Functional Bowel Disease.
Functional bowel disorders refer to disorders of gut-brain interaction that affect the intestinal tract. Irritable bowel syndrome (IBS) is the most common functional bowel disorder and affects individuals regardless of age and gender. It can result in impaired quality of life and significant health care utilization and is therefore important to recognize and manage. The diagnosis of IBS is based on clinical symptoms. IBS is categorized based on predominant bowel habit (constipation, diarrhea, mixed, or unclassified), and the treatment of IBS is individually tailored based on subtype and symptom severity.


Inhibition of miR30a-3p by sulforaphane enhances gap junction intercellular communication in pancreatic cancer.
The therapy resistance of pancreatic cancer is associated with the loss of gap junction intercellular communication and connexin 43 expression. The broccoli isothiocyanate sulforaphane restored these features and therapy sensitivity. We investigated whether microRNA signaling is involved. Established cell lines and a patient tissue array (n = 96) were evaluated by miRNA and gene array, bioinformatics, expression studies, in situ hybridization and immunohistochemistry. Sulforaphane inhibited the expression of our top candidate miR30a-3p. Upon transfection of miR30a-3p inhibitors, the gemcitabine bystander effect, Cx43 expression and intercellular communication increased, whereas miR30a-3p mimics inhibited the luciferase activity of a Cx43 3'-UTR construct. miR30a-3p-overexpressing tumor xenografts had a decreased tumor volume and increased gemcitabine sensitivity. In patient tissues, a higher expression of miR30a-3p and a lower expression of Cx43 correlated with malignancy. These findings provide new knowledge and suggest sulforaphane as cotreatment for pancreatic cancer.


Time-dependent VOC-profile of decomposed human and animal remains in laboratory environment.
A validated method using a thermal desorber combined with a gas chromatograph coupled to a mass spectrometer was used to identify the volatile organic compounds released in decomposed human and animal remains after 9 and 12 months in glass jars in a laboratory environment. This is a follow-up study on a previous report where the first 6 months of decomposition of 6 human and 26 animal remains was investigated. In the first report, out of 452 identified compounds, a combination of 8 compounds was proposed as human and pig specific. The goal of the current study was to investigate if these 8 compounds were still released after 9 and 12 months. The next results were noticed: 287 compounds were identified; only 9 new compounds were detected and 173 were no longer seen. Sulfur-containing compounds were less prevalent as compared to the first month of decomposition. The appearance of nitrogen-containing compounds and alcohols was increasingly evident during the first 6 months, and the same trend was seen in the following 6 months. Esters became less important after 6 months. From the proposed human and pig specific compounds, diethyl disulfide was only detected during the first months of decomposition. Interestingly, the 4 proposed human and pig specific esters, as well as pyridine, 3-methylthio-1-propanol and methyl(methylthio)ethyl disulfide were still present after 9 and 12 months of decomposition. This means that these 7 human and pig specific markers can be used in the development of training aids for cadaver dogs during the whole decomposition process. Diethyl disulfide can be used in training aids for the first month of decomposition.


Changes in brain and spinal tryptophan and 5-hydroxyindoleacetic acid levels following acute morphine administration in normal and arthritic rats.
The effects of morphine (10 mg/kg/s.c.) on tryptophan (TRP), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels were studied in normal and arthritic rats. (1) In normal rats morphine induced a discrete but significant increase of 5-HIAA levels in the forebrain and the spinal cord. (2) By contrast, in rats suffering from experimentally induced arthritis large modifications were apparent. The basal levels of TRP, 5-HT and 5-HIAA were significantly higher than in normal rats. Morphine induced clear increases of 5-HIAA and TRP in the forebrain, the brain stem and the spinal cord, without any modification of 5-HT. The effects were dose-dependent and suppressed by naloxone (1 mg/kg/i.m.). Statistical analysis clearly revealed that arthritic rats were much more sensitive to morphine. The results support the hypothesis of an activation of a 5-HT descending pathway by morphine which parallels the activation of the ascending pathway previously demonstrated by several authors and confirmed here.


Synthesis, antiplatelet and antithrombotic activities of new 2-substituted benzopyrano[4,3-d]pyrimidin-4-cycloamines and 4-amino/cycloamino-benzopyrano[4,3-d]pyrimidin-5-ones.
Atherothrombotic coronary artery disease, associated with deep vein thrombosis, is one of the most common causes of death worldwide. Recently, antiplatelet combination therapy using agents with different mechanisms of action, such as aspirin, dipyridamole, and thienopyridines, seems to be an attractive preventive approach. Moreover, several large, randomized clinical trials support combination therapy with aspirin plus warfarin in high-risk patients with atherosclerotic heart disease. Our research on the benzopyrano[4,3-d]pyrimidine system gave rise to the synthesis of a large number of compounds endowed with in vitro anti-aggregating activity. Several SAR considerations suggest that the benzopyranopyrimidine system is an appropriate scaffold to obtain molecules that are able to act simultaneously in different pathways of aggregation. Now, we report the synthesis of new 2-substituted benzopyrano[4,3-d]pyrimidin-4-cycloamines and 4-amino/cycloamino-benzopyrano[4,3-d]pyrimidin-5-ones and the results of the pharmacological study on haemostasis. Some tested compounds showed a large-spectrum antiplatelet activity in vitro, and are more potent than aspirin as antithrombotics in vivo but, at variance with aspirin, they do not increase bleeding. This paper describes novel antithrombotic compounds with an interesting pharmacological profile and a potentially attractive benefit/risk ratio, with their mechanism of action generally, but not exclusively, dependent on antiplatelet activity, deserving further investigations.


Evaluation of Intra- and Interscanner Reliability of MRI Protocols for Spinal Cord Gray Matter and Total Cross-Sectional Area Measurements.
In vivo quantification of spinal cord atrophy in neurological diseases using MRI has attracted increasing attention. To compare across different platforms the most promising imaging techniques to assess human spinal cord atrophy. Test/retest multiscanner study. Twelve healthy volunteers. Three different 3T scanner platforms (Siemens, Philips, and GE) / optimized phase sensitive inversion recovery (PSIR), T1 -weighted (T1 -w), and T2 *-weighted (T2 *-w) protocols. On all images acquired, two operators assessed contrast-to-noise ratio (CNR) between gray matter (GM) and white matter (WM), and between WM and cerebrospinal fluid (CSF); one experienced operator measured total cross-sectional area (TCA) and GM area using JIM and the Spinal Cord Toolbox (SCT). Coefficient of variation (COV); intraclass correlation coefficient (ICC); mixed effect models; analysis of variance (t-tests). For all the scanners, GM/WM CNR was higher for PSIR than T2 *-w (P < 0.0001) and WM/CSF CNR for T1 -w was the highest (P < 0.0001). For TCA, using JIM, median COVs were smaller than 1.5% and ICC >0.95, while using SCT, median COVs were in the range 2.2-2.75% and ICC 0.79-0.95. For GM, despite some failures of the automatic segmentation, median COVs using SCT on T2 *-w were smaller than using JIM manual PSIR segmentations. In the mixed effect models, the subject was always the main contributor to the variance of area measurements and scanner often contributed to TCA variance (P < 0.05). Using JIM, TCA measurements on T2 *-w were different than on PSIR (P = 0.0021) and T1 -w (P = 0.0018), while using SCT, no notable differences were found between T1 -w and T2 *-w (P = 0.18). JIM and SCT-derived TCA were not different on T1 -w (P = 0.66), while they were different for T2 *-w (P < 0.0001). GM area derived using SCT/T2 *-w versus JIM/PSIR were different (P < 0.0001). The present work sets reference values for the magnitude of the contribution of different effects to cord area measurement intra- and interscanner variability. 1 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2019;49:1078-1090.


Targeting carbonic anhydrases for the management of hypoxic metastatic tumors.
Several isoforms of the metalloenzyme carbonic anhydrase (CA, EC 126.96.36.199) are connected with tumorigenesis. Hypoxic tumors overexpress CA IX and XII as a consequence of HIF activation cascade, being involved in pH regulation, metabolism, and metastases formation. Other isoforms (CA I, II, III, IV) were also reported to be present in some tumors. Some CA isoforms are biomarkers for disease progression or response to therapy. Inhibitors, antibodies, and other procedures for targeting these enzymes for the treatment of tumors/metastases are discussed. Sulfonamides and coumarins represent the most investigated classes of inhibitors, but carboxylates, selenium, and tellurium-containing inhibitors were also investigated. Hybrid drugs of CA inhibitors with other antitumor agents for multitargeted therapy were reported. Targeting CAs present in solid or hematological tumors with selective, targeted inhibitors is a validated approach, which has been consolidated in the last years. A host of new preclinical data and several clinical trials of antibodies and small-molecule inhibitors are ongoing, which connected with the large number of new chemotypes/procedures discovered to be effective, may lead to a breakthrough in this therapeutic area. The scientific/patent literature has been searched for on PubMed, ScienceDirect, Espacenet, and PatentGuru, from 2018 to 2023.


The relation of non-culpable traffic incidents to bus drivers' celeration behavior.
The driver celeration behavior theory predicts that celerations are associated with incidents for which the driver has some responsibility in causing, but not other incidents. The hypothesis was tested in 25 samples of repeated measurements of bus drivers' celeration behavior against their incidents for two years. The results confirmed the prediction; in 18 samples, the correlation for culpable incidents only was higher than for all incidents, despite the higher means of the latter. Non-culpable incidents had correlations close to zero with celeration. It was pointed out that most individual crash prediction studies have not made this differentiation, and thus probably yielded underestimates of the associations sought, although the effect is not strong, due to non-culpable accident involvements being few (less than a third of the total). The methods for correct identification of culpable incident involvements were discussed.


[Substance use among adolescents: Addiction or self-handicap strategy?]
Self-handicapping strategies consist of creating or declaring obstacles to oneself before a situation of accomplishment that threatens the self, as might be the case during an academic assessment or a sporting competition, in order to protect oneself from a possible failure or to valorise oneself in the event of success. It turns out that beyond the physiological effects sought and the dependence linked to the product, the consumption of psychoactive substances can serve as an excuse for users in the event of failure, thus protecting their sense of competence or enhancing it in the event of success, for having succeeded in spite of their consumption, which is known to have a negative impact on performance.


