Design of the Nationwide Nursery School Survey on Child Health Throughout the Great East Japan Earthquake.
The Great East Japan Earthquake inflicted severe damage on the Pacific coastal areas of northeast Japan. Although possible health impacts on aged or handicapped populations have been highlighted, little is known about how the serious disaster affected preschool children's health. We conducted a nationwide nursery school survey to investigate preschool children's physical development and health status throughout the disaster. The survey was conducted from September to December 2012. We mailed three kinds of questionnaires to nursery schools in all 47 prefectures in Japan. Questionnaire "A" addressed nursery school information, and questionnaires "B1" and "B2" addressed individuals' data. Our targets were children who were born from April 2, 2004, to April 1, 2005 (those who did not experience the disaster during their preschool days) and children who were born from April 2, 2006, to April 1, 2007 (those who experienced the disaster during their preschool days). The questionnaire inquired about disaster experiences, anthropometric measurements, and presence of diseases. In total, 3624 nursery schools from all 47 prefectures participated in the survey. We established two nationwide retrospective cohorts of preschool children; 53,747 children who were born from April 2, 2004, to April 1, 2005, and 69,004 children who were born from April 2, 2006, to April 1, 2007. Among the latter cohort, 1003 were reported to have specific personal experiences with the disaster. With the large dataset, we expect to yield comprehensive study results about preschool children's physical development and health status throughout the disaster.


Evaluation of the Effect of Antibiotics and Splints on the Result of Septal Mucosal Culture After Septoplasty.
Post operation infection after septoplasty is very rare, possibly due to excessive nasal blood supply. Most otorhinolaryngologists recommend antibiotics after septoplasty; however, controversial results were available. Therefore, this study was designed to investigate the effect of antibiotics after septoplasty. In this study, 90 patients who were candidates for septoplasty were entered the study and divided into three groups. The first group did not receive any oral antibiotics after septoplasty. The second group took 500 mg of oral cephalexin. The third group, for whom splints were used, also received cephalexin. The culture of the nasal mucosa was prepared before and two weeks after surgery and compared between groups. Then, the amount and types of mucosa microorganisms were reported. Data were analyzed using SPSS16. The growth significantly increased in the first group (p = 0.051) and reduced in the second group (p < 0.001). While a decreased growth rate was observed in the third group, it was not statistically significant (p = 0.12). The present study highlighted the beneficial role of prophylactic antibiotics administration in patients without splints on bacterial growth, while it had no effect in patients with splints. The online version contains supplementary material available at 10.1007/s12070-023-03665-w.


Two cases of spontaneous rupture of the uterine artery in the perinatal period: A case report.
Uterine artery spontaneous rupture is a rare but potentially life-threatening complication during pregnancy and puerperium. The lack of typical symptoms makes it difficult to diagnose, which can result in serious consequences for both the mother and fetus. Case 1 presented with fainting and lower abdominal discomfort, while Case 2 developed hypotension after delivery and remained in poor condition even after rehydration. Both cases were diagnosed with uterine artery spontaneous rupture, with intraoperative findings revealing ruptures in different branches of the uterine artery. Both cases underwent surgical interventions, with laparoscopic surgery performed in Case 1 and repair of the ruptured artery in Case 2. Both cases had successful outcomes, with the ruptured arteries repaired and the patients discharged from the hospital within a week after surgery. Uterine artery spontaneous rupture is a rare but potentially life-threatening complication that may present with atypical symptoms. Early diagnosis and prompt surgical intervention are crucial in preventing serious complications for both the mother and fetus. Clinicians should maintain a high level of suspicion for this condition when evaluating patients presenting with unexplained symptoms or signs of peritoneal irritation during pregnancy and puerperium.


Assessment of heavy metals contamination and water quality characterization in the Nanming River, Guizhou Province.
The analysis to assess the water quality and potential ecological risks in sediments was carried out by means of the distribution characteristics of nutrient properties and heavy metals in water, and heavy metals in sediments from the Nanming River. The results from nutrient properties demonstrated that the majority of TN and TP exceeded the permissible limit and concentrated within the study area. The concentrations of heavy metal in water were lower than the permissible limits but may pose potential threat to aquatic ecosystems. Based on the potential ecological risk results of heavy metals in sediments, Cd posed risk to ecological environment, and the serious contaminations mainly existed in the center of Guiyang City. The multivariate statistical analyses were used to support the idea that the Upstream Area and Midstream Area were significantly dominated by NH4+, TP, TN and CODMn in water. Furthermore, landscape characteristics and hydrology condition better explained the certain trend of water quality. Finally, identifying relationship between nutrient properties and heavy metals that are key ecological components of ecosystem can potentially aid the advances for restoration of geochemical transformations and give rise to river restoration efforts.


Comprehensive Gene Mutation Profiling of Circulating Tumor DNA in Ovarian Cancer: Its Pathological and Prognostic Impact.
Liquid biopsies from circulating tumor DNA (ctDNA) have been employed recently as a non-invasive diagnostic tool for detecting cancer-specific gene mutations. Here, we show the comprehensive gene mutation profiles of ctDNA in 51 patients with different histological subtypes of stage I-IV ovarian cancer, and their association with clinical outcomes. The ctDNA extracted from pre-treatment patients' plasma were analyzed using Cancer Personalized Profiling by Deep Sequencing targeting 197 genes. Of 51 patients, 48 (94%) showed one or more non-synonymous somatic mutations, including TP53 (37.3%), APC (17.6%), KRAS (15.7%), EGFR (13.7%), MET (11.8%), PIK3CA (11.8%), NPAP1 (11.8%), and ALK (9.8%). The most frequently mutated genes were as follows: TP53 in high-grade serous carcinoma (66.7%), APC in clear cell carcinoma (30.8%), PIK3CA in endometrioid carcinoma (40%), and KRAS in mucinous carcinoma (66.7%). Higher cell-free (cf)DNA concentration significantly correlated with worse progression-free survival (PFS) in all patients as well as stage III-IV patients (p = 0.01 and 0.005, respectively). Further, patients with any pathogenic mutations showed significantly worse PFS (p = 0.048). Blood tumor mutational burden detected from ctDNA did not significantly correlate with the histological subtypes or survival. Collectively, clinico-genomic profiles of individual ovarian cancer patients could be identified using ctDNA and may serve as a useful prognostic indicator. These findings suggest that ctDNA-based gene profiling might help in establishing personalized therapeutic strategies.


Formate-reduced E. coli formate dehydrogenase H: The reinterpretation of the crystal structure suggests a new reaction mechanism.
Re-evaluation of the crystallographic data of the molybdenum-containing E. coli formate dehydrogenase H (Boyington et al. Science 275:1305-1308, 1997), reported in two redox states, reveals important structural differences for the formate-reduced form, with large implications for the reaction mechanism proposed in that work. We have re-refined the reduced structure with revised protocols and found substantial rearrangement in some parts of it. The original model is essentially correct but an important loop close to the molybdenum active site was mistraced, and, therefore, catalytic relevant residues were located in wrong positions. In particular selenocysteine-140, a ligand of molybdenum in the original work, and essential for catalysis, is no longer bound to the metal after reduction of the enzyme with formate. These results are incompatible with the originally proposed reaction mechanism. On the basis of our new interpretation, we have revised and proposed a new reaction mechanism, which reconciles the new X-ray model with previous biochemical and extended X-ray absorption fine structure data.


Cortical negative DC deflections following middle cerebral artery occlusion and KCl-induced spreading depression: effect on blood flow, tissue oxygenation, and electroencephalogram.
In the periphery of ischemic brain lesions, transient spreading depression-like direct current (DC) deflections occur that may be of pathophysiological importance for determining the volume of the ischemic infarct. The effect of these deflections on cerebral blood flow, tissue oxygen tension, and electrophysiology was studied in rats submitted to intraluminal thread occlusion of the middle cerebral artery (MCA) and compared with the changes following potassium chloride (KCl)-induced spreading depression of intact animals. Immediately after MCA occlusion, cortical laser-Doppler flow (LDF) in the periphery of the MCA territory sharply decreased to 35 +/- 14% of control (mean +/- SD; p < 0.05), tissue PO2 declined from 28 +/- 4 to 21 +/- 3 mm Hg (p < 0.05), and EEG power fell to approximately 80% of control. During 7-h occlusion, 3-11 DC deflections with a mean duration of 5.2 +/- 4.8 min occurred at irregular intervals, and EEG power gradually declined to 66 +/- 16% of control (p < 0.05). During the passage of DC deflections, LDF did not change, but PO2 further declined to 19 +/- 4 mm Hg (p < 0.05). KCl-induced depolarizations of intact rats were significantly shorter (1.4 +/- 0.5 min; p < 0.05) and were accompanied by a 43% increase in LDF (p < 0.05) and a slight but significant increase in tissue PO2 from 22 +/- 4 to 25 +/- 4 mm Hg (p < 0.05). The comparison of periinfarct and KCl-induced depolarizations demonstrates that oxygen requirements are not coupled to an appropriate flow response in the periinfarct zone with severely reduced blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)


Endotracheal cuff undersizing diagnosed by computed tomography: Case report.
We herein report a case in which the trachea could be completely sealed only when the cuff pressure reached 100 cmH2O. An excessive cross-sectional area of the trachea is a rare phenomenon, but we believe that our case will be helpful for clinicians who encounter similar situations.


Integrating climate change into habitat conservation plans under the U.S. endangered species act.
Habitat Conservation Plans (HCPs) under the Endangered Species Act (ESA) are an important mechanism for the acquisition of land and the management of terrestrial and aquatic ecosystems. HCPs have become a vital means of protecting endangered and threatened species and their habitats throughout the United States, particularly on private land. The scientific consensus that climate is changing and that these changes will impact the viability of species has not been incorporated into the conservation strategies of recent HCPs, rendering plans vulnerable biologically. In this paper we review the regulatory context for incorporating climate change into HCPs and analyze the extent to which climate change is linked to management actions in a subset of large HCPs. We conclude that most current plans do not incorporate climate change into conservation actions, and so we provide recommendations for integrating climate change into the process of HCP development and implementation. These recommendations are distilled from the published literature as well as the practice of conservation planning and are structured to the specific needs of HCP development and implementation. We offer nine recommendations for integrating climate change into the HCP process: (1) identify species at-risk from climate change, (2) explore new strategies for reserve design, (3) increase emphasis on corridors, linkages, and connectivity, (4) develop anticipatory adaptation measures, (5) manage for diversity, (6) consider assisted migration, (7) include climate change in scenarios of water management, (8) develop future-oriented management actions, and (9) increase linkages between the conservation strategy and adaptive management/monitoring programs.


