Increase in Streptococcus pneumoniae serotype 3 associated parapneumonic pleural effusion/empyema after the introduction of PCV13 in Germany.
Pediatric pneumococcal pneumonia complicated by parapneumonic pleural effusion/empyema (PPE/PE) remains a major concern despite general immunization with pneumococcal conjugate vaccines (PCVs). In a nationwide pediatric hospital surveillance study in Germany we identified 584 children <18 years of age with bacteriologically confirmed PPE/PE from October 2010 to June 2018. Streptococcus pneumoniae was identified by culture and/or PCR of blood samples and/or pleural fluid and serotyped. S. pneumoniae was identified in 256 of 584 (43.8%) children by culture (n = 122) and/or PCR (n = 207). The following pneumococcal serotypes were detected in 114 children: serotype 3 (42.1%), 1 (25.4%), 7F (12.3%), 19A (7.9%), other PCV13 serotypes (4.4%) and non-PCV13 serotypes (7.9%). Between October 2010 and June 2014 serotype 1 (38.1%) and serotype 3 (25.4%) were most prevalent, whereas between July 2014 and June 2018 serotype 3 (62.7%) and non-PCV13 serotypes (15.7%) were dominant. Compared to children with other pneumococcal serotypes, children with serotype 3 associated PPE/PE were younger (median 3.2 years [IQR 2.1-4.3 years] vs. median 5.6 years [IQR 3.8-8.2 years]; p < 0.001) and more frequently admitted to intensive care (43 [89.6%] vs. 48 [73.8%]; p = 0.04). Seventy-six of 114 (66.7%) children with pneumococcal PPE/PE had been vaccinated with pneumococcal vaccines. Thirty-nine of 76 (51.3%) had received a vaccine covering the serotype detected. Thirty of these 39 breakthrough cases were age-appropriately vaccinated with PCV13 and considered vaccine failures, including 26 children with serotype 3, three children with serotype 19A and one child with serotype 1. Following the introduction of PCV13 in general childhood vaccination we observed a strong emergence of serotype 3 associated PPE/PE in the German pediatric population, including a considerable number of younger children with serotype 3 vaccine breakthrough cases and failures. Future PCVs should not only cover newly emerging serotypes, but also include a more effective component against serotype 3.


18F-FDG PET Predicts Hematologic Toxicity in Patients with Locally Advanced Anal Cancer Treated With Chemoradiation.
Hematologic toxicity (HT) during chemoradiation therapy (CRT) for anal cancer can lead to treatment breaks that compromise efficacy. We hypothesized that CRT-induced HT correlates with changes in active bone marrow (ABM) characterized by pre-/post-CRT positron emission tomography (PET)/computed tomography. Data from 36 patients with anal cancer who were treated with 18F-fluorodeoxyglucose PET/computed tomography scans 2 weeks before and 6 to 16 weeks after CRT were analyzed. Complete blood counts with differential within 2 weeks from, weekly during, and 2 week after treatment were obtained. HT was defined as baseline complete blood count change to nadir and posttreatment recovery. Total bone marrow was segmented into 2 subregions: lumbosacral (LS) pelvis (L5 vertebrae, sacrum, and coccyx) and lower pelvis (LP) (ilium, femoral head/neck, and greater and lesser trochanter). PET ABM was characterized as the volume having standard uptake value (SUV) greater than the mean uptake of unirradiated extrapelvic bone marrow. PET variables of pre-/post-CRT and HT predictors were analyzed by linear regression. Average pelvic ABM was significantly reduced from 52% to 41% in pre- to post-CRT PET scans for all patients (P = .0012). Regional analysis indicated significant post-CRT reduction of LS-ABM (P < .0001) and LP-ABM (P = .006). Linear regression analysis identified post-CRT SUVmean, differential ΔSUVmean, and ΔABM as correlating significantly with pre- and posttreatment HT. ΔWBC linearly correlated with ΔABM of LS and LP pelvis (P = .033 and P = .028, respectively). Dosimetrically, ABM was sensitive to higher radiation doses (>50 Gy) in terms of acute hematologic ΔWBC (P = .021) and ΔANC(P = .028). HT increased with increasing volume of ABM receiving 40 Gy. The results also suggest that ABM V40 Gy ≤ 20% to 25% may significantly reduce the risk of HT. HT was significantly associated with ΔABM in patients with anal cancer who were treated with CRT. LS-ABM was a robust surrogate for evaluating CRT-induced HT. Our results suggest implementation of ABM dosimetric constraints, V40 Gy ≤ 20-25%, may significantly reduce HT and lead to decreased treatment delays associated with clinical outcomes.


Outcome and complication comparison for intramedullary nail versus open reduction internal fixation in humeral diaphyseal fractures for 2800 matched patient pairs utilizing the Nationwide Readmissions Database.
Open reduction internal fixation (ORIF) and intramedullary nail fixation (IMN) are the predominant repair methods for operative treatment of humeral diaphyseal fractures; however, the optimal method is not fully elucidated. The purpose of this study was to analyze whether IMN or ORIF humeral diaphyseal surgeries result in a significantly higher prevalence of adverse outcomes and whether these outcomes were age dependent. We hypothesize there is no difference in reoperation rates and complications between IMN and ORIF for humeral diaphyseal fractures. Data collected from 2015 to 2017 from the Nationwide Readmissions Database were evaluated to compare the prevalence of six adverse outcomes: radial nerve palsy, infections, nonunion, malunion, delayed healing, and revisions. Patients treated for a primary humeral diaphyseal fracture with either IMN or ORIF were matched and compared (n = 2,804 pairs). Patients with metastatic cancer were excluded. Following an ORIF procedure, there was a greater odds of undergoing revision surgery (p = 0.03) or developing at least one of the complications of interest (p = 0.03). In the age-stratified analysis, no significant differences were identified in the prevalence of adverse outcomes between the IMN and ORIF cohorts in the 0-19, 20-39, and 40-59 age groups. Patients who were 60 + had 1.89 times the odds of experiencing at least one complication and 2.04 times the odds of undergoing a revision after an ORIF procedure versus an IMN procedure (p = 0.03 for both). IMN and ORIF for humeral diaphyseal fractures are comparable in regard to complications revision rates in patients under the age of 60. Meanwhile, patients 60 + years show a statistically significant increase in the odds of undergoing revision surgery or experiencing complications following an ORIF. Since IMN appears to be more beneficial to older patients, being 60 + years old should be considered when determining fracture repair techniques for patients presenting with primary humeral diaphyseal fractures.


The potential etiologic role of tumor necrosis factor in mediating multiple organ dysfunction in rats following intestinal ischemia-reperfusion injury.
Endogenous inflammatory cytokines may function as mediators in the development of remote organ damage in response to local ischemic insult. This study was designed to (a) explore the potential role of tumor necrosis factor (TNF) formation in the pathogenesis of systemic tissue injury, (b) determine the relationship between induction of TNF and gut-derived endotoxemia and/or bacterial translocation, and (c) evaluate the protective effect of anti-TNF monoclonal antibody (MoAb) for vital organs following intestinal ischemia-reperfusion in rats. Animals were subjected to superior mesenteric artery occlusion (SMAO) for 45 min. Systemic plasma TNF levels increased rapidly after the onset of reperfusion, reaching a peak value 2 h later (P < 0.01). TNF elevation was found to be associated with gut origin endotoxemia, where the maximal TNF levels occurred approximately 2 h after the initial appearance of endotoxin in portal vein. Prophylactic treatment with anti-TNF MoAb markedly blunted the elevation in plasma TNF levels and afforded protection from the development of hypotension, vital organs dysfunction, and metabolic acidosis. Significant improvement in 48-h survival rate was observed by administration of anti-TNF MoAb prior to inducing ischemia (P = 0.007). These findings suggest that intestinal ischemia-reperfusion could result in TNF production, which may play a key role in mediating subsequent septic response and systemic tissue injury. It seems likely that passage of endotoxin and bacteria from the gut can be responsible for the TNF formation


Comparison of the TDx-FLM II and lecithin to sphingomyelin ratio assays in predicting fetal lung maturity.
We evaluated the usefulness of the TDx-FLM II and lecithin to sphingomyelin (L/S) ratio assays in predicting fetal lung maturity. We retrospectively reviewed 218 consecutive paired TDx-FLM II and L/S ratio results. Women who delivered viable infants within 72 hours of amniotic fluid collection (n=109) were included in the analysis of sensitivity and specificity. Concordance between tests was determined for all women tested during the study period, and in the subset of women who delivered viable infants within 72 hours of amniotic fluid collection. There were 9 respiratory distress syndrome (RDS)-affected infants born during the study period. Both the TDx-FLM II and L/S ratios had 100% sensitivity in detecting RDS at their best apparent cut-offs. There was a trend towards increased specificity of the L/S ratio compared with the TDx-FLM II (80% for L/S vs 73% for FLM II). The overall concordance between the TDx-FLM II and L/S ratio was approximately 75%. The TDx-FLM II and L/S ratios are both sensitive tests for RDS; however, there is not good concordance between the two. The results provide new insight into the optimal use, in sequential or reflex cascade testing, of the TDx-FLM II and L/S ratio.


2-Deoxy-D-glucose-induced decrements in operant and reflex pain thresholds.
Acute exposure to many environmental stressors induces significant analgesia. The present study examined whether 2-deoxy-D-glucose (2-DG), an antimetabolic glucose analogue, which induces glucoprivation and peripheral sympatho-adrenal discharge, would also produce analgesia as measured by either an operant liminal escape or a reflex tail-pinch procedure. In the liminal escape paradigm, 9 rats were tested at weekly intervals in 6 randomly selected testing conditions: 30 min pre-test injections of four 2-DG doses (100, 225, 350 and 700 mg/kg, IP) and 180 min pre-test injections of the 2 higher doses. Moderate analgesia occurred at the lower 2-DG doses 30 min after injection, while profound analgesia occurred at the higher doses. After 180 min, only the 700 mg/kg 2-DG dose produced moderate analgesia, which was further enhanced by food deprivation. Rats tested in the tail-pinch paradigm displayed a similar dose-dependent analgesia course. These results demonstrate that 2-DG decreases nociceptive sensitivity, possibly through stress-induced activation of an intrinsic pain-inhibitory system.


[The secretory action of various C-5-alkylsubstituted histamines and N alpha-methyl-histamines on anaesthetized cats with Heidenhain pouches (author's transl)].
In particular, the action of N alpha-methyl-histamine has to be considered since its secretory response is approximately 1.5 times greater than that of histamine and its secretion lasted for a longer period of time. After C-5-alkylsubstitution, both 5-methyl-histamine and N alpha,5-dimethyl-histamine showed secretory action comparable to that of histamine; the agonistic activity, however, decreased with increasing chain length.


