Increased chemokines levels in patients with chronic obstructive pulmonary disease: correlation with quantitative computed tomography metrics.
We sought to explore the relationships between multiple chemokines with spirometry, inflammatory mediators and CT findings of emphysema, small airways disease and bronchial wall thickness. All patients with COPD (n = 65) and healthy control subjects (n = 23) underwent high-resolution CT, with image analysis determining the low attenuation area (LAA), ratio of mean lung attenuation on expiratory and inspiratory scans (E/I MLD) and bronchial wall thickness of inner perimeter of a 10-mm diameter airway (Pi10). At enrollment, subjects underwent pulmonary function studies, chemokines and inflammatory mediators measurements. Multiple chemokines (CCL2, CCL3, CCL5, CX3CL1, CXCL8, CXCL9, CXCL10, CXCL11 and CXCL12) and inflammatory mediators (MMP-9, MMP-12, IL-18 and neutrophil count) were markedly increased in the serum of COPD patients compared with healthy controls. There were associations between small airway disease (E/I MLD) and CCL11, CXCL8, CXCL10, CXCL11, CXCL12 and CX3CL1. Especially CXCL8 and CX3CL1 are strongly associated with E/I MLD (r = 0.74, p < 0.001; r = 0.76, p < 0.001, respectively). CXCL8, CXCL12 and CX3CL1 were moderately positively correlated with emphysema (%LAA) (r = 0.49, p < 0.05; r = 0.51, p < 0.05; r = 0.54, p < 0.01, respectively). Bronchial wall thickness (Pi10)showed no significant differences between the COPD and healthy controls,,but there was an association between Pi10 and FEV1% in COPD patients (r=-0.420, p = 0.048). Our statistical results showed that there were not any associations between airway wall thickness (Pi10) and chemokines. Pulmonary chemokines levels are closely associated with the extent of gas trapping, small airways disease and emphysema identified on high-resolution chest CT scan. This study combines quantitative CT analysis with multiplex chemokines and inflammatory mediators to identify a new role of pathological changes in COPD.


Host species preference and larval performance in the wood-boring beetlePhoracantha semipunctata F.
Adults of the wood-boring beetlePhoracantha semipunctata F. showed variability in their attractiveness to five varieties ofEucalyptus when presented with an array of logs in a natural setting. Logs of two host varieties (E. camaldulensis Dehnhardt and the hybridE. trabutii) attracted two to three times more adult beetles than did logs of other host species (E. cladocalyx F.,E. grandis Hill ex Maiden andE. tereticornis Small). In the field, high oviposition rates byP. semipunctata adults resulted in severe competition among larvae. Larval survivorship was low in field logs ofE. trabutii and high inE. cladocalyx logs, although these hosts were the most and least attractive to the adult beetles, respectively. However, when logs were hand infested at low larval densities, survivorship ofP. semipunctata larvae was highest in logs of bothE. camaldulensis andE. trabutii. These findings suggest that adult beetles in the field were most attracted to those logs ofEucalyptus species that represented the highest quality hosts for their progeny under conditions of reduced larval competition.


Effects of simvastatin on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, after oral and intravenous administration in rats: possible role of P-glycoprotein and CYP3A4 inhibition by simvastatin.
The purpose of this study was to investigate the possible effects of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in rats. HMG-CoA reductase inhibitors and diltiazem are sometimes prescribed as a combination therapy for the prevention or treatment of cardiovascular diseases. The effect of simvastatin on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity was evaluated. Simvastatin inhibited CYP3A4 enzyme activity in a concentration-dependent manner with a 50% inhibition concentration (IC(50)) of 3.0 μM. In addition, simvastatin significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. The pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined after oral and intravenous administration of diltiazem to rats in the presence and absence of simvastatin (0.3 and 1.0 mg/kg). The areas under the plasma concentration-time curve (AUC) and the peak concentration (C(max)) of diltiazem were significantly (p < 0.05, 1.0 mg/kg) increased by 45.2% and 35.2%, respectively, in the presence of simvastatin compared to control. Consequently, the absolute bioavailability (AB) values of diltiazem in the presence of simvastatin (1.0 mg/kg) were significantly (p < 0.05) higher (44.8%) than that of the control group. Moreover, the relative bioavailability (RB) of diltiazem was 1.21- to 1.45-fold greater than that in the control group. The metabolite-parent AUC ratio (MR) in the presence of simvastatin (1.0 mg/kg) significantly decreased compared to the control group. This result implied that simvastatin effectively inhibited the metabolism of diltiazem. The increase in diltiazem oral bioavailability might be attributable to enhanced absorption in the small intestine via the inhibition of P-gp and to reduced first-pass metabolism of diltiazem via the inhibition of the CYP3A subfamily in the small intestine and/or in the liver rather than renal elimination of diltiazem by simvastatin.


Pancreatoduodenectomy for pancreatic head tumors in the elderly - Systematic review and meta-analysis.
The age at which patients are undergoing pancreatoduodenectomy is increasing worldwide. The data on the outcome of this surgical procedure in the elderly is constantly expanding. This meta-analysis aims to assess the safety of pancreatoduodenectomy in elderly population, primarily focusing on morbidity and mortality. We searched the Medline, Embase and Cochrane databases to identify eligible studies. The most recent search was performed on 10th April 2017. Inclusion criteria were: (1) comparison of the characteristics and perioperative outcomes of older patients versus younger patients undergoing pancreatoduodenectomy; (2) objective evaluation of mortality or overall morbidity; and (3), publication in English. Exclusion criteria were: (1) a lack of comparative data; (2) a lack of primary outcomes or insufficient data to analyze; (3) a focus on procedures other than pancreatoduodenectomy; or (4), the impossibility of extraction of data specifically concerning pancreatoduodenectomy. Primary outcomes were overall morbidity and mortality. Secondary outcomes analyzed postoperative complications, R0 rate and length of hospital stay. 45 eligible studies were chosen, with a combined total of 21,295 patients. Older patients compared to younger patients had a higher risk of death (2.26% vs. 4.54%; RR: 2.23; 95% CI 1.74-2.87) and a higher complication rate (47.23% vs. 39.35%; RR: 1.17; 95% CI 1.12-1.24). There were no differences in pancreatic fistula occurrence (p = 0.27), bile leakage (p = 0.81), postoperative hemorrhage (p = 0.08), or R0 rate (p = 0.92). Our review confirms, that in the case of pancreatoduodenectomy, advanced age is a risk factor for increased non-surgical morbidity and, by extension, higher mortality.


Comparison of solid phase extraction, saponification and gel permeation chromatography for the clean-up of microwave-assisted biological extracts in the analysis of polycyclic aromatic hydrocarbons.
The feasibility of different clean-up procedures was studied for the determination of polycyclic aromatic hydrocarbons (PAHs) in biota samples such as oysters, mussels and fish liver. In this sense, once the samples were extracted--essentially with acetone and in a microwave system--and before they could be analysed by gas chromatography-mass spectrometry (GC-MS), three different approaches were studied for the clean-up step: solid phase extraction (SPE), microwave-assisted saponification (MAS) and gel permeation chromatography (GPC). The main aim of this work was to maximise the recoveries of PAHs and to minimise the presence of interfering compounds in the last extract. In the case of SPE, Florisil cartridges of 1, 2 and 5 g, and silica cartridges of 5 g were studied. In that case, and with oysters and mussels, microwave-assisted extraction and 5 g Florisil cartridges provided good results. In addition, the concentrations obtained for Standard Reference Material (SRM) NIST 2977 (mussel tissue) were in good agreement with the certified values. In the case of microwave-assisted saponification, the extracts were not as clean as those obtained with 5 g Florisil and this fact lead to overestimate the concentration of the heaviest PAHs. Finally, the cleanest extracts were obtained by GPC. The method was successfully applied to mussels, oysters and hake liver, and the results obtained for NIST 2977 (mussel tissue) were within the confidence interval of the certified reference material for most of the certified analytes.


Neuroprotective Effect of Apigenin on Depressive-Like Behavior: Mechanistic Approach.
Apigenin, as a natural flavonoid present in several plants is characterized with potential anticancer, antioxidant, and anti-inflammatory properties. Recent studies proposed that apigenin affects depression disorder through unknown mechanistic pathways. The effects of apigenin's anti-depressive properties on streptozocin-mediated depression have been investigated through the evaluation of behavioral tests, oxidative stress, cellular energy homeostasis and inflammatory responses. The results demonstrated anti-depressive properties of apigenin in behavioral test including forced swimming and splash tests and oxidative stress biomarkers such as reduced glutathione, lipid peroxidation, total antioxidant power and coenzyme Q10 levels. Apigenin, also, demonstrated its regulatory potency in cellular energy homeostasis and immune system gene expression through inhibiting Nlrp3 and Tlr4 overexpression. Furthermore, failure in energy production as the key factor in various psychiatric disorders was reversed by apigenin modulating effect on AMPK gene expression. Overall, 20 mg/kg of apigenin was recognized as the dose suitable for minimizing the undesirable adverse effects in the STZ-mediated depression model proposed in this study. Our data suggested that apigenin could be able to adjust behavioral dysfunction, biochemical biomarkers and recovered cellular antioxidant level in depressed animals. The surprising results were achieved by raise in COQ10 level, which could regulate the overexpression of the AMPK gene in stressful conditions. The regulatory effect of apigenin in inflammatory signaling pathways such as Nlrp3, and Tlr4 gene expression was studied at the surface part of the hippocampus.


Immunomodulation by placenta-derived decidua stromal cells. Role of histocompatibility, accessory cells and freeze-thawing.
Human placenta-derived decidua stromal cells (DSCs) are newly introduced stromal cells that have successfully been used in several clinical trials for the treatment of acute inflammatory diseases. Despite published data about DSCs, deeper exploration of mechanisms of action and crosstalk with other immune cells need to be explored. In mixed lymphocyte culture (MLC), the splenocytes from Balb/c or B6 mice were stimulated using mitogen (concanavalin A), allogeneic (B6 or Balb/c splenocytes) or xenogeneic activation with human peripheral blood mononuclear cells. When 10% of the mouse bone marrow-derived-MSC, being autologous, allogeneic or haploidentical (from F1), was added, >95% inhibition was seen. Using human (h)-DSCs, the inhibitory capacity was a median 68% as a xenogeneic immunomodulatory cell when used in mitogen and allogeneic setting in mice MLC. However, when human peripheral blood mononuclear cells were used as stimulator for mouse splenocyte (xenogeneic MLC), hDSC showed a median inhibition of 88%. We explored the presence and function of monocytes in the immunomodulatory function of stromal cells. CD14+ monocyte cells reduced the immunosuppressive effect by hDSC. hDSCs did not show any inhibitory effect on natural killer cell activation and proliferation by interleukin-2. In contrast DSCs increased natural killer proliferation by a median of 58%. Fresh or frozen-thawed hDSCs had similar inhibitory effects on human T-cell proliferation (both allo-stimulation and mitogen stimulation) in vitro. Cell viability at room temperature during 24 h was similar using fresh or freeze-thawed DSCs. To conclude, histocompatibility and CD14+ monocyte cells had an impact on hDSC immunomodulation but frozen-thawed or freshly prepared cells did not.