SegR-Net: A deep learning framework with multi-scale feature fusion for robust retinal vessel segmentation.
Retinal vessel segmentation is an important task in medical image analysis and has a variety of applications in the diagnosis and treatment of retinal diseases. In this paper, we propose SegR-Net, a deep learning framework for robust retinal vessel segmentation. SegR-Net utilizes a combination of feature extraction and embedding, deep feature magnification, feature precision and interference, and dense multiscale feature fusion to generate accurate segmentation masks. The model consists of an encoder module that extracts high-level features from the input images and a decoder module that reconstructs the segmentation masks by combining features from the encoder module. The encoder module consists of a feature extraction and embedding block that enhances by dense multiscale feature fusion, followed by a deep feature magnification block that magnifies the retinal vessels. To further improve the quality of the extracted features, we use a group of two convolutional layers after each DFM block. In the decoder module, we utilize a feature precision and interference block and a dense multiscale feature fusion block (DMFF) to combine features from the encoder module and reconstruct the segmentation mask. We also incorporate data augmentation and pre-processing techniques to improve the generalization of the trained model. Experimental results on three fundus image publicly available datasets (CHASE_DB1, STARE, and DRIVE) demonstrate that SegR-Net outperforms state-of-the-art models in terms of accuracy, sensitivity, specificity, and F1 score. The proposed framework can provide more accurate and more efficient segmentation of retinal blood vessels in comparison to the state-of-the-art techniques, which is essential for clinical decision-making and diagnosis of various eye diseases.


Weight change and clinical outcomes in heart failure with reduced ejection fraction: insights from EMPEROR-Reduced.
Baseline body mass index (BMI) and weight loss promoted by sodium-glucose cotransporter 2 inhibitors may impact outcomes in patients with heart failure with reduced ejection fraction (HFrEF). We assessed in the EMPEROR-Reduced population treated with empagliflozin versus placebo the relationship between baseline BMI, weight loss and effects on the primary (time to first hospitalization for heart failure [HHF] or cardiovascular death) and key secondary outcomes. We categorized patients according to their baseline BMI: <20 kg/m2 (n = 180); 20 to <25 kg/m2 (n = 1038); 25 to <30 kg/m2 (n = 1345); 30 to <35 kg/m2 (n = 774) and ≥35 kg/m2 (n = 393). The treatment effect of empagliflozin on the primary outcome was consistent across all BMI categories (hazard ratios in subgroups 0.66-0.88, interaction trend p = 0.32), as was the effect on total (first plus recurrent) HHF (interaction trend p = 0.31). Empagliflozin reduced the rate of estimated glomerular filtration rate decline consistently across the BMI categories (interaction trend p = 0.67). Overall, incidence rates of any or serious adverse events were comparable between the treatment groups across all BMI categories. A total of 313 (17.4%) patients treated with empagliflozin experienced a weight loss of more than 5% at week 52 versus 230 (12.8%) in placebo. When analysed separately within each treatment group, presence of weight loss was similarly associated with an increased risk of all-cause mortality. The benefits of empagliflozin versus placebo were consistently present across all BMI categories in HFrEF patients. Weight loss was associated with higher risk of all-cause mortality, regardless of treatment group.


MicroRNA-155 suppresses activation-induced cytidine deaminase-mediated Myc-Igh translocation.
MicroRNAs (miRNAs) are small noncoding RNAs that regulate vast networks of genes that share miRNA target sequences. To examine the physiologic effects of an individual miRNA-mRNA interaction in vivo, we generated mice that carry a mutation in the putative microRNA-155 (miR-155) binding site in the 3'-untranslated region of activation-induced cytidine deaminase (AID), designated Aicda(155) mice. AID is required for immunoglobulin gene diversification in B lymphocytes, but it also promotes chromosomal translocations. Aicda(155) caused an increase in steady-state Aicda mRNA and protein amounts by increasing the half-life of the mRNA, resulting in a high degree of Myc-Igh translocations. A similar but more pronounced translocation phenotype was also found in miR-155-deficient mice. Our experiments indicate that miR-155 can act as a tumor suppressor by reducing potentially oncogenic translocations generated by AID.


Diurnal modulation of phosphoenolpyruvate carboxylation in pea leaves and roots as related to tissue malate concentrations and to the nitrogen source.
Phosphoenolpyruvate (PEP) carboxylation was measured as dark 14CO2 fixation in leaves and roots (in vivo) or as PEP carboxylase (PEPCase) activity in desalted leaf and roof extracts (in vitro) from Pisum sativum L. cv. Kleine Rheinländerin. Its relation to the malate content and to the nitrogen source (nitrate or ammonium) was investigated. In tissue from nitrate-grown plants, PEP carboxylation varied diurnally, showing an increase upon illumination and a decrease upon darkening. Diurnal variations in roots were much lower than in leaves. Fixation rates in leaves remained constantly low in continuous darkness or high in continuous light. Dark CO2 fixation of leaf slices also decreased when leaves were preilluminated for 1 h in CO2-free air, suggesting that the modulation of dark CO2 fixation was related to assimilate availability in leaves and roots. Phosphoenolpyruvate carboxylase activity was also measured in vitro. However, no difference in maximum enzyme activity was found in extracts from illuminated or darkened leaves, and the response to substrate and effectors (PEP, malate, glucose-6-phosphate, pH) was also identical. The serine/threonine protein kinase inhibitors K252b, H7 and staurosporine, and the protein phosphatase 2A inhibitors okadaic acid and cantharidin, fed through the leaf petiole, did not have the effects on dark CO2 fixation predicted by a regulatory system in which PEPCase is modulated via reversible protein phosphorylation. Therefore, it is suggested that the diurnal modulation of PEP carboxylation in vivo in leaves and roots of pea is not caused by protein phosphorylation, but rather by direct allosteric effects. Upon transfer of plants to ammonium-N or to an N-free nutrient solution, mean daily malate levels in leaves decreased drastically within 4-5 d. At that time, the diurnal oscillations of PEP carboxylation in vivo disappeared and rates remained at the high light-level. The coincidence of the two events suggests that PEPCase was de-regulated because malate levels became very low. The drastic decrease of leaf malate contents upon transfer of plants from nitrate to ammonium nutrition was apparently not caused by increased amino acid or protein synthesis, but probably by higher decarboxylation rates.


Longitudinal examination of social and environmental influences on motivation for physical activity.
Physical activity behavior is influenced by numerous factors including motivation, social interactions, and the walkability of the environment. To examine how social contexts and environmental features affect physical activity motivational processes across time. Participants (N=104) completed 3 monthly online surveys assessing self-determination theory constructs, social partners in physical activity, neighborhood walkability, and weekly physical activity. Longitudinal path analysis examined the degree to which physical activity was predicted by individual goals, orientation, and autonomy support and whether these associations were meditated by motivation and moderated by the social and environmental contexts of physical activity. The effect of controlled exercise orientations on physical activity was mediated by autonomous motivation. This association was stronger among those who perceived less crime in their neighborhoods. To improve the ability to tailor physical activity counseling it is important to understand how each person views exercise situations and to understand his/her social and neighborhood environments.


Use of oral anticoagulants and its associated factors among nonvalvular atrial fibrillation patients with new-onset acute ischemic stroke: A report from the China Atrial Fibrillation Registry study.
The adherence of oral anticoagulant (OAC) therapy among nonvalvular atrial fibrillation (NVAF) patients with acute ischemic stroke (AIS) in China during recent years was unclear, and the possible factors that influenced the initiation and persistent use of OAC were needed to be explored. A total of 1085 NVAF patients, who experienced new-onset and nonfatal AIS from August 2011 to December 2020 during follow-ups in the China Atrial Fibrillation Registry (China-AF), were enrolled. Information including patients' demographic characteristics, medical history, medication usage, which were collected before and after the index stroke, were used in the analysis. OAC was initiated in 40% (434/1085) NVAF patients within 3 months after new-onset AIS. High-reimbursement-rate insurance coverage (odds ratio [OR]: 1.51, 95% confidence interval [CI]: 1.03-2.22, p = .036), 3-month-peri-stroke AF episodes (OR: 2.63, 95% CI: 1.88-3.69, p < .001), and pre-stroke OAC usage (OR: 8.92, 95% CI: 6.01-13.23, p < .001), were positively associated with initiation of OAC within 3 months after new-onset AIS, while age (OR: 0.98, 95% CI: 0.96-1.00, p = .024), female (OR: 0.63, 95% CI: 0.44-0.90, p = .012) and higher modified HASBLED score (OR: 0.45, 95% CI: 0.37-0.55, p < .001) were negatively associated with it. Among 3-month-post-stroke OAC users, history of radiofrequency ablation (hazard ratio: 1.65, 95% CI: 1.16-2.35; p = .006) was positively associated with non-persistence of OAC usage. In China, the proportion of NVAF patients who initiated OAC therapy since new-onset AIS was still low. More efforts are needed on improving patients' adherence to anticoagulant therapy.


Evaluation of a new immunoassay for determination of phenytoin and phenobarbital: results of a European collaborative control study.
The performance of a new enzyme multiplied immunoassay technique (EMIT) was compared with other current methods, namely gas-liquid chromatography and thin-layer chromatography, for the determination of phenytoin and phenobarbital in serum. Forty-three serum samples were sent as unknowns to the participating laboratories for determination. The precision of repeated determinations was very similar for EMIT and chromatography. There was good agreement among gas chromatography, thin-layer chromatography, and EMIT results. Interlaboratory variability was lower for EMIT determinations of both antiepileptic drugs. The rapid analysis of small samples, made possible by the EMIT system, could have beneficial effects on the treatment of epilepsies.


