whole blood. Liquid and solid mass fractions of samples with hematocrit ranging from 15% to 60% were measured after protein precipitation of samples using a whole blood/precipitating reagent ratio of 1:4. Relative supernatant volumes as a function of hematocrit were determined. Liquid volume variation was consistent with a predicted variation in the internal standard concentration of only approximately +/-1% across this hematocrit range. Data were in close agreement with calculations based simply on protein density and concentration. Hematocrit affects the injected mass of internal standard in assays that utilize protein precipitation for sample preparation, due to predictable variation in solids and liquid fractions. The effect is small, however, compared to the typical variation observed for injected mass of internal standard.


Co-assembling peptides as defined matrices for endothelial cells.
Self-assembling peptides and peptide derivatives bearing cell-binding ligands are increasingly being investigated as defined cell culture matrices and as scaffolds for regenerative medicine. In order to systematically refine such scaffolds to elicit specific desired cell behaviors, ligand display should ideally be achieved without inadvertently altering other physicochemical properties such as viscoelasticity. Moreover, for in vivo applications, self-assembled biomaterials must exhibit low immunogenicity. In the present study, multi-peptide co-assembling hydrogels based on the beta-sheet fibrillizing peptide Q11 (QQKFQFQFEQQ) were designed such that they presented RGDS or IKVAV ligands on their fibril surfaces. In co-assemblies of the ligand-bearing peptides with Q11, ligand incorporation levels capable of influencing the attachment, spreading, morphology, and growth of human umbilical vein endothelial cells (HUVECs) did not significantly alter the materials' fibrillization, beta-turn secondary structure, or stiffness. RGDS-Q11 specifically increased HUVEC attachment, spreading, and growth when co-assembled into Q11 gels, whereas IKVAV-Q11 exerted a more subtle influence on attachment and morphology. Additionally, Q11 and RGDS-Q11 were minimally immunogenic in mice, making Q11-based biomaterials attractive candidates for further investigation as defined, modular extracellular matrices for applications in vitro and in vivo.


Inhibition of barnacle larval settlement and crustacean toxicity of some hoplonemertine pyridyl alkaloids.
Hoplonemertines are carnivorous marine worms, which prey upon crustaceans and annelids. They paralyze their prey by injecting alkaloids with a stylet-bearing proboscis. The dermis of these animals also secretes alkaloids to repel predators. Besides affecting central and peripheral nervous system nicotinic receptors, some pyridyl alkaloids also activate certain chemoreceptor neurons in crustacean walking legs, which sense environmental chemicals. Anabaseine (2-[3-pyridyl]-3,4,5,6-tetrahydropyridyl) and 2,3'-bipyridyl (2,3'-BP) are two nemertine alkaloids, which potently paralyze crustaceans. Anabaseine is an agonist of vertebrate as well as invertebrate nicotinic receptors. While 2,3'-BP is non-toxic to mice, it is toxic to crustaceans. We tested a variety of nemertine pyridyl alkaloids for inhibition of barnacle (Balanus amphitrite) larval settlement and for crustacean toxicity in order to determine whether toxicity could be dissociated from inhibition of larval settlement. We prepared eight C-methylated 2,3'-BP isomers to determine where substitution is permitted without loss of activity. Anti-settlement and toxicity activities were not always related. For instance, 4'-methyl-2,3'-BP displayed only 3% of the crayfish paralytic activity of 2,3'-BP, but inhibited settlement almost 2-fold more effectively. Two other isomers displaying exceptional anti-settlement activity were the 4- and 5-methyl-2,3'-BPs; these also displayed high crustacean toxicity. Nemertelline inhibited barnacle settlement at concentrations similar to 2,3'-BP but was 136-fold less toxic when injected into crayfish. Thus, certain bipyridyls and tetrapyridyls may be useful anti-fouling additives.


Antithrombin III infusion improves anticoagulation in congenital diaphragmatic hernia patients on extracorporeal membrane oxygenation.
Achieving effective anticoagulation during neonatal extracorporeal membrane oxygenation (ECMO) without increasing the risk of hemorrhage remains challenging. The use of antithrombin III (AT-III) for this purpose has been examined, but studies have been limited to intermittent bolus dosing. We aimed to evaluate the efficacy and safety of an institutionally developed AT-III continuous infusion protocol in neonates receiving ECMO for the treatment of congenital diaphragmatic hernia (CDH). In this single center, retrospective study, all neonates with a CDH who received ECMO support during the study period were included. Data on anticoagulation labs and therapy, life-threatening bleeding, and circuit changes were analyzed. Eleven patients were divided into two groups: patients with AT-III continuous infusion (n = 5) and without (n = 6). There were no differences in the gestational age (p = 0.29), sex (p = 1.00), ECMO duration (p = 0.59), or initial AT-III levels (p = 0.76) between groups. Patients in the AT-III infusion group had on average 18.5% higher AT-III levels (p < 0.0001). Patients receiving continuous AT-III infusions spent a significantly higher percentage of ECMO time within the therapeutic range, measured using anti-Factor Xa levels (64.9±4.2% vs. 29.1±8.57%, p = 0.008), and required fewer changes to the heparin infusion rate (6.48±0.88 vs 2.38±0.36 changes/day changes/day, p = 0.005). Multivariate analysis revealed continuous infusion of AT-III did not increase the rate of intracranial or surgical bleeding (p = 0.27). AT-III as a continuous infusion in CDH neonates on ECMO provides a decreased need to modify heparin infusion and more consistent therapeutic anticoagulation without increasing the risk of life-threatening bleeding.


Minimally invasive transforaminal lumbar interbody fusion: a review of techniques and outcomes.
Review of published literature. To review the available medical literature reporting results after minimally invasive transforaminal lumbar interbody fusion (MIS TLIF) and evaluate functional and radiographic outcomes with those following open TLIF and open posterior lumbar interbody fusion (PLIF) procedures. Minimally invasive spine techniques aim to reduce approach-related surgical morbidity without compromising operative and clinical outcomes. MIS TLIF is increasingly being used for the management of various lumbar degenerative diseases. Despite the limited number of well-designed clinical studies, the available published data suggest potential advantages over its open posterior-approach lumbar interbody fusion counterparts. Such benefits include less intraoperative blood loss, less need for blood transfusions, shorter hospital course, and less postoperative pain. Literature examining posterior-approach interbody fusion techniques (PLIF, TLIF, and MIS TLIF) was collected using the National Center for Biotechnology Information database and PubMed/MEDLINE, and summarized for discussion. Literature reports of MIS TLIF generally show comparable or improved clinical outcomes when compared with those following open posterior interbody fusion techniques. Additionally, significantly less blood loss, hospital stay, and complications were generally reported, despite slightly longer duration of surgery, especially during early cases in a surgeon's experience. More studies designed to provide class I or II data will be needed in the future to further solidify the favorable results observed so far with the MIS TLIF procedure.


Association between preoperative erectile dysfunction and prostate cancer features--an analysis from the Duke Prostate Center Database.
Erectile dysfunction (ED) is related to several co-morbidities including obesity, metabolic syndrome, cigarette smoking, and low testosterone, all of which have been reported to be associated with adverse prostate cancer features. To examine whether preoperative ED has a relationship with adverse prostate cancer features in patients who underwent radical prostatectomy (RP). We analyzed data from our institution on 676 patients who underwent RP between 2001 and 2010. Crude and adjusted logistic regression models were used to investigate the association between preoperative ED and several pathological parameters. The log-rank test and multivariate proportional hazards model were conducted to determine the association of preoperative ED with biochemical recurrence (BCR). The expanded prostate cancer index composite (EPIC) instrument was used to evaluate preoperative erectile function (EF). Preoperative normal EF was defined as EPIC-SF ≥ 60 points while ED was defined as preoperative EPIC-SF lower than 60 points. Preoperatively, a total of 343 (50.7%) men had normal EF and 333 (49.3%) men had ED. After adjusting for covariates, preoperative ED was identified a risk factor for positive extracapsular extension (OR 1.57; P = 0.029) and high percentage of tumor involvement (OR 1.56; P = 0.047). In a Kaplan-Meier curve, a trend was identified that patients with ED had higher incidence of BCR than men with normal EF (P = 0.091). Moreover, using a multivariate Cox model, higher preoperative EF was negatively associated with BCR (HR 0.99; P = 0.014). These results suggest that the likelihood for adverse pathological outcomes as well as BCR following prostatectomy is higher among men with preoperative ED, though these results require validation in larger datasets. The present study indicates that preoperative ED might be a surrogate for adverse prostate cancer outcomes following RP.