Comparison of the immunological memory after DNA vaccination and protein vaccination against anthrax in sheep.
Currently available live spore vaccines against anthrax in animals have many drawbacks, one of which is their presumed inability to induce a long lasting immunity. In the present study we compared the immunological memory after a protein vaccination with DNA vaccinations in sheep. The antigen used was the protective antigen (PA83) of Bacillus anthracis. Sheep were vaccinated three times with either PA83 plus alhydrogel, or with one of four different plasmid DNA formulations, which all encoded either the full-length PA83 or its domain 4. Two pDNA formulations included Vaxfectin adjuvant, the other two were injected in PBS without adjuvant. Initially, the antibody titres of protein vaccinated sheep were significantly higher than the titres of pDNA vaccinated sheep. After 5 months, however, the antibody titres of protein vaccinated sheep had dropped remarkably, while the titres of all four pDNA vaccinated groups were either stable or had increased. Humoral responses of sheep immunised with pDNA formulated with Vaxfectin adjuvant were higher than the responses of the corresponding groups that received pDNA in PBS only.


Sun Protection Habits and Attitudes Among Healthcare Personnel in a Mediterranean Population.
Health professionals are key agents in healthcare promotion. In the field of skin cancer, they play a crucial role in the development of prevention strategies in the community. This paper aims to describe the sun exposure attitudes and habits of public healthcare professionals in the western Costa del Sol (Spain). A cross-sectional descriptive study was conducted in the Costa del Sol healthcare district to analyse sun exposure and protection practices and habits, and attitudes to tanning and sun protection. The respondents, all healthcare personnel in various professional categories and workplace situations, were asked to complete a self-administered questionnaire. Six hundred forty-three workers in the Costa del Sol healthcare district took part in the study. Of these participants, 450 were healthcare professionals. Of the 450 health professionals, 226 (50.2 %) were nurses or auxiliary nursing staff, and the remaining 224 were doctors. These two groups presented differences regarding habits of sun exposure: 15.3 % of the doctors went to the beach at least 30 days a year, compared to 30.9 % of the nurses (p < 0.001). With respect to workplace situation, there were differences (p < 0.001) between the sunburn events reported by healthcare staff who worked in hospitals (52.4 %) compared to those working in primary healthcare (30.4 %); comparable differences were found with respect to attitudes toward the use of sunscreen creams (p = 0.014). This study identifies two distinct subgroups within healthcare personnel: on one hand, primary healthcare professionals, who are key agents for future policy strategies, and on the other, specialist healthcare professionals, who are more likely to suffer sunburn events and therefore toward whom strategies should be addressed to encourage them to change their sun exposure attitudes and habits and sun protection practices.


Projections from brain stem nuclei to the spinal trigeminal nucleus in the cat.
Afferent projections to the trigeminal nucleus oralis and caudalis from the brain stem have been investigated by the use of retrograde transport of horseradish peroxidase in the cat. Both n. oralis and n. caudalis receive a projection from nucleus raphe magnus but not from other raphe nuclei in the medulla or pons. N. oralis and n. caudalis receive a bilateral projection from n. paragigantocellularis lateralis. N. oralis receives a projection from n. reticularis gigantocellularis and n. reticularis parvocellularis but not from n. reticularis magnocellularis. N. caudalis receives only sparse projections from n. reticularis gigantocellularis, n. reticularis parvocellularis and n. reticularis magnocellularis but receives an input from a layer of cells over the pyramids in the rostral medulla, here named n. paramagnocellularis ventralis. The study also revealed the presence of ascending and descending interconnections between n. oralis and n. caudalis, as well as contralateral trigeminal interconnections. Projections from the medial vestibular nuclei, n. praepositus hypoglossi and the facial nucleus to the spinal trigeminal nucleus were also noted. Since the spinal trigeminal nucleus has only sensory functions, the results indicate the source of projections, mainly from raphe and reticular nuclei, which are involved in sensory control in the trigeminal system.


Comparative clinical studies of ototoxicity and nephrotoxicity of amikacin and gentamicin.
A comparative study of the oto- and nephrotoxicity of amikacin and gentamicin was carried out prospectively. Twenty-six gentamicin-treated patients and 27 amikacin-treated patients were monitored for changes in auditory and renal function during and after therapy. Thirteen of those treated with gentamicin and 20 of those treated with amikacin underwent vestibular caloric testing which could be evaluated for evidence of toxicity. In four (15.4%) of the gentamicin-treated patients, nephrotoxicity developed; no such toxicity was seen in the amikacin-treated patients. This difference may have been due to a fortuitously higher incidence of pretreatment renal impairment in the gentamicin-treated group. In two gentamicin-treated patients (7.7%), ototoxicity developed (one auditory, one vestibular), and in two amikacin-treated patients (7.4%), auditory toxicity developed. Statistical analysis of oto- and nephrotoxicity and their risk factors was not attempted because of the small numbers of patients who could be evaluated. Additional patients are being studied.


UJA-3DFD: a program to compute the 3D fractal dimension from MRI data.
This work presents a computer program for computing the 3D fractal dimension (3DFD) from magnetic-resonance images of the brain. The program is based on an algorithm that calculates the 3D box counting of the entire volume of the brain, and also of its 3D skeletonization. The validity and accuracy of the software has been confirmed using solids with well-known 3DFD values. The usefulness of the program developed is demonstrated by its successful characterization of several neurodegenerative diseases.


Quality-of-care indicators for oesophageal cancer surgery: A review.
Quality-of-care indicators are measurable elements of practice performance that can assess the (change in) quality of the care provided. To date, the literature on quality-of-care indicators for oesophageal cancer surgery has not been reviewed. We performed a review of the literature on quality-of-care indicators for oesophageal cancer surgery. The indicators were classified by their nature of care provision (structural, process, or outcome). One hundred thirty articles were included. For structural measures, most evidence was found for the inverse relationship between hospital or surgeon volume and post-operative mortality. Few articles described the required infrastructural and organisational elements for oesophageal cancer surgery. Regarding process measures, the most common indicators were determinants of patient selection for surgery. Other process indicators with considerable evidence were found (e.g., multidisciplinary team management), though the number of studies was small. For outcome indicators, the level of evidence for pathological outcome measures was strong. Data on post-operative complications as outcome indicators varied widely. Since there is considerable variation in the evaluation of quality of care, the uniform use of well-defined quality-of-care indicators to measure and document practice performance holds the promise of improving outcome in patients who undergo oesophageal cancer surgery.


Structural insights into the ligand binding domain of GluD1 and GluD2 receptors.
GluD1 and GluD2 subunits (also known as delta 1 and 2) are the members of the delta family of ionotropic glutamate receptors. They are particularly puzzling, since they are unable to bind glutamate, but rather bind glycine and d-serine via their classical ligand binding domain (LBD). While GluD2 has been the subject of intensive research over the past decades, it is only recently that GluD1 received similar interest and very few studies compare the properties of these two membrane proteins. In their research article included in this issue, Masternak et al. resolved the 3D structure of the GluD1 LBD, compared its d-serine sensitivity with that of GluD2 and identified critical residues involved in the dynamics of the LBD.


New steroidal derivatives synthesized using 3beta-hydroxyandrosten-17-one as starting material.
In this study, we synthesized some new substituted steroidal derivatives using 3beta-hydroxyandrosten-17-one (dehydroepiandrosterone) as starting material. The synthesized steroidal derivatives 1-11 were evaluated for their androgenic-anabolic activities compared to testosterone as positive control. Details of the synthesis, spectroscopic data and toxicity (LD50) of synthesized compounds are reported.


Absorption of paraquat and diquat from the airways of the perfused rat lung.
The uptake of paraquat dichloride (bis-N-[14C]methyl-4,4'-bipyridilium chloride) and diquat dibromide (N,N-ethylene-[U-14C]2,2'-bipyridilium dibromide monohydrate) from the airways and by the vasculature of the isolated and perfused rat lung (IPL) were studied. A semilogarithmic plot of the percent unabsorbed with time revealed a bi-exponential decay, suggesting at least two phases of removal of paraquat and diquat from the airways. The rapid initial process was similar for both herbicides. The slow component had at t1/2 of 355.98 min for paraquat and 75.03 min for diquat. This second process may represent the storage pool associated with the pulmonary toxicity of paraquat. When paraquat or diquat was presented to the capillary side of the lung, long-term storage was not evident. Uptake by the lung occurred from the pulmonary circulation with similar velocity. These data suggest that the energy-dependent uptake observed with lung slices probably represents airway transport and may be associated with cell membranes lining the alveolus.


Prodromal features in first-psychotic episodes of major affective and schizoaffective disorders.
Study aims were to analyze psychopathological details of prodromes leading to first-lifetime psychotic episodes and apply them to improve prediction of final diagnoses. Comprehensive records of subjects with final diagnoses of bipolar I (BD-I; n = 216), schizoaffective (SzAffD; n = 71), or psychotic major-depressive (MDD; n = 42) disorders in the Harvard-McLean First-Psychotic Episode Project were analyzed to identify psychopathological details of prodromes leading to first-lifetime episodes with psychotic features and their ability to predict final diagnoses tested with multivariable logistic regression modeling. While held blind to final diagnoses, we identified 84 distinct psychopathological characteristics of prodromes to first-psychotic episodes, including perceptual disturbances, affective symptoms, sleep disturbances, onset rate, and duration. Prevalence of 19 factors appeared to differ among final diagnoses, and were tested with multivariable regression modeling. Significantly and independently more associated with final diagnoses of MDD than BD-I were 7 features: suicidal ideation, somatic delusions, anorexia, lack of insomnia, older presenting age, depressive symptoms, and lack of impulsivity; 9 others were associated more with later SzAffD than MDD or BD-I: lack of insomnia, homicidal behavior, lack of excitement, visual hallucinations, command hallucinations, longer prodrome, male sex, responding to internal stimuli, and younger age at presentation. Historical-retrospective and prospective assessments may have misidentified some prodromal features, and subjects with final psychotic-MDD diagnosis were relatively few. Psychopathological features identified during prodromes leading to first-episodes with psychotic features predicted and distinguished among final diagnoses of MDD, BD-I, and SzAffD. The findings add to growing impressions that early psychopathology has value in predicting final diagnoses of major affective and schizoaffective disorders.