Characterization of aerobic spore-forming bacteria associated with industrial dairy processing environments and product spoilage.
Due to changes in the design of industrial food processing and increasing international trade, highly thermoresistant spore-forming bacteria are an emerging problem in food production. Minimally processed foods and products with extended shelf life, such as milk products, are at special risk for contamination and subsequent product damages, but information about origin and food quality related properties of highly heat-resistant spore-formers is still limited. Therefore, the aim of this study was to determine the biodiversity, heat resistance, and food quality and safety affecting characteristics of aerobic spore-formers in the dairy sector. Thus, a comprehensive panel of strains (n=467), which originated from dairy processing environments, raw materials and processed foods, was compiled. The set included isolates associated with recent food spoilage cases and product damages as well as isolates not linked to product spoilage. Identification of the isolates by means of Fourier-transform infrared spectroscopy and molecular methods revealed a large biodiversity of spore-formers, especially among the spoilage associated isolates. These could be assigned to 43 species, representing 11 genera, with Bacillus cereus s.l. and Bacillus licheniformis being predominant. A screening for isolates forming thermoresistant spores (TRS, surviving 100°C, 20 min) showed that about one third of the tested spore-formers was heat-resistant, with Bacillus subtilis and Geobacillus stearothermophilus being the prevalent species. Strains producing highly thermoresistant spores (HTRS, surviving 125°C, 30 min) were found among mesophilic as well as among thermophilic species. B. subtilis and Bacillus amyloliquefaciens were dominating the group of mesophilic HTRS, while Bacillus smithii and Geobacillus pallidus were dominating the group of thermophilic HTRS. Analysis of spoilage-related enzymes of the TRS isolates showed that mesophilic strains, belonging to the B. subtilis and B. cereus groups, were strongly proteolytic, whereas thermophilic strains displayed generally a low enzymatic activity and thus spoilage potential. Cytotoxicity was only detected in B. cereus, suggesting that the risk of food poisoning by aerobic, thermoresistant spore-formers outside of the B. cereus group is rather low.


Characterization of a novel merozoite surface protein of Plasmodium vivax, Pv41.
Since the genome of Plasmodium vivax was sequenced, few proteins have been characterized as highly immunogenic and candidates for inclusion in a vivax malaria vaccine. The P. vivax 41 (Pv41) protein has a signal peptide, one glutamate-rich domain in its central region, and two sexual stage s48/45 domains, and is characterized as a gametocyte surface protein; however, this protein may be expressed principally on the merozoite surface of parasites. The previous study reported the transcription, blood-stage expression, and subcellular localization of Pv41 within the parasite. In this study, the recombinant Pv41 protein was expressed as a soluble form, of a molecular mass ~44 kDa, by a cell-free expression system and was specifically recognized by animal immune sera and vivax patient sera. Evaluation of the human humoral immune response to Pv41 indicated a high immunogenicity, with 62.5% sensitivity and 95% specificity, by protein array. Immunofluorescence assays (IFA) using polyclonal anti-Pv41 antibodies showed that Pv41 was localized on the merozoite surface. The high immunogenicity of Pv41 indicates its potential as a vivax malaria vaccine candidate antigen, particularly in light of its location on the merozoite surface of the parasite.


Inhibition of extracellular signal-regulated kinase 1/2 augments nitric oxide production in lipopolysaccharide-stimulated RAW264.7 macrophage cells.
The present study was conducted to determine effects of U0126, a specific inhibitor of mitogen-activated kinase kinase 1/2, on production of nitric oxide (NO) in RAW264.7 macrophage cells. U0126 significantly enhanced NO production in lipopolysaccharide (LPS) but not CpG DNA or interferon-gamma-stimulated RAW264.7 cells. In contrast, U0124, a negative control for U0126, did not affect LPS-induced NO production. Further, a series of inhibitors of p38, phosphatidyl-inositol 3-kinase and Janus tyrosine kinase rather caused suppression in LPS-stimulated RAW264.7 cells. U0126 was found to definitely inhibit phosphorylation of extracellular signal-regulated kinase (Erk) 1/2 and augment the levels of inducible type of NO synthase. Antisense oligonucleotides of Erk1/2 also augmented LPS-induced NO production. Inactivation of Erk1/2 by U0126 furthermore inhibited LPS-induced activating protein-1 activation, but not nuclear factor-kappaB activation. The results suggest that Erk1/2 might negatively regulate NO production in LPS-stimulated RAW264.7 cells.


Clinical value of cortical bursting in preterm infants with intraventricular haemorrhage.
In healthy preterm infants, cortical burst rate and temporal dynamics predict important measures such as brain growth. We hypothesised that in preterm infants with germinal matrix-intraventricular haemorrhage (GM-IVH), cortical bursting could provide prognostic information. We determined how cortical bursting was influenced by the injury, and whether this was related to developmental outcome. Single-centre retrospective cohort study at University College London Hospitals, UK. 33 infants with GM-IVH ≥ grade II (median gestational age: 25 weeks). We identified 47 EEGs acquired between 24 and 40 weeks corrected gestational age as part of routine clinical care. In a subset of 33 EEGs from 25 infants with asymmetric injury, we used the least-affected hemisphere as an internal comparison. We tested whether cortical burst rate predicted survival without severe impairment (median 2 years follow-up). In asymmetric injury, cortical burst rate was lower over the worst- than least-affected hemisphere, and bursts over the worst-affected hemisphere were less likely to immediately follow bursts over the least-affected hemisphere than vice versa. Overall, burst rate was lower in cases of GM-IVH with parenchymal involvement, relative to milder structural injury grades. Higher burst rate modestly predicted survival without severe language (AUC 0.673) or motor impairment (AUC 0.667), which was partly mediated by structural injury grade. Cortical bursting can index the functional injury after GM-IVH: perturbed burst initiation (rate) and propagation (inter-hemispheric dynamics) likely reflect associated grey matter and white matter damage. Higher cortical burst rate is reassuring for a positive outcome.


A descriptive study of 'non-cases' and referral rates to an early intervention for psychosis service.
Despite there being approximately 200 early intervention services for psychosis worldwide, little is known about the referral rates to these services, the diagnoses and needs of individuals found not to have a first episode of psychosis (FEP). Firstly, we aimed to describe the diagnoses for individuals who were found not to have a FEP (non-cases) following an assessment using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders IV (SCID). We then aimed to examine the referral rates of cases and non-cases to an early intervention service. All individuals referred to the early intervention service underwent a clinical assessment using the SCID. In a 4-year period, there were 632 referrals to the early intervention service for psychosis, and of these, 53% (n = 338) were found to have a FEP, 5% (n = 34) were found to have an at-risk mental state for psychosis and 41% (n = 260) were found to be 'non-cases'. This represents a ratio of 1.9:1 of referrals to cases, or approximately 2:1. Of the non-cases, 27% (n = 62) satisfied criteria for a mood disorder, with major depressive disorder the commonest diagnosis. A further 18% (n = 42) of non-cases satisfied criteria for an anxiety disorder and nearly half of these were diagnosed with social phobia. The ratio of referrals to cases was not consistent over time and rose from 1.3:1 in the first year to 2:1 in the fourth year. A large proportion of individuals referred to an early intervention for psychosis service were found not to have psychotic disorder, however they still have significant needs regarding their mental health.


Differential protein profiling of synovial fluid from rheumatoid arthritis and osteoarthritis patients using LC-MALDI TOF/TOF.
The purpose of this study was to identify those proteins relatively more abundant in the synovial fluid (SF) of patients suffering from rheumatoid arthritis (RA) and osteoarthritis (OA) using high performance liquid chromatography coupled to mass spectrometry. 20 individual SF samples from each disease were pooled into two groups (RA and OA) to reduce the contribution of extreme individual values. Prior to the proteomic analysis, samples were immunodepleted from the top 20 most abundant plasma proteins, to enrich the lower-abundance protein fractions. Then, they were subjected to protein size fractioning and in-gel digestion, followed by reversed-phase peptide separation in a nano-LC system and subsequent peptide identification by MALDI-TOF/TOF. This strategy led to the identification of 136 different proteins in SF, which is the largest number of SF proteins described up to date by proteomics. A relative quantification of the proteins between RA and OA was carried out by spectral counting analysis. In RA, our results show a greater relative abundance of proteins related to complement activation, inflammation and the immune response, such as the major matrix metalloproteinases and several neutrophil-related proteins. In OA, we detected an increase in proteins involved in the formation and remodeling of the extracellular matrix (ECM), such as fibronectin, kininogen-1, cartilage acidic protein 1 and cartilage oligomeric matrix protein. The results obtained for MMP-1, BGH3, fibronectin and gelsolin were verified by immunoblotting analyses. Some of the novel proteins identified in this work might be relevant not only for increasing knowledge on the etiopathogenesis of RA and OA processes, but also as putative disease biomarkers, as their presence in SF is a prior step to their dilution in serum. This article is part of a Special Issue entitled: Proteomics: The clinical link.


Synthesis of an anti-inflammatory 10,10a-dihydro-1H,5H-imidazo[1,5-b)isoquinoline-1,3(2H)-dione.
A new synthesis of imidazo[1,5-b]isoquinolines is reported. 2-[2-(Piperidino)ethyl]-10,10a-dihydro-1H,5H-imidazo[1,5-b]isoquinoline-1,3(2H)-dione hydrochloride was found to posses anti-inflammatory activity.


Parents' Perspectives on Their Child's Social Experience in the Context of Childhood Chronic Illness: A Qualitative Study.
Many children suffer from a serious chronic illness. These children have greater risks of developing psychosocial difficulties, associated with school absenteeism and missed social opportunities. Through parents' perspectives, this study aimed to gain a holistic understanding of children's social experience in the context of chronic illness. We conducted semi-structured interviews with parents of a child with a serious chronic illness exploring their child's school experience. Two researchers coded social experiences using an iterative process, involving regular team discussions. Theoretical thematic analysis and content analysis were both performed, using the social ecological model as a theoretical framework. Forty-nine parents participated (43 mothers, 6 fathers; child mean age 11.51 years; 21 female children, 28 male children; 6 different chronic illness groups). According to parents, the main facilitators to the social experience of their children involved parents themselves, the school, social networks and peers, as they were all able to provide social support and opportunities for social development. However, peers were also a source of bullying and peer pressure, and sometimes lacked understanding and empathy. As shown by the social ecological model, social functioning between chronically-ill children and their peers can be influenced by many factors. More specifically, parents have expressed their ability for promoting positive experiences between their children and their peers. Practice Implications Considering the complexity of social functioning, future research and interventions should provide holistic support for children with chronic illnesses.


Consonant and vowel perception and production: early English-French bilinguals and English monolinguals.
This study is a comparative analysis of the English phonetic systems of 10 fluent adult English-French bilinguals who acquired their two languages prior to age 8 and who were English-dominant, and of 10 adult English monolinguals. The objective of the study was to determine whether or not early English-dominant bilinguals perceive and produce speech as English monolinguals do. Discrimination and identification tests of synthetic (d-t) and (i-I) continua and speech production tests revealed that the bilinguals' discrimination and production of (d) and (t) and their production of (I) did not differ significantly from the monolinguals'. However, the bilinguals' identification of (d-t) and (i-I) and one aspect of their production of (i) did differ significantly from that of the monolinguals. The present results indicate that early bilingualism can yield monolingual-like performance in at least one of the bilinguals' languages, but only with respect to certain aspects of the phonetic system. These findings are viewed in light of sound-class distinctions, the perception-production dichotomy, and bilingual phonetic transfer and restructuring.