Social capital and health: a review of prospective multilevel studies.
This article presents an overview of the concept of social capital, reviews prospective multilevel analytic studies of the association between social capital and health, and discusses intervention strategies that enhance social capital. We conducted a systematic search of published peer-reviewed literature on the PubMed database and categorized studies according to health outcome. We identified 13 articles that satisfied the inclusion criteria for the review. In general, both individual social capital and area/workplace social capital had positive effects on health outcomes, regardless of study design, setting, follow-up period, or type of health outcome. Prospective studies that used a multilevel approach were mainly conducted in Western countries. Although we identified some cross-sectional multilevel studies that were conducted in Asian countries, including Japan, no prospective studies have been conducted in Asia. Prospective evidence from multilevel analytic studies of the effect of social capital on health is very limited at present. If epidemiologic findings on the association between social capital and health are to be put to practical use, we must gather additional evidence and explore the feasibility of interventions that build social capital as a means of promoting health.


Pediatric flexible fiberoptic bronchoscopy through the laryngeal mask airway.
To determine the usefulness and safety of the laryngeal mask airway (LMA) as an adjunct to pediatric flexible fiberoptic bronchoscopy (FOB). A case-series retrospective study. Pediatric otolaryngology tertiary referral center, outpatient and inpatient operating suites. Retrospective review of charts of children who had FOB performed with the use of LMA by the pediatric otolaryngology service. The patients were ages 3 months to 18 years with respiratory symptoms requiring FOB for diagnosis. Use of LMA to support airway during FOB with spontaneous ventilation with the patients under general anesthesia. Ability to perform airway evaluation with FOB and LMA; number and type of complications. Seventeen patients, ages 3 months to 18 years (median age, 39 months) underwent FOB with use of LMA. In 2 patients use of LMA failed-1 from airway obstruction with LMA in place, which required intubation, and another who could not have LMA appropriately placed. Fifteen patients underwent uncomplicated FOB through the LMA. None of these 15 patients required unplanned endotracheal intubation. Two patients with mandibular hypoplasia required LMA use for airway evaluation when the glottis could not be visualized at direct laryngoscopy. The LMA is a safe and effective adjunct to pediatric FOB. Laryngeal mask airway use for FOB allows evaluation of the airway during spontaneous ventilation without an endotracheal tube or a face mask. Larger fiberoptic scopes can be used through the LMA compared with pediatric FOB performed through the nose or through an endotracheal tube.


Chemometric determination of lipidic parameters in serum using ATR measurements of dry films of solvent extracts.
Attenuated total reflectance (ATR) infrared spectroscopy of dried organic extracts of serum samples has been evaluated as a fast method for the determination of triglycerides, cholesterol, high density lipoprotein (HDL) and low density lipoprotein (LDL). After careful selection of solvents based on green parameters, serum samples were extracted using hexane-isopropanol and ethyl acetate-ethanol mixtures. Microscopy studies and comparison with standard spectra were performed in order to investigate whether the proposed methodology is suitable for the quantification of lipids in serum samples. The results of these preliminary studies confirmed that the variations in the IR spectra of sample extracts could be related quantitatively to variations in the concentrations of the target analytes. Then, ATR spectra of the dried sample extracts were obtained and direct measurement of the spectra were carried out and modelled using partial least squares (PLS) and reference concentrations. PLS models obtained from the extracts of the two mixtures were compared with those obtained from direct measurement of sera samples. The prediction errors obtained using the proposed approach were considerably (between 27 and 72%) better than those obtained by the direct measurements of sera. For triglycerides and cholesterol relative errors below 9% and 12% respectively were obtained with this method, which are comparable to the tolerance for the errors of the control analysis established at the hospital. For HDL and LDL, the errors found were between 18 and 20%. The incorporation of a preprocessing extraction step, involves time and solvent consumption. However, the results obtained provide evidence that the proposed method provides, in a few minutes and using simple instrumentation and with minimum cost, important information about the lipidic profile of patients sera at a good screening confidence level.


Systematic review of randomized trials of the effect of exercise on bone mass in pre- and postmenopausal women.
Studies of the effect of exercise programs on bone mass appear inconsistent. Our objective was to systematically review and meta-analyze randomized trials of the effect of exercise on bone mass in pre- and postmenopausal women. A computerized MEDLINE search was conducted for the years 1966-1997. Thirty-five randomized trials were identified. Meta-analytic methods were used to statistically pool results of studies of the effect of impact (e.g., aerobics) and non-impact (e.g., weight training) exercise on the lumbar spine and femoral neck. The most studied bone site was the lumbar spine in postmenopausal women (15 studies), where both impact [1.6% bone loss prevented, 95% confidence intervals (CI): 1.0%-2.2%] and non-impact (1.0%, 95% CI: 0.4%-1.6%) exercise programs had a positive effect. Results for the lumbar spine in premenopausal women (eight studies) were similar: 1.5% (95% CI: 0.6%-2.4%) less bone loss (or net gain) after impact exercise and 1.2% (95% CI: 0.7%-1.7%) after non-impact exercise. Impact exercise programs appeared to have a positive effect at the femoral neck in postmenopausal women (five studies), 1.0% (95% CI: 0.4%-1.6%) bone loss prevented, and possibly in premenopausal women, 0.9% (95% CI: -0.2%-2.0%) bone loss prevented. There were too few trials to draw conclusions from meta-analyses of the effect of non-impact exercise on the neck of femur. This systematic review of randomized trials shows that both impact and non-impact exercise have a positive effect at the lumbar spine in pre- and postmenopausal women. Impact exercise probably has a positive effect at the femoral neck. More studies are required to determine the optimal intensity and type of exercise.


Mitochondrial aconitase binds to the 3' untranslated region of the mouse hepatitis virus genome.
Mouse hepatitis virus (MHV), a member of the Coronaviridae, contains a polyadenylated positive-sense single-stranded genomic RNA which is 31 kb long. MHV replication and transcription take place via the synthesis of negative-strand RNA intermediates from a positive-strand genomic template. A cis-acting element previously identified in the 3' untranslated region binds to trans-acting host factors from mouse fibroblasts and forms at least three RNA-protein complexes. The largest RNA-protein complex formed by the cis-acting element and the lysate from uninfected mouse fibroblasts has a molecular weight of about 200 kDa. The complex observed in gel shift assays has been resolved by second-dimension sodium dodecyl sulfate-polyacrylamide gel electrophoresis into four proteins of approximately 90, 70, 58, and 40 kDa after RNase treatment. Specific RNA affinity chromatography also has revealed the presence of a 90-kDa protein associated with RNA containing the cis-acting element bound to magnetic beads. The 90-kDa protein has been purified from uninfected mouse fibroblast crude lysates. Protein microsequencing identified the 90-kDa protein as mitochondrial aconitase. Antibody raised against purified mitochondrial aconitase recognizes the RNA-protein complex and the 90-kDa protein, which can be released from the complex by RNase digestion. Furthermore, UV cross-linking studies indicate that highly purified mitochondrial aconitase binds specifically to the MHV 3' protein-binding element. Increasing the intracellular level of mitochondrial aconitase by iron supplementation resulted in increased RNA-binding activity in cell extracts and increased virus production as well as viral protein synthesis at early hours of infection. These results are particularly interesting in terms of identification of an RNA target for mitochondrial aconitase, which has a cytoplasmic homolog, cytoplasmic aconitase, also known as iron regulatory protein 1, a well-recognized RNA-binding protein. The binding properties of mitochondrial aconitase and the functional relevance of RNA binding appear to parallel those of cytoplasmic aconitase.


Pressure-pain threshold algometric measurement in patients with greater trochanteric pain after total hip arthroplasty.
The evaluation of tenderness associated with greater trochanteric pain (GTP) syndrome is amenable to bias and depends on the examiner's experience. In this study, we tested whether the use of an electronic pressure algometer enhanced the reliability of this evaluation. Pressure-pain threshold (PPT) was measured with an electronic algometer in 18 patients who developed GTP after total hip arthroplasty and in matched controls. Both groups were evaluated with visual analog scale. The PPT measurements showed large interindividual variability across patients. The correspondence of the PPT measurements in asymptomatic patients was good. We found good validity for the algometer used. The PPT ratio of 0.8 (affected vs. unaffected side) can be used as a cut-off ratio. The PPT measurements at the greater trochanter (local pain) were significantly lower than at the ilio-tibial band (radiated pain). There was no correlation between PPT measurements and visual analog scales. Despite the acceptable sensitivity and specificity of pressure algometer, because of low positive predictive value and large interindividual variability, pressure algometer has a limited value as a screening test. The examination of tenderness associated with GTP is facilitated by the used algometer. It is the intraindividual body-side PPT differences that yield the most sensitive measurement for the assessment of deep pain. A cut-off value of 0.8 can be used for diagnostic purposes. Interindividual differences might be considerable and could mask pathologic diagnostic findings.