Referring and Specialist Physician Gender and Specialist Billing.
While a gender pay gap in medicine has been well documented, relatively little research has addressed mechanisms that mediate gender differences in referral income for specialists. To examine gender-based disparities in medical and surgical specialist referrals in Ontario, Canada. This cross-sectional study included referrals for specialist care ascertained from Ontario Health Insurance Plan physician billings for fiscal year 2018 to 2019. Participants were specialist physicians who received new patient consultations from April 1, 2018, to March 31, 2019, and the associated referring physicians. Data were analyzed from April 2018 to March 2020, including a 12-month follow-up period. Specialist and referring physician gender (female or male). Revenue per referral was defined based on an episode-of-care approach as total billings for a 12-month period from the initial consultation. Mean total billings for female and male specialists were compared and the differential divided into the portion owing to referral volume vs referral revenue. Difference-in-differences multivariable regression analysis was used to estimate gender-based differences in revenue per referral. For each referring physician, gender-based differences in referral patterns were examined using case-control analysis, in which specialists who received a referral were compared with matched control specialists who did not receive a referral. This analysis considered the gender of the specialist and concordance between the gender of the referring physician and specialist, among other characteristics. Of 7 621 365 new referrals, 32 824 referring physicians, of whom 13 512 (41.2%) were female (mean [SD] age, 46.3 [11.6] years) and 19 312 (58.8%) were male (mean [SD] age, 52.9 [13.5] years), made referrals to 13 582 specialists, of whom 4890 (36.0%) were female (mean [SD] age, 45.6 [11.0] years) and 8692 (64.0%) were male (mean [SD] age, 51.8 [13.0] years). Male specialists received more mean (SD) referrals than did female specialists (633 [666] vs 433 [515]), and the mean (SD) revenue per referral was higher for males ($350 [$474]) compared with females ($316 [$393]). Adjusted analysis demonstrated a -4.7% (95% CI, -4.9% to -4.5%) difference in the revenue per referral between male and female specialists. Multivariable regression analysis found that physicians referred more often to specialists of the same gender (odds ratio, 1.04; 95% CI, 1.03-1.04) but had higher odds of referring to male specialists (odds ratio, 1.10; 95% CI, 1.09-1.11). In this cross-sectional study of the gender pay gap in specialist referral income, the number and revenue from referrals received differed by gender, as did the odds of receiving a referral from a physician of the same gender. Future research should examine the effectiveness of different policies to address this gap, such as a centralized, gender-blinded referral system.


Morton neuroma: comparative results of two conservative methods.
The initial treatment of Morton neuromas consists of conservative methods that include shoe modifications and steroid injections. The purpose of this prospective study was to compare the efficacy of these two methods to determine which is more effective as the initial treatment method. Eighty-two patients with Morton neuromas were randomly assigned to receive either footwear modification with orthoses or steroid injections as initial treatment. Outcomes were evaluated at 1 month, 6 months, and 12 months. Patient satisfaction was significantly better (p < 0.01) in the group treated with steroid injections than those treated with shoe modifications at all three followup intervals. At 12-month followup, 82% of those treated with steroid injections had complete or partial relief of pain compared to 63% of those treated with footwear modifications alone. Steroid injections as initial treatment and shoe modifications with steroid injections at 6 months appear to give better results in Morton neuromas than shoe modifications alone, but the difference in the two groups were not statistically significant at one year followup.


Adding Indoximod to Hypofractionated Radiotherapy with Anti-PD-1 Checkpoint Blockade Enhances Early NK and CD8+ T-Cell-Dependent Tumor Activity.
There is growing interest in combinations of immunogenic radiotherapy (RT) and immune checkpoint blockade, but clinical responses are still limited. Therefore, we tested the triple therapy with an inhibitor of the indoleamine 2,3-dioxygenase pathway, which like immune checkpoints, downregulates the antitumor immune response. Triple treatment with hypofractionated RT (hRT) + anti-PD-1 antibody (αPD1) + indoximod was compared with the respective mono- and dual therapies in two syngeneic mouse models. The tumors did not regress following treatment with hRT + αPD1. The αPD1/indoximod combination was not effective at all. In contrast, triple treatment induced rapid, marked tumor regression, even in mice with a large tumor. The effects strongly depended on CD8+ T cells and partly on natural killer (NK) cells. Numbers and functionality of tumor-specific CD8+ T cells and NK cells were increased, particularly early during treatment. However, after 2.5-3 weeks, all large tumors relapsed, which was accompanied by increased apoptosis of tumor-infiltrating lymphocytes associated with a non-reprogrammable state of exhaustion, terminal differentiation, and increased activation-induced cell death, which could not be prevented by indoximod in these aggressive tumor models. Some mice with a smaller tumor were cured. Reirradiation during late regression (day 12), but not after relapse, cured almost all mice with a large B16-CD133 tumor, and strongly delayed relapse in the less immunogenic 4T1 model, depending on CD8+ T cells. Our findings may serve as a rationale for the clinical evaluation of this triple-combination therapy in patients with solitary or oligometastatic tumors in the neoadjuvant or the definitive setting.


Higher affective congruency in the approach-avoidance task is associated with insular deactivation to dynamic facial expressions.
Individuals exhibit a natural bias to approach positive social cues (e.g., smiling face) and to avoid negative ones, which may be altered in psychiatric conditions. Computerized approach/avoidance training to promote affectively congruent behavior has proven useful in modulating such biases. Here, we investigate how exposure to a higher rate of congruency impacts neural processing of social-affective cues. While undergoing functional magnetic resonance imaging (fMRI), twenty-four individuals completed two versions of the approach-avoidance task (AAT), in which they had to approach or avoid dynamic facial expressions of either happiness or disgust. In the high congruency condition, congruent responses (i.e. approaching happy faces, avoiding disgusted faces) were more frequent. The balanced condition had equal amounts of congruent and incongruent responses. Processing of congruent approach-avoidance actions towards social cues was associated with lower recruitment of the right anterior insula in the congruency-intensive relative to the balanced condition. Differential activation between the high congruency and balanced condition in the right hippocampus was negatively related to individuals' trait avoidance tendency. These findings are consistent with reduced affective neural processing of social cues when being exposed to congruent AAT contexts. These neural foci could be important targets when assessing the effectiveness of affective congruency training protocols.


Induction of autophagy-dependent ferroptosis to eliminate drug-tolerant human retinoblastoma cells.
Carboplatin is the most used first-line drug for the treatment of human retinoblastoma (RB), a rare form of cancer in infancy and childhood. However, the clinical application of carboplatin is restricted due to the emergence of acquired multi-drug resistance (MDR) after long-term treatment. Here, we report a new strategy to eliminate MDR RB cells by inducing autophagy-dependent ferroptosis. Compared with parent cells, carboplatin-resistant human RB cells have higher autophagy activity, which drives the formation of MDR to other chemotherapeutic drugs (e.g., etoposide and vincristine). In addition to confirming the traditional strategy of inhibiting autophagy to overcome MDR, we also establish an approach of inducing selective ferritinophagy to eliminate drug-resistant cells. We evaluate the effectiveness and safety of 4-octyl itaconate, a cell-permeable derivative of the metabolite itaconate, in inducing ferritinophagy-dependent ferroptosis in the treatment of MDR RB cells in vitro and in xenograft mouse models. These findings may provide essential clues for initiating clinical trials that target autophagy-dependent ferroptosis to kill drug-tolerant persistent cells during RB therapy.


Early supplemental parenteral nutrition is associated with increased infectious complications in critically ill trauma patients.
Parenteral nutrition (PN) is often used in severely injured patients when caloric goals are not achieved enterally. The purpose of this study is to determine whether early administration of parenteral nutrition is associated with an increased risk for infection after severe injury. Retrospective cohort study of severely injured blunt trauma patients enrolled from eight trauma centers participating in the "Inflammation and the Host Response to Injury" (Glue Grant) study. We compared patients receiving PN within 7 days after injury with a control group that did not receive early PN. We then focused on patients who tolerated at least some enteral nutrition (EN) during the first week and evaluated the potential influence of supplemental PN on outcomes in this "enteral tolerant" subgroup. Primary outcomes included occurrence of a nosocomial infection after the first postinjury week. Secondary outcomes included type of infection and hospital mortality. Of 567 patients enrolled, 95 (17%) received early PN. Early PN use was associated with a greater risk of nosocomial infection (relative risk [RR] = 2.1; 95% CI, 1.6 to 2.6; p < 0.001). In the enteral-tolerant subgroup (n = 249), early PN was also associated with an increase in nosocomial infections (RR = 1.6; 95% CI, 1.2 to 2.1; p = 0.005) in part because of an increased risk of bloodstream infection (RR = 2.8; 95% CI, 1.5 to 5.3; p = 0.002). Mortality tended to be higher in patients receiving additional EN and PN versus EN alone (RR = 2.3; 95% CI, 1.0 to 5.2; p = 0.06). In critically ill trauma patients who are able to tolerate at least some EN, early PN administration can contribute to increased infectious morbidity and worse clinical outcomes.


Vitamin K dependent carboxylation: study of diastereoisomeric gamma-methylglutamic acid containing peptidic substrates.
Two pentapeptides Phe-Leu-X-Glu-Val where X is either the L-threo-gamma-methylglutamic acid or the L-erythro isomer have been synthesized and tested as substrates in the vitamin K dependent carboxylation. The gamma-methylglutamic residue is not carboxylated and both peptides are inhibitors of the carboxylation of the reference peptide Phe-Leu-Glu-Glu-Val. The threo containing isomer has a much better affinity than the reference and is the best inhibitor of this reaction described so far.


Regulation of nitric oxide synthase isoforms by estrogen in the human endometrium.
To examine the influence of estrogen on the expression of nitric oxide synthase (NOS) isoforms in human endometrial surface epithelial cell line (HES) and primary endometrial cells. Laboratory-based investigation. Academic center. The expression of NOS isoform protein levels and mRNA was determined following estrogen/progesterone stimulation. NOS protein and mRNA levels in HES and primary endometrial cells. Estradiol 17-beta (E2) induced a dose- and time-dependent increase in the expression of eNOS mRNA and protein and iNOS protein in HES cells which could be blocked by the estrogen receptor antagonist ICI 182,780. Estradiol increased the expression of eNOS mRNA and protein in primary endometrial cells. Estrogen also induced phosphorylation of eNOS which could not be blocked by ICI 182,780. Progesterone in physiologic concentrations augmented the effect of estrogen on the expression of both eNOS and peNOS but not of iNOS. ICI 182,780 in high concentrations stimulated the expression of iNOS protein while inhibiting eNOS. Estradiol through a genomic mechanism stimulates the expression of NOS isoforms in endometrial derived primary and HES cells. This effect is potentiated by progesterone.