Immunohistochemical expression of cancer stem cell related markers CD44 and CD133 in endometrial cancer.
The goal of this study was to detect the presence of cancer stem cell markers CD44 and CD133 in immunohistochemically stained samples of endometrial cancer and correlate their expression with clinicopathological variables to identify the impact of CD44 or CD133 expression on tumor behavior and endometrial carcinogenesis. Marker expression was analyzed in 62 endometrial cancer samples (57 endometrioid carcinoma and 5 carcinosarcoma) and 15 proliferative endometrium samples. We detected CD133 and CD44 expression in 87.09% and 79.03% respectively of the studied endometrial cancers, and the expression was significantly different from the normal group. CD44 expression decreased with myometrial invasive depth and lymph-vascular space invasion (LVSI), and these inverse relationships were significant (p=0.034, p=0.019, respectively). CD133 was more expressed by early stage tumor (FIGO I-II) compared with those having FIGO III to IV stage disease (p=0.021). The most notable conclusion of the present study is that CD44 and CD133 might participate in early-stage endometrial cancer carcinogenesis, and their overexpression may facilitate the early diagnosis of endometrial cancers. Analysis of our results supports the hypothesis that CD44 expression tends to decrease as the disease becomes invasive and progressive. So, we concluded that CD44 down-regulation might warn of a more aggressive course and may have a link with poorly prognosis carcinosarcomas. Further examination of the expression and function of CD44 and CD133 with a greater number of carcinosarcomas is warranted.


Selective labelling of diazepam-insensitive GABAA receptors in vivo using [3H]Ro 15-4513.
Classical benzodiazepines (BZs), such as diazepam, bind to GABAA receptors containing alpha1, alpha2, alpha3 or alpha5 subunits that are therefore described as diazepam-sensitive (DS) receptors. However, the corresponding binding site of GABAA receptors containing either an alpha4 or alpha6 subunit do not bind the classical BZs and are therefore diazepam-insensitive (DIS) receptors; a difference attributable to a single amino acid (histidine in alpha1, alpha2, alpha3 and alpha5 subunits and arginine in alpha4 and alpha6). Unlike classical BZs, the imidazobenzodiazepines Ro 15-4513 and bretazenil bind to both DS and DIS populations of GABAA receptors. In the present study, an in vivo assay was developed using lorazepam to fully occupy DS receptors such that [3H]Ro 15-4513 was then only able to bind to DIS receptors. When dosed i.v., [3H]Ro 15-4513 rapidly entered and was cleared from the brain, with approximately 70% of brain radioactivity being membrane-bound. Essentially all membrane binding to DS+DIS receptors could be displaced by unlabelled Ro 15-4513 or bretazenil, with respective ID50 values of 0.35 and 1.2 mg kg(-1). A dose of 30 mg kg(-1) lorazepam was used to block all DS receptors in a [3H]Ro 15-1788 in vivo binding assay. When predosed in a [3H]Ro 15-4513 binding assay, lorazepam blocked [3H]Ro 15-4513 binding to DS receptors, with the remaining binding to DIS receptors accounting for 5 and 23% of the total (DS plus DIS) receptors in the forebrain and cerebellum, respectively. The in vivo binding of [3H]Ro 15-4513 to DIS receptors in the presence of lorazepam was confirmed using alpha1H101R knock-in mice, in which alpha1-containing GABAA receptors are rendered diazepam insensitive by mutation of the histidine that confers diazepam sensitivity to arginine. In these mice, and in the presence of lorazepam, there was an increase of in vivo [3H]Ro 15-4513 binding in the forebrain and cerebellum from 4 and 15% to 36 and 59% of the total (i.e. DS plus DIS) [3H]Ro 15-4513 binding observed in the absence of lorazepam.


Cardiac MRI Evaluation of Myocarditis.
Cardiac MRI (CMR) is the non-invasive test of choice for the assessment of myocarditis. In 2009, the Lake Louise Criteria for the diagnosis of myocarditis using CMR were first released. The decade since that time has vastly improved our understanding of CMR's strengths and limitations. Traditional CMR methods including T2-weighted imaging and late gadolinium enhancement have proven their diagnostic value, but diagnostic performance is dependent on patient presentation. Newer parametric mapping techniques have begun to be more comprehensively studied and may improve diagnostic accuracy of CMR in an expanded set of clinical scenarios. Additionally, the prognostic value of CMR has begun to solidify. These advances culminated in an update to the Lake Louise Criteria at the end of 2018. In this review, we discuss the evolution of the diagnostic criteria for CMR in the assessment of myocarditis. We also discuss the pathophysiologic premises behind the use of specific MRI sequences and an up-to-date summary of their individual utility.


Phosphorus uptake into algal biofilms in a lowland chalk river.
This paper examines the growth and uptake of phosphorus into algal biofilms in the River Kennet, a lowland chalk (Cretaceous-age) stream in southern England. Algal biofilms were grown on artificial plastic substrates (templates) placed (i) on the riverbed and (ii) within the mid-water column. Experiments were set up to examine differences in growth rates of newly colonising biofilms compared with biofilms left to accumulate for periods of up to 6 months. Rates of algal biofilm production were measured by the chlorophyll a concentration that had accumulated per cm2 over the number of days that the biofilm template had been immersed in the river water. An algal biofilm bloom occurred in early spring, prior to peak suspended chlorophyll a concentrations within the water column. Biofilm samples collected in February and March had the highest chlorophyll a and total phosphorus concentrations. The biofilm bloom corresponded with increased solar radiation and declining river flow conditions. Periodic increases in soluble reactive phosphorus concentrations in the overlying river water did not correspond with any significant increase in biofilm production. These results suggest that light, rather than phosphorus is a key factor for biofilm growth in the River Kennet. Higher rates of chlorophyll a development in mid-water column biofilms may be linked to greater light exposure; however, maximum total-P concentrations were similar for both bed and water column biofilms. Newly colonising biofilms exhibited higher chlorophyll a and total-P concentrations than biofilms left to accumulate over longer terms, suggesting that fresh substrate availability promotes high rates of biofilm growth. Both 'condensed and organic' P (stored in biomass) and 'inorganic' (mineral) P fractions within the biofilms were present in varying proportions, although the early spring biofilm bloom resulted in maximum proportions and absolute concentrations of 'condensed and organic' P. Calcite was the only crystalline mineral detected within the biofilms. Ratios of Ca:inorganic P are largely consistent with the presence of CaCO3-P co-precipitates, although one very low value suggested that there may also be additional sources of inorganic P, possibly P adsorbed to clays or organics within the biofilm. However, poor linkages between CaCO3 and inorganic P concentrations suggest that, although the inorganic P fraction within the biofilm may be derived largely from CaCO3-P co-precipitation, the subsequent processes controlling overall CaCO3 and inorganic P concentrations in the biofilm are complex.


Synthetic Approaches to L-Iduronic Acid and L-Idose: Key Building Blocks for the Preparation of Glycosaminoglycan Oligosaccharides.
L-Iduronic acid (IdoA) is an important monosaccharide component of glycosaminoglycans (GAGs) such as heparin, heparan sulfate and dermatan sulfate. GAGs are complex, highly sulfated polysaccharides that mediate a multitude of physiological and pathological processes via their interactions with a range of diverse proteins. The main challenge in the synthesis of GAG oligosaccharides is the efficient gram-scale preparation of IdoA building blocks since neither IdoA nor L-idose is commercially available or readily accessible from natural sources. In this review, the different synthetic approaches for the preparation of IdoA and its derivatives, including L-idose, are presented and discussed. Derivatives of the latter are often used in GAG synthesis and are elaborated to IdoA via selective oxidation at C-6 after incorporation into a GAG chain. Particular focus will be given to the preparation of IdoA synthons most commonly used for GAG oligosaccharide synthesis, and on the progress made since the last systematic review in this area.


Chemoradiation therapy: localized esophageal, gastric, and pancreatic cancer.
Chemoradiation plays an important role in management of locally advanced gastrointestinal tumors. This article reviews data regarding chemoradiation for tumors of the upper gastrointestinal tract. For esophageal and gastroesophageal junction cancers, chemoradiation is standard of care in the preoperative setting. In gastric cancer, 2 standards have emerged: definitively treating with perioperative chemotherapy alone and using chemoradiation postoperatively. For pancreatic cancer, the benefit of radiation is less well defined. The future of treatment sites lies in trials evaluating new chemotherapy regimens, alternative systemic therapies, and different radiation fractionation schema. Because care of these patients is complex, multimodality team evaluation before treatment is encouraged.


Coordination training in individuals with incomplete spinal cord injury: consideration of motor hierarchical structures.
Clinical commentary. To discuss the method of coordination training to enhance motor skills in persons after spinal cord injury (SCI). From the literature and clinical experience, we learn that basic motor skills like walking are refined and maintained through the millions of repetitions that take place as part of normal development. These coordinated patterns function effectively as a form of training to the system because of the presence of neural pathways that mediate commands between higher and lower levels of the central nervous system (CNS). When these pathways are disrupted as a result of a lesion, the question that arises is whether retraining can be effective. The question is directed at the common practice among rehabilitation professionals to prescribe and carry out tireless repetitions of coordinated motor activities in people with SCI lesions. We discuss this fundamental question from the perspective of understanding differences in maturation and function of higher motor centres and lower motor centres.


A non-invasive genomic diagnostic method for bladder cancer using size-based filtration and microchip electrophoresis.
Bladder cancer (BC) cells spontaneously exfoliated in the urine of patients with BC. Detection of exfoliated tumor cells has clinical significance in cancer therapy because it would enable earlier non-invasive screening, diagnosis, or prognosis of BC. In this research, a method for analyzing genetic abnormalities of BC cells collected from urine samples was developed. Target BC cells were isolated by filtration. To find conditions that achieve high cell recovery, we investigated the effects of filter type, concentration of fixative, and flow rate. Cells captured on the filter membrane were completely retrieved within 15s. Selected genes for genomic analysis, mutated genes (FGFR3, TERT and HRAS) and methylated genes (ALX4, RALL3, MT1A, and RUNX3) were amplified by polymerase chain reaction (PCR), and subsequently, were identified by microchip electrophoresis (MCE). Analysis by MCE reduces the risk of contamination, sample consumption, and analysis time. Our developed approach is economical, effectively isolates cancer cells, and permits flexible molecular characterization, all of which make this approach a promising method for non-invasive BC detection.