Peripheral genetic structure of Helicoverpa zea indicates asymmetrical panmixia.
Seasonal climatic shifts create peripheral habitats that alternate between habitable and uninhabitable for migratory species. Such dynamic peripheral habitats are potential sites where migratory species could evolve high genetic diversity resulting from convergence of immigrants from multiple regionally distant areas. Migrant populations of Helicoverpa zea (Boddie) captured during two different seasons were assessed for genetic structure using microsatellite markers and for host plant type using stable carbon isotope analysis. Individuals (N = 568) were genotyped and divided into 13 putative populations based on collection site and time. Fixation indices (F-statistics), analysis of molecular variance (AMOVA), and discriminant analysis of principal components (DAPC) were used to examine within and among population genetic variation. Mean number of alleles per locus was 10.25 (± 3.2 SD), and allelic richness ranged from 2.38 to 5.13 (± 3.2 SD). The observed and expected heterozygosity ranged from 0.07 to 0.48 and 0.08 to 0.62, respectively. Low F ST (0.01 to 0.02) and high F IS (0.08 to 0.33) values suggest captured migrants originated from breeding populations with different allele frequencies. We postulate that high genetic diversity within migrant populations and low genetic differentiation among migrant populations of H. zea are the result of asymmetrical immigration due to the high dispersal and reproductive behavior of H. zea, which may hinder the adaptation and establishment of H. zea to peripheral habitat. These findings highlight the importance of assessing peripheral population structure in relation to ecological and evolutionary dynamics of this and other highly reproductive and dispersive species.


Mechanistic study of the Aldo-keto reductase family 1 member A1 in regulating mesenchymal stem cell fate decision toward adipogenesis and osteogenesis.
Akr1A1 is a glycolytic enzyme catalyzing the reduction of aldehyde to alcohol. This study aims to delineate the role of Akr1A1 in regulating the adipo-osteogenic lineage differentiation of mesenchymal stem cells (MSCs). MSCs derived from human bone marrow and Wharton Jelly together with gain- and loss-of-function analysis as well as supplementation with the S-Nitrosoglutathione reductase (GSNOR) inhibitor N6022 were used to study the function of Akr1A1 in controlling MSC lineage differentiation into osteoblasts and adipocytes. Akr1A1 expression, PKM2 activity, and lactate production were found to be decreased in osteoblast-committed MSCs, but PGC-1α increased to induce mitochondrial oxidative phosphorylation. Increased Akr1A1 inhibited the SIRT1-dependent pathway for decreasing the expressions of PGC-1α and TAZ but increasing PPAR γ in adipocyte-committed MSCs, hence promoting glycolysis in adipogenesis. In contrast, Akr1A1 expression, PKM2 activity and lactate production were all increased in adipocyte-differentiated cells with decreased PGC-1α for switching energy utilization to glycolytic metabolism. Reduced Akr1A1 expression in osteoblast-committed cells relieves its inhibition of SIRT1-mediated activation of PGC-1α and TAZ for facilitating osteogenesis and mitochondrial metabolism. Several metabolism-involved regulators including Akr1A1, SIRT1, PPARγ, PGC-1α and TAZ were differentially expressed in osteoblast- and adipocyte-committed MSCs. More importantly, Akr1A1 was identified as a new key regulator for controlling the MSC lineage commitment in favor of adipogenesis but detrimental to osteogenesis. Such information should be useful to develop perspective new therapeutic agents to reverse the adipo-osteogenic differentiation of BMSCs, in a way to increase in osteogenesis but decrease in adipogenesis.


LncRNA-H19 silencing suppresses synoviocytes proliferation and attenuates collagen-induced arthritis progression by modulating miR-124a.
Long non-coding RNA H19 (lncRNA-H19) is highly expressed in fibroblast-like synoviocytes (FLS) from patients with RA. The present study aimed to clarify the pathological significance and regulatory mechanisms of lncRNA-H19 in FLS. Mice with CIA were locally injected with LV-shH19. The progression of CIA was explored by measuring arthritic index (AI), paw thickness (PT) and histologic analysis. The growth and cell cycle of human synoviocyte MH7A were assessed by CCK-8 and flow cytometric analysis. The putative binding sites between lncRNA-H19 and miR-124a were predicted online, and the binding was identified by luciferase assay. RT-qPCR, Western blot and luciferase assay were performed to explore the molecular mechanisms between liver X receptor (LXR), lncRNA-H19, miR-124a and its target genes. The expression of lncRNA-H19 was closely associated with the proliferation of synoviocytes and knockdown of lncRNA-H19 significantly ameliorated the progression of CIA, reflected by decreased AI, PT and cartilage destruction. Notably, lncRNA-H19 competitively bound to miR-124a, which directly targets CDK2 and MCP-1. It was confirmed that lncRNA-H19 regulates the proliferation of synoviocytes by acting as a sponge of miR-124a to modulate CDK2 and MCP-1 expression. Furthermore, the agonists of LXR inhibited lncRNA-H19-mediated miR-124a-CDK2/MCP-1 signalling pathway in synoviocytes. The 'lncRNA-H19-miR-124a-CDK2/MCP-1' axis plays an important role in LXR anti-arthritis. Regulation of the miR-124a-CDK2/MCP-1 pathway by lncRNA-H19 plays a crucial role in the proliferation of FLS. Targeting this axis has therapeutic potential in the treatment of RA and may represent a novel strategy for RA treatment.


Conserved oligomeric Golgi (COG) complex genes functioning in defense are expressed in root cells undergoing a defense response to a pathogenic infection and exhibit regulation my MAPKs.
The conserved oligomeric Golgi (COG) complex maintains correct Golgi structure and function during retrograde trafficking. Glycine max has 2 paralogs of each COG gene, with one paralog of each gene family having a defense function to the parasitic nematode Heterodera glycines. Experiments presented here show G. max COG paralogs functioning in defense are expressed specifically in the root cells (syncytia) undergoing the defense response. The expressed defense COG gene COG7-2-b is an alternate splice variant, indicating specific COG variants are important to defense. Transcriptomic experiments examining RNA isolated from COG overexpressing and RNAi roots show some COG genes co-regulate the expression of other COG complex genes. Examining signaling events responsible for COG expression, transcriptomic experiments probing MAPK overexpressing roots show their expression influences the relative transcript abundance of COG genes as compared to controls. COG complex paralogs are shown to be found in plants that are agriculturally relevant on a world-wide scale including Manihot esculenta, Zea mays, Oryza sativa, Triticum aestivum, Hordeum vulgare, Sorghum bicolor, Brassica rapa, Elaes guineensis and Saccharum officinalis and in additional crops significant to U.S. agriculture including Beta vulgaris, Solanum tuberosum, Solanum lycopersicum and Gossypium hirsutum. The analyses provide basic information on COG complex biology, including the coregulation of some COG genes and that MAPKs functioning in defense influence their expression. Furthermore, it appears in G. max and likely other crops that some level of neofunctionalization of the duplicated genes is occurring. The analysis has identified important avenues for future research broadly in plants.


Near infrared quantum dots in biomedical applications: current status and future perspective.
To address the requirements of biomedical applications including biosensing, bioimaging, and drug delivery, fluorescent nanomaterials served as efficient tools in many cases. Among them, near-infrared quantum dots (NIR QDs) have been used as novel fluorescent labels for their binary advantages of both QDs and NIR light. In this review, through collecting references in recent 10 years, we have introduced basic structures and properties of NIR QDs and summarized the classification and the related synthetic methods. This review also highlights the functionalization and surface bioconjugation of NIR QDs, and their biomedical applications in biosensing, bioimaging, and drug delivery. This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > In Vitro Nanoparticle-Based Sensing Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.


Transferability of Molecular Potentials for 2D Molybdenum Disulphide.
An ability of different molecular potentials to reproduce the properties of 2D molybdenum disulphide polymorphs is examined. Structural and mechanical properties, as well as phonon dispersion of the 1H, 1T and 1T' single-layer MoS2 (SL MoS2) phases, were obtained using density functional theory (DFT) and molecular statics calculations (MS) with Stillinger-Weber, REBO, SNAP and ReaxFF interatomic potentials. Quantitative systematic comparison and discussion of the results obtained are reported.


Cortical dysfunction in schizophrenia during auditory word and tone working memory demonstrated by functional magnetic resonance imaging.
Verbal learning and memory deficits are among the most severe cognitive deficits observed in schizophrenia. We have demonstrated that such deficits do not extend to working memory for tones in a substantial number of patients even when verbal working memory is impaired. In this study we used functional magnetic resonance imaging to study the neural basis of this dissociation of auditory verbal and nonverbal working memory in individuals with schizophrenia. While undergoing functional magnetic resonance imaging, 12 schizophrenic patients and 12 matched control subjects performed auditory Word Serial Position Task and Tone Serial Position Task. Both tasks produced activation in frontal cortex and temporal and parietal lobes of the cerebrum in both groups. While robust activation was observed in the left inferior frontal gyrus (areas 6, 44, and 45) in the control group during the Word Serial Position Task, activation in the patient group was much reduced in these areas and failed to show the same task-specific activation as in controls. Reduced activation in patients was not confined to the inferior frontal gyrus, but also extended to a medial area during the Tone Serial Position Task and to premotor and anterior temporal lobe areas during both tasks. These findings support the hypothesis that abnormalities in cortical hemodynamic response in the inferior frontal gyrus underlie the verbal working memory deficit in schizophrenia. The relationship of verbal working memory deficits to other cognitive functions suggests that abnormal functioning in the speech-related areas may reflect a critical substrate of a broad range of cognitive dysfunctions associated with schizophrenia.