Facilitating maintenance of stormwater ponds: comparison of analytical methods for determination of metal pollution.
Stormwater ponds are widely used for controlling runoff quality through the sedimentation of particles and associated pollutants. Their maintenance requires regular removal and disposal of accumulated material. This necessitates an assessment of material hazardousness, including potential hazard due to its contamination by metals. Here we analyze 32 stormwater pond sediment samples from 17 facilities using several chemical analysis methods (total extraction, sequential extraction, diffusive gradients in thin-films DGT, and pore water extraction) in order to consider the complementarity and comparability of the different approaches. No clear relationship was found between analyses that have the potential to measure similar metal fractions (DGT and either fraction 1 of the sequential extraction (adsorbed and exchangeable metals and carbonates) or pore water concentrations). Loss on ignition (LOI) had a significant positive correlation with an indicator of the environmental risk developed in this paper (∑ranks) that incorporates different metals, speciations, and environmental endpoints. Large variations in metal levels were observed between ponds. As clustering was limited between the different analyses, a comprehensive analysis of different parameters is still needed to fully understand metal speciation and bioavailability.


Synthesis of urchin-like Co3O4 spheres for application in oxygen evolution reaction.
For oxygen evolution electrocatalysis of water splitting, unique urchin-shaped Co3O4 spheres were successfully grown on nickel foam by hydrothermal synthesis of Co(OH)F precursor and subsequent annealing method. The formation process was investigated by the evolution of phase structure and morphology with hydrothermal reaction time. And it can be explained by a 'disks-flowers-urchins' mechanism. Moreover, the Co3O4 urchins/NF exhibits considerable catalytic properties. It shows a low overpotential of 308 mV at a current density of 20 mA cm-2 in alkaline solution. In the meantime, such material has a small Tafel slope of 82.1 mV dec-1, large electrochemical active surface area and good long-term stability. The obvious promotion of oxygen evolution reaction performance can be attributed to the special morphology and the direct attachment to the substrate, which improve the exposed active sites, lower the internal resistance and accelerate the charge transport. Thus, the Co3O4 urchins/NF not only has a great potential promising behavior, but also provides the basis for subsequent performance improvement.


Interstitial emphysema of the stomach due to perforated appendicitis.
There are three recognised variations of gas within the wall of the stomach (interstitial emphysema, cystic pneumatosis and emphysematous gastritis). Only 26 cases of interstitial emphysema have been described, with an overall mortality of 42%, and we report the first known case of this rare phenomenon associated with acute appendicitis. A description of the clinical and radiological features of these three types of intramural stomach gas is presented and the literature pertinent to interstitial emphysema is reviewed.


Production of a polar metabolite of 1,25-dihydroxyvitamin D3 in a rat liver perfusion system.
When radiolabeled 1,25-dihydroxyvitamin D3 is added to the perfusion medium of a rat liver perfusion system, a polar metabolite of 1,25-dihydroxyvitamin D3 is formed in the liver and excreted in the bile. Addition of radiolabeled 1,25-dihydroxyvitamin D3 to the perfusion medium without a liver in the circuit results in no formation of the polar metabolite. These data suggest that a polar metabolite of 1,25-dihydroxyvitamin D3 is formed in the liver prior to being excreted in bile. Moreover, it is likely that polar metabolites of 1,25-dihydroxyvitamin D3 present in the bile of rats in vivo are formed in the liver.


Vascular resistance in primary open angle glaucoma.
To explore any difference in vascular resistance between normal and glaucoma subjects using a continuous wave Doppler technique. The Resistance Index, RI, was calculated in two orbital vessels of 20 glaucoma patients all of whom had pressures over 23 mmHg and 15 age matched normal subjects. The haemodynamic relationship between the supratrochlear and a vessel at the optic disc, presumed central retinal artery, is expressed as RIST/RICRA. In 30 normal eyes the ratio was >1 m, in 10 glaucoma patients it was >1. In those glaucoma eyes which were <1, 14 improved after treatment to >1. The remaining 16 eyes which showed no change in the ratio were the eyes with moderate to severe field loss. An altered, increased, peripheral vascular resistance with reduced diastolic flow in small orbital vessels has been demonstrated in glaucoma subjects. This was not altered by treatment in the more severely affected eyes.


Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS syndrome) with prominent supraglottic larynx involvement: a case-based review.
Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS syndrome) is a recently described genetic disorder that gathers autoinflammatory symptoms and myeloid dysplasia. The first description was reported in 2020, and subsequently, a growing number of cases have been described worldwide. Herein, we describe a case of a 72-year-old male patient with VEXAS syndrome with p.Met41Val mutation of the UBA1 gene, prominent supraglottic larynx involvement, and costochondritis. To our knowledge, this is the first report of VEXAS syndrome in Colombia and South America. This disease could present features of relapsing polychondritis, polyarteritis nodosa, giant cell arteritis, and Sweet syndrome, associated with hematologic involvement, including cytopenias, myelodysplastic syndrome, or thromboembolic disease. Supraglottic larynx chondritis and costochondritis are atypical manifestations. These features were proposed previously to differentiate relapsing polychondritis from VEXAS syndrome but are not entirely reliable like in the case described. A diagnosis of VEXAS should be considered in male patients with incomplete or complete features of the previously described conditions, refractory to treatment, requiring high-dose glucocorticoids, and associated progressive hematologic abnormalities. Key Points • VEXAS syndrome is a recently described genetic (somatic mutations in UBA1 gene) disorder that gathers autoinflammatory and hematologic manifestations. • VEXAS syndrome should be considered in male patients with incomplete or complete features of relapsing polychondritis, polyarteritis nodosa, giant cell arteritis, and Sweet syndrome, refractory to treatment, associated with hematologic involvement, including cytopenias, myelodysplastic syndrome, or thromboembolic disease. • Glucocorticoids ameliorate symptoms effectively. However, other treatment options are limited due to a lack of evidence. Traditional immunosuppressants and biological therapy have been used empirically with limited efficacy and a transient effect. Bone marrow transplant offers a curative approach, but it has high morbidity and mortality.


tert-butyl hydroperoxide-dependent microsomal release of iron and lipid peroxidation. II. Evidence for the involvement of nonheme, nonferritin iron in lipid peroxidation.
In a previous study tert-butyl hydroperoxide (t-BOOH) was found to promote reductive release of nonheme, nonferritin iron from rat liver microsomes. The reaction was catalyzed by cytochrome P450 and was strictly contingent on the availability of ADP. In this study, t-BOOH was also found to promote microsomal lipid peroxidation, as evidenced by formation of malondialdehyde. t-BOOH-dependent lipid peroxidation was stimulated by ADP, and four lines of evidence suggested that such stimulation was mediated by reductive release and subsequent redox cycling of nonheme, nonferritin iron. First, lipid peroxidation was stimulated by the same concentration of ADP that promoted iron release. Second, depletion of nonheme, nonferritin iron by pretreatment of rats with phenobarbital decreased the stimulation of lipid peroxidation by ADP. Third, the effect of ADP was maximal when the concentration of t-BOOH was adjusted to values that yielded maximum iron release. Fourth, the effect of ADP was abolished by bathophenanthroline, which is known to chelate ferrous iron in a redox inactive form. These results suggest that the reductive release of nonheme, nonferritin iron exacerbates the deleterious effects of t-BOOH on microsomal lipids.


Refractory swallowing-induced paroxysmal supraventricular tachycardia.
A 51-year-old female with a two-year history of palpitations associated with swallowing was evaluated by intracardiac electrophysiologic studies. Intracardiac recordings documented the presence of an ectopic left atrial focus induced by swallowing with no evidence of accessory pathway conduction. Gastrointestinal evaluation did not demonstrate any significant disorder. The tachycardia was refractory to all pharmacologic therapy including investigational therapy with mexiletine and amiodarone.


Release and hemodynamic influence of nitro-glycerine-derived nitric oxide in endotoxemic rats.
Nitric oxide released from nitro-glycerine (NG) has been considered to improve the microcirculation. Septic conditions are, however, associated with excessive formation of nitric oxide (NO), which is formed from l-arginine by the inducible NO synthase (iNOS) activity. Since the characteristics and influence of NG-derived NO in sepsis remains unclear, the major aims of the present study were to quantify the release and to determine the effects of NO formed from NG on systemic blood pressure under endotoxemic conditions. Four hours following endotoxin challenge (10 mg/kg intraperitoneally), rats received an infusion of NG (0.5 or 5.0 micromol/kg/h) over 45 min. We determined the changes in blood pressure and the NO concentrations generated in brain, heart, intestine, kidney, liver, and lung by means of NO trapping and EPR technique. NG infusion in control rats and endotoxin challenge decreased systemic blood pressure to the same extent. However, in rats subjected to endotoxin challenge NG infusion did not affect the blood pressure. The endotoxin-induced increase in tissue NO concentrations were found to be 15-folds higher than tissue levels of NO following NG infusion. Our results suggest that under endotoxic shock conditions in rats NG may not additionally affect the systemic blood pressure. This may relate to the excessive tissue NO levels induced by endotoxin that are not further increased by NG.


[Characteristic EEG--findings in moyamoya syndrome in children: case report and overview].
Specific alterations of EEG tracings with Moyamoya syndrome are only observed in children. They consist in a gradual frequency decrease and amplitude activation after hyperventilation. This is referred to as re-build-up phenomenon. Thus, a tentative diagnosis of Moyamoya syndrome in children may be based on the EEG finding, to be radiologically confirmed by angiography.


Macroscopic healing of esophagitis does not improve esophageal motility.
The purpose of the present study was to prospectively determine if healing of esophagitis as assessed by endoscopy results in improved esophageal motility. Thirty-one patients with erosive esophagitis who were randomized to receive either omeprazole 20 mg once daily or placebo completed the double-blind study. All patients underwent endoscopy and esophageal motility before treatment and at four weeks after treatment. Twenty-two healthy volunteers underwent esophageal manometry and served as normal controls. Manometric tracings were coded, randomized, and analyzed blindly. Compared to normal controls, patients with esophagitis had significantly lower LESP, decreased amplitude of peristaltic contractions, and increased occurrence of abnormal contractions. Omeprazole was superior to placebo in healing of esophagitis. However, healing of esophagitis was not associated with any improvement in esophageal motility. The manometric data suggest that the motility disturbance seen in esophagitis is not secondary to the esophagitis but rather a primary phenomenon. The lack of improvement of esophageal motility with healing may explain the high recurrence of esophagitis in clinical trials following discontinuation of omeprazole.