Recommendations for objective cardiovascular assessment to inform clinical exercise prescription: An Exercise Physiologist and Physiotherapist expert consensus.
Exercise is beneficial in managing cardiovascular health. Objective assessments of cardiovascular function assist in identifying the presence or absence of exertional symptoms, and functional and physiological thresholds necessary to inform safe and effective exercise programmes. This study aimed to generate expert consensus on assessments of cardiovascular function to support clinical decision-making for professionals providing clinical exercise services. Three-round e-Delphi. Expert Exercise Physiologists and Physiotherapists were recruited to participate in an e-Delphi. Experts were asked to list all objective cardiovascular assessments deemed necessary to inform safe and effective exercise prescription. In subsequent e-Delphi rounds, experts rated the importance of each item, provided a rationale to support their assertions, and reconsidered others' ratings and rationale to shift or reaffirm their position. These results were then translated into a clinical guidance document by the authors in consultation with a Cardiologist and an experienced Exercise Physiologist with expertise in cardiovascular assessment. Thirty-one experts participated in the e-Delphi and fourteen participants completed all three rounds. Forty objective assessments were initially suggested. Six items reached consensus by the end of Round 2 (resting and exercise heart rate, resting, exercise, and recovery blood pressure, and peak exercise-induced rating of perceived exertion). One additional item reached consensus in Round 3 (exercise oxygen saturation). In the absence of research evidence, the collective experience and insights of an expert panel can inform an evidence gap. Further research is required to determine the feasibility of implementing these seven assessments in practice where CV assessment is indicated.


circ-NOL10 regulated by MTDH/CASC3 inhibits breast cancer progression and metastasis via multiple miRNAs and PDCD4.
Circular RNAs (circRNAs) play important roles in carcinogenesis. Here, we investigated the mechanisms and clinical significance of circ-NOL10, a highly repressed circRNA in breast cancer. Subsequently, we also identified RNA-binding proteins (RBPs) that regulate circ-NOL10. Bioinformatics analysis was utilized to predict regulatory RBPs as well as circ-NOL10 downstream microRNAs (miRNAs) and mRNA targets. RNA immunoprecipitation, luciferase assay, fluorescence in situ hybridization, cell proliferation, wound healing, Matrigel invasion, cell apoptosis assays, and a xenograft model were used to investigate the function and mechanisms of circ-NOL10 in vitro and in vivo. The clinical value of circ-NOL10 was evaluated in a large cohort of breast cancer by quantitative real-time PCR. Circ-NOL10 is downregulated in breast cancer and associated with aggressive characteristics and shorter survival time. Upregulation of circ-NOL10 promotes apoptosis, decreases proliferation, and inhibits invasion and migration. Furthermore, circ-NOL10 binds multiple miRNAs to alleviate carcinogenesis by regulating PDCD4. CASC3 and metadherin (MTDH) can bind directly to circ-NOL10 with characterized motifs. Accordingly, ectopic expression or depletion of CASC3 or MTDH leads to circ-NOL10 expression changes, suggesting that these two RBPs modulate circ-NOL10 in cancer cells. circ-NOL10 is a novel biomarker for diagnosis and prognosis in breast cancer. These results highlight the importance of therapeutic targeting of the RBP-noncoding RNA (ncRNA) regulation network.


On the fidelity of DNA replication. Effect of metal activators during synthesis with avian myeloblastosis virus DNA polymerase.
The effect of metal activators on the fidelity of DNA synthesis has been examined. Using the DNA polymerase from avian myeloblastosis virus, the accuracy of Co2+-, M2+-, and Ni2+-activated DNA synthesis was determined with different polynucleotide templates. With poly[d(A-T)] as the template, the error frequency for dCMP incorporation was 1:1400, 1:1100, and 1:600 for Mg2+, Co2+, and Mn2+, respectively, at maximally activating concentrations. The error frequency was invariant with respect to [Mg2+] but increased with greater than activating concentrations of Co2+ and Mn2+. This increase resulted from differential rates of complementary and noncomplementary nucleotide incorporation. The enhanced error frequency was nonspecific as it occurred with all polynucleotide templates and with all noncomplementary deoxy- and ribonucleotides which were tested. Nearest neighbor analyses of the reaction products indicated that the noncomplementary deoxynucleotides were incorporated as single base substitutions. The fidelity of Ni2+-activated DNA synthesis was invariant with respect to [Ni2+] and was similar to that obtained using Mg2+. During DNA synthesis with Mg2+, the addition of Co2+, Mn2+, or Ni2+ resulted in a decrease in the fidelity of DNA synthesis. The relationship between decreases in the fidelity of DNA synthesis and metal mutagenesis, or carcinogenesis, or both, is considered.


Walking in the Light: How History of Physical Activity, Sunlight, and Vitamin D Account for Body Fat-A UK Biobank Study.
The high prevalence of vitamin D deficiency and obesity drives the need for successful strategies that elevate vitamin D levels, prevent adipogenesis, and stimulate lipolysis. This study provides a theoretical model to evaluate how physical activity (PA) and sunlight exposure influence serum vitamin D levels and regional adiposity. This study hypothesized a posteriori that sunlight is associated with undifferentiated visceral adiposity by increasing the ratio of brown to white adipose tissue. Using 10-year longitudinal data, accelerometry, a sun-exposure questionnaire, and regional adiposity quantified by dual-energy x-ray absorptiometry imaging, a structural-equation mediation model of growth curves was constructed with a data-driven methodology. Sunlight and PA conjointly increased serum vitamin D. Changes in vitamin D levels partially mediated how sunlight and PA impacted adiposity in visceral and subcutaneous regions within a subjective PA model. In an objective PA model, vitamin D was a mediator for subcutaneous regions only. Interestingly, sunlight was associated with less adiposity in subcutaneous regions but greater adiposity in visceral regions. Sunlight and PA may increase vitamin D levels. For the first time, this study characterizes a positive association between sunlight and visceral adiposity. Further investigation and experimentation are necessary to clarify the physiological role of sunlight exposure on adipose tissue.


Translation dysregulation in neurodegenerative diseases: a focus on ALS.
RNA translation is tightly controlled in eukaryotic cells to regulate gene expression and maintain proteome homeostasis. RNA binding proteins, translation factors, and cell signaling pathways all modulate the translation process. Defective translation is involved in multiple neurological diseases including amyotrophic lateral sclerosis (ALS). ALS is a progressive neurodegenerative disorder and poses a major public health challenge worldwide. Over the past few years, tremendous advances have been made in the understanding of the genetics and pathogenesis of ALS. Dysfunction of RNA metabolisms, including RNA translation, has been closely associated with ALS. Here, we first introduce the general mechanisms of translational regulation under physiological and stress conditions and review well-known examples of translation defects in neurodegenerative diseases. We then focus on ALS-linked genes and discuss the recent progress on how translation is affected by various mutant genes and the repeat expansion-mediated non-canonical translation in ALS.


Improved quality of life in asthma patients under long-term therapy: Assessed by AHQ-Japan.
Assessment of the effects of long-term management on patient quality of life (QOL) would be extremely useful for determining asthma treatment strategies. However, no studies have evaluated QOL over an extended period of time. This study evaluated the changes in QOL, drug management and disease severity in the same asthma patients at an interval of approximately 9 years. We re-surveyed asthma patients enrolled in a survey conducted in 2004 to evaluate the effects of approximately a decade of treatment on disease severity and QOL assessed by the Japanese Asthma Health Questionnaire (AHQ-JAPAN). A total of 2179 patients were enrolled in the study from 93 centres, and 1332 patients were included in the per-protocol analysis. Usage rates of inhaled corticosteroids (ICS) for treatment of stable asthma were over 90% at both time points. The AHQ-JAPAN total score improved significantly from 22.2±19.7 in 2004 to 19.7±19.9 in 2013 (P<.001). Significant improvements were also observed in 5 of 6 subscales of AHQ-JAPAN, with Social Activity constituting the sole exception. Asthma severity declined and QOL assessed by AHQ-JAPAN improved, which is considered as a reflection of improved asthma control at least partly attributable to widespread use of anti-inflammatory drugs as represented by ICS. The study also revealed the presence of those with poor QOL, especially in patients with concomitant respiratory diseases, and an increase in severe persistent asthma cases, warranting further long-term efforts at improving QOL. UMIN 000010483.


The effect of a ruthenium precursor on the low-temperature ammonia synthesis activity over Ru/CeO2.
Catalysts supported on CeO2 were prepared using various Ru precursors. The H2-TPR profile of the catalyst was obtained beginning at -70 °C for the first time, and a previously unreported reduction peak was observed at approximately 50 °C. The lower peak temperature was associated with a higher ammonia synthesis activity.


Molecular cloning and complete nucleotide sequence of the repeated unit and flanking gene of the scallop Pecten maximus mitochondrial DNA: putative replication origin features.
In the bivalve mollusc Pecten maximus, the size of the mitochondrial DNA molecules ranges from 20 to 25.8 kbp. This variability is mainly correlated with the occurrence of a variable domain composed with two to five 1.6-kbp repeated units tandemly arrayed in the genome. DNA fragments spanning the 1,586-base-pair-long repeated element and the nearest flanking gene have been cloned and sequenced. This sequence was analyzed regarding its base composition and potential secondary structures. The repeated unit domain was positioned and oriented with regard to the known flanking gene. It ends 2 base pairs upstream relative to the beginning of the tRNAgly gene. The peculiar properties of the repeated unit were compared with those of the 1,442-bp repeated element found in the mitochondrial genome of the deep sea scallop Placopecten magellanicus. This comparison provided evidence for the absence of nucleotide conservation, except for a small sequence engaged in a secondary structure, but argued for a strong pressure maintaining domains with specific nucleotide content. A possible role for the conserved sequence is discussed.


Analysis of binding ability of two tetramethylpyridylporphyrins to albumin and its complex with bilirubin.
An interaction between 5,10,15,20-tetrakis-(N-methyl-x-pyridyl)porphyrins, x=2; 4 (TMPyPs) with bovine serum albumin (BSA) and its bilirubin (BR) complex was investigated by UV-Viz and fluorescence spectroscopy under imitated physiological conditions involving molecular docking studies. The parameters of forming intermolecular complexes (binding constants, quenching rate constants, quenching sphere radius etc.) were determined. It was showed that the interaction between proteins and TMPyPs occurs via static quenching of protein fluorescence and has predominantly hydrophobic and electrostatic character. It was revealed that obtained complexes are relatively stable, but in the case of TMPyP4 binding with proteins occurs better than TMPyP2. Nevertheless, both TMPyPs have better binding ability with free protein compared to BRBSA at the same time. The influence of TMPyPs on the conformational changes in protein molecules was studied using synchronous fluorescence spectroscopy. It was found that there is no competition of BR with TMPyPs for binging sites on protein molecule and BR displacement does not occur. Molecular docking calculations have showed that TMPyPs can bind with albumin via tryptophan residue in the hydrophilic binding site of protein molecule but it is not one possible interaction way.