[Application of PROTACs in Hematological Malignancies--Review].
Proteolysis-targeting chimeras (PROTACs) are heterobifunctional small molecules by utilizing the ubiquitin proteasome system (UPS) to degrade proteins of interest. PROTACs have exhibited unprecedented efficacy and specificity in degrading various oncogenic proteins because of their unique mechanism of action, ability to target "undruggable" and mutant proteins. A series of PROTACs have been developed to degrade multiple key protein targets for the treatment of hematologic malignancy. Notably, PROTACs that target BCL-XL, IRAK4, STAT3 and BTK have entered clinical trials. The known PROTACs that have the potential to be used to treat various hematological malignancies are systematically summarized in this review.


Comparison of low-dose oxytocin and dinoprostone for labor induction in postterm pregnancies: a randomized controlled prospective study.
The aim of this study was to compare the efficacy of oxytocin and dinoprostone in achieving successful labor induction and vaginal delivery in postterm women with an unfavorable cervix. Postterm women with an uncomplicated pregnancy and a Bishop score of ≤6 were randomized to receive either dinoprostone vaginal pessary (Propess®) or low-dose oxytocin. The primary outcomes were the length of the induction-to-delivery period and the incidence of vaginal delivery. A total of 144 women were available for the analysis. The overall vaginal delivery rates were 75% (54/72) for the dinoprostone group and 80.6% (58/72; p = 0.35) for the oxytocin group; the mean induction-to-vaginal delivery interval was 13.3 and 10.3 h in the dinoprostone and the oxytocin group, respectively (p = 0.003). Uterine hyperstimulation was 7.4% compared with 6.8% (p = 0.8), and abnormal fetal heart rate was 26.4% compared with 18% (p = 0.2), respectively. Both oxytocin and dinoprostone seem to have similar obstetric outcomes in postterm pregnancies with an unfavorable cervix, except for a significant superiority of oxytocin for delivery in a shorter period.


Solitary fibrous pleural tumor.
Solitary fibrous pleural tumors are rare masses of mesenchymal origin that may be mistaken for mesothelioma. A positive staining of vimentin, negative staining of cytoplasmic keratin, and expression of the CD34 antigen can confirm the presence of a solitary fibrous pleural tumor. Although most tumors of this type are benign, they possess a malignant potential and thus should be excised. We report a case of a 63-year-old man who had an inconclusive biopsy of a lung lesion 15 years ago. Further testing after excision revealed a solitary fibrous pleural tumor. A brief discussion of the clinical presentation and incidence of these tumors is included.


Novel immunoassay for TSH measurement in rats.
Measuring thyroid hormones is an important aspect for the study of metabolism and for monitoring diseases in both human and animal models. The traditional method for hormone measurement in rats is the radioimmunoassay (RIA). However, the RIA is associated with some practical disadvantages, including the use of radioactive material, the need for specialized equipment and expert staff, the short shelf-life of kits according to the half-life of the radioisotope and high costs. The objective of this study was to develop a new cost-effective method for measuring TSH levels in rats that avoids the use of radioactive material. We developed an in-house competitive immunoassay using a reference standard, polyclonal antibody produced in rabbits and biotinylated antigen. This method was tested in 64 Wistar rats that were divided into a control group (n = 41) and a group with hypothyroidism (n = 23). Our assay demonstrated an analytical sensitivity of 0.24 ng/mL (n = 12) and an intra-assay coefficient of variation (CV) of 8.9% for sera with TSH levels of 1.5 ng/mL and 13.2% for sera with TSH levels of 17.5 ng/mL (n = 14). The inter-assay CV was 13.5% for sera with TSH levels of 1.4 ng/mL and 14.5% for TSH levels of 18.2 ng/mL (n = 5). The analysis of mean TSH levels in control rats (5.06 ± 0.5701) and hypothyroid rats (51.09 ± 5.136) revealed a statistically significant difference (p < 0.001) between the groups. This method showed good sensitivity, can be automated and is low-cost compared with RIA. Our method offers a viable alternative for TSH measurement in rats.


Markers of coagulation and platelet activation during percutaneous mitral valvuloplasty.
The effect of percutaneous mitral valvuloplasty (PMV) on markers of coagulation and platelet activation was investigated to assess whether coagulation or platelet activation take place during and after PMV even under conditions of full heparinization. Before PMV, all the hemostatic parameters studied were in the normal range compared with those of a control group. Two hours after PMV the levels of prothrombin fragment F1 and 2 (F1+2) (1.6+/-0.6 nmol/l versus 0.8+/-0.3 nmol/l, P < 0.005), plasma thrombin-antithrombin III (TAT) complexes (5.4+/-3.2 ng/ml versus 2.2+/-0.9 ng/ml) and beta-thromboglobulin (119+/-70 ng/ml versus 42.2+/-41 ng/ml) had increased significantly compared with those measured at basal conditions. Activated partial thromboplastin time was significantly prolonged (152+/-40 s versus 21+/-5 s), reflecting full heparinization. Levels of fibrinogen, F1+2, TAT and beta-thromboglobulin remained increased 72 h after PMV. We conclude that patients with severe, symptomatic mitral stenosis undergoing PMV need a more specific antithrombotic therapy or a more prolonged and perhaps less intensive heparinization.


nMOWChIP-seq: low-input genome-wide mapping of non-histone targets.
Genome-wide profiling of interactions between genome and various functional proteins is critical for understanding regulatory processes involved in development and diseases. Conventional assays require a large number of cells and high-quality data on tissue samples are scarce. Here we optimized a low-input chromatin immunoprecipitation followed by sequencing (ChIP-seq) technology for profiling RNA polymerase II (Pol II), transcription factor (TF), and enzyme binding at the genome scale. The new approach produces high-quality binding profiles using 1,000-50,000 cells. We used the approach to examine the binding of Pol II and two TFs (EGR1 and MEF2C) in cerebellum and prefrontal cortex of mouse brain and found that their binding profiles are highly reflective of the functional differences between the two brain regions. Our analysis reveals the potential for linking genome-wide TF or Pol II profiles with neuroanatomical origins of brain cells.


Characterization of a Helicobacter hepaticus putA mutant strain in host colonization and oxidative stress.
Helicobacter hepaticus is a gram-negative, spiral-shaped microaerophilic bacterium associated with chronic intestinal infection leading to hepatitis and colonic and hepatic carcinomas in susceptible strains of mice. In the closely related human pathogen Helicobacter pylori, L-proline is a preferred respiratory substrate and is found at significantly high levels in the gastric juice of infected patients. A previous study of the proline catabolic PutA flavoenzymes from H. pylori and H. hepaticus revealed that Helicobacter PutA generates reactive oxygen species during proline oxidation by transferring electrons from reduced flavin to molecular oxygen. We further explored the preference for proline as a respiratory substrate and the potential impact of proline metabolism on the redox environment in Helicobacter species during host infection by disrupting the putA gene in H. hepaticus. The resulting putA knockout mutant strain was characterized by oxidative stress analysis and mouse infection studies. The putA mutant strain of H. hepaticus exhibited increased proline levels and resistance to oxidative stress relative to that of the wild-type strain, consistent with proline's role as an antioxidant. The significant increase in stress resistance was attributed to higher proline content, as no upregulation of antioxidant genes was observed for the putA mutant strain. The wild-type and putA mutant H. hepaticus strains displayed similar levels of infection in mice, but in mice challenged with the putA mutant strain, significantly reduced inflammation was observed, suggesting a role for proline metabolism in H. hepaticus pathogenicity in vivo.


Telementoring: use of augmented reality in orthopaedic education: AAOS exhibit selection.
Virtual interactive presence (VIP) is a new technology that allows an individual to deliver real-time virtual assistance to another geographically remote individual via a standard Internet connection. The objectives of this pilot study were to evaluate the efficiency and performance of a VIP system implemented in an operating room setting, determine the potential utility of the system for guidance of surgical procedures, and assess the safety of the system. Following institutional review board approval, fifteen patients underwent arthroscopic shoulder procedures. Two VIP stations were used, one in the operating room and the other in an adjoining dictation room. The attending surgeon proctored operating resident surgeons from the dictation room until his physical presence was required in the operating room. Following each procedure, the attending surgeon, resident surgeons, and three surgical staff members completed a Likert-scale questionnaire regarding the educational utility, efficiency of use, and safety of the system. The operative time was also compared with historical data. Both attending and resident surgeons assigned a favorable rating to the utility of the VIP to highlight anatomy and provide feedback to the resident (p > 0.05 for the difference). Both groups agreed that the system was easy to use and that safety was not compromised (p > 0.05). The majority of resident and attending surgeon responses indicated no perceptible lag between motions (95% and 100%, respectively; p > 0.99) and no interference of the VIP system with the surgical procedure (85% and 100%, respectively; p = 0.24). The mean operative times with and without VIP use did not differ significantly for rotator cuff repair (p = 0.90) or for treatment of instability (p = 0.57). This pilot study revealed that the VIP technology was efficient, safe, and effective as a teaching tool. The attending and resident surgeons agreed that training was enhanced, and this occurred without increasing operative times. Furthermore, the attending surgeon believed that this technology improved teaching effectiveness. These results are promising, and further objective quantification is warranted.