Long-term outcomes in children with high-risk neuroblastoma treated with autologous stem cell transplantation.
We retrospectively analysed the outcomes of children transplanted for high-risk neuroblastoma (NB) at a single institution predominantly transplanted with total body irradiation and chemotherapy. The aims of this study were to determine the prognostic impact of clinical and biological features and to document long-term health outcomes. Forty patients were transplanted with a single unpurged autograft. Fourteen patients died from disease progression and two from late complications of treatment. Twenty-three patients are alive at a median of 4.6 years from diagnosis. Kaplan-Meier estimates of overall survival at 2, 5 and 10 years are 76+/-7.0, 60.2+/-8.4 and 54.7+/-9.3% following transplant. Response to induction therapy was significantly associated with survival (P<0.01). Long-term complications included growth (100%) and pubertal failure (83%), hearing impairment (73%), orthopaedic complications (63%), renal impairment (47%) and thyroid abnormalities (36%). Intrinsic and acquired resistance to chemotherapy remains the major obstacle to improving outcomes in high-risk NB. Although patients with chemo-sensitive disease are less likely to experience a relapse, substantial therapy-related toxicities result in poor long-term health outcomes for survivors.


Multimodal 3D medical image registration guided by shape encoder-decoder networks.
Nonlinear multimodal image registration, for example, the fusion of computed tomography (CT) and magnetic resonance imaging (MRI), fundamentally depends on a definition of image similarity. Previous methods that derived modality-invariant representations focused on either global statistical grayscale relations or local structural similarity, both of which are prone to local optima. In contrast to most learning-based methods that rely on strong supervision of aligned multimodal image pairs, we aim to overcome this limitation for further practical use cases. We propose a new concept that exploits anatomical shape information and requires only segmentation labels for both modalities individually. First, a shape-constrained encoder-decoder segmentation network without skip connections is jointly trained on labeled CT and MRI inputs. Second, an iterative energy-based minimization scheme is introduced that relies on the capability of the network to generate intermediate nonlinear shape representations. This further eases the multimodal alignment in the case of large deformations. Our novel approach robustly and accurately aligns 3D scans from the multimodal whole-heart segmentation dataset, outperforming classical unsupervised frameworks. Since both parts of our method rely on (stochastic) gradient optimization, it can be easily integrated in deep learning frameworks and executed on GPUs. We present an integrated approach for weakly supervised multimodal image registration. Achieving promising results due to the exploration of intermediate shape features as registration guidance encourages further research in this direction.


Analysis of autonomic outcomes in APOLLO, a phase III trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis.
Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, debilitating disease often resulting in early-onset, life-impacting autonomic dysfunction. The effect of the RNAi therapeutic, patisiran, on autonomic neuropathy manifestations in patients with hATTR amyloidosis with polyneuropathy in the phase III APOLLO study is reported. Patients received patisiran 0.3 mg/kg intravenously (n = 148) or placebo (n = 77) once every 3 weeks for 18 months. Patisiran halted or reversed polyneuropathy and improved quality of life from baseline in the majority of patients. At baseline, patients in APOLLO had notable autonomic impairment, as demonstrated by the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire autonomic neuropathy domain. At 18 months, patisiran improved autonomic neuropathy symptoms compared with placebo [COMPASS-31, least squares (LS) mean difference, - 7.5; 95% CI: - 11.9, - 3.2; Norfolk QOL-DN autonomic neuropathy domain, LS mean difference, - 1.1; - 1.8, - 0.5], nutritional status (modified body mass index, LS mean difference, 115.7; - 82.4, 149.0), and vasomotor function (postural blood pressure, LS mean difference, - 0.3; - 0.5, - 0.1). Patisiran treatment also led to improvement from baseline at 18 months for COMPASS-31 (LS mean change from baseline, - 5.3; 95% CI: - 7.9, - 2.7) and individual domains, orthostatic intolerance (- 4.6; - 6.3, - 2.9) and gastrointestinal symptoms (- 0.8; - 1.5, - 0.2). Rapid worsening of all study measures was observed with placebo, while patisiran treatment resulted in stable or improved scores compared with baseline. Patisiran demonstrates benefit across a range of burdensome autonomic neuropathy manifestations that deteriorate rapidly without early and continued treatment.


Systematic Review and Meta-Analysis of Home-Based Rehabilitation on Improving Physical Function Among Home-Dwelling Patients With a Stroke.
To evaluate the effects of home-based rehabilitation on improving physical function in home-dwelling patients after a stroke. Various electronic databases, including PubMed, Cumulative Index to Nursing and Allied Health, Embase, the Cochrane Central Register of Controlled Trials, and 2 Chinese data sets (ie, Chinese Electronic Periodical Services and China Knowledge Resource Integrated) were searched for studies published before March 20, 2019. Randomized controlled trials conducted to examine the effect of home-based rehabilitation on improving physical function in home-dwelling patients with a stroke and published in English or Chinese were included. In total, 49 articles in English (n=23) and Chinese (n=26) met the inclusion criteria. Data related to patient characteristics, study characteristics, intervention details, and outcomes were extracted by 2 independent reviewers. A random-effects model with a sensitivity analysis showed that home-based rehabilitation exerted moderate improvements on physical function in home-dwelling patients with a stroke (g=0.58; 95% CI, 0.45∼0.70). Moderator analyses revealed that those patients with stroke of a younger age, of male sex, with a first-ever stroke episode, in the acute stage, and receiving rehabilitation training from their caregiver showed greater improvements in physical function. Home rehabilitation can improve functional outcome in survivors of stroke and should be considered appropriate during discharge planning if continuation care is required.


Proposal for a new N-stage classification system for intrahepatic cholangiocarcinoma.
The number of metastatic lymph nodes (MLNs) is not considered in the nodal status (N classification) of intrahepatic cholangiocarcinoma (ICC) in the current 8thEdition of the American Joint Committee on Cancer (AJCC) staging system. The aim of this study was to find out the optimal cut-off point based on the number of MLNs and establish a modified AJCC staging system for ICC according to the new N category. A total of 675 ICC patients diagnosed between 2004 and 2015 were retrieved from the Surveillance, Epidemiology and End Results (SEER) database. The optimal cut-off value of MLNs affecting survival was determined by X-tile software. The relative discriminative power was assessed by Harrell's concordance index (C-index) and Akaike information criterion (AIC). The proposed new nodal category subdivided patients into three groups (N0, no MLN; N1, 1-3 MLNs; and N2, ≥ 4 MLNs) with significantly different overall survival (P < 0.001). Multivariable analysis revealed that the new nodal category was an independent prognostic factor (P < 0.001). Both the C-index and AIC for our modified staging system were better than those for the 8th AJCC edition (0.574 [95% confidence interval 0.533-0.615] versus 0.570 [95% confidence interval 0.527-0.613], and 853.30 versus 854.21, respectively). The modified AJCC staging system based on the number of MLNs may prove to be a useful alternative for predicting survival of ICC patients in clinical practice.


Complement factor H interferes with Mycobacterium bovis BCG entry into macrophages and modulates the pro-inflammatory cytokine response.
Mycobacterium tuberculosis is an accomplished intracellular pathogen, particularly within the macrophage and this is of the utmost importance in the host-pathogen stand-off observed in the granuloma during latent tuberculosis. Contact with innate immune molecules is one of the primary interactions that can occur with the pathogen M. tuberculosis once inhaled. Complement proteins may play a role in facilitating M. tuberculosis interactions with macrophages. Here, we demonstrate that factor H, a complement regulatory protein that down-regulates complement alternative pathway activation, binds directly to the model organism M. bovis BCG. Binding of factor H reaches saturation at 5-10μg of factor H/ml, well below the plasma level. C4 binding protein (C4BP) competed with factor H for binding to mycobacteria. Factor H was also found to inhibit uptake of M. bovis BCG by THP-1 macrophage cells in a dose-dependent manner. Real-time qPCR analysis showed stark differential responses of pro- and anti-inflammatory cytokines during the early stages of phagocytosis, as evident from elevated levels of TNF-α, IL-1β and IL-6, and a concomitant decrease in IL-10, TGF-β and IL-12 levels, when THP-1:BCG interaction took place in the presence of factor H. Our results suggest that factor H can interfere with mycobacterial entry into macrophages and modulate inflammatory cytokine responses, particularly during the initial stages of infection, thus affecting the extracellular survival of the pathogen. Our results offer novel insights into complement activation-independent functions of factor H during the host-pathogen interaction in tuberculosis.


Catalytic efficiency of raw and hydrolyzed eggshell in the oxidation of crystal violet and dye bathing wastewater by thermally activated peroxide oxidation method.
In this study, hydrochar-based-eggshell was prepared via the subcritical water medium (SCWM) and used as a catalyst in the thermally activated peroxide oxidation (TAPO) approach for crystal violet and dye bathing wastewater degradation. The catalytic activities for the raw eggshell (RES) and hydrochar-based-eggshell (HES) were compared. RES and HES were characterized using a scanning electron microscope (SEM),energy-dispersive X-ray spectroscopy (SEM-EDX), and Fourier transforms infrared spectroscopy (FT-IR). The affecting parameters on the degradation process were optimized using response surface methodology (RSM). The effects of temperature (293-333 K), amount of catalyst (5-25 mg/50 mL), the concentration of H2O2 (0-8 mM), and treatment time (10-70 min) on the TAPO method were investigated using central composite design (CCD). For the crystal violet removal, two models were developed. Both models were significant and can be used to describe the design space. Also, the dye bathing wastewater degradation was described by another developed model, which had a high correlation coefficient (R2 = 0.97). In general, catalytic activity for HES was higher than RES. The degradation of crystal violet reached 98.10% when a 20 mg HES catalyst and 6 mM H2O2 at 323 K for 55 min were used. While 97% of the color of dye bathing wastewater was removed in 55 min at 323 K using 25 mg of HES and 4 mM H2O2. This study showed that the hydrolyzed eggshells could be used in the oxidation of crystal violet and dye bathing wastewater by the thermally activated peroxide oxidation method.


French experts report on MUTYH-associated polyposis (MAP).
Recent years have been characterised by an improvement in our knowledge of genetic determinism of adenomatous polyposes and by the description in 2002 of a new entity called "MUTYH-associated polyposis" (MAP), related to biallelic mutations of this gene. Its autosomal recessive mode of inheritance contrasts with the autosomal dominant inheritance of the classical "familial adenomatous polyposis" (FAP), associated with an APC germline mutation. Although some phenotypic features may be of value to distinguish these two conditions, their clinical "spectra" largely overlap and the differential diagnosis may be difficult. The purpose of this expertise conducted under the auspices of the French Institut National du Cancer (INCa) was to assess the current state of knowledge on MUTYH-associated polyposis and to establish some recommendations in the field of molecular analysis (indications of tests and analysis strategies for affected patients and their relatives) and of clinical management based on available data in the literature, on the results from the French molecular genetics laboratories performing MUTYH analysis and on the opinions of biologists and clinicians experts (genetic counsellors and gastroenterologists). The risk of colorectal cancer among relatives carrying a monoallelic MUTYH mutation was also studied.