Flux profile at focal area of concentrating solar dishes.
We analytically, experimentally and computationally explore the solar radiation flux distribution in the interior region of a spherical mirror and compare it to that of a paraboloidal one with the same aperture area. Our investigation has been performed in the framework of geometrical optics. It is shown that despite one can assign a quasi focus, at half the radius, to a spherical mirror, the light concentration occurs as well on an extended line region which starts at half-radius on the optical axis. In contrast to a paraboloidal concentrator, a spherical mirror can concentrate the radiation parallel to its optical axis both in a point-focus and in a line-focus manner. The envelope of the reflected rays is also obtained. It is shown that the flux distribution has an axial symmetry. The radial dependence of the flux on a flat circular receiver is obtained. The flux longitudinal dependence is shown to exhibit three distinctive regions in the interval [0, R] (R is mirror radius). We obtain the radiational (optical) concentration ratio characteristics and find the optimal location of the flat receiver of a given size at which the concentration ratio is maximised. In contrast to a parabolic mirror, it is shown that this location depends on the receiver size. Our findings offers that in spherical mirrors one can alternatively use a line receiver and gains a considerable thermal energy harvest. Our results are supported by Monte Carlo ray tracing performed by Zemax optical software. Experimental validation has been performed in lab with a silver-coated lens as the spherical mirror.


Galactorrhea After Nipple-Sparing Mastectomy: Case Report, Review of the Literature, and Algorithmic Approach to Management.
Nipple discharge is a rare but possible occurrence after nipple-sparing mastectomy (NSM). This study presents the first case of galactorrhea in a female patient after NSM. Although milky discharge due to physiologic lactation related to pregnancy is more common, galactorrhea is still possible and should be worked up appropriately to ensure that all breast tissue has been removed and that there are no other more worrisome causes.


Crystal structure of vascular endothelial growth factor-B in complex with a neutralising antibody Fab fragment.
Vascular endothelial growth factor (VEGF) B effects blood vessel formation by binding to VEGF receptor 1. To study the specifics of the biological profile of VEGF-B in both physiological and pathological angiogenesis, a neutralising anti-VEGF-B antibody (2H10) that functions by inhibiting the binding of VEGF-B to VEGF receptor 1 was developed. Here, we present the structural features of the 'highly ordered' interaction of the Fab fragment of this antibody (Fab-2H10) with VEGF-B. Two molecules of Fab-2H10 bind to symmetrical binding sites located at each pole of the VEGF-B homodimer, giving a unique U-shaped topology to the complex that has not been previously observed in the VEGF family. VEGF-B residues essential for binding to the antibody are contributed by both monomers of the cytokine. Our detailed analysis reveals that the neutralising effect of the antibody occurs by virtue of the steric hindrance of the receptor-binding interface. These findings suggest that functional complementarity between VEGF-B and 2H10 can be harnessed both in analysing the therapeutic potential of VEGF-B and as an antagonist of receptor activation.


Polychromatic corneal and conjunctival crystals secondary to clofazimine therapy in a leper.
A 67-year-old man had a diagnosis of dapsone-resistant lepromatous leprosy. He received clofazimine (Lamprene) at a dosage of 100 mg twice daily. After 3 years of therapy, results of slit-lamp examination disclosed myriad polychromatic crystals diffusely involving the cornea and perilimbal conjunctiva of both eyes. Thick sections (1 micron) from a conjunctival biopsy showed numerous rectangular-to-rhomboidal crystals within stromal fibroblasts and macrophages. By electron microscopy, these cells contained elongated, membrane-bound, cleft-like spaces that corresponded to the sites where crystals had been present previously. Additionally, complex lipid inclusions were observed in mesenchymal cells as well as in endothelial cells and pericytes of blood vessels. The ocular side effects of clofazimine therapy are reviewed. Clofazimine-induced keratopathy should be included in the differential diagnosis of patients with polychromatic crystalline deposits in the corneas. To the best of the authors' knowledge, this complication of clofazimine therapy has not been described previously.


Acclimation to extremely high ammonia levels in continuous biomethanation process and the associated microbial community dynamics.
Acclimatized anaerobic communities to high ammonia levels can offer a solution to the ammonia toxicity problem in biogas reactors. In the current study, a stepwise acclimation strategy up to 10g NH4+-N L-1, was performed in mesophilic (37±1°C) continuously stirred tank reactors. The reactors were co-digesting (20/80 based on volatile solid) cattle slurry and microalgae, a protein-rich, 3rd generation biomass. Throughout the acclimation period, methane production was stable with more than 95% of the uninhibited yield. Next generation 16S rRNA gene sequencing revealed a dramatic microbiome change throughout the ammonia acclimation process. Clostridium ultunense, a syntrophic acetate oxidizing bacteria, increased significantly alongside with hydrogenotrophic methanogen Methanoculleus spp., indicating strong hydrogenotrophic methanogenic activity at extreme ammonia levels (>7g NH4+-N L-1). Overall, this study demonstrated for the first time that acclimation of methanogenic communities to extreme ammonia levels in continuous AD process is possible, by developing a specialised acclimation AD microbiome.


AIDS-related Kaposi's Sarcoma: evaluation of potential new prognostic factors and assessment of the AIDS Clinical Trial Group Staging System in the Haart Era--the Italian Cooperative Group on AIDS and Tumors and the Italian Cohort of Patients Naive From Antiretrovirals.
To assess potential new prognostic factors and to validate the AIDS Clinical Trials Group (ACTG) for AIDS-related Kaposi's sarcoma (AIDS-KS) staging system in the highly active antiretroviral therapy (HAART) era. We collected epidemiologic, clinical, staging, and survival data from 211 patients with AIDS-KS enrolled in two prospective Italian human immunodeficiency virus (HIV) cohort studies. We included in the analysis all patients with the diagnosis of KS made from January 1996, the time at which HAART became available in Italy. In the univariate analysis, survival was not influenced by sex, age, level of HIV viremia at KS diagnosis, HAART at KS diagnosis (HAART-naïve v HAART-experienced), or type of HAART combination. Regarding ACTG classification, the 3-year survival rate was 85% for T0 patients and 69% for T1 patients (P =.007), 83% for S0 patients and 63% for S1 patients (P =.003), and 83% for I0 patients and 71% for I1 patients (P =.06). In the multivariate analysis, only the combination of poor tumor stage (T1) and poor systemic disease (S1) risk identified patients with unfavorable prognosis. The 3-year survival rate of patients with T1S1 was 53%, which was significantly lower compared with the 3-year survival rates of patients with T0S0, T1S0, and T0S1, which were 88%, 80%, and 81%, respectively (P =.0001). In the era of HAART, a refinement of the original ACTG staging system is needed. CD4 level does not seem to provide prognostic information. Two different risk categories are identified: a good risk (T0S0, T1S0, T0S1) and a poor risk (T1S1).


Efficacy of several additives to modulate the phase behavior of biomedical polymers: A comprehensive and comparative outlook.
Several new classes of polymeric materials are being introduced with unique properties. Thermoresponsive polymers (TRPs) are one of the most fascinating and emerging class of biomaterials in biomedical research. The design of TRPs with good response to temperature and its ability to exhibit coil to globular transition behavior near to physiological temperature made them more promising materials in the field of biomaterials and biomedicines. Instead of numerous studies on TRPs, the mechanistic interplay among several additives and TRPs is still not understood clearly and completely. The lack of complete understanding of biomolecular interactions of various additives with TRPs is limiting their applications in interdisciplinary science as well as pharmaceutical industry. There is a great need to provide a collective and comprehensive information of various additives and their behavior on widely accepted biopolymers, TRPs such as poly(N-isopropylacrylamide) (PNIPAM), poly(vinyl methyl ether) (PVME), poly(N-vinylcaprolactum) (PVCL) and poly(ethylene glycol)-poly(propylene glycol)-poly(ethylene glycol) (PEG-PPG-PEG) in aqueous solution. Obviously, as the literature on the influence of various additives on TRPs is very vast, therefore we focus our review only on these four selected TRPs. Additives such as polyols, methylamines, surfactants and denaturants basically made the significant changes in water structure associated to polymer via their entropy variation which is the direct influence of their directly or indirectly binding abilities. Eventually, this review addresses a brief overview of the most recent literature of applications based phase behavior of four selected TRPs in response to external stimuli. The work enhances the knowledge for use of TRPs in the advanced development of drug delivery system and in many more pharmaceutical applications. These kinds of studies provide powerful impact in exploring the utility range of polymeric materials in various field of science.


Biocontrol of a perennial legume, Sesbania punicea, using a florivorous weevil, Trichapion lativentre: weed population dynamics with a scarcity of seeds.
The establishment in South Africa of a florivorous, apionid weevil, Trichapion lativentre, on Sesbania punicea, a leguminous weed of South American origin, has reduced seed production of the plants by >98%. Surveys of the age structure and density of plants in infestations of S. punicea throughout South Africa have shown that the rate of recruitment of seedlings has drastically declined within a few years in many areas, due to the weevils. However, there has unexpectedly not been a corresponding decline in the density of mature plants in extant infestations of S. punicea. In spite of this, T. lativentre has curtailed the rate of spread of the weed into uninvaded habitats and has impeded reinvasion into areas cleared of infestations by mechanical means or by another complimentary biocontrol agent.


Electrospun nanofibers of a phosphorylated polymer--a bioinspired approach for bone graft applications.
Biomaterials based on bioinspired mineralization are expected to offer osteoconductive and osteoinductive scaffolds for bone regeneration. An important role in the mediation of in vivo biomineralization process is played by highly anionic non-collagenous phosphoproteins (NCP) bound to the collagen matrix. Inspired by this fact, synthetic analogues of the NCPs like polyvinyl phosphonic acid which provide surface nucleation sites have been employed successfully for mineralization of hard tissues. In this study, electrospun nanofibrous scaffolds of partially phosphorylated polyvinyl alcohol (PPVA) are prepared and studied for matrix mineralization and maturation of human pre-osteoblasts like MG63 cells. Partial phosphorylation was found to affect many solution properties of PVA like increase in surface tension, conductivity and semi-crystalline intermolecular hydrogen bond formations narrowing down the electrospinning window for PPVA. In vitro mineralization under SBF treatment was uniform along the length of fibers on PPVA nanofibers. Further, MG63 cells showed increased adherence and proliferation on PPVA nanofibers and the expression of alkaline phosphatase activity and cell-matrix calcium levels were about two times higher than PVA nanofibers. The study established fabrication of electrospun nanofibers of a partially phosphorylated polymer, PVA resulting in improved osteoconduction and expression of early markers of osteoinduction in MG63 cells.