Liana species decline in Congo basin contrasts with global patterns.
Lianas, woody climbing plants, are increasing in many tropical forests, with cascading effects such as decreased forest productivity, carbon sequestration, and resilience. Possible causes are increasing forest fragmentation, CO2 fertilization, and drought. Determining the primary changing species and their underlying vital rates help explain the liana trends. We monitored over 17,000 liana stems for 13 yr in 20 ha of old-growth forest in the Congo Basin, and here we report changes and vital rates for the community and for the 87 most abundant species. The total liana abundance declined from 15,007 lianas in 1994 to 11,090 in 2001 to 9,978 in 2007. Over half (52%) of the evaluated species have significantly declining populations, showing that the community response is not the result of changes in a few dominant species only. Species density change (i.e., the change in number of individuals per hectare) decreased with mortality rate, tended to increase with recruitment rate, but was independent of growth rate. Species change was independent of functional characteristics important for plant responses to fragmentation, CO2 , and drought, such as lifetime light requirements, climbing and dispersal mechanism, and leaf size. These results indicate that in Congo lianas do not show the reputed global liana increase, but rather a decline, and that elements of the reputed drivers underlying global liana change do not apply to this DR Congo forest. We suggest warfare in the Congo Basin to have decimated the elephant population, leading to less disturbance, forest closure, and declining liana numbers. Our results imply that, in this tropical forest, local causes (i.e., disturbance) override more global causes of liana change resulting in liana decline, which sharply contrasts with the liana increase observed elsewhere.


An Estimate of Attributable Cases of Alzheimer Disease and Vascular Dementia due to Modifiable Risk Factors: The Impact of Primary Prevention in Europe and in Italy.
Up to 53.7% of all cases of dementia are assumed to be due to Alzheimer disease (AD), while 15.8% are considered to be due to vascular dementia (VaD). In Europe, about 3 million cases of AD could be due to 7 potentially modifiable risk factors: diabetes, midlife hypertension and/or obesity, physical inactivity, depression, smoking, and low educational level. To estimate the number of VaD cases in Europe and the number of AD and VaD cases in Italy attributable to these 7 potentially modifiable risk factors. Assuming the nonindependence of the 7 risk factors, the adjusted combined population attributable risk (PAR) was estimated for AD and VaD. In Europe, adjusted combined PAR was 31.4% for AD and 37.8% for VaD. The total number of attributable cases was 3,033,000 for AD and 873,000 for VaD. In Italy, assuming a 20% reduction of the prevalence of each risk factor, adjusted combined PAR decreased from 45.2 to 38.9% for AD and from 53.1 to 46.6% for VaD, implying a 6.4 and 6.5% reduction in the prevalence of AD and VaD, respectively. A relevant reduction of AD and VaD cases in Europe and Italy could be obtained through primary prevention.


Coalitional affiliation as a missing link between ethnic polarization and well-being: An empirical test from the European Social Survey.
Many studies converge in suggesting (a) that ethnic and racial minorities fare worse than host populations in reported well-being and objective measures of health and (b) that ethnic/racial diversity has a negative impact on various measures of social trust and well-being, including in the host or majority population. However, there is much uncertainty about the processes that connect diversity variables with personal outcomes. In this paper, we are particularly interested in different levels of coalitional affiliation, which refers to people's social allegiances that guide their expectations of social support, in-group strength and cohesion. We operationalize coalitional affiliation as the extent to which people rely on a homogeneous social network, and we measure it with indicators of friendships across ethnic boundaries and frequency of contact with friends. Using multi-level models and data from the European Social Survey (Round 1, 2002-2003) for 19 countries, we demonstrate that coalitional affiliation provides an empirically reliable, as well as theoretically coherent, explanation for various effects of ethnic/racial diversity.


Recovery of plant communities after ecological restoration of forestry-drained peatlands.
Ecological restoration is expected to reverse the loss of biodiversity and ecosystem services. Due to the low number of well-replicated field studies, the extent to which restoration recovers plant communities, and the factors underlying possible shortcomings, are not well understood even in medium term. We compared the plant community composition of 38 sites comprising pristine, forestry-drained, and 5 or 10 years ago restored peatlands in southern Finland, with special interest in understanding spatial variation within studied sites, as well as the development of the numbers and the abundances of target species. Our results indicated a recovery of community composition 5-10 years after restoration, but there was significant heterogeneity in recovery. Plant communities farthest away from ditches were very similar to their pristine reference already 10 years after restoration. In contrast, communities in the ditches were as far from the target as the drained communities. The recovery appears to be characterized by a decline in the number and abundance of species typical to degraded conditions, and increase in the abundance of characteristic peatland species. However, we found no increase above the drained state in the number of characteristic peatland species. Our results suggest that there is a risk of drawing premature conclusions on the efficiency of ecological restoration with the current practice of short-term monitoring. Our results also illustrate fine-scale within-site spatial variability in the degradation and recovery of the plant communities that should be considered when evaluating the success of restoration. Overall, we find the heterogeneous outcome of restoration observed here promising. However, low recovery in the number of characteristic species demonstrates the importance of prioritizing restoration sites, and addressing the uncertainty of recovery when setting restoration targets. It appears that it is easier to eradicate unwanted species than regain characteristic species by restoration.


Associations between gender, torture, and health: A 5-year retrospective cohort analysis.
Our purpose was to identify longitudinal associations between torture exposure, physical and mental health outcomes, and gender in a cohort of 143 war-affected Karen adults five years post resettlement. Results showed that participants who self-reported primary torture experiences had higher rates of certain mental and physical health diagnoses. We observed gender differences in health over time in the cohort. Findings have implications for how primary care and public health providers implement war trauma screening tools and timelines, targeted healthcare services, and community resources to promote health and prevent disease in populations that have trauma from torture or war.


Molecular characterization of the Aspergillus fumigatus NCS-1 homologue, NcsA.
Here, we characterize the Aspergillus fumigatus homologue ncsA Neuronal Calcium Sensor. We showed that ncsA is not an essential gene and ncsA growth was decreased in the presence of EGTA and SDS. Furthermore, the ncsA mutant is more resistant to calcium chloride. NcsA:mRFP localizes to the cytoplasm and its cellular localization is not affected by the cellular response to either calcium chloride or EGTA. The ncsA mutant strain is more sensitive to voriconazole, itraconazole, and amphotericin. Polar growth in the DeltancsA mutant was also considerably more affected by lovastatin than in the wild type strain. The Spitzenkörper can be visualized in both strains and although the vacuolar system does not seem to be very different, there is an increase in the staining intensity on the germling surface of the ncsA strain. NcsA promotes pmcA and pmcB expression and therefore there is a reduced expression of these ion pumps in the DeltancsA mutant background, and also of other genes involved in the response to calcium in A. fumigatus. The ncsA inactivation mutation is not causing loss of virulence in a low dose murine infection when compared to the corresponding wild type strain.


Periodontal status in patients with diseases of hepatobiliary system, burdened with tobacco and drug addiction.
The aim: To study the effect of drug addiction and smoking on the status of periodontal tissues in patients with hepatobiliary pathology. Materials and methods: 58 smokers, 63 drug addicts with hepatobiliary pathology were examined and 92 persons of comparison group (with inflammatory periodontal diseases affected by hepatobiliary pathology, without addiction). Examination of patients included determination of iodine number by Svrakov, S-L and Stallard hygiene indices, PMA index and index PBI. Results: The results of examination of smokers are worse in patients with cirrhosis than in patients with chronic toxic hepatitis and non-alcoholic steatohepatitis and also the results of these two groups was significantly worse than that of the comparison group (iodine number by Svrakov - 1,4 times and 1,3 times higher, PMA index - 1,7 times and 1,4 times worse, in accordance). The results of the study showed that drug addicts patients are worse values in patients with cirrhosis than in patients with chronic toxic hepatitis and non-alcoholic steatohepatitis and also the results of these two groups was significantly worse than that of the comparison group (iodine number by Svrakov - 1,5 times and 1,4 times higher, PMA index - 1,7 times and 1,5 times worse, in accordance). Conclusions: Presence of hepatobiliary pathology in smokers and drug addicts increases the risk of periodontal diseases.