Immunoadjuvant action of liposomes: comparison with other adjuvants.
Dehydration-rehydration vesicles (DRV liposomes) composed of equimolar phospholipid and cholesterol and containing bovine serum albumin (BSA) were used together with free BSA to immunize Balb/C mice. Primary and secondary immune responses (IgG1) to the liposomal antigen, as measured by ELISA in mouse sera, were similar for egg phosphatidylcholine (PC) and distearoyl phosphatidylcholine (DSPC) DRV, and much greater than those elicited by free BSA. The adjuvanticity of PC DRV was compared with that of aluminium salts (alum), complete Freund's adjuvant (CFA) and N-acetyl muramyl-L-threonyl-D-isoglutamine ([Thr1]MDP), the latter used as such or in a liposome form co-entrapped with the antigen. DRV (with or without co-entrapped [Thr1]MDP), and alum were equally strong in producing primary and secondary immune responses (IgG1) to BSA. Such responses were significantly higher than those achieved with CFA and [Thr1]MDP alone. The implications of these results for the potential role of liposomes as immunological adjuvants in vaccines are discussed.


SCFFbx2-E3-ligase-mediated degradation of BACE1 attenuates Alzheimer's disease amyloidosis and improves synaptic function.
BACE1 (β-secretase) plays a central role in the β-amyloidogenesis of Alzheimer's disease (AD). The ubiquitin-proteasome system, a major intracellular protein quality control system, has been implicated recently in BACE1 metabolism. We report that the SCF(Fbx2) -E3 ligase is involved in the binding and ubiquitination of BACE1 via its Trp 280 residue of F-box-associated domain. Physiologically, we found that Fbx2 was expressed in various intracellular organelles in brain neurons and that BACE1 is colocalized with Fbx2 and the amyloid precursor protein (APP), mainly at the early endosome and endoplasmic reticulum. The former are believed to be the major intracellular compartments where the APP is cleaved by BACE1 and β-amyloid is produced. Importantly, we found that overexpression of Fbx2 in the primary cortical and hippocampal neurons derived from Tg2576 transgenic mice significantly promoted BACE1 degradation and reduced β-amyloid production. In the search for specific endogenous modulators of Fbx2 expression, we found that PPARγ coactivator-1α (PGC-1α) was capable of promoting the degradation of BACE1 through a mechanism involving Fbx2 gene expression. Interestingly, we found that the expression of both Fbx2 and PGC-1α was significantly decreased in the brains of aging Tg2576 mice. Our in vivo studies using a mouse model of AD revealed that exogenous adenoviral Fbx2 expression in the brain significantly decreased BACE1 protein levels and activity, coincidentally reducing β-amyloid levels and rescuing synaptic deficits. Our study is the first to suggest that promoting Fbx2 in the brain may represent a novel strategy for the treatment of AD.


Timed Up and Go in men and women with Multiple Sclerosis: Effect of muscular strength.
People with Multiple Sclerosis (pwMS) often exhibit generalized weakness that affects several activities of daily life, particularly those relying on balance and gait. While it is known that such a symptom has a strong impact on mobility, to what extent muscular strength is linked with functional mobility in men and women with MS remains mostly unexplored. The aim of this study is to assess the existence of possible sex-related differences in functional mobility in pwMS, also considering the muscular strength capacity. Functional mobility and hand-grip strength (HGS) were assessed in 49 pwMS with mild-moderate disability using instrumental Timed-up-and-go (TUG) test carried out using an inertial sensor and digital dynamometry. We investigated the existence of sex-related differences in the duration of each TUG sub-phase and their correlation with the HGS. No sex-related differences in TUG performance (either in terms of overall or sub-phase time) were found. Similar large negative correlations were found in men and women with MS between HGS and overall TUG and walking phase duration. However, changes in strength have a more marked impact in women as indicated by the different slope of the HGS-TUG time relationship., In women, HGS also appears significantly correlated with all TUG sub-phases, while in men this occurs only for overall TUG and walking time. Rehabilitation and training programs for pwMS should take into account the peculiar features associated with the interaction between strength and mobility specific for each individual's sex to optimize their effectiveness.


Reduction and the intracellular translocation of EphB2 in Tg2576 mice and the effects of β-amyloid.
EphB2 is a member of receptor tyrosine kinases (RTKs) family that is essential for the cell adhesion, neural crest migration, axon guidance and synaptogenesis in the nervous system. Recent studies show that preservation of EphB2 in a transgenic mouse model of Alzheimer's disease (AD) rescues the cognitive deficit, suggesting a crucial role of EphB2 in AD. However, the expression and distribution profiles of EphB2 in the early stage of AD have not been reported. Immunohistochemistry, immunoblot and immunofluorescence were used to analyse the level of EphB2 in Tg2576 mice at different ages and in cultured neurones with Aβ treatment at different times. EphB2 was reduced in an age-dependent manner in the olfactory bulb and the hippocampus of Tg2576 mice. The decrease of EphB2 appeared earlier in the olfactory bulb than the hippocampus, and reduction of EphB2 appeared earlier than that of MAP2, a dendritic cytoskeleton marker. In the cortex, EphB2 displayed a significant translocation from the neuronal processes to the cell bodies with ageing. In primary hippocampal neuronal cultures, Aβ42 treatment also induced the decrement of EphB2 that was prior to the decline of MAP2. Our findings provide the first evidence for an age- and region-dependent reduction and intracellular translocation of EphB2 in Tg2576 mice, and the foremost decrement of EphB2 in the olfactory bulb may represent an early sign of AD.


A study on prediction methods for a cardiovascular strong-coupling simulation.
We investigated numerical methods for predictors in a multiscale cardiovascular simulation model. The proposed method predicts initial approximations for the iterative convergence calculations of the strong coupling method using the smoothing spline to remove errors from values of past timesteps and using the linear and second-order extrapolation. The new coupling algorithm was used for coupling a left ventricular finite element model to a myocardial excitation-contraction model. We performed experiments with different values for the smoothing parameter λ and with linear and second-order extrapolations. λ = 1 with the linear extrapolation gave the best results. It reduced computation time by 91% compared to the strong coupling method. With the use of the smoothing spline, distance between the initial approximation and converged solution reduced by 62%, while the average number of iterations reduced by 32%. The smoothing spline can be used to improve the accuracy of predictors and reduce the number of iterations needed for the computation of the convergence procedure.


Food Away from Home and Childhood Obesity.
Childhood obesity is associated with a number of serious health risks that can persist into adulthood. While trends in food away from home and fast-food consumption have paralleled trends in childhood obesity, it is important to identify whether this is a causal relationship. This paper reviews recent literature in this area to summarize if there is a consensus in research findings. We group the literature into two areas - consumption of and access to food away from home (FAFH). While no consensus findings have been reached in either area, the evidence of an association between FAFH consumption and childhood obesity has gained strength. Further, there is evidence that FAFH meals add calories to children's diets. The literature on the role of FAFH access and childhood obesity has continued producing mixed results.


Predictive factors for overall quality of life in patients with advanced cancer.
This study examined which domains/symptoms from the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 15 Palliative (QLQ-C15-PAL), an abbreviated version of the health-related EORTC QLQ-C30 questionnaire designed for palliative cancer patients, were predictive of overall quality of life (QOL) in advanced cancer patients. Patients with advanced cancer from six countries completed the QLQ-C15-PAL at consultation and at one follow-up point. Univariate and multivariate regression analyses were conducted to determine the predictive value of the EORTC QLQ-C15-PAL functional/symptom scores for global QOL (question 15). Three hundred forty-nine patients completed the EORTC QLQ-C15-PAL at baseline. In the total patient sample, worse emotional functioning, pain, and appetite loss were the most significant predictive factors for worse QOL. In the subgroup of patients with bone metastases (n = 240), the domains mentioned above were also the most significant predictors, whereas in patients with brain metastases (n = 109), worse physical and emotional functioning most significantly predicted worse QOL. One-month follow-up in 267 patients revealed that the significant predictors changed somewhat over time. For example, in the total patient sample, physical functioning, fatigue, and appetite loss were significant predictors at the follow-up point. A sub-analysis of predictive factors affecting QOL by primary cancer (lung, breast, and prostate) was also conducted for the total patient sample. Deterioration of certain EORTC QLQ-C15-PAL functional/symptom scores significantly contributes to worse overall QOL. Special attention should be directed to managing factors most influential on overall QOL to ensure optimal management of advanced cancer patients.


Prognostic value of C-reactive protein in cirrhosis: external validation from the CANONIC cohort.
The variations in C-reactive protein (CRP) levels have been reported to have prognostic significance in decompensated cirrhotic patients. We aimed to provide an external validation of a prognostic model combining model for end-stage liver disease (MELD) and 'sustained high CRP levels' as main variables and to optimize the model to the context of liver transplantation by focusing on 3-month mortality with no consideration of severe chronic extrahepatic diseases. Data from cirrhotic patients enrolled in the CANONIC study were collected. Multivariate analyses used the competing risk model. The prognostic performance [area under receiver operating characteristic curve (AUROC)] of the model incorporating CRP variations within 15 days was compared with that of the MELD score alone. 583 decompensated cirrhotic patients with Child-Pugh more than B7 and serial CRP measures available were included. Of these, 111 patients had baseline CRP at least 29 mg/l and 60 still had CRP at least 29 mg/l at day 15±6 (group A). Multivariate analysis (competing risk) identified three predictors of 3-month mortality: high MELD score [hazard ratio (HR)=1.14; 95% confidence intervals (CI): 1.11-1.17, P<0.001], age (HR=1.04; 95% CI: 1.02-1.06, P<0.001), and group A (HR=1.69; 95% CI: 1.01-2.81, P=0.046). The performance of the three variables taken together for predicting 3-month mortality was 0.796 (AUROC), which was significantly higher than that of the MELD score (AUROC=0.769; P=0.019). In Child-Pugh higher than B7 cirrhotic patients with decompensation, prognostic models incorporating variations in CRP within 15 days and age predict 3-month mortality better than the MELD score alone. Such models would improve the ranking of candidates for liver transplantation by differentiating the severe patients with persistent systemic inflammation and intermediate MELD scores.