Hormone therapy and the progression of coronary-artery atherosclerosis in postmenopausal women.
In postmenopausal women with coronary artery disease, conjugated equine estrogen with or without continuous administration of medroxyprogesterone acetate has failed to slow the progression of atherosclerosis. Whether 17beta-estradiol (the endogenous estrogen molecule) alone or administered sequentially with medroxyprogesterone acetate can slow the progression of atherosclerosis is unknown. We conducted a double-blind, placebo-controlled trial in 226 postmenopausal women (mean age, 63.5 years) who had at least one coronary-artery lesion. Participants were randomly assigned to usual care (control group), estrogen therapy with micronized 17beta-estradiol alone (estrogen group), or 17beta-estradiol plus sequentially administered medroxyprogesterone acetate (estrogen-progestin group). In all patients the low-density lipoprotein (LDL) cholesterol level was reduced to a target of less than 130 mg per deciliter. The primary outcome was the average per-participant change between base-line and follow-up coronary angiograms in the percent stenosis measured by quantitative coronary angiography. After a median of 3.3 years of follow-up, the mean (+/-SE) change in the percent stenosis in the 169 participants who had a pair of matched angiograms was 1.89+/-0.78 percentage points in the control group, 2.18+/-0.76 in the estrogen group, and 1.24+/-0.80 in the estrogen-progestin group (P=0.66 for the comparison among the three groups). The mean difference in the percent stenosis between the estrogen group and the control group was 0.29 percentage point (95 percent confidence interval, -1.88 to 2.46), and the mean difference between the estrogen-progestin group and the control group was -0.65 (95 percent confidence interval, -2.87 to 1.57). In older postmenopausal women with established coronary-artery atherosclerosis, 17beta-estradiol either alone or with sequentially administered medroxyprogesterone acetate had no significant effect on the progression of atherosclerosis.


Factors favoring retrograde aortic dissection after endovascular aortic arch repair.
To assess factors predisposing patients to retrograde type A aortic dissection (RTAD) who have undergone hybrid aortic arch repair. From 2001 to 2013, 32 patients underwent hybrid aortic arch repair in our department: 19 in zone 1 and 13 in zone 0. Among these patients, 6 experienced RTAD (18.7%): 3 in zone 0 (23%), 3 in zone 1 (15.8%). Preoperative computed tomography scans of these 32 patients were evaluated. A morphologic assessment of the aortic arch, ascending aorta, and aortic root was performed. Other potential risk factors were investigated. Binary logistic regression was performed to test for possible associations with RTAD. Five patients were successfully converted to open repair. Patients who had RTAD were similar to those who did not, across pertinent variables, including age, type of device, diameter of the ascending aorta, and presence of a bicuspid aortic valve (all P > .1). Incidence of RTAD was observed to be higher among women (P = .034), patients with stent-graft oversizing ≥10% (P = .018), and patients treated with a stent-graft of diameter >42 mm (P = .01). Aortic morphology analysis showed that an indexed aortic diameter of ≥20 mm/m(2) (P = .003); aortic root morphology, specifically loss of the sinotubular junction (P = .004); and presence of an aortic arch malformation (P = .03) were correlated with risk of RTAD. Two patients in the zone-0 group with severe angulation (>120°) between the ascending and the transverse aorta suffered RTAD. The occurrence of RTAD after hybrid aortic arch repair is common. To prevent this complication, preoperative screening of the aortic arch, ascending aorta, and aortic root morphology is critical.


Tamoxifen-induced alterations in the expression of selected matrix metalloproteinases (MMP-2, -9, -10, and -13) and their tissue inhibitors (TIMP-2 and -3) in the chicken ovary.
Matrix metalloproteinases (MMPs) are a family of peptidases that disintegrate extracellular matrix (ECM) molecules associated with tissue remodeling, including reproductive tissues. Their actions are largely controlled by specific tissue inhibitors of MMPs (TIMPs). The role and regulation of MMPs in the chicken ovary is largely unknown. The aim of the present study was to examine the effect of tamoxifen (TMX; estrogen receptor modulator) treatment on the expression of selected members of the MMP system in the laying hen ovary. The activity of MMP-2 and -9 was also examined. Real-time polymerase chain reaction and western blot analyses revealed changes in mRNA and/or protein expression of MMP-2, -9, -10, -13, TIMP-2, and TIMP-3 in the following ovarian follicles after TMX treatment: white (WF), yellowish (YF), small yellow (SYF), and the largest yellow preovulatory (F3-F1). The response to TMX depended on the stage of follicle development and the layer of follicular wall. Moreover, ovarian regression following TMX treatment was accompanied by both an increase in total activity of MMP-2 in the theca layer of F3-F2 and granulosa layer of F2, and a decrease in total activity of MMP-2 in the WF, YF, and SYF, and MMP-9 in theca of F3-F1. In conclusion, the TMX-induced changes in MMP-2, -9, -10, and -13, and TIMP-2 and -3 mRNA expression, as well as MMP-2 and -9 activity, were dependent on tissue and the stage of follicular maturation. Our findings strongly suggests a role for estrogen in regulating the transcription, translation, and/or posttranslational activity of members of the MMP system. Further, these components may be involved in the orchestration of ECM turnover and cellular functions during ovary regression, which occur under conditions of reduced estrogenic activity.


Changes in the lower ionosphere during the eclipse--a preliminary report of the Canadian Programme: (1) introduction.
Ground-based radio investigations and four rocket launches were carried out in Canada to study the effect of the eclipse on the solar radiation and electron densities in the lower ionosphere (below about 150 km). The following four articles describe the experiment.


Impact of seed-applied fungicide and insecticide on Azospirillum brasilense survival and wheat growth-promoting ability.
The use of Azospirillum brasilense as a crop inoculant has increased in recent years. Thus, the compatibility of the inoculation technology with seed treatments using pesticides needs to be evaluated. In this study, we evaluated the effect of an insecticide and fungicide formulation on A. brasilense strain FP2 population by culturing and culture-independent approaches. In addition, we evaluated the impact of these pesticides on the ability of A. brasilense to promote plant growth by monitoring biometric traits (root and shoot dry mass and length) of wheat grown in Greenhouse conditions. Seed pesticide dressings, mainly fungicide, led to a significant mortality of A. brasilense over time. The ability of A. brasilense to promote wheat growth also decreased due to pesticide treatments combined with sowing delay. Considering that pesticides confer fitness advantages to the wheat in field condition, our results suggest that sowing within the first 4 h after inoculation maintain the beneficial effects of A. brasilense on wheat growth promotion. Furthermore, we conclude that inoculation and treatment of seeds with pesticides may be compatible techniques when carried out immediately before sowing.


Lack of glomerular hemodynamic stimulation after infusion of branched-chain amino acids.
Renal hemodynamics (Inutest. CPAH) were studied in five adult volunteers infused on separate occasions with branched-chain amino acids (BCAA), a mixture of nonessential and essential amino acids of the same volume, osmolality and nitrogen content, and 0.9% saline solution. BCAA infusion caused moderate renal vasoconstriction, a slight increase of GFR and a progressive rise of the filtration fraction (FF), whereas the amino acids mixture induced a significantly higher increase of GFR and a state of renal vasodilatation without altering the FF. The volume expansion with 0.9% saline did not cause any notable hemodynamic modification except for reduced FF. This study demonstrates that whereas a state of hyperfiltration and hyperemia is specifically induced by an amino acid mixture independently of volume expansion and osmolar load, the administration of BCAA provides nitrogen without renal hemodynamic stimulation.


Preferential uptake of cytotoxic porphyrins from hematoporphyrin derivative in murine L929 fibroblasts and Chinese hamster ovary K1 epithelial cells.
Photodynamically induced loss of clonogenicity of murine L929 fibroblasts and Chinese hamster ovary K1 epithelial cells was determined with two different assays. It appeared that the loss of clonogenicity was much higher when 20 cells/cm2 were incubated with hematoporphyrin derivative (HPD) and illuminated, than when confluent cell layers were incubated with the same amount of HPD and illuminated prior to plating out. This dependency of cell killing on the experimental protocol was also observed when protoporphyrin (90-95% pure) was used as photosensitizer, but not when the cells were photodynamically treated with rose bengal or exposed to mitomycin C. Further, when cell layers were incubated with the residual solution that remained after the previous incubation of a confluent cell layer with HPD, illumination of these layers appeared to be almost non-toxic, although the overall porphyrin concentration in the residual solution was only slightly lower than in HPD. These results indicate that the porphyrins, responsible for loss of clonogenicity, are present in relatively small amounts in HPD and unpurified protoporphyrin and are preferentially taken up by the cells. Although 2-aminoisobutyric acid transport and DNA synthesis are among the most photosensitive targets with HPD, photodynamic treatment of L929 cells with the residual solution did not result in inhibition of the transport system and DNA synthesis. In contrast, the K+ content of the cells still decreased considerably, when utilizing the porphyrins, remaining in the residual solution as sensitizer. This indicates that under the present experimental conditions the disturbance of the membrane barrier function does not contribute to loss of clonogenicity of these cells and, moreover, that the photodynamically induced K+ leakage is caused by a component of HPD other than inhibition of 2-aminoisobutyric acid transport and DNA synthesis.


Systematic review and meta-analysis of cold snare polypectomy and hot snare polypectomy for colorectal polyps.
Cold snare polypectomy (CSP) has become increasingly utilized to resect colorectal polyps, given its efficacy and safety. This study aims to compare CSP and hot snare polypectomy (HSP) for resecting small (< 10 mm) and large (10-20 mm) colorectal lesions. Relevant publications were obtained from Cochrane Library, Embase, Google Scholar, PubMed, and Web of Science databases. The publication search was limited by English-language and human studies. Pooled mean difference and odds ratios (ORs) were calculated for outcomes of interest. Twenty-three studies were included in this meta-analysis. Pooled OR of delayed post-polypectomy bleeding (DPPB) in the CSP group versus the HSP group was 0.29 (P = 0.0001, I2 = 29%). Subgroup analysis according to lesion size showed a significant reduction in the DPPB rate in lesion sizes 10-20 mm (pooled OR 0.08, P = 0.003, I2 = 0%) and < 10 mm (pooled OR 0.35, P = 0.001, I2 = 27%). Pooled OR of major bleeding in the CSP group was 0.23 (P = 0.0004, I2 = 0%). Subgroup analysis by lesion size revealed a significant decrease in the rate of major bleeding in the CSP group for both lesion sizes 10-20 mm (pooled OR 0.11, P = 0.04) and < 10 mm (pooled OR 0.26, P = 0.003). Complete resection, en bloc resection, and recurrence rate were comparable in the two groups. Cold snare polypectomy was associated with a lower rate of DPPB and lower risk of major bleeding compared with HSP in both small and large polyps. CSP should be considered as the polypectomy technique of choice for colorectal polyps.