Cytoskeleton proteins are modulators of mutant tau-induced neurodegeneration in Drosophila.
Tauopathies, including Alzheimer's disease and fronto-temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), are a group of neurodegenerative disorders characterized by the presence of intraneuronal filamentous inclusions of aberrantly phosphorylated-tau. Tau is a neuronal microtubule-associated protein involved in microtubule assembly and stabilization. Currently, the molecular mechanisms underlying tau-mediated cellular toxicity remain elusive. To address the determinants of tau neurotoxicity, we first characterized the cellular alterations resulting from the over-expression of a mutant form of human tau associated with FTDP-17 (tau V337M) in Drosophila. We found that the over-expression of tau V337M, in Drosophila larval motor neurons, induced disruption of the microtubular network at presynaptic nerve terminals and changes in neuromuscular junctions morphological features. Secondly, we performed a misexpression screen to identify genetic modifiers of the tau V337M-mediated rough eye phenotype. The screening of 1250 mutant Drosophila lines allowed us to identify several components of the cytoskeleton, and particularly from the actin network, as specific modifiers of tau V337M-induced neurodegeneration. Furthermore, we found that numerous tau modulators identified in our screen were involved in the maintenance of synaptic function. Taken together, these findings suggest that disruption of the microtubule network in presynaptic nerve terminals could constitute early events in the pathological process leading to synaptic dysfunction in tau V337M pathology.


The role of iron in ferritin- and haemosiderin-mediated lipid peroxidation in liposomes.
Ferritin and haemosiderin were shown, by the measurement of malondialdehyde production and loss of polyunsaturated fatty acids, to stimulate lipid peroxidation in liposomes. At pH 7.4 ascorbate was additionally required to achieve peroxidation; however, peroxidation occurred at pH 4.5 in the presence of iron-proteins alone. The damage was completely inhibited by the incorporation of chain-breaking antioxidants (alpha-tocopherol and butylated hydroxytoluene) into the liposomes. Metal chelators (desferrioxamine and EDTA) also completely inhibited lipid peroxidation. These and further results indicate that, at pH 4.5, even in the absence of a reducing agent, iron is released from haemosiderin and can mediate oxidative damage to a lipid membrane.


Fulminant Lewy body disease.
The clinical distinction between Parkinson's disease (PD) with dementia (PDD) and dementia with Lewy bodies (DLB) is challenged by most neuropathological studies showing nearly identical changes in both conditions. We report an unusual case of PD evolving into a rapidly progressive dementia leading to death within 3 months that showed nearly all clinical features of DLB. At autopsy, numerous Lewy bodies and Lewy neurites were found in several areas of the brainstem, the limbic system, and the neocortex, consistent with pure DLB. This case demonstrates that Lewy body disease may exhibit a dramatic course without any coexisting pathology and exemplifies that PD, PDD, and DLB may sometimes represent sequential, yet overlapping, phenotypes of a same clinicopathological entity.


Solvent-controlled spin-coating method for large-scale area deposition of two-dimensional silica nanosphere assembled layers.
In this article, we show that introducing a N,N-dimethyl-formamide (DMF) solvent for silica nanosphere (SNS) monolayer spin-coating can offer a low-cost and simple spin-coating approach for SNS monolayer deposition even on large-area silicon surfaces. From our method, more than 95% monolayer coverage for a 2 in round Si surface was achieved, which is one of the highest reported coverage by a spin-coating method. We prove that DMF offers highly enhanced wettability and slow solvent evaporation rate compared to a conventional solvent, water, in addition to excellent SNS dispersibility in solution preventing SNS cluster deposition on the surface and consequently produces a close-packed SNS monolayer with good uniformity over the surface. In addition, the benefits of DMF are retained as the deposition area increases indicating its high tolerance to spin-coating area. Better than 90% SNS monolayer coverage on a 4 in Si substrate was achieved with the DMF spin-coating method. Moreover, DMF has the advantage that SNS spin-coating can be done under common ambient laboratory conditions with 100% pure DMF unlike previous approaches which require humidity and temperature controls or additional surfactant additions to the solution.


Genomic characterization of Salmonella Uzaramo for human invasive infection.
Salmonella is composed of a wide variety of serovars, causing human self-limited gastrointestinal illnesses or invasive infections. Invasive non-typhoidal Salmonella (iNTS) is well documented, with high mortality for children and immunocompromised adults in sub-Saharan Africa and has recently been reported in Southeast Asia. However, iNTS in China remains unknown. In May 2019, a case of invasive infection caused by Salmonella enterica serovar Uzaramo (S. Uzaramo) was reported for the first time in China. Phylogenomic analysis was performed by genomic sequencing the available contextualized isolates, which separated the two Chinese strains into different sublineages. Both phenotypic and genomic characterization demonstrated that the S. Uzaramo isolates showed in general low antimicrobial resistance potential, except one isolated from lake-water in China. Additional comparative genomic analysis and Caenorhabditis elegans killing assays suggested a unique combination of virulence factors, including typhoid toxin and tcf fimbrial adhesin, which might play a role in the invasive infection. This study highlights that the transparency of global surveillance genomic data could accelerate understanding of virulence and antimicrobial resistance makeup of a previously unknown threat.


Mortality and life-years lost due to alcohol: a comparison of acute and chronic causes.
(i) To estimate the numbers of deaths and person-years of life lost (PYLL) due to high-risk alcohol consumption in Australia during 1997, using current estimates of consumption. (ii) To compare the number of deaths and PYLL due to acute conditions associated with bouts of intoxication and chronic conditions associated with long-term misuse of alcohol. All Australian deaths during 1997 related to conditions considered to be partially or wholly caused by high-risk alcohol consumption were extracted from the Australian Bureau of Statistics Mortality Datafile and adjusted by alcohol aetiologic fractions calculated for Australia in 1997. A life-table method was used to estimate the PYLL for deaths from alcohol-caused conditions. Numbers of all deaths and PYLL due to chronic and acute alcohol-related conditions. Of the 3290 estimated alcohol-caused deaths in 1997, chronic conditions (eg, alcoholic liver cirrhosis and alcohol dependence) accounted for 42%, acute conditions (eg, alcohol-related road injuries and assaults) for 28% and mixed (chronic and acute) for 30%. Of the 62914 estimated potential life years lost, acute conditions were responsible for 46%, chronic for 33% and mixed for 21%. The average number of years of life lost through deaths from acute conditions was more than twice that from chronic conditions, because the former mostly involved younger people. In view of the societal burdens imposed by premature deaths, more effective public health strategies are needed to reduce the harm associated with occasional high-risk drinking (as well as sustained high-risk drinking), especially among young people.


Toll-Like Receptor-4 Dependent Small Intestinal Immune Responses Following Murine Arcobacter Butzleri Infection.
Sporadic cases of gastroenteritis have been attributed to Arcobacter butzleri infection, but information about the underlying immunopathological mechanisms is scarce. We have recently shown that experimental A. butzleri infection induces intestinal, extraintestinal and systemic immune responses in gnotobiotic IL-10(-/-) mice. The aim of the present study was to investigate the immunopathological role of Toll-like Receptor-4, the receptor for lipopolysaccharide and lipooligosaccharide of Gram-negative bacteria, during murine A. butzleri infection. To address this, gnotobiotic IL-10(-/-) mice lacking TLR-4 were generated by broad-spectrum antibiotic treatment and perorally infected with two different A. butzleri strains isolated from a patient (CCUG 30485) or fresh chicken meat (C1), respectively. Bacteria of either strain stably colonized the ilea of mice irrespective of their genotype at days 6 and 16 postinfection. As compared to IL-10(-/-) control animals, TLR-4(-/-) IL-10(-/-) mice were protected from A. butzleri-induced ileal apoptosis, from ileal influx of adaptive immune cells including T lymphocytes, regulatory T-cells and B lymphocytes, and from increased ileal IFN-γ secretion. Given that TLR-4-signaling is essential for A. butzleri-induced intestinal inflammation, we conclude that bacterial lipooligosaccharide or lipopolysaccharide compounds aggravate intestinal inflammation and may thus represent major virulence factors of Arcobacter. Future studies need to further unravel the molecular mechanisms of TLR-4-mediated A. butzleri-host interactions.


[Oral hormonal contraception: more or less estrogens?].
The availability of desogestrel with two doses of estrogen, makes a more elastic use in a number of situations in different users. In the author's experience, some preferences are mentioned. Use 20 mcg: a) in adolescents without acne; b) in thin users, less than 60 Kg. weight; c) in those with a large bosom and heavy cyclic bleedings; d) in obese patients, who have reached their ideal weight; e) in those women over 35 years or close to menopause and in those soon after menopause, if they are asymptomatic. Use 30 mcg: a) in adolescents with acne; b) in patients with a small or flat bosom and with scanty cyclic bleedings; c) in those heavier than 60 Kg. d) in obese patients on reducing treatment until they reach their ideal weight.