Treatment of retinoblastoma. Results obtained from a prospective study of 51 patients.
During 4 years, 51 patients with retinoblastoma were studied (unilateral 32, and bilateral 19). Treatment consisted of enucleation of those eyes which showed massive involvement followed by radiotherapy when there was optic nerve and/or orbit involvement. Systemic chemotherapy was administered to all patients who underwent nonsurgical treatment and when the histologic examination showed choroidal optic nerve head and/or optic nerve involvement or residual tumor after enucleation. When there was compromise of the central nervous system intrathecal chemotherapy was administered. Nonsurgical treatment consisted of radiotherapy and/or light coagulation. Survival was 90.6% for unilateral cases and 84.2% for the bilateral. The median follow-up was 31 months and 29 months, respectively. Of 19 conservated eyeballs, 16 preserve useful vision (63%).


Pattern of expression of cyclooxygenase-2 in malignant transformation of sinonasal inverted papilloma.
Cyclooxygenases (COXs) are enzymes that catalyze the conversion of arachidonic acid to prostaglandins. Many studies have suggested that COX-2, the inducible form of COX, is important in carcinogenesis. However, little is known about the pattern of expression of COX-2 in a multistep process of malignant transformation of sinonasal inverted papilloma (IP). In this study, we investigated COX-2 expression in IPs, IPs with dysplasia, IPs with squamous cell carcinoma (SCC), and primary SCCs of sinonasal tract. A retrospective study was conducted. The setting was a tertiary care referral center. The expression of COX-2 was evaluated by immunohistochemistry in 56, 7, 18, and 17 cases of IPs, IPs with dysplasia, IPs with SCC, and primary SCCs, respectively. Furthermore, we investigated the possible correlation between the expression of COX-2 and clinicopathologic variables in patients with IPs with SCC and primary SCC patients. Positive immunoreactivity for COX-2 was observed in 3 (5.4%) of 56 IPs, 7 (38.9%) of 18 IPs with SCC, and 7 (41.2%) of 17 primary SCCs, whereas it was not observed in IPs with dysplasia. The percentage of tumors with COX-2-positive immunostaining was significantly higher in IPs with SCC and primary SCCs compared with benign IPs. There was no significant correlation between the expression of COX-2 and clinicopathologic variables, such as tumor stage, histologic differentiation, and the proportion of malignant areas in patients with IPs with SCC. Cyclooxygenase-2 may play an important role in the process of malignant transformation from IP to SCC.


Ketamine, sleep, and depression: current status and new questions.
Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has well-described rapid antidepressant effects in clinical studies of individuals with treatment-resistant major depressive disorder (MDD). Preclinical studies investigating the effects of ketamine on brain-derived neurotrophic factor (BDNF) and on sleep slow wave activity (SWA) support its use as a prototype for investigating the neuroplastic mechanisms presumably involved in the mechanism of rapidly acting antidepressants. This review discusses human EEG slow wave sleep parameters and plasma BDNF as central and peripheral surrogate markers of plasticity, and their use in assessing ketamine's effects. Acutely, ketamine elevates BDNF levels, as well as early night SWA and high-amplitude slow waves; each of these measures correlates with change in mood in depressed patients who respond to ketamine. The slow wave effects are limited to the first night post-infusion, suggesting that their increase is part of an early cascade of events triggering improved mood. Increased total sleep and decreased waking occur during the first and second night post infusion, suggesting that these measures are associated with the enduring treatment response observed with ketamine.


Miltefosine triggers a strong proinflammatory cytokine response during visceral leishmaniasis: role of TLR4 and TLR9.
Visceral leishmaniasis (VL) caused by the protozoan parasite, Leishmania donovani, is associated with irregular fever, weight loss, hepatosplenomegaly and anemia. The therapeutic arsenal against VL is limited and the recent advent of a novel immunomodulatory drug, Miltefosine has shown promising results for effective treatment of VL but its dependence on Toll like receptors (TLR) has not been explored. In this study, we have shown that the non-cytotoxic dose (5 μM) of Miltefosine could render significant protection corresponding to 88% and 95% reduction in intracellular parasite load at 24 h and 48 h in L. donovani infected THP1 cells. This was accompanied by a strong proinflammatory cytokine response in the form of IFN-γ, IL-12 and TNF-α as evident by enzyme linked immunosorbent assay (ELISA) and real time PCR (RT-PCR). This Miltefosine induced proinflammatory cytokine response in infected THP1 cells was also accompanied by simultaneous 10- and 12-fold increase in TLR4 mRNA and TLR9 mRNA. These changes in cytokine response and TLR expression were also studied in peripheral blood mononuclear cells (PBMC) of VL patients treated with Miltefosine by RT-PCR which showed similar results as in THP1 cells. Thereby, suggesting a probable dependence of Miltefosine on TLR4 and TLR9 in triggering a proinflammatory response.


Quality of the singing voice in sopranos. Influence of the text and the musical accompaniment in the opera singing.
Opera singing voice uses different technical tools for artistic purposes. We want to define if the quality of the sung sound is affected by an aware work on the musical accompaniment and the text. We analyse the acoustic signal and the subjective perception. The pitch studied in the soprano voice is A4 (880 Hz) with the vowel /a/. We have chosen a tone and a vowel that can be generated by different strategies in terms of phonoresonance adjustments. We have carried out a prospective study with 20 sopranos, without voice pathology, who have sung a phrase from the aria Deh, vieni non tarda and another from the aria Dove sono i bei momenti from the opera Le nozze di Figaro, by W.A. Mozart. First, each phrase sung spontaneously was recorded and then a second time, after a proposed work on the content of the text and musical aspects of the accompaniment such as: rhythm, harmony, texture and direction of the phrase. The participants prolonged the emission of the A4 for more than three seconds, maintaining the context of the sentence. The acoustic signal has been analysed using the PRAAT programme and a VAS (Visual Analogue Scale) questionnaire has been used to collect subjective perceptions. The mean age was 36 ± 11 years (range between 20 and 58) and the mean number of years singing was 17 ± 12 years (range between 3 and 35). No statistically significant differences were found, although an improvement in the VAS was seen in the second sentence after the intervention. The acoustic analysis parameters are stable, and the VAS tends to improve when an awareness of the text and the instrumental accompaniment is carried out.


Crystal structure of Sr2CdPt2 containing linear platinum chains.
The ternary inter-metallic title phase, distrontium cadmium diplatinum, was prepared from stoichiometric amounts of the elements at 1123 K for one day. The crystal structure adopts the ortho-rhom-bic Ca2GaCu2 structure type in space group Immm. Its main features are characterized by linear (Pt-Pt⋯Pt-Pt) n chains that are aligned along [010] and condensed through cadmium atoms forming Cd-centred Pt2Cd2/2 rectangles to build up sheets parallel to (001). These sheets are connected to each other via alternating (001) sheets of strontium atoms along [001]. The strontium sheets consists of corrugated Sr4 units that are condensed to each other through edge-sharing parallel to [100].


Incremental diagnostic value of dipyridamole echocardiography and exercise thallium 201 scintigraphy in the assessment of presence and extent of coronary artery disease.
The incremental diagnostic information of two noninvasive tests for the detection of coronary artery disease (CAD), dipyridamole echocardiography, and exercise 201Tl myocardial scintigraphy was assessed in a series of 102 patients with ordered logistic regression and receiver-operating characteristic curves. Patients were selected from those referred to our cardiovascular centers with the clinical suspicion of CAD. After clinical evaluation, all patients underwent both noninvasive tests during hospitalization 2 weeks before coronary arteriography. The coronary arteriogram was used as a gold standard: CAD was defined as the presence of one or more vessels with 50% or greater narrowing of the luminal diameter. Clinical data were 73.0% +/- 5.7% accurate in the prediction of CAD. The addition of dipyridamole echocardiographic data to the clinical model yielded a diagnostic accuracy of 88.3% +/- 4.3% (p < 0.00001), whereas the addition of thallium scintigraphic parameters to the clinical model improved diagnostic accuracy to 93.8% +/- 2.6% (p < 0.00001). A significant increase in accuracy to 97.2% +/- 1.4% was achieved when thallium scintigraphic data were added to the clinical and dipyridamole-echocardiographic model (p < 0.00001). Both noninvasive methods for detection of CAD, DET, and ETS showed a good diagnostic accuracy especially when tests-derived parameters were combined with clinical data by means of relative logistic models; nevertheless the ETS model showed a higher sensitivity in comparison with the DET model, essentially in presence of a lower extent of CAD.


Long-term Clinical Outcomes of Radiofrequency Catheter Ablation versus Permanent Pacemaker Implantation in Patients with Tachycardia-Bradycardia Syndrome.
Pacemaker (PM) implantation is a well-accepted treatment option for patients with paroxysmal atrial fibrillation (AF) and related tachycardia-bradycardia syndrome (TBS). Data on the long-term clinical outcomes after radiofrequency catheter ablation (RFCA) or PM implantation are sparse. The medical records of 217 patients with TBS were retrospectively assessed. Outcomes in patients who underwent RFCA (n=108, 49.8%) were compared to those with PM implantation (n=109, 50.2%). The clinical outcomes were sinus rhythm maintenance, conversion to persistent AF, additional procedure or crossover, and the composite of cardiovascular hospitalization and death. During the follow-up period (mean 3.5±2.0 years), the RFCA group, compared to the PM group, showed better sinus rhythm maintenance (adjusted hazard ratio [aHR], 0.27; 95% confidence interval [CI], 0.15-0.46; p=0.002) and less progression to persistent AF (aHR, 0.20; 95% CI, 0.06-0.63; p=0.006). Additional procedure or crossover did not differ significantly between the groups (aHR, 2.07; 95% CI, 0.71-6.06; p=0.185 and aHR, 0.69; 95% CI, 10.8-2.67; p=0.590, respectively). Most RFCA patients (92.6%) did not require pacemaker implantation during long term follow-up period (>3.5 years). The composite endpoint of cardiovascular rehospitalization and death was not significantly different between the groups (aHR, 0.92; 95% CI, 0.50-1.66; p=0.769). RFCA is an effective alternative to PM implantation in patients with TBS. In these patients, successful RF ablation of AF is related to a higher rate of sinus rhythm maintenance compared to PM implantation, and the composite outcome of cardiovascular rehospitalization and death is similar.