An assessment of the indirect high intensity ultrasonic assisted cleavage of complex proteomes with immobilized trypsin.
The indirect high intensity ultrasonic assisted cleavage of complex proteomes using immobilized trypsin has been assessed. It has been found that the formation of aggregates between the beds supporting the immobilized trypsin is promoted. This affects the efficiency of the digestion process, which can be 100 times lower than the digestion efficiency obtained with in-solution trypsin. Through the use of isotopic peptide labelling with 18-O, it has been quantified that the digestion efficiency over serum samples can be 1.2-100 times higher for the 70% of the peptides when indirect ultrasonication is replaced by direct ultrasonication. Therefore, direct high intensity ultrasonic assisted cleavage of proteins is proposed as an alternative to be combined with immobilized trypsin.


Incidence of ablation-induced esophageal lesions and gastroparesis in patients undergoing ablation index guided high power short duration atrial fibrillation ablation.
Aim of this study was to evaluate the incidence of ablation-induced endoscopically detected esophageal lesions (EDEL) and gastroparesis in patients undergoing high-power short-duration (HPSD) atrial fibrillation (AF) ablation using different target ablation index (AI) values. Consecutive patients undergoing AF ablation were included. Radiofrequency (RF) ablation was performed using HPSD ablation (50 W, target AI of 320 and 350 (group 1) and 380 (group 2) at posterior wall). Postablation endoscopy was performed in all patients. In total, 233 patients (66.8 ± 10 years; 52% male) were included consecutively (n = 137 patients in group 1 and n = 96 patients in group 2). Mean AI values und RF time at posterior wall was significantly higher and longer in group 2 compared to group 1 patients (413 ± 9 vs. 392 ± 19 AI, p < 0.01; 9.0 ± 0.8 s vs. 7.8 ± 0.7 s, p < 0.01). Esophageal endoscopy revealed esophageal lesions or gastroparesis in 43 of 233 patients (18.5%) in the total cohort (13.1% in group 1 and 26.0% in group 2; p = 0.02). Incidence of EDEL was 8.0% and 13.5% in group 1 and group 2, respectively. According to logistic analysis incidence of EDEL and/or gastroparesis was significantly lower in patients with a higher body mass index and higher in group 2 patients compared to group 1 patients. The incidence of EDEL or gastroparesis in patients undergoing HPSD AF ablation was 18.5% in the total cohort. The risk of EDEL and gastroparesis was associated with a higher AI target value of 380 compared to 320 and 350 at posterior wall and was reversely associated with body mass index.


Segregation and rapid turnover of EDEM1 by an autophagy-like mechanism modulates standard ERAD and folding activities.
EDEM1 is a crucial regulator of endoplasmic reticulum (ER)-associated degradation (ERAD) that extracts non-native glycopolypeptides from the calnexin chaperone system. Under normal growth conditions, the intralumenal level of EDEM1 must be low to prevent premature interruption of ongoing folding programs. We report that in unstressed cells, EDEM1 is segregated from the bulk ER into LC3-I-coated vesicles and is rapidly degraded. The rapid turnover of EDEM1 is regulated by a novel mechanism that shows similarities but is clearly distinct from macroautophagy. Cells with defective EDEM1 turnover contain unphysiologically high levels of EDEM1, show enhanced ERAD activity and are characterized by impaired capacity to efficiently complete maturation of model glycopolypeptides. We define as ERAD tuning the mechanisms operating in the mammalian ER at steady state to offer kinetic advantage to folding over disposal of unstructured nascent chains by selective and rapid degradation of ERAD regulators.


Mycology: The overlooked but obvious process of fungal-induced fossil biomineralization.
The ability of fungi to mineralize substrates is a common but underestimated phenomenon. Now, researchers have demonstrated the usefulness of this process in fossilization by documenting the formation of hydroxyapatite nanofibres. This opens new avenues in palaeomycology and palaeontology.


Discovery of a new Hepatozoon species namely Hepatozoon viperoi sp. nov. in nose-horned vipers in Türkiye.
Although Hepatozoon spp. remains the most prevalent intracellular protozoa infecting snakes, it was reported only in a few snake species of the Colubridae family in Türkiye. Moreover, studies on these hemoparasites are not available in venomous nose-horned vipers from Türkiye. In this study, we investigated Hepatozoon spp. in three individual Vipera ammodytes using morphological and molecular methods. Our results were positive for intraerythrocytic Hepatozoon spp. gamonts in all three snakes, exhibiting low parasitemia. The microscopic findings were further confirmed through molecular data. A genus-specific PCR assay targeting the 18S rRNA gene region of Hepatozoon spp., was performed using HemoF/HemoR and Hep300/Hep900 primers. The obtained sequences were concatenated and used in phylogenetic analyses in comparison with different Hepatozoon species. Although our (OP377741) isolate was separated into a different branch, it was clustered with the isolates of H. massardi (KC342526), H. cevapii (KC342525), and H. annulatum (ON262426) from Brazilian snakes. Moreover, gene similarity and pair-wise distance between our isolate and other Hepatozoon species infecting snakes were found to be 89.30-98.63% and 0.009-0.077, respectively. Hence, we reported a new species of Hepatozoon, namely Hepatozoon viperoi sp. nov. infecting V. ammodytes. Since the literature does not indicate the existence of such a Hepatozoon species in V. ammodytes in different countries, our data may contribute to the expanding knowledge of Hepatozoon species in snakes, providing new insights into the biodiversity of the haemogregarine protozoan parasite.


Optimization, physicochemical characterization, and antimicrobial activity of a novel simvastatin nano-niosomal gel against E. coli and S. aureus.
Niosomes, as a kind of drug delivery system, is widely used for the topical delivery of lipophilic drugs. Optimization of niosomes plays an essential role in enhancing their therapeutic efficiencies. This study aims to prepare an optimized niosomal formulation of simvastatin (nSIM), a lipophilic member of statins, through the experiment (Response Surface methodology). Optimized niosomes were characterized in size, polydispersity index (PDI), entrapment efficiency (EE), stability, releasing pattern, and antimicrobial activity. The different molar ratio of surfactant and cholesterol were applied to prepare various formulation of simvastatin loaded niosome. Mean particle size and size distribution were analyzed by dynamic light scattering. Antibacterial activity was determined by MIC and MBC tests against Staphylococcus aureus and Escherichia coli. The release rate of simvastatin from noisome nanoparticles was studied by the Franz diffusion cell method. The release pattern was studied through zero order, first order, Higuchi, Korsmeyer-Peppas, and Hixson-Crowell kinetics models. Optimized niosomes were obtained by span 80, drug to cholesterol ratio of 0.4 with 7 min sonication time. Mean particle size, PDI, zeta potential, and entrapment efficiency (EE%) of optimized nSIM were obtained about 168 nm, 0.34, -32.40, and 96 %, respectively. The niosomes significantly decreased the drug's releasing rate and enhanced antibacterial activity against S. aureus and E. Coli. It was found that the release pattern of drug followed the Higuchi kinetic model which means drug release is by diffusion. Overall, our findings indicated that the prepared simvastatin loaded niosomes showed good stability and biological properties than free drug. Our study suggests that niosomal formulation could be considered as a promising strategy for the delivery of poor water-soluble drugs that enhance antibacterial activity.


A single combination gene therapy treats multiple age-related diseases.
Comorbidity is common as age increases, and currently prescribed treatments often ignore the interconnectedness of the involved age-related diseases. The presence of any one such disease usually increases the risk of having others, and new approaches will be more effective at increasing an individual's health span by taking this systems-level view into account. In this study, we developed gene therapies based on 3 longevity associated genes (fibroblast growth factor 21 [FGF21], αKlotho, soluble form of mouse transforming growth factor-β receptor 2 [sTGFβR2]) delivered using adeno-associated viruses and explored their ability to mitigate 4 age-related diseases: obesity, type II diabetes, heart failure, and renal failure. Individually and combinatorially, we applied these therapies to disease-specific mouse models and found that this set of diverse pathologies could be effectively treated and in some cases, even reversed with a single dose. We observed a 58% increase in heart function in ascending aortic constriction ensuing heart failure, a 38% reduction in α-smooth muscle actin (αSMA) expression, and a 75% reduction in renal medullary atrophy in mice subjected to unilateral ureteral obstruction and a complete reversal of obesity and diabetes phenotypes in mice fed a constant high-fat diet. Crucially, we discovered that a single formulation combining 2 separate therapies into 1 was able to treat all 4 diseases. These results emphasize the promise of gene therapy for treating diverse age-related ailments and demonstrate the potential of combination gene therapy that may improve health span and longevity by addressing multiple diseases at once.


Estimation of bone-on-bone contact forces in the tibiofemoral joint during walking.
In this study, the tibiofemoral contact forces were estimated from standard gait analysis data of adult walking. Knee angles, ground reaction forces, and external flexion-extension knee moments together with lines of action and moment arms of the force bearing structures in the knee previously determined were used to obtain bone-on-bone contact forces. The heel strike, the onset of single limb stance and terminal extension before toe-off each corresponded to a significant turning point on the force versus gait cycle curve. The tibiofemoral bone-on-bone peak forces calculated reached an estimated three times bodyweight. The estimated joint loads are clinically relevant and can either be used directly for evaluation of subjects in a gait analysis, or indirectly in studies of the knee joint where models simulating loading conditions are used to investigate various pathologies.


Sphingosine 1-phosphate is a missing link between chronic inflammation and colon cancer.
In this issue of Cancer Cell, Liang and colleagues demonstrated that sphingosine kinase 1, the enzyme that catalyzes formation of the biologically active lipid sphingosine 1-phosphate, drives a malicious amplification loop involving sphingosine 1-phosphate receptor 1 and the NF-κB/IL-6/STAT3 pathway. This appears critical for progression from chronic inflammation to colon cancer.