Telomere dysfunction: a potential cancer predisposition factor.
Genetic instability associated with telomere dysfunction (i.e., short telomeres) is an early event in tumorigenesis. We investigated the association between telomere length and cancer risk in four ongoing case-control studies. All studies had equal numbers of case patients and matched control subjects (92 for head and neck cancer, 135 for bladder cancer, 54 for lung cancer, and 32 for renal cell carcinoma). Telomere length was measured in peripheral blood lymphocytes from study participants. Genetic instability was assessed with the comet assay. Patient and disease characteristics were collected and analyzed for associations with risk for these cancers. All statistical tests were two-sided. Telomeres were statistically significantly shorter in patients with head and neck cancer (6.5 kilobases [kb]) than in control subjects (7.4 kb) (difference = 0.9 kb, 95% confidence interval [CI] = 0.5 to 1.2 kb; P<.001). Nine percent of patients with head and neck cancer were in the longest quartile of telomere length, whereas 59% were in the shortest quartile. Similar patterns were observed for lung, renal cell, and bladder cancer. When subjects were categorized into telomere length quartiles defined by the distribution in control subjects, the following inverse relationship between telomere length and cancer risk was observed: adjusted odds ratios [ORs] for decreasing quartiles = 0.84 (95% CI = 0.36 to 1.97), 1.77 (95% CI = 0.72 to 4.36), and 5.11 (95% CI = 1.90 to 13.77). In stratified analysis, we found a suggestive greater-than-additive interaction between smoking status and telomere length: for ever smokers with short telomeres, OR = 25.05 (95% CI = 6.91 to 90.73); for never smokers with short telomeres, OR = 6.18 (95% CI = 1.72 to 22.13); and for ever smokers with long telomeres, OR = 6.49 (95% CI = 1.54 to 27.38). Telomere length was statistically significantly and inversely associated with baseline and mutagen-induced genetic instability. Short telomeres appear to be associated with increased risks for human bladder, head and neck, lung, and renal cell cancers.


Biotinidase deficiency: initial clinical features and rapid diagnosis.
Biotinidase deficiency is the primary defect in most individuals with late-onset multiple carboxylase deficiency. We have reviewed the presenting clinical features of 31 children with the disorder. Seizures, either alone or with other neurological or cutaneous findings, are the most frequent initial symptom observed. Other neurological symptoms, such as hypotonia, ataxia, hearing loss, optic atrophy, and developmental delay, are seen, in addition to skin rash and alopecia. The disorder is also characterized by ketolactic acidosis and organic aciduria. Biotinidase activity may be diagnosed using a simple, rapid, semiquantitative colorimetric procedure. Samples of whole blood spotted on the same filter paper used by most states to screen for phenylketonuria and other inborn errors of metabolism may be sent to an appropriate reference laboratory. None of the common anticonvulsants or sedatives used to treat newborns and children interfere with the test. Because biotinidase deficiency can be treated readily with biotin, this disorder should be considered in children with infantile seizures, especially in the presence of other characteristic neurological or cutaneous features.


Human MICL (CLEC12A) is differentially glycosylated and is down-regulated following cellular activation.
C-type lectins are the most diverse and prevalent lectin family in immunity. Particular interest has recently been attracted by the C-type lectin-like receptors on NK cells, which appear to regulate the activation/inhibitory balance of these cells, controlling cytotoxicity and cytokine production. We previously identified a human C-type lectin-like receptor, closely related to both the beta-glucan receptor and the lectin-like receptor for oxidized-LDL, named MICL (myeloid inhibitory C-type lectin-like receptor), which we had shown using chimeric analysis to function as an inhibitory receptor. Using a novel MICL-specific monoclonal antibody, we show here that human MICL is expressed primarily on myeloid cells, including granulocytes, monocytes, macrophages, and dendritic cells. Although MICL was highly N-glycosylated in primary cells, the level of glycosylation was found to vary between cell types. MICL surface expression was down-regulated during inflammatory/activation conditions in vitro, as well as during an in vivo model of acute inflammation, which we characterize here. This suggests that human MICL may be involved in the control of myeloid cell activation during inflammation.


Methadone- and buprenorphine-related ambulance attendances: a population-based indicator of adverse events.
This study examined the nature and extent of methadone- and buprenorphine-related morbidity through a retrospective analysis of ambulance service records (N = 243) in Melbourne, Australia. Cases in which methadone and buprenorphine were implicated are examined. Demographic and presenting characteristics, transport outcomes, and other substance use were explored. There were 84 buprenorphine-related attendances and 159 methadone-related attendances recorded on the database over the 4-year period. Presenting signs (respiratory rate and Glasgow Coma Scale score) were lower in the methadone-related attendances. Most of the attendances resulted in transport to hospital. Most presentations did not involve traditional signs of opioid overdose, a finding that warrants further investigation. This is the first article to describe characteristics of methadone- and buprenorphine-related ambulance attendances, with results suggesting this may be a useful way to monitor harms associated with these medications in the future.


The IL-33/ST2 pathway: therapeutic target and novel biomarker.
For many years, the interleukin-1 receptor family member ST2 was an orphan receptor that was studied in the context of inflammatory and autoimmune disease. However, in 2005, a new cytokine--interleukin-33 (IL-33)--was identified as a functional ligand for ST2. IL-33/ST2 signalling is involved in T-cell mediated immune responses, but more recently, an unanticipated role in cardiovascular disease has been demonstrated. IL-33/ST2 not only represents a promising cardiovascular biomarker but also a novel mechanism of intramyocardial fibroblast-cardiomyocyte communication that may prove to be a therapeutic target for the prevention of heart failure.


Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy.
Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. When these tumors are in advanced stages, few therapeutic options are available. Therefore, it is essential to search for new treatments to fight this disease. In this study, we investigated the effects of cannabinoids--a novel family of potential anticancer agents--on the growth of HCC. We found that Δ(9)-tetrahydrocannabinol (Δ(9)-THC, the main active component of Cannabis sativa) and JWH-015 (a cannabinoid receptor 2 (CB(2)) cannabinoid receptor-selective agonist) reduced the viability of the human HCC cell lines HepG2 (human hepatocellular liver carcinoma cell line) and HuH-7 (hepatocellular carcinoma cells), an effect that relied on the stimulation of CB(2) receptor. We also found that Δ(9)-THC- and JWH-015-induced autophagy relies on tribbles homolog 3 (TRB3) upregulation, and subsequent inhibition of the serine-threonine kinase Akt/mammalian target of rapamycin C1 axis and adenosine monophosphate-activated kinase (AMPK) stimulation. Pharmacological and genetic inhibition of AMPK upstream kinases supported that calmodulin-activated kinase kinase β was responsible for cannabinoid-induced AMPK activation and autophagy. In vivo studies revealed that Δ(9)-THC and JWH-015 reduced the growth of HCC subcutaneous xenografts, an effect that was not evident when autophagy was genetically of pharmacologically inhibited in those tumors. Moreover, cannabinoids were also able to inhibit tumor growth and ascites in an orthotopic model of HCC xenograft. Our findings may contribute to the design of new therapeutic strategies for the management of HCC.


Metal chelate grafting at the surface of mesoporous silica nanoparticles (MSNs): physico-chemical and biomedical imaging assessment.
Mesoporous silica nanoparticles (MSNs) are being developed as drug delivery vectors. Biomedical imaging (MRI and PET) enables their tracking in vivo, provided their surface is adequately grafted with imaging probes (metal chelates). However, MSNs are characterized by huge specific surfaces, and high-quality metal chelate anchoring procedures must be developed and validated, to demonstrate that their detection in vivo is associated to the presence of nanoparticles and not to detached metal chelates. MCM-48 nanospheres (M48SNs, 150 nm diam., 3-D pore geometry) were synthesized and functionalized with diethylenetriaminepentaacetic acid (DTPA). The strong grafting of DTPA was confirmed by 29Si MAS-NMR, XPS, FTIR and TGA. The particles were labeled with paramagnetic ions Gd3+ (for MRI) as well as radioactive ions 64Cu2+ (for PET; half-life: 12.7 h). Gd3+-DTPA-M48SNs formed a stable colloid in saline media for at least 6 months, without any sign of aggregation. The relaxometric properties were measured at various magnetic fields. The strength of DTPA binding at the surface of MSNs was also assessed in vivo, by injecting mice (i.v.) with Gd3+/64Cu2+-DTPA-M48SNs. Vascular retention and urinary clearance were monitored by MRI, whereas the PET modality provided dynamic and quantitative assessment of biodistribution and blood/organ clearance. No significant 64Cu activity was detectable in the bladder. The study confirmed the very limited detachment of DTPA from M48SNs cores once injected in vivo. The transit of MSNs through the liver and intestinal tract, does not lead to evidence of Gd3+/64Cu2+-DTPA in the urine. This physico-chemical and biodistribution study confirms the quality of DTPA attachment at the surface of the particles, necessary to allow further development of PET/MRI-assisted MSN-vectorized drug delivery procedures.