Magnetic Resonance Imaging Findings in Symptomatic Patients After Arthroscopic Partial Meniscectomy for Torn Discoid Lateral Meniscus.
To evaluate the change in the thickness and width of the residual meniscus using magnetic resonance imaging (MRI) in patients who underwent arthroscopic partial meniscectomy for discoid lateral meniscus (DLM), to assess whether the degeneration of the articular cartilage in the lateral compartment of the knee progressed, and to evaluate clinical results. Among the patients who underwent arthroscopic partial meniscectomy for DLM between January 1997 and December 2011, those who were aged 40 or below at surgery were followed up for at least 3 years, and received at least 2 follow-up MRIs that were retrospectively reviewed. MRIs were done in symptomatic knees. Using MRI, the relative thickness and width were measured in the anterior horn, midportion, and posterior horn. To determine whether the degeneration of the lateral compartment would progress, the articular cartilage was graded based on the Outerbridge classification in MRIs. The clinical results were evaluated using the Lysholm score. A total of 20 patients (21 knees) were included. The average follow-up period was 6.8 years. In residual meniscus, the relative thickness of the midportion decreased from 9.0% ± 2.4% to 7.3% ± 2.3% (P < .001), the relative thickness of the anterior horn decreased from 15.6% ± 4.3% to 14.3% ± 6.7% (P = .030), and the relative thickness of the posterior horn decreased from 20.0% ± 4.4% to 16.7% ± 6.7% (P = .019). A decrease in the relative width was observed in the midportion (12.4% ± 4.8% to 10.9% ± 4.9%, P = .003). No significant changes in size were observed in the medial meniscus. A progression of degeneration in the lateral compartment was observed. However, the clinical results did not present significant changes. In symptomatic patients after arthroscopic partial meniscectomy for DLM, the thickness and width of the residual meniscus decreases over time. The arthritic change of the lateral compartment of the knee progressed. However, the change in the size of the residual meniscus was of unknown clinical significance. Level IV, therapeutic case series.


Comparison of fibrin networks in plasma and fibrinogen solution.
Mass-Length ratio of fibrin fibres (microT and microP) derived independently from turbidity and permeability respectively, in networks made in fibrinogen solution and plasma, have been compared under similar conditions of clotting. Amount of fibrinogen conversion to fibrin was similar in both systems when high thrombin concentrations were used. But networks in plasma had significantly thicker fibres (higher microT and microP) than those in fibrinogen solution. This difference arises from differing kinetics of fibrin assembly in the two systems. When lower thrombin concentration is used, fibrin fibre thickness (as indicated by microP and microT) is increased in fibrinogen solution but the fibrin content of the network remains unaltered. In plasma, on the other hand, the fibrin content of the network is decreased, microT remains relatively unchanged while microP increases. The thrombin concentration dependence of the fibrin content of the network in plasma and the bimodal distribution of fibrin fibre thickness explain the breakdown in correlation between microP and microT.


Comparative electrophysiologic effects of intravenous and oral procainamide in patients with sustained ventricular arrhythmias.
Thirty-three patients with sustained ventricular arrhythmias underwent electrophysiologic testing after intravenous and again after oral procainamide administration. Two groups were identified: group 1 included 15 patients with concordant serum procainamide concentrations with less than a 3 micrograms/ml difference after intravenous (mean 8.6 +/- 2.7) and oral (mean 8.8 +/- 2.7) procainamide administration, with mean N-acetylprocainamide concentrations of 1.0 +/- 0.6 and 6.2 +/- 2.8 micrograms/ml, respectively. Group 2 included 18 patients with discordant serum procainamide concentrations after intravenous (mean 9.5 +/- 5.9 micrograms/ml) and oral (mean 14.1 +/- 5.2 micrograms/ml) procainamide, with mean N-acetylprocainamide concentrations of 0.9 +/- 0.5 and 10.7 +/- 5.7 micrograms/ml, respectively. In group 1, response to programmed stimulation was the same after intravenous and oral procainamide administration, with no inducible ventricular arrhythmia in 5 of 15 patients. In group 2, 3 of 18 patients had no inducible arrhythmia after intravenous compared with 7 of 18 patients after oral procainamide administration. There was a different response to programmed stimulation after oral compared with intravenous procainamide in 6 of 18 patients in group 2 but in none of 15 patients in group 1 (p = 0.02). The effective procainamide concentration was greater than the ineffective concentration in five of the six patients with a discordant response, and the effective route of administration was oral in five of the six patients. The change in ventricular refractoriness in group 1 was similar after intravenous (28 +/- 23 ms) and oral (29 +/- 19 ms) procainamide, whereas in group 2, refractoriness was increased more after oral (33 +/- 21 ms) than intravenous (20 +/- 17 ms) procainamide administration and paralleled the difference in procainamide concentration.(ABSTRACT TRUNCATED AT 250 WORDS)


Surgical treatment of type A acute aortic dissection with cerebral malperfusion: a systematic review.
Type A acute aortic dissection (TAAAD) complicated with cerebral malperfusion (CM) is a life-threatening condition associated with high mortality, poor outcomes, and the optimal surgical management remains controversial. The aim of this review was to report the current results of surgical interventions of these patients. A systematic review was performed using PubMed and MEDLINE search for cases underwent surgical repair for TAAAD with CM. Demographics, neurological symptom, the time from onset of symptoms to operation, operation data, mortality, neurological outcome, and follow-up were reviewed. A total of 363 patients with mean age of 65.7 ± 13 years underwent surgical repair for TAAAD with CM were identified in 12 retrospective studies. In-hospital mortality was 20.1%. Mean duration of follow-up was 40.1 ± 37.6 months. The involved supra-aortic branch vessels were RCCA (n = 99), LCCA (n = 25), B-CCA (n = 52), CCA (n = 131), IA (n = 19), and LSA (n = 8). Time from onset of neurological symptoms to surgery was 13.3 h. Antegrade and/or retrograde cerebral perfusion were applied. Postoperatively, improved, unchanged and worsened neurological status was occurred in 54.3%, 27.1%, and 8.5%, respectively in 199 patients. The outcomes of surgical treatment of TAAAD complicated with CM indicate acceptable early mortality and morbidity. It is reasonable to perform lifesaving surgery on these patients. Early central surgical repair and reperfusion of brain may improve the outcomes.


Group schema therapy for personality disorders: A pilot study for implementation in acute psychiatric in-patient settings.
Group schema therapy (GST) has been proposed as a novel long-term treatment programme for borderline and cluster C personality disorders. We implemented a short-term GST programme (12-15 sessions, based on the manual by Farrell and Shaw (2012), including both cognitive / behavioural and experiential interventions for in-patients (n=9) with either borderline or cluster C personality disorders (and axis I co-morbidities) treated in a (sub)acute psychiatric in-patient setting. We evaluated pre- and post-treatment self-report of maladaptive and adaptive schema modes (using the SMI) and early maladaptive schemas (YSQ-3), as well as overall symptom severity (brief symptom check list, BSCL-53-S), patient satisfaction (ZUF-8) and group climate and coherence (GCQ-S). We found significant reduction of symptoms, and trend-level improvement for schema mode activation, but not maladaptive schemas. Effect sizes of Cohen's d=0.857 for symptoms and d=0.693 for maladaptive schema mode reduction were, however, lower than previous GST trials in in-patient settings with a longer treatment phase and outpatient GST trials using the Farrell and Shaw-model, indicating importance of duration in ST treatment. Our findings in this uncontrolled study provide first evidence that GST (based on the Farrell and Shaw model) can be implemented and adapted for use in short-term in-patient (sub)acute settings.


In vitro protective effects of plants frequently used traditionally in cancer prevention in Thai traditional medicine: An ethnopharmacological study.
Thai traditional medicine (TTM) has been used widely in cancer management in Thailand. Although several Thai medicinal plants were screened for pharmacological activities related to cancer treatment, such evidence still suffers from the lack of linking with TTM knowledge. To document knowledge and species used in cancer prevention in TTM and to preliminary investigate pharmacological activities related to the documented knowledge of twenty-six herbal drugs used in cancer/mareng prevention. Fieldwork gathering data on TTM concept and herbal medicines used in cancer prevention was performed with TTM practitioners across Thailand. Later, water and ethanol extracts from twenty-six herbal drugs mentioned as being used in cancer prevention were screened for their protective effect against tert-butyl hydroperoxide-induced cell death in HepG2 cells. Then active extracts were investigated for their effects on NQO1 activity, glutathione level, and safety in normal rat hepatocytes. The fieldwork helped in the development of TTM cancer prevention strategy and possible experimental models to test the pharmacological activities of selected medicinal plants. Fifteen plant extracts showed significant protective effect by restoring the cell viability to 40-59.3%, which were comparable or better than the positive control EGCG. Among them, ethanol extracts from S. rugata and T. laurifolia showed the most promising chemopreventive properties by significantly increased NQO1 activity, restored GSH level from oxidative damage, as well as showed non-toxic effect in normal rat hepatocytes. TTM knowledge in cancer prevention was documented and used in the planning of pharmacological experiment to study herbal medicines, especially in cancer, inflammation, and other chronic diseases. The proposed strategy should be applied to in vivo and clinical studies in order to further confirm the validity of such a strategy. Other traditional medical systems that use integrated approaches could also apply our strategy to develop evidence that supports a more rational uses in traditional medicine.


Spatial summation for pain perception: interaction of inhibitory and excitatory mechanisms.
To study the relation between size of the surface stimulated and perceived pain intensity (spatial summation effect), subjects sequentially immersed predetermined segments of the surface of their arm, between the fingertips and the shoulder, in circulating nociceptive hot water. Immersion sessions were of three types: (i) increasing session (immersion beginning at fingertips and increasing to shoulder); (ii) decreasing session (immersion beginning at shoulder and decreasing to fingertips); and (iii) whole arm+increasing session (preliminary immersion of the whole arm up to shoulder, followed by an increasing session from fingertips to shoulder). Results showed a positive spatial summation effect (pain perception positively correlated to the size of the surface stimulated) during both the decreasing session and the whole arm+increasing session. However, no spatial summation effect was found during the increasing session (fingertips to shoulder). In addition, pain perceived for a surface area was less intense during the decreasing session compared to the increasing session. One possible explanation for the lack of a spatial summation effect during the increasing session is that inhibitory mechanisms are gradually recruited at the same time as excitatory afferences, thus 'cancelling out' any measurable spatial summation effect. The results obtained during the decreasing session and the whole arm+increasing session may be explained by inhibitory mechanisms being fully recruited at the beginning of the session with the immersion of the largest surface area (whole arm). The results are a shift of the pain perception curve and a positive relation between the surface stimulated and pain perception.