Identification of sero-reactive Brucella melitensis cytosoluble proteins which discriminate between antibodies elicited by infection and Rev.1 vaccination in sheep.
Distinction between Brucella melitensis infected and vaccinated sheep is needed to fully achieve ovine brucellosis eradication in several countries. For this purpose, we probed immunoblots of cytosoluble protein extract (CPE) of the rough (R) B. melitensis strain B115 with sera of Brucella-free, naturally infected, B. melitensis H38 experimentally infected and B. melitensis Rev.1 vaccinated sheep to identify immunogenic Brucella cytosoluble proteins which may lead to the development of more useful diagnostic tests and which may eventually differentiate vaccinated sheep from infected sheep. Brucella-free sheep sera showed IgM antibody reactivity to protein bands between 19 and 92 kDa. The use of conjugate specific for sheep IgG avoided non specific reactivity to all these bands except to the 39 and 50 kDa bands which were still detected in some Brucella-free sheep sera. In sera of B. melitensis H38 experimentally infected sheep, a specific IgG antibody response was observed against proteins of molecular masses of 19, 24, 28, 32, 39, 50 and 54 kDa. These proteins were also variably detected by IgG of sera from naturally infected sheep. Other proteins of 10, 12, 23, 36, 38, 42, 46, 68, 80 and 92 kDa were also detected by the latter sera. In sera from B. melitensis Rev.1 vaccinated sheep, an IgG antibody response was only observed against proteins with molecular masses of 39 and 50 kDa. These results suggest that the 19, 24, 28, 32 and 54 kDa proteins (the first recognized after experimental infection and that provoked a consistent humoral response during natural infection) could be interesting to develop serological tests for differentiating B. melitensis infection from B. melitensis Rev.1 vaccination.


Advanced and amplified BOLD fluctuations in high-grade gliomas.
Glioma grade along with patient's age and general health are used for treatment planning and prognosis. To characterize and quantify the spontaneous blood oxygen level-dependent (BOLD) fluctuations in gliomas using measures based on T2*-weighted signal time-series and to distinguish between high- and low-grade gliomas. Retrospective. Twenty-one patients with high-grade and 13 patients with low-grade gliomas confirmed on histology were investigated. Dynamic T2*-weighted (multislice single-shot echo-planar-imaging) magnetic resonance imaging (MRI) was performed on a 3T system with an 8-element receive-only head coil to measure the BOLD fluctuations. In addition, a dynamic T1 -weighted (3D fast field echo) dynamic contrast-enhanced (DCE) perfusion scan was performed. Three BOLD measures were determined: the temporal shift (TS), amplitude of low frequency fluctuations (ALFF), and regional homogeneity (ReHo). DCE perfusion-based cerebral blood volume (CBV) and time-to-peak (TTP) maps were concurrently evaluated for comparison. An analysis-of-variance test was first used. When the test appeared significant, post-hoc analysis was performed using analysis-of-covariance with age as covariate. Logistic regression and receiver-operator characteristic curve analysis were also performed. TS was significantly advanced in high-grade gliomas compared to the contralateral cortex (P = 0.01) and low-grade gliomas (P = 0.009). In high-grade gliomas, ALFF and CBV were significantly higher than the contralateral cortex (P = 0.041 and P = 0.008, respectively) and low-grade gliomas (P = 0.036 and P = 0.01, respectively). ReHo and TTP did not show significant differences between high- and low-grade gliomas (P = 0.46 and P = 0.42, respectively). The area-under-curve was above 0.7 only for the TS, ALFF, and CBV measures. Advanced and amplified hemodynamic fluctuations manifest in high-grade gliomas, but not in low-grade gliomas, and can be assessed using BOLD measures. Preliminary results showed that quantification of spontaneous fluctuations has potential for hemodynamic characterization of gliomas and distinguishing between high- and low-grade gliomas. 4 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018;47:1616-1625.


Development of a virus-induced gene-silencing system for functional analysis of the RPS2-dependent resistance signalling pathways in Arabidopsis.
Virus-induced gene silencing (VIGS) offers a rapid and high throughput technique platform for the analysis of gene function in plants. Although routinely used in some Solanaceous species, VIGS system has not been well established in Arabidopsis thaliana (L.) Heynh. We have recently reported some factors that potentially influence tobacco rattle virus (TRV)-mediated VIGS of phytoene desaturase (PDS) and actin gene expression in Arabidopsis. In this study, we have further established that the Agrobacterium strain used for agro-inoculation significantly affects the VIGS efficiency. Strain GV3101 was highly effective; C58C1 and LBA4404 were invalid, while EHA105 was plant growth stage-dependent for TRV-induced gene silencing. Furthermore, the VIGS procedure optimised for the PDS gene was applied for the functional analysis of the disease resistance gene RPS2-mediated resistance pathway. Silencing of RPS2 led to loss of resistance to the otherwise avirulence strain of Pseudomonas syringae pv. tomato DC3000 carrying the avirulence gene AvrRpt2. Silencing of RIN4, a RPS2 repressor gene, gave rise to conversion of compatible interaction to incompatible. Silencing of NDR1, RAR1 and HSP90, known to be required for the RPS2-mediated resistance, resulted in loss of the resistance, while silencing of EDS1 and SGT1b, which are not required for the RPS2-mediated resistance, caused no change of the resistance. These results indicate that the optimised procedure for the TRV-based VIGS is a potentially powerful tool for dissecting the signal transduction pathways of disease resistance in Arabidopsis.


Combined modality therapy for laryngeal cancer with superselective intra-arterial cisplatin infusion and concomitant radiotherapy.
Concomitant radiotherapy and superselective arterial infusion of cisplatin for laryngeal cancer has shown excellent therapeutic outcomes. It is expected to be a reasonable treatment option for laryngeal cancer, especially in locally advanced cases.


Environmental lighting alters the infection process in an animal model of AIDS.
In this study, we examined the effects of altered environmental lighting on the infection process of a murine leukemia virus, E-55(+), which induces a thymic lymphoma/leukemia in 100% of BALB.K mice inoculated as adults. One to two weeks after inoculation, high levels of proviral DNA are usually found. This is followed by an asymptomatic period of many weeks during which proviral DNA becomes essentially undetectable. Leukemia develops approximately 28 weeks postinoculation. In this experiment, one group of mice was exposed a consistent 10L: 14D cycle while a second was maintained in constant light (LL). A third group was exposed to a rotating cycle characterized by phase shifting a 10L: 14D cycle every three 24-h days (rLD). All cycles began 2 weeks prior to inoculation and were maintained thereafter. Animals were sacrificed at 1, 5, 10, and 15 weeks, and hematopoietic tissue was examined for proviral DNA content. At 1 week, LL- and rLD-exposed animals showed considerably less proviral DNA in bone marrow and spleen compared with controls. At 15 weeks, thymuses from controls were showing signs of infection whereas tissue from LL and rLD mice remained at background levels. We conclude that environmental lighting does alter the infective pattern displayed by this retrovirus, although whether this effect is mediated by changes in the target stem cells or through immunoenhancement has not yet been determined.


Water-Soluble O-, S- and Se-Functionalized Cyclic Acetyl-triaza-phosphines. Synthesis, Characterization and Application in Catalytic Azide-alkyne Cycloaddition.
The 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (DAPTA) derivatives, viz. the already reported 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane 5-oxide (DAPTA=O, 1), the novel 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane-5-sulfide (DAPTA=S, 2), and 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane-5-selenide (DAPTA=Se, 3), have been synthesized under mild conditions. They are soluble in water and most common organic solvents and have been characterized using 1H and 31P NMR spectroscopy and, for 2 and 3, also by single crystal X-ray diffraction. The effect of O, S, or Se at the phosphorus atom on the structural features of the compounds has been investigated, also through the analyses of Hirshfeld surfaces. The presence of 1-3 enhances the activity of copper for the catalytic azide-alkyne cycloaddition reaction in an aqueous medium. The combination of cheaply available copper (II) acetate and compound 1 has been used as a catalyst for the one-pot and 1,4-regioselective procedure to obtain 1,2,3-triazoles with high yields and according to 'click rules'.


Assessment of titrimetric and photometric methods for the determination of chymotrypsin catalytic activity in stool.
In this report a method for the spectrophotometric measurement of stool chymotrypsin (CT) is presented and compared to the more commonly used titrimetric method. Homogenisation of specimen and dissolution of CT is examined in detail. The advantages of the photometric method lie in the small size of sample required, and its easy adaptation to manual or automated analysis with a CT-specific amide substrate.


Thumb and first webspace reconstruction in nonsyndromic congenital mitten hand with symbrachydactyly.
Nonsyndromic congenital mitten hand with thumb and index finger syndactyly is rare. Reconstruction of this condition is challenging, requiring repositioning of the thumb and creation of a wide and deep first webspace. The aim of this paper is to describe the characteristics of patients with this condition and also to describe our surgical technique. We describe our technique in 16 consecutive children utilizing complete mobilization of the first metacarpal and thumb as an island flap on the neurovascular bundle, with a rotational osteotomy to reposition the thumb in pronation. In addition, a dorsal M flap was used to reconstruct the first webspace. Patients in this series also had varying degrees of symbrachydactyly with hypoplastic or aplastic phalanges of the central digits. There were 9 male and 7 female patients, with a mean age of 24.4 ± 22.4 months at the time of surgery. Mean follow-up was 19.1 ± 18.3 months. All reconstructions healed well. The mean thumb web distance in the affected hands was 4.2 cm (range 3.5 to 5). All reconstructed thumbs had a good opposition. Two children initially had mild hypertrophic scarring, which resolved with pressure gloves. No other complications were observed. One-stage reconstruction of the thumb and first webspace can be effectively achieved with our technique of complete mobilization of the thumb unit, rotational osteotomy, and a dorsal interdigitating M flap.


Potential for Treatment of Neurodegenerative Diseases with Natural Products or Synthetic Compounds that Stabilize Microtubules.
No effective therapeutics to treat neurodegenerative diseases exist, despite significant attempts to find drugs that can reduce or rescue the debilitating symptoms of tauopathies such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis, or Pick's disease. A number of in vitro and in vivo models exist for studying neurodegenerative diseases, including cell models employing induced-pluripotent stem cells, cerebral organoids, and animal models of disease. Recent research has focused on microtubulestabilizing agents, either natural products or synthetic compounds that can prevent the axonal destruction caused by tau protein pathologies. Although promising results have come from animal model studies using brainpenetrant natural product microtubule-stabilizing agents, such as paclitaxel analogs that can access the brain, epothilones B and D, and other synthetic compounds such as davunetide or the triazolopyrimidines, early clinical trials in humans have been disappointing. This review aims to summarize the research that has been carried out in this area and discuss the potential for the future development of an effective microtubule stabilizing drug to treat neurodegenerative disease.