[Flunarizine in epilepsy. Evaluation of a 4-month supplementary treatment in patients resistant to treatment with existing antiepileptics].
Twenty patients affected with a form of epilepsy resistant to treatment received 10 to 20 mg of flunarizine per day in addition to the anti-epileptic medication. The majority of the patients suffered from partial epilepsy with or without secondary generalization. The flunarizine treatment was evaluated after four months. On the whole, flunarizine was well tolerated. The number of attacks was reduced by 50% or more in half the patients.


Mutated and non-mutated TP53 as targets in the treatment of leukaemia.
TP53 is mutated in 10-20% of cases of chronic lymphocytic leukaemia (CLL) and 3-8% of cases of acute myeloid leukaemia (AML). Recently, two classes of compounds that restore the function of p53 in tumours have been described. PRIMA-1 (p53-dependent reactivation and induction of massive apoptosis) restores the wild-type conformation of mutant TP53, whereas RITA (reactivation of p53 and induction of tumour cell apoptosis) increases intracellular levels of p53. We evaluated the effects of RITA alone and in combination with PRIMA-1 or conventional cytostatics on leukaemic cells isolated from AML and CLL patients. AML samples with -17, which are more resistant to daunorubicin and cytarabine compared with samples without -17, were effectively killed by PRIMA-1. RITA, which stabilizes the function of wild-type p53, induced apoptosis in AML cells. In contrast to that seen with PRIMA-1, AML patient samples without -17 were significantly more sensitive to RITA. Similarly, RITA exerted dose-dependent apoptosis and cytotoxicity in CLL cells, which was significantly more pronounced in samples without hemizygous TP53 deletion. Notably, a synergistic effect was observed in all CLL samples with RITA and fludarabine in combination. In both AML and CLL cells exposure to RITA resulted in induction of intracellular p53. We conclude that small molecules targeting p53 might be of clinical importance in the future for treating drug-resistant leukaemia.


Multiple pregnancy: antepartum management.
The critical aspects of twin pregnancy begin with early diagnosis. After that, diet, bed rest, and frequent visits to the physician's office will enhance fetal outcome. Additionally, frequent ultrasound evaluations to assess fetal growth and fetal surveillance are also invaluable adjuncts. Prompt treatment of any medical or obstetrical complications will contribute to an overall improvement in maternal and fetal outcome.


Revitalizing mouse diphyodontic dentition formation by inhibiting the sonic hedgehog signaling pathway.
Tooth regeneration depends on the longevity of the dental epithelial lamina. However, the exact mechanism of dental lamina regression has not yet been clarified. To explore the role of the Sonic hedgehog (Shh) signaling pathway in regression process of the rudimentary successional dental lamina (RSDL) in mice, we orally administered a single dose of a Shh signaling pathway inhibitor to pregnant mice between embryonic day 13.0 (E13.0) and E17.0. We observed that the Shh signaling pathway inhibitor effectively inhibited the expression of Shh signaling pathway components and revitalized RSDL during E15.0-E17.0 by promoting cell proliferation. In addition, mRNA-seq, reverse transcription plus polymerase chain reaction (RT-qPCR), and immunohistochemical analyses indicated that diphyodontic dentition formation might be related to FGF signal up-regulation and the Sostdc1-Wnt negative feedback loop. Overall, our results indicated that the Shh signaling pathway may play an initial role in preventing further development of mouse RSDL in a time-dependent manner.


[Significance of the study of the pachymetric index in the evaluation of the process of eye adaptation to contact lenses].
The authors have examined the thickness of the cornea in 270 patients with weak and moderate myopia during adaptation of the eye to soft or rigid contact lenses. They have revealed a linear correlation between the period of wearing the lens and the degree of the pachometric index change during adaptation of the eye to contact lenses. The maximum permissible period for daily wearing of contact lenses have been determined, not involving essential shifts in water-salt metabolism of the cornea. Optimal schedules for managing the adaptation process with rigid and soft contact lenses have been developed, based on the regularities of the corneal thickness changes related to the length of the lens wearing.


Architecture of the sugar binding sites in carbohydrate binding proteins--a computer modeling study.
Different sugars, Gal, GalNAc and Man were docked at the monosaccharide binding sites of Erythrina corallodenron (EcorL), peanut lectin (PNA), Lathyrus ochrus (LOLI), and pea lectin (PSL). To study the lectin-carbohydrate interactions, in the complexes, the hydroxymethyl group in Man and Gal favors, gg and gt conformations respectively, and is the dominant recognition determination. The monosaccharide binding site in lectins that are specific to Gal/GalNAc is wider due to the additional amino acid residues in loop D as compared to that in lectins specific to Man/Glc, and affects the hydrogen bonds of the sugar involving residues from loop D, but not its orientation in the binding site. The invariant amino acid residues Asp from loop A, and Asn and an aromatic residue (Phe or Tyr) in loop C provides the basic architecture to recognize the common features in C4 epimers. The invariant Gly in loop B together with one or two residues in the variable region of loop D/A holds the sugar tightly at both ends. Loss of any one of these hydrogen bonds leads to weak interaction. While the subtle variations in the sequence and conformation of peptide fragment that resulted due to the size and location of gaps present in amino acid sequence in the neighborhood of the sugar binding site of loop D/A seems to discriminate the binding of sugars which differ at C4 atom (galacto and gluco configurations). The variations at loop B are important in discriminating Gal and GalNAc binding. The present study thus provides a structural basis for the observed specificities of legume lectins which uses the same four invariant residues for binding. These studies also bring out the information that is important for the design/engineering of proteins with the desired carbohydrate specificity.


Author Correction: Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis.
A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-19869-5.


Gene therapy progress and prospects: viral trafficking during infection.
The intracellular steps involved in viral infection, namely cytoplasmic trafficking and nuclear import, are critical events in the viral life cycle that have lagged behind other areas of viral research. This review examines recent advances in our understanding of these steps for viruses commonly employed as viral gene delivery vectors. Steps governing the cytoplasmic trafficking and nuclear import of Herpes Simplex virus, Human Immunodeficiency virus and Adenovirus are reviewed in this article.


The prepurse-string suture technique for gastric defect after endoscopic full-thickness resection (with video).
Endoscopic full-thickness resection (EFTR) is the main treatment for gastric tumors originating from the muscularis propria or gastric extra-luminal growth tumors. Successful closure of the gastric wall defect is a critical step during EFTR.The aim of this retrospective study was to evaluate the feasibility and safety of the endoscopic prepurse-string suture (p-EPSS) technique using an endoloop and several metallic clips during EFTR to close the perforation.Twenty-five patients with gastric tumors originated from the muscularis propria or with gastric extra-luminal growth tumors who received EFTR were analyzed at the Renmin Hospital of Wuhan University from June 2016 to May 2017. Patient characteristics, tumor characteristics, operation time length, and postoperative complications were evaluated in all patients.All the 25 patients underwent a successful EFTR. Complete closure of gastric defects was also achieved. The mean operation time length was 31 ± 14 minutes. The mean maximum size of tumor of was 1.7 ± 1.0 cm (range 0.5-4.5 cm). No severe postoperative complications occurred, such as massive bleeding, gastric leak, peritonitis, or abdominal abscess. No patient needed surgical intervention. Wounds were well healed 1 month after EFTR. No tumor metastasis and recurrence were observed during the follow-up period (median, 7 months).The p-EPSS technique using endoloop and several sterile repositionable hemostasis clips is safe and feasible for closing gastric perforation during EFTR.


High temperature ultrasonic transducers for imaging and measurements in a liquid Pb/Bi eutectic alloy.
In some nuclear reactors or accelerator-driven systems (ADS) the core is intended to be cooled by means of a heavy liquid metal, for example, lead-bismuth (Pb/Bi) eutectic alloy. For safety and licensing reasons, an imaging method of the interior of ADS, based on application of ultrasonic waves, has thus to be developed. This paper is devoted to description of developed various ultrasonic transducers suitable for long term imaging and measurements in the liquid Pb/Bi alloy. The results of comparative experimental investigations of the developed transducers of different designs in a liquid Pb/Bi alloy up to 450 degrees C are presented. Prototypes with different high temperature piezoelectric materials were investigated: PZT, bismuth titanate (Bi4Ti3O12), lithium niobate (LiNbO3), gallium orthophosphate (GaPO4) and aluminum nitride (A1N). For acoustic coupling with the metal alloy, it was proposed to coat the active surface of the transducers by diamond like carbon (DLC). The radiation robustness was assessed by exposing the transducers to high gamma dose rates in one of the irradiation facilities at SCK x CEN. The experimental results proved that the developed transducers are suitable for long-term operation in harsh conditions.


HBV/HIV co-infection: the dynamics of HBV in South African patients with AIDS.
As sub-Saharan Africa is highly endemic for hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections, and their co-infection requires special management, we aimed to assess the serological and molecular characteristics of HBV in patients with AIDS. This was a cross-sectional, case control study, which enrolled 200 patients with AIDS and 200 HIV-negative controls. HBV serology was done in all participants and HCV serology in participants with a hepatitis B core antibody (anti-HBc) only serological pattern. Nested HBV polymerase chain reaction (PCR) and HBV viral load assays were used for HBV molecular detection. Hepatitis B surface antigen (HBsAg) prevalence was 3-fold higher while the 'anti-HBc only' pattern was 6-fold higher in the AIDS group compared with the controls. Mean HBV viral load was significantly higher in HBsAg-positive patients with CD4+ cell counts <100 cells/μl than in patients with CD4+ cell counts of 100-200 cells/μl (p=0.019). There were markedly reduced hepatitis B surface antibody (anti-HBs) titres in the AIDS group compared with the controls (p=0.002). A significant proportion of AIDS patients with an 'anti-HBc only' pattern had CD4+ cell counts <100 cells/μl (p=0.004). Occult HBV prevalence was 3.5% in the AIDS group compared with 1% in the controls (p=0.092). When occult HBV infection was taken into consideration, the overall HBV prevalence became 10% in the AIDS group and 3% in the control group. We showed an increased HBV prevalence in patients with AIDS and identified a CD4+ cell count <100 cells/μl as a major risk factor for the 'anti-HBc only' pattern and increased HBV replication. These data have significant public health implications for HBV in developing countries, especially in areas where antiretroviral (ARV) guidelines do not cater for HBV/HIV co-infection.