Locomotor activity of the terrestrial slug, Limax maximus: response to progressive dehydration.
The circadian locomotor rhythm of the terrestrial slug, Limax maximus, was measured with activity wheels during exposure to both humid and drying conditions. Slugs kept in wet wheels (100% RH) remained fully hydrated while those in dry wheels (less than 30% RH) experienced progressive dehydration. Transfer of slugs from a wet wheel to a dry wheel resulted in an increase in the intensity and duration of their patterned locomotor activity that persisted for 3 days. Once the slugs were returned to wet wheels, their locomotor activity returned to normal.


Genomic Analysis Reveals Distinct Subtypes in Two Rare Cases of Primary Ovarian Lymphoma.
Primary (localized) non-Hodgkin lymphoma (NHL) of the ovary is extremely rare; only a few cases have been reported in the literature. We report two cases of primary ovarian lymphoma (POL), one involving bilateral ovaries in a 15-year-old girl and other involving one ovary in a 5-year-old girl. This report describes detailed clinical, histopathological, and imaging findings, along with the review of literature of primary diffuse large B-cell lymphoma (DLBCL) arising from an ovary. In addition, we describe findings of targeted capture panel sequencing on both tumors and identify the major genetic mutations that are recurrently mutated in pan-cancers. Compared to the genomic mutation features of major subtypes of DLBCL, we distinguish that each POL belongs to distinctive subtypes, GCB (germinal center B-cell subtype) DLBCL and ABC (activated B-cell subtype) DLBCL, respectively. The findings from the genomic analysis may help to understand the pathogenesis of POL and to guide potential targeted therapy in the future.


Simultaneous bilateral magnetic resonance imaging of the femoral arteries in peripheral arterial disease patients.
To image the femoral arteries in peripheral arterial disease (PAD) patients using a bilateral receive coil. An eight-channel surface coil array for bilateral MRI of the femoral arteries at 3T was constructed and evaluated. The bilateral array enabled imaging of a 25-cm segment of the superficial femoral arteries (SFA) from the profunda to the popliteal. The array provided improved the signal-to-noise ratio (SNR) at the periphery and similar SNR in the middle of a phantom compared to three other commercially available coils (4-channel torso, quadrature head, whole body). Multicontrast bilateral images of the in vivo SFA with 1 mm in-plane resolution made it possible to directly compare lesions in the index SFA to the corresponding anatomical site in the contralateral vessel without repositioning the patient or coil. A set of bilateral time-of-flight, T1-weighted, T2-weighted, and proton density-weighted images was acquired in a clinically acceptable exam time of ≈45 minutes. The developed bilateral coil is well suited for monitoring dimensional changes in atherosclerotic lesions of the SFA.


Posttranslational control of transcription factor FixK2, a key regulator for the Bradyrhizobium japonicum-soybean symbiosis.
Rhizobial FixK-like proteins play essential roles in activating genes for endosymbiotic life in legume root nodules, such as genes for micro-oxic respiration. In the facultative soybean symbiont, Bradyrhizobium japonicum, the FixK(2) protein is the key player in a complex regulatory network. The fixK(2) gene itself is activated by the 2-component regulatory system FixLJ in response to a moderate decrease of the oxygen tension, and the FixK(2) protein distributes and amplifies this response to the level of approximately 200 target genes. Unlike other members of the cAMP receptor protein family, to which FixK(2) belongs, the FixK(2) protein does not appear to be modulated by small effector molecules. Here, we show that a critical, single cysteine residue (C183) near the DNA-binding domain of FixK(2) confers sensitivity to oxidizing agents and reactive oxygen species. Oxidation-dependent inactivation occurs not only in vitro, as shown with cell-free transcription assays, but also in vivo, as shown by microarray-assisted transcriptome analysis of the FixK(2) regulon. The oxidation mechanism may involve a reversible dimerization by intermolecular disulfide-bridge formation and a direct, irreversible oxidation at the cysteine thiol, depending on the oxidizing agent. Mutational exchange of C183 to alanine renders FixK(2) resistant to oxidation, yet allows full activity, shown again both in vitro and in vivo. We hypothesize that posttranslational modification by reactive oxygen species is a means to counterbalance the cellular pool of active FixK(2), which would otherwise fill unrestrictedly through FixLJ-dependent synthesis.


Coarse-graining of microscopic dynamics into a mesoscopic transient potential model.
We show that a mesoscopic coarse-grained dynamics model which incorporates the transient potential can be formally derived from an underlying microscopic dynamics model. As a microscopic dynamics model, we employ the overdamped Langevin equation. By utilizing the path probability and the Onsager-Machlup type action, we calculate the path probability for the coarse-grained mesoscopic degrees of freedom. The action for the mesoscopic degrees of freedom can be simplified by incorporating the transient potential. Then the dynamic equation for the mesoscopic degrees of freedom can be simply described by the Langevin equation with the transient potential (LETP). As a simple and analytically tractable approximation, we introduce additional degrees of freedom which express the state of the transient potential. Then we approximately express the dynamics of the system as the the combination of the LETP and the dynamics model for the transient potential. The resulting dynamics model has the same dynamical structure as the responsive particle dynamics type models [W. J. Briels, Soft Matter 5, 4401 (2009)1744-683X10.1039/b911310j] and the multichain slip-spring type models [T. Uneyama and Y. Masubuchi, J. Chem. Phys. 137, 154902 (2012)JCPSA60021-960610.1063/1.4758320]. As a demonstration, we apply our coarse-graining method with the LETP to a single particle dynamics in a supercooled liquid, and compare the results of the LETP with the molecular dynamics simulations and other coarse-graining models.


Mapping brain recovery after concussion: From acute injury to 1 year after medical clearance.
To test the hypothesis that concussion-related brain alterations seen at symptomatic injury and medical clearance to return to play (RTP) will have dissipated by 1 year after RTP. For this observational study, 24 athletes with concussion were scanned longitudinally within 1 week after injury, at RTP, and 1 year after RTP. A large control cohort of 122 athletes were also scanned before the season. Each imaging session assessed global functional connectivity (Gconn) and cerebral blood flow (CBF), along with white matter fractional anisotropy (FA) and mean diffusivity (MD). The main effects of concussion on MRI parameters were evaluated at each postinjury time point. In addition, covariation was assessed between MRI parameters and clinical measures of acute symptom severity and time to RTP. Different aspects of brain physiology showed different patterns of recovery over time. Both Gconn and FA displayed no significant effects at 1 year after RTP, whereas CBF and MD exhibited persistent long-term effects. The effects of concussion on MRI parameters were also dependent on acute symptom severity and time to RTP for all postinjury time points. This study provides the first longitudinal evaluation of concussion focused on time of RTP and 1 year after medical clearance, using multiple different MRI measures to assess brain structure and function. These findings significantly enhance our understanding of the natural course of brain recovery after a concussion.


User testing of a Scottish Intercollegiate Guideline Network public guideline for the parents of children with autism.
The Scottish Intercollegiate Guidelines Network (SIGN) is the leading national clinical guideline producer in Scotland. Improved design and dissemination of guidelines produced for the public can empower people to take an active role in self-management and shared decision-making. The public version of the guideline examined covered getting assessed and diagnosed with autism, and approaches that can help. The aim of this study was to test a public version of a guideline for the parents of children and young people with autism, implement improvements, and identify what works in making it usable and accessible. We recruited mothers from across Scotland. User testing involved formal 'think aloud' semi-structured interviews that guided users through the booklet. Interviews took place individually and were recorded and transcribed. Key findings were identified and themed using the honeycomb user experience model. Fourteen user-testing interviews were conducted. Facilitators for usability and desirability of the guideline included the chunking of text, consistent use of colour and boxes to highlight important information. Simple language, written in a tone of partnership, helped to engage mothers. Value arose from the guidelines ability to explain the process of diagnosis and make mothers feel empowered in their relationships with healthcare professionals. There was a lack of consensus on the usefulness of rating the strength of evidence and recommendations. There was a marked similarity between what was important to the mothers and what has been found to be important to other groups. The involvement of service users and carers in the guidelines development was key to its credibility. One size does not fit all in presenting evidence-based recommendations to the public and it is a challenge to provide sufficient information while avoiding information overload. Recommendations and evidence levels are suitable for use in public versions, but these should be kept as simple as possible.


Rural surgery: the Australian experience.
A significant proportion of the Australian population resides nonmetropolitan regions. For the majority of these smaller regional centers, the surgical service delivery has been traditionally provided by either solo or two-person surgical practices. As medical students' interest in rural practice declined, new models were created to ensure medical care in these areas. This article outlines the past and current state of medical care in rural areas, highlighting models used in Port Augusta, Mount Gambier, and Port Lincoln. It concludes that these models are successful and should be further developed.