Health and problem behavior among people with intellectual disabilities.
Good health significantly improves a person's quality of life. However, people with intellectual disabilities disproportionately have more health problems than the general population. Further complicating the matter is that people with more severe disabilities often cannot verbalize health complications they are experiencing, which leads to health problems being undiagnosed and untreated. It is plausible these conditions can interact with reinforcement contingencies to maintain problem behavior because of the increased incidence of health problems among people with intellectual disabilities. This paper reviews common health problems influencing problem behavior and reinforcement processes. A clear implication of this review is the need for comprehensive functional assessments of problem behavior involving behavior analysts and health professionals.


[Spina ventosa, a historic disease].
We report a case of tuberculous dactylitis--spina ventosa--in a 5 year-old girl from a French upper class family. Being today an unusual affection, the diagnosis of spina ventosa can be missed. Symptoms and means of diagnosis are reviewed.


Synthesis and Characterization of Dibenzo[a,f]pentalene: Harmonization of the Antiaromatic and Singlet Biradical Character.
Mesityl derivatives of the unknown dibenzopentalene isomer dibenzo[a,f]pentalene were synthesized. The molecular geometry and physical properties of dibenzo[a,f]pentalene were investigated. Dibenzo[a,f]pentalene combines a large antiaromatic and appreciable singlet open-shell character, properties not shared by well-known isomer dibenzo[a,e]pentalene.


Prediction of G4 formation in live cells with epigenetic data: a deep learning approach.
G-quadruplexes (G4s) are secondary structures abundant in DNA that may play regulatory roles in cells. Despite the ubiquity of the putative G-quadruplex-forming sequences (PQS) in the human genome, only a small fraction forms G4 structures in cells. Folded G4, histone methylation and chromatin accessibility are all parts of the complex cis regulatory landscape. We propose an approach for prediction of G4 formation in cells that incorporates epigenetic and chromatin accessibility data. The novel approach termed epiG4NN efficiently predicts cell-specific G4 formation in live cells based on a local epigenomic snapshot. Our results confirm the close relationship between H3K4me3 histone methylation, chromatin accessibility and G4 structure formation. Trained on A549 cell data, epiG4NN was then able to predict G4 formation in HEK293T and K562 cell lines. We observe the dependency of model performance with different epigenetic features on the underlying experimental condition of G4 detection. We expect that this approach will contribute to the systematic understanding of correlations between structural and epigenomic feature landscape.


Identification of evodiamine as a suppressor of prostate cancer progression by reducing AR transcriptional activity via targeting Src.
Evodiamine (EVO) is a bioactive alkaloid that exerts antitumor activity in various cancers, including prostate cancer (PCa). In this paper, we further investigated the molecular mechanisms underlying the anti-PCa effect of evodiamine. In the present study, cell proliferation, colony formation, migration, and invasion were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, and transwell assays, respectively. Animal studies were used to evaluate the effect of evodiamine on the tumorigenicity of LNCaP cells in vivo. The expression levels of steroid receptor coactivator (Src), androgene receptor (AR), and prostate-specific antigen (PSA) were detected by western blot, quantitative real-time PCR (qRT-PCR) or ELISA assay. Association between Src and AR was examined by Co-Immunoprecipitation (CoIP). The impact of evodiamine on AR-mediated transcriptional activity was confirmed by dual-luciferase reporter assay. The results showed that evodiamine reduced LNCaP and 22Rv1 cell proliferation, colony formation, migration, and invasion induced by dihydrotestosterone (DHT) in vitro, as well as diminished tumor growth in vivo. Mechanistically, evodiamine directly targeted Src and reduced DHT-induced Src activation. Moreover, the restoration of Src activation abolished evodiamine-mediated suppression of proliferation, migration, and invasion of DHT-treated LNCaP and 22Rv1 cells. Furthermore, evodiamine inhibited DHT-induced AR transcriptional activity through targeting Src. As a conclusion, our findings demonstrate the antitumor property of evodiamine in PCa by blocking AR transcriptional activity through targeting Src and provide a rationale for developing evodiamine as a promising antitumor agent against PCa.


Phase stability and the effect of lattice distortions on electronic properties and half-metallic ferromagnetism of Co2FeAl Heusler alloy: an ab initio study.
Density functional theory calculations within the generalized gradient approximation are employed to study the ground state of Co2FeAl. Various magnetic configurations are considered to find out its most stable phase. The ferromagnetic ground state of the Co2FeAl is energetically observed with an optimized lattice constant of 5.70 Å. After that, the system was subjected under uniform and non-uniform strains, to see their effects on spin polarization (P) and half-metallicity. The effect of spin-orbit coupling is considered in the present study. Half-metallicity (and 100% P) is retained only under uniform strains started from 0 to +4%, and dropped rapidly from 90% to 16% for the negative strains started from -1% to -6%. We find that the present system is much sensitive under tetragonal distortions as half-metallicity (and 100% P) is preserved only for the cubic case. The main reason for the loss of half-metallicity is due to the shift of the bands with respect to the Fermi level (E F). We also discuss the influence of these results on spintronics devices.


Computational approach for identification of Anopheles gambiae miRNA involved in modulation of host immune response.
MicroRNAs (miRNAs) are small, noncoding RNAs that play key roles in regulating gene expression in animals, plants, and viruses, which involves in biological processes including development, cancer, immunity, and host-microorganism interactions. In this present study, we have used the computational approach to identify potent miRNAs involved in Anopheles gambiae immune response. Analysis of 217,261 A. gambiae ESTs and further study of RNA folding revealed six new miRNAs. The minimum free energy of the predicted miRNAs ranged from -27.2 to -62.63 kcal/mol with an average of -49.38 kcal/mol. While its A + U % ranges from 50 to 65 % with an average value of 57.37 %. Phylogenetic analysis of the predicted miRNAs revealed that aga-miR-277 was evolutionary highly conserved with more similarity with other mosquito species. Observing further the target identification of the predicted miRNA, it was noticed that the aga-miR-2304 and aga-miR-2390 are involved in modulation of immune response by targeting the gene encoding suppressin and protein prophenoloxidase. Further detailed studies of these miRNAs will help in revealing its function in modulation of A. gambiae immune response with respect to its parasite.


Condyloma acuminatum and condyloma-like lesions of the oral cavity: a study of 11 cases with an intraductal component.
We studied the clinicopathological features of 11 condyloma and condyloma-like lesions of the oral cavity with an unusual mixed pattern of exophytic and intraductal growth. The latter manifest as involvement of minor salivary gland ducts by the proliferative squamous lesions. This pattern of ductal involvement has not been previously described in oral condyloma. The clinical history was available for nine patients ranging in age from 17 to 73 years. Two were female and seven male. The buccal mucosa (five cases) was the most common site of occurrence, followed by the floor of mouth (two cases), lingual frenum (two cases), and hard palate (one case). All lesions exhibited exophytic and intraductal growth. The latter manifested itself as extension of the lesions into the excretory ducts of minor salivary glands. Underlying minor salivary glands, present in many of the excisional biopsy specimens, typically showed changes of obstructive atrophy. The exophytic components of all cases exhibited some degree of parakeratosis, and cryptic invaginations of parakeratin were typically present. Koilocytes were present in seven lesions and were equivocal in four. Mucous cells were present in the intraductal component of all cases and the intraductal component was never keratinized, but often papillary. A mild stromal-based, lymphocytic host response was present in three. A variably prominent neutrophilic infiltrate was present in the exophytic component of eight. Dysplasia was not present in any case. Five of 11 cases were positive with anti-human papillomavirus (HPV) and two of 11 cases were positive for in-situ hybridization probes directed against HPV 6/11. All cases were negative for HPV 16/18 and 13/33/35. Oral condyloma acuminatum may involve the excretory ducts of minor salivary glands. The diagnosis of oral condyloma acuminatum is difficult, as these lesions share considerable histological overlap with squamous papilloma. Finally, the relationship between these two lesions is incompletely understood.


Mesenchymal Stem Cell-Derived Extracellular Vesicles in the Management of COVID19-Associated Lung Injury: A Review on Publications, Clinical Trials and Patent Landscape.
The unprecedented COVID-19 pandemic situation forced the scientific community to explore all the possibilities from various fields, and so far we have seen a lot of surprises, eureka moments and disappointments. One of the approaches from the cellular therapists was exploiting the immunomodulatory and regenerative potential of mesenchymal stromal cells (MSCs), more so of MSC-derived extracellular vesicles (EVs)-particularly exosomes, in order to alleviate the cytokine storm and regenerate the damaged lung tissues. Unlike MSCs, the EVs are easier to store, deliver, and are previously shown to be as effective as MSCs, yet less immunogenic. These features attracted the attention of many and thus led to a tremendous increase in publications, clinical trials and patent applications. This review presents the current landscape of the field and highlights some interesting findings on MSC-derived EVs in the context of COVID-19, including in silico, in vitro, in vivo and case reports. The data strongly suggests the potential of MSC-derived EVs as a therapeutic regime for the management of acute lung injury and associated complications in COVID-19 and beyond.


Needle electromyography: basic concepts and patterns of abnormalities.
Needle electromyography (EMG) records electrical signals generated from muscle fibers and interprets the signals to characterize underlying pathologic changes that are occurring in motor units within muscles. Different types of spontaneously firing waveforms and motor unit potential changes occur with different neuromuscular disorders. The performance of reliable EMG studies depends on the technical skills of the physician in inserting, moving, recording with a needle electrode, and analyzing electric signals recorded from muscle. This article reviews the technique of needle EMG and recognition and interpretation of various EMG waveforms. The author presents several demonstrative videos at www.neurologic.theclinics.com.


Multiple pulmonary arteriovenous fistulas in childhood.
Three cases of multiple pulmonary arteriovenous fistulas are described in children who presented at five months, two and nine years of age. Mass spectrometry was used to measure pulmonary blood flow and, in two cases, the intrapulmonary right-to-left shunt. The shunt fractions were 51% and 35%, with no significant change on breathing 100% oxygen. In one case, effective pulmonary blood flow was measured during cardiac catheterisation by the argon-freon rebreathing method and agreed closely with that found from the Fick, principle with measured oxygen consumption. Treatment consisted of surgical ligation of a lower lobe pulmonary artery in the youngest child, balloon embolisation in the second, and initial surgical oversewing of a single large fistula followed twenty months later by steel coil embolisation in the third. The last and oldest child is well and no longer cyanosed. The first two children died seven months after treatment with evidence of progression of their pulmonary arteriovenous fistulas. The first of these, who also had an atrial septal defect and discordant thoraco-abdominal arrangement, died of heart failure. Autopsies on both children confirmed extensive involvement of both lungs by arteriovenous fistulas. In one case who had a diffuse, telangiectatic form of pulmonary arteriovenous fistulas, microscopic serial reconstructions of lung tissue revealed that anastomoses occurred between arteries accompanying terminal bronchioles and intra-acinar arteries and adjacent veins. Occlusion of the pulmonary arteries supplying the fistulas led to extensive fibrosis within them, and was associated with enlargement of the corresponding bronchial arterial circulation.