Comparative one-month safety and effectiveness of five leading new-generation devices for transcatheter aortic valve implantation.
Transcatheter aortic valve implantation (TAVI) for aortic stenosis is becoming an appealing alternative to surgical aortic valve replacement in high-risk patients and to medical therapy for inoperable ones. Several new-generation TAVI devices have been recently introduced, but comparative analyses are lacking. We aimed to compare 1-month outcomes associated with such five leading new-generation TAVI devices exploiting data collected in the prospective observational RISPEVA (Registro Italiano GISE sull'impianto di Valvola Aortica Percutanea) Study. We queried the dataset of the ongoing RISPEVA study to retrieve baseline, procedural and 1-month outcome details of patients undergoing TAVI with Acurate, Evolut, Portico, Lotus, and Sapien3. Analysis was based on unadjusted and propensity score-adjusted methods. We included 1976 patients, 234 (11.8%) treated with Acurate, 703 (35.6%) with Evolut, 151 (7.6%) with Lotus, 347 (17.6%) with Portico, and 541 (27.4%) with Sapien3. Unadjusted analysis for baseline features highlighted several significant differences, and other discrepancies were found for procedural features. Despite these differences, device and procedural success were similarly high (ranging from 98.0% to 99.4%, p > 0.05). However, procedural valve migration appeared more common with Acurate (p = 0.007), and major bleeding with Sapien3 (p = 0.002). Unadjusted analysis for 1-month outcomes also highlighted significant differences in the composite of death, stroke, myocardial infarction, major vascular complication, major bleeding, or renal failure (favoring Portico, p < 0.001), major vascular complications (favoring Lotus, p < 0.001), renal failure (favoring Portico, p = 0.035), and permanent pacemaker implantation (favoring Acurate, p < 0.001). Propensity score-adjusted analyses showed lower rates of major adverse events with Evolut and Portico (p < 0.05), major vascular complications with Lotus and Portico (p < 0.05), renal failure with Sapien3 (p < 0.05) and permanent pacemaker implantation with Acurate (p < 0.05). In conclusion, new-generation TAVI devices have different profiles of early comparative safety and efficacy. These findings should be taken into account for individualized decision making and patient management.


Large numbers of random point and cluster mutations within the adenovirus VA I gene allow characterization of sequences required for efficient transcription.
We have isolated clones with well over 100 randomly dispersed point mutations distributed throughout the 5' half of chemically synthesized adenovirus type 2 VA I genes. In addition, we have isolated clusters of mutations targeted to the regions corresponding to the A and B block consensus sequences of eukaryotic tRNA and adenovirus VA genes. In vitro analyses of these constructs have allowed us to survey in detail the importance of DNA sequence to transcriptional efficiency. Our analyses demonstrate that certain constructs with radically substituted A block regions can be transcribed efficiently. In contrast, there is little tolerance for variation in the sequence within the B block region. We propose that the B block sequence should be R-G-A/T-T-C-R-A-N-N-C for optimal transcriptional efficiency of the VA I gene in mammalian cells.


Evaluation of the pooled sample method in Infinium MethylationEPIC BeadChip array by comparison with individual samples.
The pooled sample method is used in epigenomic research and expression analysis and is a cost-effective screening approach for small amounts of DNA. Evaluation of the pooled sample method in epigenomic studies is performed using the Illumina Infinium Methylation 450K BeadChip array; however, subsequent reports on the updated 850K array are lacking. A previous study demonstrated that the methylation levels obtained from individual samples were accurately replicated using pooled samples but did not address epigenome-wide association study (EWAS) statistics. The DNA quantification method, which is important for the homogeneous mixing of DNA in the pooled sample method, has since become fluorescence-based, and additional factors need to be considered including the resolution of batch effects of microarray chips and the heterogeneity of the cellular proportions from which the DNA samples are derived. In this study, four pooled samples were created from 44 individual samples, and EWAS statistics for differentially methylated positions (DMPs) and regions (DMRs) were conducted for individual samples and compared with the statistics obtained from the pooled samples. The methylation levels could be reproduced fairly well in the pooled samples. This was the case for the entire dataset and when limited to the top 100 CpG sites, consistent with a previous study using the 450K BeadChip array. However, the statistical results of the EWAS for the DMP by individual samples were not replicated in pooled samples. Qualitative analyses highlighting methylation within an arbitrary candidate gene were replicable. Focusing on chr 20, the statistical results of EWAS for DMR from individual samples showed replicability in the pooled samples as long as they were limited to regions with a sufficient effect size. The pooled sample method replicated the methylation values well and can be used for EWAS in DMR. This method is sample amount-effective and cost-effective and can be utilized for screening by carefully understanding the effective features and disadvantages of the pooled sample method and combining it with candidate gene analyses.


XML knowledge database of MRI-derived eye models.
In a model-based approach, MR images were used to build a database of individual eye models. In order to store the features of the specific eye morphology in an extensible, structured and Internet-accessible database, an appropriate XML structure was implemented. A document type definition was developed that managed the data of the correlated feature space and defined associations via training data sets. The classification and retrieval system has been implemented in Java and successfully applied to classify data sets. Classified data were then added to the database. The presented approach can be easily transferred to similar classification implementations.


A novel de novo heterozygous ALPL nonsense mutation associated with adult hypophosphatasia.
Using genetic, clinical, biochemical, and radiographic assessment and bioinformatic approaches, we present an unusual case of adult HPP caused by a novel de novo heterozygous nonsense mutation in the alkaline phosphatase (ALPL). Hypophosphatasia (HPP) is caused by genetic alterations of the ALPL gene, encoding the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). Here, the purpose was to perform clinical and molecular investigation in a 36-year-old Caucasian woman suspected to present adult HPP. Medical and dental histories were obtained for the proposita and family members, including biochemical, radiographic, and dental assessments. ALPL mutational analysis was performed by the Sanger sequencing method, and the functional impact prediction of the identified mutations was assessed by bioinformatic methods. We identified a novel heterozygous nonsense mutation in the ALPL gene (NM_000478.6:c.768G>A; W[TGG]>*[TGA]) associated with spontaneous vertebral fracture, severe back pain, musculoskeletal pain, low bone density, and short-rooted permanent teeth loss. Functional prediction analysis revealed that the Trp256Ter mutation led to a complete loss of TNSALP crown domain and extensive loss of other functional domains (calcium-binding domain, active site vicinity, and zinc-binding site) and over 60% loss of homodimer interface residues, suggesting that the mutant TNSALP molecules are nonfunctional and form unstable homodimers. Genotyping of the ALPL in the proposita's parents, sister, and niece revealed that in this case, HPP occurred due to a de novo mutation. The present study describes a novel genotype-phenotype and structure-function relationship for HPP, contributing to a better molecular comprehension of HPP etiology and pathophysiology.


A colorimetric sensor for Staphylococcus aureus detection based on controlled click chemical-induced aggregation of gold nanoparticles and immunomagnetic separation.
Staphylococcus aureus (S. aureus) is a pathogen closely associated with foodborne diseases. We prepared a reliable colorimetric sensor to detect S. aureus using click chemical reaction and immunomagnetic separation. Aptamer-functionalized and ALP-labeled Fe3O4 NPs act as separation and signal transduction elements. Under the optimized conditions, the Cu+ generated by signal transduction triggers a click chemistry reaction, which causes the aggregation of azides and alkyne-AuNPs and a color change. The net extinction ratio of Δ(A530/A760) was linearly correlated with the S. aureus concentration from 10 to 106 cfu mL-1, and the limit detection was 2.4 cfu mL-1. The recoveries were 91.15 ~ 106.36% for the analysis of spiked food and water samples without pre-enrichment. Therefore, we believe that the detection platform can be easily and accurately used for S. aureus detection, providing a broad prospect for on-site visual detection.


In silico molecular docking and dynamic simulation of eugenol compounds against breast cancer.
Breast cancer is one of the most severe problems, and it is the primary cause of cancer-related death in females worldwide. The adverse effects and therapeutic resistance development are among the most potent clinical issues for potent medications for breast cancer treatment. The eugenol molecules have a significant affinity for breast cancer receptors. The aim of the study has been on the eugenol compounds, which has potent actions on Erα, PR, EGFR, CDK2, mTOR, ERBB2, c-Src, HSP90, and chemokines receptors inhibition. Initially, the drug-likeness property was examined to evaluate the anti-breast cancer activity by applying Lipinski's rule of five on 120 eugenol molecules. Further, structure-based virtual screening was performed via molecular docking, as protein-like interactions play a vital role in drug development. The 3D structure of the receptors has been acquired from the protein data bank and is docked with 87 3D PubChem and ZINC structures of eugenol compounds, and five FDA-approved anti-cancer drugs using AutoDock Vina. Then, the compounds were subjected to three replica molecular dynamic simulations run of 100 ns per system. The results were evaluated using root mean square deviation (RMSD), root mean square fluctuation (RMSF), and protein-ligand interactions to indicate protein-ligand complex stability. The results confirm that Eugenol cinnamaldehyde has the best docking score for breast cancer, followed by Aspirin eugenol ester and 4-Allyl-2-methoxyphenyl cinnamate. From the results obtained from in silico studies, we propose that the selected eugenols can be further investigated and evaluated for further lead optimization and drug development.


Effect of target luminance on microfluctuations of accommodation.
It is feasible that small temporal variations in steady-state accommodation may provide feedback to the accommodation control system through changes in retinal image contrast and that this feedback may be used to maintain an optimal accommodation response. The complex waveform of microfluctuations is dominated by two distinct regions of activity; a low frequency component (LFC < 0.6 Hz) and a high frequency component (1.0 < or = HFC < or = 2.3 Hz). Whereas the HFCs appear to be correlated with some intraocular manifestation of arterial pulse the contribution of the LFCs to the control of steady-state accommodation is unclear. The present study investigates the effect of target luminance on the waveform of accommodative microfluctuations. Three young emmetropic observers viewed monocularly a high contrast (90%) Maltese cross target placed at a vergence equal to their dark-focus level of accommodation in a Badal stimulus system. The luminance of the target was varied from 0.002 to 11.63 cd m-2 in nine equal logarithmic steps. Five continuous accommodation signals were collected for each viewing condition at a sampling rate of 102.4 Hz, and average power spectra subsequently calculated with a frequency resolution of 0.1 Hz. One-way ANOVA revealed a significant variation in the root-mean-square (r.m.s.) value of the microfluctuations (F = 19.795, d.f. 124, P = 0.0001) which could be attributed mainly to increases in the r.m.s. value for the two lowest luminances (0.002 and 0.004 cd m-2). Power spectrum analysis revealed that these changes in the microfluctuations could be attributed to increases of power in the LFC.(ABSTRACT TRUNCATED AT 250 WORDS)


Clinicopathologic significance of legumain overexpression in cancer: a systematic review and meta-analysis.
Since reports on the clinical significance of legumain in cancer have shown inconsistent results, we systematically evaluated clinical indicators of legumain in cancer. We searched the Cochrane Library, PubMed, Embase, and EBSCO databases and the Wangfang and CNKI databases in China by using "legumain" and ("neoplasms" OR "cancer") as search terms. We included case-controlled studies of legumain and cancer. The quality of the studies was evaluated by using Lichtenstein's guidelines, and valid data was extracted for analysis. In total, 10 articles were included in this study. Meta-analysis showed that legumain was overexpressed in cancer compared with in normal tissue and was higher in stage III-IV disease than in I-II disease. Moreover, legumain overexpression was correlated with poor prognosis and clinical stage. Furthermore, Cancer Genome Atlas data showed that among patients with rectal cancer, those with tumors overexpressing legumain had shorter overall survival than those in the low expression group (P < 0.05). Legumain appears to be involved in tumor development and deterioration; thus, it can potentially be developed into both a marker for monitoring and diagnosing tumors and a therapeutic target.