Resistance trends and risk factors of extended spectrum β-lactamases in Escherichia coli infections in Aleppo, Syria.
Recently, there has been a notable surge in urinary tract infections (UTIs) by extended spectrum β-lactamase (ESBL)-producing Escherichia coli, which considerably limits treatment options. This study aimed to determine prevalence, phenotypic patterns, and ESBL-production status of E coli in isolates from UTI patients along with uncovering locally relevant risk factors for contracting ESBL-producing E coli infections. One hundred four nonrepetitive urine samples were collected from 3 major hospitals in Aleppo, Syria. Antibiotic susceptibility and ESBL production were studied by disc diffusion and double disk synergy tests according to Clinical Laboratory Standards Institute guidelines. Epidemiologic analysis was done using χ(2) and multivariate logistic regression tests. This study revealed high prevalence of multidrug-resistant (MDR) E coli reaching 63%, whereas ESBL-producing E coli exceeded 52%. The latter exhibited alarmingly elevated levels of coresistance to non-β-lactam antibiotics leading to vast increase in MDR rates in comparison with non-ESBL-producing E coli (83.6% vs 12.2%, respectively). We found previous exposure to third-generation cephalosporins and fluoroquinolones to be a significant risk factor for ESBL-producing E coli infections, in addition to other known factors such as hospitalization and catheterization. Tigecycline and carbapenems demonstrated near perfect efficacy against tested E coli, so they rank high among treatment options.


Cost-effectiveness of pathogen reduction technology for plasma and platelets in Québec: A focus on potential emerging pathogens.
The last economic evaluation of pathogen reduction technology (PRT) in Canada was conducted in 2007. We reassessed the cost-effectiveness of PRT in the province of Québec (which has its own blood supplier) and included an evaluation of the potential impact of emerging pathogens on cost-effectiveness. Decision analytic Markov models were developed to simulate the costs and quality-adjusted life-years (QALY) associated with PRT as an addition to existing safety measures for plasma and platelet products (except for bacterial culture). Models accounted for several infectious and noninfectious transfusion reactions, recipients' productivity losses ensuing from these reactions, and the impact of PRT on platelet function. Scenario analyses were conducted to evaluate the impact of a new highly contagious human immunodeficiency virus (HIV)-like or West Nile virus (WNV)-like pathogen, assuming various epidemiological scenarios. In the base case, the incremental cost-effectiveness ratio (ICER) of PRT was estimated at $8,088,974/QALY gained. Assuming the presence of an HIV-like pathogen, the ICER was $265,209/QALY gained in the "average transmission" scenario, $1,274,445/QALY gained in the "rapid testing scenario," and $123,063/QALY gained in the "highly contagious" scenario. Assuming the presence of a WNV-like pathogen, the ICER was $7,469,167/QALY gained in the "average transmission" scenario and $6,652,769/QALY gained in the "highly contagious" scenario. The cost-effectiveness of PRT may substantially improve in the event of a new, blood-borne pathogen. Given their significant impact on cost-effectiveness, the emergence of new pathogens should be considered when deciding whether to adopt PRT.


Mammary epithelial cell: influence of extracellular matrix composition and organization during development and tumorigenesis.
Stromal-epithelial interactions regulate mammary gland development and are critical for the maintenance of tissue homeostasis. The extracellular matrix, which is a proteinaceous component of the stroma, regulates mammary epithelial growth, survival, migration and differentiation through a repertoire of transmembrane receptors, of which integrins are the best characterized. Integrins modulate cell fate by reciprocally transducing biochemical and biophysical cues between the cell and the extracellular matrix, facilitating processes such as embryonic branching morphogenesis and lactation in the mammary gland. During breast development and cancer progression, the extracellular matrix is dynamically altered such that its composition, turnover, processing and orientation change dramatically. These modifications influence mammary epithelial cell shape, and modulate growth factor and hormonal responses to regulate processes including branching morphogenesis and alveolar differentiation. Malignant transformation of the breast is also associated with significant matrix remodeling and a progressive stiffening of the stroma that can enhance mammary epithelial cell growth, perturb breast tissue organization, and promote cell invasion and survival. In this review, we discuss the role of stromal-epithelial interactions in normal and malignant mammary epithelial cell behavior. We specifically focus on how dynamic modulation of the biochemical and biophysical properties of the extracellular matrix elicit a dialogue with the mammary epithelium through transmembrane integrin receptors to influence tissue morphogenesis, homeostasis and malignant transformation.


Berberine Administration in Treatment of Colitis: A Review.
Berberine (Brb) is one of the well-known naturally occurring compounds exclusively found in Berberis vulgaris and other members of this family, such as Berberis aristata, Berberis aroatica, and Berberis aquifolium. This plant-derived natural compound has a variety of therapeutic impacts, including anti-oxidant, anti-inflammatory, anti-diabetic, and anti-tumor. Multiple studies have demonstrated that Brb has great anti-inflammatory activity and is capable of reducing the levels of proinflammatory cytokines, while it enhances the concentrations of anti-inflammatory cytokines, making it suitable for the treatment of inflammatory disorders. Colitis is an inflammatory bowel disease with chronic nature. Several factors are involved in the development of colitis and it appears that inflammation and oxidative stress are the most important ones. With respect to the anti-inflammatory and antioxidant effects of Brb, its administration seems to be beneficial in the treatment of colitis. In the present review, the protective effects of Brb in colitis treatment and its impact on molecular pathways are discussed.


The motility of mollicutes.
Recent experiments show that the conformation of filament proteins play a role in the motility and morphology of many different types of bacteria. Conformational changes in the protein subunits may produce forces to drive propulsion and cell division. Here we present a molecular mechanism by which these forces can drive cell motion. Coupling of a biochemical cycle, such as ATP hydrolysis, to the dynamics of elastic filaments enable elastic filaments to propagate deformations that generate propulsive forces. We demonstrate this possibility for two classes of wall-less bacteria called mollicutes: the swimming of helical-shaped Spiroplasma, and the gliding motility of Mycoplasma.


LncRNA RPPH1 promotes colorectal cancer metastasis by interacting with TUBB3 and by promoting exosomes-mediated macrophage M2 polarization.
Metastasis is a well-known poor prognostic factor in cancer. However, the mechanisms how long non-coding RNAs (lncRNAs) regulate metastasis in colorectal cancer (CRC) remain largely unknown. Besides, tumor-associated macrophages (TAMs) play an important role in tumor progression, yet the contribution of lncRNA-mediated crosstalk between TAMs and CRC cells to tumor progression is not well understood. In this study, we report that lncRNA RPPH1 was significantly upregulated in CRC tissues, and the RPPH1 overexpression was associated with advanced TNM stages and poor prognosis. RPPH1 was found to promote CRC metastasis in vitro and in vivo. Mechanistically, RPPH1 induced epithelial-mesenchymal transition (EMT) of CRC cells via interacting with β-III tubulin (TUBB3) to prevent its ubiquitination. Furthermore, CRC cell-derived exosomes transported RPPH1 into macrophages which mediate macrophage M2 polarization, thereby in turn promoting metastasis and proliferation of CRC cells. In addition, exosomal RPPH1 levels in blood plasma turned out to be higher in treatment-naive CRC patients but lower after tumor resection. Compared to CEA and CA199, exosomal RPPH1 in CRC plasma displayed a better diagnostic value (AUC = 0.86). Collectively, RPPH1 serves as a potential therapeutic and diagnostic target in CRC.


Structural transition and unusually strong antiferromagnetic superexchange coupling in perovskite KAgF3.
High-purity samples of potassium trifluoroargentate(II), KAgF3, have been obtained via a novel synthetic pathway. This compound is found to exhibit an order-disorder phase transition around 230 K. Susceptibility measurements indicate that KAgF3 exhibits strong antiferromagnetic (AFM) coupling reminiscent of that found in copper(II) oxides.


Is decentralisation the real solution? A three country study.
Decentralisation in the health care sector has been perceived in these last years as a means to revamp the performance of health care systems. Many European countries have undergone this process of delegating funding and/or management responsibilities to sub-layers of government. However, there has also been a recentralisation of health care systems in Nordic states, which typically had a highly decentralised model of service provision and funding. Three country cases will be analysed (Italy, Spain and Norway) and light will be shed on some possible difficulties that Italy and Spain might experience, given their present health decentralised structure. Moreover, there will be an analysis of the reasons that led to recentralisation of health care in Norway. The scope is to make people aware that decentralisation per se is not always successful. The three country cases highlight possible drawbacks that can arise from decentralisation.


VANISHING RETINAL DETACHMENT.
The purpose of this report is to describe a case of rhegmatogenous retinal detachment in the setting of chronic kidney disease that exhibited complete retinal reattachment after serial hemodialysis. Retrospective case report. A 58-year-old woman with acute vision loss was found to have a macula-involving rhegmatogenous retinal detachment. Due to chronic kidney disease, she continued with routinely scheduled hemodialysis for 1 week until surgical clearance was obtained. Preoperative examination revealed complete reattachment of the retina with a persistent retinal tear. Barrier laser was applied to the tear and the retina remained attached until the most recent follow-up 8 months later. The workup of alternate etiologies was unrevealing. This case describes a temporal association between hemodialysis and resolution of subretinal fluid due to rhegmatogenous retinal detachment. A potential causal linkage is suggested based on shifting fluid dynamics associated with hemodialysis. A shift in treatment paradigm is not advised.


Structure-function subsystem model and computational lesions of the central nervous system's rostral sector (forebrain and midbrain).
The craniote central nervous system has been divided into rostral, intermediate, and caudal sectors, with the rostral sector containing the vertebrate forebrain and midbrain. Here, network science tools were used to create and analyze a rat hierarchical structure-function subsystem model of intrarostral sector neural connectivity between gray matter regions. The hierarchy has 109 bottom-level subsystems and three upper-level subsystems corresponding to voluntary behavior control, cognition, and affect; instinctive survival behaviors and homeostasis; and oculomotor control. As in previous work, subsystems identified based on their coclassification as network communities are revealed as functionally related. We carried out focal perturbations of neural structural connectivity comprehensively by computationally lesioning each region of the network, and the resulting effects on the network's modular (subsystem) organization were systematically mapped and measured. The pattern of changes was found to be correlated with three structural attributes of the lesioned region: region centrality (degree, strength, and betweenness), region position in the hierarchy, and subsystem distribution of region neural outputs and inputs. As expected, greater region centrality results, on average, in stronger lesion impact and more distributed lesion effects. In addition, our analysis suggests that strongly functionally related regions, belonging to the same bottom-level subsystem, exhibit similar effects after lesioning. These similarities account for coherent patterns of disturbances that align with subsystem boundaries and propagate through the network. These systematic lesion effects and their similarity across functionally related regions are of potential interest for theoretical, experimental, and clinical studies.