Effects of haemodynamically atrio-ventricular optimized His bundle pacing on heart failure symptoms and exercise capacity: the His Optimized Pacing Evaluated for Heart Failure (HOPE-HF) randomized, double-blind, cross-over trial.
Excessive prolongation of PR interval impairs coupling of atrio-ventricular (AV) contraction, which reduces left ventricular pre-load and stroke volume, and worsens symptoms. His bundle pacing allows AV delay shortening while maintaining normal ventricular activation. HOPE-HF evaluated whether AV optimized His pacing is preferable to no-pacing, in a double-blind cross-over fashion, in patients with heart failure, left ventricular ejection fraction (LVEF) ≤40%, PR interval ≥200 ms and either QRS ≤140 ms or right bundle branch block. Patients had atrial and His bundle leads implanted (and an implantable cardioverter-defibrillator lead if clinically indicated) and were randomized to 6 months of pacing and 6 months of no-pacing utilizing a cross-over design. The primary outcome was peak oxygen uptake during symptom-limited exercise. Quality of life, LVEF and patients' holistic symptomatic preference between arms were secondary outcomes. Overall, 167 patients were randomized: 90% men, 69 ± 10 years, QRS duration 124 ± 26 ms, PR interval 249 ± 59 ms, LVEF 33 ± 9%. Neither peak oxygen uptake (+0.25 ml/kg/min, 95% confidence interval [CI] -0.23 to +0.73, p = 0.3) nor LVEF (+0.5%, 95% CI -0.7 to 1.6, p = 0.4) changed with pacing but Minnesota Living with Heart Failure quality of life improved significantly (-3.7, 95% CI -7.1 to -0.3, p = 0.03). Seventy-six percent of patients preferred His bundle pacing-on and 24% pacing-off (p < 0.0001). His bundle pacing did not increase peak oxygen uptake but, under double-blind conditions, significantly improved quality of life and was symptomatically preferred by the clear majority of patients. Ventricular pacing delivered via the His bundle did not adversely impact ventricular function during the 6 months.


Photocatalysis of S-metolachlor in aqueous suspension of magnetic cerium-doped mTiO2 core-shell under simulated solar light.
Magnetic cerium-doped mesoporous titanium dioxide was synthesized by combining sol-gel method and calcination using tetrabutanate and ammonium cerium nitrate as precursors and Pluronic P123 as a template coating on iron oxide covered with carbon in ethanol. The magnetic Ce-doped catalyst showed only anatase structure with a slight increase in lattice parameters compared to the undoped catalyst. The Ce LIII-edge X-ray absorption near-edge spectroscopy (XANES) spectra showed Ce3+, and the cerium substitution doping into titanium dioxide was proposed. Degradation of S-metolachlor in aqueous magnetic photocatalyst suspension followed (pseudo) first-order kinetics in the presence of 0.5 g L-1 of γ-Fe2O3@firstname.lastname@example.com mol% Ce-mTiO2 with a half-life of 55.18 ± 1.63 min. Fifteen degradation products were identified, and their transformation routes of the photocatalytic degradation were then proposed. Complementary toxicity assessment of the treated S-metolachlor solution was undertaken with Environment Canada's algal microplate assay measuring growth inhibition (72-h IC50) in the freshwater chlorophyte Pseudokirchneriella subcapitata. This test method revealed a significant decrease in toxicity (1.7-fold reduction after 180 min of irradiation treatment), thereby confirming that the by-products formed following photocatalysis would be less harmful from an environmental point of view. Photocatalytic degradation of S-metolachlor thus appears to hold promise as a cost-effective treatment technology to diminish the presence of this herbicide in aquatic systems.


Development mutants of Streptomyces coeruleorubidus, a producer of anthracyclines: isolation and preliminary characterization.
The wild strain Streptomyces coeruleorubidus JA 10092 was found to segregate into two spontaneous morphological variants (spo-1 and bld-1) with a different ability to form aerial mycelium in media with glucose as the main carbon source. Six new types of developmental mutants were obtained from the bald variant bld-1 after treatment with mutagens (UV light, gamma radiation, nitrous acid) and after natural selection. Formation of the aerial mycelium was fully suppressed in the bld-2 type growing on media both with glucose and with starch. The other types were bald only on starch media, forming the aerial mycelium on media with glucose; types spo-2, spo-3, spo-4 and spo-5 differed in size, shape and surface structure of spores, the type whi formed asporogenous aerial hyphae.


Neural retinal contribution to the slow negative potential of the canine electroretinogram.
To establish the normal waveform of the electrical responses from canine eyes, electroretinograms and the light peak were recorded in hybrid and beagle dogs under general anesthesia and artificial ventilation. The neural retinal and retinal pigment epithelial components were pharmacologically isolated by intravitreal glutamate injection and systemic sodium iodate administration, respectively. The a- and b-waves elicited by either flash or rectangular stimuli, the oscillatory potentials elicited by flash stimuli and the light peak elicited either by a single maintained illumination or by repetitive stimuli were almost identical with those of other vertebrates thus far studied. In contrast, in response to rectangular (several-second duration) stimuli, the c-wave was usually absent and was replaced by a slow cornea-negative potential that had a time course similar to that of the c-wave in other species. This slow negative potential was elicited at such low stimulus intensities that the a-wave was absent, was deepened by an intravenous administration of sodium iodate, was not affected by an intravitreal injection of sodium glutamate and was shallowed during the light peak. These results suggest that the slow negative potential that replaces the c-wave consists of large slow PIII, small retinal pigment epithelial c-wave and negligible contribution from the late photoreceptor potential and the dc component of the PII.


[Hyperplasia of chromaffin cells in adrenocortical hyperplasia and adenoma].
To study whether there is chromaffin cells hyperplasia in adrenocortical hyperplasia and adenoma. Chromaffin cells with chromogranin A were marked by immunohistochemistry method. In 52 cases of adrenocortical hyperplasia and adenoma 3 were associated with eochromocyte hyperplasia and 5 with micro-pheochromocytoma. Six of the 8 cases were characterized by hypercortiso (or aldostero)-hypercatecholamine clinically. Few cases of adrenocortical hyperplasia and adenoma may be associated with pheochromocytic hyperplasia and micro-pheochromocytoma, and may be characterized by symptoms of hypercortiso (or aldostero)-hypercatecholamine.


Herbimycin A attenuates apoptosis during heat stress in rats.
Expression of heat shock proteins (HSPs) as a heat stress response is associated with acquisition of thermotolerance. Herbimycin A is a tyrosine kinase inhibitor that has been shown to induce HSPs. The present study aims to investigate the effects of herbimycin A on thermotolerance in rats subjected to heat stress exposure. Herbimycin A induced hsp70 to peak levels 12 h post-injection in rats without heat stress. No change in hsp70 levels was observed in the vehicle- and saline-treated rats. In rats exposed to heat stress at 45 degrees C for 25 min, 12 h post-treatment, lower peak temperatures were attained in herbimycin A-treated group as compared to the vehicle- and saline-treated groups. Terminal transferase-mediated d-UTP nick end labeling (TUNEL) showed that a significant decrease in apoptosis of hepatocytes in herbimycin A-treated rats as compared to the vehicle- and saline-treated rats. Caspase-3 activation was also lower in herbimycin A-treated rats, compared to the vehicle- and saline-treated rats. The present study has demonstrated that herbimycin A is effective for development of thermotolerance and therefore protects rats from heat stress.


Central Corneal Thickness in Aphakic Children With Microcornea-Microphthalmia.
To study the central corneal thickness (CCT) in eyes with microcornea and aphakia and without glaucoma, compare it with normal controls, and correlate it with the measured intraocular pressure (IOP). The study was conducted on 62 eyes of 31 aphakic children with microcornea. Controls (20 children) were selected from age-matched children presenting for routine refraction. Detailed anterior-segment and fundus examinations were conducted. The CCT and the axial length were measured. Medical records of the study patients were reviewed for the stability of the ocular parameters over time to exclude glaucoma. The mean±SD age of the study patients and controls were 4.0 (±3.1, 1.0 to 12.0) and 3.1 (±2.7, 0.6 to 12.0) years, respectively. The mean±SD CCT, the corneal diameter, the measured IOP, the cup/disc ratio, and the axial length of the study patients and the controls were 667.01±72.90 μm, 8.9±0.8 mm, 10.9±5.7 mm Hg, 0.1±0.1, 20.35±2.90 mm and 545.22±28.14 μm, 11.7±0.5 mm, 5.3±1.8 mm Hg, 0.1±0.1, and N/A, respectively. The difference between the study eyes and the controls in the CCT and the measured IOP was statistically significant (P<0.05). Aphakic eyes with microcornea have thicker CCTs and greater measured IOPs than normal eyes. Hence, the measurement of CCT is recommended in the assessment of aphakic eyes with microcornea for possible glaucoma. The measured IOP, although a reliable parameter, in isolation does not provide a diagnosis of glaucoma and must be viewed in conjunction with other patient findings, such as the cup/disc ratio, the progression of which over time must be considered for a more solid diagnosis.


Prolonged exposure to lead lowers the threshold of pentylenetetrazole-induced seizures in rats.
The aim of this work was to study the effects of prolonged exposure to lead on the threshold of experimental seizures induced by pentylenetetrazole (PTZ). The 120 Wistar male rats were allocated randomly into four groups; (A) controls, and lead-treatment groups (B, C, and D) that received lead acetate in the drinking water for a period of 30 days at concentrations of 250, 500, and 1,000 ppm, respectively. After exposure, a trial of PTZ-induced seizures was conducted in all groups, and blood contents of lead were determined by atomic absorption spectrophotometry. Blood lead contents increased in a dose-dependent manner. Time elapsed to develop the first myoclonic jerk and the tonic-clonic seizure was less in all lead-exposed groups than in controls. This effect was greater in the groups administered 500 and 1,000 ppm of lead. The required doses of PTZ to induce myoclonic jerks and tonic-clonic seizures were lower in lead-exposed rats than in controls. We found a reduction in the threshold for seizures in rats whose blood contents of lead were similar to those of humans from some areas of urban centers with high levels of air pollution.