Cardiac computed tomography in current cardiology guidelines.
Practice guidelines issued by professional societies significantly impact cardiology practice throughout the world. They increasingly incorporate cardiac CT imaging. This review systematically analyzes clinical practice guidelines issued by the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) and the European Society of Cardiology (ESC) as well as the multi-societal appropriateness criteria in their latest versions as of September 1st, 2015, in order to identify the extent to which they include recommendations to use cardiac CT in specific clinical situations.


Stimulation of epipharyngeal receptors can produce significant bronchoconstriction or bronchodilation: dependence upon unilateral forced nostril breathing?
It is suggested that the disagreement in the literature on whether stimulation of epipharyngeal receptors produces bronchoconstriction or bronchodilation may be explicated by the factor of unilateral forced nostril breathing.


Radiation-induced temporal lobe injury after intensity modulated radiotherapy in nasopharyngeal carcinoma patients: a dose-volume-outcome analysis.
To identify the radiation volume effect and significant dosimetric parameters for temporal lobe injury (TLI) and determine the radiation dose tolerance of the temporal lobe (TL) in nasopharyngeal carcinoma (NPC) patients treated with intensity modulated radiation therapy (IMRT). Twenty NPC patients with magnetic resonance imaging (MRI)-diagnosed unilateral TLI were reviewed. Dose-volume data was retrospectively analyzed. Paired samples t-tests showed all dosimetric parameters significantly correlated with TLI, except the TL volume (TLV) and V₇₅ (the TLV that received ≥75 Gy, P = 0.73 and 0.22, respectively). Receiver operating characteristic (ROC) curves showed V₁₀ and V₂₀ (P = 0.552 and 0.11, respectively) were the only non-significant predictors from V₁₀ to V₇₀ for TLI. D(0.5cc) (dose to 0.5 ml of the TLV) was an independent predictor for TLI (P < 0.001) in multivariate analysis; the area under the ROC curve for D(0.5cc) was 0.843 (P < 0.001), and the cutoff point 69 Gy was deemed as the radiation dose limit. The distribution of high dose 'hot spot' regions and the location of TLI were consistent. A D0.5cc of 69 Gy may be the dose tolerance of the TL. The risk of TLI was highly dependent on high dose 'hot spots' in the TL; physicians should be cautious of such 'hot spots' in the TL during IMRT treatment plan optimization, review and approval.


An Integrated Epigenomic and Genomic View on Phyllodes and Phyllodes-like Breast Tumors.
Fibroepithelial lesions (FL) of the breast, in particular, phyllodes tumors (PT) and fibroadenomas, pose a significant diagnostic challenge. There are no generally accepted criteria that distinguish benign, borderline, malignant PT and fibroadenomas. Combined genome-wide DNA methylation and copy number variant (CNV) profiling is an emerging strategy to classify tumors. We compiled a series of patient-derived archival biopsy specimens reflecting the FL spectrum and histological mimickers including clinical follow-up data. DNA methylation and CNVs were determined by well-established microarrays. Comparison of the patterns with a pan-cancer dataset assembled from public resources including "The Cancer Genome Atlas" (TCGA) and "Gene Expression Omnibus" (GEO) suggests that FLs form a methylation class distinct from both control breast tissue as well as common breast cancers. Complex CNVs were enriched in clinically aggressive FLs. Subsequent fluorescence in situ hybridization (FISH) analysis detected respective aberrations in the neoplastic mesenchymal component of FLs only, confirming that the epithelial component is non-neoplastic. Of note, our approach could lead to the elimination of the diagnostically problematic category of borderline PT and allow for optimized prognostic patient stratification. Furthermore, the identified recurrent genomic aberrations such as 1q gains (including MDM4), CDKN2a/b deletions, and EGFR amplifications may inform therapeutic decision-making.


The 2', 3'-cyclic AMP 3'-phosphohydrolase in normal and psoriatic epidermis.
The activity of the enzyme 2', 3'-cyclic AMP 3'-phosphohydrolase is significantly greater in the 'involved' psoriatic skin than in the 'uninvolved' psoriatic skin or in skin samples taken from persons having clinically normal skin. Although the physiological function of this enzyme is not established, it is possible that, besides being associated with myelin, it may also play some role in cell proliferation and maturation, probably at the membrane level.


The National Cancer Data Base report on endometrial carcinoma in African-American women.
Although the incidence of uterine carcinoma is lower among African-American women compared with white women, the mortality rates are higher for African-American patients. This report is part of an ongoing series on gynecologic malignancies in African-American women. Hospital registry reports collected by the National Cancer Data Base were used to describe some of the differences in case presentation and management characteristics of endometrial carcinoma in these two groups. The cases represented 52,307 Non-Hispanic white and 3226 African-American women diagnosed with primary carcinoma of the endometrium between 1988-1994. More African-American patients were diagnosed with less favorable histologies than white patients, at more advanced stages of disease, and with less tumor differentiation. Income had no effect on stage or grade. African-American patients were treated less often for their tumor at every stage of diagnosis compared with white women. Income generally had no effect on whether treatment was provided, but limited income was associated with a lack of treatment in African-American patients with American Joint Committee on Cancer Stage IV tumors. African-American women were less frequently treated surgically and, among surgically treated patients at advanced stages of disease, they received adjuvant radiotherapy less often and chemotherapy more often than white patients. Five-year survival was poorer for African-American women, even for patients with the more favorable Stage I adenocarcinoma who were treated surgically. All patients, regardless of race, should be treated appropriately as dictated by medical and prognostic factors and not by race. Although no screening methods currently exist for endometrial carcinoma, the development of procedures for identifying patients at risk for the prognostic factors that lead to a poor outcome should be a primary focus.


Clinical Research Abstracts of the British Equine Veterinary Association Congress 2015.
Injury to the superficial digital flexor tendon (SDFT) is common in equids, with a high risk of re-injury associated with changes in tendon stiffness. In vivo measurement of limb stiffness has been shown to correlate with tendon stiffness after injury [1] but requires kinematic analysis which is impractical in a clinical setting. We have developed a simple system for measuring limb stiffness statically, which could be used as a tool for monitoring SDFT healing. To validate a goniometric measurement of limb stiffness. Cross sectional study. Initially, forelimb stiffness indices were determined at the walk for 6 equids using a validated kinematic analysis [1]. Limb stiffness indices were then calculated using portable floor scales to record ground reaction force (GRF), and an electrogoniometer to record metacarpophalangeal joint angle. Goniometric limb stiffness indices were subsequently measured in 11 horses ranging from 2 to 20 years of age, with no clinical evidence of SDFT injury. Strength and significance of correlation and agreement between the measurement methods was assessed and association between limb stiffness, limb (left vs. right), weight and age of horse and were calculated. There were strong positive correlations between GRF and joint angle (R(2) = 0.98) and between the static and kinematic methods (R = 0.78, P<0.01). There was a positive correlation between limb stiffness and weight (R(2) = 0.85, P<0.01), but no association with age or limb. This study validated the measurement of limb stiffness in a clinical setting. The positive correlation of limb stiffness and weight supports the theory of an optimised limb spring [2] for energy-efficient cursorial locomotion which may, in turn, provide a clinically-relevant measure of running efficiency and therefore the quality of tendon healing post injury. Ethical animal research: Owner consent was obtained. None. Competing interests: None declared.


Prognosis of posterior osteophyte after anterior cervical decompression and fusion in patients with cervical spondylotic myelopathy using three-dimensional computed tomography study.
Inadequacy of posterior osteophyte resection in anterior cervical decompression and fusion (ACDF) surgery has long been a clinical concern as it may influence surgical outcome. There has been no agreement on the prognosis in the presence of remnant posterior osteophytes. This study retrospectively investigated 26 cervical spondylotic myelopathy patients after ACDF in whom a remnant posterior osteophyte was identified by long-term follow-up CT scans (minimum of 2 years). Remnant posterior osteophytes and osseous spinal canal were measured and compared between pre-operation CT and long-term post-operation CT. The post-operative clinical outcomes were also studied. The remnant osteophytes did not obviously decrease in size in any patient and significantly enlarged in 10 patients, with a new posterior osteophyte developing in one patient. In patients whose remnant osteophyte is enlarged, the incidence of pseudoarthrosis, as well as clinical deterioration during follow-up was significantly higher than patients with stable osteophytes. Contrary to previous reports, none of the remnant posterior osteophytes decreased obviously in size during follow up. Despite the persistence of posterior osteophytes, ACDF is still effective in CSM treatment. Posterior osteophyte enlargement at fused segment appears to be associated with symptomatic pseudoarthrosis and clinical deterioration after surgery.


Removal of BRCA1/CtIP/ZBRK1 repressor complex on ANG1 promoter leads to accelerated mammary tumor growth contributed by prominent vasculature.
BRCA1 exerts transcriptional repression through interaction with CtIP in the C-terminal BRCT domain and ZBRK1 in the central domain. A dozen genes, including angiopoietin-1 (ANG1), a secreted angiogenic factor, are corepressed by BRCA1 and CtIP based on microarray analysis of mammary epithelial cells in 3D culture. BRCA1, CtIP, and ZBRK1 form a complex that coordinately represses ANG1 expression via a ZBRK1 recognition site in the ANG1 promoter. Impairment of this complex upregulates ANG1, which stabilizes endothelial cells that form a capillary-like network structure. Consistently, Brca1-deficient mouse mammary tumors exhibit accelerated growth, pronounced vascularization, and overexpressed ANG1. These results suggest that, besides its role in maintaining genomic stability, BRCA1 directly regulates the expression of angiogenic factors to modulate the tumor microenvironment.