A mixed method approach to understanding the factors surrounding delayed diagnosis of type one diabetes.
This study examined delayed type one diabetes (T1D) diagnosis, along with the associated severity markers, in the United States. Qualitative reflection was explored to add depth of understanding. 975 parents of a minor child with T1D were recruited through snowball, social media requests to complete a 55-question online survey on the experience of diagnosis. 34% of children with T1D had a delayed diagnosis. When compared to those without a delayed diagnosis, these children were more likely to have an Emergency Room diagnosis (39.8% vs. 24.6%), be transported by ambulance or life flight (30.7% vs. 15.3%), be hospitalized (93.7% vs. 83.9%), spend time in an Intensive Care Unit (42.2% vs. 21.3%), and be in diabetic ketoacidosis (DKA) (42.2% vs. 21.3%). Younger children were at increased risk, with higher rates of DKA and fewer days of symptoms. Many parents experienced frustration receiving a prompt diagnosis for their child, including an inability to schedule a physician appointment, proper glucose testing, and concerns being dismissed by professionals. More physician and parent education is needed. Doctors should conduct glucose screenings when diabetes symptoms are present. Parents need education to recognize excessive thirst and frequent urination as reasons to seek medical treatment.


A comparison of face-to-face and remote assessment of inter-rater reliability on the Hamilton Depression Rating Scale via videoconferencing.
Poor inter-rater reliability (IRR) is an important methodological factor that may contribute to failed trials. The sheer number of raters at diverse sites in multicenter trials presents a formidable challenge in calibration. Videoconferencing allows for the evaluation of IRR of raters at diverse sites by enabling raters at different sites to each independently interview a common patient. This is a more rigorous test of IRR than passive rating of videotapes. To evaluate the potential impact of videoconferencing on IRR, we compared IRR obtained via videoconference to IRR obtained using face-to-face interviews. Four raters at three different locations were paired using all pair-wise combinations of raters. Using videoconferencing, each paired rater independently conducted an interview with the same patient, who was at a third, central location. Raters were blind to each others' scores. ICC from this cohort (n=22) was not significantly different from the ICC obtained by a cohort using two face-to-face interviews (n=21) (0.90 vs. 0.93, respectively) nor from a cohort using one face-to-face interview and one remote interview (n=21) (0.88). The mean Hamilton Depression Rating Scale (HAMD) scores obtained were not significantly different. There appears to be no loss of signal using remote methods of calibration compared with traditional face-to-face methods.


Separation of purine and pyrimidine bases by ion chromatography with direct conductivity detection.
A simple, rapid and accurate method for the simultaneous determination of four purine and pyrimidine bases (cytosine, 5-methylcytosine, adenine and N6-methyladenine) has been developed. The quantitative determination of these bases was accomplished by ion chromatography (IC) with direct conductivity detection (CD) based on their ionization in acidic medium without chemical suppression. The recovery of cytosine, 5-methylcytosine, and adenine in calf thymus DNA was more than 98% (n=3) and the relative standard deviation (RSD, n=5) less than 2.4%. In a single chromatographic run, the four bases could be separated and determined in less than 10 min. The detection limits were found to be 0.05 microg/mL for cytosine, 0.08 microg/mL for 5-methylcytosine, 0.07 microg/mL for adenine, and 0.07 microg/mL for N6-methyladenine. Linear ranges were 0.2-95.1 microg/mL for cytosine (r2=0.9996), 0.3-196.6 microg/mL for 5-methylcytosine (r2=0.9994), 0.3-105.5 microg/mL for adenine (r2=0.9998), and 0.3-159.1 microg/mL for N6-methyladenine (r2=0.9999). With the proposed method, purine and pyrimidine bases could be successfully detected in calf thymus DNA. We also determined these bases in calf thymus DNA using RP-HPLC. Compared to RP-HPLC, the IC method offers advantages such as high selectivity and simple mobile phase.


Relationship between membrane fluidity and adrenoceptor binding in depression.
Membrane fluidity and adrenergic receptor binding were studied in platelets of depressed patients before and during treatment with desmethylimipramine to investigate the relationship between the alpha 2-adrenergic receptor and its membrane environment in depression. Most samples came from a previous study in which we observed higher 3H-para-aminoclonidine (3H-PAC) binding in platelets from depressed patients compared to healthy subjects. Fluidity was measured by steady state diphenylhexatriene (DPH) anisotropy in both purified plasma membranes and in intracellular membrane preparations from platelets. No differences were observed in DPH membrane fluidity, per se, indicating that fluidity changes probably do not underlie either the increased alpha 2-adrenergic receptor binding in depression or the normalization of binding during treatment. However, lower intracellular membrane fluidity was correlated with higher binding to 3H-PAC site-1 in healthy subjects, but not in depressed patients. Thus, during depression there may be a disruption in the normal relationship between the adrenergic receptor and its membrane environment.


Marinobufagenin is an upstream modulator of Gadd45a stress signaling in preeclampsia.
Preeclampsia (PE) is a hypertensive disorder of pregnancy, in which marinobufagenin (MBG), a circulating cardiotonic steroid, is increased. The Gadd45a stress sensor protein is an upstream modulator of the pathophysiological changes observed in PE. However, the effects of MBG on Gadd45a stress signaling remain unknown. We examined the expression of Gadd45a, the sFlt-1 receptor, and p38, as well as caspase 3 and 8 activities in placental samples from four groups of rats. These were: normal pregnant (NP, n=8); pregnant rats which received weekly injections of desoxycorticosterone acetate and 0.9% saline as their drinking water (PDS, n=9); normal pregnant rats injected with MBG (NPM, n=8); and PDS rats injected with resibufogenin (RBG), an in vivo antagonist of MBG (PDSR, n=8). Utilizing human cytotrophoblast (CTB) cells, we examined the effect of MBG on these stress signaling proteins in vitro. Placental Gadd45a expression, caspase 3 and 8 activities, sFlt-1 concentrations, and sFlt-1 receptor expression were significantly higher in PDS and NPM compared to NP and PDSR rats. Gadd45a protein was significantly upregulated in the CTB cells when MBG was present in concentrations ≥1nM. Treatment with MBG (≥1nM) also significantly arrested cell cycle progression and activated the expression of the Gadd45a-mediated stress signaling proteins. Inhibition of Gadd45a through RNAi-mediation attenuated MBG-induced CTB cell stress signaling. In conclusion, MBG is involved in the alteration in Gadd45a stress signaling both in vivo and in vitro and RBG prevents these changes when administered in vivo.


Factors that influence the development of avulsion of the levator ani muscle in eutocic deliveries: 3-4D transperineal ultrasound study.
Levator ani muscle (LAM) lesions are the most frequent injuries of the pelvic floor during delivery. Ten to 36% of women report this lesion during their first delivery. Many risk factors have been proposed but very few evaluate the aspects that can influence during natural vaginal delivery. A prospective observational trial was conducted involving 74 primiparous women following vaginal delivery. Maternal, fetal and obstetric characteristics were analyzed. A transperineal three or four-dimensional (3D-4D) ultrasound was offered six months after delivery in order to evaluate avulsions and anomalies of the hiatus. Seventy four women were included, three of them did not show up for ultrasound evaluation. Sixty two (87.3%) demonstrated no avulsion in comparison with nine (12.7%) who did. Five of these lesions were unilateral and four bilateral. Mean newborn weight was 3193 g in the "no avulsion group" versus 3470 g in the "avulsion" group (p=0.025). According to the results, the most important risk factor established, for avulsion during natural childbirth, was the newborn weight. This contrasts with many other authors who have established that birth weight has no impact on these lesions. The most important factor intervening in the avulsion of LAM during natural vaginal delivery is the newborn weight. Patients with diagnosed avulsions present an enlarged urogenital hiatus during valsalva and maximal contraction.


Clinical predictors for buserelin acetate treatment of uterine fibroids: a prospective study of 40 women.
Buserelin acetate, a luteinizing hormone-releasing hormone agonist, is known to be effective in the shrinkage of uterine fibroids. A prospective trial was undertaken (1) to compare the efficacy of intranasal (IN) and subcutaneous (SC) administration of buserelin acetate and (2) to assess if tumor regression correlated with fibroid size and/or patient age. Forty patients were randomly allocated to receive 6 months of either IN buserelin acetate (n = 21) or SC buserelin acetate (n = 19). Four patients did not complete the study and were excluded from statistical analysis. Fibroid regression occurred in all 36 patients. Overall regression to 66% or less of the initial fibroid volume occurred in 70% of subjects. There was no significant difference in fibroid shrinkage between the two administration routes. A significant positive correlation was found between initial fibroid size and subsequent fibroid regression, with larger tumors being more likely to shrink than smaller fibroids. No correlation was found between the patient's age and the extent of fibroid regression.


Serum protein electrophoresis: an interesting diagnosis tool to distinguish viral from bacterial community-acquired pneumonia.
29-69 % of pneumonias are microbiologically documented because it can be considered as an invasive procedure with variable test sensitivity. However, it drastically impacts therapeutic strategy in particular the use of antibiotics. Serum protein electrophoresis (SPEP) is a routine and non-invasive test commonly used to identify serum protein disorders. As virus and bacteria may induce different globulins production, we hypothesize that SPEP can be used as an etiological diagnosis test. Retrospective study conducted from 1/1/13 until 5/1/15 among patient hospitalized for an acute community-acquired pneumonia based on fever, crackles and radiological abnormalities. α/β, α/γ, β/γ globulins and albumin/globulin (A/G) ratio were calculated from SPEP. Data were analyzed in 3 groups: documented viral (DVP) or bacterial pneumonia (DBP) and supposedly bacterial pneumonia (SBP). We used ANOVA statistic test with multiple comparisons using CI95 and ROC curve to compare them. 109 patients included divided into DBP (n = 16), DVP (n = 26) and SBP (n = 67). Mean age was 62 ± 18 year-old with a sex ratio M/F of 1.3. Underlying conditions (e.g. COPD, diabetes) were comparable between groups in multivariate analysis. Means of A/G ratio were 0.80 [0.76-0.84], 0.96 [0.91-1.01], 1.08 [0.99-1.16] respectively for DBP, SBP and DVP (p = 0.0002). A/G ratio cut-off value of 0.845 has a sensitivity of 87.5 % and a specificity of 73.1 %. A/G ratio seems to be an easy diagnostic tool to differentiate bacterial from viral pneumonia. A/G ratio cut-off value below 0.845 seems to be predictable of a bacterial origin and support the use of antibiotics.