Transmission dynamics of the COVID-19 epidemic in England.
The ongoing coronavirus disease 2019 (COVID-19) pandemic has caused a tremendous health burden and impact on the world economy. The UK Government implemented the biggest lockdown of society during peacetime in British history at the end of March 2020, aiming to contain the rapid spread of the virus. The UK lockdown was maintained for 7 weeks, but the effectiveness of the control measures in suppressing disease transmission remains incompletely understood. A Bayesian SEIR (susceptible-exposed-infected-removed) epidemiological model was used to rebuild the local transmission dynamics of the spread of COVID-19 in nine regions of England. The basic reproduction number (R0) in England was found to be relatively high compared with China. The estimate of the temporally varying effective reproduction number (Rt) suggests that the control measures, especially the forced lockdown, were effective to reduce transmissibility and curb the COVID-19 epidemic. Although the overall incidence rate in the UK has declined, forecasting highlights the possibility of a second epidemic wave in several regions. This study enhances understanding of the current outbreak and the effectiveness of control measures in the UK.


Angina pectoris in patients with HIV/AIDS: prevalence and risk factors.
The incidence of ischemic heart disease is higher in patients with HIV/AIDS. However, the frequency of angina pectoris in these patients is still not known. Literature about this subject is still scarce. To evaluate the prevalence of angina pectoris and risk factors for coronary disease and to examine the association between traditional risk factors and HIV-related risk factors and angina pectoris. An epidemiological cross-sectional study, analyzed as case-control study, involving 584 patients with HIV/AIDS. Angina pectoris was identified by Rose questionnaire, classified as definite or possible. Information regarding risk factors was obtained through a questionnaire, biochemical laboratory tests, medical records and anthropometric measures taken during consultations at AIDS treatment clinics in Pernambuco, Brazil, from June 2007 to February 2008. To adjust the effect of each factor in relation to others, multiple logistic regression was used. There was a preponderance of men (63.2%); mean ages were 39.8 years for men, 36.8 years for women. The prevalence of definite and possible angina were 11% and 9.4%, respectively, totaling 20.4%, with independent associations between angina and smoking (OR = 2.88; 95% CI: 1.69-4.90), obesity (OR = 1.62; 95% CI: 0.97-2.70), family history of heart attack (OR = 1.70; 95% CI: 1.00-2.88), low schooling (OR = 2.11; 95% CI: 1.24-3.59), and low monthly income (OR = 2.93; 95% CI: 1.18-7.22), even after adjustment for age. This study suggests that angina pectoris is underdiagnosed, even in patients with medical monitoring, revealing lost opportunities in identification and prevention of cardiovascular morbidity.


Metal-Organic Framework-Derived Homologous Sulfide Heterojunction for Robust Enzyme-Like Self-Driven Bacteria-Killing through Enhanced Electron Transfer.
Infectious diseases caused by various bacteria pose a serious threat to human health, and the emergence of drug-resistant bacteria has forced humans to develop new and effective antimicrobial agents and strategies. Herein, a metal-organic framework-derived Bi2 S3 /FeS2 heterojunction (BFS) is synthesized, and the materials-microorganism interface is further constructed. Through interfacial electron transfer, electrons are transferred from the bacteria to the BFS surface, disrupting the balance of the bacterial electron transport chain and inhibiting the metabolic activity of the bacteria. Moreover, BFS has enzyme-like (oxidase and peroxidase) properties and can produce a large amount of reactive oxygen species to kill additional bacteria. In vitro antibacterial results show that the antibacterial efficiency of BFS against both Staphylococcus aureus and Escherichia coli reaches more than 99.9% after 4 h of co-culture under dark conditions. Meanwhile, in vivo experiments show that BFS can effectively kill bacteria and promote wound healing. This work shows that BFS could be a novel, effective nanomaterial for the treatment of bacterial infections by constructing the materials-microorganism interface.


Spontaneous Bone Regeneration of Distal Half Ulnar Segment After Open Fracture of Forearm in a Pediatric Case.
Loss of the radius with open fractures of the forearm is rarely reported in pediatric cases and to the authors' knowledge, cases of segmental loss of the distal half of the ulna have not been previously reported. A 6-year-old girl was admitted with a Gustilo-Anderson type IIIB open forearm fracture and loss of the distal half of the ulna after a motor vehicle accident. Serial debridement was performed and a Kirschner wire was inserted into the distal half of the ulna. Unexpectedly, the ulna regenerated and the defect healed 4 weeks later. Soft tissue coverage was achieved with a skin graft and uneventful healing ensued. Eight weeks later, the bone was spontaneously and completely reconstituted. This case report demonstrates that substantial defects of the ulna may be spontaneously reconstituted over time.


Directed evolution of the transcription factor Gal4 for development of an improved transcriptional regulation system in Saccharomyces cerevisiae.
As a well-characterized eukaryotic DNA binding transcription factor, Gal4 has been extensively employed to construct controllable gene expression systems in Saccharomyces cerevisiae. The problem of insufficient inducibility arises in the constructs with multiples genes under control of GAL promoters due to the low expression level and activity of the native Gal4. In order to obtain improved transcriptional regulation systems for multi-gene pathways, Gal4 mutants with improved activity were created by directed evolution. During the preliminary screening, five positive Gal4 variants were isolated based on the lycopene-indicated high-throughput screening method. Analysis of the mutation sites revealed that the majority of positive mutations are localized in the middle homology region with unspecified function, suggesting an important role of this domain in transactivation of Gal4. Through combinatorial site-directed mutagenesis, the best variant Gal4T406A/V413A was obtained, which successfully increased the transcription of PGAL-driven lycopene pathway genes and led to 48 % higher lycopene accumulation relative to the wild-type Gal4. This study demonstrates the viability of modifying Gal4 activity by directed evolution for elevated expression of PGAL-driven genes and therefore enhanced production of the target metabolite.


A tale of three acaropathogenic fungi in Israel: Hirsutella, Meira and Acaromyces.
We review published and unpublished studies conducted in Israel with six acaropathogenic fungi, assayed in order to control the citrus rust mite, Phyllocoptruta oleivora (Ashmead) (CRM). Hirsutella thompsonii Fisher was introduced twice, killed 80-90% of the exposed mites, but due to its requirements for near-saturation humidities was deemed unsuitable for local outdoors conditions. Hirsutella kirchneri (Rostrup) Minter et al. and Hirsutella necatrix Minter et al. were also introduced and assayed against CRM and spider mites, but their efficacy was unsatisfactory. Three indigenous fungi found to be associated with mites, Meira geulakonigii, Meira argovae and Acaromyces ingoldii--all three recently described by Boekhout, Gerson, Scorzetti & Sztejnberg--were assayed against several mites. Meira geulakonigii killed 80-90% of several spider mites and of the CRM, and caused some mortality of Iphiseius degenerans (Berlese), one out of three phytoseiid predators assayed. Mortality was not due to parasitization; extracts from the media in which the fungi had developed caused considerable mite death, suggesting that it was a result of fungal toxins. Data from a field study indicated that spraying blastoconidia of M. geulakonigii on grapefruits infested by CRM significantly reduced pest-incurred damage from 23 to 13%. Applying qRT-PCR methodology indicated that M. geulakonigii was endophytic within sealed grapefruit flowers and in the flavedo of the fruits' peel. Neither in the laboratory nor in the field was any evidence ever obtained that this fungus damaged the plants, leading us to hypothesize that M. geulakonigii serves as a "body guard" of grapefruits (and perhaps other plants as well). All three fungi suffered very little mortality after being exposed to various insecticides and acaricides that are in current local use (with the exception of sulfur). The ability of M. geulakonigii to reduce mite numbers without affecting the host plant, the minimal fungal effect on some predatory mites, its endophytic nature along with the apparent tolerance of M. geulakonigii to many insecticides and acaricides, suggest that this fungus could be suitable for integrated pest management (IPM) program.


Production and scavenging of reactive oxygen species in Fagus sylvatica seeds during storage at varied temperature and humidity.
The accumulation of reactive oxygen species (ROS) in seed tissues plays an important role in the loss of seed viability during storage. In the present study, we examined whether the loss of germination capacity and viability of beech (Fagus sylvatica L.) seeds during storage under different temperatures (4, 20 and 30 degrees C) and relative humidity levels (45% and 75% RH) is associated with: (1) an increase in the level of ROS, such as superoxide radical (O2*-), oxygen peroxide (H2O2); and, (2) changes in low molecular antioxidants (ascorbate and glutathione) and enzymatic scavengers such as ascorbate peroxidase dehydroascorbate reductase, glutathione reductase, catalase, superoxide dismutase and guaiacol peroxidase. Beech seeds progressively lost their ability to germinate during 9 weeks of storage under the above conditions. The deleterious effects of temperature treatments increased with growing seed moisture content at higher humidity. The loss of seed viability was correlated with the generation of ROS during storage, which was more intensive at higher temperatures and humidity levels. The ascorbate content significantly increased in seeds stored in all temperature and humidity variants, when the seeds lost the ability to germinate to a large degree. At the same time, glutathione content dramatically decreased, but it was possible to observe a defensive reaction in seeds stored at 20 degrees C. Activities of all scavenging enzymes, measured after slow imbibition of seeds, significantly increased in comparison to the non-treated control (8-9% MC, -10 degrees C). This increase was higher in embryo axes than in cotyledons. Our results suggest that the loss of viability of beech seeds during storage at different temperatures, above zero, and at different humidity levels is closely related to ROS production, and that the antioxidative system is not sufficient to protect them.


Structural alterations of extraocular muscle associated with Apert's syndrome.
An inferior oblique muscle from a patient with Apert's syndrome was examined by light and electron microscopy. Alterations in the muscle fibres, the myoneural junctions, and intramuscular nerves were observed. These data are not compatible with the widespread notion that motility disturbances in this syndrome are solely due to mechanical limitations.


An improved spatial subsidy approach for ecological compensation in coastal seascapes for resilient land-sea management.
Human activities are considered a critical impact factor for decision-making in coupled human-nature systems, such as conservation of coastal systems. Identifying key human activities that cause significant habitat degradation for coastal species remains challenging. We improved the spatial subsidy approach to identify and prioritize control strategies for human-caused distribution shifts of marine species. We applied this method to a threatened Indo-Pacific humpback dolphin (Sousa chinensis) in Xiamen Bay, China. Our results indicate that (1) a significant distribution shift for humpback dolphins from existing nature reserves to peripheral waters occurred from 2011 to 2014; (2) coastal tourism and industrial and urban construction had more significant negative impacts on humpback dolphins than maritime transportation and reclamation; and (3) proactive management should be implemented for maritime transportation and reclamation, while reactive management should be implemented for coastal tourism and industrial and urban construction. Human impact analysis, combined with spatially explicit modeling, contributes to determining the spatial alternatives for conservation planning. In response to possible ecological damage caused by human activities, the improved spatial subsidy results help provide knowledge and platforms for ecological compensation.