Effects of secondary metabolites produced by different cyanobacterial populations on the freshwater zooplankters Brachionus calyciflorus and Daphnia pulex.
Cyanobacterial blooms in eutrophic water bodies are a worldwide problem. Combined effects of mixtures of secondary metabolites produced by different cyanobacterial species on aquatic fauna are still not well recognised. We compared the survivorship of Brachionus calyciflorus Pallas (Rotifera) and Daphnia pulex Leyding (Cladocera) exposed to pure microcystin LR (MC-LR), anatoxin-a (ANTX) and to five extracts obtained from bloom-forming cyanobacteria Microcystis, Planktothrix and Dolichospermum. The obtained results revealed different response of the organisms to high concentrations of pure MC-LR, ANTX and complex cyanobacterial extracts. The extracts' toxicity to invertebrates was higher than that exerted by pure cyanotoxins and was dependent on the composition of cyanobacterial metabolites: Microcystis spp. extract containing anabaenopeptins A and B, aeruginosamide, four variants of cyanopeptolins and five MCs was not toxic to either of the organisms, whereas Planktothrix agardhii extract (I), containing anabaenopeptins A, B, F, 915, oscillamide Y, five different aeruginosins and four variants of MC was more toxic to daphnids than to rotifers. The extracts of another P. agarhdii (II) biomass and two different biomass samples of Dolichospermum spp. also affected survivorship of the rotifer and cladoceran, however, to various extent. It strongly suggests that non-ribosomal oligopeptides, other than MCs, had essential contribution to the observed toxicity to invertebrates and their effects on particular species or populations can vary depending on the secondary metabolite profiles of cyanobacteria.


Fallopian tube disease: limited value of treatment with fallopian tube catheterization.
Therapeutic role of fallopian tube catheterization was prospectively studied in patients with bilateral fallopian tube obstruction. Catheterization was performed in 42 patients with bilateral obstruction; 36 of the patients (67 fallopian tubes) underwent recanalization. Fifty-two tubes with 54 proximal obstructions were successfully recanalized (technical success rate, 96%), 36 with selective catheterization and 16 with coaxial techniques. Among 13 tubes blocked at the distal portion of the tube, six tubes were negotiated. Perforation or subintimal injury occurred in three tubes, and one patient eventually had a tubal pregnancy. During follow-up of 3 months to 4 years, five patients had conceived, including the patient with a tubal pregnancy and one patient who experienced spontaneous abortion during the first trimester. Fallopian tube catheterization is technically highly successful and diagnostically useful. However, its role in treating fallopian tube diseases is limited, and patients with distally blocked tubes are not good candidates for this procedure.


Genetics of tardive dyskinesia.
Tardive dyskinesia (TD) is one of the most serious adverse side effects of antipsychotic drugs and is an important topic of pharmacogenetic studies. Since there is a genetic susceptibility for developing this adverse reaction, and given that it is hard to predict its development prior to or during the early period of medication, the genetic study of TD is a promising research topic that has a direct clinical application. Moreover, such studies would improve our understanding of the genetic mechanism(s) underlying abnormal dyskinetic movement. A substantial number of case-control association studies of TD have been performed, with numbers of studies focusing on the genes involved in antipsychotic drug metabolism, such as those for cytochrome P450 (CYP) and oxidative stress related genes as well as various neurotransmitter related genes. These studies have produced relatively consistent though controversial findings for certain polymorphisms such as CYP2D6*10, DRD2 Taq1A, DRD3 Ser9Gly, HTR2A T102C, and MnSOD Ala9Val. Moreover, the application of the genome-wide association study (GWAS) to the susceptibility of TD has revealed certain associated genes that previously were never considered to be associated with TD, such as the rs7669317 on 4q24, GLI2 gene, GABA pathway genes, and HSPG2 gene. Although a substantial number of genetic studies have investigated TD, many of the positive findings have not been replicated or are inconsistent, which could be due to differences in study design, sample size, and/or subject ethnicity. We expect that more refined research will be performed in the future to resolve these issues, which will then enable the genetic prediction of TD and clinical application thereof.


Immobilization of viral antigens on filter paper for a [125I]staphylococcal protein A immunoassay: a rapid and sensitive technique for detection of herpes simplex virus antigens and antiviral antibodies.
A new technique is described for the rapid detection and quantitation of herpes simplex virus (HSV) antigens and antiviral antibodies. It involves immobilization of HSV antigens on filter paper discs and subsequent analysis by 125I-labeled staphylococcal protein A (SPA) radioimmunoassay. A specially designed 96-well filtration device is employed which serves both as an incubation chamber and as a filtration manifold. It is rapid, simple, sensitive and specific, and requires only small volumes of antiserum and few target cells. The results may be readily and objectively quantitated. This technique permits the simultaneous assay of a large number of specimens in less than 1 h. Its sensitivity is considerably greater than that of other currently used immunologic techniques, and it is amenable to automation. These characteristics suggest that this [125I]SPA immunofiltration technique may be applicable to the rapid diagnosis of viral infections.


Comparison of oncological outcomes for hand-assisted and pure laparoscopic radical nephroureterectomy: results from the Taiwan Upper Tract Urothelial Cancer Collaboration Group.
Laparoscopic radical nephroureterectomy (LNU) has gradually become the new standard treatment for localized upper tract urothelial cancer (UTUC). With more blunt dissection and tactile sensation, hand-assisted LNU might shorten the operative time compared with the pure laparoscopic approach. However, whether the use of the hand-assisted or the pure laparoscopic approach has an effect on oncological outcomes remains unclear. We retrospectively identified 629 patients with non-metastatic UTUC who underwent hand-assisted (n = 515) or pure LNU (n = 114) at 9 hospitals in Taiwan between 2004 and 2019. Overall survival, cancer-specific survival, recurrence-free survival, and bladder recurrence-free survival were compared between these two groups using inverse-probability of treatment weighting (IPTW) derived from the propensity scores for baseline covariate adjustment. The median follow-up period was 32.9 and 28.7 months in the hand-assisted and the pure groups, respectively. IPTW-adjusted Cox proportional hazards models showed that the laparoscopic approach (pure vs. hand-assisted) was not significantly associated with all-cause mortality (HR 0.79, 95% CI 0.49-1.24, p = 0.304), cancer-specific mortality (HR 0.88, 95% CI 0.51-1.51, p = 0.634), or extra-vesical recurrence (HR 0.65, 95% CI 0.41-1.04, p = 0.071). However, the pure laparoscopic approach was significantly associated with lower intra-vescial recurrence (HR 0.64, 95% CI 0.43-0.96, p = 0.029) for patients who underwent LNU. Kaplan-Meier curves also revealed that the pure laparoscopic approach was associated with better bladder recurrence-free survival compared with the hand-assisted laparoscopic approach in both the original cohort and the IPTW-adjusted cohort (log-rank p = 0.042 and 0.027, respectively). The performance of hand-assisted or pure LNU does not significantly affect the all-cause mortality, cancer-specific mortality, or extra-vesical recurrence for patients with non-metastatic UTUC. However, the hand-assisted laparoscopic approach could increase the risk of intra-vesical recurrence for patients who undergo LNU.


Postoperative Considerations in Inflammatory Bowel Disease.
Treatment of inflammatory bowel disease (IBD) is often multidimensional, requiring both medical and surgical therapies at different times throughout the course of the disease. Both medical and surgical treatments may be used in the acute setting, during a flare, or in a more elective maintenance role. These treatments should be planned as complementary and synergistic. Gastroenterologists and colorectal surgeons should collaborate to create a cohesive treatment plan, arranging the sequence and timing of various treatments. This article reviews the anticipated postoperative recovery after surgical treatment of IBD, possible postoperative complications, and considerations of timing surgery with medical therapy.


Detection of tissue factor-positive extracellular vesicles using the ExoView R100 system.
Tissue factor (TF) is essential for hemostasis. TF-expressing extracellular vesicles (TF+ EVs) are released in pathological conditions, such as trauma and cancer, and are linked to thrombosis. Detection of TF+ EV antigenically in plasma is challenging due to their low concentration but may be of clinical utility. We hypthesised that ExoView can allow for direct measurement of TF+ EV in plasma, antigenically. We utilized the anti-TF monoclonal antibody 5G9 to capture TF EV onto specialized ExoView chips. This was combined with fluorescent TF+ EV detection using anti-TF monoclonal antibody IIID8-AF647. We measured tumor cell-derived (BxPC-3) TF+ EV and TF+ EVs from plasma derived from whole blood with or without lipopolysaccharide (LPS) stimulation. We used this system to analyze TF+ EVs in 2 relevant clinical cohorts: trauma and ovarian cancer. We compared ExoView results with an EV TF activity assay. BxPC-3-derived TF+ EVs were identified with ExoView using 5G9 capture with IIID8-AF647 detection. 5G9 capture with IIID8-AF647 detection was significantly higher in LPS+ samples than in LPS samples and correlated with EV TF activity (R2 = 0.28). Trauma patient samples had higher levels of EV TF activity than healthy controls, but activity did not correlate with TF measurements made by ExoView (R2 = 0.15). Samples from patients with ovarian cancer have higher levels of EV TF activity than those from healthy controls, but activity did not correlate with TF measurement by ExoView (R2 = 0.0063). TF+ EV measurement is possible in plasma, but the threshold and potential clinical applicability of ExoView R100, in this context, remain to be established.


IgG4-related Disease Presenting as Isolated Cicatrising Conjunctivitis.
A 46-year-old male presented with a 12-month history of trichiasis and was found to have significant, progressive cicatrization of the tarsal conjunctiva causing entropion of the upper and lower eyelids. A biopsy confirmed the diagnosis of IgG4-related cicatrizing conjunctivitis in the absence of any other organ involvement, a previously unreported manifestation of this immune-mediated disease.


Treatment modality and vasospasm after aneurysmal subarachnoid hemorrhage.
Vasospasm is the leading source of neurological morbidity after aneurysmal subarachnoid hemorrhage. Our objective was to evaluate the impact of treatment modality on vasospasm, delayed cerebral infarction, and clinical deterioration caused by delayed cerebral ischemia (CD-DCI). We reviewed an institutional cohort, comparing rates of vasospasm, delayed cerebral infarction, and CD-DCI between patients managed with only microsurgical clipping and those treated with only endovascular coiling within 72 hours of rupture. Age, sex, smoking status, Hunt-Hess grade, and Fisher grade were adjusted for in a multivariate regression model. Two hundred three patients were treated with clipping and 52 with coiling. There was no significant difference in patient age, sex, smoking status, aneurysm location, and presenting clinical (Hunt-Hess) and radiographic (Fisher) grade between these two groups. Sixty-percent of patients had moderate or severe vasospasm after clipping compared with 38% after coiling (Multivariate odds ratio [OR] 2.32, 95% confidence interval [95% CI] 1.21-4.47, P = 0.01). Clipping was associated with a greater number of territories with vasospasm (mean of 3.1 vs. 2.3, P = 0.03 after multivariate analysis). Delayed radiographic cerebral infarction was more common in the clipping group (17% vs. 6%, multivariate OR 3.66, 95% CI 1.06-12.71, P = 0.04). For CD-DCI, a trend was seen as 16% of patients treated with clipping had CD-DCI compared with 6% of patients treated with coiling (multivariate OR 3.11, 95% CI 0.89-10.86, P = 0.07). We demonstrate significantly lower rates of vasospasm and delayed infarction after endovascular coiling of ruptured aneurysms.