Health-related quality of life in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis treated with certolizumab pegol.
Inflammatory joint diseases cause pain and disability. The objective of this study was to measure the quality of life of patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis treated with certolizumab pegol and compare the results with those of the general population. Using a cross-sectional design and sociodemographic and clinical variables, adherence to treatment and quality of life data were collected using the Euroqol-5d-5L (EQ-5D) questionnaire. The quality of life of the general population was obtained from the Spanish National Health Survey. Answers to the EQ-5D questionnaire were analyzed in both groups using two-part models, which measure the probability of having perfect health as well as the disutility caused by the disease. The sample included 59 patients with high adherence (92.3%). The mean utility value was 0.78 and pain was the most affected dimen sion. The reduction in utility (EQ-5D index) of patients with inflammatory joint disease as compared to the general population was 0.127. The subjects of the study showed a significantly lower quality of life than the general population despite effective control of the disease. Two- part models facilitate the interpretation of quality-of-life studies using the EQ- 5D.


Association of smoking and concomitant metformin use with cardiovascular events and mortality in people newly diagnosed with type 2 diabetes.
The cardiovascular and mortality risk in patients with incident type 2 diabetes (T2D) in relation to smoking status and concurrent use of metformin is not well known. A cohort study was performed in 82,205 incident T2D patients from the U.K. Clinical Practice Research Datalink. In the present study, the risks of myocardial infarction (MI), stroke, and mortality in incident T2D patients were evaluated in relation to their smoking status with and without concurrent use of metformin. Over a median 5.4 years of follow-up, of patients without a history of cardiovascular disease (CVD) before a diagnosis of diabetes (n = 63,166), current smokers with and without metformin had an 8% (hazard ratio [HR] 1.08; 95% confidence interval [CI] 0.81, 1.45) and 32% (HR 1.32; 95% CI 1.07, 1.65) increased risk of MI or stroke, respectively, compared with non-smokers without metformin treatment. The respective HRs (95% CI) for mortality in these patients were 0.96 (0.83, 1.11) and 1.86 (1.68, 2.07). The HR for mortality among ex-smokers with and without concurrent metformin treatment was 0.92 (95% CI 0.83, 1.11) and 1.19 (95% CI 1.10, 1.30), respectively. Similar beneficial modifiable effects of metformin among ex- and current smokers were observed in patients with CVD before diagnosis of diabetes (n = 19,039). In T2D patients, concurrent treatment with metformin attenuates the observed higher cardiovascular and mortality risk in ex- and current smokers. In addition to smoking cessation support, treatment with metformin, particularly in ex- and current smokers, should be encouraged.


Integrated bioinformatics analysis for conducting a prognostic model and identifying immunotherapeutic targets in gastric cancer.
Gastric cancer is the third leading cause of death from cancer worldwide and has a poor prognosis. Practical risk scores and prognostic models for gastric cancer are lacking. While immunotherapy has succeeded in some cancers, few gastric cancer patients benefit from immunotherapy. Immune genes and the tumor microenvironment (TME) are essential for cancer progression and immunotherapy response. However, the roles of immune genes and the tumor microenvironment in immunotherapy remain unclear. The study aimed to construct a prognostic prediction model and identify immunotherapeutic targets for gastric cancer (GC) patients by exploring immune genes and the tumor microenvironment. An immune-related risk score (IRRS) model, including APOH, RNASE2, F2R, DEFB126, CXCL6, and CXCL3 genes, was constructed for risk stratification. Patients in the low-risk group, which was characterized by elevated tumor mutation burden (TMB) have higher survival rate. The risk level was remarkably correlated with tumor-infiltrating immune cells (TIICs), the immune checkpoint molecule expression, and immunophenoscore (IPS). CXCL3 and CXCL6 were significantly upregulated in gastric cancer tissues compared with normal tissues using the UALCAN database and RT-qPCR. The nomogram showed good calibration and moderate discrimination in predicting overall survival (OS) at 1-, 3-, and 5- year for gastric cancer patients using risk-level and clinical characteristics. Our findings provided a risk stratification and prognosis prediction tool for gastric cancer patients and further the research into immunotherapy in gastric cancer.


Immunoreactive insulin in serum and seminal plasma of diabetic and nondiabetic men and its role in the regulation of spermatozoal activity.
Concentrations of immunoreactive insulin (IRI) and, in some cases, testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured in serum and seminal plasma (SP). IRI levels were usually higher in SP. They were unaffected by masturbation; circulating testosterone, LH, and FSH levels were also unaffected. The IRI concentration was higher in the second (vesicular) fraction of split ejaculates. Semen quality was unrelated to IRI in SP in normal and diabetic (chlorpropamide-maintained) men. The addition of insulin in vitro to washed spermatozoa from diabetic and nondiabetic men had no effect on oxygen and glucose uptake or on lactate production and spermatozoal motility. Furthermore, administration of L-arginine to infertile men for 3 months (4 gm/day) was followed in four of seven men by significant increases in IRI concentrations in blood and SP. However, neither semen quality nor fertility was improved.


Visual attention in behaving cats: attention shifts and sustained attention episodes are accompanied by distinct electrocortical activities.
We analyse a particular class of fast electrocortical rhythms that occur in a limited part of the primary visual cortex (BA 18) during eye saccades in behaving cats placed in a lit environment. Their high frequency (50-132 Hz) contrasts with that of two other classes of rhythms recorded in the same cortical area, the 25-45 Hz visual rhythms (40 Hz) that we previously showed to accompany sustained focused attention, and the alpha rhythms (approximately 10 Hz), that occur in situations of rest. These "very fast visual rhythms" (VFVRs) consist of two brief successive trains, a first one of low amplitude preceding the saccade onset, and a second one, much larger, during the saccade itself. The possibility is considered, that the first train subtends a presaccadic attention shift, and the second, a change of gaze towards a new target through the interception saccade. ECoG activities can thus well distinguish between attention shift and sustained attention.


Evaluating the granularity balance of hierarchical relationships within large biomedical terminologies towards quality improvement.
Organizing the descendants of a concept under a particular semantic relationship may be rather arbitrarily carried out during the manual creation processes of large biomedical terminologies, resulting in imbalances in relationship granularity. This work aims to propose scalable models towards systematically evaluating the granularity balance of semantic relationships. We first utilize "parallel concepts set (PCS)" and two features (the length and the strength) of the paths between PCSs to design the general evaluation models, based on which we propose eight concrete evaluation models generated by two specific types of PCSs: single concept set and symmetric concepts set. We then apply those concrete models to the IS-A relationship in FMA and SNOMED CT's Body Structure subset, as well as to the Part-Of relationship in FMA. Moreover, without loss of generality, we conduct two additional rounds of applications on the Part-Of relationship after removing length redundancies and strength redundancies sequentially. At last, we perform automatic evaluation on the imbalances detected after the final round for identifying missing concepts, misaligned relations and inconsistencies. For the IS-A relationship, 34 missing concepts, 80 misalignments and 18 redundancies in FMA as well as 28 missing concepts, 114 misalignments and 1 redundancy in SNOMED CT were uncovered. In addition, 6,801 instances of imbalances for the Part-Of relationship in FMA were also identified, including 3,246 redundancies. After removing those redundancies from FMA, the total number of Part-Of imbalances was dramatically reduced to 327, including 51 missing concepts, 294 misaligned relations, and 36 inconsistencies. Manual curation performed by the FMA project leader confirmed the effectiveness of our method in identifying curation errors. In conclusion, the granularity balance of hierarchical semantic relationship is a valuable property to check for ontology quality assurance, and the scalable evaluation models proposed in this study are effective in fulfilling this task, especially in auditing relationships with sub-hierarchies, such as the seldom evaluated Part-Of relationship.


[Breastfeeding and rooming-in in the management of neonatal abstinence syndrome. Scoping review].
At present, more babies are born with neonatal abstinence syndrome due to the increased use of certain substances by their mothers while pregnant. The therapeutic approaches for this syndrome vary in clinical practice, and in some centres, breastfeeding and rooming-in are interrupted. The aim of this work was to analyse the effects of breastfeeding and rooming-in in infants with neonatal abstinence syndrome by conducting a scoping review of the related literature in PubMed and CINAHL. Eleven papers were included, which showed that breastfeeding and rooming-in reduced hospital stay and the need for and duration of pharmacological treatment. In addition, rooming-in decreased the likelihood of admission to the Neonatal Intensive Care Unit, although there was no improvement of the severity of neonatal abstinence syndrome signs. Breastfed infants had milder withdrawal signs and, although they were more likely to be readmitted than formula-fed infants were, there were no statistically significant differences. There was no evidence that rooming-in decreased hospital readmission after discharge. Our findings support the maintenance of cohabitation and breastfeeding whenever possible in the management of this neonatal abstinence syndrome, so as not to worsen the conditions of the neonate, while introducing measures to ensure mother-child safety.


Occult enteric infection by Ancylostoma caninum: a previously unrecognized zoonosis.
Human disease caused by the canine hookworm Ancylostoma caninum and a high incidence of eosinophilic enteritis have been reported from northern Queensland, Australia. The aim of this study was to evaluate patients with unexplained abdominal pain and a possible association with cryptic infections by A. caninum. The clinical and demographic features of patients from this region with eosinophilic enteritis (group A1, n = 42), obscure abdominal pain associated with (group A2, n = 105) and without (group A3, n = 84) blood eosinophilia were reviewed and sera were tested against A. caninum excretory-secretory antigens by enzyme-linked immunosorbent assay (ELISA) and Western blot. Four additional patients, two with confirmed A. caninum, had hookworm infection. The level of dog ownership in these four groups was 79%-100%, higher than in the local population (P < 0.001). The ELISA tested positive in 71% of A1, 67% of A2, and 30% of A3, versus 8% in controls (P < 0.002). All cases tested were positive on Western blot versus 10% of controls (P < 0.0001). The ELISA values increased with chronicity and decreased during convalescence. We conclude occult human A. caninum infections are common and are characterized by eosinophilic enteritis and obscure abdominal pain with or without blood eosinophilia. The diagnosis can be confirmed by serology.