Intra-sexual variation in male reproduction in teleost fish: a comparative approach.
The occurrence of intra-sexual variation in reproduction is a widespread phenomenon in teleosts. One such form of variation consists in the occurrence of alternative male types: males that invest resources in mate attraction and males that exploit the investment of the former males, by trying to sneak fertilizations during spawning. These alternative reproductive tactics can be classified according to their plasticity during the life span of the individuals (i.e., fixed vs. sequential vs. reversible). Furthermore, the differences between morphs within a given species may involve a set of different traits, including reproductive behavior, the differentiation of male morphological traits, and the patterns of gonad tissue allocation and the differentiation of gonadal accessory glands. In this paper, we review the available data on four species exhibiting different types of intra-sexual plasticity in reproduction that have been studied in our lab. The data on the proximate mechanisms, androgens and forebrain arginine-vasotocin (AVT), underlying these alternative tactics suggest that between-morph differences in androgen levels, especially in 11-ketotestosterone, are especially present in species where the alternative male types have evolved morphological traits that are tactic-specific (i.e., sexual polymorphisms) and that differences in AVT appear to be related to between-morph differences in the expression of courtship behavior. Therefore, this comparative approach leads us to propose that the different endocrine systems are involved in the differentiation of different sets of traits that make up alternative phenotypes, and that the differentiation of alternative tactics is not controlled by a single endocrine system (e.g., androgens).


Imipramine administration induces changes in the phosphorylation of FAK and PYK2 and modulates signaling pathways related to their activity.
Antidepressants can modify neuronal functioning by affecting many levels of signal transduction pathways that are involved in neuroplasticity. We investigated whether the phosphorylation status of focal adhesion kinase (FAK/PTK2) and its homolog, PYK2/PTK2B, and their complex with the downstream effectors (Src kinase, p130Cas, and paxillin) are affected by administration of the antidepressant drug, imipramine. The treatment influence on the levels of ERK1/2 kinases and their phosphorylated forms (pERK1/2) or the Gαq, Gα11 and Gα12 proteins were also assessed. Rats were injected with imipramine (10 mg/kg, twice daily) for 21 days. The levels of proteins investigated in their prefrontal cortices were measured by Western blotting. Imipramine induced contrasting changes in the phosphorylation of FAK and PYK2 at Tyr397 and Tyr402, respectively. The decreased FAK phosphorylation and increased PYK2 phosphorylation were reflected by changes in the levels of their complex with Src and p130Cas, which was observed predominantly after chronic imipramine treatment. Similarly only chronic imipramine decreased the Gαq expression while Gα11 and Gα12 proteins were untouched. Acute and chronic treatment with imipramine elevated ERK1 and ERK2 total protein levels, whereas only the pERK1 was significantly affected by the drug. The enhanced activation of PYK2 observed here could function as compensation for FAK inhibition. These data demonstrate that treatment with imipramine, which is a routine in counteracting depressive disorders, enhances the phosphorylation of PYK2, a non-receptor kinase instrumental in promoting synaptic plasticity. This effect documents as yet not considered target in the mechanism of imipramine action.


Activation of indigenous denitrifying bacteria and enhanced nitrogen removal via artificial mixing in a drinking water reservoir: Insights into gene abundance, community structure, and co-existence model.
Nitrogen pollution poses a severe threat to aquatic ecosystems and human health. This study investigated the use of water lifting aerators for in situ nitrogen reduction in a drinking water reservoir. The reservoir was thoroughly mixed and oxygenated after using water-lifting aerators for 42 days. The average total nitrogen concentration, nitrate nitrogen, and ammonium nitrogen-in all water layers-decreased significantly (P < 0.01), with a reduction efficiency of 35 ± 3%, 34 ± 2%, and 70 ± 6%, respectively. Other pollutants, including organic matter, phosphorus, iron, and manganese, were also effectively removed. Quantitative polymerase chain reactions indicated that bacterial nirS gene abundance was enhanced 26.34-fold. High-throughput sequencing, phylogenetic tree, and network analysis suggested that core indigenous nirS-type denitrifying bacteria, such as Dechloromonas, Simplicispira, Thauera, and Azospira, played vital roles in nitrogen and other pollutant removal processes. Furthermore, structural equation modeling revealed that nitrogen removal responded positively to WT, DO, and nirS gene abundance. Our findings provide a promising strategy for nitrogen removal in oligotrophic drinking water reservoirs with carbon deficiencies.


Revisiting the Relationships Between Genomic G + C Content, RNA Secondary Structures, and Optimal Growth Temperature.
Over twenty years ago Galtier and Lobry published a manuscript entitled "Relationships between Genomic G + C Content, RNA Secondary Structure, and Optimal Growth Temperature" in the Journal of Molecular Evolution that showcased the lack of a relationship between genomic G + C content and optimal growth temperature (OGT) in a set of about 200 prokaryotes. Galtier and Lobry also assessed the relationship between RNA secondary structures (rRNA stems, tRNAs) and OGT, and in this case a clear relationship emerged. Increasing structured RNA G + C content (particularly in regions that are double-stranded) correlates with increased OGT. Both of these fundamental relationships have withstood test of many additional sequences and spawned a variety of different applications that include prediction of OGT from rRNA sequence and computational ncRNA identification approaches. In this work, I present the motivation behind Galtier and Lobry's original paper and the larger questions addressed by the work, how these questions have evolved over the last two decades, and the impact of Galtier and Lobry's manuscript in fields beyond these questions.


Paratylenchus Ilicis n. Sp. (Nematoda: Paratylenchinae) Associated with Holly from the Netherlands and New Taxonomical and Phylogenetic Support for the Synonymization of Cacopaurus with Paratylenchus.
Paratylenchus ilicis n. sp. was found associated with holly in the Netherlands and was described based on morphology, morphometrics, rRNA and mitochondrial cox1 genes, phylogenetic relationships with other Paratylenchus species, host information and geographical distribution. This species can be morphologically diagnosed based on its light brown, slightly obese to obese females with tubercles on cuticle, lateral bands widening into an ovoid field around vulva level, stylet length of 70 μm to 100 μm, outstretched to reflexed ovary, rounded sperm-filled spermatheca, vagina opening into a thick-walled rounded space, absence of vulval flaps and vulva at 89% to 95% of body length, very short tail in all life stages, and a characteristic finger-like tail tip in juveniles (J2). The new species is morphologically closest to Cacopaurus pestis but differs based on the absence of a scutellum-like differentiation in the lateral field, the ovaries that can be outstretched or reflexed, and the finger-like tail tip in J2. Furthermore, both species were found to be molecularly distant from one another, found in different habitats, and are associated with different hosts. The high morphological similarity between Cacopaurus and Paratylenchus and our phylogenetic analyses, revealing that the former is embedded within different Paratylenchus clades and thus polyphyletic, provide new evidences for the synonymization of Cacopaurus with Paratylenchus.


Cooperative group trials in pediatric oncology: the surgeon's role.
The early history of the pediatric cooperative group trials is reviewed, and the surgeons who played a critical role in their formation are discussed. The vital information provided from the tumor specimens submitted as part of the protocols is presented, as well as how this information advanced our management of infants and children treated on current protocols of the Children's Oncology Group. Finally, a survey of the surgeons currently active in the clinical trials defined the "critical lessons" learned from the sequence of protocols by the cooperative groups which have advanced our surgical treatment of patients today.


The oxidative phosphorylation inhibitor IM156 suppresses B-cell activation by regulating mitochondrial membrane potential and contributes to the mitigation of systemic lupus erythematosus.
Current treatment strategies for autoimmune diseases may not sufficiently control aberrant metabolism in B-cells. To address this concern, we investigated a biguanide derivative, IM156, as a potential regulator for B-cell metabolism in vitro and in vivo on overactive B-cells stimulated by the pro-inflammatory receptor TLR-9 agonist CpG oligodeoxynucleotide, a mimic of viral/bacterial DNA. Using RNA sequencing, we analyzed the B-cell transcriptome expression, identifying the major molecular pathways affected by IM156 in vivo. We also evaluated the anti-inflammatory effects of IM156 in lupus-prone NZB/W F1 mice. CD19+B-cells exhibited higher mitochondrial mass and mitochondrial membrane potential compared to T-cells and were more susceptible to IM156-mediated oxidative phosphorylation inhibition. In vivo, IM156 inhibited mitochondrial oxidative phosphorylation, cell cycle progression, plasmablast differentiation, and activation marker levels in CpG oligodeoxynucleotide-stimulated mouse spleen B-cells. Interestingly, IM156 treatment significantly increased overall survival, reduced glomerulonephritis and inhibited B-cell activation in the NZB/W F1 mice. Thus, our data indicated that IM156 suppressed the mitochondrial membrane potentials of activated B-cells in mice, contributing to the mitigation of lupus activity. Hence, IM156 may represent a therapeutic alternative for autoimmune disease mediated by B-cell hyperactivity.


What diagnosis does not tell: the case for a noncategorical approach to chronic illness in childhood.
Medical training, practice and research are traditionally organized around body systems and disease categories. There is, however, a disciplinary split over the question of whether the clinical diagnosis is the central issue in describing an individual with an illness. Data from two studies, one institutional and one population based (The Pediatric Ambulatory Care Treatment Study and the National Health Examination Survey--Cycles II and III), are used to test the usefulness of diagnostic groupings in examining correlates of illness. A series of analyses of variance with the diagnostic groupings as the independent variable and a range of psychological, social and educational measures as the dependent variables reveal only the number of significant differences expected by chance. The only area in which a pattern of significant differences is found in the family's interaction with the health care delivery system. These results indicate that there is more variability within diagnostic groupings than between them and suggest that diagnosis is not a helpful categorization in the examination of psychological and social variables. While not surprising to social scientists, these data suggest the need for a major reorientation of the research paradigm when examining the psychological, social, rehabilitative and preventive issues raised by chronic illness in children and families.


Expert meeting report: towards a joint European roadmap to address the unmet needs and priorities of paediatric asthma patients on biologic therapy.
A digital multidisciplinary European expert meeting took place on the 9 July 2020 to identify the unmet needs of paediatric severe asthma patients, and set the priorities for clinical and research activities ahead https://bit.ly/3CeLBHB.