Unexpected complications following therapeutic embolization.
Unexpected complications may follow therapeutic embolization, even though no apparent technical errors have occurred. This report includes four cases of facial palsy following middle meningeal artery embolization, one case of aspiration pneumonia following glomus tumor embolization, and a case of pulmonary embolization following embolization of a spinal arteriovenous malformation.


Implementing the Verbal Behavior Milestones Assessment and Placement Program (VB-MAPP): Teaching Assessment Techniques.
The Verbal Behavior Milestones Assessment and Placement Program (VB-MAPP) is an assessment tool used with individuals diagnosed with autism spectrum disorder and other language delays (Sundberg 2008). The milestones assessment section of the VB-MAPP is used to determine an individual's current skill level. The results of the milestones assessment can be used to identify instructional goals and objectives. The current study examined the effects of behavioral skills training (BST) on the administration of the milestones assessment by two educational professionals. The BST intervention resulted in immediate increases in performance for both participants.


Proposal of Classification of Aneurysms Coexisting with AVM and Possible Treatment Strategies.
To describe the classification of aneurysms coexisting with arteriovenous malformations (AVMs) and their endovascular treatment. Based on the basis of radiological findings and clinical features, 59 aneurysms coexisting with AVMs were classified into four different types: intranidal, flow-related (proximal and distal), and unrelated. These aneurysms were treated by endovascular techniques with or without AVM embolization. Clinical outcome was assessed using the modified Rankin Scale (mRS). 59 aneurysms coexisting with AVMs were found in 39 patients. There were 11 unrelated aneurysms, 18 proximal flow-related aneurysms, 11 distal flow-related aneurysms and 19 intranidal aneurysms. In the 11 unrelated aneurysms, 4 were caused subarachnoid hemorrhage. In 11 distal flow-related aneurysms near the AVM, 7 caused a major hemorrhage. Six of the 19 intranidal aneurysms presented with hemorrhage. In contrast, only 3 of the 14 proximal flow-related aneurysms on major feeding arteries caused hemorrhage. Aneurysms coexisting with AVMs could be classified into four types and this classification may provide a rationale for endovascular treatment.


Frances's story of nursing art: The most wonderful person in the world.
This story is the second in a series constructed from a study designed to describe how the art of nursing was perceived and understood by patients during a critical illness. Two in-depth interviews were conducted during the recovery phase of this person's illness to answer the question "When is nursing (considered) art?" The initial lead-in to the discussion was, "Tell me a story about a nursing situation that really stood out in your mind-one that was significant and meaningful," and, "What was the experience like for you?" The interviews were tape recorded, transcribed, condensed into a short story, and shared with the participant. The researcher also composed a "response" to the person's story that personally expressed what the story triggered for her. Undergraduate students were invited to reflect and respond to the "aesthetic face" of nursing from the perspective of a person who was nursed while critically ill. Two examples of student response are included.


Severe bilateral hypertensive retinopathy and optic neuropathy in a patient with pheochromocytoma.
We present a case of severe bilateral hypertensive retinopathy and optic neuropathy due to pheochromocytoma. A 31-year-old woman presented with severe bilateral visual acuity loss associated with headaches and photophobia. Ophthalmoscopy showed bilateral optic disc edema, soft exudates, macular star, flame-shaped hemorrhages and arterial narrowing. The situation was more severe in the right eye. Fluorescein angiography confirmed the diagnosis of hypertensive retinopathy. Arterial blood pressure was 220/145 mmHg. A thorough systemic control revealed a right adrenal gland mass. Catecholamine secretion was normal. After ablation, the tumor proved to be a pheochromocytoma, and immunohistochemistry showed dopamine secretion. Postoperative evolution was uncomplicated. Antihypertensive treatment lasted only a few months. Visual acuity was restored and the retinal alterations disappeared 8 months after surgery. Severe hypertensive retinopathy with optic neuropathy may be a consequence of malignant hypertension due to a pheochromocytoma. It is reversible after ablation of the tumor. Early diagnosis is of vital importance and relies on hormonal investigation and immunohistochemistry.


Clinical Effectiveness of Cardiac Noninvasive Diagnostic Testing in Patients Discharged From the Emergency Department for Chest Pain.
Background More than 4 million cardiac noninvasive diagnostic tests are performed annually in the United States. However, questions remain regarding their effectiveness in improving clinical outcomes. We sought to evaluate whether noninvasive diagnostic tests were associated with lower rates of myocardial infarction or cardiovascular death when compared with no testing. Methods and Results We performed a retrospective, population-based cohort study of adults evaluated for chest pain and discharged home from an emergency department in Ontario, Canada. Propensity score matching was employed to reduce confounding between the testing and nontesting groups. There were 370 863 patients evaluated in our cohort. Rates of the composite outcome were low for both groups after propensity-score matching (0.29% and 0.78% for the nontesting group at 90 days and 1 year, respectively, and 0.34% and 0.68% for the noninvasive diagnostic test group at 90 days and 1 year respectively). Over 1 year, patients undergoing noninvasive diagnostic testing had a small but statistically significant lower hazard of developing the composite outcome of myocardial infarction or cardiovascular mortality (hazard ratio, 0.87; 95% CI, 0.78-0.96 [P<0.01]), which appears to be driven by the high-risk subgroup (hazard ratio, 0.75; 95% CI, 0.61-0.92 [P<0.01]). Conclusions We report a lower observed rate of the composite outcome of cardiovascular death or myocardial infarction associated with noninvasive diagnostic testing following evaluation for chest pain in the emergency department. This lower rate was driven by the high-risk subgroup. These results suggest that risk-based testing should be considered for patients discharged from the emergency department for chest pain.


A miRNA-based gene therapy nanodrug synergistically enhances pro-inflammatory antitumor immunity against melanoma.
MicroRNA (miRNA)-based gene therapy is a robust approach to treating human cancers. However, the low target specificity and safety issues associated with viral vectors have limited the clinical use of miRNA therapeutics. In the present study, we aimed to develop a biocompatible nanocarrier to deliver the tumor suppressor miR-30a-5p for gene therapy of ocular melanoma. The quasi-mesoporous magnetic nanospheres (MMNs) were prepared by polyelectrolytes-mediated self-assembling Fe3O4 nanocrystals; the cationic polymer capped quasi-mesoporous inner tunnels of the MMNs facilitate high miRNA loading and protect from nuclease degradation. Then, the outer layer of the MMNs was modified with a disulfide bond bridged very low molecular weight polyethyleneimine (PEI) network to form redox-responsive nanospheres (rMMNs) that enhance the miRNA payload and enable miRNA release under glutathione-dominant tumor microenvironment. The miR-30a-5p loaded rMMNs nanodrug (miR-30a-5p@rMMNs) upregulated miR-30a-5p level and inhibited malignant phenotypes of ocular melanoma by targeting the transcription factor E2F7 both in vitro and in vivo. Additionally, rMMNs act as an enhancer to increase cancer cell apoptosis by modulating M1-like macrophage polarization and activating Fenton reaction. Thus, the rMMNs is a promising miRNA carrier for gene therapy and could enhance pro-inflammatory immunity in melanoma and other cancers. STATEMENT OF SIGNIFICANCE: • miR-30a-5p@rMMNs inhibited malignant phenotypes of ocular melanoma both in vitro and in vivo. • The rMMNs promoted M1 macrophage polarization thus synergistically enhancing pro-inflammatory anti-tumor immunity against melanoma. • The rMMNs showed no obvious toxicity under the injection dose.


An original study of ChatGPT-3.5 and ChatGPT-4 Dermatological Knowledge Level based on the Dermatology Specialty Certificate Examinations.
The global use of artificial intelligence has the potential to revolutionize the healthcare industry. Despite the fact that artificial intelligence is becoming more popular, there is still a lack of evidence on its use in dermatology. The study aimed to determine the capacity of ChatGPT-3.5 and ChatGPT-4 to support dermatological knowledge and clinical decision-making in medical practice. Three dermatology specialty certificate tests, in English and Polish, consisting of 120 single-best-answer, multiple-choice format questions each, were used to assess ChatGPT-3.5 and ChatGPT-4 performance. ChatGPT-4 exceeded the 60% pass rate in every performed test, with a minimum of 80% and 70% correct answers for the English and Polish versions, respectively. ChatGPT-4 performed significantly better on each exam (p<0.01), regardless of the language, compared to ChatGPT-3.5. Furthermore, ChatGPT-4 answered clinical picture-type questions with an average accuracy of 92.98% and 84.21% for English and Polish questions respectively. The difference between the tests in Polish and English did not turn out to be significant but still, ChatGPT-3.5 and ChatGPT-4 in English performed better overall than in Polish by an average of 8 percentage points for each test. Incorrect ChatGPT answers were highly correlated with a lower difficulty index, which denotes questions with higher difficulty in most of the tests. (p<0.05). The dermatological knowledge level of ChatGPT was high, with a significantly better performance of ChatGPT-4 than ChatGPT-3.5. Although the use of ChatGPT will not replace the doctor's final decision, physicians should support artificial intelligence development in dermatology to raise the standards of medical care.


Identifying economical route for crude glycerol valorization: Biodiesel versus polyhydroxy-butyrate (PHB).
Crude glycerol, a by-product of biodiesel industry, has been used for production of biodiesel and polyhydroxy-alkanoates. But question is: which product is economically favorable using crude glycerol as substrate? In this study, energy balance and economic assessment has been carried out for crude glycerol valorization for B10 biodiesel and polyhydroxy-butyrate (PHB) production. For same quantity of crude glycerol utilized, energy ratio for B10 production was higher than PHB production while unit production cost for B10 was lower than that of PHB. For 50 million L plant capacity of biodiesel, unit production cost was 0.77 $/L B10 while for 2 million kg plant capacity of PHB, unit production cost was 4.88 $/kg PHB. Thus, in present scenario production of biodiesel seems economically better than production of PHA with crude glycerol as raw material. This study is useful for researchers, environmental scientists and industries in identifying effective route for crude glycerol valorization.