Non-disease specific patient-reported outcome measures of health-related quality of life in juvenile idiopathic arthritis: a systematic review of current research and practice.
Juvenile idiopathic arthritis (JIA), as a chronic condition, is associated with symptoms negatively impacting health-related quality of life (HRQL). Regarding growing interest in the implementation of the patient-reported outcome measures (PROMs), we aimed to review the non-disease specific PROMs addressing HRQL assessment, potentially useful in the clinical care of JIA and daily practice. A systematic literature search was conducted using MEDLINE/PubMed, Google Scholar, Scopus and Embase databases (1990 to 2021), with a focus on the recent 5-years period. Entry keywords included the terms: "children", "adolescents", "JIA", "chronic diseases", "HRQL", "PROMs" and wordings for the specific tools. Several available PROMs intended to measure HRQL, non-specific to JIA, were identified. The presented outcomes differed in psychometric properties, yet all were feasible in assessing HRQL in healthy children and those with chronic diseases. Both EQ-5D-Y and PedsQL have already been tested in JIA, showing relevant reliability, validity, and similar efficiency as disease-specific measurements. For PROMIS® PGH-7 and PGH-7 + 2, such validation and cross-cultural adaptation need to be performed. Considering the future directions in pediatric rheumatology, the large-scale implementation of PROMIS® PGH-7 and PGH-7 + 2 in JIA offers a particularly valuable opportunity. The PROMs reflect the patient perception of the chronic disease and allow to understand child's opinions. The PROMs may provide an important element of the holistic medical care of patients with JIA and a standardized tool for clinical outcomes, monitoring disease severity and response to treatment.


Insight on the effect of Ni and Ni-N co-doping on SnO2 anode materials for lithium-ion batteries.
With the increased demand for high-rate performance Li-ion batteries, it is necessary to find available methods to improve the rate properties of SnO2 electrodes. It is noteworthy that doping was considered to be a feasible means. The electronic structures and diffusion energy barriers of Ni-doped and Ni-N co-doped SnO2 were calculated based on density functional theory. The results estimated that the energy gaps of Ni-doped and Ni-N co-doped SnO2 are 1.07 eV and 0.94 eV, which both are smaller than the value of 2.08 eV of SnO2. These exhibit that the conduction properties of SnO2 can be enhanced by doping with the Ni or Ni-N atoms. Moreover, the diffusion properties of Li can also be improved by doping with Ni-N atoms due to the diffusion energy barrier of Li from the B to C point for Ni-N co-doped SnO2 being 0.12 eV smaller than the value of 0.24 eV for the pristine SnO2. Meanwhile, the diffusion energy barriers of Li along other pathways for Ni-N co-doped SnO2 are almost the same as 0.24 eV for SnO2. These results show that both the electronic and ionic conductivity of SnO2 can be enhanced by Ni-N co-doping, which provides a theoretical explanation to promote the rate properties of SnO2 by Ni-N co-doping as anode materials for Li-ion batteries.


Myofibrillar protein oxidation affects filament charges, aggregation and water-holding.
Hypochlorous acid (HClO) is a strong oxidant that is able to mediate protein oxidation. In order to study the effect of oxidation on charges, aggregation and water-holding of myofibrillar proteins, extracted myofibrils were oxidized by incubation with different concentrations of HClO (0, 1, 5, and 10mM). Loss of free thiols, loss of histidine and formation of carbonyls were greater with increasing oxidation level and the particle size increased. Water-holding in the 5 and 10mM HClO groups were greater than in the non-oxidized control. Isoelectric focusing (IEF) showed that the isoelectric point (pI) of oxidized proteins were lower compared to non-oxidized ones. The lower pI values of oxidized proteins suggests that oxidation increased the overall net negative charge of myofibrillar proteins solubilized for IEF. Here we propose a hypothesis that oxidation-induced increase in net negative charges is the driving force for improved water-holding in myofibrils, whereas protein cross-linking and aggregation have an opposing effect by decreasing the water-holding.


Impaired vibrotactile sense at low frequencies in fingers in autoantibody positive and negative diabetes.
Vibration thresholds in index and little finger pulps in subjects with autoantibody [GADA, IA-2A and/or ICA] positive and negative diabetes 20 years after diagnosis were higher than in age-matched controls at low frequencies (8 and 16 Hz), irrespective of HbA1c values, indicating selective impairment of Meissner's corpuscles and/or their innervating axons.


Aberrant SERPINE1 DNA methylation is involved in carboplatin induced epithelial-mesenchymal transition in epithelial ovarian cancer.
Resistance to platinum-based therapeutic agents is the major contributor to epithelial ovarian cancer (EOC) mortality. There is an urgent need to better understand the underlying mechanisms. Here we investigated the role of serpins in EOC chemoresistance and related mechanisms, and found that SERPINE1 played an important role in chemoresistance in A2780cp cells. A2780cp and A2780s cells were used in our study. Microarray screening was used to identify the gene expression change under carboplatin treatment. A cell-counting kit-8 was used to detect the sensitivity of ovarian cancer cells after treatment. The expression of SERPINE1 was silenced by siRNA. The levels of SERPINE1 and epithelial-mesenchymal transition (EMT)-related proteins were confirmed by Western blot. MassArray EpiTYPER quantitative DNA methylation analysis was introduced to evaluate the methylation of the promoter of SERPINE1. Microarray data showed that SERPINE1 and SERPINE2 increased most dramatically under carboplatin treatment in A2780cp cells. Carboplatin treatment could significantly increase the expression of SERPINE1 and induce the EMT process, with decreased expression of E-cadherin and increased expression of Vimentin, Snail and Twist. Knockdown of SERPINE1, but not SERPINE2, in A2780cp cells could inhibit the EMT process. We also found that hypomethylation in the promoter of SERPINE1 might result in the increased expression of SERPINE1 and subsequent EMT process in A2780cp cells. Our study suggested that SERPINE1 may be a promising therapeutic target for chemoresistance.


Determination of biomarkers of tobacco smoke exposure in oral fluid using solid-phase extraction and gas chromatography-tandem mass spectrometry.
A new, simple and sensitive method was described for the simultaneous determination of nicotine, cotinine and trans-3'-hydroxycotinine in oral fluid samples using solid-phase extraction and gas chromatography/tandem mass spectrometry (GC-MS/MS). This technique was developed using only 0.2 mL of sample, and deuterated analogues were used as internal standards. The method was found to be linear between 0.5 and 1000 ng/mL, with determination coefficients higher than 0.996 for all analytes. Intra- and interday precision and accuracy were in conformity with the criteria normally accepted in bioanalytical method validation. All analytes were stable in the samples for at least 24h at room temperature, for at least 72 h at 25°C in processed samples and for at least three freeze/thaw cycles. Absolute recoveries ranged from 89 to 92% for all analytes. GC-MS/MS has demonstrated to be a powerful tool for the simultaneous quantitation of the analytes, providing adequate selectivity and sensitivity. In addition, its performance characteristics allow its routine use in the analysis of biomarkers of tobacco smoke exposure, extending the window of analyte detection in nicotine cessation programs, using a sample amount as low as 0.2 mL of human oral fluid.


Distribution of the androgen receptor in the diencephalon and the pituitary gland in goats: Co-localisation with corticotrophin releasing hormone, arginine vasopressin and corticotrophs.
Previously it has been shown that androgen suppresses transportation-induced increases in plasma adrenocorticotropic hormone (ACTH), possibly by suppressing the secretion of corticotrophin releasing hormone (CRH) or arginine vasopressin (AVP) from the hypothalamus, or secretion of ACTH from the pituitary gland. The aim of the present study was to examine androgen target sites in the caprine diencephalon and pituitary gland using immunohistochemical methods. The androgen receptor (AR) was expressed strongly in the bed nucleus of the stria terminalis, the medial preoptic area, the arcuate nucleus, the ventromedial hypothalamic nucleus and the suprachiasmatic nucleus in the diencephalon. Between 8% and 11% of CRH and AVP neurons in the paraventricular hypothalamic nucleus (PVN) expressed AR. In the pituitary gland, 7.1% of corticotrophs expressed AR. The results are consistent with the proposal that androgen acts directly and indirectly on CRH and/or AVP neurons in the PVN. The possibility of a direct action of androgen on the corticotrophs in the pituitary gland was also considered.


Pre- and postsynaptic effects of SKF64139, a phenylethanolamine N-methyltransferase inhibitor, in conscious normotensive rats.
We investigated in conscious normotensive rats the effect of SKF64139 (2 mg i.v.), a potent phenylethanolamine N-methyltransferase (PNMT) inhibitor, on blood pressure responses to norepinephrine (40, 80, and 160 ng i.v.); methoxamine (2.5, 5 and 10 micrograms i.v.), a directly active sympathomimetic agent that is not taken up by adrenergic nerves; and tyramine (20, 40, and 80 micrograms i.v.), an indirectly acting sympathomimetic amine. The pressor effect of norepinephrine was not changed by 2 mg of SKF64139, while those of methoxamine and tyramine were significantly reduced. The dose-response curve to exogenous norepinephrine was also evaluated following blockade of norepinephrine uptake in the nerve endings using 0.25 mg desipramine i.v. This dose of desipramine had no effect on blood pressure increase induced by methoxamine. In rats pretreated with the neuronal uptake inhibitor desipramine in a dose that did not affect alpha-adrenoceptors, SKF64139 significantly decreased the pressor responses to norepinephrine. Increasing the dose of SKF64139 to 8 mg i.v. resulted in a significant fall in base-line blood pressure and in a blunted blood pressure response to norepinephrine. These data demonstrate that in vivo the PNMT inhibitor SKF64139 blocks alpha-adrenoceptors and inhibits neuronal uptake. The alpha-adrenoceptor blocking properties of SKF65139 are masked by simultaneous blockade of norepinephrine uptake when agonists with affinity for the uptake system are used. These findings need to be taken into account when interpreting cardiovascular effects of the PNMT inhibitor SKF64139.


The effects of physical work, mental work, and quantity on children's time perception.
An experiment was conducted to examine the effects of work and quantity cues on children's time perception. Ninety-seven children in kindergarten and Grades 2, 4, and 6 lifted and transferred pipes under eight different conditions, after which they reproduced the perceived time taken to move the pipes. The conditions varied by quantity (two/four pipes), by mental work (no-matching/matching), and by physical work (light/heavy pipes). Significant main effects were found for quantity, physical work, and mental work, and for the quantity x age and mental work x physical work interactions. These results can help to disentangle possible confounds among these variables in the classic Piagetian experiments about their effects on time judgment and perception.


Percutaneous intentional extraluminal (subintimal) recanalization: how to do it yourself.
A new and simple technique to treat long superficial femoral artery occlusions is explained step by step. Both authors have extensive experience with this technique of percutaneous intentional extraluminal (subintimal) recanalization and this paper is based on their personal experience. Technical considerations, indications, pitfalls, possible complications and results are discussed.